Cleveland Clinic Journal of Medicine

To the Editor: I enjoyed the dermatology update in the May 2015 issue.¹ I would like to inquire about the clinical management of the patient in case 3, a 58-year­old man with biopsy-proven malignant melanoma surrounded by intense inflammatory infiltrate. The tumor was excised with standard margins, but distal metastases developed 2 years later. The depth of invasion of the primary tumor was not revealed, but could this patient have benefited from sentinel lymph node biopsy immediately after the initial excision?

To the Editor: I enjoyed the dermatology update in the May 2015 issue.¹ I would like to inquire about the clinical management of the patient in case 3, a 58-year­old man with biopsy-proven malignant melanoma surrounded by intense inflammatory infiltrate. The tumor was excised with standard margins, but distal metastases developed 2 years later. The depth of invasion of the primary tumor was not revealed, but could this patient have benefited from sentinel lymph node biopsy immediately after the initial excision?

To the Editor: I enjoyed the dermatology update in the May 2015 issue.¹ I would like to inquire about the clinical management of the patient in case 3, a 58-year­old man with biopsy-proven malignant melanoma surrounded by intense inflammatory infiltrate. The tumor was excised with standard margins, but distal metastases developed 2 years later. The depth of invasion of the primary tumor was not revealed, but could this patient have benefited from sentinel lymph node biopsy immediately after the initial excision?

In Reply: Thank you for your important question. Examination of the excision specimen of the patient’s primary cutaneous melanoma lesion demonstrated a Breslow depth of 1.92 mm. He did indeed undergo sentinel lymph node biopsy at the time of excision. Histologic examination of the biopsy specimen was negative for evidence of metastatic melanoma. Despite this, he obviously developed metastatic disease several years later.

As you allude to, sentinel lymph node biopsy is an important minimally invasive procedure in patients with melanoma. Morton et al¹ compared it with nodal observation and found that in patients with at least intermediate-thickness cutaneous melanoma, sentinel node biopsy significantly prolonged disease-free survival for all patients and improved melanoma-specific survival rates for patients with nodal metastases from intermediate-thickness melanomas (1.2–3.5 mm).¹ However, it remains an imperfect procedure, and a percentage of patients develop recurrence or metastasis despite a negative biopsy. In a recent study by Jones et al,² 16% of melanoma patients in a cohort with a negative sentinel node biopsy developed recurrence.² In these unfortunate patients, medications such as CTLA-4 inhibitors and PD-1 inhibitors now offer hope for prolonged survival.

In Reply: Thank you for your important question. Examination of the excision specimen of the patient’s primary cutaneous melanoma lesion demonstrated a Breslow depth of 1.92 mm. He did indeed undergo sentinel lymph node biopsy at the time of excision. Histologic examination of the biopsy specimen was negative for evidence of metastatic melanoma. Despite this, he obviously developed metastatic disease several years later.

As you allude to, sentinel lymph node biopsy is an important minimally invasive procedure in patients with melanoma. Morton et al¹ compared it with nodal observation and found that in patients with at least intermediate-thickness cutaneous melanoma, sentinel node biopsy significantly prolonged disease-free survival for all patients and improved melanoma-specific survival rates for patients with nodal metastases from intermediate-thickness melanomas (1.2–3.5 mm).¹ However, it remains an imperfect procedure, and a percentage of patients develop recurrence or metastasis despite a negative biopsy. In a recent study by Jones et al,² 16% of melanoma patients in a cohort with a negative sentinel node biopsy developed recurrence.² In these unfortunate patients, medications such as CTLA-4 inhibitors and PD-1 inhibitors now offer hope for prolonged survival.

In Reply: Thank you for your important question. Examination of the excision specimen of the patient’s primary cutaneous melanoma lesion demonstrated a Breslow depth of 1.92 mm. He did indeed undergo sentinel lymph node biopsy at the time of excision. Histologic examination of the biopsy specimen was negative for evidence of metastatic melanoma. Despite this, he obviously developed metastatic disease several years later.

As you allude to, sentinel lymph node biopsy is an important minimally invasive procedure in patients with melanoma. Morton et al¹ compared it with nodal observation and found that in patients with at least intermediate-thickness cutaneous melanoma, sentinel node biopsy significantly prolonged disease-free survival for all patients and improved melanoma-specific survival rates for patients with nodal metastases from intermediate-thickness melanomas (1.2–3.5 mm).¹ However, it remains an imperfect procedure, and a percentage of patients develop recurrence or metastasis despite a negative biopsy. In a recent study by Jones et al,² 16% of melanoma patients in a cohort with a negative sentinel node biopsy developed recurrence.² In these unfortunate patients, medications such as CTLA-4 inhibitors and PD-1 inhibitors now offer hope for prolonged survival.

Children are not the only people affected by attention-deficit/hyperactivity disorder (ADHD). Characterized by high levels of inattention, overactivity, and impulsivity, ADHD affects 5% of school-aged children, but also 4% of adults.^1–3 Adults with untreated ADHD are likely to develop serious psychosocial problems that manifest as unemployment, arrests, divorce, underachievement, and psychiatric comorbidities.^4,5

However, many clinicians are reluctant to manage adults with ADHD, partly because of concerns about misuse of the stimulant drugs they must prescribe to treat it.

Here, we outline an approach whereby clinicians can diagnose and treat adult ADHD while taking “universal precautions” to discourage misuse of the medications involved.

RECOGNIZING ADHD IN ADULTS

ADHD is characterized by developmentally inappropriate levels of inattention, impulsiveness, and hyperactivity that arise in childhood and result in impairments that often persist.

The presentation of ADHD in adults may be influenced by the longevity of their ADHD, associated sequelae (eg, low self-esteem and interpersonal, educational, and occupational difficulties), and comorbid disorders.⁶ There are neither reliable biomarkers nor neuropsychological tests for diagnosis, and persons with ADHD typically have a complex presentation with at least one comorbidity.^6,7

In patients diagnosed in childhood, difficulties with organization as well as initiating, maintaining, and completing tasks become more prominent in adulthood and hyperactivity tends to subside. Adult impulsivity may present as edginess, shopping sprees, quitting jobs, and risky behaviors.⁶

Overall, the clinical manifestations of ADHD in adolescents and adults include inattention, difficulties with task completion, disorganization, and executive dysfunction—all skills critical to managing the various roles of adult life.

OBSTACLES TO EFFECTIVE TREATMENT

In the past, ADHD treatment was routinely discontinued during adolescence, as it was unclear whether adults still had significant symptoms or benefited from treatment.^8,9 Now, available ADHD guidelines suggest that children and adults who respond to pharmacotherapy should continue it for as long as it remains effective. In this context, there is increasing recognition of adult ADHD as a valid and treatable disorder.¹⁰

Adults with ADHD tend to lack critical skills to manage the various roles of adult life

One of the challenges clinicians face is the reliability of adult recall of childhood ADHD. A controlled, prospective 16-year follow-up study found that of all adults retrospectively given a diagnosis of childhood ADHD, only 27% actually had the disorder.¹¹ This study suggests that retrospective diagnoses of childhood ADHD made solely on the basis of self-reports are unlikely to be valid.

Another obstacle is that traditional medical education has seldom included training in adult ADHD.^8,12 In a UK study, clinicians felt that they lacked training and knowledge to assess and manage adult ADHD patients.⁹

Even if adult ADHD is recognized, diagnosis is just the first step of care.¹³ These patients require ongoing management and follow-up assessments.

Although practice patterns vary, efforts to encourage doctors to provide adult ADHD care may be hindered by the fact that the gold standard of treatment is stimulant medication.^4,10 Medications approved by the US Food and Drug Administration for adult ADHD include the stimulants lisdexamfetamine, osmotic-release methylphenidate, mixed amphetamine salts extended release, dexmethylphenidate extended release, and the nonstimulant atomoxetine.⁶ While stimulants are generally more efficacious for ADHD symptoms than nonstimulants, they are associated with misuse and diversion.¹⁴

UNIVERSAL PRECAUTIONS: A SIMPLIFIED APPROACH

The universal-precautions approach to prescribing stimulants aims to allay physician concerns and promote appropriate medication use to allow for proper management of this disorder.¹⁵ These precautions, to be applied to all adult ADHD patients for whom stimulants are being considered, include careful diagnosis and consideration of comorbidities, baseline risk stratification, informed consent processes, treatment agreements, periodic reassessments of treatment response, and meticulous documentation.

DIAGNOSIS

A frequently used screening assessment for adult ADHD is the ADHD Rating Scale (ADHD RS), which consists of two subscales for assessing hyperactivity/impulsivity and inattentiveness.¹⁶ ADHD can be classified into one of three subtypes based on symptoms: inattentive, hyperactive, or combined type. Symptoms must persist for at least 6 months for a diagnosis to be made. Other ADHD scales include the Conners Adult ADHD Rating Scales and the Brown Attention-Deficit Disorder Scales.⁴

High scores on screening scales must be interpreted within the clinical context. Clinicians need to ask about ADHD symptoms, establish their presence in various settings, and determine if these symptoms interfere with functioning. A diagnosis of adult ADHD also requires evidence of symptoms beginning in childhood.¹⁷ According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, inattentive or hyperactive-impulsive symptoms must be present before age 12 in two or more settings and interfere with function and development.

Although self-reporting screening tools are helpful, these tests are not reliable for diagnostic purposes, and collateral information is also required.

Neuropsychological testing may detect impairments in persons with ADHD. The most consistently employed neuropsychological tests to evaluate ADHD include the Conners Continuous Performance Test, Stroop Color and Word Test, Trail-making Test, verbal fluency tests, Controlled Oral Word Association Test, and the Weschler Adult Intelligence Scale.⁶

COMORBIDITY

Epidemiologic studies suggest that adults with ADHD develop many psychiatric problems including anxiety, depression, and substance use disorders.^7,16 Table 1 illustrates common comorbidities and their associated prevalence in the ADHD patient.⁷

Comorbid psychiatric disorders may affect the presentation of adult ADHD. For instance, adults with comorbid depression and ADHD are more likely to present with heightened irritability and difficulties concentrating on tasks than those with either condition alone.¹⁸ Similarly, antisocial personality disorder is more common in adults with ADHD.¹⁹ Such patients exhibit stable antisocial behavior (lying, stealing, and aggression) as well as medication misuse.^5,14,19

While these comorbid disorders may obscure the ADHD diagnosis, their recognition is essential to effectively manage adult ADHD. In sum, a careful evaluation of the adult, including elucidating both ADHD and comorbid symptoms, functionality in several domains, and the degree of impairment, should precede initiating pharmacotherapy for adult ADHD.

