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Diagnosing and treating opioid dependence
• Ask all patients about the inappropriate use of substances, including prescription opioids. A
• Recommend pharmacotherapy for patients entering treatment for opioid dependence. A
• Warn patients who are opioid dependent about the risk of accidental fatal overdose, particularly with relapse. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Sam M, age 48, is in your office for the first time in more than 2 years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he’s depressed. While taking a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she’s back to work and pain-free. So you’re taken aback when Sam asks you to refill his wife’s oxycodone prescription for lingering pain that often keeps her up at night.
If Sam were your patient, would you suspect opioid dependence?
Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:
- Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.1
- The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,2 with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.3
- More than 75% of opioids used for nonmedical purposes were prescribed for someone else.4
The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.5 Still others have a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.6 Rapid progression from misuse of opioids to dependence is most likely in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.7
Understanding the terms. Before we continue, a word about terminology is in order. “Misuse” generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, while “drug addiction” is the repeated use of a drug despite resulting harm. Here we will use “opioid dependence” to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and “opioid withdrawal” to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).8 Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term “opioid dependence” with “opioid use disorder” to reduce the confusion associated with these definitions.9
Assessing illicit opioid use: Start with a targeted question
Most patients who are opioid dependent do not seek treatment for it,10 and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for family physicians to identify patients who are abusing opioids and ensure that they get the help they need.
Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)11,12—but they have not been found to be significantly better than a careful substance abuse history.13
Straightforward questions. You can start by asking, “Do you take any medications for pain?” If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, “Do you use any other drugs in a serious way? Marijuana? Opioids like Percocet, Vicodin, or Oxycontin?” Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See “Opioid dependence: Red flags to keep in mind”.14-16)
“Brief” protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit http://www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.17,18 Family physicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.17
Suspect opioid dependence in a patient who:
- describes pain resulting from back or orthopedic injuries without corresponding documentation or imaging
- requests a specific opioid for pain management
- shows little interest in a physical exam, diagnostic testing, or nonpharmacological remedies
- talks about changes in work or relationship status
- ceases to participate in activities or hobbies that previously occupied a considerable amount of his or her time. This may signal social isolation or indicate that the patient is spending a great deal of time in pursuit of opioids.
Additional steps before initiating treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.
A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient’s situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may involve hospitalization.19
Assess the patient’s desire for help. After the initial assessment, it is often helpful to categorize the patient’s “stage of change” (precontemplation, contemplation, preparation, action, or maintenance),20 and to tailor your next step accordingly. A patient who denies that opioid use is a problem or is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.21 Consider a question that encourages him or her to express reasons for change, such as: “How would you like your current situation to be different?” As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.
CASE When you question Sam about his interest in oxycodone, he breaks down. He’s been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he’s nauseous, depressed, and unable to sleep—and looking to you for help.
Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.
Recommending treatment and following up
Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a physician specializing in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacological treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care physician. Which approach to pursue should be guided by evidence-based recommendations (TABLE)17,22-27 and jointly decided by physician and patient.
TABLE
Treating opioid dependence: Key clinical recommendations
| Recommendation | Evidence (SOR) | Comments |
|---|---|---|
| Screen all patients for substance use, including opioids. Brief interventions and referral to treatment when appropriate may reduce opioid use17,22 | Consistent findings from RCTs; evidence-based guideline (A) | SBIRT reduces self-reported opioid use; efforts to replicate such reports with objective evidence (eg, toxicology screens) are underway |
| Recommend maintenance medication (ie, buprenorphine, naltrexone, methadone) for all patients entering treatment for opioid dependence with physiological dependence; methadone is the safest for pregnant women23-25 | Consistent findings from RCTs; evidence-based guideline (A) | Methadone is the gold standard for pregnant women; further studies are needed to determine the safety of in utero exposure to buprenorphine and naltrexone |
| Keep patients on maintenance medication for ≥3 months; higher relapse rates are noted when medication is discontinued in <3 months23,24 | Consistent findings from RCTs (A) | Relapse rates are higher when maintenance medication is discontinued in <3 months |
| Caution patients with opioid dependence of the risk for accidental overdose and death with relapse and take action—eg, offering naloxone rescue kits to patients and families, as appropriate26 | Consistent findings from RCTs and prospective cohort studies; evidence-based guideline (A) | |
| Take steps to prevent diversion and accidental ingestion of agonist therapies, using tools such as frequent toxicology screens, random pill counts, and designated pharmacies, and monitoring adherence to psychosocial treatment26,27 | Practice guideline (consensus) (C) | |
| RCTs, randomized clinical trials; SBIRT, Screening, Brief Intervention, and Referral to Treatment; SOR, strength of recommendation. | ||
Medication plays a key role in recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel movements) that have been disrupted by opioid use.28 When continued for ≥3 months, medication has been shown to improve outcomes.23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), vs 7% of those undergoing a brief buprenorphine-naloxone taper.24
There are risks associated with medication-assisted therapy, however. The ones of greatest concern are a potential increase in drug-drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.2,30
Buprenorphine, a partial mu-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacy, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Physicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration code (“X”) license. 31
Buprenorphine has a high affinity for, and a slow dissociation from, mu-opioid receptors, resulting in the displacement of other opioids from the mu receptor and less severe withdrawal.32 As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near maximal, effect at 16 mg, thereby lowering the risk for overdose.33 A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.34
Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d), and the lack of approval by the US Food and Drug Administration (FDA) for use during pregnancy.
Buprenorphine maintenance involves 3 phases: induction, stabilization, and maintenance.38 Induction takes place in a clinician’s office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,23,24 and longer-term maintenance (of indefinite duration) is frequently required.
Naltrexone is a mu-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.39 Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.
Although agonists can be started in the first day or 2 after a patient decides to stop using opioids, patients must be opioid-free for ≥7 days before starting naltrexone. That’s because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the 7-day “washout” period, you can treat opioid withdrawal symptoms with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.
Oral naltrexone’s effectiveness as a treatment for opioid dependence has been limited by poor adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.40,41
Methadone is a full mu-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at http://www.samhsa.gov/mobile/treatmentlocator.aspx).
Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.42 Its slow metabolism and long half-life increase the risk for overdose.
Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don’t have to come to the clinic every day).43 New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.44
Methadone remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone’s efficacy, particularly in lower doses, is similar to that of buprenorphine,45 its adverse effect profile is worse. Adverse effects include drug-drug interactions, the potential for respiratory depression (especially when combined with alcohol or sedatives), QTc prolongation (which requires monitoring by electrocardiogram), sedation, and weight gain, and should be considered before selecting methadone as a maintenance pharmacotherapy.30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,47 both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.
Behavioral interventions are a vital part of the picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.24,48 Nonetheless, most clinicians consider counseling to be a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.6,49
CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg buprenorphine/naloxone daily as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings 2 to 3 times a week. At a follow-up appointment with you 6 months later, he reports that he has been abstinent from oxycodone for 6 months, his sleep is improved, and he feels better about his chances of finding another job.
Your role in safeguarding the patient
With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial, as well. Warn patients of the risk of accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.
There are other steps you can take to safeguard patients—eg, providing naloxone rescue kits to patients and their families when appropriate. You can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.26,27,50
Regular monitoring, urine drug screens (see TABLE W1), and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is likely to improve the outcome of treatment, as well.
TABLE W1
Pharmacokinetics of common opioids: Time detectable in urine*
| Drug (half-life) | Time detectable in urine | Comment |
|---|---|---|
| Codeine (2.5-3 h) | 48 h | Pharmacogenetic-dependent effects may affect detection |
| Fentanyl Transdermal (17 h) Submucosal (7 h) | Not usually detected in urine (lack of metabolites) | Excretion of transdermal fentanyl can last days |
| Hydromorphone IR (2.3 h) ER (18.6 h) | 2-4 d | Significant interpatient variability |
| Methadone (8-59 h) | 3 d | |
| Morphine (1.5-2 h) | 48-72 h | 90% eliminated within 24 h |
| Oxycodone IR (3.2 h) ER (4.5 h) | Often not detected in urine | High-fat meals may increase serum concentrations of ER formulation |
| Propoxyphene Parent drug (6-12 h) Metabolite (30-36 h) | 6-48 h | |
| ER, extended release; IR, immediate release. *Previously appeared in: McBane S, Weige N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633. Sources: Clinical Pharmacology [online]. Tampa, FL: Gold Standard Inc; 2010. Available at: http://cp.gsm.com. Accessed March 5, 2010; Drug Facts and Comparisons [online]. 2010. Available at: http://www.factsandcomparisons.com/. Accessed March 5, 2010. | ||
CORRESPONDENCE Kevin P. Hill, MD, MHS, McLean Hospital, 115 Mill Street, Belmont, MA 02478; khill@mclean.harvard.edu
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2. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-1321.
3. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS Data Brief. 2009;(22):1-8.4.
4. Substance Abuse and Mental Health Services Administration. Results From the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2010. NSDUH Series H-38A, HHS publication SMA 10-4856. Available at: http://www.samhsa.gov/data/NSDUH/2k9NSDUH/2k9Results.htm. Accessed August 22, 2012.
5. Hser YI, Huang D, Brecht ML, et al. Contrasting trajectories of heroin, cocaine, and methamphetamine use. J Addict Dis. 2008;27:13-21.
6. Veilleux JC, Colvin PJ, Anderson J, et al. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2011;30:155-166.
7. George O, Koob GF. Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2011;35:232-247.
8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev (DSM-IV-TR). Arlington, Va: American Psychiatric Association; 2000.
9. American Psychiatric Association. R 19 opioid use disorder. http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460. Updated April 30, 2012. Accessed June 20, 2012.
10. Substance Abuse and Mental Health Services Administration. Results From the 2008 National Survey on Drug Use and Health: National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2009. NSDUH Series H-36, HHS publication SMA 09-4434. Available at: http://www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed August 22, 2012.
11. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94:135-140.
12. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.
13. US Preventive Services Task Force. Screening for Illicit Drug Use: U.S. Preventive Services Task Force Recommendation Statement. January 2008. Available at: http://www.uspreventiveservicestaskforce.org/uspstf08/druguse/drugrs.htm. Accessed May 7, 2012.
14. Gourlay D, Caplan Y, Heit H. Urine Drug Testing in Clinical Practice: Dispelling the Myths and Designing Strategies. San Francisco, Calif: California Academy of Family Physicians; 2006.
15. Jackman R, Purvis J, Mallett B. Chronic nonmalignant pain in primary care. Am Fam Physician. 2008;78:1155-1162.
16. McBane S, Weigle N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633.
17. Madras BK, Compton WM, Avula D, et al. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009;99:280-295.
18. The InSight Project Research Group. SBIRT outcomes in Houston: final report on InSight, a hospital district-based program for patients at risk for alcohol or drug use problems. Alcohol Clin Exp Res. 2009;33:1374-1381.
19. Borges G, Walters EE, Kessler RC. Associations of substance use, abuse, and dependence with subsequent suicidal behavior. Am J Epidemiol. 2000;151:781-789.
20. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51:390-395.
21. Smedslund G, Berg RC, Hammerstrom KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;(5):CD008063.-
22. Gryczynski J, Mitchell SG, Peterson TR, et al. The relationship between services delivered and substance use outcomes in New Mexico’s Screening, Brief Intervention, Referral and Treatment (SBIRT) Initiative. Drug Alcohol Depend. 2011;118:152-157.
23. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA. 2008;300:2003-2011.
24. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68:1238-1246.
25. Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101:491-503.
26. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.
27. Zacny J, Bigelow G, Compton P, et al. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend. 2003;69:215-232.
28. Kreek MJ. Rationale for maintenance pharmacotherapy of opiate dependence. Res Publ Assoc Res Nerv Ment Dis. 1992;70:205-230.
29. Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.-
30. McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010;19:4-16.
31. Office of National Drug Control Policy Reauthorization Act of 2006 (ONDCPRA), HR 6344, 109th Cong, 2nd Sess (2006).
32. Lewis JW, Walter D. Buprenorphine—background to its development as a treatment for opiate dependence. In: Blaine JD, ed. Buprenorphine: An Alternative Treatment for Opioid Dependence. Rockville, Md: National Institute on Drug Abuse; 1992:5-11. NIDA Research Monograph, No. 121. Available at: http://archives.drugabuse.gov/pdf/monographs/121.pdf. Accessed August 22, 2012.
33. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.
34. Alho H, Sinclair D, Vuori E, et al. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend. 2007;88:75-78.
35. Hallinan R, Byrne A, Agho K, et al. Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008;5:684-692.
36. Rapeli P, Fabritius C, Alho H, et al. Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls. BMC Clin Pharmacol. 2007;7:5.-
37. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469-2475.
38. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, Md: Substance Abuse and Mental Health Services Administration; 2004. Treatment Improvement Protocol (TIP) Series 40. DHHS publication SMA 04-3939.
39. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300:2303-2305.
40. Hulse GK, Morris N, Arnold-Reed D, et al. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry. 2009;66:1108-1115.
41. US Food and Drug Administration. FDA approves injectable drug to treat opioid-dependent patients. October 12, 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm229109.htm. Accessed September 11, 2012.
42. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther. 1972;13 (5 pt 1):633-637.
43. Stitzer M, Bigelow G, Lawrence C, et al. Medication take-home as a reinforcer in a methadone maintenance program. Addict Behav. 1977;2:9-14.
44. Code of Federal Regulations. Title 42.8.12. Federal Opioid Treatment Standards. October 2010.
45. Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290-1297.
46. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
47. Ball JC, Lange WR, Myers CP, et al. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav. 1988;29:214-226.
48. Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006;355:365-374.
49. Defulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend. 2012;120:48-54.
50. Savage SR. Management of opioid medications in patients with chronic pain and risk of substance misuse. Curr Psychiatry Rep. 2009;11:377-384.
• Ask all patients about the inappropriate use of substances, including prescription opioids. A
• Recommend pharmacotherapy for patients entering treatment for opioid dependence. A
• Warn patients who are opioid dependent about the risk of accidental fatal overdose, particularly with relapse. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Sam M, age 48, is in your office for the first time in more than 2 years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he’s depressed. While taking a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she’s back to work and pain-free. So you’re taken aback when Sam asks you to refill his wife’s oxycodone prescription for lingering pain that often keeps her up at night.
If Sam were your patient, would you suspect opioid dependence?
Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:
- Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.1
- The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,2 with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.3
- More than 75% of opioids used for nonmedical purposes were prescribed for someone else.4
The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.5 Still others have a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.6 Rapid progression from misuse of opioids to dependence is most likely in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.7
Understanding the terms. Before we continue, a word about terminology is in order. “Misuse” generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, while “drug addiction” is the repeated use of a drug despite resulting harm. Here we will use “opioid dependence” to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and “opioid withdrawal” to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).8 Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term “opioid dependence” with “opioid use disorder” to reduce the confusion associated with these definitions.9
Assessing illicit opioid use: Start with a targeted question
Most patients who are opioid dependent do not seek treatment for it,10 and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for family physicians to identify patients who are abusing opioids and ensure that they get the help they need.
Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)11,12—but they have not been found to be significantly better than a careful substance abuse history.13
Straightforward questions. You can start by asking, “Do you take any medications for pain?” If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, “Do you use any other drugs in a serious way? Marijuana? Opioids like Percocet, Vicodin, or Oxycontin?” Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See “Opioid dependence: Red flags to keep in mind”.14-16)
“Brief” protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit http://www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.17,18 Family physicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.17
Suspect opioid dependence in a patient who:
- describes pain resulting from back or orthopedic injuries without corresponding documentation or imaging
- requests a specific opioid for pain management
- shows little interest in a physical exam, diagnostic testing, or nonpharmacological remedies
- talks about changes in work or relationship status
- ceases to participate in activities or hobbies that previously occupied a considerable amount of his or her time. This may signal social isolation or indicate that the patient is spending a great deal of time in pursuit of opioids.
Additional steps before initiating treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.
A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient’s situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may involve hospitalization.19
Assess the patient’s desire for help. After the initial assessment, it is often helpful to categorize the patient’s “stage of change” (precontemplation, contemplation, preparation, action, or maintenance),20 and to tailor your next step accordingly. A patient who denies that opioid use is a problem or is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.21 Consider a question that encourages him or her to express reasons for change, such as: “How would you like your current situation to be different?” As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.
CASE When you question Sam about his interest in oxycodone, he breaks down. He’s been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he’s nauseous, depressed, and unable to sleep—and looking to you for help.
Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.
Recommending treatment and following up
Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a physician specializing in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacological treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care physician. Which approach to pursue should be guided by evidence-based recommendations (TABLE)17,22-27 and jointly decided by physician and patient.
TABLE
Treating opioid dependence: Key clinical recommendations
| Recommendation | Evidence (SOR) | Comments |
|---|---|---|
| Screen all patients for substance use, including opioids. Brief interventions and referral to treatment when appropriate may reduce opioid use17,22 | Consistent findings from RCTs; evidence-based guideline (A) | SBIRT reduces self-reported opioid use; efforts to replicate such reports with objective evidence (eg, toxicology screens) are underway |
| Recommend maintenance medication (ie, buprenorphine, naltrexone, methadone) for all patients entering treatment for opioid dependence with physiological dependence; methadone is the safest for pregnant women23-25 | Consistent findings from RCTs; evidence-based guideline (A) | Methadone is the gold standard for pregnant women; further studies are needed to determine the safety of in utero exposure to buprenorphine and naltrexone |
| Keep patients on maintenance medication for ≥3 months; higher relapse rates are noted when medication is discontinued in <3 months23,24 | Consistent findings from RCTs (A) | Relapse rates are higher when maintenance medication is discontinued in <3 months |
| Caution patients with opioid dependence of the risk for accidental overdose and death with relapse and take action—eg, offering naloxone rescue kits to patients and families, as appropriate26 | Consistent findings from RCTs and prospective cohort studies; evidence-based guideline (A) | |
| Take steps to prevent diversion and accidental ingestion of agonist therapies, using tools such as frequent toxicology screens, random pill counts, and designated pharmacies, and monitoring adherence to psychosocial treatment26,27 | Practice guideline (consensus) (C) | |
| RCTs, randomized clinical trials; SBIRT, Screening, Brief Intervention, and Referral to Treatment; SOR, strength of recommendation. | ||
Medication plays a key role in recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel movements) that have been disrupted by opioid use.28 When continued for ≥3 months, medication has been shown to improve outcomes.23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), vs 7% of those undergoing a brief buprenorphine-naloxone taper.24
There are risks associated with medication-assisted therapy, however. The ones of greatest concern are a potential increase in drug-drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.2,30
Buprenorphine, a partial mu-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacy, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Physicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration code (“X”) license. 31
Buprenorphine has a high affinity for, and a slow dissociation from, mu-opioid receptors, resulting in the displacement of other opioids from the mu receptor and less severe withdrawal.32 As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near maximal, effect at 16 mg, thereby lowering the risk for overdose.33 A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.34
Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d), and the lack of approval by the US Food and Drug Administration (FDA) for use during pregnancy.
Buprenorphine maintenance involves 3 phases: induction, stabilization, and maintenance.38 Induction takes place in a clinician’s office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,23,24 and longer-term maintenance (of indefinite duration) is frequently required.
Naltrexone is a mu-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.39 Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.
Although agonists can be started in the first day or 2 after a patient decides to stop using opioids, patients must be opioid-free for ≥7 days before starting naltrexone. That’s because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the 7-day “washout” period, you can treat opioid withdrawal symptoms with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.
Oral naltrexone’s effectiveness as a treatment for opioid dependence has been limited by poor adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.40,41
Methadone is a full mu-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at http://www.samhsa.gov/mobile/treatmentlocator.aspx).
Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.42 Its slow metabolism and long half-life increase the risk for overdose.
Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don’t have to come to the clinic every day).43 New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.44
Methadone remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone’s efficacy, particularly in lower doses, is similar to that of buprenorphine,45 its adverse effect profile is worse. Adverse effects include drug-drug interactions, the potential for respiratory depression (especially when combined with alcohol or sedatives), QTc prolongation (which requires monitoring by electrocardiogram), sedation, and weight gain, and should be considered before selecting methadone as a maintenance pharmacotherapy.30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,47 both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.
Behavioral interventions are a vital part of the picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.24,48 Nonetheless, most clinicians consider counseling to be a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.6,49
CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg buprenorphine/naloxone daily as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings 2 to 3 times a week. At a follow-up appointment with you 6 months later, he reports that he has been abstinent from oxycodone for 6 months, his sleep is improved, and he feels better about his chances of finding another job.
Your role in safeguarding the patient
With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial, as well. Warn patients of the risk of accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.
There are other steps you can take to safeguard patients—eg, providing naloxone rescue kits to patients and their families when appropriate. You can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.26,27,50
Regular monitoring, urine drug screens (see TABLE W1), and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is likely to improve the outcome of treatment, as well.
TABLE W1
Pharmacokinetics of common opioids: Time detectable in urine*
| Drug (half-life) | Time detectable in urine | Comment |
|---|---|---|
| Codeine (2.5-3 h) | 48 h | Pharmacogenetic-dependent effects may affect detection |
| Fentanyl Transdermal (17 h) Submucosal (7 h) | Not usually detected in urine (lack of metabolites) | Excretion of transdermal fentanyl can last days |
| Hydromorphone IR (2.3 h) ER (18.6 h) | 2-4 d | Significant interpatient variability |
| Methadone (8-59 h) | 3 d | |
| Morphine (1.5-2 h) | 48-72 h | 90% eliminated within 24 h |
| Oxycodone IR (3.2 h) ER (4.5 h) | Often not detected in urine | High-fat meals may increase serum concentrations of ER formulation |
| Propoxyphene Parent drug (6-12 h) Metabolite (30-36 h) | 6-48 h | |
| ER, extended release; IR, immediate release. *Previously appeared in: McBane S, Weige N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633. Sources: Clinical Pharmacology [online]. Tampa, FL: Gold Standard Inc; 2010. Available at: http://cp.gsm.com. Accessed March 5, 2010; Drug Facts and Comparisons [online]. 2010. Available at: http://www.factsandcomparisons.com/. Accessed March 5, 2010. | ||
CORRESPONDENCE Kevin P. Hill, MD, MHS, McLean Hospital, 115 Mill Street, Belmont, MA 02478; khill@mclean.harvard.edu
• Ask all patients about the inappropriate use of substances, including prescription opioids. A
• Recommend pharmacotherapy for patients entering treatment for opioid dependence. A
• Warn patients who are opioid dependent about the risk of accidental fatal overdose, particularly with relapse. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Sam M, age 48, is in your office for the first time in more than 2 years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he’s depressed. While taking a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she’s back to work and pain-free. So you’re taken aback when Sam asks you to refill his wife’s oxycodone prescription for lingering pain that often keeps her up at night.
If Sam were your patient, would you suspect opioid dependence?
Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:
- Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.1
- The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,2 with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.3
- More than 75% of opioids used for nonmedical purposes were prescribed for someone else.4
The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.5 Still others have a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.6 Rapid progression from misuse of opioids to dependence is most likely in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.7
Understanding the terms. Before we continue, a word about terminology is in order. “Misuse” generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, while “drug addiction” is the repeated use of a drug despite resulting harm. Here we will use “opioid dependence” to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and “opioid withdrawal” to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).8 Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term “opioid dependence” with “opioid use disorder” to reduce the confusion associated with these definitions.9
Assessing illicit opioid use: Start with a targeted question
Most patients who are opioid dependent do not seek treatment for it,10 and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for family physicians to identify patients who are abusing opioids and ensure that they get the help they need.
Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)11,12—but they have not been found to be significantly better than a careful substance abuse history.13
Straightforward questions. You can start by asking, “Do you take any medications for pain?” If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, “Do you use any other drugs in a serious way? Marijuana? Opioids like Percocet, Vicodin, or Oxycontin?” Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See “Opioid dependence: Red flags to keep in mind”.14-16)
“Brief” protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit http://www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.17,18 Family physicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.17
Suspect opioid dependence in a patient who:
- describes pain resulting from back or orthopedic injuries without corresponding documentation or imaging
- requests a specific opioid for pain management
- shows little interest in a physical exam, diagnostic testing, or nonpharmacological remedies
- talks about changes in work or relationship status
- ceases to participate in activities or hobbies that previously occupied a considerable amount of his or her time. This may signal social isolation or indicate that the patient is spending a great deal of time in pursuit of opioids.
Additional steps before initiating treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.
A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient’s situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may involve hospitalization.19
Assess the patient’s desire for help. After the initial assessment, it is often helpful to categorize the patient’s “stage of change” (precontemplation, contemplation, preparation, action, or maintenance),20 and to tailor your next step accordingly. A patient who denies that opioid use is a problem or is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.21 Consider a question that encourages him or her to express reasons for change, such as: “How would you like your current situation to be different?” As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.
CASE When you question Sam about his interest in oxycodone, he breaks down. He’s been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he’s nauseous, depressed, and unable to sleep—and looking to you for help.
Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.
Recommending treatment and following up
Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a physician specializing in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacological treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care physician. Which approach to pursue should be guided by evidence-based recommendations (TABLE)17,22-27 and jointly decided by physician and patient.