BASELINE RISK STRATIFICATION: RISK FACTORS FOR STIMULANT MISUSE

After diagnosing ADHD, the prescriber must assess the risk for misuse of stimulant medications.²⁰

One study revealed that nonmedical use of stimulant medications occurred in only 2% of the 4,300 people surveyed.²¹ Among the misusers, 66% had obtained medication from family or friends. Another 34% had stolen medication, and 20% had obtained prescriptions from a physician by falsely reporting symptoms. The study also assessed motivation for misuse. In this sample, 40% of misuse was to enhance performance, 34% was for recreation, and 23% was to stay awake.²¹

Other studies show that misuse of stimulant medications is common among youth in the United States, reporting that 18% of college students use some formulation of prescription stimulants.²²

Still more research suggests that childhood conduct disorder or illicit drug use results in a higher risk of stimulant medication misuse.²⁰ Additional risk factors for misuse include male sex, white ethnicity, upper-class background, Jewish or no religious affiliation, affiliation with a sorority or fraternity, off-campus housing, and a low grade-point average.²³

Table 2 illustrates clinical interventions providers can use, once they have risk-stratified their patients, to monitor for stimulant misuse.

HOW SHOULD THESE RISK FACTORS AFFECT TREATMENT?

Although no formal scoring system exists to help clinicians risk-stratify these patients, the presence of multiple risk factors suggests the need for vigilance.¹⁴ Physicians should prescribe agents with less potential for abuse and monitor these patients more intensely.

Short-acting stimulant medications are the most likely to be abused, as phasic dopamine increase is more reinforcing than therapeutic dopamine release.²⁴ Longer-acting stimulant medications are less likely to be abused, and they provide better symptom relief, as tonic dopamine release maintains a steady state and increases the therapeutic efficacy of these medications.²⁵ For example, methylphenidate extended-release tablets have an osmotic oral controlled-release system and are less likely to be crushed for recreational inhalation.^6,14

Lisdexamfetamine is a prodrug therapeutically inert until converted to d-amphetamine when lysine is cleaved from the molecule. This medication may be a good option for patients at high risk of misuse because it is tamper-resistant. However, it still may be subject to misuse for performance enhancement.^26,27

The nonstimulant atomoxetine is also approved for ADHD, has no abuse potential, and may be particularly useful when anxiety, mood, and substance use disorders co-occur with ADHD.⁶ Rarely, atomoxetine can damage the liver, and liver function tests should be monitored if right upper quadrant pain develops.^4,10

Other nonapproved agents such as bupropion and desipramine also have been used empirically and off-label for ADHD.^4,10

Overall, treatment should be selected according to the risk of misuse of stimulant medication and the patient’s comorbidities.

INFORMED CONSENT

Informed consent may help patients appreciate the risks and benefits of the treatment options and develop realistic expectations about treatment.²⁶ Patients are instructed to take their stimulant medications as prescribed and are informed of the risks of combining stimulants with other substances, particularly those that may interact with stimulants (eg, cocaine) and raise the risk of seizures and cardiovascular complications.

Stimulant medications lead to elevations in blood pressure and heart rate, although  large-scale studies have shown no increase in the rate of serious cardiovascular events when these drugs are used appropriately.⁶ Less serious side effects associated with stimulant medications include insomnia, weight loss, decreased appetite, dry mouth, headache, and rarely, depression and anxiety.⁶

Patients need to be warned about diversion and abuse liability of stimulant medications, as well as alternative treatments.

The nonstimulant atomoxetine has no reinforcing properties but also raises the blood pressure and heart rate.⁶ As with stimulants, these elevations are generally minimal, time-limited, and of minor clinical significance.^4,10 Frequent reasons to prescribe atomoxetine include poor tolerability of stimulants and a history of substance abuse. In addition, women with ADHD and high levels of emotional dysregulation or social anxiety appear to be particularly responsive to atomoxetine.⁶

Another consideration is cognitive behavioral therapy, which can augment the effects of pharmacotherapy.⁴ Cognitive behavioral therapy focuses on time management, prioritization, organization, problem-solving, motivation, and emotional regulation.⁴

Finally, patients also need to understand the possible consequences of nontreatment.⁵ Adults with untreated ADHD have high rates of academic and occupational difficulties, anti-social behaviors, and other forms of psychosocial adversity.^4,5

Overall, this process should involve discussing risks and benefits of treatment options with the patient and promoting joint decision-making.

TREATMENT AGREEMENTS

Stimulant medications are classified by the US Drug Enforcement Administration as schedule II substances due to their abuse potential.²⁰

It is important to inform patients of the addictive nature of the medication and to instruct them on how to store stimulants safely.²⁷ Patients need to know that giving away or selling these medications is illegal.²⁷

After diagnosing adult ADHD, assess the risk for misuse of stimulant medications

Treatment agreements establish rules for prescribing and are signed by the patient before initiating therapy.^28,29 Patients are expected to attend all of their appointments, receive their prescriptions from one doctor, and obtain their medication from one pharmacy. These agreements may also require patients to submit to monitoring with random urine drug screens.²⁹ Overall, they underscore the need for patients to follow a treatment plan in order to continue therapy with controlled substances.²⁹

Manning²⁷ recommends using agreements for high-risk college students prescribed stimulant medications. Red flags for misuse include signs of active substance use (eg, intoxication, a pattern of “lost” prescriptions, and doctor-shopping).²⁷

The effectiveness in reducing risk of misuse in the adult ADHD population has not yet been investigated. Nonetheless, a method of communicating the seriousness of stimulant misuse to adult patients is essential to ADHD care.

STAYING ON TRACK

In the clinical setting, treatment response is measured not just by symptom reduction, but also by functional improvement. Thus, clinicians and patients must set functional goals whenever possible.²⁷ Successful progress toward these goals justifies continuation of therapy, whereas lack of improvement signals the need to reconsider stimulant therapy.²⁷

MONITORING AND DOCUMENTATION

Adults with ADHD present with varying levels of functional impairment and comorbidities, which may require different levels of monitoring.³⁰ Not all patients with ADHD respond optimally to stimulant medications or tolerate them well.^31,32 Hence, monitoring parameters for therapeutic change and adverse outcomes are important in that they guide the alteration or even discontinuation of pharmacotherapy.^4,6,14

Documenting the decision-making process to continue stimulant medications under certain circumstances is also essential. Documentation should include discussion of goals and expectations, risks and benefits, and alternatives to stimulant use.

In adults, risk of stimulant medication misuse adds a new layer of complexity to monitoring.^13,14 Adults may get multiple prescriptions from multiple providers, seek early refills, fill prescriptions at different pharmacies, or alter formulations. Many states track stimulant prescription use, and prescribers can use this information to determine if patients are refilling their prescriptions appropriately or obtaining stimulants from more than one provider.

Although these monitoring strategies are useful,⁶ it is prudent to structure the level of monitoring according to the patient’s risk of adverse events or medication misuse.^14,27 Gourlay and Heit¹⁵ proposed the following “four-A” mnemonic for four domains to be explored at each visit in patients receiving pain medicine. This mnemonic can be applied to adult ADHD patients to more accurately monitor the patient throughout treatment.

THE ‘FOUR-A’ MNEMONIC

ADHD symptoms

Several ADHD scales can be used to track symptom changes over time.³³ However, these self-report scales may be subject to positive illusory bias, a phenomenon observed in individuals with ADHD in which they tend to overrate their functioning,³⁴ which may limit the accuracy of self-report scales.³⁵

Activities of daily living

Since patients with ADHD tend to overrate their functioning in various aspects of living, collateral information should be gathered to corroborate patient self-reports whenever possible.

Adverse events

Blood pressure, heart rate, and weight should be assessed at baseline and monitored during stimulant treatment. Other symptoms to monitor include gastrointestinal distress, headache, aggression, depression, appetite, and sleeping habits.^4,6 More intensive monitoring (eg, electrocardiography) may be indicated for those with hypertension and cardiovascular risk factors.

Aberrant behavior

Monitoring for misuse and diversion of stimulant medications is essential, as ADHD itself is a risk factor for addiction.^20,21 Pill counts, prescription monitoring programs, urine drug screens, and collateral informants have all been proposed but not studied in monitoring for the misuse of stimulant medications.²⁷ Before prescribing, it is prudent to check the prescription monitoring program, get a urine drug screen, and discuss any positive findings with the patient.^36,37

Short-acting stimulant medications are the most likely to be abused

Treatment agreements ensure that patients are aware of the consequences of misuse and allow the clinician to reference prior discussion when terminating treatment with stimulants.

LIVES CAN BE ENHANCED

ADHD is a common disorder that arises in childhood and can persist throughout life. Adults with untreated ADHD are at risk of severe impairments in various domains of functioning. Stimulant medications are an effective treatment but may be diverted into the street market. Using the universal-precautions model may reduce the risks of both nontreatment of ADHD and misuse of stimulants.

Accordingly, clinicians need to confirm the ADHD diagnosis, assess comorbidities, estimate risk of misuse, and provide informed consent prior to prescribing. Subsequent monitoring should involve the use of treatment agreements and evaluating treatment response, paying particular attention to ADHD symptom control but also to level of function, adverse effects, and aberrant behavior.

With these principles in mind, clinicians can address the risks of misuse and potentially enhance the lives of people who may have been suffering substantially due to lack of appropriate care.

Children are not the only people affected by attention-deficit/hyperactivity disorder (ADHD). Characterized by high levels of inattention, overactivity, and impulsivity, ADHD affects 5% of school-aged children, but also 4% of adults.^1–3 Adults with untreated ADHD are likely to develop serious psychosocial problems that manifest as unemployment, arrests, divorce, underachievement, and psychiatric comorbidities.^4,5

However, many clinicians are reluctant to manage adults with ADHD, partly because of concerns about misuse of the stimulant drugs they must prescribe to treat it.

Here, we outline an approach whereby clinicians can diagnose and treat adult ADHD while taking “universal precautions” to discourage misuse of the medications involved.

RECOGNIZING ADHD IN ADULTS

ADHD is characterized by developmentally inappropriate levels of inattention, impulsiveness, and hyperactivity that arise in childhood and result in impairments that often persist.

The presentation of ADHD in adults may be influenced by the longevity of their ADHD, associated sequelae (eg, low self-esteem and interpersonal, educational, and occupational difficulties), and comorbid disorders.⁶ There are neither reliable biomarkers nor neuropsychological tests for diagnosis, and persons with ADHD typically have a complex presentation with at least one comorbidity.^6,7

In patients diagnosed in childhood, difficulties with organization as well as initiating, maintaining, and completing tasks become more prominent in adulthood and hyperactivity tends to subside. Adult impulsivity may present as edginess, shopping sprees, quitting jobs, and risky behaviors.⁶

Overall, the clinical manifestations of ADHD in adolescents and adults include inattention, difficulties with task completion, disorganization, and executive dysfunction—all skills critical to managing the various roles of adult life.

OBSTACLES TO EFFECTIVE TREATMENT

In the past, ADHD treatment was routinely discontinued during adolescence, as it was unclear whether adults still had significant symptoms or benefited from treatment.^8,9 Now, available ADHD guidelines suggest that children and adults who respond to pharmacotherapy should continue it for as long as it remains effective. In this context, there is increasing recognition of adult ADHD as a valid and treatable disorder.¹⁰

Adults with ADHD tend to lack critical skills to manage the various roles of adult life

One of the challenges clinicians face is the reliability of adult recall of childhood ADHD. A controlled, prospective 16-year follow-up study found that of all adults retrospectively given a diagnosis of childhood ADHD, only 27% actually had the disorder.¹¹ This study suggests that retrospective diagnoses of childhood ADHD made solely on the basis of self-reports are unlikely to be valid.

Another obstacle is that traditional medical education has seldom included training in adult ADHD.^8,12 In a UK study, clinicians felt that they lacked training and knowledge to assess and manage adult ADHD patients.⁹

Even if adult ADHD is recognized, diagnosis is just the first step of care.¹³ These patients require ongoing management and follow-up assessments.

Although practice patterns vary, efforts to encourage doctors to provide adult ADHD care may be hindered by the fact that the gold standard of treatment is stimulant medication.^4,10 Medications approved by the US Food and Drug Administration for adult ADHD include the stimulants lisdexamfetamine, osmotic-release methylphenidate, mixed amphetamine salts extended release, dexmethylphenidate extended release, and the nonstimulant atomoxetine.⁶ While stimulants are generally more efficacious for ADHD symptoms than nonstimulants, they are associated with misuse and diversion.¹⁴

UNIVERSAL PRECAUTIONS: A SIMPLIFIED APPROACH

The universal-precautions approach to prescribing stimulants aims to allay physician concerns and promote appropriate medication use to allow for proper management of this disorder.¹⁵ These precautions, to be applied to all adult ADHD patients for whom stimulants are being considered, include careful diagnosis and consideration of comorbidities, baseline risk stratification, informed consent processes, treatment agreements, periodic reassessments of treatment response, and meticulous documentation.

DIAGNOSIS

A frequently used screening assessment for adult ADHD is the ADHD Rating Scale (ADHD RS), which consists of two subscales for assessing hyperactivity/impulsivity and inattentiveness.¹⁶ ADHD can be classified into one of three subtypes based on symptoms: inattentive, hyperactive, or combined type. Symptoms must persist for at least 6 months for a diagnosis to be made. Other ADHD scales include the Conners Adult ADHD Rating Scales and the Brown Attention-Deficit Disorder Scales.⁴

High scores on screening scales must be interpreted within the clinical context. Clinicians need to ask about ADHD symptoms, establish their presence in various settings, and determine if these symptoms interfere with functioning. A diagnosis of adult ADHD also requires evidence of symptoms beginning in childhood.¹⁷ According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, inattentive or hyperactive-impulsive symptoms must be present before age 12 in two or more settings and interfere with function and development.

Although self-reporting screening tools are helpful, these tests are not reliable for diagnostic purposes, and collateral information is also required.

Neuropsychological testing may detect impairments in persons with ADHD. The most consistently employed neuropsychological tests to evaluate ADHD include the Conners Continuous Performance Test, Stroop Color and Word Test, Trail-making Test, verbal fluency tests, Controlled Oral Word Association Test, and the Weschler Adult Intelligence Scale.⁶

COMORBIDITY

Epidemiologic studies suggest that adults with ADHD develop many psychiatric problems including anxiety, depression, and substance use disorders.^7,16 Table 1 illustrates common comorbidities and their associated prevalence in the ADHD patient.⁷

Comorbid psychiatric disorders may affect the presentation of adult ADHD. For instance, adults with comorbid depression and ADHD are more likely to present with heightened irritability and difficulties concentrating on tasks than those with either condition alone.¹⁸ Similarly, antisocial personality disorder is more common in adults with ADHD.¹⁹ Such patients exhibit stable antisocial behavior (lying, stealing, and aggression) as well as medication misuse.^5,14,19

While these comorbid disorders may obscure the ADHD diagnosis, their recognition is essential to effectively manage adult ADHD. In sum, a careful evaluation of the adult, including elucidating both ADHD and comorbid symptoms, functionality in several domains, and the degree of impairment, should precede initiating pharmacotherapy for adult ADHD.

BASELINE RISK STRATIFICATION: RISK FACTORS FOR STIMULANT MISUSE

After diagnosing ADHD, the prescriber must assess the risk for misuse of stimulant medications.²⁰

One study revealed that nonmedical use of stimulant medications occurred in only 2% of the 4,300 people surveyed.²¹ Among the misusers, 66% had obtained medication from family or friends. Another 34% had stolen medication, and 20% had obtained prescriptions from a physician by falsely reporting symptoms. The study also assessed motivation for misuse. In this sample, 40% of misuse was to enhance performance, 34% was for recreation, and 23% was to stay awake.²¹

Other studies show that misuse of stimulant medications is common among youth in the United States, reporting that 18% of college students use some formulation of prescription stimulants.²²

Still more research suggests that childhood conduct disorder or illicit drug use results in a higher risk of stimulant medication misuse.²⁰ Additional risk factors for misuse include male sex, white ethnicity, upper-class background, Jewish or no religious affiliation, affiliation with a sorority or fraternity, off-campus housing, and a low grade-point average.²³

Table 2 illustrates clinical interventions providers can use, once they have risk-stratified their patients, to monitor for stimulant misuse.

HOW SHOULD THESE RISK FACTORS AFFECT TREATMENT?

Although no formal scoring system exists to help clinicians risk-stratify these patients, the presence of multiple risk factors suggests the need for vigilance.¹⁴ Physicians should prescribe agents with less potential for abuse and monitor these patients more intensely.

Short-acting stimulant medications are the most likely to be abused, as phasic dopamine increase is more reinforcing than therapeutic dopamine release.²⁴ Longer-acting stimulant medications are less likely to be abused, and they provide better symptom relief, as tonic dopamine release maintains a steady state and increases the therapeutic efficacy of these medications.²⁵ For example, methylphenidate extended-release tablets have an osmotic oral controlled-release system and are less likely to be crushed for recreational inhalation.^6,14

Lisdexamfetamine is a prodrug therapeutically inert until converted to d-amphetamine when lysine is cleaved from the molecule. This medication may be a good option for patients at high risk of misuse because it is tamper-resistant. However, it still may be subject to misuse for performance enhancement.^26,27

The nonstimulant atomoxetine is also approved for ADHD, has no abuse potential, and may be particularly useful when anxiety, mood, and substance use disorders co-occur with ADHD.⁶ Rarely, atomoxetine can damage the liver, and liver function tests should be monitored if right upper quadrant pain develops.^4,10

Other nonapproved agents such as bupropion and desipramine also have been used empirically and off-label for ADHD.^4,10

Overall, treatment should be selected according to the risk of misuse of stimulant medication and the patient’s comorbidities.

INFORMED CONSENT

Informed consent may help patients appreciate the risks and benefits of the treatment options and develop realistic expectations about treatment.²⁶ Patients are instructed to take their stimulant medications as prescribed and are informed of the risks of combining stimulants with other substances, particularly those that may interact with stimulants (eg, cocaine) and raise the risk of seizures and cardiovascular complications.

Stimulant medications lead to elevations in blood pressure and heart rate, although  large-scale studies have shown no increase in the rate of serious cardiovascular events when these drugs are used appropriately.⁶ Less serious side effects associated with stimulant medications include insomnia, weight loss, decreased appetite, dry mouth, headache, and rarely, depression and anxiety.⁶

Patients need to be warned about diversion and abuse liability of stimulant medications, as well as alternative treatments.

The nonstimulant atomoxetine has no reinforcing properties but also raises the blood pressure and heart rate.⁶ As with stimulants, these elevations are generally minimal, time-limited, and of minor clinical significance.^4,10 Frequent reasons to prescribe atomoxetine include poor tolerability of stimulants and a history of substance abuse. In addition, women with ADHD and high levels of emotional dysregulation or social anxiety appear to be particularly responsive to atomoxetine.⁶

Another consideration is cognitive behavioral therapy, which can augment the effects of pharmacotherapy.⁴ Cognitive behavioral therapy focuses on time management, prioritization, organization, problem-solving, motivation, and emotional regulation.⁴

Finally, patients also need to understand the possible consequences of nontreatment.⁵ Adults with untreated ADHD have high rates of academic and occupational difficulties, anti-social behaviors, and other forms of psychosocial adversity.^4,5

Overall, this process should involve discussing risks and benefits of treatment options with the patient and promoting joint decision-making.

TREATMENT AGREEMENTS

Stimulant medications are classified by the US Drug Enforcement Administration as schedule II substances due to their abuse potential.²⁰

It is important to inform patients of the addictive nature of the medication and to instruct them on how to store stimulants safely.²⁷ Patients need to know that giving away or selling these medications is illegal.²⁷

After diagnosing adult ADHD, assess the risk for misuse of stimulant medications

Treatment agreements establish rules for prescribing and are signed by the patient before initiating therapy.^28,29 Patients are expected to attend all of their appointments, receive their prescriptions from one doctor, and obtain their medication from one pharmacy. These agreements may also require patients to submit to monitoring with random urine drug screens.²⁹ Overall, they underscore the need for patients to follow a treatment plan in order to continue therapy with controlled substances.²⁹

Manning²⁷ recommends using agreements for high-risk college students prescribed stimulant medications. Red flags for misuse include signs of active substance use (eg, intoxication, a pattern of “lost” prescriptions, and doctor-shopping).²⁷

The effectiveness in reducing risk of misuse in the adult ADHD population has not yet been investigated. Nonetheless, a method of communicating the seriousness of stimulant misuse to adult patients is essential to ADHD care.

STAYING ON TRACK

In the clinical setting, treatment response is measured not just by symptom reduction, but also by functional improvement. Thus, clinicians and patients must set functional goals whenever possible.²⁷ Successful progress toward these goals justifies continuation of therapy, whereas lack of improvement signals the need to reconsider stimulant therapy.²⁷

MONITORING AND DOCUMENTATION

Adults with ADHD present with varying levels of functional impairment and comorbidities, which may require different levels of monitoring.³⁰ Not all patients with ADHD respond optimally to stimulant medications or tolerate them well.^31,32 Hence, monitoring parameters for therapeutic change and adverse outcomes are important in that they guide the alteration or even discontinuation of pharmacotherapy.^4,6,14

Documenting the decision-making process to continue stimulant medications under certain circumstances is also essential. Documentation should include discussion of goals and expectations, risks and benefits, and alternatives to stimulant use.

In adults, risk of stimulant medication misuse adds a new layer of complexity to monitoring.^13,14 Adults may get multiple prescriptions from multiple providers, seek early refills, fill prescriptions at different pharmacies, or alter formulations. Many states track stimulant prescription use, and prescribers can use this information to determine if patients are refilling their prescriptions appropriately or obtaining stimulants from more than one provider.