TABLE
Treating opioid dependence: Key clinical recommendations
| Recommendation | Evidence (SOR) | Comments |
|---|---|---|
| Screen all patients for substance use, including opioids. Brief interventions and referral to treatment when appropriate may reduce opioid use17,22 | Consistent findings from RCTs; evidence-based guideline (A) | SBIRT reduces self-reported opioid use; efforts to replicate such reports with objective evidence (eg, toxicology screens) are underway |
| Recommend maintenance medication (ie, buprenorphine, naltrexone, methadone) for all patients entering treatment for opioid dependence with physiological dependence; methadone is the safest for pregnant women23-25 | Consistent findings from RCTs; evidence-based guideline (A) | Methadone is the gold standard for pregnant women; further studies are needed to determine the safety of in utero exposure to buprenorphine and naltrexone |
| Keep patients on maintenance medication for ≥3 months; higher relapse rates are noted when medication is discontinued in <3 months23,24 | Consistent findings from RCTs (A) | Relapse rates are higher when maintenance medication is discontinued in <3 months |
| Caution patients with opioid dependence of the risk for accidental overdose and death with relapse and take action—eg, offering naloxone rescue kits to patients and families, as appropriate26 | Consistent findings from RCTs and prospective cohort studies; evidence-based guideline (A) | |
| Take steps to prevent diversion and accidental ingestion of agonist therapies, using tools such as frequent toxicology screens, random pill counts, and designated pharmacies, and monitoring adherence to psychosocial treatment26,27 | Practice guideline (consensus) (C) | |
| RCTs, randomized clinical trials; SBIRT, Screening, Brief Intervention, and Referral to Treatment; SOR, strength of recommendation. | ||
Medication plays a key role in recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel movements) that have been disrupted by opioid use.28 When continued for ≥3 months, medication has been shown to improve outcomes.23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), vs 7% of those undergoing a brief buprenorphine-naloxone taper.24
There are risks associated with medication-assisted therapy, however. The ones of greatest concern are a potential increase in drug-drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.2,30
Buprenorphine, a partial mu-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacy, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Physicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration code (“X”) license. 31
Buprenorphine has a high affinity for, and a slow dissociation from, mu-opioid receptors, resulting in the displacement of other opioids from the mu receptor and less severe withdrawal.32 As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near maximal, effect at 16 mg, thereby lowering the risk for overdose.33 A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.34
Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d), and the lack of approval by the US Food and Drug Administration (FDA) for use during pregnancy.
Buprenorphine maintenance involves 3 phases: induction, stabilization, and maintenance.38 Induction takes place in a clinician’s office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,23,24 and longer-term maintenance (of indefinite duration) is frequently required.
Naltrexone is a mu-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.39 Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.
Although agonists can be started in the first day or 2 after a patient decides to stop using opioids, patients must be opioid-free for ≥7 days before starting naltrexone. That’s because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the 7-day “washout” period, you can treat opioid withdrawal symptoms with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.
Oral naltrexone’s effectiveness as a treatment for opioid dependence has been limited by poor adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.40,41
Methadone is a full mu-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at http://www.samhsa.gov/mobile/treatmentlocator.aspx).
Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.42 Its slow metabolism and long half-life increase the risk for overdose.
Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don’t have to come to the clinic every day).43 New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.44
Methadone remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone’s efficacy, particularly in lower doses, is similar to that of buprenorphine,45 its adverse effect profile is worse. Adverse effects include drug-drug interactions, the potential for respiratory depression (especially when combined with alcohol or sedatives), QTc prolongation (which requires monitoring by electrocardiogram), sedation, and weight gain, and should be considered before selecting methadone as a maintenance pharmacotherapy.30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,47 both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.
Behavioral interventions are a vital part of the picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.24,48 Nonetheless, most clinicians consider counseling to be a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.6,49
CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg buprenorphine/naloxone daily as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings 2 to 3 times a week. At a follow-up appointment with you 6 months later, he reports that he has been abstinent from oxycodone for 6 months, his sleep is improved, and he feels better about his chances of finding another job.
Your role in safeguarding the patient
With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial, as well. Warn patients of the risk of accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.
There are other steps you can take to safeguard patients—eg, providing naloxone rescue kits to patients and their families when appropriate. You can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.26,27,50
Regular monitoring, urine drug screens (see TABLE W1), and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is likely to improve the outcome of treatment, as well.
TABLE W1
Pharmacokinetics of common opioids: Time detectable in urine*
| Drug (half-life) | Time detectable in urine | Comment |
|---|---|---|
| Codeine (2.5-3 h) | 48 h | Pharmacogenetic-dependent effects may affect detection |
| Fentanyl Transdermal (17 h) Submucosal (7 h) | Not usually detected in urine (lack of metabolites) | Excretion of transdermal fentanyl can last days |
| Hydromorphone IR (2.3 h) ER (18.6 h) | 2-4 d | Significant interpatient variability |
| Methadone (8-59 h) | 3 d | |
| Morphine (1.5-2 h) | 48-72 h | 90% eliminated within 24 h |
| Oxycodone IR (3.2 h) ER (4.5 h) | Often not detected in urine | High-fat meals may increase serum concentrations of ER formulation |
| Propoxyphene Parent drug (6-12 h) Metabolite (30-36 h) | 6-48 h | |
| ER, extended release; IR, immediate release. *Previously appeared in: McBane S, Weige N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633. Sources: Clinical Pharmacology [online]. Tampa, FL: Gold Standard Inc; 2010. Available at: http://cp.gsm.com. Accessed March 5, 2010; Drug Facts and Comparisons [online]. 2010. Available at: http://www.factsandcomparisons.com/. Accessed March 5, 2010. | ||
CORRESPONDENCE Kevin P. Hill, MD, MHS, McLean Hospital, 115 Mill Street, Belmont, MA 02478; khill@mclean.harvard.edu
1. Centers for Disease Control and Prevention (CDC). Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2010;59:705-709.
2. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-1321.
3. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS Data Brief. 2009;(22):1-8.4.
4. Substance Abuse and Mental Health Services Administration. Results From the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2010. NSDUH Series H-38A, HHS publication SMA 10-4856. Available at: http://www.samhsa.gov/data/NSDUH/2k9NSDUH/2k9Results.htm. Accessed August 22, 2012.
5. Hser YI, Huang D, Brecht ML, et al. Contrasting trajectories of heroin, cocaine, and methamphetamine use. J Addict Dis. 2008;27:13-21.
6. Veilleux JC, Colvin PJ, Anderson J, et al. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2011;30:155-166.
7. George O, Koob GF. Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2011;35:232-247.
8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev (DSM-IV-TR). Arlington, Va: American Psychiatric Association; 2000.
9. American Psychiatric Association. R 19 opioid use disorder. http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460. Updated April 30, 2012. Accessed June 20, 2012.
10. Substance Abuse and Mental Health Services Administration. Results From the 2008 National Survey on Drug Use and Health: National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2009. NSDUH Series H-36, HHS publication SMA 09-4434. Available at: http://www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed August 22, 2012.
11. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94:135-140.
12. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.
13. US Preventive Services Task Force. Screening for Illicit Drug Use: U.S. Preventive Services Task Force Recommendation Statement. January 2008. Available at: http://www.uspreventiveservicestaskforce.org/uspstf08/druguse/drugrs.htm. Accessed May 7, 2012.
14. Gourlay D, Caplan Y, Heit H. Urine Drug Testing in Clinical Practice: Dispelling the Myths and Designing Strategies. San Francisco, Calif: California Academy of Family Physicians; 2006.
15. Jackman R, Purvis J, Mallett B. Chronic nonmalignant pain in primary care. Am Fam Physician. 2008;78:1155-1162.
16. McBane S, Weigle N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633.
17. Madras BK, Compton WM, Avula D, et al. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009;99:280-295.
18. The InSight Project Research Group. SBIRT outcomes in Houston: final report on InSight, a hospital district-based program for patients at risk for alcohol or drug use problems. Alcohol Clin Exp Res. 2009;33:1374-1381.
19. Borges G, Walters EE, Kessler RC. Associations of substance use, abuse, and dependence with subsequent suicidal behavior. Am J Epidemiol. 2000;151:781-789.
20. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51:390-395.
21. Smedslund G, Berg RC, Hammerstrom KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;(5):CD008063.-
22. Gryczynski J, Mitchell SG, Peterson TR, et al. The relationship between services delivered and substance use outcomes in New Mexico’s Screening, Brief Intervention, Referral and Treatment (SBIRT) Initiative. Drug Alcohol Depend. 2011;118:152-157.
23. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA. 2008;300:2003-2011.
24. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68:1238-1246.
25. Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101:491-503.
26. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.
27. Zacny J, Bigelow G, Compton P, et al. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend. 2003;69:215-232.
28. Kreek MJ. Rationale for maintenance pharmacotherapy of opiate dependence. Res Publ Assoc Res Nerv Ment Dis. 1992;70:205-230.
29. Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.-
30. McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010;19:4-16.
31. Office of National Drug Control Policy Reauthorization Act of 2006 (ONDCPRA), HR 6344, 109th Cong, 2nd Sess (2006).
32. Lewis JW, Walter D. Buprenorphine—background to its development as a treatment for opiate dependence. In: Blaine JD, ed. Buprenorphine: An Alternative Treatment for Opioid Dependence. Rockville, Md: National Institute on Drug Abuse; 1992:5-11. NIDA Research Monograph, No. 121. Available at: http://archives.drugabuse.gov/pdf/monographs/121.pdf. Accessed August 22, 2012.
33. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.
34. Alho H, Sinclair D, Vuori E, et al. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend. 2007;88:75-78.
35. Hallinan R, Byrne A, Agho K, et al. Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008;5:684-692.
36. Rapeli P, Fabritius C, Alho H, et al. Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls. BMC Clin Pharmacol. 2007;7:5.-
37. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469-2475.
38. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, Md: Substance Abuse and Mental Health Services Administration; 2004. Treatment Improvement Protocol (TIP) Series 40. DHHS publication SMA 04-3939.
39. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300:2303-2305.
40. Hulse GK, Morris N, Arnold-Reed D, et al. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry. 2009;66:1108-1115.
41. US Food and Drug Administration. FDA approves injectable drug to treat opioid-dependent patients. October 12, 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm229109.htm. Accessed September 11, 2012.
42. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther. 1972;13 (5 pt 1):633-637.
43. Stitzer M, Bigelow G, Lawrence C, et al. Medication take-home as a reinforcer in a methadone maintenance program. Addict Behav. 1977;2:9-14.
44. Code of Federal Regulations. Title 42.8.12. Federal Opioid Treatment Standards. October 2010.
45. Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290-1297.
46. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
47. Ball JC, Lange WR, Myers CP, et al. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav. 1988;29:214-226.
48. Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006;355:365-374.
49. Defulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend. 2012;120:48-54.
50. Savage SR. Management of opioid medications in patients with chronic pain and risk of substance misuse. Curr Psychiatry Rep. 2009;11:377-384.
1. Centers for Disease Control and Prevention (CDC). Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2010;59:705-709.
2. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-1321.
3. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS Data Brief. 2009;(22):1-8.4.
4. Substance Abuse and Mental Health Services Administration. Results From the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2010. NSDUH Series H-38A, HHS publication SMA 10-4856. Available at: http://www.samhsa.gov/data/NSDUH/2k9NSDUH/2k9Results.htm. Accessed August 22, 2012.
5. Hser YI, Huang D, Brecht ML, et al. Contrasting trajectories of heroin, cocaine, and methamphetamine use. J Addict Dis. 2008;27:13-21.
6. Veilleux JC, Colvin PJ, Anderson J, et al. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2011;30:155-166.
7. George O, Koob GF. Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2011;35:232-247.
8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev (DSM-IV-TR). Arlington, Va: American Psychiatric Association; 2000.
9. American Psychiatric Association. R 19 opioid use disorder. http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460. Updated April 30, 2012. Accessed June 20, 2012.
10. Substance Abuse and Mental Health Services Administration. Results From the 2008 National Survey on Drug Use and Health: National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2009. NSDUH Series H-36, HHS publication SMA 09-4434. Available at: http://www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed August 22, 2012.
11. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94:135-140.
12. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.
13. US Preventive Services Task Force. Screening for Illicit Drug Use: U.S. Preventive Services Task Force Recommendation Statement. January 2008. Available at: http://www.uspreventiveservicestaskforce.org/uspstf08/druguse/drugrs.htm. Accessed May 7, 2012.
14. Gourlay D, Caplan Y, Heit H. Urine Drug Testing in Clinical Practice: Dispelling the Myths and Designing Strategies. San Francisco, Calif: California Academy of Family Physicians; 2006.
15. Jackman R, Purvis J, Mallett B. Chronic nonmalignant pain in primary care. Am Fam Physician. 2008;78:1155-1162.
16. McBane S, Weigle N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633.
17. Madras BK, Compton WM, Avula D, et al. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009;99:280-295.
18. The InSight Project Research Group. SBIRT outcomes in Houston: final report on InSight, a hospital district-based program for patients at risk for alcohol or drug use problems. Alcohol Clin Exp Res. 2009;33:1374-1381.
19. Borges G, Walters EE, Kessler RC. Associations of substance use, abuse, and dependence with subsequent suicidal behavior. Am J Epidemiol. 2000;151:781-789.
20. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51:390-395.
21. Smedslund G, Berg RC, Hammerstrom KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;(5):CD008063.-
22. Gryczynski J, Mitchell SG, Peterson TR, et al. The relationship between services delivered and substance use outcomes in New Mexico’s Screening, Brief Intervention, Referral and Treatment (SBIRT) Initiative. Drug Alcohol Depend. 2011;118:152-157.
23. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA. 2008;300:2003-2011.
24. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68:1238-1246.
25. Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101:491-503.
26. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.
27. Zacny J, Bigelow G, Compton P, et al. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend. 2003;69:215-232.
28. Kreek MJ. Rationale for maintenance pharmacotherapy of opiate dependence. Res Publ Assoc Res Nerv Ment Dis. 1992;70:205-230.
29. Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.-
30. McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010;19:4-16.
31. Office of National Drug Control Policy Reauthorization Act of 2006 (ONDCPRA), HR 6344, 109th Cong, 2nd Sess (2006).
32. Lewis JW, Walter D. Buprenorphine—background to its development as a treatment for opiate dependence. In: Blaine JD, ed. Buprenorphine: An Alternative Treatment for Opioid Dependence. Rockville, Md: National Institute on Drug Abuse; 1992:5-11. NIDA Research Monograph, No. 121. Available at: http://archives.drugabuse.gov/pdf/monographs/121.pdf. Accessed August 22, 2012.
33. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.
34. Alho H, Sinclair D, Vuori E, et al. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend. 2007;88:75-78.
35. Hallinan R, Byrne A, Agho K, et al. Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008;5:684-692.
36. Rapeli P, Fabritius C, Alho H, et al. Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls. BMC Clin Pharmacol. 2007;7:5.-
37. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469-2475.
38. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, Md: Substance Abuse and Mental Health Services Administration; 2004. Treatment Improvement Protocol (TIP) Series 40. DHHS publication SMA 04-3939.
39. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300:2303-2305.
40. Hulse GK, Morris N, Arnold-Reed D, et al. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry. 2009;66:1108-1115.
41. US Food and Drug Administration. FDA approves injectable drug to treat opioid-dependent patients. October 12, 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm229109.htm. Accessed September 11, 2012.
42. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther. 1972;13 (5 pt 1):633-637.
43. Stitzer M, Bigelow G, Lawrence C, et al. Medication take-home as a reinforcer in a methadone maintenance program. Addict Behav. 1977;2:9-14.
44. Code of Federal Regulations. Title 42.8.12. Federal Opioid Treatment Standards. October 2010.
45. Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290-1297.
46. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
47. Ball JC, Lange WR, Myers CP, et al. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav. 1988;29:214-226.
48. Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006;355:365-374.
49. Defulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend. 2012;120:48-54.
50. Savage SR. Management of opioid medications in patients with chronic pain and risk of substance misuse. Curr Psychiatry Rep. 2009;11:377-384.
Acamprosate: For discomfort of early alcohol abstinence
Acamprosate, a gamma-aminobutyric acid (GABA) analogue used worldwide to treat alcohol dependence, is available in this country (Table 1). The agent appears to reduce discomfort—including restlessness, anxiety, dysphoria, and insomnia—common within the first 6 months of alcohol abstinence. In clinical trials, it prolonged abstinence in alcohol-dependent patients who completed an initial detoxification and were receiving relapse prevention treatment.
HOW IT WORKS
Acamprosate’s chemical structure resembles both GABA and taurine, an endogenous amino acid derivative that enhances GABA-ergic activity.1 The drug’s synthetic structure facilitates its passage across the blood-brain barrier, and the brain mediates its major effect.
Table 1
Acamprosate: Fast facts
| Brand name: |
| Campral |
| Class: |
| GABA analogue |
| FDA-approved indication: |
| Maintaining abstinence in alcohol-dependent patients |
| Approval date: |
| July 29, 2004 |
| Manufacturer: |
| Forest Pharmaceuticals |
| Dosing form: |
| 333-mg tablets |
| Recommended dosage: |
| Adults age |
The mechanisms by which acamprosate promotes abstinence in alcohol dependence are unknown. The drug may bind to N-methyl-D-aspartate (NMDA) glutamate receptors and work as a partial antagonist, but direct ligand activity does not appear to cause most of its central actions. Rather, acamprosate interacts with glutamate and GABA to normalize the hyperexcitability that accompanies early abstinence (Table 2).
Table 2
Acamprosate’s proposed mechanisms of action*
| Neurotransmitter interactions | Pharmacologic effect | Clinical effect |
| Glutamatergic system (NMDA receptor) | Blocks increased glutamate release in nucleus accumbens during alcohol withdrawal; may bind to receptor site as partial antagonist | Decreased arousal, craving, and dysphoria associated with early abstinence |
| GABAergic system (GABAAreceptor) | Normalizes alcohol-induced decrease in basal GABA concentrations in nucleus accumbens | Same as above |
| Neuromodulator interactions | ||
| Taurine | Increases extracellular taurine concentrations in nucleus accumbens; taurine shifts the glutamate/GABA balance in favor of GABAergic activity | Mimics increase in taurine seen with acute alcohol intake, likely facilitating GABA normalization |
| * Based on animal models of alcohol dependence | ||
| Source: reference 3 | ||
PHARMACOKINETICS
Acamprosate’s bioavailability is relatively poor (11%), so it is prescribed to be taken three times daily. Although patients in clinical practice often have trouble following frequent daily dosing schedules, subjects in one study reportedly had little difficulty adhering to this regimen.2
Acamprosate’s half-life is approximately 13 hours, and it reaches peak plasma concentrations in 3.5 to 9.5 hours. Pharmaceutical studies indicate that food does not significantly affect absorption.
Although 666 mg tid has shown efficacy in clinical trials, the blood level at which acamprosate becomes therapeutic has not been determined.
The drug reaches steady-state blood levels within 1 week, meaning it will not be fully effective for 5 to 7 days but may still reach therapeutic blood levels during that time. Advise patients that adverse effects may not clear for 5 to 7 days after discontinuation.
Acamprosate does not bind with plasma proteins, so it will not interact with drugs that do. The drug, which is renally excreted in an unmetabolized state, has not been found to interact adversely with commonly prescribed antidepressants, anxiolytics, antipsychotics, alcohol, or disulfiram.3 How acamprosate interacts with renally excreted drugs such as lithium is unknown.
In two studies following 24 healthy volunteers4 and 23 alcohol-dependent patients,5 concomitant naltrexone, 50 to 100 mg/d, and acamprosate, 2 to 3 g/d, increased acamprosate plasma concentrations as much as 25%, but did not change plasma levels of naltrexone or its major metabolite. Naltrexone might delay gastric emptying, thereby increasing acamprosate absorption.
EFFICACY
Acamprosate with psychosocial treatment increased total abstinent days in:
- 15 randomized, controlled trials (RCT) conducted in Europe6
- a meta-analysis of 12 methodologically comparable RCTs conducted in Europe7
- an open-label trial in France that studied acamprosate as an adjunct to treatment-as-usual in primary care settings.2
Acamprosate may improve patient retention in substance abuse treatment, which predicts favorable outcomes.7 Patients receiving acamprosate and treatment-as-usual reported fewer alcohol-related problems and improved quality of life compared with treatment-as-usual alone.2 Reduced subjective craving for alcohol is difficult to study and has not been sufficiently shown.
Combined pharmacotherapy. It is unclear whether acamprosate and naltrexone or disulfiram are more effective than acamprosate alone.3,6,7
In one multi-center, placebo-controlled trial, a subgroup of severely alcohol-dependent patients sought acamprosate/disulfiram therapy. The combination was shown to be safe and increased total abstinent days compared with acamprosate or disulfiram alone, but effectiveness could not be determined because of the self-selection bias of those who requested combined pharmacotherapy.
In one 12-week RCT,8 naltrexone/acamprosate therapy was more effective than acamprosate alone—but not more effective than naltrexone alone—in reducing time to first drink and relapse to heavy drinking.
The multi-center COMBINE (Combining Medications and Behavioral Interventions) study,9 funded by the National Institute on Alcohol Abuse and Alcoholism, is comparing the efficacy of naltrexone, acamprosate, and both agents when given with low-intensity psychosocial treatment or moderate-intensity, alcohol-specific psychosocial treatment. Preliminary safety, tolerability, and adherence results with the acamprosate/naltrexone combination have been promising. Efficacy findings are expected later this year.
SAFETY
Acamprosate is contraindicated in patients with severely compromised renal function (creatinine clearance
The drug is safe for patients with mild to moderate alcohol-related liver disease as defined by the Child-Pugh classification of hepatic impairment.10 For a patient with severe liver disease, consult his or her gastroenterologist to gauge risks and benefits, as acamprosate can cause adverse GI effects.
Acamprosate has not been tested in children or the elderly, although one study suggests efficacy in alcohol-dependent adolescents ages 16 to 19.7. The agent’s safety during pregnancy or lactation is unknown.
TOLERABILITY
Acamprosate has been well-tolerated in clinical trials. Discontinuation rates because of adverse effects have been similar in treatment and placebo groups.7
GI side effects are most common, with overall rates of 17% and 11% among acamprosate and placebo groups, respectively.7 Diarrhea may be transient and may also resolve with a reduced dosage.6
Slightly higher rates of suicidal ideation were reported among patients taking acamprosate vs those taking placebo (1.4 % vs. 0.5% in short-term [10 Screen all patients taking acamprosate for suicidal ideation or behavior.
Other reported side effects include headache, abdominal pain, nausea and vomiting, dyspepsia, flatulence, pruritus, rash, drowsiness, and dizziness. Acamprosate has no abuse potential and low potential for toxicity in overdose. Higher acamprosate plasma levels during combined acamprosate/naltrexone treatment may increase risk of diarrhea.9
CLINICAL IMPLICATIONS
Drinking alcohol while taking acamprosate will not make a patient sick, which makes it an alternative for patients who fear the harsh effects of “slipping up” while taking disulfiram.
Also, acamprosate does not interact with prescription opioids. By contrast, naltrexone is contraindicated in patients taking opioids for pain.
Related resources
- Campral Web site. www.campral.com
- National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov
- National Institute on Drug Abuse. www.nida.nih.gov
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Naltrexone • ReVia
Disclosure
Drs. Connery and Weiss receive research/grant support from Ortho-McNeil Pharmaceutical. Dr. Weiss is also a speaker for Forest Laboratories.
1. Dahchour A, De Witte P. Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 2000;60:343-62.
2. Kiritze-Topor P, Huas D, Rosenzweig C, et al. A pragmatic trial of acamprosate in the treatment of alcohol dependence in primary care. Alcohol Alcohol 2004;39:520-7.
3. Kiefer F, Wiedemann K. Combined therapy: what does acamprosate and naltrexone combination tell us? Alcohol Alcohol 2004;39:542-7.
4. Mason BJ, Goodman AM, Dixon RM, et al. A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Neuropsychopharmacology 2002;27:596-606.
5. Johnson BA, O’Malley SS, Ciraulo DA, et al. Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. J Clin Psychopharmacol 2003;23:281-93.
6. Overman GP, Teter CJ, Guthrie SK. Acamprosate for the adjunctive treatment of alcohol dependence. Ann Pharmacother 2003;37:1090-9.
7. Carmen B, Angeles M, Ana M, Maria AJ. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811-28.
8. Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2003;60:92-9.
9. The COMBINE study research group. Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: rationale and methods. Alcohol Clin Exp Res 2003;27:1107-22.
10. Campral prescribing information. Available at: http://www.campral.com. Accessed Jan. 7, 2005.
Acamprosate, a gamma-aminobutyric acid (GABA) analogue used worldwide to treat alcohol dependence, is available in this country (Table 1). The agent appears to reduce discomfort—including restlessness, anxiety, dysphoria, and insomnia—common within the first 6 months of alcohol abstinence. In clinical trials, it prolonged abstinence in alcohol-dependent patients who completed an initial detoxification and were receiving relapse prevention treatment.
HOW IT WORKS
Acamprosate’s chemical structure resembles both GABA and taurine, an endogenous amino acid derivative that enhances GABA-ergic activity.1 The drug’s synthetic structure facilitates its passage across the blood-brain barrier, and the brain mediates its major effect.
Table 1
Acamprosate: Fast facts
| Brand name: |
| Campral |
| Class: |
| GABA analogue |
| FDA-approved indication: |
| Maintaining abstinence in alcohol-dependent patients |
| Approval date: |
| July 29, 2004 |
| Manufacturer: |
| Forest Pharmaceuticals |
| Dosing form: |
| 333-mg tablets |
| Recommended dosage: |
| Adults age |
The mechanisms by which acamprosate promotes abstinence in alcohol dependence are unknown. The drug may bind to N-methyl-D-aspartate (NMDA) glutamate receptors and work as a partial antagonist, but direct ligand activity does not appear to cause most of its central actions. Rather, acamprosate interacts with glutamate and GABA to normalize the hyperexcitability that accompanies early abstinence (Table 2).
Table 2
Acamprosate’s proposed mechanisms of action*
| Neurotransmitter interactions | Pharmacologic effect | Clinical effect |
| Glutamatergic system (NMDA receptor) | Blocks increased glutamate release in nucleus accumbens during alcohol withdrawal; may bind to receptor site as partial antagonist | Decreased arousal, craving, and dysphoria associated with early abstinence |
| GABAergic system (GABAAreceptor) | Normalizes alcohol-induced decrease in basal GABA concentrations in nucleus accumbens | Same as above |
| Neuromodulator interactions | ||
| Taurine | Increases extracellular taurine concentrations in nucleus accumbens; taurine shifts the glutamate/GABA balance in favor of GABAergic activity | Mimics increase in taurine seen with acute alcohol intake, likely facilitating GABA normalization |
| * Based on animal models of alcohol dependence | ||
| Source: reference 3 | ||
PHARMACOKINETICS
Acamprosate’s bioavailability is relatively poor (11%), so it is prescribed to be taken three times daily. Although patients in clinical practice often have trouble following frequent daily dosing schedules, subjects in one study reportedly had little difficulty adhering to this regimen.2
Acamprosate’s half-life is approximately 13 hours, and it reaches peak plasma concentrations in 3.5 to 9.5 hours. Pharmaceutical studies indicate that food does not significantly affect absorption.