Although these monitoring strategies are useful,⁶ it is prudent to structure the level of monitoring according to the patient’s risk of adverse events or medication misuse.^14,27 Gourlay and Heit¹⁵ proposed the following “four-A” mnemonic for four domains to be explored at each visit in patients receiving pain medicine. This mnemonic can be applied to adult ADHD patients to more accurately monitor the patient throughout treatment.

THE ‘FOUR-A’ MNEMONIC

ADHD symptoms

Several ADHD scales can be used to track symptom changes over time.³³ However, these self-report scales may be subject to positive illusory bias, a phenomenon observed in individuals with ADHD in which they tend to overrate their functioning,³⁴ which may limit the accuracy of self-report scales.³⁵

Activities of daily living

Since patients with ADHD tend to overrate their functioning in various aspects of living, collateral information should be gathered to corroborate patient self-reports whenever possible.

Adverse events

Blood pressure, heart rate, and weight should be assessed at baseline and monitored during stimulant treatment. Other symptoms to monitor include gastrointestinal distress, headache, aggression, depression, appetite, and sleeping habits.^4,6 More intensive monitoring (eg, electrocardiography) may be indicated for those with hypertension and cardiovascular risk factors.

Aberrant behavior

Monitoring for misuse and diversion of stimulant medications is essential, as ADHD itself is a risk factor for addiction.^20,21 Pill counts, prescription monitoring programs, urine drug screens, and collateral informants have all been proposed but not studied in monitoring for the misuse of stimulant medications.²⁷ Before prescribing, it is prudent to check the prescription monitoring program, get a urine drug screen, and discuss any positive findings with the patient.^36,37

Short-acting stimulant medications are the most likely to be abused

Treatment agreements ensure that patients are aware of the consequences of misuse and allow the clinician to reference prior discussion when terminating treatment with stimulants.

LIVES CAN BE ENHANCED

ADHD is a common disorder that arises in childhood and can persist throughout life. Adults with untreated ADHD are at risk of severe impairments in various domains of functioning. Stimulant medications are an effective treatment but may be diverted into the street market. Using the universal-precautions model may reduce the risks of both nontreatment of ADHD and misuse of stimulants.

Accordingly, clinicians need to confirm the ADHD diagnosis, assess comorbidities, estimate risk of misuse, and provide informed consent prior to prescribing. Subsequent monitoring should involve the use of treatment agreements and evaluating treatment response, paying particular attention to ADHD symptom control but also to level of function, adverse effects, and aberrant behavior.

With these principles in mind, clinicians can address the risks of misuse and potentially enhance the lives of people who may have been suffering substantially due to lack of appropriate care.

Children are not the only people affected by attention-deficit/hyperactivity disorder (ADHD). Characterized by high levels of inattention, overactivity, and impulsivity, ADHD affects 5% of school-aged children, but also 4% of adults.^1–3 Adults with untreated ADHD are likely to develop serious psychosocial problems that manifest as unemployment, arrests, divorce, underachievement, and psychiatric comorbidities.^4,5

However, many clinicians are reluctant to manage adults with ADHD, partly because of concerns about misuse of the stimulant drugs they must prescribe to treat it.

Here, we outline an approach whereby clinicians can diagnose and treat adult ADHD while taking “universal precautions” to discourage misuse of the medications involved.

RECOGNIZING ADHD IN ADULTS

ADHD is characterized by developmentally inappropriate levels of inattention, impulsiveness, and hyperactivity that arise in childhood and result in impairments that often persist.

The presentation of ADHD in adults may be influenced by the longevity of their ADHD, associated sequelae (eg, low self-esteem and interpersonal, educational, and occupational difficulties), and comorbid disorders.⁶ There are neither reliable biomarkers nor neuropsychological tests for diagnosis, and persons with ADHD typically have a complex presentation with at least one comorbidity.^6,7

In patients diagnosed in childhood, difficulties with organization as well as initiating, maintaining, and completing tasks become more prominent in adulthood and hyperactivity tends to subside. Adult impulsivity may present as edginess, shopping sprees, quitting jobs, and risky behaviors.⁶

Overall, the clinical manifestations of ADHD in adolescents and adults include inattention, difficulties with task completion, disorganization, and executive dysfunction—all skills critical to managing the various roles of adult life.

OBSTACLES TO EFFECTIVE TREATMENT

In the past, ADHD treatment was routinely discontinued during adolescence, as it was unclear whether adults still had significant symptoms or benefited from treatment.^8,9 Now, available ADHD guidelines suggest that children and adults who respond to pharmacotherapy should continue it for as long as it remains effective. In this context, there is increasing recognition of adult ADHD as a valid and treatable disorder.¹⁰

Adults with ADHD tend to lack critical skills to manage the various roles of adult life

One of the challenges clinicians face is the reliability of adult recall of childhood ADHD. A controlled, prospective 16-year follow-up study found that of all adults retrospectively given a diagnosis of childhood ADHD, only 27% actually had the disorder.¹¹ This study suggests that retrospective diagnoses of childhood ADHD made solely on the basis of self-reports are unlikely to be valid.

Another obstacle is that traditional medical education has seldom included training in adult ADHD.^8,12 In a UK study, clinicians felt that they lacked training and knowledge to assess and manage adult ADHD patients.⁹

Even if adult ADHD is recognized, diagnosis is just the first step of care.¹³ These patients require ongoing management and follow-up assessments.

Although practice patterns vary, efforts to encourage doctors to provide adult ADHD care may be hindered by the fact that the gold standard of treatment is stimulant medication.^4,10 Medications approved by the US Food and Drug Administration for adult ADHD include the stimulants lisdexamfetamine, osmotic-release methylphenidate, mixed amphetamine salts extended release, dexmethylphenidate extended release, and the nonstimulant atomoxetine.⁶ While stimulants are generally more efficacious for ADHD symptoms than nonstimulants, they are associated with misuse and diversion.¹⁴

UNIVERSAL PRECAUTIONS: A SIMPLIFIED APPROACH

The universal-precautions approach to prescribing stimulants aims to allay physician concerns and promote appropriate medication use to allow for proper management of this disorder.¹⁵ These precautions, to be applied to all adult ADHD patients for whom stimulants are being considered, include careful diagnosis and consideration of comorbidities, baseline risk stratification, informed consent processes, treatment agreements, periodic reassessments of treatment response, and meticulous documentation.

DIAGNOSIS

A frequently used screening assessment for adult ADHD is the ADHD Rating Scale (ADHD RS), which consists of two subscales for assessing hyperactivity/impulsivity and inattentiveness.¹⁶ ADHD can be classified into one of three subtypes based on symptoms: inattentive, hyperactive, or combined type. Symptoms must persist for at least 6 months for a diagnosis to be made. Other ADHD scales include the Conners Adult ADHD Rating Scales and the Brown Attention-Deficit Disorder Scales.⁴

High scores on screening scales must be interpreted within the clinical context. Clinicians need to ask about ADHD symptoms, establish their presence in various settings, and determine if these symptoms interfere with functioning. A diagnosis of adult ADHD also requires evidence of symptoms beginning in childhood.¹⁷ According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, inattentive or hyperactive-impulsive symptoms must be present before age 12 in two or more settings and interfere with function and development.

Although self-reporting screening tools are helpful, these tests are not reliable for diagnostic purposes, and collateral information is also required.

Neuropsychological testing may detect impairments in persons with ADHD. The most consistently employed neuropsychological tests to evaluate ADHD include the Conners Continuous Performance Test, Stroop Color and Word Test, Trail-making Test, verbal fluency tests, Controlled Oral Word Association Test, and the Weschler Adult Intelligence Scale.⁶

COMORBIDITY

Epidemiologic studies suggest that adults with ADHD develop many psychiatric problems including anxiety, depression, and substance use disorders.^7,16 Table 1 illustrates common comorbidities and their associated prevalence in the ADHD patient.⁷

Comorbid psychiatric disorders may affect the presentation of adult ADHD. For instance, adults with comorbid depression and ADHD are more likely to present with heightened irritability and difficulties concentrating on tasks than those with either condition alone.¹⁸ Similarly, antisocial personality disorder is more common in adults with ADHD.¹⁹ Such patients exhibit stable antisocial behavior (lying, stealing, and aggression) as well as medication misuse.^5,14,19

While these comorbid disorders may obscure the ADHD diagnosis, their recognition is essential to effectively manage adult ADHD. In sum, a careful evaluation of the adult, including elucidating both ADHD and comorbid symptoms, functionality in several domains, and the degree of impairment, should precede initiating pharmacotherapy for adult ADHD.

BASELINE RISK STRATIFICATION: RISK FACTORS FOR STIMULANT MISUSE

After diagnosing ADHD, the prescriber must assess the risk for misuse of stimulant medications.²⁰

One study revealed that nonmedical use of stimulant medications occurred in only 2% of the 4,300 people surveyed.²¹ Among the misusers, 66% had obtained medication from family or friends. Another 34% had stolen medication, and 20% had obtained prescriptions from a physician by falsely reporting symptoms. The study also assessed motivation for misuse. In this sample, 40% of misuse was to enhance performance, 34% was for recreation, and 23% was to stay awake.²¹

Other studies show that misuse of stimulant medications is common among youth in the United States, reporting that 18% of college students use some formulation of prescription stimulants.²²

Still more research suggests that childhood conduct disorder or illicit drug use results in a higher risk of stimulant medication misuse.²⁰ Additional risk factors for misuse include male sex, white ethnicity, upper-class background, Jewish or no religious affiliation, affiliation with a sorority or fraternity, off-campus housing, and a low grade-point average.²³

Table 2 illustrates clinical interventions providers can use, once they have risk-stratified their patients, to monitor for stimulant misuse.

HOW SHOULD THESE RISK FACTORS AFFECT TREATMENT?

Although no formal scoring system exists to help clinicians risk-stratify these patients, the presence of multiple risk factors suggests the need for vigilance.¹⁴ Physicians should prescribe agents with less potential for abuse and monitor these patients more intensely.

Short-acting stimulant medications are the most likely to be abused, as phasic dopamine increase is more reinforcing than therapeutic dopamine release.²⁴ Longer-acting stimulant medications are less likely to be abused, and they provide better symptom relief, as tonic dopamine release maintains a steady state and increases the therapeutic efficacy of these medications.²⁵ For example, methylphenidate extended-release tablets have an osmotic oral controlled-release system and are less likely to be crushed for recreational inhalation.^6,14

Lisdexamfetamine is a prodrug therapeutically inert until converted to d-amphetamine when lysine is cleaved from the molecule. This medication may be a good option for patients at high risk of misuse because it is tamper-resistant. However, it still may be subject to misuse for performance enhancement.^26,27

The nonstimulant atomoxetine is also approved for ADHD, has no abuse potential, and may be particularly useful when anxiety, mood, and substance use disorders co-occur with ADHD.⁶ Rarely, atomoxetine can damage the liver, and liver function tests should be monitored if right upper quadrant pain develops.^4,10

Other nonapproved agents such as bupropion and desipramine also have been used empirically and off-label for ADHD.^4,10

Overall, treatment should be selected according to the risk of misuse of stimulant medication and the patient’s comorbidities.

INFORMED CONSENT

Informed consent may help patients appreciate the risks and benefits of the treatment options and develop realistic expectations about treatment.²⁶ Patients are instructed to take their stimulant medications as prescribed and are informed of the risks of combining stimulants with other substances, particularly those that may interact with stimulants (eg, cocaine) and raise the risk of seizures and cardiovascular complications.

Stimulant medications lead to elevations in blood pressure and heart rate, although  large-scale studies have shown no increase in the rate of serious cardiovascular events when these drugs are used appropriately.⁶ Less serious side effects associated with stimulant medications include insomnia, weight loss, decreased appetite, dry mouth, headache, and rarely, depression and anxiety.⁶

Patients need to be warned about diversion and abuse liability of stimulant medications, as well as alternative treatments.

The nonstimulant atomoxetine has no reinforcing properties but also raises the blood pressure and heart rate.⁶ As with stimulants, these elevations are generally minimal, time-limited, and of minor clinical significance.^4,10 Frequent reasons to prescribe atomoxetine include poor tolerability of stimulants and a history of substance abuse. In addition, women with ADHD and high levels of emotional dysregulation or social anxiety appear to be particularly responsive to atomoxetine.⁶

Another consideration is cognitive behavioral therapy, which can augment the effects of pharmacotherapy.⁴ Cognitive behavioral therapy focuses on time management, prioritization, organization, problem-solving, motivation, and emotional regulation.⁴

Finally, patients also need to understand the possible consequences of nontreatment.⁵ Adults with untreated ADHD have high rates of academic and occupational difficulties, anti-social behaviors, and other forms of psychosocial adversity.^4,5

Overall, this process should involve discussing risks and benefits of treatment options with the patient and promoting joint decision-making.

TREATMENT AGREEMENTS

Stimulant medications are classified by the US Drug Enforcement Administration as schedule II substances due to their abuse potential.²⁰

It is important to inform patients of the addictive nature of the medication and to instruct them on how to store stimulants safely.²⁷ Patients need to know that giving away or selling these medications is illegal.²⁷

After diagnosing adult ADHD, assess the risk for misuse of stimulant medications

Treatment agreements establish rules for prescribing and are signed by the patient before initiating therapy.^28,29 Patients are expected to attend all of their appointments, receive their prescriptions from one doctor, and obtain their medication from one pharmacy. These agreements may also require patients to submit to monitoring with random urine drug screens.²⁹ Overall, they underscore the need for patients to follow a treatment plan in order to continue therapy with controlled substances.²⁹

Manning²⁷ recommends using agreements for high-risk college students prescribed stimulant medications. Red flags for misuse include signs of active substance use (eg, intoxication, a pattern of “lost” prescriptions, and doctor-shopping).²⁷

The effectiveness in reducing risk of misuse in the adult ADHD population has not yet been investigated. Nonetheless, a method of communicating the seriousness of stimulant misuse to adult patients is essential to ADHD care.

STAYING ON TRACK

In the clinical setting, treatment response is measured not just by symptom reduction, but also by functional improvement. Thus, clinicians and patients must set functional goals whenever possible.²⁷ Successful progress toward these goals justifies continuation of therapy, whereas lack of improvement signals the need to reconsider stimulant therapy.²⁷

MONITORING AND DOCUMENTATION

Adults with ADHD present with varying levels of functional impairment and comorbidities, which may require different levels of monitoring.³⁰ Not all patients with ADHD respond optimally to stimulant medications or tolerate them well.^31,32 Hence, monitoring parameters for therapeutic change and adverse outcomes are important in that they guide the alteration or even discontinuation of pharmacotherapy.^4,6,14

Documenting the decision-making process to continue stimulant medications under certain circumstances is also essential. Documentation should include discussion of goals and expectations, risks and benefits, and alternatives to stimulant use.

In adults, risk of stimulant medication misuse adds a new layer of complexity to monitoring.^13,14 Adults may get multiple prescriptions from multiple providers, seek early refills, fill prescriptions at different pharmacies, or alter formulations. Many states track stimulant prescription use, and prescribers can use this information to determine if patients are refilling their prescriptions appropriately or obtaining stimulants from more than one provider.

Although these monitoring strategies are useful,⁶ it is prudent to structure the level of monitoring according to the patient’s risk of adverse events or medication misuse.^14,27 Gourlay and Heit¹⁵ proposed the following “four-A” mnemonic for four domains to be explored at each visit in patients receiving pain medicine. This mnemonic can be applied to adult ADHD patients to more accurately monitor the patient throughout treatment.

THE ‘FOUR-A’ MNEMONIC

ADHD symptoms

Several ADHD scales can be used to track symptom changes over time.³³ However, these self-report scales may be subject to positive illusory bias, a phenomenon observed in individuals with ADHD in which they tend to overrate their functioning,³⁴ which may limit the accuracy of self-report scales.³⁵

Activities of daily living

Since patients with ADHD tend to overrate their functioning in various aspects of living, collateral information should be gathered to corroborate patient self-reports whenever possible.

Adverse events

Blood pressure, heart rate, and weight should be assessed at baseline and monitored during stimulant treatment. Other symptoms to monitor include gastrointestinal distress, headache, aggression, depression, appetite, and sleeping habits.^4,6 More intensive monitoring (eg, electrocardiography) may be indicated for those with hypertension and cardiovascular risk factors.

Aberrant behavior

Monitoring for misuse and diversion of stimulant medications is essential, as ADHD itself is a risk factor for addiction.^20,21 Pill counts, prescription monitoring programs, urine drug screens, and collateral informants have all been proposed but not studied in monitoring for the misuse of stimulant medications.²⁷ Before prescribing, it is prudent to check the prescription monitoring program, get a urine drug screen, and discuss any positive findings with the patient.^36,37

Short-acting stimulant medications are the most likely to be abused

Treatment agreements ensure that patients are aware of the consequences of misuse and allow the clinician to reference prior discussion when terminating treatment with stimulants.

LIVES CAN BE ENHANCED

ADHD is a common disorder that arises in childhood and can persist throughout life. Adults with untreated ADHD are at risk of severe impairments in various domains of functioning. Stimulant medications are an effective treatment but may be diverted into the street market. Using the universal-precautions model may reduce the risks of both nontreatment of ADHD and misuse of stimulants.

Accordingly, clinicians need to confirm the ADHD diagnosis, assess comorbidities, estimate risk of misuse, and provide informed consent prior to prescribing. Subsequent monitoring should involve the use of treatment agreements and evaluating treatment response, paying particular attention to ADHD symptom control but also to level of function, adverse effects, and aberrant behavior.

With these principles in mind, clinicians can address the risks of misuse and potentially enhance the lives of people who may have been suffering substantially due to lack of appropriate care.

Wounds that fail to heal become more than mere skin lesions. Pain, malodor, and the accompanying psychological distress often complicate nonhealing wounds and impair quality of life.¹ Management of malodor requires perseverance, sensitivity, and familiarity with tools and procedures that range from surgical debridement to medical-grade honey.

Chronic, nonhealing wounds are defined as persisting for more than 6 months.² These lesions are incapable of undergoing anatomic and functional repair on their own. Commonly encountered nonhealing wounds include pressure ulcers, venous stasis ulcers, arterial insufficiency ulcers, and malignant cutaneous wounds.

Typically, the patient with a nonhealing wound is frail, debilitated, medically complex, and often faced with one or more life-limiting illnesses. Complete wound healing may therefore be unrealistic, and optimal wound management becomes the goal of care.^3,4

Healthcare providers encounter nonhealing wounds in varied settings—acute inpatient, outpatient, long-term, and home care. For instance, in the home care setting, a study of 383 patients enrolled in hospice found that 35% had skin ulcers and wounds.³ Half of those affected had pressure ulcers, 20% had ischemic ulcers, and 30% had other skin disorders such as stasis ulcers, burns, skin tears, and tumors. A larger study, also in hospice patients, found that 26% had pressure ulcers and 10% more developed them within 6 months.⁵

While pressure ulcers are the most common nonhealing wounds, malignant or fungating wounds are found in 5% to 10% of patients with metastatic disease, usually with cancers of the breast, head, and neck.⁶

The three major causes of wound malodor are slough, infection, and exudate

Maximizing wound care provides comfort, relieves suffering, and promotes quality of life.^3,7 To achieve these goals, clinicians must be familiar with strategies to manage complications associated with nonhealing wounds such as pain, malodor, and psychosocial adverse effects. Of these complications, malodor has been pointed out by both patients and caregivers as the most distressing.⁸

This article focuses on wound malodor, discusses the processes that cause wounds to emit an offensive smell, and outlines a comprehensive management approach.

MRS. A., AGE 61, WITH STAGE IV BREAST CANCER

Mrs. A., 61 years old, had a fungating mass in her left breast, which began as a small nodule and progressively enlarged to deform her breast over several months. Her oncologist subsequently staged the extent of her cancer as stage IV after workup revealed lung metastasis. Mrs. A. and her family decided to forgo cancer treatment, including radiotherapy, and to transition to hospice care after discussions with the oncologist.

Mrs. A. lived at home with her husband. Her daughter and three grandchildren all lived nearby.

When her hospice physician arrived at her home to meet her, a strong, pungent, and nauseating smell greeted him as he entered her bedroom. The patient said that for the past few months she had been increasingly distressed by the revolting odor. She rarely left home and had been ashamed to have people visit her, including her family.

On examination, the physician noticed a large fungating mass with yellowish discharge and necrotic tissue in her left breast. In addition to mild pain, she was immensely bothered by the strong odor coming from her breast.

THE IMPACT OF MALODOR

As seen in the case of Mrs. A., malodor has grave effects, both physical and psychological. Patients experience impaired or socially unacceptable body image, social rejection, personal shame, and embarrassment.^9,10 Feelings of fear, anxiety, and depression are common. If left uncontrolled, malodor results in social isolation, reluctance to engage in social activities, diminished appetite, and nausea. In addition, malodor is a constant reminder of patients’ pain and cancer, and it results in further suffering.¹¹

Reactions of family members and caregivers can worsen the situation.^9,12 Expressions of revulsion limit contact and inhibit intimacy, especially near the end of life. Caregivers are often frustrated and distressed over their inability to control the malodor. The environment becomes uninhabitable, and the malodor can permeate clothing, furniture, and living quarters.