Although 666 mg tid has shown efficacy in clinical trials, the blood level at which acamprosate becomes therapeutic has not been determined.
The drug reaches steady-state blood levels within 1 week, meaning it will not be fully effective for 5 to 7 days but may still reach therapeutic blood levels during that time. Advise patients that adverse effects may not clear for 5 to 7 days after discontinuation.
Acamprosate does not bind with plasma proteins, so it will not interact with drugs that do. The drug, which is renally excreted in an unmetabolized state, has not been found to interact adversely with commonly prescribed antidepressants, anxiolytics, antipsychotics, alcohol, or disulfiram.3 How acamprosate interacts with renally excreted drugs such as lithium is unknown.
In two studies following 24 healthy volunteers4 and 23 alcohol-dependent patients,5 concomitant naltrexone, 50 to 100 mg/d, and acamprosate, 2 to 3 g/d, increased acamprosate plasma concentrations as much as 25%, but did not change plasma levels of naltrexone or its major metabolite. Naltrexone might delay gastric emptying, thereby increasing acamprosate absorption.
EFFICACY
Acamprosate with psychosocial treatment increased total abstinent days in:
- 15 randomized, controlled trials (RCT) conducted in Europe6
- a meta-analysis of 12 methodologically comparable RCTs conducted in Europe7
- an open-label trial in France that studied acamprosate as an adjunct to treatment-as-usual in primary care settings.2
Acamprosate may improve patient retention in substance abuse treatment, which predicts favorable outcomes.7 Patients receiving acamprosate and treatment-as-usual reported fewer alcohol-related problems and improved quality of life compared with treatment-as-usual alone.2 Reduced subjective craving for alcohol is difficult to study and has not been sufficiently shown.
Combined pharmacotherapy. It is unclear whether acamprosate and naltrexone or disulfiram are more effective than acamprosate alone.3,6,7
In one multi-center, placebo-controlled trial, a subgroup of severely alcohol-dependent patients sought acamprosate/disulfiram therapy. The combination was shown to be safe and increased total abstinent days compared with acamprosate or disulfiram alone, but effectiveness could not be determined because of the self-selection bias of those who requested combined pharmacotherapy.
In one 12-week RCT,8 naltrexone/acamprosate therapy was more effective than acamprosate alone—but not more effective than naltrexone alone—in reducing time to first drink and relapse to heavy drinking.
The multi-center COMBINE (Combining Medications and Behavioral Interventions) study,9 funded by the National Institute on Alcohol Abuse and Alcoholism, is comparing the efficacy of naltrexone, acamprosate, and both agents when given with low-intensity psychosocial treatment or moderate-intensity, alcohol-specific psychosocial treatment. Preliminary safety, tolerability, and adherence results with the acamprosate/naltrexone combination have been promising. Efficacy findings are expected later this year.
SAFETY
Acamprosate is contraindicated in patients with severely compromised renal function (creatinine clearance
The drug is safe for patients with mild to moderate alcohol-related liver disease as defined by the Child-Pugh classification of hepatic impairment.10 For a patient with severe liver disease, consult his or her gastroenterologist to gauge risks and benefits, as acamprosate can cause adverse GI effects.
Acamprosate has not been tested in children or the elderly, although one study suggests efficacy in alcohol-dependent adolescents ages 16 to 19.7. The agent’s safety during pregnancy or lactation is unknown.
TOLERABILITY
Acamprosate has been well-tolerated in clinical trials. Discontinuation rates because of adverse effects have been similar in treatment and placebo groups.7
GI side effects are most common, with overall rates of 17% and 11% among acamprosate and placebo groups, respectively.7 Diarrhea may be transient and may also resolve with a reduced dosage.6
Slightly higher rates of suicidal ideation were reported among patients taking acamprosate vs those taking placebo (1.4 % vs. 0.5% in short-term [10 Screen all patients taking acamprosate for suicidal ideation or behavior.
Other reported side effects include headache, abdominal pain, nausea and vomiting, dyspepsia, flatulence, pruritus, rash, drowsiness, and dizziness. Acamprosate has no abuse potential and low potential for toxicity in overdose. Higher acamprosate plasma levels during combined acamprosate/naltrexone treatment may increase risk of diarrhea.9
CLINICAL IMPLICATIONS
Drinking alcohol while taking acamprosate will not make a patient sick, which makes it an alternative for patients who fear the harsh effects of “slipping up” while taking disulfiram.
Also, acamprosate does not interact with prescription opioids. By contrast, naltrexone is contraindicated in patients taking opioids for pain.
Related resources
- Campral Web site. www.campral.com
- National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov
- National Institute on Drug Abuse. www.nida.nih.gov
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Naltrexone • ReVia
Disclosure
Drs. Connery and Weiss receive research/grant support from Ortho-McNeil Pharmaceutical. Dr. Weiss is also a speaker for Forest Laboratories.
Acamprosate, a gamma-aminobutyric acid (GABA) analogue used worldwide to treat alcohol dependence, is available in this country (Table 1). The agent appears to reduce discomfort—including restlessness, anxiety, dysphoria, and insomnia—common within the first 6 months of alcohol abstinence. In clinical trials, it prolonged abstinence in alcohol-dependent patients who completed an initial detoxification and were receiving relapse prevention treatment.
HOW IT WORKS
Acamprosate’s chemical structure resembles both GABA and taurine, an endogenous amino acid derivative that enhances GABA-ergic activity.1 The drug’s synthetic structure facilitates its passage across the blood-brain barrier, and the brain mediates its major effect.
Table 1
Acamprosate: Fast facts
| Brand name: |
| Campral |
| Class: |
| GABA analogue |
| FDA-approved indication: |
| Maintaining abstinence in alcohol-dependent patients |
| Approval date: |
| July 29, 2004 |
| Manufacturer: |
| Forest Pharmaceuticals |
| Dosing form: |
| 333-mg tablets |
| Recommended dosage: |
| Adults age |
The mechanisms by which acamprosate promotes abstinence in alcohol dependence are unknown. The drug may bind to N-methyl-D-aspartate (NMDA) glutamate receptors and work as a partial antagonist, but direct ligand activity does not appear to cause most of its central actions. Rather, acamprosate interacts with glutamate and GABA to normalize the hyperexcitability that accompanies early abstinence (Table 2).
Table 2
Acamprosate’s proposed mechanisms of action*
| Neurotransmitter interactions | Pharmacologic effect | Clinical effect |
| Glutamatergic system (NMDA receptor) | Blocks increased glutamate release in nucleus accumbens during alcohol withdrawal; may bind to receptor site as partial antagonist | Decreased arousal, craving, and dysphoria associated with early abstinence |
| GABAergic system (GABAAreceptor) | Normalizes alcohol-induced decrease in basal GABA concentrations in nucleus accumbens | Same as above |
| Neuromodulator interactions | ||
| Taurine | Increases extracellular taurine concentrations in nucleus accumbens; taurine shifts the glutamate/GABA balance in favor of GABAergic activity | Mimics increase in taurine seen with acute alcohol intake, likely facilitating GABA normalization |
| * Based on animal models of alcohol dependence | ||
| Source: reference 3 | ||
PHARMACOKINETICS
Acamprosate’s bioavailability is relatively poor (11%), so it is prescribed to be taken three times daily. Although patients in clinical practice often have trouble following frequent daily dosing schedules, subjects in one study reportedly had little difficulty adhering to this regimen.2
Acamprosate’s half-life is approximately 13 hours, and it reaches peak plasma concentrations in 3.5 to 9.5 hours. Pharmaceutical studies indicate that food does not significantly affect absorption.
Although 666 mg tid has shown efficacy in clinical trials, the blood level at which acamprosate becomes therapeutic has not been determined.
The drug reaches steady-state blood levels within 1 week, meaning it will not be fully effective for 5 to 7 days but may still reach therapeutic blood levels during that time. Advise patients that adverse effects may not clear for 5 to 7 days after discontinuation.
Acamprosate does not bind with plasma proteins, so it will not interact with drugs that do. The drug, which is renally excreted in an unmetabolized state, has not been found to interact adversely with commonly prescribed antidepressants, anxiolytics, antipsychotics, alcohol, or disulfiram.3 How acamprosate interacts with renally excreted drugs such as lithium is unknown.
In two studies following 24 healthy volunteers4 and 23 alcohol-dependent patients,5 concomitant naltrexone, 50 to 100 mg/d, and acamprosate, 2 to 3 g/d, increased acamprosate plasma concentrations as much as 25%, but did not change plasma levels of naltrexone or its major metabolite. Naltrexone might delay gastric emptying, thereby increasing acamprosate absorption.
EFFICACY
Acamprosate with psychosocial treatment increased total abstinent days in:
- 15 randomized, controlled trials (RCT) conducted in Europe6
- a meta-analysis of 12 methodologically comparable RCTs conducted in Europe7
- an open-label trial in France that studied acamprosate as an adjunct to treatment-as-usual in primary care settings.2
Acamprosate may improve patient retention in substance abuse treatment, which predicts favorable outcomes.7 Patients receiving acamprosate and treatment-as-usual reported fewer alcohol-related problems and improved quality of life compared with treatment-as-usual alone.2 Reduced subjective craving for alcohol is difficult to study and has not been sufficiently shown.
Combined pharmacotherapy. It is unclear whether acamprosate and naltrexone or disulfiram are more effective than acamprosate alone.3,6,7
In one multi-center, placebo-controlled trial, a subgroup of severely alcohol-dependent patients sought acamprosate/disulfiram therapy. The combination was shown to be safe and increased total abstinent days compared with acamprosate or disulfiram alone, but effectiveness could not be determined because of the self-selection bias of those who requested combined pharmacotherapy.
In one 12-week RCT,8 naltrexone/acamprosate therapy was more effective than acamprosate alone—but not more effective than naltrexone alone—in reducing time to first drink and relapse to heavy drinking.
The multi-center COMBINE (Combining Medications and Behavioral Interventions) study,9 funded by the National Institute on Alcohol Abuse and Alcoholism, is comparing the efficacy of naltrexone, acamprosate, and both agents when given with low-intensity psychosocial treatment or moderate-intensity, alcohol-specific psychosocial treatment. Preliminary safety, tolerability, and adherence results with the acamprosate/naltrexone combination have been promising. Efficacy findings are expected later this year.
SAFETY
Acamprosate is contraindicated in patients with severely compromised renal function (creatinine clearance
The drug is safe for patients with mild to moderate alcohol-related liver disease as defined by the Child-Pugh classification of hepatic impairment.10 For a patient with severe liver disease, consult his or her gastroenterologist to gauge risks and benefits, as acamprosate can cause adverse GI effects.
Acamprosate has not been tested in children or the elderly, although one study suggests efficacy in alcohol-dependent adolescents ages 16 to 19.7. The agent’s safety during pregnancy or lactation is unknown.
TOLERABILITY
Acamprosate has been well-tolerated in clinical trials. Discontinuation rates because of adverse effects have been similar in treatment and placebo groups.7
GI side effects are most common, with overall rates of 17% and 11% among acamprosate and placebo groups, respectively.7 Diarrhea may be transient and may also resolve with a reduced dosage.6
Slightly higher rates of suicidal ideation were reported among patients taking acamprosate vs those taking placebo (1.4 % vs. 0.5% in short-term [10 Screen all patients taking acamprosate for suicidal ideation or behavior.
Other reported side effects include headache, abdominal pain, nausea and vomiting, dyspepsia, flatulence, pruritus, rash, drowsiness, and dizziness. Acamprosate has no abuse potential and low potential for toxicity in overdose. Higher acamprosate plasma levels during combined acamprosate/naltrexone treatment may increase risk of diarrhea.9
CLINICAL IMPLICATIONS
Drinking alcohol while taking acamprosate will not make a patient sick, which makes it an alternative for patients who fear the harsh effects of “slipping up” while taking disulfiram.
Also, acamprosate does not interact with prescription opioids. By contrast, naltrexone is contraindicated in patients taking opioids for pain.
Related resources
- Campral Web site. www.campral.com
- National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov
- National Institute on Drug Abuse. www.nida.nih.gov
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Naltrexone • ReVia
Disclosure
Drs. Connery and Weiss receive research/grant support from Ortho-McNeil Pharmaceutical. Dr. Weiss is also a speaker for Forest Laboratories.
1. Dahchour A, De Witte P. Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 2000;60:343-62.
2. Kiritze-Topor P, Huas D, Rosenzweig C, et al. A pragmatic trial of acamprosate in the treatment of alcohol dependence in primary care. Alcohol Alcohol 2004;39:520-7.
3. Kiefer F, Wiedemann K. Combined therapy: what does acamprosate and naltrexone combination tell us? Alcohol Alcohol 2004;39:542-7.
4. Mason BJ, Goodman AM, Dixon RM, et al. A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Neuropsychopharmacology 2002;27:596-606.
5. Johnson BA, O’Malley SS, Ciraulo DA, et al. Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. J Clin Psychopharmacol 2003;23:281-93.
6. Overman GP, Teter CJ, Guthrie SK. Acamprosate for the adjunctive treatment of alcohol dependence. Ann Pharmacother 2003;37:1090-9.
7. Carmen B, Angeles M, Ana M, Maria AJ. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811-28.
8. Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2003;60:92-9.
9. The COMBINE study research group. Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: rationale and methods. Alcohol Clin Exp Res 2003;27:1107-22.
10. Campral prescribing information. Available at: http://www.campral.com. Accessed Jan. 7, 2005.
1. Dahchour A, De Witte P. Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 2000;60:343-62.
2. Kiritze-Topor P, Huas D, Rosenzweig C, et al. A pragmatic trial of acamprosate in the treatment of alcohol dependence in primary care. Alcohol Alcohol 2004;39:520-7.
3. Kiefer F, Wiedemann K. Combined therapy: what does acamprosate and naltrexone combination tell us? Alcohol Alcohol 2004;39:542-7.
4. Mason BJ, Goodman AM, Dixon RM, et al. A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Neuropsychopharmacology 2002;27:596-606.
5. Johnson BA, O’Malley SS, Ciraulo DA, et al. Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. J Clin Psychopharmacol 2003;23:281-93.
6. Overman GP, Teter CJ, Guthrie SK. Acamprosate for the adjunctive treatment of alcohol dependence. Ann Pharmacother 2003;37:1090-9.
7. Carmen B, Angeles M, Ana M, Maria AJ. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811-28.
8. Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2003;60:92-9.
9. The COMBINE study research group. Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: rationale and methods. Alcohol Clin Exp Res 2003;27:1107-22.
10. Campral prescribing information. Available at: http://www.campral.com. Accessed Jan. 7, 2005.
5 keys to improve counseling for dual-diagnosis patients
Psychiatrists frequently encounter dual-diagnosis patients (Box) and may often wonder which to treat first—the substance abuse or the psychiatric comorbidity. Five principles can help you counsel dual-diagnosis patients more effectively. Briefly, they are to:
- appreciate this population’s heterogeneity
- adopt a longitudinal treatment approach, reassessing patients’ progress and adjusting interventions as needed over time
- be empathic rather than confrontational
- realize that treatment often proceeds in stages—not on a smooth, linear path
- recognize the importance of medication compliance.
ASSESSMENT
Different patients, different problems. All counseling of dual-diagnosis patients begins with a thorough assessment aimed at making an accurate diagnosis and understanding the relationship between the co-existing disorders. Although some people refer to “dual-diagnosis patients” as a single entity, these patients differ according to:
The National Institute of Mental Health’s Epidemiologic Catchment Area study documented high rates of substance use disorders in patients with psychiatric disorders.1 Lifetime prevalence of co-occurrence was 61% for bipolar disorder (the highest of any Axis I disorder),47% for schizophrenia, and 36% for panic disorder.
Dual-diagnosis patients face a more bleak prognosis than those with a single disorder, including higher rates of relapse, hospitalization, violence, incarceration, homelessness, and serious infections such as hepatitis and HIV.2 Unfortunately, these findings have not always led to effective treatments.
These patients represent a heterogeneous group and require individualized treatment. For example, abstinence from alcohol or drugs may worsen psychiatric symptoms in a patient with posttraumatic stress disorder and substance abuse. On the other hand, abstinence would be expected to improve the symptoms of a patient with comorbid major depressive disorder and substance abuse.
- diagnosis, with a myriad of potential combinations of substance use and psychiatric disorders
- severity of disorder, with some having a predominant psychiatric or substance use problem and others experiencing severe courses of both problems
- causes of their substance abuse and psychiatric disorders, based in part on which problem is primary and which is secondary
- level of motivation for treatment and their treatment goals.
Primary versus secondary disorders. How to distinguish “primary” from “secondary” disorders in dually diagnosed patients has prompted much research and debate.
A psychiatric disorder is typically called primary when it can be viewed as independent from the substance use disorder. The term “secondary psychiatric disorder” connotes that the substance use disorder is causing the psychiatric symptoms. For example, alcohol-dependent patients in detoxification programs often have depressive symptoms, some of which abate with abstinence. They are frequently diagnosed as having “secondary depression,” or—in DSM-IV diagnostic terms—substance-induced mood disorder.
Unfortunately, distinguishing primary from secondary disorders is sometimes difficult because of patients’ poor memory, recall bias, and inadequate periods of sobriety (“I’ve been drinking for a long time and have been depressed for a long time, so I don’t remember what I was like when I was sober”). Thus, the diagnostic assessment is generally accomplished over time, rather than in a single interview.
Our research3 and clinical experience have taught us that patients’ recall about the relationship between their substance use and psychiatric symptoms often changes over time. Determining the “primary” disorder may also have limited validity in predicting treatment response.4
Stages of Change model. The Stages of Change model5,6 is useful for assessing a dually diagnosed patient’s motivation to change, although its use in addictive disorders has been challenged.7,8 According to the transtheoretical model developed by Prochaska et al (Table 1),5 people generally make behavioral changes in stages defined by their level of willingness to make these changes.
When counseling the dually diagnosed patient, it is useful to assess readiness to change and to suggest behavioral steps the patient is able and willing to make. Thus, it would not be appropriate to discuss drug refusal methods with a patient who does not see his substance use as a problem. Rather, addressing this patient’s ambivalence would be more useful.
Table 1
5 stages of change: The transtheoretical model of behavior change
| Stage of change | Patient behavior |
|---|---|
| Precontemplation | No intention to change behavior in the foreseeable future; little or no awareness of problems |
| Contemplation | Aware that a problem exists; seriously thinking about overcoming it but no commitment to take action |
| Preparation | Intends to take action within the next month; has tried unsuccessfully to take action in the past year |
| Action | Modifies behavior, experiences, or environment to overcome problems |
| Maintenance | Works to prevent relapse and consolidate gains attained during action stage; for addictive behaviors, maintenance extends indefinitely from 6 months after the initial action |
| Source: Prochaska JO. Transtheoretical model: Stages of Change. Cancer Prevention Research Center, University of Rhode Island. http://www.uri.edu/research/cprc/TTM/StagesOfChange.htm | |
It is important to note that many patients move back and forth between stages of readiness to change. For example, a patient in the action stage (entering treatment and pursuing a goal of abstinence) may revert to contemplation and again question whether he or she has a serious substance abuse problem. We recommend that clinicians reassess patients regularly and continue to match interventions with the current level of motivation.
WHICH DISORDER IS TREATED FIRST?
Three approaches are used for treating the coexisting problems of dual-diagnosis patients—sequential, parallel, and integrated.
Sequential treatment addresses the more acute disorder first; the other disorder receives greater attention later. This model is commonly used with hospital treatment, in which comparatively little attention would be paid to substance use in a patient who is acutely psychotic.
Parallel treatment addresses each disorder contemporaneously but in different settings (such as at a substance abuse program on Monday and a mental health center on Thursday).
One limitation of the sequential and parallel models is that psychiatric and substance abuse programs typically have different orientations. A lack of comprehensive assessment may leave the substance abuse or psychiatric disorder underdiagnosed, depending on the setting. Staff members may also project negative attitudes toward patients with psychiatric or substance use disorders if they know comparatively little about the diagnosis and treatment of the other type of disorder. Treatment in two settings also can lead to communication problems and differences of opinion among the treating clinicians.
Integrated treatment, in which both disorders are treated simultaneously in the same setting, has shown favorable outcomes in several initial studies.9 11 Different integrated treatment models have been described, which vary according to the psychiatric disorders’ nature and the treatment’s theoretical orientation. Integrated treatment strategies include:
- focusing on psychiatric and substance abuse issues simultaneously or in alternating sessions
- providing intense case management
- stressing the importance of medication compliance.12
COUNSELING PRINCIPLES
As mentioned, a careful history and thorough assessment are the keys to effectively treating the dually diagnosed patient.
Assess how the patient perceives the relationship between his substance use disorder and psychiatric symptoms. For example, ask, “What do you see as the relationship between your drinking and your depression, if any?”
As part of this process, explore both the immediate and long-term relationships between the two phenomena. For example, some patients will say that drinking offers them immediate relief from their depressive symptoms but exacerbates their depression the following day. Encouraging patients to look beyond the immediate—often positive—effects of their substance use may help them understand the negative consequences of continued use.
Review previous periods of recovery and relapse. For patients who have had substantial periods of recovery, it is important to acknowledge these successes and to ask in an upbeat and admiring way, “How did you do it?” This approach may remind patients of past successes and counterbalance their frequent feelings of discouragement and hopelessness.
Table 2
4 phases in treating the dually diagnosed patient
| Phase | Therapeutic goals |
|---|---|
| Engagement | Build an alliance Attract patient to treatment program |
| Persuasion | Convince engaged patient to accept longer-term, abstinence-based treatment |
| Active treatment | Help patient develop attitudes and techniques essential to maintain sobriety |
| Relapse prevention | Help patient maintain gains made in active treatment and cope with lapses/relapses should they occur |
To help clarify the relationship between coexisting disorders, ask patients about psychiatric symptoms they have experienced during periods of substance use and recovery. Taking a relapse history can help you and the patient identify decisions and behaviors he or she must avoid (such as stopping medication, failing to attend treatment, or engaging in high-risk activities as in going to bars).
PHASES OF TREATMENT
Four phases of dual-diagnosis treatment—engagement, persuasion, active treatment, and relapse prevention—have been described, along with their therapeutic goals (Table 2).13 Consider these phases when treating this population, even though most patients do not proceed through them in an orderly, linear fashion.
Engagement. At the onset, the therapist tries to build an alliance and begins to establish trust and credibility.
Persuasion involves helping the patient comprehend the need to seriously address his or her substance use. It is important during engagement and persuasion stages to be empathic, using reflective listening and validating techniques.
Helping the patient see the discrepancy between his or her long-term goals and current behavior can create the impetus for change. Linking the substance use and psychiatric symptoms and exploring their impact on each other may help the patient understand the problem.
Ambivalence and resistance are normal reactions to this process of change, so avoid arguing with the patient. Confrontation—long a common strategy in substance abuse treatment—is losing favor and is being supplanted in many cases by a more supportive, empathic approach.14 Indeed, patients with co-occurring psychiatric illness generally respond particularly poorly to confrontation.
Active treatment focuses on techniques to achieve abstinence, including alcohol and drug refusal skills, methods to deal with craving, and ways to recognize and avoid situations that present a high risk for relapse.
Relapse prevention reinforces gains made in previous stages. Here, the patient learns how to identify and deal with risky situations and how to handle a “slip” if it occurs.
ADJUNCTIVE TREATMENTS
Self-help groups. Ask whether the patient has attended self-help groups for addiction or psychiatric illness. If so, then ask, “What did you think of the meetings? What did you like and dislike?”
Self-help groups such as Alcoholics Anonymous (AA) or the Manic-Depressive and Depressive Association (MDDA) can help enormously in the recovery process. These groups are free, readily available, and can offer patients a support network. Although many dual-diagnosis patients are reluctant to attend self-help groups, they may benefit from the support, role modeling, practical advice, and structure that these meetings offer.
Drug therapy for the dual-diagnosis patient focuses on the psychiatric disorder and is usually combined with psychosocial approaches. There is little evidence that one medication is more effective than others for these patients.
Because medication compliance is key to their effective treatment, be sure to ask patients at each visit, “Have you been taking your medication as prescribed?” Because dual-diagnosis patients have been shown to take more or less medication than prescribed,15 asking how much medication they are taking can be revealing.
Related resources
- American Academy of Addiction Psychiatry www.aaap.org
- National Institute on Drug Abuse www.nida.nih.gov
- National Institute on Alcohol Abuse and Alcoholism www.niaaa.nih.gov
Disclosure
Dr. Manwani receives research support from Abbott Laboratories.
Dr. Weiss is a speaker for Abbott Laboratories and Eli Lilly and Co.
Acknowledgment
Supported by grants K0200326, DA09400, and DA15968 from the National Institute on Drug Abuse and a grant from the Dr. Ralph and Marian C. Falk Medical Research Trust.
1. Reigier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990;264:2511-18.
2. Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv 2001;52:469-76.
3. Griffin ML, Weiss RD, Mirin SM, et al. The use of the Diagnostic Interview Schedule in drug-dependent patients. Am. J Drug Alcohol Abuse 1987;13(3):281-91.
4. Mason BJ, Kocsis JH, Ritvo EC, et al. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA 1996;275(10):761-7.
5. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change: applications to addictive behaviors. Am Psychol 1992;47:1102-14.
6. Connors GJ, Donovan DM, DiClemente CC. Substance abuse treatment and the stages of change. New York: Guilford Press, 2001.
7. Carey KB, Purnine DM, Maisto SA, et al. Assessing readiness to change substance abuse: a critical review of instruments. Clinical Psychol 1999;6:245-66.