Managing malodor can be emotionally draining, physically daunting, and frustrating for healthcare professionals, as several methods are usually employed, often in a trial-and-error approach, to achieve an acceptable degree of odor control. In addition, clinicians must face the challenge of treating malodorous wounds at very close distance without reacting in a way that offends or alarms patients and family members.¹³

MALODOR PRODUCTION: WHERE IS THAT SMELL COMING FROM?

All wounds can produce an odor.¹⁴ Wounds that are expected to heal typically emit a faint but not unpleasant odor, akin to fresh blood. Wounds colonized by Pseudomonas aeruginosa produce a fruity or grapelike odor that is tolerable. Malodor occurs with wounds infected by other gram-negative organisms or anaerobic bacteria.¹⁵ Similarly, wounds covered by necrotic tissue smell like decaying flesh.

Three major causes

The three major causes of wound malodor are slough, infection, and exudate (Figure 1).

Slough is dead or necrotic tissue, usually resulting from vascular compromise. Arterial ulcers, pressure ulcers, and malignant wounds all form slough from capillary occlusion, subsequent ischemia, and tissue necrosis.

Infection. Devitalized tissue, an ideal medium in which bacteria thrive, becomes the source of infection. Anaerobic bacteria are usually implicated in malodor. These include Bacteroides fragilis, Bacteroides prevotella, Clostridium perfringens, and Fusobacterium nucleatum.^16,17 Anaerobic organisms produce putrescine and cadaverine, which are largely responsible for the offensive odor.^16,18 Volatile fatty acids such as propionic, butyric, isovaleric, and valeric acid are formed from lipid catabolism by anaerobes and add to malodor.¹⁷ Aerobic bacteria such as Proteus, Klebsiella, and Pseudomonas species supercolonize necrotic tissue as well and contribute to malodor.^17,18

Exudate. Since nonhealing wounds undergo repeated cycles of inflammation, infection, and necrosis, accumulation of exudate becomes inevitable. Exudate typically is a pus-like fluid containing serum, fibrin, and white blood cells, which leak from blood vessels. In addition, bacteria that colonize chronic wounds filled with necrotic tissue activate proteases that degrade and liquefy dead tissue, thereby forming extensive amounts of exudate.¹⁹

Apart from slough, infection, and exudate, poor general hygiene and dressings left on for too long may contribute to malodor.¹⁶ Moisture-retentive dressings such as hydrocolloids leave an odor after removal. Dressings that liquefy upon contact with the wound surface leave a pus-like, potentially malodorous material.

MALODOR ASSESSMENT: DO YOU SMELL SOMETHING?

Various ways to document wound malodor can prove useful in guiding assessment and treatment. Descriptions such as “foul,” “putrid,” “fishy,” or “filled the room” vividly portray the initial presentation. A 10-point numerical scale similar to a numerical pain scale or a visual analogue scale can be used as a subjective measure.

Other grading methods, which to the authors’ knowledge are not validated, may be helpful. In a study that focused on patients suffering from malodorous gynecologic malignancies, von Gruenigen et al²⁰ used a 0-to-3 scale:

• 0 Absent
• 1 Not offensive
• 2 Offensive but tolerable
• 3 Offensive and intolerable.

A scale often adapted by other authors was devised by Baker and Haig,²¹ which clearly defines four classes:

• 1 Strong—odor is evident upon entering the room (6 to 10 feet from the patient) with the dressing intact
• 2 Moderate—odor is evident upon entering the room with dressing removed
• 3 Slight—odor is evident at close proximity to the patient when the dressing is removed
• 4 No odor—no odor is evident, even at the patient’s bedside with the dressing removed.

COMPREHENSIVE MANAGEMENT: HOW DO WE WIN THE ‘RACE’?

The acronym RACE outlines an approach to dealing with malodor. It stands for removal of necrotic tissue; antibacterials; odor concealers; and education and support (Table 1).

Remove necrotic tissue

An important step in eliminating malodor is to remove necrotic tissue. This starts with debridement, which decreases the incidence of infection and hastens wound closure.^22,23 Table 2 compares the different types of debridement.

Sharp or surgical debridement involves the use of a scalpel or scissors. This type of debridement may increase the risk of bleeding, pain, and malignant cell seeding in fungating wounds.^4,24

Enzymatic debridement employs chemicals with proteolytic action (eg, collagenase) to digest extracellular proteins in wounds.^18,25

Mechanical debridement involves aggressive therapies such as forceful irrigation and hydrotherapy, which may fail to discriminate between necrotic and viable tissues.^18,26

Biological debridement using maggots, which ingest bacteria and devitalized tissue, may cause increased wound bleeding and may be unacceptable for patients and families.^24,27

Autolytic debridement is often recommended, particularly if complete healing is not the primary goal.^17,24,28,29 Autolysis uses proteolytic enzymes and phagocytic cells present in the wound bed and wound fluid to clear devitalized tissue. It is easy, inexpensive, noninvasive, and painless,⁴ and it requires less frequent dressing changes relative to standard dressing or wet-to-dry dressing.

Autolytic debridement is commonly accomplished using hydrocolloid and hydrogel dressings.^15,29 Hydrocolloids are adhesive, occlusive, and conformable dressings that are suitable for wounds with low to moderate amounts of exudate. Upon contact with the wound surface, the dressing absorbs the exudate, forms a gel layer, and maintains a moist environment. Hydrocolloids are not recommended for infected wounds or for those with copious exudate as they may lead to maceration around the wound. A disadvantage of hydrocolloid dressings is their tendency to generate brown, often malodorous exudate when removed.

On the other hand, hydrogels in amorphous gel, dressing, sheet, or impregnated gauze form are water-based products that create a moist environment similar to hydrocolloids. Aside from causing minimal trauma to the wound bed when removed, the dressing’s cooling effect may bring some pain relief. Hydrogels are appropriate for dry wounds and for those with minimal exudate.

After debridement, the wound is cleansed and irrigated. A number of cleansers and solutions are available, but normal saline is a cheap alternative. To irrigate, experts recommend an 18- or 20-gauge intravenous catheter attached to a 30- or 60-mL syringe.¹⁵ This technique provides 8 to 15 psi of pressure, enough to cleanse the wound without causing tissue trauma.

Antibacterials and absorption

Antibacterials. Topical antibiotics have several advantages over systemic antibiotics in treating chronic wounds.^30,31 These include a high and sustained concentration of the antimicrobial at the site of infection, limited potential for systemic absorption and toxicity, reduced potential for antibiotic resistance, and drawing of the patient’s and caregiver’s attention to the wound.

Metronidazole is the most widely used topical antibacterial for malodor management. Its efficacy is likely due to the predominant involvement of anaerobic bacteria in foul-smelling wounds. Topical metronidazole is available as a gel and as a cream. A systematic review showed that on average, topical metronidazole was used once daily for 14 consecutive days.¹⁹ The layer of topical metronidazole is typically covered with a nonadherent primary dressing followed by an absorbent secondary dressing.

The best clinical evidence for topical metronidazole consists of case reports and series.^32–35 The largest of these studies was done by Finlay et al, who treated 47 patients with malodorous benign and malignant cutaneous wounds with 0.75% metronidazole gel daily.³² Forty-five (96%) of the patients reported significantly decreased odor by 14 days, as well as decreased pain, discharge, and surrounding cellulitis.

A randomized, placebo-controlled trial conducted by Bale et al had equivocal findings.⁹ All 41 patients who received metronidazole gel reported a decrease in malodor within 3 days of starting it. However, 76% of patients who received placebo also reported malodor control; in the final analysis, no significant difference was noted in the success rate between the two groups.

Metronidazole tablets can be crushed and sprinkled over the wound. As with metronidazole gel or cream, the crushed tablets are applied daily and covered by a primary nonadherent dressing and an absorbent secondary dressing. This off-label use of metronidazole serves as a cheaper alternative to commercially available topical preparations. To our knowledge, there has been no head-to-head trial comparing the two topical strategies.

Systemic metronidazole, often given orally, has been recommended if evidence of deep tissue or systemic infection is noted¹⁵ and in cases of fungating wounds with fistulas invading either the gastrointestinal or genitourinary tracts.¹⁸ Side effects such as nausea, neuropathy, and alcohol intolerance (ie, disulfiram reaction) may occur, which are not seen with topical metronidazole.

Both topical and systemic metronidazole can be used together on a time-limited basis for extensive malodorous wounds, such as fungating malignant wounds or stage IV sacral pressure ulcers.

Other antimicrobial agents used to treat malodor include silver-containing products, iodine-containing topical agents, mupirocin, bacitracin, neomycin, and polymyxin B.

Honey has been used for wound care since the era of the ancient Egyptians

Honey was used for wound care by the ancient Egyptians, and it is still used.³⁶ Its beneficial effects include antimicrobial, debriding, deodorizing, anti-inflammatory, and granulation tissue-stimulating. Honey has even been shown to significantly decrease skin colonization with various kinds of bacteria, including methicillin-resistant Staphylococcus aureus.³⁷ Medical-grade honey is preferred over table honey, as the latter is nonsterile and can contain Clostridium spores, which contaminate the wound.³⁸

Yogurt and buttermilk lower the pH of the wound and control bacterial proliferation to control malodor.^39,40 Either is applied for 10 to 15 minutes after the wound is cleansed and is then washed off thoroughly.

Absorbent dressings are used either over a layer of topical metronidazole and a nonadherent primary dressing or as a primary dressing itself. An absorbent dressing containing activated charcoal is used for rapid improvement, although cost may be prohibitive, especially in developing countries.^13,19 Another type of absorbent dressing, composed of polyester impregnated with sodium chloride, has been found to be useful in malodor control.⁴¹ An important pointer is to maintain a tight seal around the absorbent dressing to prevent leakage of exudate.

Concealers

Aromatics used to conceal malodor include scented candles, incense, fragrant flowers and plants, and air-freshener sprays. When circumstances allow, candles are good options since they conceal malodor by emitting fragrance, and the flame burns off foul-smelling chemicals. Aromatics such as coffee beans, vanilla beans, and cider vinegar can be placed in a pan and left under the patient’s bed or close to it. Drops of peppermint oil or oil of wintergreen can be placed on wound dressings.

Other odor concealers are adsorbent materials that attract and cause ions and molecules to adhere to their surface. Examples are charcoal, baking soda, and cat litter. As with other aromatics, these materials are placed in pans and left under the bed or near the patient.

Aromatics can have disadvantages, as certain scents, especially strong ones, can be nauseating for patients. Some fragrances trigger asthma or skin irritation. Patients and caregivers can be left with an unpleasant association of certain fragrances with malodor by conditioning.^15,17,18

Education and support

Concerns of the patient and family members need to be heard, addressed promptly, and reassessed with each visit, since uncontrolled malodor can be a chief source of caregiver fatigue.