8. Sutton S. Back to the drawing board? A review of applications of the transtheoretical model to substance use. Addiction 2001;96:175-86.
9. Drake RE, McHugo GJ, Noordsy DL. Treatment of alcoholism among schizophrenic outpatients: 4-year outcomes. Am J Psychiatry 1993;150:328-9.
10. Hellerstein DJ, Rosenthal RN, Miner CR. A prospective study of integrated outpatient treatment for substance-abusing schizophrenic patients. Am J Addict 1995;4:33-42.
11. Drake RE, Yovetich NA, Bebout RR, et al. Integrated treatment for dually diagnosed homeless adults. J Nerv Ment Dis 1997;185:298-305.
12. Weiss RD, Najavits LM, Hennessy G. Overview of treatment modalities for dual diagnosis patients: pharmacotherapy, psychotherapy, and twelve-step programs. In: Kranzler HR, Tinsley J (eds). Dual diagnosis: substance abuse and comorbid disorders. (2nd ed). New York: Marcel Dekker. In press.
13. Osher FC, Kofoed LL. Treatment of patients with psychiatric and psychoactive substance abuse disorders. Hosp Community Psychiatry 1989;40(10):1025-30.
14. Miller WR, Rollnick S. Motivational interviewing: preparing for change (2nd ed). New York: Guilford Press, 2002.
15. Weiss RD, Greenfield SF, Najavits LM, et al. Medication compliance among patients with bipolar disorder and substance use disorder. J Clin Psychiatry 1998;59(4):172-4.
Psychiatrists frequently encounter dual-diagnosis patients (Box) and may often wonder which to treat first—the substance abuse or the psychiatric comorbidity. Five principles can help you counsel dual-diagnosis patients more effectively. Briefly, they are to:
- appreciate this population’s heterogeneity
- adopt a longitudinal treatment approach, reassessing patients’ progress and adjusting interventions as needed over time
- be empathic rather than confrontational
- realize that treatment often proceeds in stages—not on a smooth, linear path
- recognize the importance of medication compliance.
ASSESSMENT
Different patients, different problems. All counseling of dual-diagnosis patients begins with a thorough assessment aimed at making an accurate diagnosis and understanding the relationship between the co-existing disorders. Although some people refer to “dual-diagnosis patients” as a single entity, these patients differ according to:
The National Institute of Mental Health’s Epidemiologic Catchment Area study documented high rates of substance use disorders in patients with psychiatric disorders.1 Lifetime prevalence of co-occurrence was 61% for bipolar disorder (the highest of any Axis I disorder),47% for schizophrenia, and 36% for panic disorder.
Dual-diagnosis patients face a more bleak prognosis than those with a single disorder, including higher rates of relapse, hospitalization, violence, incarceration, homelessness, and serious infections such as hepatitis and HIV.2 Unfortunately, these findings have not always led to effective treatments.
These patients represent a heterogeneous group and require individualized treatment. For example, abstinence from alcohol or drugs may worsen psychiatric symptoms in a patient with posttraumatic stress disorder and substance abuse. On the other hand, abstinence would be expected to improve the symptoms of a patient with comorbid major depressive disorder and substance abuse.
- diagnosis, with a myriad of potential combinations of substance use and psychiatric disorders
- severity of disorder, with some having a predominant psychiatric or substance use problem and others experiencing severe courses of both problems
- causes of their substance abuse and psychiatric disorders, based in part on which problem is primary and which is secondary
- level of motivation for treatment and their treatment goals.
Primary versus secondary disorders. How to distinguish “primary” from “secondary” disorders in dually diagnosed patients has prompted much research and debate.
A psychiatric disorder is typically called primary when it can be viewed as independent from the substance use disorder. The term “secondary psychiatric disorder” connotes that the substance use disorder is causing the psychiatric symptoms. For example, alcohol-dependent patients in detoxification programs often have depressive symptoms, some of which abate with abstinence. They are frequently diagnosed as having “secondary depression,” or—in DSM-IV diagnostic terms—substance-induced mood disorder.
Unfortunately, distinguishing primary from secondary disorders is sometimes difficult because of patients’ poor memory, recall bias, and inadequate periods of sobriety (“I’ve been drinking for a long time and have been depressed for a long time, so I don’t remember what I was like when I was sober”). Thus, the diagnostic assessment is generally accomplished over time, rather than in a single interview.
Our research3 and clinical experience have taught us that patients’ recall about the relationship between their substance use and psychiatric symptoms often changes over time. Determining the “primary” disorder may also have limited validity in predicting treatment response.4
Stages of Change model. The Stages of Change model5,6 is useful for assessing a dually diagnosed patient’s motivation to change, although its use in addictive disorders has been challenged.7,8 According to the transtheoretical model developed by Prochaska et al (Table 1),5 people generally make behavioral changes in stages defined by their level of willingness to make these changes.
When counseling the dually diagnosed patient, it is useful to assess readiness to change and to suggest behavioral steps the patient is able and willing to make. Thus, it would not be appropriate to discuss drug refusal methods with a patient who does not see his substance use as a problem. Rather, addressing this patient’s ambivalence would be more useful.
Table 1
5 stages of change: The transtheoretical model of behavior change
| Stage of change | Patient behavior |
|---|---|
| Precontemplation | No intention to change behavior in the foreseeable future; little or no awareness of problems |
| Contemplation | Aware that a problem exists; seriously thinking about overcoming it but no commitment to take action |
| Preparation | Intends to take action within the next month; has tried unsuccessfully to take action in the past year |
| Action | Modifies behavior, experiences, or environment to overcome problems |
| Maintenance | Works to prevent relapse and consolidate gains attained during action stage; for addictive behaviors, maintenance extends indefinitely from 6 months after the initial action |
| Source: Prochaska JO. Transtheoretical model: Stages of Change. Cancer Prevention Research Center, University of Rhode Island. http://www.uri.edu/research/cprc/TTM/StagesOfChange.htm | |
It is important to note that many patients move back and forth between stages of readiness to change. For example, a patient in the action stage (entering treatment and pursuing a goal of abstinence) may revert to contemplation and again question whether he or she has a serious substance abuse problem. We recommend that clinicians reassess patients regularly and continue to match interventions with the current level of motivation.
WHICH DISORDER IS TREATED FIRST?
Three approaches are used for treating the coexisting problems of dual-diagnosis patients—sequential, parallel, and integrated.
Sequential treatment addresses the more acute disorder first; the other disorder receives greater attention later. This model is commonly used with hospital treatment, in which comparatively little attention would be paid to substance use in a patient who is acutely psychotic.
Parallel treatment addresses each disorder contemporaneously but in different settings (such as at a substance abuse program on Monday and a mental health center on Thursday).
One limitation of the sequential and parallel models is that psychiatric and substance abuse programs typically have different orientations. A lack of comprehensive assessment may leave the substance abuse or psychiatric disorder underdiagnosed, depending on the setting. Staff members may also project negative attitudes toward patients with psychiatric or substance use disorders if they know comparatively little about the diagnosis and treatment of the other type of disorder. Treatment in two settings also can lead to communication problems and differences of opinion among the treating clinicians.
Integrated treatment, in which both disorders are treated simultaneously in the same setting, has shown favorable outcomes in several initial studies.9 11 Different integrated treatment models have been described, which vary according to the psychiatric disorders’ nature and the treatment’s theoretical orientation. Integrated treatment strategies include:
- focusing on psychiatric and substance abuse issues simultaneously or in alternating sessions
- providing intense case management
- stressing the importance of medication compliance.12
COUNSELING PRINCIPLES
As mentioned, a careful history and thorough assessment are the keys to effectively treating the dually diagnosed patient.
Assess how the patient perceives the relationship between his substance use disorder and psychiatric symptoms. For example, ask, “What do you see as the relationship between your drinking and your depression, if any?”
As part of this process, explore both the immediate and long-term relationships between the two phenomena. For example, some patients will say that drinking offers them immediate relief from their depressive symptoms but exacerbates their depression the following day. Encouraging patients to look beyond the immediate—often positive—effects of their substance use may help them understand the negative consequences of continued use.
Review previous periods of recovery and relapse. For patients who have had substantial periods of recovery, it is important to acknowledge these successes and to ask in an upbeat and admiring way, “How did you do it?” This approach may remind patients of past successes and counterbalance their frequent feelings of discouragement and hopelessness.
Table 2
4 phases in treating the dually diagnosed patient
| Phase | Therapeutic goals |
|---|---|
| Engagement | Build an alliance Attract patient to treatment program |
| Persuasion | Convince engaged patient to accept longer-term, abstinence-based treatment |
| Active treatment | Help patient develop attitudes and techniques essential to maintain sobriety |
| Relapse prevention | Help patient maintain gains made in active treatment and cope with lapses/relapses should they occur |
To help clarify the relationship between coexisting disorders, ask patients about psychiatric symptoms they have experienced during periods of substance use and recovery. Taking a relapse history can help you and the patient identify decisions and behaviors he or she must avoid (such as stopping medication, failing to attend treatment, or engaging in high-risk activities as in going to bars).
PHASES OF TREATMENT
Four phases of dual-diagnosis treatment—engagement, persuasion, active treatment, and relapse prevention—have been described, along with their therapeutic goals (Table 2).13 Consider these phases when treating this population, even though most patients do not proceed through them in an orderly, linear fashion.
Engagement. At the onset, the therapist tries to build an alliance and begins to establish trust and credibility.
Persuasion involves helping the patient comprehend the need to seriously address his or her substance use. It is important during engagement and persuasion stages to be empathic, using reflective listening and validating techniques.
Helping the patient see the discrepancy between his or her long-term goals and current behavior can create the impetus for change. Linking the substance use and psychiatric symptoms and exploring their impact on each other may help the patient understand the problem.
Ambivalence and resistance are normal reactions to this process of change, so avoid arguing with the patient. Confrontation—long a common strategy in substance abuse treatment—is losing favor and is being supplanted in many cases by a more supportive, empathic approach.14 Indeed, patients with co-occurring psychiatric illness generally respond particularly poorly to confrontation.
Active treatment focuses on techniques to achieve abstinence, including alcohol and drug refusal skills, methods to deal with craving, and ways to recognize and avoid situations that present a high risk for relapse.
Relapse prevention reinforces gains made in previous stages. Here, the patient learns how to identify and deal with risky situations and how to handle a “slip” if it occurs.
ADJUNCTIVE TREATMENTS
Self-help groups. Ask whether the patient has attended self-help groups for addiction or psychiatric illness. If so, then ask, “What did you think of the meetings? What did you like and dislike?”
Self-help groups such as Alcoholics Anonymous (AA) or the Manic-Depressive and Depressive Association (MDDA) can help enormously in the recovery process. These groups are free, readily available, and can offer patients a support network. Although many dual-diagnosis patients are reluctant to attend self-help groups, they may benefit from the support, role modeling, practical advice, and structure that these meetings offer.
Drug therapy for the dual-diagnosis patient focuses on the psychiatric disorder and is usually combined with psychosocial approaches. There is little evidence that one medication is more effective than others for these patients.
Because medication compliance is key to their effective treatment, be sure to ask patients at each visit, “Have you been taking your medication as prescribed?” Because dual-diagnosis patients have been shown to take more or less medication than prescribed,15 asking how much medication they are taking can be revealing.
Related resources
- American Academy of Addiction Psychiatry www.aaap.org
- National Institute on Drug Abuse www.nida.nih.gov
- National Institute on Alcohol Abuse and Alcoholism www.niaaa.nih.gov
Disclosure
Dr. Manwani receives research support from Abbott Laboratories.
Dr. Weiss is a speaker for Abbott Laboratories and Eli Lilly and Co.
Acknowledgment
Supported by grants K0200326, DA09400, and DA15968 from the National Institute on Drug Abuse and a grant from the Dr. Ralph and Marian C. Falk Medical Research Trust.
Psychiatrists frequently encounter dual-diagnosis patients (Box) and may often wonder which to treat first—the substance abuse or the psychiatric comorbidity. Five principles can help you counsel dual-diagnosis patients more effectively. Briefly, they are to:
- appreciate this population’s heterogeneity
- adopt a longitudinal treatment approach, reassessing patients’ progress and adjusting interventions as needed over time
- be empathic rather than confrontational
- realize that treatment often proceeds in stages—not on a smooth, linear path
- recognize the importance of medication compliance.
ASSESSMENT
Different patients, different problems. All counseling of dual-diagnosis patients begins with a thorough assessment aimed at making an accurate diagnosis and understanding the relationship between the co-existing disorders. Although some people refer to “dual-diagnosis patients” as a single entity, these patients differ according to:
The National Institute of Mental Health’s Epidemiologic Catchment Area study documented high rates of substance use disorders in patients with psychiatric disorders.1 Lifetime prevalence of co-occurrence was 61% for bipolar disorder (the highest of any Axis I disorder),47% for schizophrenia, and 36% for panic disorder.
Dual-diagnosis patients face a more bleak prognosis than those with a single disorder, including higher rates of relapse, hospitalization, violence, incarceration, homelessness, and serious infections such as hepatitis and HIV.2 Unfortunately, these findings have not always led to effective treatments.
These patients represent a heterogeneous group and require individualized treatment. For example, abstinence from alcohol or drugs may worsen psychiatric symptoms in a patient with posttraumatic stress disorder and substance abuse. On the other hand, abstinence would be expected to improve the symptoms of a patient with comorbid major depressive disorder and substance abuse.
- diagnosis, with a myriad of potential combinations of substance use and psychiatric disorders
- severity of disorder, with some having a predominant psychiatric or substance use problem and others experiencing severe courses of both problems
- causes of their substance abuse and psychiatric disorders, based in part on which problem is primary and which is secondary
- level of motivation for treatment and their treatment goals.
Primary versus secondary disorders. How to distinguish “primary” from “secondary” disorders in dually diagnosed patients has prompted much research and debate.
A psychiatric disorder is typically called primary when it can be viewed as independent from the substance use disorder. The term “secondary psychiatric disorder” connotes that the substance use disorder is causing the psychiatric symptoms. For example, alcohol-dependent patients in detoxification programs often have depressive symptoms, some of which abate with abstinence. They are frequently diagnosed as having “secondary depression,” or—in DSM-IV diagnostic terms—substance-induced mood disorder.
Unfortunately, distinguishing primary from secondary disorders is sometimes difficult because of patients’ poor memory, recall bias, and inadequate periods of sobriety (“I’ve been drinking for a long time and have been depressed for a long time, so I don’t remember what I was like when I was sober”). Thus, the diagnostic assessment is generally accomplished over time, rather than in a single interview.
Our research3 and clinical experience have taught us that patients’ recall about the relationship between their substance use and psychiatric symptoms often changes over time. Determining the “primary” disorder may also have limited validity in predicting treatment response.4
Stages of Change model. The Stages of Change model5,6 is useful for assessing a dually diagnosed patient’s motivation to change, although its use in addictive disorders has been challenged.7,8 According to the transtheoretical model developed by Prochaska et al (Table 1),5 people generally make behavioral changes in stages defined by their level of willingness to make these changes.
When counseling the dually diagnosed patient, it is useful to assess readiness to change and to suggest behavioral steps the patient is able and willing to make. Thus, it would not be appropriate to discuss drug refusal methods with a patient who does not see his substance use as a problem. Rather, addressing this patient’s ambivalence would be more useful.
Table 1
5 stages of change: The transtheoretical model of behavior change
| Stage of change | Patient behavior |
|---|---|
| Precontemplation | No intention to change behavior in the foreseeable future; little or no awareness of problems |
| Contemplation | Aware that a problem exists; seriously thinking about overcoming it but no commitment to take action |
| Preparation | Intends to take action within the next month; has tried unsuccessfully to take action in the past year |
| Action | Modifies behavior, experiences, or environment to overcome problems |
| Maintenance | Works to prevent relapse and consolidate gains attained during action stage; for addictive behaviors, maintenance extends indefinitely from 6 months after the initial action |
| Source: Prochaska JO. Transtheoretical model: Stages of Change. Cancer Prevention Research Center, University of Rhode Island. http://www.uri.edu/research/cprc/TTM/StagesOfChange.htm | |
It is important to note that many patients move back and forth between stages of readiness to change. For example, a patient in the action stage (entering treatment and pursuing a goal of abstinence) may revert to contemplation and again question whether he or she has a serious substance abuse problem. We recommend that clinicians reassess patients regularly and continue to match interventions with the current level of motivation.
WHICH DISORDER IS TREATED FIRST?
Three approaches are used for treating the coexisting problems of dual-diagnosis patients—sequential, parallel, and integrated.
Sequential treatment addresses the more acute disorder first; the other disorder receives greater attention later. This model is commonly used with hospital treatment, in which comparatively little attention would be paid to substance use in a patient who is acutely psychotic.
Parallel treatment addresses each disorder contemporaneously but in different settings (such as at a substance abuse program on Monday and a mental health center on Thursday).
One limitation of the sequential and parallel models is that psychiatric and substance abuse programs typically have different orientations. A lack of comprehensive assessment may leave the substance abuse or psychiatric disorder underdiagnosed, depending on the setting. Staff members may also project negative attitudes toward patients with psychiatric or substance use disorders if they know comparatively little about the diagnosis and treatment of the other type of disorder. Treatment in two settings also can lead to communication problems and differences of opinion among the treating clinicians.
Integrated treatment, in which both disorders are treated simultaneously in the same setting, has shown favorable outcomes in several initial studies.9 11 Different integrated treatment models have been described, which vary according to the psychiatric disorders’ nature and the treatment’s theoretical orientation. Integrated treatment strategies include:
- focusing on psychiatric and substance abuse issues simultaneously or in alternating sessions
- providing intense case management
- stressing the importance of medication compliance.12
COUNSELING PRINCIPLES
As mentioned, a careful history and thorough assessment are the keys to effectively treating the dually diagnosed patient.
Assess how the patient perceives the relationship between his substance use disorder and psychiatric symptoms. For example, ask, “What do you see as the relationship between your drinking and your depression, if any?”
As part of this process, explore both the immediate and long-term relationships between the two phenomena. For example, some patients will say that drinking offers them immediate relief from their depressive symptoms but exacerbates their depression the following day. Encouraging patients to look beyond the immediate—often positive—effects of their substance use may help them understand the negative consequences of continued use.
Review previous periods of recovery and relapse. For patients who have had substantial periods of recovery, it is important to acknowledge these successes and to ask in an upbeat and admiring way, “How did you do it?” This approach may remind patients of past successes and counterbalance their frequent feelings of discouragement and hopelessness.
Table 2
4 phases in treating the dually diagnosed patient
| Phase | Therapeutic goals |
|---|---|
| Engagement | Build an alliance Attract patient to treatment program |
| Persuasion | Convince engaged patient to accept longer-term, abstinence-based treatment |
| Active treatment | Help patient develop attitudes and techniques essential to maintain sobriety |
| Relapse prevention | Help patient maintain gains made in active treatment and cope with lapses/relapses should they occur |
To help clarify the relationship between coexisting disorders, ask patients about psychiatric symptoms they have experienced during periods of substance use and recovery. Taking a relapse history can help you and the patient identify decisions and behaviors he or she must avoid (such as stopping medication, failing to attend treatment, or engaging in high-risk activities as in going to bars).
PHASES OF TREATMENT
Four phases of dual-diagnosis treatment—engagement, persuasion, active treatment, and relapse prevention—have been described, along with their therapeutic goals (Table 2).13 Consider these phases when treating this population, even though most patients do not proceed through them in an orderly, linear fashion.
Engagement. At the onset, the therapist tries to build an alliance and begins to establish trust and credibility.
Persuasion involves helping the patient comprehend the need to seriously address his or her substance use. It is important during engagement and persuasion stages to be empathic, using reflective listening and validating techniques.
Helping the patient see the discrepancy between his or her long-term goals and current behavior can create the impetus for change. Linking the substance use and psychiatric symptoms and exploring their impact on each other may help the patient understand the problem.
Ambivalence and resistance are normal reactions to this process of change, so avoid arguing with the patient. Confrontation—long a common strategy in substance abuse treatment—is losing favor and is being supplanted in many cases by a more supportive, empathic approach.14 Indeed, patients with co-occurring psychiatric illness generally respond particularly poorly to confrontation.
Active treatment focuses on techniques to achieve abstinence, including alcohol and drug refusal skills, methods to deal with craving, and ways to recognize and avoid situations that present a high risk for relapse.
Relapse prevention reinforces gains made in previous stages. Here, the patient learns how to identify and deal with risky situations and how to handle a “slip” if it occurs.
ADJUNCTIVE TREATMENTS
Self-help groups. Ask whether the patient has attended self-help groups for addiction or psychiatric illness. If so, then ask, “What did you think of the meetings? What did you like and dislike?”
Self-help groups such as Alcoholics Anonymous (AA) or the Manic-Depressive and Depressive Association (MDDA) can help enormously in the recovery process. These groups are free, readily available, and can offer patients a support network. Although many dual-diagnosis patients are reluctant to attend self-help groups, they may benefit from the support, role modeling, practical advice, and structure that these meetings offer.
Drug therapy for the dual-diagnosis patient focuses on the psychiatric disorder and is usually combined with psychosocial approaches. There is little evidence that one medication is more effective than others for these patients.
Because medication compliance is key to their effective treatment, be sure to ask patients at each visit, “Have you been taking your medication as prescribed?” Because dual-diagnosis patients have been shown to take more or less medication than prescribed,15 asking how much medication they are taking can be revealing.
Related resources
- American Academy of Addiction Psychiatry www.aaap.org
- National Institute on Drug Abuse www.nida.nih.gov
- National Institute on Alcohol Abuse and Alcoholism www.niaaa.nih.gov
Disclosure
Dr. Manwani receives research support from Abbott Laboratories.
Dr. Weiss is a speaker for Abbott Laboratories and Eli Lilly and Co.
Acknowledgment
Supported by grants K0200326, DA09400, and DA15968 from the National Institute on Drug Abuse and a grant from the Dr. Ralph and Marian C. Falk Medical Research Trust.
1. Reigier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990;264:2511-18.
2. Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv 2001;52:469-76.
3. Griffin ML, Weiss RD, Mirin SM, et al. The use of the Diagnostic Interview Schedule in drug-dependent patients. Am. J Drug Alcohol Abuse 1987;13(3):281-91.
4. Mason BJ, Kocsis JH, Ritvo EC, et al. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA 1996;275(10):761-7.
5. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change: applications to addictive behaviors. Am Psychol 1992;47:1102-14.
6. Connors GJ, Donovan DM, DiClemente CC. Substance abuse treatment and the stages of change. New York: Guilford Press, 2001.
7. Carey KB, Purnine DM, Maisto SA, et al. Assessing readiness to change substance abuse: a critical review of instruments. Clinical Psychol 1999;6:245-66.
8. Sutton S. Back to the drawing board? A review of applications of the transtheoretical model to substance use. Addiction 2001;96:175-86.
9. Drake RE, McHugo GJ, Noordsy DL. Treatment of alcoholism among schizophrenic outpatients: 4-year outcomes. Am J Psychiatry 1993;150:328-9.
10. Hellerstein DJ, Rosenthal RN, Miner CR. A prospective study of integrated outpatient treatment for substance-abusing schizophrenic patients. Am J Addict 1995;4:33-42.
11. Drake RE, Yovetich NA, Bebout RR, et al. Integrated treatment for dually diagnosed homeless adults. J Nerv Ment Dis 1997;185:298-305.
12. Weiss RD, Najavits LM, Hennessy G. Overview of treatment modalities for dual diagnosis patients: pharmacotherapy, psychotherapy, and twelve-step programs. In: Kranzler HR, Tinsley J (eds). Dual diagnosis: substance abuse and comorbid disorders. (2nd ed). New York: Marcel Dekker. In press.
13. Osher FC, Kofoed LL. Treatment of patients with psychiatric and psychoactive substance abuse disorders. Hosp Community Psychiatry 1989;40(10):1025-30.
14. Miller WR, Rollnick S. Motivational interviewing: preparing for change (2nd ed). New York: Guilford Press, 2002.
15. Weiss RD, Greenfield SF, Najavits LM, et al. Medication compliance among patients with bipolar disorder and substance use disorder. J Clin Psychiatry 1998;59(4):172-4.
1. Reigier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990;264:2511-18.
2. Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv 2001;52:469-76.
3. Griffin ML, Weiss RD, Mirin SM, et al. The use of the Diagnostic Interview Schedule in drug-dependent patients. Am. J Drug Alcohol Abuse 1987;13(3):281-91.
4. Mason BJ, Kocsis JH, Ritvo EC, et al. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA 1996;275(10):761-7.
5. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change: applications to addictive behaviors. Am Psychol 1992;47:1102-14.
6. Connors GJ, Donovan DM, DiClemente CC. Substance abuse treatment and the stages of change. New York: Guilford Press, 2001.
7. Carey KB, Purnine DM, Maisto SA, et al. Assessing readiness to change substance abuse: a critical review of instruments. Clinical Psychol 1999;6:245-66.
8. Sutton S. Back to the drawing board? A review of applications of the transtheoretical model to substance use. Addiction 2001;96:175-86.
9. Drake RE, McHugo GJ, Noordsy DL. Treatment of alcoholism among schizophrenic outpatients: 4-year outcomes. Am J Psychiatry 1993;150:328-9.
10. Hellerstein DJ, Rosenthal RN, Miner CR. A prospective study of integrated outpatient treatment for substance-abusing schizophrenic patients. Am J Addict 1995;4:33-42.
11. Drake RE, Yovetich NA, Bebout RR, et al. Integrated treatment for dually diagnosed homeless adults. J Nerv Ment Dis 1997;185:298-305.
12. Weiss RD, Najavits LM, Hennessy G. Overview of treatment modalities for dual diagnosis patients: pharmacotherapy, psychotherapy, and twelve-step programs. In: Kranzler HR, Tinsley J (eds). Dual diagnosis: substance abuse and comorbid disorders. (2nd ed). New York: Marcel Dekker. In press.
13. Osher FC, Kofoed LL. Treatment of patients with psychiatric and psychoactive substance abuse disorders. Hosp Community Psychiatry 1989;40(10):1025-30.
14. Miller WR, Rollnick S. Motivational interviewing: preparing for change (2nd ed). New York: Guilford Press, 2002.
15. Weiss RD, Greenfield SF, Najavits LM, et al. Medication compliance among patients with bipolar disorder and substance use disorder. J Clin Psychiatry 1998;59(4):172-4.
Pharmacotherapy of alcohol dependence: How and when to use disulfiram and naltrexone
Alcohol dependence is one of the leading causes of morbidity and mortality in the United States. Approximately 10% of Americans will develop alcoholism at some point in their lives,1 and an estimated 100,000 individuals die each year due to alcohol-related medical complications, automobile accidents, and homicides.2 Alcohol dependence also costs the U.S. billions of dollars annually in health care costs, lost productivity, incarceration, and property destruction.
The search for effective pharmacologic treatments has long been a focus of research. Disulfiram, which causes an aversive reaction when combined with alcohol, was for many years the only medication in use. More recently, the opiate antagonist naltrexone has also been used to treat alcohol-dependent patients.
The homotaurine derivative, acamprosate, has recently shown great promise. Though used widely in Europe,3 it is not approved for use in this country.
This article will therefore focus on disulfiram and naltrexone: their pharmacology, efficacy, side effects, and dosing strategies. We also will present guidelines for discussing each medication with patients and for deciding which, if either, to prescribe.
Differences in pharmacology
Disulfiram Since the serendipitous discovery of its reactive property with alcohol in the 1940s, disulfiram has been used in the pharmacological treatment of alcoholism. The agent disrupts alcohol metabolism by inhibiting the action of aldehyde dehydrogenase, thus blocking the conversion of acetaldehyde to acetate. Accumulation of acetaldehyde, the first metabolite of ethanol, causes numerous unpleasant effects, including flushing, weakness, and nausea.4 In addition to acting on aldehyde dehydrogenase, disulfiram inhibits dopamine-β-hydroxylase.5
Disulfiram is absorbed from the gastrointestinal tract and is rapidly distributed to tissues and organs. It begins to affect alcohol metabolism within 1 to 2 hours, with a peak at 12 hours. It is slowly excreted from the body over the next 2 weeks, although its effects may be lost sooner as the body secretes new enzyme.4
The ethanol-disulfiram reaction is characterized by flushing, throbbing in the head and neck, respiratory difficulty, vomiting, sweating, thirst, weakness, and hypotension ( Table 1). In some cases, the reaction can be fatal.
Naltrexone Following its approval for use in treating opioid dependence in the mid-1980s, the opiate antagonist naltrexone was approved nearly a decade ago for use in treating individuals with alcohol dependence. Research interest in the use of naltrexone for this purpose grew from theories that the endogenous opiate system may be involved in the development of alcohol dependence.6 Two simultaneously published studies in 1992 showed the benefit of naltrexone in alcohol dependence;7-8 this led to its approval by the Food and Drug Administration.
Naltrexone is metabolized to its major metabolite, 6-β-naltrexol, and is then excreted in the urine as both the original compound and this metabolite.9 The half-life of naltrexone in chronic administration is approximately 10 hours; the half-life of 6-β-naltrexol is 12 to 16 hours.
Comparison of efficacy
Disulfiram Results concerning efficacy have been mixed. Initial studies showed promising effects but were limited to anecdotal evidence and case studies. More recent studies have addressed issues relating to proper control groups, compliance, and motivation in evaluating disulfiram’s effect on alcohol consumption. Early studies used placebo groups to control for the effects of counseling or regular medical monitoring. However, no controls were employed to distinguish between the psychological effects of disulfiram (e.g., fear of a reaction) and its pharmacologic effects.
Table 1
SYMPTOMS OF AN ETHANOL-DISULFIRAM REACTION
| • Flushing | • Sweating |
| • Throbbing in head and neck | • Thirst |
| • Respiratory difficulty | • Weakness |
| • Vomiting | • Hypotension |
| The intensity of the reaction is generally related to the amount of alcohol and disulfiram consumed. Because even small amounts of alcohol may cause a reaction, individuals taking disulfiram should avoid all forms of alcohol, including certain mouthwashes and cough syrups. Patients also should be instructed to read the ingredients of foods and medications they consume. | |
| While the recommended daily dose for disulfiram ranges from 125 mg to 500 mg, individuals can vary widely in their reactions. Dosages below 250 mg/d have failed to produce aversive reactions in some individuals who drink alcohol. Dosages of 250 mg/d or higher, however, may cause toxic side effects, including a more severe reaction with alcohol. Clinicians should be aware that in a few patients, the dosage needed to produce an aversive reaction may be higher than the dosage that produces toxicity.4 | |
| The authors generally prescribe 125 mg/d, which is at the low end of the usual dose range, since the fear of a reaction—not the reaction itself—is the major therapeutic action of disulfiram. Moreover, a lower dosage diminishes (but by no means eliminates) the likelihood of a highly dangerous alcohol-disulfiram reaction. | |
Fuller and Roth10 addressed this concern by designing a double-blind study that consisted of 3 groups. Group 1 received disulfiram 250 mg/d, group 2 received 1 mg/d (a pharmacologically ineffective dose), and group 3 received a placebo. Importantly, patients in both groups 1 and 2 were informed that they were receiving disulfiram and were warned of a possible ethanol-disulfiram reaction. At a 6-month follow-up, patients receiving disulfiram showed a small but significant increase in abstinence compared with those receiving placebo. Interestingly, there was no difference between patients receiving 250 mg of disulfiram and those receiving the ineffective 1 mg dose, suggesting that the primary action of disulfiram is the fear of a reaction with alcohol, not the agent’s pharmacologic effects.
A number of studies have shown that patients who agree to take disulfiram and continue taking it are generally highly motivated; such patients unsurprisingly experience better treatment outcomes.
In the largest controlled, blinded study of disulfiram performed to date, Fuller et al11 evaluated disulfiram treatment in 605 male veterans randomly assigned to disulfiram 250 mg a day, disulfiram 1 mg a day, or placebo. No significant differences were found between groups in total abstinence or time to first drink. Among patients who participated in all assessments and who drank at least once during the study, however, those receiving 250 mg had fewer drinking days than those in either control group.
The authors concluded that disulfiram may help reduce drinking frequency after a return to drinking, but does not contribute to continuous abstinence or to delay in time to first drink. Notably, despite a medication compliance rate of only 20%, a significant relationship existed between medication compliance and complete abstinence, regardless of treatment group. O’Farrell and colleagues14 have studied ways to increase compliance with disulfiram, developing the concept of the “Antabuse contract,” in which the patient takes disulfiram in front of a significant other as part of a couple’s therapy program.
How long should a patient continue taking disulfiram? Unfortunately, the ideal length of disulfiram treatment has not been established. While most randomized trials only administer disulfiram for a few months, research by Ojehagen et al15 has shown that long-term treatment (greater than 12 months) with disulfiram is significantly related to positive drinking outcomes during the 2 years following treatment.
Naltrexone The two initial landmark studies of naltrexone for alcohol dependence were published nearly a decade ago. Volpicelli et al7 conducted a double-blind, placebo-controlled trial of naltrexone 50 mg/d for 12 weeks with 70 male veterans who also received intensive psychosocial alcohol rehabilitation. Study participants who received naltrexone had fewer drinking days, less craving for alcohol, and a lower rate of full-blown relapse than did patients who received placebo. The major effect of naltrexone occurred among patients who sampled alcohol; only half of those on naltrexone progressed from first drink to a full-blown relapse, compared to a 95% rate of relapse among those who initiated drinking while receiving placebo.
O’Malley et al8 also found naltrexone to be more effective than placebo and found an interesting interaction with psychosocial treatment. Individuals who received weekly abstinence-oriented supportive therapy were more likely to be continuously abstinent from alcohol at the end of the 12-week study period. Those who received naltrexone along with cognitive behavioral coping skills therapy were least likely to progress to a full-blown relapse if they did drink.
More recently, Anton et al12 conducted a double-blind, placebo-controlled trial of naltrexone in 131 patients, all of whom received cognitive behavioral therapy (CBT). Those receiving naltrexone had a significantly longer period prior to relapse, fewer drinking days, and fewer drinks per drinking day than the placebo group. No significant differences were reported between the groups in time prior to the first drink.
These studies suggest that naltrexone may diminish the likelihood of progression from first drink to full-blown relapse. This may occur through the agent’s attenuation of the reinforcing effects of alcohol.13 While naltrexone does not fully block alcohol the way it blocks opioid drugs, the reduction in alcohol’s positive effects may help naltrexone responders to contain their “slips” and prevent progression to a full-blown relapse.
The difference in adverse effects
Disulfiram Adverse effects (see Table 2) arise from 3 main causes:
- Medical complications during an ethanol-disulfiram reaction;
- Toxicity due to disulfiram or its metabolites;
- Interactions between disulfiram and other medications.
Table 2
HOW DISULFIRAM, NALTREXONE WORK
| Disulfiram | Naltrexone | |
|---|---|---|
| Mechanism of action | Interrupts metabolism of alcohol, leads to a buildup of acetaldehyde | Opiate antagonist, may attenuate reinforcing property of alcohol |
| Recommended dose* | 25-500 mg | 50 mg |
| Side effects and adverse events | Drowsiness, impotence, headache, acne, metallic aftertaste, hepatitis, neuritis, ethanoldisulfiram reaction | Nausea, vomiting, headache, anxiety, dizziness, fatigue, insomnia, elevated liver enzymes |
| *Physicians Desk Reference 55th ed. Montvale, NJ: Medical Economics, 2001 | ||
Medical complications arising from an ethanol-disulfiram reaction can include tachycardia, hypotension, and electrocardiographic changes. Fatalities have been reported due to myocardial infarction or cerebrovascular accident.5 As a result, people with a history of severe myocardial disease should generally not be prescribed disulfiram.
Side effects from disulfiram itself include drowsiness, impotence, headache, acne, and a metallic or garlic-like aftertaste. Toxicity can also lead to psychiatric reactions such as increased depression and psychosis, possibly because of the inhibition of dopamine β–hydroxylase.5
Hepatic and neurological reactions are the most commonly reported toxic reactions.19 Disulfiram-induced hepatitis usually occurs within 2 months of initiation of treatment, but may occur up to 6 months after starting disulfiram.20 This form of liver toxicity is believed to be an allergic or hypersensitivity reaction and can lead to hepatic necrosis and death due to liver failure. Some clinicians recommend obtaining liver function tests at regular intervals (e.g., at baseline, 2 weeks, 4 weeks, then monthly for 6 months), although the optimal frequency of testing after week 2 is not well established.
Neurological reactions make up approximately 20% of the overall reported side effects from disulfiram, with the most frequent diagnosis being polyneuropathy. Other important reported adverse neurological effects include optic and peripheral neuritis.19
Disulfiram interacts with a number of medications, primarily by slowing down their metabolism and thus increasing risk of toxicity. These drugs include phenytoin, theophylline, anticoagulant drugs, isoniazid, and amitriptyline.19 Prior to starting treatment with disulfiram, phenytoin serum levels should be obtained and monitored throughout treatment. Dosage of oral anticoagulant drugs such as warfarin should also be monitored carefully.
Naltrexone The most common side effect is nausea, which typically occurs in the first week of treatment. In the largest study of naltrexone published to date, approximately 10% of naltrexone-treated subjects reported this side effect.16 Other side effects include headache, anxiety, dizziness, fatigue, vomiting, and insomnia.16
Elevated liver enzymes have been reported with use,17 so liver function should be monitored in patients receiving this medication.
It is unclear how often liver function tests should be performed. One text18 recommends baseline assessment of liver function, monthly monitoring for 3 months, then testing every 2 to 6 months afterwards if results are normal.
Other clinical considerations
Disulfiram Individuals with a history of allergy to thiuram derivatives used in rubber vulcanization or pesticides should not be given disulfiram. Caution should also be used with patients suffering from myocardial disease, diabetes mellitus, cirrhosis, hypothyroidism, seizure disorder, or impaired renal function. Finally, patients should not take disulfiram unless they have abstained from alcohol for at least 12 hours.
Naltrexone Although the recommended dosage of naltrexone for alcohol dependence is 50 mg/d, some patients who experience side effects at that dosage may tolerate 25 mg/d, so starting at this lower dose is often advisable. Some researchers are analyzing the effects of higher dosages (e.g., 100 mg/d) because of evidence that higher blood levels of 6-β-naltrexol might improve treatment outcome.9 The optimal dosage of naltrexone for alcohol dependence is currently not settled, however, and may vary among patients.
Patients should be free of opiates for at least 7 days prior to initiating naltrexone; in the case of methadone, a 10- to 14-day opiate-free interval is prudent. Clinicans should wait approximately 4 days after the patient’s last drink before initiating therapy, since starting naltrexone earlier may lead to more side effects.
Educating patients about both agents
Disulfiram This medication is not to be prescribed lightly; only patients who are fully aware of its potential risks should be taking it. Patients need to be both willing and able to avoid alcohol both in beverage and disguised forms (e.g., alcohol-laced cough syrups).
One useful question to ask patients is, “Can you imagine yourself drinking on disulfiram?” Patients who admit that disulfiram would not deter them from drinking, or who cannot commit to avoiding alcohol in any form, should not use this medication.
Naltrexone Some alcohol-dependent patients are interested in taking naltrexone because they have heard that it may diminish the likelihood of progression from initial drink to full-blown relapse, thus helping them to become controlled drinkers.
Bear in mind that naltrexone does not convert alcohol-dependent individuals into controlled drinkers. Rather, you should tell patients that naltrexone may help them return to abstinence more quickly in the event that they do slip. This statement is consistent with the data about naltrexone and helps to establish and reinforce the goal of abstinence for alcohol-dependent patients.
Which medication for which patient?
When considering which, if either, medication to prescribe for an alcohol-dependent patient, you should initially determine whether contraindications exist. (A rubber allergy would preclude disulfiram, for example.) Then obtain a medical evaluation, including liver function tests, prior to initiating either medication.
While the guidelines for adequate liver function to initiate these medications is a matter of controversy, some clinicians recommend that liver enzymes should be twice the upper limit of normal or better, and that the medications should be stopped if liver function tests are 3 times the upper limit of normal or worse. Some clinicians use more liberal or conservative guidelines, although most recommend that an elevated bilirubin contraindicates the use of either agent.
Assuming that the patient is medically able to take either one, tell the patient that there are 2 medications approved for the treatment of alcohol dependence, and briefly describe each. Then ask the patient if he or she is potentially interested in either. Many patients will opt for no pharmacotherapy, some for naltrexone, and a smaller portion for disulfiram. This choice may vary over time, however, based on the patient’s clinical status. By remaining flexible and sharing this decision-making process with the patient, you increase the likelihood of medication compliance.
Current evidence suggests that both disulfiram and naltrexone are effective only in conjunction with alcohol-focused psychosocial treatment; this may include professional alcoholism treatment, support groups such as Alcoholics Anonymous, or, ideally, a combination of the two.
Monitoring compliance and side effects is also critical. By integrating pharmacologic and psychosocial approaches for alcohol-dependent patients, outcomes can be improved for this prevalent and highly treatable population.
Related resources
- The National Institute on Alcohol Abuse and Alcoholism (NIAAA) www.niaaa.nih.gov
- American Academy of Addiction Psychiatry (AAAP) www.aaap.org
- American Society of Addiction Medicine (ASAM) www.asam.org
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Isoniazid • Laniazid, Nydrazid
- Naltrexone • ReVia
- Warfarin • Coumadin, Miradon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article.
1. Caetano R, Tam TW. Prevalence and correlates of DSM-IV and ICD-10 alcohol dependence. Alcohol Alcohol. 1995;30(2):177-186.
2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270(18):2207-2212.
3. Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: A clinical review. J Clin Psychiatry. 2001;62(Suppl 20):42-48.
4. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Medicine. 1990;88(6):647-655.
5. Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol consumption. N Engl J Med. 1981;305(21):1255-1262.
6. Cohen G, Collins M. Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science. 1970;167:1749-1751.
7. Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.
8. O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.
9. McCaul ME, Wand GS, Rohde C, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156:1758-1764.
10. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: An evaluation of 128 men. Ann Intern Med. 1979;90(6):901-904.
11. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA. 1986;256(11):1449-1455.
12. Anton RF, Moak DH, Waid LR, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758-1764.
13. Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;151(10):1463-1467.
14. O’Farrell TJ, Allen JP, Litten RZ. Disulfiram (Antabuse) contracts in treatment of alcoholism. In: Integrating behavioral therapies with medications in the treatment of drug dependence (NIDA research monograph 150). ed by JDBlaine JD and L Onken. Washington, D.C.: National Institute on Drug Abuse, 1995;65-91.
15. Ojehagen A, Skjaerris A, Berglund M. Long-term use of aversive drugs in outpatient alcoholism treatment. Acta Psychiatr Scand. 1991;84(2):185-190.
16. Croop RS, Faulkner EB, Labriola DF, et al. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. Arch Gen Psychiatry. 1997;54(12):1130-1135.
17. Atkinson RL, Berke LK, Drake CR, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419-422.
18. O’Brien CP, Cornish JW. Opioids: Antagonists and partial agonists. In: The American Psychiatric Press Textbook of Substance Abuse Treatment. 2nd ed. Galanter M, Kleber HD, eds. Washington DC: American Psychiatric Press, 1999;281-294.
19. Poulsen HE, Loft S, Andersen M, Andersen JR. Disulfiram therapy—Adverse drug reactions and interactions. Acta Psychiatr Scand. 1992;86:59-66.
20. Mason NA. Disulfiram-induced hepatitis: Case report and review of the literature. DICP. 1989;23(11):872-874.
Alcohol dependence is one of the leading causes of morbidity and mortality in the United States. Approximately 10% of Americans will develop alcoholism at some point in their lives,1 and an estimated 100,000 individuals die each year due to alcohol-related medical complications, automobile accidents, and homicides.2 Alcohol dependence also costs the U.S. billions of dollars annually in health care costs, lost productivity, incarceration, and property destruction.
The search for effective pharmacologic treatments has long been a focus of research. Disulfiram, which causes an aversive reaction when combined with alcohol, was for many years the only medication in use. More recently, the opiate antagonist naltrexone has also been used to treat alcohol-dependent patients.
The homotaurine derivative, acamprosate, has recently shown great promise. Though used widely in Europe,3 it is not approved for use in this country.
This article will therefore focus on disulfiram and naltrexone: their pharmacology, efficacy, side effects, and dosing strategies. We also will present guidelines for discussing each medication with patients and for deciding which, if either, to prescribe.
Differences in pharmacology
Disulfiram Since the serendipitous discovery of its reactive property with alcohol in the 1940s, disulfiram has been used in the pharmacological treatment of alcoholism. The agent disrupts alcohol metabolism by inhibiting the action of aldehyde dehydrogenase, thus blocking the conversion of acetaldehyde to acetate. Accumulation of acetaldehyde, the first metabolite of ethanol, causes numerous unpleasant effects, including flushing, weakness, and nausea.4 In addition to acting on aldehyde dehydrogenase, disulfiram inhibits dopamine-β-hydroxylase.5
Disulfiram is absorbed from the gastrointestinal tract and is rapidly distributed to tissues and organs. It begins to affect alcohol metabolism within 1 to 2 hours, with a peak at 12 hours. It is slowly excreted from the body over the next 2 weeks, although its effects may be lost sooner as the body secretes new enzyme.4
The ethanol-disulfiram reaction is characterized by flushing, throbbing in the head and neck, respiratory difficulty, vomiting, sweating, thirst, weakness, and hypotension ( Table 1). In some cases, the reaction can be fatal.
Naltrexone Following its approval for use in treating opioid dependence in the mid-1980s, the opiate antagonist naltrexone was approved nearly a decade ago for use in treating individuals with alcohol dependence. Research interest in the use of naltrexone for this purpose grew from theories that the endogenous opiate system may be involved in the development of alcohol dependence.6 Two simultaneously published studies in 1992 showed the benefit of naltrexone in alcohol dependence;7-8 this led to its approval by the Food and Drug Administration.
Naltrexone is metabolized to its major metabolite, 6-β-naltrexol, and is then excreted in the urine as both the original compound and this metabolite.9 The half-life of naltrexone in chronic administration is approximately 10 hours; the half-life of 6-β-naltrexol is 12 to 16 hours.
Comparison of efficacy
Disulfiram Results concerning efficacy have been mixed. Initial studies showed promising effects but were limited to anecdotal evidence and case studies. More recent studies have addressed issues relating to proper control groups, compliance, and motivation in evaluating disulfiram’s effect on alcohol consumption. Early studies used placebo groups to control for the effects of counseling or regular medical monitoring. However, no controls were employed to distinguish between the psychological effects of disulfiram (e.g., fear of a reaction) and its pharmacologic effects.
Table 1
SYMPTOMS OF AN ETHANOL-DISULFIRAM REACTION
| • Flushing | • Sweating |
| • Throbbing in head and neck | • Thirst |
| • Respiratory difficulty | • Weakness |
| • Vomiting | • Hypotension |
| The intensity of the reaction is generally related to the amount of alcohol and disulfiram consumed. Because even small amounts of alcohol may cause a reaction, individuals taking disulfiram should avoid all forms of alcohol, including certain mouthwashes and cough syrups. Patients also should be instructed to read the ingredients of foods and medications they consume. | |
| While the recommended daily dose for disulfiram ranges from 125 mg to 500 mg, individuals can vary widely in their reactions. Dosages below 250 mg/d have failed to produce aversive reactions in some individuals who drink alcohol. Dosages of 250 mg/d or higher, however, may cause toxic side effects, including a more severe reaction with alcohol. Clinicians should be aware that in a few patients, the dosage needed to produce an aversive reaction may be higher than the dosage that produces toxicity.4 | |
| The authors generally prescribe 125 mg/d, which is at the low end of the usual dose range, since the fear of a reaction—not the reaction itself—is the major therapeutic action of disulfiram. Moreover, a lower dosage diminishes (but by no means eliminates) the likelihood of a highly dangerous alcohol-disulfiram reaction. | |
Fuller and Roth10 addressed this concern by designing a double-blind study that consisted of 3 groups. Group 1 received disulfiram 250 mg/d, group 2 received 1 mg/d (a pharmacologically ineffective dose), and group 3 received a placebo. Importantly, patients in both groups 1 and 2 were informed that they were receiving disulfiram and were warned of a possible ethanol-disulfiram reaction. At a 6-month follow-up, patients receiving disulfiram showed a small but significant increase in abstinence compared with those receiving placebo. Interestingly, there was no difference between patients receiving 250 mg of disulfiram and those receiving the ineffective 1 mg dose, suggesting that the primary action of disulfiram is the fear of a reaction with alcohol, not the agent’s pharmacologic effects.
A number of studies have shown that patients who agree to take disulfiram and continue taking it are generally highly motivated; such patients unsurprisingly experience better treatment outcomes.
In the largest controlled, blinded study of disulfiram performed to date, Fuller et al11 evaluated disulfiram treatment in 605 male veterans randomly assigned to disulfiram 250 mg a day, disulfiram 1 mg a day, or placebo. No significant differences were found between groups in total abstinence or time to first drink. Among patients who participated in all assessments and who drank at least once during the study, however, those receiving 250 mg had fewer drinking days than those in either control group.
The authors concluded that disulfiram may help reduce drinking frequency after a return to drinking, but does not contribute to continuous abstinence or to delay in time to first drink. Notably, despite a medication compliance rate of only 20%, a significant relationship existed between medication compliance and complete abstinence, regardless of treatment group. O’Farrell and colleagues14 have studied ways to increase compliance with disulfiram, developing the concept of the “Antabuse contract,” in which the patient takes disulfiram in front of a significant other as part of a couple’s therapy program.
How long should a patient continue taking disulfiram? Unfortunately, the ideal length of disulfiram treatment has not been established. While most randomized trials only administer disulfiram for a few months, research by Ojehagen et al15 has shown that long-term treatment (greater than 12 months) with disulfiram is significantly related to positive drinking outcomes during the 2 years following treatment.
Naltrexone The two initial landmark studies of naltrexone for alcohol dependence were published nearly a decade ago. Volpicelli et al7 conducted a double-blind, placebo-controlled trial of naltrexone 50 mg/d for 12 weeks with 70 male veterans who also received intensive psychosocial alcohol rehabilitation. Study participants who received naltrexone had fewer drinking days, less craving for alcohol, and a lower rate of full-blown relapse than did patients who received placebo. The major effect of naltrexone occurred among patients who sampled alcohol; only half of those on naltrexone progressed from first drink to a full-blown relapse, compared to a 95% rate of relapse among those who initiated drinking while receiving placebo.
O’Malley et al8 also found naltrexone to be more effective than placebo and found an interesting interaction with psychosocial treatment. Individuals who received weekly abstinence-oriented supportive therapy were more likely to be continuously abstinent from alcohol at the end of the 12-week study period. Those who received naltrexone along with cognitive behavioral coping skills therapy were least likely to progress to a full-blown relapse if they did drink.
More recently, Anton et al12 conducted a double-blind, placebo-controlled trial of naltrexone in 131 patients, all of whom received cognitive behavioral therapy (CBT). Those receiving naltrexone had a significantly longer period prior to relapse, fewer drinking days, and fewer drinks per drinking day than the placebo group. No significant differences were reported between the groups in time prior to the first drink.
These studies suggest that naltrexone may diminish the likelihood of progression from first drink to full-blown relapse. This may occur through the agent’s attenuation of the reinforcing effects of alcohol.13 While naltrexone does not fully block alcohol the way it blocks opioid drugs, the reduction in alcohol’s positive effects may help naltrexone responders to contain their “slips” and prevent progression to a full-blown relapse.
The difference in adverse effects
Disulfiram Adverse effects (see Table 2) arise from 3 main causes:
- Medical complications during an ethanol-disulfiram reaction;
- Toxicity due to disulfiram or its metabolites;
- Interactions between disulfiram and other medications.