Foremost in formulating a patient- and family-centered malodor management strategy is to commit to controlling malodor as much as possible. Regular follow-up appointments should be made, whether in the office or at home, to check on the patient’s progress and address new and ongoing concerns. Symptoms accompanying malodor, such as pain, bleeding, and sleep disturbance, need to be addressed, as they all affect quality of life.¹ Audience-appropriate educational materials should be made available.²⁶ Online resources that patients and families can explore include the websites of the Wound Ostomy and Continence Nurses Society (www.wocn.org) and the Association for the Advancement of Wound Care (aawconline.org).

Avoid expressing distress at odors in front of or within hearing of patients and families

Healthcare professionals need to be prepared to deal with problems and complications involving patients and family members that may arise in the course of treatment.¹² Problems include the cost and local unavailability of dressing supplies, insurance coverage for dressings and topical agents, lack of assistance at home, and fear of changing dressings. A cardinal rule for healthcare providers is to avoid expressing distress at odors in front of or within hearing of patients and families.

OTHER STRATEGIES: WHAT ELSE CAN WE DO?

Curcumin, the main biologically active compound in the herb turmeric, applied directly to wounds three times daily as an ointment, has been shown to have odor-controlling properties.⁴²

Sugar paste has been reported to control malodor by drawing out exudative and tissue fluid osmotically, and inhibiting bacterial growth.^16,17 Water is mixed with sugar (ie, granulated, caster, or powdered) to form a paste, with additives like glycerin and polyethylene glycol used to alter the consistency. Thick clay-like paste is good for wounds with large cavities, while thin paste is useful for wounds with small or superficial openings. The paste is applied twice daily and is covered by an absorbent dressing.

Pressure relief is vital in managing pressure ulcers.^18,43 Repositioning every 2 hours and using special devices, such as mattress overlays, alternating pressure mattresses, and low air loss mattresses, are frequently employed techniques.

If circumstances permit and when congruent with the patient’s goals of care, intra-arterial chemotherapy and radiotherapy can be contemplated for malignant fungating wounds.^44,45

Other strategies include opening the windows during dressing changes, increasing the frequency of dressing changes, promptly removing used dressings from the house, and ensuring good general hygiene.

CASE RESOLUTION

After telling her that he was committed to control the malodor or, if possible, eliminate it, Mrs. A.’s doctor prepared two lists of materials—one for himself and one for Mrs. A.’s husband. He returned the next day, brought out his supplies, asked Mrs. A. to lie in bed, and invited her husband to assist him.

He cleansed and irrigated the breast lesion with normal saline, making sure to remove as much dead tissue as he could. He applied a layer of metronidazole cream to the wound cavity, then covered it with a nonadherent dressing. He then covered the wound with gauze, sealed the edges with medical adhesive tape, and applied a few drops of oil of wintergreen to the surface. A pan of charcoal briquettes was put under the bed, and a candle with Mrs. A.’s favorite scent was lit by the bedside. The physician then instructed Mrs. A.’s husband to repeat the procedure once daily for 1 week.

After 2 weeks, Mrs. A. and her husband said the foul odor had greatly decreased. She appeared more cheerful and energetic, especially after her grandchildren visited a few days earlier. The physician then instructed the husband to stop using metronidazole cream and to apply a hydrocolloid dressing every 3 days instead. He advised them to continue the rest of the process of applying a few drops of oil of wintergreen on the dressing surface, placing a pan of charcoal briquettes under the bed, and lighting a scented candle by the bedside.

FINISH THE RACE!

Complex nonhealing wounds are encountered across various healthcare settings. Wound malodor is an important component of nonhealing wounds, which adversely affects patients, families, and healthcare providers. Infection, slough, and exudate are the major causes of wound malodor. The essential steps to reduce malodor are to remove necrotic tissue, use antibacterial and odor-absorbing agents, apply appropriate odor “concealers,” educate families, and formulate a patient- and family-centered strategy (Table 1).
 

Acknowledgment: The authors would like to thank Sue Reif, CNP, for her assistance in completing the manuscript.

Wounds that fail to heal become more than mere skin lesions. Pain, malodor, and the accompanying psychological distress often complicate nonhealing wounds and impair quality of life.¹ Management of malodor requires perseverance, sensitivity, and familiarity with tools and procedures that range from surgical debridement to medical-grade honey.

Chronic, nonhealing wounds are defined as persisting for more than 6 months.² These lesions are incapable of undergoing anatomic and functional repair on their own. Commonly encountered nonhealing wounds include pressure ulcers, venous stasis ulcers, arterial insufficiency ulcers, and malignant cutaneous wounds.

Typically, the patient with a nonhealing wound is frail, debilitated, medically complex, and often faced with one or more life-limiting illnesses. Complete wound healing may therefore be unrealistic, and optimal wound management becomes the goal of care.^3,4

Healthcare providers encounter nonhealing wounds in varied settings—acute inpatient, outpatient, long-term, and home care. For instance, in the home care setting, a study of 383 patients enrolled in hospice found that 35% had skin ulcers and wounds.³ Half of those affected had pressure ulcers, 20% had ischemic ulcers, and 30% had other skin disorders such as stasis ulcers, burns, skin tears, and tumors. A larger study, also in hospice patients, found that 26% had pressure ulcers and 10% more developed them within 6 months.⁵

While pressure ulcers are the most common nonhealing wounds, malignant or fungating wounds are found in 5% to 10% of patients with metastatic disease, usually with cancers of the breast, head, and neck.⁶

The three major causes of wound malodor are slough, infection, and exudate

Maximizing wound care provides comfort, relieves suffering, and promotes quality of life.^3,7 To achieve these goals, clinicians must be familiar with strategies to manage complications associated with nonhealing wounds such as pain, malodor, and psychosocial adverse effects. Of these complications, malodor has been pointed out by both patients and caregivers as the most distressing.⁸

This article focuses on wound malodor, discusses the processes that cause wounds to emit an offensive smell, and outlines a comprehensive management approach.

MRS. A., AGE 61, WITH STAGE IV BREAST CANCER

Mrs. A., 61 years old, had a fungating mass in her left breast, which began as a small nodule and progressively enlarged to deform her breast over several months. Her oncologist subsequently staged the extent of her cancer as stage IV after workup revealed lung metastasis. Mrs. A. and her family decided to forgo cancer treatment, including radiotherapy, and to transition to hospice care after discussions with the oncologist.

Mrs. A. lived at home with her husband. Her daughter and three grandchildren all lived nearby.

When her hospice physician arrived at her home to meet her, a strong, pungent, and nauseating smell greeted him as he entered her bedroom. The patient said that for the past few months she had been increasingly distressed by the revolting odor. She rarely left home and had been ashamed to have people visit her, including her family.

On examination, the physician noticed a large fungating mass with yellowish discharge and necrotic tissue in her left breast. In addition to mild pain, she was immensely bothered by the strong odor coming from her breast.

THE IMPACT OF MALODOR

As seen in the case of Mrs. A., malodor has grave effects, both physical and psychological. Patients experience impaired or socially unacceptable body image, social rejection, personal shame, and embarrassment.^9,10 Feelings of fear, anxiety, and depression are common. If left uncontrolled, malodor results in social isolation, reluctance to engage in social activities, diminished appetite, and nausea. In addition, malodor is a constant reminder of patients’ pain and cancer, and it results in further suffering.¹¹

Reactions of family members and caregivers can worsen the situation.^9,12 Expressions of revulsion limit contact and inhibit intimacy, especially near the end of life. Caregivers are often frustrated and distressed over their inability to control the malodor. The environment becomes uninhabitable, and the malodor can permeate clothing, furniture, and living quarters.

Managing malodor can be emotionally draining, physically daunting, and frustrating for healthcare professionals, as several methods are usually employed, often in a trial-and-error approach, to achieve an acceptable degree of odor control. In addition, clinicians must face the challenge of treating malodorous wounds at very close distance without reacting in a way that offends or alarms patients and family members.¹³

MALODOR PRODUCTION: WHERE IS THAT SMELL COMING FROM?

All wounds can produce an odor.¹⁴ Wounds that are expected to heal typically emit a faint but not unpleasant odor, akin to fresh blood. Wounds colonized by Pseudomonas aeruginosa produce a fruity or grapelike odor that is tolerable. Malodor occurs with wounds infected by other gram-negative organisms or anaerobic bacteria.¹⁵ Similarly, wounds covered by necrotic tissue smell like decaying flesh.

Three major causes

The three major causes of wound malodor are slough, infection, and exudate (Figure 1).

Slough is dead or necrotic tissue, usually resulting from vascular compromise. Arterial ulcers, pressure ulcers, and malignant wounds all form slough from capillary occlusion, subsequent ischemia, and tissue necrosis.

Infection. Devitalized tissue, an ideal medium in which bacteria thrive, becomes the source of infection. Anaerobic bacteria are usually implicated in malodor. These include Bacteroides fragilis, Bacteroides prevotella, Clostridium perfringens, and Fusobacterium nucleatum.^16,17 Anaerobic organisms produce putrescine and cadaverine, which are largely responsible for the offensive odor.^16,18 Volatile fatty acids such as propionic, butyric, isovaleric, and valeric acid are formed from lipid catabolism by anaerobes and add to malodor.¹⁷ Aerobic bacteria such as Proteus, Klebsiella, and Pseudomonas species supercolonize necrotic tissue as well and contribute to malodor.^17,18

Exudate. Since nonhealing wounds undergo repeated cycles of inflammation, infection, and necrosis, accumulation of exudate becomes inevitable. Exudate typically is a pus-like fluid containing serum, fibrin, and white blood cells, which leak from blood vessels. In addition, bacteria that colonize chronic wounds filled with necrotic tissue activate proteases that degrade and liquefy dead tissue, thereby forming extensive amounts of exudate.¹⁹

Apart from slough, infection, and exudate, poor general hygiene and dressings left on for too long may contribute to malodor.¹⁶ Moisture-retentive dressings such as hydrocolloids leave an odor after removal. Dressings that liquefy upon contact with the wound surface leave a pus-like, potentially malodorous material.

MALODOR ASSESSMENT: DO YOU SMELL SOMETHING?

Various ways to document wound malodor can prove useful in guiding assessment and treatment. Descriptions such as “foul,” “putrid,” “fishy,” or “filled the room” vividly portray the initial presentation. A 10-point numerical scale similar to a numerical pain scale or a visual analogue scale can be used as a subjective measure.

Other grading methods, which to the authors’ knowledge are not validated, may be helpful. In a study that focused on patients suffering from malodorous gynecologic malignancies, von Gruenigen et al²⁰ used a 0-to-3 scale:

• 0 Absent
• 1 Not offensive
• 2 Offensive but tolerable
• 3 Offensive and intolerable.