Table 2
HOW DISULFIRAM, NALTREXONE WORK
| Disulfiram | Naltrexone | |
|---|---|---|
| Mechanism of action | Interrupts metabolism of alcohol, leads to a buildup of acetaldehyde | Opiate antagonist, may attenuate reinforcing property of alcohol |
| Recommended dose* | 25-500 mg | 50 mg |
| Side effects and adverse events | Drowsiness, impotence, headache, acne, metallic aftertaste, hepatitis, neuritis, ethanoldisulfiram reaction | Nausea, vomiting, headache, anxiety, dizziness, fatigue, insomnia, elevated liver enzymes |
| *Physicians Desk Reference 55th ed. Montvale, NJ: Medical Economics, 2001 | ||
Medical complications arising from an ethanol-disulfiram reaction can include tachycardia, hypotension, and electrocardiographic changes. Fatalities have been reported due to myocardial infarction or cerebrovascular accident.5 As a result, people with a history of severe myocardial disease should generally not be prescribed disulfiram.
Side effects from disulfiram itself include drowsiness, impotence, headache, acne, and a metallic or garlic-like aftertaste. Toxicity can also lead to psychiatric reactions such as increased depression and psychosis, possibly because of the inhibition of dopamine β–hydroxylase.5
Hepatic and neurological reactions are the most commonly reported toxic reactions.19 Disulfiram-induced hepatitis usually occurs within 2 months of initiation of treatment, but may occur up to 6 months after starting disulfiram.20 This form of liver toxicity is believed to be an allergic or hypersensitivity reaction and can lead to hepatic necrosis and death due to liver failure. Some clinicians recommend obtaining liver function tests at regular intervals (e.g., at baseline, 2 weeks, 4 weeks, then monthly for 6 months), although the optimal frequency of testing after week 2 is not well established.
Neurological reactions make up approximately 20% of the overall reported side effects from disulfiram, with the most frequent diagnosis being polyneuropathy. Other important reported adverse neurological effects include optic and peripheral neuritis.19
Disulfiram interacts with a number of medications, primarily by slowing down their metabolism and thus increasing risk of toxicity. These drugs include phenytoin, theophylline, anticoagulant drugs, isoniazid, and amitriptyline.19 Prior to starting treatment with disulfiram, phenytoin serum levels should be obtained and monitored throughout treatment. Dosage of oral anticoagulant drugs such as warfarin should also be monitored carefully.
Naltrexone The most common side effect is nausea, which typically occurs in the first week of treatment. In the largest study of naltrexone published to date, approximately 10% of naltrexone-treated subjects reported this side effect.16 Other side effects include headache, anxiety, dizziness, fatigue, vomiting, and insomnia.16
Elevated liver enzymes have been reported with use,17 so liver function should be monitored in patients receiving this medication.
It is unclear how often liver function tests should be performed. One text18 recommends baseline assessment of liver function, monthly monitoring for 3 months, then testing every 2 to 6 months afterwards if results are normal.
Other clinical considerations
Disulfiram Individuals with a history of allergy to thiuram derivatives used in rubber vulcanization or pesticides should not be given disulfiram. Caution should also be used with patients suffering from myocardial disease, diabetes mellitus, cirrhosis, hypothyroidism, seizure disorder, or impaired renal function. Finally, patients should not take disulfiram unless they have abstained from alcohol for at least 12 hours.
Naltrexone Although the recommended dosage of naltrexone for alcohol dependence is 50 mg/d, some patients who experience side effects at that dosage may tolerate 25 mg/d, so starting at this lower dose is often advisable. Some researchers are analyzing the effects of higher dosages (e.g., 100 mg/d) because of evidence that higher blood levels of 6-β-naltrexol might improve treatment outcome.9 The optimal dosage of naltrexone for alcohol dependence is currently not settled, however, and may vary among patients.
Patients should be free of opiates for at least 7 days prior to initiating naltrexone; in the case of methadone, a 10- to 14-day opiate-free interval is prudent. Clinicans should wait approximately 4 days after the patient’s last drink before initiating therapy, since starting naltrexone earlier may lead to more side effects.
Educating patients about both agents
Disulfiram This medication is not to be prescribed lightly; only patients who are fully aware of its potential risks should be taking it. Patients need to be both willing and able to avoid alcohol both in beverage and disguised forms (e.g., alcohol-laced cough syrups).
One useful question to ask patients is, “Can you imagine yourself drinking on disulfiram?” Patients who admit that disulfiram would not deter them from drinking, or who cannot commit to avoiding alcohol in any form, should not use this medication.
Naltrexone Some alcohol-dependent patients are interested in taking naltrexone because they have heard that it may diminish the likelihood of progression from initial drink to full-blown relapse, thus helping them to become controlled drinkers.
Bear in mind that naltrexone does not convert alcohol-dependent individuals into controlled drinkers. Rather, you should tell patients that naltrexone may help them return to abstinence more quickly in the event that they do slip. This statement is consistent with the data about naltrexone and helps to establish and reinforce the goal of abstinence for alcohol-dependent patients.
Which medication for which patient?
When considering which, if either, medication to prescribe for an alcohol-dependent patient, you should initially determine whether contraindications exist. (A rubber allergy would preclude disulfiram, for example.) Then obtain a medical evaluation, including liver function tests, prior to initiating either medication.
While the guidelines for adequate liver function to initiate these medications is a matter of controversy, some clinicians recommend that liver enzymes should be twice the upper limit of normal or better, and that the medications should be stopped if liver function tests are 3 times the upper limit of normal or worse. Some clinicians use more liberal or conservative guidelines, although most recommend that an elevated bilirubin contraindicates the use of either agent.
Assuming that the patient is medically able to take either one, tell the patient that there are 2 medications approved for the treatment of alcohol dependence, and briefly describe each. Then ask the patient if he or she is potentially interested in either. Many patients will opt for no pharmacotherapy, some for naltrexone, and a smaller portion for disulfiram. This choice may vary over time, however, based on the patient’s clinical status. By remaining flexible and sharing this decision-making process with the patient, you increase the likelihood of medication compliance.
Current evidence suggests that both disulfiram and naltrexone are effective only in conjunction with alcohol-focused psychosocial treatment; this may include professional alcoholism treatment, support groups such as Alcoholics Anonymous, or, ideally, a combination of the two.
Monitoring compliance and side effects is also critical. By integrating pharmacologic and psychosocial approaches for alcohol-dependent patients, outcomes can be improved for this prevalent and highly treatable population.
Related resources
- The National Institute on Alcohol Abuse and Alcoholism (NIAAA) www.niaaa.nih.gov
- American Academy of Addiction Psychiatry (AAAP) www.aaap.org
- American Society of Addiction Medicine (ASAM) www.asam.org
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Isoniazid • Laniazid, Nydrazid
- Naltrexone • ReVia
- Warfarin • Coumadin, Miradon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article.
Alcohol dependence is one of the leading causes of morbidity and mortality in the United States. Approximately 10% of Americans will develop alcoholism at some point in their lives,1 and an estimated 100,000 individuals die each year due to alcohol-related medical complications, automobile accidents, and homicides.2 Alcohol dependence also costs the U.S. billions of dollars annually in health care costs, lost productivity, incarceration, and property destruction.
The search for effective pharmacologic treatments has long been a focus of research. Disulfiram, which causes an aversive reaction when combined with alcohol, was for many years the only medication in use. More recently, the opiate antagonist naltrexone has also been used to treat alcohol-dependent patients.
The homotaurine derivative, acamprosate, has recently shown great promise. Though used widely in Europe,3 it is not approved for use in this country.
This article will therefore focus on disulfiram and naltrexone: their pharmacology, efficacy, side effects, and dosing strategies. We also will present guidelines for discussing each medication with patients and for deciding which, if either, to prescribe.
Differences in pharmacology
Disulfiram Since the serendipitous discovery of its reactive property with alcohol in the 1940s, disulfiram has been used in the pharmacological treatment of alcoholism. The agent disrupts alcohol metabolism by inhibiting the action of aldehyde dehydrogenase, thus blocking the conversion of acetaldehyde to acetate. Accumulation of acetaldehyde, the first metabolite of ethanol, causes numerous unpleasant effects, including flushing, weakness, and nausea.4 In addition to acting on aldehyde dehydrogenase, disulfiram inhibits dopamine-β-hydroxylase.5
Disulfiram is absorbed from the gastrointestinal tract and is rapidly distributed to tissues and organs. It begins to affect alcohol metabolism within 1 to 2 hours, with a peak at 12 hours. It is slowly excreted from the body over the next 2 weeks, although its effects may be lost sooner as the body secretes new enzyme.4
The ethanol-disulfiram reaction is characterized by flushing, throbbing in the head and neck, respiratory difficulty, vomiting, sweating, thirst, weakness, and hypotension ( Table 1). In some cases, the reaction can be fatal.
Naltrexone Following its approval for use in treating opioid dependence in the mid-1980s, the opiate antagonist naltrexone was approved nearly a decade ago for use in treating individuals with alcohol dependence. Research interest in the use of naltrexone for this purpose grew from theories that the endogenous opiate system may be involved in the development of alcohol dependence.6 Two simultaneously published studies in 1992 showed the benefit of naltrexone in alcohol dependence;7-8 this led to its approval by the Food and Drug Administration.
Naltrexone is metabolized to its major metabolite, 6-β-naltrexol, and is then excreted in the urine as both the original compound and this metabolite.9 The half-life of naltrexone in chronic administration is approximately 10 hours; the half-life of 6-β-naltrexol is 12 to 16 hours.
Comparison of efficacy
Disulfiram Results concerning efficacy have been mixed. Initial studies showed promising effects but were limited to anecdotal evidence and case studies. More recent studies have addressed issues relating to proper control groups, compliance, and motivation in evaluating disulfiram’s effect on alcohol consumption. Early studies used placebo groups to control for the effects of counseling or regular medical monitoring. However, no controls were employed to distinguish between the psychological effects of disulfiram (e.g., fear of a reaction) and its pharmacologic effects.
Table 1
SYMPTOMS OF AN ETHANOL-DISULFIRAM REACTION
| • Flushing | • Sweating |
| • Throbbing in head and neck | • Thirst |
| • Respiratory difficulty | • Weakness |
| • Vomiting | • Hypotension |
| The intensity of the reaction is generally related to the amount of alcohol and disulfiram consumed. Because even small amounts of alcohol may cause a reaction, individuals taking disulfiram should avoid all forms of alcohol, including certain mouthwashes and cough syrups. Patients also should be instructed to read the ingredients of foods and medications they consume. | |
| While the recommended daily dose for disulfiram ranges from 125 mg to 500 mg, individuals can vary widely in their reactions. Dosages below 250 mg/d have failed to produce aversive reactions in some individuals who drink alcohol. Dosages of 250 mg/d or higher, however, may cause toxic side effects, including a more severe reaction with alcohol. Clinicians should be aware that in a few patients, the dosage needed to produce an aversive reaction may be higher than the dosage that produces toxicity.4 | |
| The authors generally prescribe 125 mg/d, which is at the low end of the usual dose range, since the fear of a reaction—not the reaction itself—is the major therapeutic action of disulfiram. Moreover, a lower dosage diminishes (but by no means eliminates) the likelihood of a highly dangerous alcohol-disulfiram reaction. | |
Fuller and Roth10 addressed this concern by designing a double-blind study that consisted of 3 groups. Group 1 received disulfiram 250 mg/d, group 2 received 1 mg/d (a pharmacologically ineffective dose), and group 3 received a placebo. Importantly, patients in both groups 1 and 2 were informed that they were receiving disulfiram and were warned of a possible ethanol-disulfiram reaction. At a 6-month follow-up, patients receiving disulfiram showed a small but significant increase in abstinence compared with those receiving placebo. Interestingly, there was no difference between patients receiving 250 mg of disulfiram and those receiving the ineffective 1 mg dose, suggesting that the primary action of disulfiram is the fear of a reaction with alcohol, not the agent’s pharmacologic effects.
A number of studies have shown that patients who agree to take disulfiram and continue taking it are generally highly motivated; such patients unsurprisingly experience better treatment outcomes.
In the largest controlled, blinded study of disulfiram performed to date, Fuller et al11 evaluated disulfiram treatment in 605 male veterans randomly assigned to disulfiram 250 mg a day, disulfiram 1 mg a day, or placebo. No significant differences were found between groups in total abstinence or time to first drink. Among patients who participated in all assessments and who drank at least once during the study, however, those receiving 250 mg had fewer drinking days than those in either control group.
The authors concluded that disulfiram may help reduce drinking frequency after a return to drinking, but does not contribute to continuous abstinence or to delay in time to first drink. Notably, despite a medication compliance rate of only 20%, a significant relationship existed between medication compliance and complete abstinence, regardless of treatment group. O’Farrell and colleagues14 have studied ways to increase compliance with disulfiram, developing the concept of the “Antabuse contract,” in which the patient takes disulfiram in front of a significant other as part of a couple’s therapy program.
How long should a patient continue taking disulfiram? Unfortunately, the ideal length of disulfiram treatment has not been established. While most randomized trials only administer disulfiram for a few months, research by Ojehagen et al15 has shown that long-term treatment (greater than 12 months) with disulfiram is significantly related to positive drinking outcomes during the 2 years following treatment.
Naltrexone The two initial landmark studies of naltrexone for alcohol dependence were published nearly a decade ago. Volpicelli et al7 conducted a double-blind, placebo-controlled trial of naltrexone 50 mg/d for 12 weeks with 70 male veterans who also received intensive psychosocial alcohol rehabilitation. Study participants who received naltrexone had fewer drinking days, less craving for alcohol, and a lower rate of full-blown relapse than did patients who received placebo. The major effect of naltrexone occurred among patients who sampled alcohol; only half of those on naltrexone progressed from first drink to a full-blown relapse, compared to a 95% rate of relapse among those who initiated drinking while receiving placebo.
O’Malley et al8 also found naltrexone to be more effective than placebo and found an interesting interaction with psychosocial treatment. Individuals who received weekly abstinence-oriented supportive therapy were more likely to be continuously abstinent from alcohol at the end of the 12-week study period. Those who received naltrexone along with cognitive behavioral coping skills therapy were least likely to progress to a full-blown relapse if they did drink.
More recently, Anton et al12 conducted a double-blind, placebo-controlled trial of naltrexone in 131 patients, all of whom received cognitive behavioral therapy (CBT). Those receiving naltrexone had a significantly longer period prior to relapse, fewer drinking days, and fewer drinks per drinking day than the placebo group. No significant differences were reported between the groups in time prior to the first drink.
These studies suggest that naltrexone may diminish the likelihood of progression from first drink to full-blown relapse. This may occur through the agent’s attenuation of the reinforcing effects of alcohol.13 While naltrexone does not fully block alcohol the way it blocks opioid drugs, the reduction in alcohol’s positive effects may help naltrexone responders to contain their “slips” and prevent progression to a full-blown relapse.
The difference in adverse effects
Disulfiram Adverse effects (see Table 2) arise from 3 main causes:
- Medical complications during an ethanol-disulfiram reaction;
- Toxicity due to disulfiram or its metabolites;
- Interactions between disulfiram and other medications.
Table 2
HOW DISULFIRAM, NALTREXONE WORK
| Disulfiram | Naltrexone | |
|---|---|---|
| Mechanism of action | Interrupts metabolism of alcohol, leads to a buildup of acetaldehyde | Opiate antagonist, may attenuate reinforcing property of alcohol |
| Recommended dose* | 25-500 mg | 50 mg |
| Side effects and adverse events | Drowsiness, impotence, headache, acne, metallic aftertaste, hepatitis, neuritis, ethanoldisulfiram reaction | Nausea, vomiting, headache, anxiety, dizziness, fatigue, insomnia, elevated liver enzymes |
| *Physicians Desk Reference 55th ed. Montvale, NJ: Medical Economics, 2001 | ||
Medical complications arising from an ethanol-disulfiram reaction can include tachycardia, hypotension, and electrocardiographic changes. Fatalities have been reported due to myocardial infarction or cerebrovascular accident.5 As a result, people with a history of severe myocardial disease should generally not be prescribed disulfiram.
Side effects from disulfiram itself include drowsiness, impotence, headache, acne, and a metallic or garlic-like aftertaste. Toxicity can also lead to psychiatric reactions such as increased depression and psychosis, possibly because of the inhibition of dopamine β–hydroxylase.5
Hepatic and neurological reactions are the most commonly reported toxic reactions.19 Disulfiram-induced hepatitis usually occurs within 2 months of initiation of treatment, but may occur up to 6 months after starting disulfiram.20 This form of liver toxicity is believed to be an allergic or hypersensitivity reaction and can lead to hepatic necrosis and death due to liver failure. Some clinicians recommend obtaining liver function tests at regular intervals (e.g., at baseline, 2 weeks, 4 weeks, then monthly for 6 months), although the optimal frequency of testing after week 2 is not well established.
Neurological reactions make up approximately 20% of the overall reported side effects from disulfiram, with the most frequent diagnosis being polyneuropathy. Other important reported adverse neurological effects include optic and peripheral neuritis.19
Disulfiram interacts with a number of medications, primarily by slowing down their metabolism and thus increasing risk of toxicity. These drugs include phenytoin, theophylline, anticoagulant drugs, isoniazid, and amitriptyline.19 Prior to starting treatment with disulfiram, phenytoin serum levels should be obtained and monitored throughout treatment. Dosage of oral anticoagulant drugs such as warfarin should also be monitored carefully.
Naltrexone The most common side effect is nausea, which typically occurs in the first week of treatment. In the largest study of naltrexone published to date, approximately 10% of naltrexone-treated subjects reported this side effect.16 Other side effects include headache, anxiety, dizziness, fatigue, vomiting, and insomnia.16
Elevated liver enzymes have been reported with use,17 so liver function should be monitored in patients receiving this medication.
It is unclear how often liver function tests should be performed. One text18 recommends baseline assessment of liver function, monthly monitoring for 3 months, then testing every 2 to 6 months afterwards if results are normal.
Other clinical considerations
Disulfiram Individuals with a history of allergy to thiuram derivatives used in rubber vulcanization or pesticides should not be given disulfiram. Caution should also be used with patients suffering from myocardial disease, diabetes mellitus, cirrhosis, hypothyroidism, seizure disorder, or impaired renal function. Finally, patients should not take disulfiram unless they have abstained from alcohol for at least 12 hours.
Naltrexone Although the recommended dosage of naltrexone for alcohol dependence is 50 mg/d, some patients who experience side effects at that dosage may tolerate 25 mg/d, so starting at this lower dose is often advisable. Some researchers are analyzing the effects of higher dosages (e.g., 100 mg/d) because of evidence that higher blood levels of 6-β-naltrexol might improve treatment outcome.9 The optimal dosage of naltrexone for alcohol dependence is currently not settled, however, and may vary among patients.
Patients should be free of opiates for at least 7 days prior to initiating naltrexone; in the case of methadone, a 10- to 14-day opiate-free interval is prudent. Clinicans should wait approximately 4 days after the patient’s last drink before initiating therapy, since starting naltrexone earlier may lead to more side effects.
Educating patients about both agents
Disulfiram This medication is not to be prescribed lightly; only patients who are fully aware of its potential risks should be taking it. Patients need to be both willing and able to avoid alcohol both in beverage and disguised forms (e.g., alcohol-laced cough syrups).
One useful question to ask patients is, “Can you imagine yourself drinking on disulfiram?” Patients who admit that disulfiram would not deter them from drinking, or who cannot commit to avoiding alcohol in any form, should not use this medication.
Naltrexone Some alcohol-dependent patients are interested in taking naltrexone because they have heard that it may diminish the likelihood of progression from initial drink to full-blown relapse, thus helping them to become controlled drinkers.
Bear in mind that naltrexone does not convert alcohol-dependent individuals into controlled drinkers. Rather, you should tell patients that naltrexone may help them return to abstinence more quickly in the event that they do slip. This statement is consistent with the data about naltrexone and helps to establish and reinforce the goal of abstinence for alcohol-dependent patients.
Which medication for which patient?
When considering which, if either, medication to prescribe for an alcohol-dependent patient, you should initially determine whether contraindications exist. (A rubber allergy would preclude disulfiram, for example.) Then obtain a medical evaluation, including liver function tests, prior to initiating either medication.
While the guidelines for adequate liver function to initiate these medications is a matter of controversy, some clinicians recommend that liver enzymes should be twice the upper limit of normal or better, and that the medications should be stopped if liver function tests are 3 times the upper limit of normal or worse. Some clinicians use more liberal or conservative guidelines, although most recommend that an elevated bilirubin contraindicates the use of either agent.
Assuming that the patient is medically able to take either one, tell the patient that there are 2 medications approved for the treatment of alcohol dependence, and briefly describe each. Then ask the patient if he or she is potentially interested in either. Many patients will opt for no pharmacotherapy, some for naltrexone, and a smaller portion for disulfiram. This choice may vary over time, however, based on the patient’s clinical status. By remaining flexible and sharing this decision-making process with the patient, you increase the likelihood of medication compliance.
Current evidence suggests that both disulfiram and naltrexone are effective only in conjunction with alcohol-focused psychosocial treatment; this may include professional alcoholism treatment, support groups such as Alcoholics Anonymous, or, ideally, a combination of the two.
Monitoring compliance and side effects is also critical. By integrating pharmacologic and psychosocial approaches for alcohol-dependent patients, outcomes can be improved for this prevalent and highly treatable population.
Related resources
- The National Institute on Alcohol Abuse and Alcoholism (NIAAA) www.niaaa.nih.gov
- American Academy of Addiction Psychiatry (AAAP) www.aaap.org
- American Society of Addiction Medicine (ASAM) www.asam.org
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Isoniazid • Laniazid, Nydrazid
- Naltrexone • ReVia
- Warfarin • Coumadin, Miradon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article.
1. Caetano R, Tam TW. Prevalence and correlates of DSM-IV and ICD-10 alcohol dependence. Alcohol Alcohol. 1995;30(2):177-186.
2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270(18):2207-2212.
3. Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: A clinical review. J Clin Psychiatry. 2001;62(Suppl 20):42-48.
4. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Medicine. 1990;88(6):647-655.
5. Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol consumption. N Engl J Med. 1981;305(21):1255-1262.
6. Cohen G, Collins M. Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science. 1970;167:1749-1751.
7. Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.
8. O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.
9. McCaul ME, Wand GS, Rohde C, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156:1758-1764.
10. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: An evaluation of 128 men. Ann Intern Med. 1979;90(6):901-904.
11. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA. 1986;256(11):1449-1455.
12. Anton RF, Moak DH, Waid LR, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758-1764.
13. Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;151(10):1463-1467.
14. O’Farrell TJ, Allen JP, Litten RZ. Disulfiram (Antabuse) contracts in treatment of alcoholism. In: Integrating behavioral therapies with medications in the treatment of drug dependence (NIDA research monograph 150). ed by JDBlaine JD and L Onken. Washington, D.C.: National Institute on Drug Abuse, 1995;65-91.
15. Ojehagen A, Skjaerris A, Berglund M. Long-term use of aversive drugs in outpatient alcoholism treatment. Acta Psychiatr Scand. 1991;84(2):185-190.
16. Croop RS, Faulkner EB, Labriola DF, et al. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. Arch Gen Psychiatry. 1997;54(12):1130-1135.
17. Atkinson RL, Berke LK, Drake CR, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419-422.
18. O’Brien CP, Cornish JW. Opioids: Antagonists and partial agonists. In: The American Psychiatric Press Textbook of Substance Abuse Treatment. 2nd ed. Galanter M, Kleber HD, eds. Washington DC: American Psychiatric Press, 1999;281-294.
19. Poulsen HE, Loft S, Andersen M, Andersen JR. Disulfiram therapy—Adverse drug reactions and interactions. Acta Psychiatr Scand. 1992;86:59-66.
20. Mason NA. Disulfiram-induced hepatitis: Case report and review of the literature. DICP. 1989;23(11):872-874.
1. Caetano R, Tam TW. Prevalence and correlates of DSM-IV and ICD-10 alcohol dependence. Alcohol Alcohol. 1995;30(2):177-186.
2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270(18):2207-2212.
3. Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: A clinical review. J Clin Psychiatry. 2001;62(Suppl 20):42-48.
4. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Medicine. 1990;88(6):647-655.
5. Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol consumption. N Engl J Med. 1981;305(21):1255-1262.
6. Cohen G, Collins M. Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science. 1970;167:1749-1751.
7. Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.
8. O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.
9. McCaul ME, Wand GS, Rohde C, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156:1758-1764.
10. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: An evaluation of 128 men. Ann Intern Med. 1979;90(6):901-904.
11. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA. 1986;256(11):1449-1455.
12. Anton RF, Moak DH, Waid LR, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758-1764.
13. Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;151(10):1463-1467.
14. O’Farrell TJ, Allen JP, Litten RZ. Disulfiram (Antabuse) contracts in treatment of alcoholism. In: Integrating behavioral therapies with medications in the treatment of drug dependence (NIDA research monograph 150). ed by JDBlaine JD and L Onken. Washington, D.C.: National Institute on Drug Abuse, 1995;65-91.
15. Ojehagen A, Skjaerris A, Berglund M. Long-term use of aversive drugs in outpatient alcoholism treatment. Acta Psychiatr Scand. 1991;84(2):185-190.
16. Croop RS, Faulkner EB, Labriola DF, et al. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. Arch Gen Psychiatry. 1997;54(12):1130-1135.
17. Atkinson RL, Berke LK, Drake CR, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419-422.
18. O’Brien CP, Cornish JW. Opioids: Antagonists and partial agonists. In: The American Psychiatric Press Textbook of Substance Abuse Treatment. 2nd ed. Galanter M, Kleber HD, eds. Washington DC: American Psychiatric Press, 1999;281-294.
19. Poulsen HE, Loft S, Andersen M, Andersen JR. Disulfiram therapy—Adverse drug reactions and interactions. Acta Psychiatr Scand. 1992;86:59-66.
20. Mason NA. Disulfiram-induced hepatitis: Case report and review of the literature. DICP. 1989;23(11):872-874.
Pharmacotherapy of alcohol dependence: How and when to use disulfiram and naltrexone
Alcohol dependence is one of the leading causes of morbidity and mortality in the United States. Approximately 10% of Americans will develop alcoholism at some point in their lives,1 and an estimated 100,000 individuals die each year due to alcohol-related medical complications, automobile accidents, and homicides.2 Alcohol dependence also costs the U.S. billions of dollars annually in health care costs, lost productivity, incarceration, and property destruction.
The search for effective pharmacologic treatments has long been a focus of research. Disulfiram, which causes an aversive reaction when combined with alcohol, was for many years the only medication in use. More recently, the opiate antagonist naltrexone has also been used to treat alcohol-dependent patients.
The homotaurine derivative, acamprosate, has recently shown great promise. Though used widely in Europe,3 it is not approved for use in this country.
This article will therefore focus on disulfiram and naltrexone: their pharmacology, efficacy, side effects, and dosing strategies. We also will present guidelines for discussing each medication with patients and for deciding which, if either, to prescribe.
Differences in pharmacology
Disulfiram Since the serendipitous discovery of its reactive property with alcohol in the 1940s, disulfiram has been used in the pharmacological treatment of alcoholism. The agent disrupts alcohol metabolism by inhibiting the action of aldehyde dehydrogenase, thus blocking the conversion of acetaldehyde to acetate. Accumulation of acetaldehyde, the first metabolite of ethanol, causes numerous unpleasant effects, including flushing, weakness, and nausea.4 In addition to acting on aldehyde dehydrogenase, disulfiram inhibits dopamine-β-hydroxylase.5
Disulfiram is absorbed from the gastrointestinal tract and is rapidly distributed to tissues and organs. It begins to affect alcohol metabolism within 1 to 2 hours, with a peak at 12 hours. It is slowly excreted from the body over the next 2 weeks, although its effects may be lost sooner as the body secretes new enzyme.4
The ethanol-disulfiram reaction is characterized by flushing, throbbing in the head and neck, respiratory difficulty, vomiting, sweating, thirst, weakness, and hypotension ( Table 1). In some cases, the reaction can be fatal.
Naltrexone Following its approval for use in treating opioid dependence in the mid-1980s, the opiate antagonist naltrexone was approved nearly a decade ago for use in treating individuals with alcohol dependence. Research interest in the use of naltrexone for this purpose grew from theories that the endogenous opiate system may be involved in the development of alcohol dependence.6 Two simultaneously published studies in 1992 showed the benefit of naltrexone in alcohol dependence;7-8 this led to its approval by the Food and Drug Administration.
Naltrexone is metabolized to its major metabolite, 6-β-naltrexol, and is then excreted in the urine as both the original compound and this metabolite.9 The half-life of naltrexone in chronic administration is approximately 10 hours; the half-life of 6-β-naltrexol is 12 to 16 hours.
Comparison of efficacy
Disulfiram Results concerning efficacy have been mixed. Initial studies showed promising effects but were limited to anecdotal evidence and case studies. More recent studies have addressed issues relating to proper control groups, compliance, and motivation in evaluating disulfiram’s effect on alcohol consumption. Early studies used placebo groups to control for the effects of counseling or regular medical monitoring. However, no controls were employed to distinguish between the psychological effects of disulfiram (e.g., fear of a reaction) and its pharmacologic effects.
Table 1
SYMPTOMS OF AN ETHANOL-DISULFIRAM REACTION
| • Flushing | • Sweating |
| • Throbbing in head and neck | • Thirst |
| • Respiratory difficulty | • Weakness |
| • Vomiting | • Hypotension |
| The intensity of the reaction is generally related to the amount of alcohol and disulfiram consumed. Because even small amounts of alcohol may cause a reaction, individuals taking disulfiram should avoid all forms of alcohol, including certain mouthwashes and cough syrups. Patients also should be instructed to read the ingredients of foods and medications they consume. | |
| While the recommended daily dose for disulfiram ranges from 125 mg to 500 mg, individuals can vary widely in their reactions. Dosages below 250 mg/d have failed to produce aversive reactions in some individuals who drink alcohol. Dosages of 250 mg/d or higher, however, may cause toxic side effects, including a more severe reaction with alcohol. Clinicians should be aware that in a few patients, the dosage needed to produce an aversive reaction may be higher than the dosage that produces toxicity.4 | |
| The authors generally prescribe 125 mg/d, which is at the low end of the usual dose range, since the fear of a reaction—not the reaction itself—is the major therapeutic action of disulfiram. Moreover, a lower dosage diminishes (but by no means eliminates) the likelihood of a highly dangerous alcohol-disulfiram reaction. | |
Fuller and Roth10 addressed this concern by designing a double-blind study that consisted of 3 groups. Group 1 received disulfiram 250 mg/d, group 2 received 1 mg/d (a pharmacologically ineffective dose), and group 3 received a placebo. Importantly, patients in both groups 1 and 2 were informed that they were receiving disulfiram and were warned of a possible ethanol-disulfiram reaction. At a 6-month follow-up, patients receiving disulfiram showed a small but significant increase in abstinence compared with those receiving placebo. Interestingly, there was no difference between patients receiving 250 mg of disulfiram and those receiving the ineffective 1 mg dose, suggesting that the primary action of disulfiram is the fear of a reaction with alcohol, not the agent’s pharmacologic effects.
A number of studies have shown that patients who agree to take disulfiram and continue taking it are generally highly motivated; such patients unsurprisingly experience better treatment outcomes.
In the largest controlled, blinded study of disulfiram performed to date, Fuller et al11 evaluated disulfiram treatment in 605 male veterans randomly assigned to disulfiram 250 mg a day, disulfiram 1 mg a day, or placebo. No significant differences were found between groups in total abstinence or time to first drink. Among patients who participated in all assessments and who drank at least once during the study, however, those receiving 250 mg had fewer drinking days than those in either control group.
The authors concluded that disulfiram may help reduce drinking frequency after a return to drinking, but does not contribute to continuous abstinence or to delay in time to first drink. Notably, despite a medication compliance rate of only 20%, a significant relationship existed between medication compliance and complete abstinence, regardless of treatment group. O’Farrell and colleagues14 have studied ways to increase compliance with disulfiram, developing the concept of the “Antabuse contract,” in which the patient takes disulfiram in front of a significant other as part of a couple’s therapy program.
How long should a patient continue taking disulfiram? Unfortunately, the ideal length of disulfiram treatment has not been established. While most randomized trials only administer disulfiram for a few months, research by Ojehagen et al15 has shown that long-term treatment (greater than 12 months) with disulfiram is significantly related to positive drinking outcomes during the 2 years following treatment.
Naltrexone The two initial landmark studies of naltrexone for alcohol dependence were published nearly a decade ago. Volpicelli et al7 conducted a double-blind, placebo-controlled trial of naltrexone 50 mg/d for 12 weeks with 70 male veterans who also received intensive psychosocial alcohol rehabilitation. Study participants who received naltrexone had fewer drinking days, less craving for alcohol, and a lower rate of full-blown relapse than did patients who received placebo. The major effect of naltrexone occurred among patients who sampled alcohol; only half of those on naltrexone progressed from first drink to a full-blown relapse, compared to a 95% rate of relapse among those who initiated drinking while receiving placebo.
O’Malley et al8 also found naltrexone to be more effective than placebo and found an interesting interaction with psychosocial treatment. Individuals who received weekly abstinence-oriented supportive therapy were more likely to be continuously abstinent from alcohol at the end of the 12-week study period. Those who received naltrexone along with cognitive behavioral coping skills therapy were least likely to progress to a full-blown relapse if they did drink.
More recently, Anton et al12 conducted a double-blind, placebo-controlled trial of naltrexone in 131 patients, all of whom received cognitive behavioral therapy (CBT). Those receiving naltrexone had a significantly longer period prior to relapse, fewer drinking days, and fewer drinks per drinking day than the placebo group. No significant differences were reported between the groups in time prior to the first drink.
These studies suggest that naltrexone may diminish the likelihood of progression from first drink to full-blown relapse. This may occur through the agent’s attenuation of the reinforcing effects of alcohol.13 While naltrexone does not fully block alcohol the way it blocks opioid drugs, the reduction in alcohol’s positive effects may help naltrexone responders to contain their “slips” and prevent progression to a full-blown relapse.
The difference in adverse effects
Disulfiram Adverse effects (see Table 2) arise from 3 main causes:
- Medical complications during an ethanol-disulfiram reaction;
- Toxicity due to disulfiram or its metabolites;
- Interactions between disulfiram and other medications.
Table 2
HOW DISULFIRAM, NALTREXONE WORK
| Disulfiram | Naltrexone | |
|---|---|---|
| Mechanism of action | Interrupts metabolism of alcohol, leads to a buildup of acetaldehyde | Opiate antagonist, may attenuate reinforcing property of alcohol |
| Recommended dose* | 25-500 mg | 50 mg |
| Side effects and adverse events | Drowsiness, impotence, headache, acne, metallic aftertaste, hepatitis, neuritis, ethanoldisulfiram reaction | Nausea, vomiting, headache, anxiety, dizziness, fatigue, insomnia, elevated liver enzymes |
| *Physicians Desk Reference 55th ed. Montvale, NJ: Medical Economics, 2001 | ||
Medical complications arising from an ethanol-disulfiram reaction can include tachycardia, hypotension, and electrocardiographic changes. Fatalities have been reported due to myocardial infarction or cerebrovascular accident.5 As a result, people with a history of severe myocardial disease should generally not be prescribed disulfiram.
Side effects from disulfiram itself include drowsiness, impotence, headache, acne, and a metallic or garlic-like aftertaste. Toxicity can also lead to psychiatric reactions such as increased depression and psychosis, possibly because of the inhibition of dopamine β–hydroxylase.5
Hepatic and neurological reactions are the most commonly reported toxic reactions.19 Disulfiram-induced hepatitis usually occurs within 2 months of initiation of treatment, but may occur up to 6 months after starting disulfiram.20 This form of liver toxicity is believed to be an allergic or hypersensitivity reaction and can lead to hepatic necrosis and death due to liver failure. Some clinicians recommend obtaining liver function tests at regular intervals (e.g., at baseline, 2 weeks, 4 weeks, then monthly for 6 months), although the optimal frequency of testing after week 2 is not well established.
Neurological reactions make up approximately 20% of the overall reported side effects from disulfiram, with the most frequent diagnosis being polyneuropathy. Other important reported adverse neurological effects include optic and peripheral neuritis.19
Disulfiram interacts with a number of medications, primarily by slowing down their metabolism and thus increasing risk of toxicity. These drugs include phenytoin, theophylline, anticoagulant drugs, isoniazid, and amitriptyline.19 Prior to starting treatment with disulfiram, phenytoin serum levels should be obtained and monitored throughout treatment. Dosage of oral anticoagulant drugs such as warfarin should also be monitored carefully.
Naltrexone The most common side effect is nausea, which typically occurs in the first week of treatment. In the largest study of naltrexone published to date, approximately 10% of naltrexone-treated subjects reported this side effect.16 Other side effects include headache, anxiety, dizziness, fatigue, vomiting, and insomnia.16
Elevated liver enzymes have been reported with use,17 so liver function should be monitored in patients receiving this medication.
It is unclear how often liver function tests should be performed. One text18 recommends baseline assessment of liver function, monthly monitoring for 3 months, then testing every 2 to 6 months afterwards if results are normal.
Other clinical considerations
Disulfiram Individuals with a history of allergy to thiuram derivatives used in rubber vulcanization or pesticides should not be given disulfiram. Caution should also be used with patients suffering from myocardial disease, diabetes mellitus, cirrhosis, hypothyroidism, seizure disorder, or impaired renal function. Finally, patients should not take disulfiram unless they have abstained from alcohol for at least 12 hours.
Naltrexone Although the recommended dosage of naltrexone for alcohol dependence is 50 mg/d, some patients who experience side effects at that dosage may tolerate 25 mg/d, so starting at this lower dose is often advisable. Some researchers are analyzing the effects of higher dosages (e.g., 100 mg/d) because of evidence that higher blood levels of 6-β-naltrexol might improve treatment outcome.9 The optimal dosage of naltrexone for alcohol dependence is currently not settled, however, and may vary among patients.
Patients should be free of opiates for at least 7 days prior to initiating naltrexone; in the case of methadone, a 10- to 14-day opiate-free interval is prudent. Clinicans should wait approximately 4 days after the patient’s last drink before initiating therapy, since starting naltrexone earlier may lead to more side effects.
Educating patients about both agents
Disulfiram This medication is not to be prescribed lightly; only patients who are fully aware of its potential risks should be taking it. Patients need to be both willing and able to avoid alcohol both in beverage and disguised forms (e.g., alcohol-laced cough syrups).
One useful question to ask patients is, “Can you imagine yourself drinking on disulfiram?” Patients who admit that disulfiram would not deter them from drinking, or who cannot commit to avoiding alcohol in any form, should not use this medication.
Naltrexone Some alcohol-dependent patients are interested in taking naltrexone because they have heard that it may diminish the likelihood of progression from initial drink to full-blown relapse, thus helping them to become controlled drinkers.
Bear in mind that naltrexone does not convert alcohol-dependent individuals into controlled drinkers. Rather, you should tell patients that naltrexone may help them return to abstinence more quickly in the event that they do slip. This statement is consistent with the data about naltrexone and helps to establish and reinforce the goal of abstinence for alcohol-dependent patients.
Which medication for which patient?
When considering which, if either, medication to prescribe for an alcohol-dependent patient, you should initially determine whether contraindications exist. (A rubber allergy would preclude disulfiram, for example.) Then obtain a medical evaluation, including liver function tests, prior to initiating either medication.
While the guidelines for adequate liver function to initiate these medications is a matter of controversy, some clinicians recommend that liver enzymes should be twice the upper limit of normal or better, and that the medications should be stopped if liver function tests are 3 times the upper limit of normal or worse. Some clinicians use more liberal or conservative guidelines, although most recommend that an elevated bilirubin contraindicates the use of either agent.
Assuming that the patient is medically able to take either one, tell the patient that there are 2 medications approved for the treatment of alcohol dependence, and briefly describe each. Then ask the patient if he or she is potentially interested in either. Many patients will opt for no pharmacotherapy, some for naltrexone, and a smaller portion for disulfiram. This choice may vary over time, however, based on the patient’s clinical status. By remaining flexible and sharing this decision-making process with the patient, you increase the likelihood of medication compliance.
Current evidence suggests that both disulfiram and naltrexone are effective only in conjunction with alcohol-focused psychosocial treatment; this may include professional alcoholism treatment, support groups such as Alcoholics Anonymous, or, ideally, a combination of the two.
Monitoring compliance and side effects is also critical. By integrating pharmacologic and psychosocial approaches for alcohol-dependent patients, outcomes can be improved for this prevalent and highly treatable population.
Related resources
- The National Institute on Alcohol Abuse and Alcoholism (NIAAA) www.niaaa.nih.gov
- American Academy of Addiction Psychiatry (AAAP) www.aaap.org
- American Society of Addiction Medicine (ASAM) www.asam.org
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Isoniazid • Laniazid, Nydrazid
- Naltrexone • ReVia
- Warfarin • Coumadin, Miradon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article.
1. Caetano R, Tam TW. Prevalence and correlates of DSM-IV and ICD-10 alcohol dependence. Alcohol Alcohol. 1995;30(2):177-186.
2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270(18):2207-2212.
3. Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: A clinical review. J Clin Psychiatry. 2001;62(Suppl 20):42-48.
4. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Medicine. 1990;88(6):647-655.
5. Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol consumption. N Engl J Med. 1981;305(21):1255-1262.
6. Cohen G, Collins M. Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science. 1970;167:1749-1751.
7. Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.
8. O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.
9. McCaul ME, Wand GS, Rohde C, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156:1758-1764.
10. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: An evaluation of 128 men. Ann Intern Med. 1979;90(6):901-904.
11. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA. 1986;256(11):1449-1455.
12. Anton RF, Moak DH, Waid LR, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758-1764.
13. Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;151(10):1463-1467.
14. O’Farrell TJ, Allen JP, Litten RZ. Disulfiram (Antabuse) contracts in treatment of alcoholism. In: Integrating behavioral therapies with medications in the treatment of drug dependence (NIDA research monograph 150). ed by JDBlaine JD and L Onken. Washington, D.C.: National Institute on Drug Abuse, 1995;65-91.
15. Ojehagen A, Skjaerris A, Berglund M. Long-term use of aversive drugs in outpatient alcoholism treatment. Acta Psychiatr Scand. 1991;84(2):185-190.
16. Croop RS, Faulkner EB, Labriola DF, et al. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. Arch Gen Psychiatry. 1997;54(12):1130-1135.
17. Atkinson RL, Berke LK, Drake CR, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419-422.
18. O’Brien CP, Cornish JW. Opioids: Antagonists and partial agonists. In: The American Psychiatric Press Textbook of Substance Abuse Treatment. 2nd ed. Galanter M, Kleber HD, eds. Washington DC: American Psychiatric Press, 1999;281-294.
19. Poulsen HE, Loft S, Andersen M, Andersen JR. Disulfiram therapy—Adverse drug reactions and interactions. Acta Psychiatr Scand. 1992;86:59-66.
20. Mason NA. Disulfiram-induced hepatitis: Case report and review of the literature. DICP. 1989;23(11):872-874.
Alcohol dependence is one of the leading causes of morbidity and mortality in the United States. Approximately 10% of Americans will develop alcoholism at some point in their lives,1 and an estimated 100,000 individuals die each year due to alcohol-related medical complications, automobile accidents, and homicides.2 Alcohol dependence also costs the U.S. billions of dollars annually in health care costs, lost productivity, incarceration, and property destruction.
The search for effective pharmacologic treatments has long been a focus of research. Disulfiram, which causes an aversive reaction when combined with alcohol, was for many years the only medication in use. More recently, the opiate antagonist naltrexone has also been used to treat alcohol-dependent patients.
The homotaurine derivative, acamprosate, has recently shown great promise. Though used widely in Europe,3 it is not approved for use in this country.
This article will therefore focus on disulfiram and naltrexone: their pharmacology, efficacy, side effects, and dosing strategies. We also will present guidelines for discussing each medication with patients and for deciding which, if either, to prescribe.
Differences in pharmacology
Disulfiram Since the serendipitous discovery of its reactive property with alcohol in the 1940s, disulfiram has been used in the pharmacological treatment of alcoholism. The agent disrupts alcohol metabolism by inhibiting the action of aldehyde dehydrogenase, thus blocking the conversion of acetaldehyde to acetate. Accumulation of acetaldehyde, the first metabolite of ethanol, causes numerous unpleasant effects, including flushing, weakness, and nausea.4 In addition to acting on aldehyde dehydrogenase, disulfiram inhibits dopamine-β-hydroxylase.5
Disulfiram is absorbed from the gastrointestinal tract and is rapidly distributed to tissues and organs. It begins to affect alcohol metabolism within 1 to 2 hours, with a peak at 12 hours. It is slowly excreted from the body over the next 2 weeks, although its effects may be lost sooner as the body secretes new enzyme.4
The ethanol-disulfiram reaction is characterized by flushing, throbbing in the head and neck, respiratory difficulty, vomiting, sweating, thirst, weakness, and hypotension ( Table 1). In some cases, the reaction can be fatal.
Naltrexone Following its approval for use in treating opioid dependence in the mid-1980s, the opiate antagonist naltrexone was approved nearly a decade ago for use in treating individuals with alcohol dependence. Research interest in the use of naltrexone for this purpose grew from theories that the endogenous opiate system may be involved in the development of alcohol dependence.6 Two simultaneously published studies in 1992 showed the benefit of naltrexone in alcohol dependence;7-8 this led to its approval by the Food and Drug Administration.
Naltrexone is metabolized to its major metabolite, 6-β-naltrexol, and is then excreted in the urine as both the original compound and this metabolite.9 The half-life of naltrexone in chronic administration is approximately 10 hours; the half-life of 6-β-naltrexol is 12 to 16 hours.
Comparison of efficacy
Disulfiram Results concerning efficacy have been mixed. Initial studies showed promising effects but were limited to anecdotal evidence and case studies. More recent studies have addressed issues relating to proper control groups, compliance, and motivation in evaluating disulfiram’s effect on alcohol consumption. Early studies used placebo groups to control for the effects of counseling or regular medical monitoring. However, no controls were employed to distinguish between the psychological effects of disulfiram (e.g., fear of a reaction) and its pharmacologic effects.
Table 1
SYMPTOMS OF AN ETHANOL-DISULFIRAM REACTION
| • Flushing | • Sweating |
| • Throbbing in head and neck | • Thirst |
| • Respiratory difficulty | • Weakness |
| • Vomiting | • Hypotension |
| The intensity of the reaction is generally related to the amount of alcohol and disulfiram consumed. Because even small amounts of alcohol may cause a reaction, individuals taking disulfiram should avoid all forms of alcohol, including certain mouthwashes and cough syrups. Patients also should be instructed to read the ingredients of foods and medications they consume. | |
| While the recommended daily dose for disulfiram ranges from 125 mg to 500 mg, individuals can vary widely in their reactions. Dosages below 250 mg/d have failed to produce aversive reactions in some individuals who drink alcohol. Dosages of 250 mg/d or higher, however, may cause toxic side effects, including a more severe reaction with alcohol. Clinicians should be aware that in a few patients, the dosage needed to produce an aversive reaction may be higher than the dosage that produces toxicity.4 | |
| The authors generally prescribe 125 mg/d, which is at the low end of the usual dose range, since the fear of a reaction—not the reaction itself—is the major therapeutic action of disulfiram. Moreover, a lower dosage diminishes (but by no means eliminates) the likelihood of a highly dangerous alcohol-disulfiram reaction. | |
Fuller and Roth10 addressed this concern by designing a double-blind study that consisted of 3 groups. Group 1 received disulfiram 250 mg/d, group 2 received 1 mg/d (a pharmacologically ineffective dose), and group 3 received a placebo. Importantly, patients in both groups 1 and 2 were informed that they were receiving disulfiram and were warned of a possible ethanol-disulfiram reaction. At a 6-month follow-up, patients receiving disulfiram showed a small but significant increase in abstinence compared with those receiving placebo. Interestingly, there was no difference between patients receiving 250 mg of disulfiram and those receiving the ineffective 1 mg dose, suggesting that the primary action of disulfiram is the fear of a reaction with alcohol, not the agent’s pharmacologic effects.
A number of studies have shown that patients who agree to take disulfiram and continue taking it are generally highly motivated; such patients unsurprisingly experience better treatment outcomes.
In the largest controlled, blinded study of disulfiram performed to date, Fuller et al11 evaluated disulfiram treatment in 605 male veterans randomly assigned to disulfiram 250 mg a day, disulfiram 1 mg a day, or placebo. No significant differences were found between groups in total abstinence or time to first drink. Among patients who participated in all assessments and who drank at least once during the study, however, those receiving 250 mg had fewer drinking days than those in either control group.
The authors concluded that disulfiram may help reduce drinking frequency after a return to drinking, but does not contribute to continuous abstinence or to delay in time to first drink. Notably, despite a medication compliance rate of only 20%, a significant relationship existed between medication compliance and complete abstinence, regardless of treatment group. O’Farrell and colleagues14 have studied ways to increase compliance with disulfiram, developing the concept of the “Antabuse contract,” in which the patient takes disulfiram in front of a significant other as part of a couple’s therapy program.
How long should a patient continue taking disulfiram? Unfortunately, the ideal length of disulfiram treatment has not been established. While most randomized trials only administer disulfiram for a few months, research by Ojehagen et al15 has shown that long-term treatment (greater than 12 months) with disulfiram is significantly related to positive drinking outcomes during the 2 years following treatment.
Naltrexone The two initial landmark studies of naltrexone for alcohol dependence were published nearly a decade ago. Volpicelli et al7 conducted a double-blind, placebo-controlled trial of naltrexone 50 mg/d for 12 weeks with 70 male veterans who also received intensive psychosocial alcohol rehabilitation. Study participants who received naltrexone had fewer drinking days, less craving for alcohol, and a lower rate of full-blown relapse than did patients who received placebo. The major effect of naltrexone occurred among patients who sampled alcohol; only half of those on naltrexone progressed from first drink to a full-blown relapse, compared to a 95% rate of relapse among those who initiated drinking while receiving placebo.
O’Malley et al8 also found naltrexone to be more effective than placebo and found an interesting interaction with psychosocial treatment. Individuals who received weekly abstinence-oriented supportive therapy were more likely to be continuously abstinent from alcohol at the end of the 12-week study period. Those who received naltrexone along with cognitive behavioral coping skills therapy were least likely to progress to a full-blown relapse if they did drink.
More recently, Anton et al12 conducted a double-blind, placebo-controlled trial of naltrexone in 131 patients, all of whom received cognitive behavioral therapy (CBT). Those receiving naltrexone had a significantly longer period prior to relapse, fewer drinking days, and fewer drinks per drinking day than the placebo group. No significant differences were reported between the groups in time prior to the first drink.
These studies suggest that naltrexone may diminish the likelihood of progression from first drink to full-blown relapse. This may occur through the agent’s attenuation of the reinforcing effects of alcohol.13 While naltrexone does not fully block alcohol the way it blocks opioid drugs, the reduction in alcohol’s positive effects may help naltrexone responders to contain their “slips” and prevent progression to a full-blown relapse.
The difference in adverse effects
Disulfiram Adverse effects (see Table 2) arise from 3 main causes:
- Medical complications during an ethanol-disulfiram reaction;
- Toxicity due to disulfiram or its metabolites;
- Interactions between disulfiram and other medications.
Table 2
HOW DISULFIRAM, NALTREXONE WORK
| Disulfiram | Naltrexone | |
|---|---|---|
| Mechanism of action | Interrupts metabolism of alcohol, leads to a buildup of acetaldehyde | Opiate antagonist, may attenuate reinforcing property of alcohol |
| Recommended dose* | 25-500 mg | 50 mg |
| Side effects and adverse events | Drowsiness, impotence, headache, acne, metallic aftertaste, hepatitis, neuritis, ethanoldisulfiram reaction | Nausea, vomiting, headache, anxiety, dizziness, fatigue, insomnia, elevated liver enzymes |
| *Physicians Desk Reference 55th ed. Montvale, NJ: Medical Economics, 2001 | ||
Medical complications arising from an ethanol-disulfiram reaction can include tachycardia, hypotension, and electrocardiographic changes. Fatalities have been reported due to myocardial infarction or cerebrovascular accident.5 As a result, people with a history of severe myocardial disease should generally not be prescribed disulfiram.
Side effects from disulfiram itself include drowsiness, impotence, headache, acne, and a metallic or garlic-like aftertaste. Toxicity can also lead to psychiatric reactions such as increased depression and psychosis, possibly because of the inhibition of dopamine β–hydroxylase.5
Hepatic and neurological reactions are the most commonly reported toxic reactions.19 Disulfiram-induced hepatitis usually occurs within 2 months of initiation of treatment, but may occur up to 6 months after starting disulfiram.20 This form of liver toxicity is believed to be an allergic or hypersensitivity reaction and can lead to hepatic necrosis and death due to liver failure. Some clinicians recommend obtaining liver function tests at regular intervals (e.g., at baseline, 2 weeks, 4 weeks, then monthly for 6 months), although the optimal frequency of testing after week 2 is not well established.
Neurological reactions make up approximately 20% of the overall reported side effects from disulfiram, with the most frequent diagnosis being polyneuropathy. Other important reported adverse neurological effects include optic and peripheral neuritis.19
Disulfiram interacts with a number of medications, primarily by slowing down their metabolism and thus increasing risk of toxicity. These drugs include phenytoin, theophylline, anticoagulant drugs, isoniazid, and amitriptyline.19 Prior to starting treatment with disulfiram, phenytoin serum levels should be obtained and monitored throughout treatment. Dosage of oral anticoagulant drugs such as warfarin should also be monitored carefully.
Naltrexone The most common side effect is nausea, which typically occurs in the first week of treatment. In the largest study of naltrexone published to date, approximately 10% of naltrexone-treated subjects reported this side effect.16 Other side effects include headache, anxiety, dizziness, fatigue, vomiting, and insomnia.16
Elevated liver enzymes have been reported with use,17 so liver function should be monitored in patients receiving this medication.
It is unclear how often liver function tests should be performed. One text18 recommends baseline assessment of liver function, monthly monitoring for 3 months, then testing every 2 to 6 months afterwards if results are normal.
Other clinical considerations
Disulfiram Individuals with a history of allergy to thiuram derivatives used in rubber vulcanization or pesticides should not be given disulfiram. Caution should also be used with patients suffering from myocardial disease, diabetes mellitus, cirrhosis, hypothyroidism, seizure disorder, or impaired renal function. Finally, patients should not take disulfiram unless they have abstained from alcohol for at least 12 hours.
Naltrexone Although the recommended dosage of naltrexone for alcohol dependence is 50 mg/d, some patients who experience side effects at that dosage may tolerate 25 mg/d, so starting at this lower dose is often advisable. Some researchers are analyzing the effects of higher dosages (e.g., 100 mg/d) because of evidence that higher blood levels of 6-β-naltrexol might improve treatment outcome.9 The optimal dosage of naltrexone for alcohol dependence is currently not settled, however, and may vary among patients.
Patients should be free of opiates for at least 7 days prior to initiating naltrexone; in the case of methadone, a 10- to 14-day opiate-free interval is prudent. Clinicans should wait approximately 4 days after the patient’s last drink before initiating therapy, since starting naltrexone earlier may lead to more side effects.
Educating patients about both agents
Disulfiram This medication is not to be prescribed lightly; only patients who are fully aware of its potential risks should be taking it. Patients need to be both willing and able to avoid alcohol both in beverage and disguised forms (e.g., alcohol-laced cough syrups).
One useful question to ask patients is, “Can you imagine yourself drinking on disulfiram?” Patients who admit that disulfiram would not deter them from drinking, or who cannot commit to avoiding alcohol in any form, should not use this medication.
Naltrexone Some alcohol-dependent patients are interested in taking naltrexone because they have heard that it may diminish the likelihood of progression from initial drink to full-blown relapse, thus helping them to become controlled drinkers.
Bear in mind that naltrexone does not convert alcohol-dependent individuals into controlled drinkers. Rather, you should tell patients that naltrexone may help them return to abstinence more quickly in the event that they do slip. This statement is consistent with the data about naltrexone and helps to establish and reinforce the goal of abstinence for alcohol-dependent patients.
Which medication for which patient?
When considering which, if either, medication to prescribe for an alcohol-dependent patient, you should initially determine whether contraindications exist. (A rubber allergy would preclude disulfiram, for example.) Then obtain a medical evaluation, including liver function tests, prior to initiating either medication.
While the guidelines for adequate liver function to initiate these medications is a matter of controversy, some clinicians recommend that liver enzymes should be twice the upper limit of normal or better, and that the medications should be stopped if liver function tests are 3 times the upper limit of normal or worse. Some clinicians use more liberal or conservative guidelines, although most recommend that an elevated bilirubin contraindicates the use of either agent.
Assuming that the patient is medically able to take either one, tell the patient that there are 2 medications approved for the treatment of alcohol dependence, and briefly describe each. Then ask the patient if he or she is potentially interested in either. Many patients will opt for no pharmacotherapy, some for naltrexone, and a smaller portion for disulfiram. This choice may vary over time, however, based on the patient’s clinical status. By remaining flexible and sharing this decision-making process with the patient, you increase the likelihood of medication compliance.
Current evidence suggests that both disulfiram and naltrexone are effective only in conjunction with alcohol-focused psychosocial treatment; this may include professional alcoholism treatment, support groups such as Alcoholics Anonymous, or, ideally, a combination of the two.
Monitoring compliance and side effects is also critical. By integrating pharmacologic and psychosocial approaches for alcohol-dependent patients, outcomes can be improved for this prevalent and highly treatable population.
Related resources
- The National Institute on Alcohol Abuse and Alcoholism (NIAAA) www.niaaa.nih.gov
- American Academy of Addiction Psychiatry (AAAP) www.aaap.org
- American Society of Addiction Medicine (ASAM) www.asam.org
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Isoniazid • Laniazid, Nydrazid
- Naltrexone • ReVia
- Warfarin • Coumadin, Miradon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article.
Alcohol dependence is one of the leading causes of morbidity and mortality in the United States. Approximately 10% of Americans will develop alcoholism at some point in their lives,1 and an estimated 100,000 individuals die each year due to alcohol-related medical complications, automobile accidents, and homicides.2 Alcohol dependence also costs the U.S. billions of dollars annually in health care costs, lost productivity, incarceration, and property destruction.
The search for effective pharmacologic treatments has long been a focus of research. Disulfiram, which causes an aversive reaction when combined with alcohol, was for many years the only medication in use. More recently, the opiate antagonist naltrexone has also been used to treat alcohol-dependent patients.
The homotaurine derivative, acamprosate, has recently shown great promise. Though used widely in Europe,3 it is not approved for use in this country.
This article will therefore focus on disulfiram and naltrexone: their pharmacology, efficacy, side effects, and dosing strategies. We also will present guidelines for discussing each medication with patients and for deciding which, if either, to prescribe.
Differences in pharmacology
Disulfiram Since the serendipitous discovery of its reactive property with alcohol in the 1940s, disulfiram has been used in the pharmacological treatment of alcoholism. The agent disrupts alcohol metabolism by inhibiting the action of aldehyde dehydrogenase, thus blocking the conversion of acetaldehyde to acetate. Accumulation of acetaldehyde, the first metabolite of ethanol, causes numerous unpleasant effects, including flushing, weakness, and nausea.4 In addition to acting on aldehyde dehydrogenase, disulfiram inhibits dopamine-β-hydroxylase.5
Disulfiram is absorbed from the gastrointestinal tract and is rapidly distributed to tissues and organs. It begins to affect alcohol metabolism within 1 to 2 hours, with a peak at 12 hours. It is slowly excreted from the body over the next 2 weeks, although its effects may be lost sooner as the body secretes new enzyme.4
The ethanol-disulfiram reaction is characterized by flushing, throbbing in the head and neck, respiratory difficulty, vomiting, sweating, thirst, weakness, and hypotension ( Table 1). In some cases, the reaction can be fatal.
Naltrexone Following its approval for use in treating opioid dependence in the mid-1980s, the opiate antagonist naltrexone was approved nearly a decade ago for use in treating individuals with alcohol dependence. Research interest in the use of naltrexone for this purpose grew from theories that the endogenous opiate system may be involved in the development of alcohol dependence.6 Two simultaneously published studies in 1992 showed the benefit of naltrexone in alcohol dependence;7-8 this led to its approval by the Food and Drug Administration.
Naltrexone is metabolized to its major metabolite, 6-β-naltrexol, and is then excreted in the urine as both the original compound and this metabolite.9 The half-life of naltrexone in chronic administration is approximately 10 hours; the half-life of 6-β-naltrexol is 12 to 16 hours.
Comparison of efficacy
Disulfiram Results concerning efficacy have been mixed. Initial studies showed promising effects but were limited to anecdotal evidence and case studies. More recent studies have addressed issues relating to proper control groups, compliance, and motivation in evaluating disulfiram’s effect on alcohol consumption. Early studies used placebo groups to control for the effects of counseling or regular medical monitoring. However, no controls were employed to distinguish between the psychological effects of disulfiram (e.g., fear of a reaction) and its pharmacologic effects.
Table 1
SYMPTOMS OF AN ETHANOL-DISULFIRAM REACTION
| • Flushing | • Sweating |
| • Throbbing in head and neck | • Thirst |
| • Respiratory difficulty | • Weakness |
| • Vomiting | • Hypotension |
| The intensity of the reaction is generally related to the amount of alcohol and disulfiram consumed. Because even small amounts of alcohol may cause a reaction, individuals taking disulfiram should avoid all forms of alcohol, including certain mouthwashes and cough syrups. Patients also should be instructed to read the ingredients of foods and medications they consume. | |
| While the recommended daily dose for disulfiram ranges from 125 mg to 500 mg, individuals can vary widely in their reactions. Dosages below 250 mg/d have failed to produce aversive reactions in some individuals who drink alcohol. Dosages of 250 mg/d or higher, however, may cause toxic side effects, including a more severe reaction with alcohol. Clinicians should be aware that in a few patients, the dosage needed to produce an aversive reaction may be higher than the dosage that produces toxicity.4 | |
| The authors generally prescribe 125 mg/d, which is at the low end of the usual dose range, since the fear of a reaction—not the reaction itself—is the major therapeutic action of disulfiram. Moreover, a lower dosage diminishes (but by no means eliminates) the likelihood of a highly dangerous alcohol-disulfiram reaction. | |
Fuller and Roth10 addressed this concern by designing a double-blind study that consisted of 3 groups. Group 1 received disulfiram 250 mg/d, group 2 received 1 mg/d (a pharmacologically ineffective dose), and group 3 received a placebo. Importantly, patients in both groups 1 and 2 were informed that they were receiving disulfiram and were warned of a possible ethanol-disulfiram reaction. At a 6-month follow-up, patients receiving disulfiram showed a small but significant increase in abstinence compared with those receiving placebo. Interestingly, there was no difference between patients receiving 250 mg of disulfiram and those receiving the ineffective 1 mg dose, suggesting that the primary action of disulfiram is the fear of a reaction with alcohol, not the agent’s pharmacologic effects.
A number of studies have shown that patients who agree to take disulfiram and continue taking it are generally highly motivated; such patients unsurprisingly experience better treatment outcomes.
In the largest controlled, blinded study of disulfiram performed to date, Fuller et al11 evaluated disulfiram treatment in 605 male veterans randomly assigned to disulfiram 250 mg a day, disulfiram 1 mg a day, or placebo. No significant differences were found between groups in total abstinence or time to first drink. Among patients who participated in all assessments and who drank at least once during the study, however, those receiving 250 mg had fewer drinking days than those in either control group.
The authors concluded that disulfiram may help reduce drinking frequency after a return to drinking, but does not contribute to continuous abstinence or to delay in time to first drink. Notably, despite a medication compliance rate of only 20%, a significant relationship existed between medication compliance and complete abstinence, regardless of treatment group. O’Farrell and colleagues14 have studied ways to increase compliance with disulfiram, developing the concept of the “Antabuse contract,” in which the patient takes disulfiram in front of a significant other as part of a couple’s therapy program.
How long should a patient continue taking disulfiram? Unfortunately, the ideal length of disulfiram treatment has not been established. While most randomized trials only administer disulfiram for a few months, research by Ojehagen et al15 has shown that long-term treatment (greater than 12 months) with disulfiram is significantly related to positive drinking outcomes during the 2 years following treatment.
Naltrexone The two initial landmark studies of naltrexone for alcohol dependence were published nearly a decade ago. Volpicelli et al7 conducted a double-blind, placebo-controlled trial of naltrexone 50 mg/d for 12 weeks with 70 male veterans who also received intensive psychosocial alcohol rehabilitation. Study participants who received naltrexone had fewer drinking days, less craving for alcohol, and a lower rate of full-blown relapse than did patients who received placebo. The major effect of naltrexone occurred among patients who sampled alcohol; only half of those on naltrexone progressed from first drink to a full-blown relapse, compared to a 95% rate of relapse among those who initiated drinking while receiving placebo.
O’Malley et al8 also found naltrexone to be more effective than placebo and found an interesting interaction with psychosocial treatment. Individuals who received weekly abstinence-oriented supportive therapy were more likely to be continuously abstinent from alcohol at the end of the 12-week study period. Those who received naltrexone along with cognitive behavioral coping skills therapy were least likely to progress to a full-blown relapse if they did drink.
More recently, Anton et al12 conducted a double-blind, placebo-controlled trial of naltrexone in 131 patients, all of whom received cognitive behavioral therapy (CBT). Those receiving naltrexone had a significantly longer period prior to relapse, fewer drinking days, and fewer drinks per drinking day than the placebo group. No significant differences were reported between the groups in time prior to the first drink.
These studies suggest that naltrexone may diminish the likelihood of progression from first drink to full-blown relapse. This may occur through the agent’s attenuation of the reinforcing effects of alcohol.13 While naltrexone does not fully block alcohol the way it blocks opioid drugs, the reduction in alcohol’s positive effects may help naltrexone responders to contain their “slips” and prevent progression to a full-blown relapse.
The difference in adverse effects
Disulfiram Adverse effects (see Table 2) arise from 3 main causes:
- Medical complications during an ethanol-disulfiram reaction;
- Toxicity due to disulfiram or its metabolites;
- Interactions between disulfiram and other medications.
Table 2
HOW DISULFIRAM, NALTREXONE WORK
| Disulfiram | Naltrexone | |
|---|---|---|
| Mechanism of action | Interrupts metabolism of alcohol, leads to a buildup of acetaldehyde | Opiate antagonist, may attenuate reinforcing property of alcohol |
| Recommended dose* | 25-500 mg | 50 mg |
| Side effects and adverse events | Drowsiness, impotence, headache, acne, metallic aftertaste, hepatitis, neuritis, ethanoldisulfiram reaction | Nausea, vomiting, headache, anxiety, dizziness, fatigue, insomnia, elevated liver enzymes |
| *Physicians Desk Reference 55th ed. Montvale, NJ: Medical Economics, 2001 | ||
Medical complications arising from an ethanol-disulfiram reaction can include tachycardia, hypotension, and electrocardiographic changes. Fatalities have been reported due to myocardial infarction or cerebrovascular accident.5 As a result, people with a history of severe myocardial disease should generally not be prescribed disulfiram.
Side effects from disulfiram itself include drowsiness, impotence, headache, acne, and a metallic or garlic-like aftertaste. Toxicity can also lead to psychiatric reactions such as increased depression and psychosis, possibly because of the inhibition of dopamine β–hydroxylase.5
Hepatic and neurological reactions are the most commonly reported toxic reactions.19 Disulfiram-induced hepatitis usually occurs within 2 months of initiation of treatment, but may occur up to 6 months after starting disulfiram.20 This form of liver toxicity is believed to be an allergic or hypersensitivity reaction and can lead to hepatic necrosis and death due to liver failure. Some clinicians recommend obtaining liver function tests at regular intervals (e.g., at baseline, 2 weeks, 4 weeks, then monthly for 6 months), although the optimal frequency of testing after week 2 is not well established.
Neurological reactions make up approximately 20% of the overall reported side effects from disulfiram, with the most frequent diagnosis being polyneuropathy. Other important reported adverse neurological effects include optic and peripheral neuritis.19
Disulfiram interacts with a number of medications, primarily by slowing down their metabolism and thus increasing risk of toxicity. These drugs include phenytoin, theophylline, anticoagulant drugs, isoniazid, and amitriptyline.19 Prior to starting treatment with disulfiram, phenytoin serum levels should be obtained and monitored throughout treatment. Dosage of oral anticoagulant drugs such as warfarin should also be monitored carefully.
Naltrexone The most common side effect is nausea, which typically occurs in the first week of treatment. In the largest study of naltrexone published to date, approximately 10% of naltrexone-treated subjects reported this side effect.16 Other side effects include headache, anxiety, dizziness, fatigue, vomiting, and insomnia.16
Elevated liver enzymes have been reported with use,17 so liver function should be monitored in patients receiving this medication.
It is unclear how often liver function tests should be performed. One text18 recommends baseline assessment of liver function, monthly monitoring for 3 months, then testing every 2 to 6 months afterwards if results are normal.
Other clinical considerations
Disulfiram Individuals with a history of allergy to thiuram derivatives used in rubber vulcanization or pesticides should not be given disulfiram. Caution should also be used with patients suffering from myocardial disease, diabetes mellitus, cirrhosis, hypothyroidism, seizure disorder, or impaired renal function. Finally, patients should not take disulfiram unless they have abstained from alcohol for at least 12 hours.
Naltrexone Although the recommended dosage of naltrexone for alcohol dependence is 50 mg/d, some patients who experience side effects at that dosage may tolerate 25 mg/d, so starting at this lower dose is often advisable. Some researchers are analyzing the effects of higher dosages (e.g., 100 mg/d) because of evidence that higher blood levels of 6-β-naltrexol might improve treatment outcome.9 The optimal dosage of naltrexone for alcohol dependence is currently not settled, however, and may vary among patients.
Patients should be free of opiates for at least 7 days prior to initiating naltrexone; in the case of methadone, a 10- to 14-day opiate-free interval is prudent. Clinicans should wait approximately 4 days after the patient’s last drink before initiating therapy, since starting naltrexone earlier may lead to more side effects.
Educating patients about both agents
Disulfiram This medication is not to be prescribed lightly; only patients who are fully aware of its potential risks should be taking it. Patients need to be both willing and able to avoid alcohol both in beverage and disguised forms (e.g., alcohol-laced cough syrups).
One useful question to ask patients is, “Can you imagine yourself drinking on disulfiram?” Patients who admit that disulfiram would not deter them from drinking, or who cannot commit to avoiding alcohol in any form, should not use this medication.
Naltrexone Some alcohol-dependent patients are interested in taking naltrexone because they have heard that it may diminish the likelihood of progression from initial drink to full-blown relapse, thus helping them to become controlled drinkers.
Bear in mind that naltrexone does not convert alcohol-dependent individuals into controlled drinkers. Rather, you should tell patients that naltrexone may help them return to abstinence more quickly in the event that they do slip. This statement is consistent with the data about naltrexone and helps to establish and reinforce the goal of abstinence for alcohol-dependent patients.
Which medication for which patient?
When considering which, if either, medication to prescribe for an alcohol-dependent patient, you should initially determine whether contraindications exist. (A rubber allergy would preclude disulfiram, for example.) Then obtain a medical evaluation, including liver function tests, prior to initiating either medication.
While the guidelines for adequate liver function to initiate these medications is a matter of controversy, some clinicians recommend that liver enzymes should be twice the upper limit of normal or better, and that the medications should be stopped if liver function tests are 3 times the upper limit of normal or worse. Some clinicians use more liberal or conservative guidelines, although most recommend that an elevated bilirubin contraindicates the use of either agent.
Assuming that the patient is medically able to take either one, tell the patient that there are 2 medications approved for the treatment of alcohol dependence, and briefly describe each. Then ask the patient if he or she is potentially interested in either. Many patients will opt for no pharmacotherapy, some for naltrexone, and a smaller portion for disulfiram. This choice may vary over time, however, based on the patient’s clinical status. By remaining flexible and sharing this decision-making process with the patient, you increase the likelihood of medication compliance.
Current evidence suggests that both disulfiram and naltrexone are effective only in conjunction with alcohol-focused psychosocial treatment; this may include professional alcoholism treatment, support groups such as Alcoholics Anonymous, or, ideally, a combination of the two.
Monitoring compliance and side effects is also critical. By integrating pharmacologic and psychosocial approaches for alcohol-dependent patients, outcomes can be improved for this prevalent and highly treatable population.
Related resources
- The National Institute on Alcohol Abuse and Alcoholism (NIAAA) www.niaaa.nih.gov
- American Academy of Addiction Psychiatry (AAAP) www.aaap.org
- American Society of Addiction Medicine (ASAM) www.asam.org
Drug brand names
- Acamprosate • Campral
- Disulfiram • Antabuse
- Isoniazid • Laniazid, Nydrazid
- Naltrexone • ReVia
- Warfarin • Coumadin, Miradon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article.
1. Caetano R, Tam TW. Prevalence and correlates of DSM-IV and ICD-10 alcohol dependence. Alcohol Alcohol. 1995;30(2):177-186.
2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270(18):2207-2212.
3. Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: A clinical review. J Clin Psychiatry. 2001;62(Suppl 20):42-48.
4. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Medicine. 1990;88(6):647-655.
5. Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol consumption. N Engl J Med. 1981;305(21):1255-1262.
6. Cohen G, Collins M. Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science. 1970;167:1749-1751.
7. Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.
8. O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.
9. McCaul ME, Wand GS, Rohde C, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156:1758-1764.
10. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: An evaluation of 128 men. Ann Intern Med. 1979;90(6):901-904.
11. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA. 1986;256(11):1449-1455.
12. Anton RF, Moak DH, Waid LR, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758-1764.
13. Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;151(10):1463-1467.
14. O’Farrell TJ, Allen JP, Litten RZ. Disulfiram (Antabuse) contracts in treatment of alcoholism. In: Integrating behavioral therapies with medications in the treatment of drug dependence (NIDA research monograph 150). ed by JDBlaine JD and L Onken. Washington, D.C.: National Institute on Drug Abuse, 1995;65-91.
15. Ojehagen A, Skjaerris A, Berglund M. Long-term use of aversive drugs in outpatient alcoholism treatment. Acta Psychiatr Scand. 1991;84(2):185-190.
16. Croop RS, Faulkner EB, Labriola DF, et al. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. Arch Gen Psychiatry. 1997;54(12):1130-1135.
17. Atkinson RL, Berke LK, Drake CR, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419-422.
18. O’Brien CP, Cornish JW. Opioids: Antagonists and partial agonists. In: The American Psychiatric Press Textbook of Substance Abuse Treatment. 2nd ed. Galanter M, Kleber HD, eds. Washington DC: American Psychiatric Press, 1999;281-294.
19. Poulsen HE, Loft S, Andersen M, Andersen JR. Disulfiram therapy—Adverse drug reactions and interactions. Acta Psychiatr Scand. 1992;86:59-66.
20. Mason NA. Disulfiram-induced hepatitis: Case report and review of the literature. DICP. 1989;23(11):872-874.
1. Caetano R, Tam TW. Prevalence and correlates of DSM-IV and ICD-10 alcohol dependence. Alcohol Alcohol. 1995;30(2):177-186.
2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270(18):2207-2212.
3. Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: A clinical review. J Clin Psychiatry. 2001;62(Suppl 20):42-48.
4. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Medicine. 1990;88(6):647-655.
5. Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol consumption. N Engl J Med. 1981;305(21):1255-1262.
6. Cohen G, Collins M. Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science. 1970;167:1749-1751.
7. Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.
8. O’Malley SS, Jaffe AJ, Chang G, et al. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.
9. McCaul ME, Wand GS, Rohde C, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156:1758-1764.
10. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: An evaluation of 128 men. Ann Intern Med. 1979;90(6):901-904.
11. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA. 1986;256(11):1449-1455.
12. Anton RF, Moak DH, Waid LR, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758-1764.
13. Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;151(10):1463-1467.
14. O’Farrell TJ, Allen JP, Litten RZ. Disulfiram (Antabuse) contracts in treatment of alcoholism. In: Integrating behavioral therapies with medications in the treatment of drug dependence (NIDA research monograph 150). ed by JDBlaine JD and L Onken. Washington, D.C.: National Institute on Drug Abuse, 1995;65-91.
15. Ojehagen A, Skjaerris A, Berglund M. Long-term use of aversive drugs in outpatient alcoholism treatment. Acta Psychiatr Scand. 1991;84(2):185-190.
16. Croop RS, Faulkner EB, Labriola DF, et al. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. Arch Gen Psychiatry. 1997;54(12):1130-1135.
17. Atkinson RL, Berke LK, Drake CR, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419-422.
18. O’Brien CP, Cornish JW. Opioids: Antagonists and partial agonists. In: The American Psychiatric Press Textbook of Substance Abuse Treatment. 2nd ed. Galanter M, Kleber HD, eds. Washington DC: American Psychiatric Press, 1999;281-294.
19. Poulsen HE, Loft S, Andersen M, Andersen JR. Disulfiram therapy—Adverse drug reactions and interactions. Acta Psychiatr Scand. 1992;86:59-66.
20. Mason NA. Disulfiram-induced hepatitis: Case report and review of the literature. DICP. 1989;23(11):872-874.