A scale often adapted by other authors was devised by Baker and Haig,²¹ which clearly defines four classes:

• 1 Strong—odor is evident upon entering the room (6 to 10 feet from the patient) with the dressing intact
• 2 Moderate—odor is evident upon entering the room with dressing removed
• 3 Slight—odor is evident at close proximity to the patient when the dressing is removed
• 4 No odor—no odor is evident, even at the patient’s bedside with the dressing removed.

COMPREHENSIVE MANAGEMENT: HOW DO WE WIN THE ‘RACE’?

The acronym RACE outlines an approach to dealing with malodor. It stands for removal of necrotic tissue; antibacterials; odor concealers; and education and support (Table 1).

Remove necrotic tissue

An important step in eliminating malodor is to remove necrotic tissue. This starts with debridement, which decreases the incidence of infection and hastens wound closure.^22,23 Table 2 compares the different types of debridement.

Sharp or surgical debridement involves the use of a scalpel or scissors. This type of debridement may increase the risk of bleeding, pain, and malignant cell seeding in fungating wounds.^4,24

Enzymatic debridement employs chemicals with proteolytic action (eg, collagenase) to digest extracellular proteins in wounds.^18,25

Mechanical debridement involves aggressive therapies such as forceful irrigation and hydrotherapy, which may fail to discriminate between necrotic and viable tissues.^18,26

Biological debridement using maggots, which ingest bacteria and devitalized tissue, may cause increased wound bleeding and may be unacceptable for patients and families.^24,27

Autolytic debridement is often recommended, particularly if complete healing is not the primary goal.^17,24,28,29 Autolysis uses proteolytic enzymes and phagocytic cells present in the wound bed and wound fluid to clear devitalized tissue. It is easy, inexpensive, noninvasive, and painless,⁴ and it requires less frequent dressing changes relative to standard dressing or wet-to-dry dressing.

Autolytic debridement is commonly accomplished using hydrocolloid and hydrogel dressings.^15,29 Hydrocolloids are adhesive, occlusive, and conformable dressings that are suitable for wounds with low to moderate amounts of exudate. Upon contact with the wound surface, the dressing absorbs the exudate, forms a gel layer, and maintains a moist environment. Hydrocolloids are not recommended for infected wounds or for those with copious exudate as they may lead to maceration around the wound. A disadvantage of hydrocolloid dressings is their tendency to generate brown, often malodorous exudate when removed.

On the other hand, hydrogels in amorphous gel, dressing, sheet, or impregnated gauze form are water-based products that create a moist environment similar to hydrocolloids. Aside from causing minimal trauma to the wound bed when removed, the dressing’s cooling effect may bring some pain relief. Hydrogels are appropriate for dry wounds and for those with minimal exudate.

After debridement, the wound is cleansed and irrigated. A number of cleansers and solutions are available, but normal saline is a cheap alternative. To irrigate, experts recommend an 18- or 20-gauge intravenous catheter attached to a 30- or 60-mL syringe.¹⁵ This technique provides 8 to 15 psi of pressure, enough to cleanse the wound without causing tissue trauma.

Antibacterials and absorption

Antibacterials. Topical antibiotics have several advantages over systemic antibiotics in treating chronic wounds.^30,31 These include a high and sustained concentration of the antimicrobial at the site of infection, limited potential for systemic absorption and toxicity, reduced potential for antibiotic resistance, and drawing of the patient’s and caregiver’s attention to the wound.

Metronidazole is the most widely used topical antibacterial for malodor management. Its efficacy is likely due to the predominant involvement of anaerobic bacteria in foul-smelling wounds. Topical metronidazole is available as a gel and as a cream. A systematic review showed that on average, topical metronidazole was used once daily for 14 consecutive days.¹⁹ The layer of topical metronidazole is typically covered with a nonadherent primary dressing followed by an absorbent secondary dressing.

The best clinical evidence for topical metronidazole consists of case reports and series.^32–35 The largest of these studies was done by Finlay et al, who treated 47 patients with malodorous benign and malignant cutaneous wounds with 0.75% metronidazole gel daily.³² Forty-five (96%) of the patients reported significantly decreased odor by 14 days, as well as decreased pain, discharge, and surrounding cellulitis.

A randomized, placebo-controlled trial conducted by Bale et al had equivocal findings.⁹ All 41 patients who received metronidazole gel reported a decrease in malodor within 3 days of starting it. However, 76% of patients who received placebo also reported malodor control; in the final analysis, no significant difference was noted in the success rate between the two groups.

Metronidazole tablets can be crushed and sprinkled over the wound. As with metronidazole gel or cream, the crushed tablets are applied daily and covered by a primary nonadherent dressing and an absorbent secondary dressing. This off-label use of metronidazole serves as a cheaper alternative to commercially available topical preparations. To our knowledge, there has been no head-to-head trial comparing the two topical strategies.

Systemic metronidazole, often given orally, has been recommended if evidence of deep tissue or systemic infection is noted¹⁵ and in cases of fungating wounds with fistulas invading either the gastrointestinal or genitourinary tracts.¹⁸ Side effects such as nausea, neuropathy, and alcohol intolerance (ie, disulfiram reaction) may occur, which are not seen with topical metronidazole.

Both topical and systemic metronidazole can be used together on a time-limited basis for extensive malodorous wounds, such as fungating malignant wounds or stage IV sacral pressure ulcers.

Other antimicrobial agents used to treat malodor include silver-containing products, iodine-containing topical agents, mupirocin, bacitracin, neomycin, and polymyxin B.

Honey has been used for wound care since the era of the ancient Egyptians

Honey was used for wound care by the ancient Egyptians, and it is still used.³⁶ Its beneficial effects include antimicrobial, debriding, deodorizing, anti-inflammatory, and granulation tissue-stimulating. Honey has even been shown to significantly decrease skin colonization with various kinds of bacteria, including methicillin-resistant Staphylococcus aureus.³⁷ Medical-grade honey is preferred over table honey, as the latter is nonsterile and can contain Clostridium spores, which contaminate the wound.³⁸

Yogurt and buttermilk lower the pH of the wound and control bacterial proliferation to control malodor.^39,40 Either is applied for 10 to 15 minutes after the wound is cleansed and is then washed off thoroughly.

Absorbent dressings are used either over a layer of topical metronidazole and a nonadherent primary dressing or as a primary dressing itself. An absorbent dressing containing activated charcoal is used for rapid improvement, although cost may be prohibitive, especially in developing countries.^13,19 Another type of absorbent dressing, composed of polyester impregnated with sodium chloride, has been found to be useful in malodor control.⁴¹ An important pointer is to maintain a tight seal around the absorbent dressing to prevent leakage of exudate.

Concealers

Aromatics used to conceal malodor include scented candles, incense, fragrant flowers and plants, and air-freshener sprays. When circumstances allow, candles are good options since they conceal malodor by emitting fragrance, and the flame burns off foul-smelling chemicals. Aromatics such as coffee beans, vanilla beans, and cider vinegar can be placed in a pan and left under the patient’s bed or close to it. Drops of peppermint oil or oil of wintergreen can be placed on wound dressings.

Other odor concealers are adsorbent materials that attract and cause ions and molecules to adhere to their surface. Examples are charcoal, baking soda, and cat litter. As with other aromatics, these materials are placed in pans and left under the bed or near the patient.

Aromatics can have disadvantages, as certain scents, especially strong ones, can be nauseating for patients. Some fragrances trigger asthma or skin irritation. Patients and caregivers can be left with an unpleasant association of certain fragrances with malodor by conditioning.^15,17,18

Education and support

Concerns of the patient and family members need to be heard, addressed promptly, and reassessed with each visit, since uncontrolled malodor can be a chief source of caregiver fatigue.

Foremost in formulating a patient- and family-centered malodor management strategy is to commit to controlling malodor as much as possible. Regular follow-up appointments should be made, whether in the office or at home, to check on the patient’s progress and address new and ongoing concerns. Symptoms accompanying malodor, such as pain, bleeding, and sleep disturbance, need to be addressed, as they all affect quality of life.¹ Audience-appropriate educational materials should be made available.²⁶ Online resources that patients and families can explore include the websites of the Wound Ostomy and Continence Nurses Society (www.wocn.org) and the Association for the Advancement of Wound Care (aawconline.org).

Avoid expressing distress at odors in front of or within hearing of patients and families

Healthcare professionals need to be prepared to deal with problems and complications involving patients and family members that may arise in the course of treatment.¹² Problems include the cost and local unavailability of dressing supplies, insurance coverage for dressings and topical agents, lack of assistance at home, and fear of changing dressings. A cardinal rule for healthcare providers is to avoid expressing distress at odors in front of or within hearing of patients and families.

OTHER STRATEGIES: WHAT ELSE CAN WE DO?

Curcumin, the main biologically active compound in the herb turmeric, applied directly to wounds three times daily as an ointment, has been shown to have odor-controlling properties.⁴²

Sugar paste has been reported to control malodor by drawing out exudative and tissue fluid osmotically, and inhibiting bacterial growth.^16,17 Water is mixed with sugar (ie, granulated, caster, or powdered) to form a paste, with additives like glycerin and polyethylene glycol used to alter the consistency. Thick clay-like paste is good for wounds with large cavities, while thin paste is useful for wounds with small or superficial openings. The paste is applied twice daily and is covered by an absorbent dressing.

Pressure relief is vital in managing pressure ulcers.^18,43 Repositioning every 2 hours and using special devices, such as mattress overlays, alternating pressure mattresses, and low air loss mattresses, are frequently employed techniques.

If circumstances permit and when congruent with the patient’s goals of care, intra-arterial chemotherapy and radiotherapy can be contemplated for malignant fungating wounds.^44,45

Other strategies include opening the windows during dressing changes, increasing the frequency of dressing changes, promptly removing used dressings from the house, and ensuring good general hygiene.

CASE RESOLUTION

After telling her that he was committed to control the malodor or, if possible, eliminate it, Mrs. A.’s doctor prepared two lists of materials—one for himself and one for Mrs. A.’s husband. He returned the next day, brought out his supplies, asked Mrs. A. to lie in bed, and invited her husband to assist him.

He cleansed and irrigated the breast lesion with normal saline, making sure to remove as much dead tissue as he could. He applied a layer of metronidazole cream to the wound cavity, then covered it with a nonadherent dressing. He then covered the wound with gauze, sealed the edges with medical adhesive tape, and applied a few drops of oil of wintergreen to the surface. A pan of charcoal briquettes was put under the bed, and a candle with Mrs. A.’s favorite scent was lit by the bedside. The physician then instructed Mrs. A.’s husband to repeat the procedure once daily for 1 week.

After 2 weeks, Mrs. A. and her husband said the foul odor had greatly decreased. She appeared more cheerful and energetic, especially after her grandchildren visited a few days earlier. The physician then instructed the husband to stop using metronidazole cream and to apply a hydrocolloid dressing every 3 days instead. He advised them to continue the rest of the process of applying a few drops of oil of wintergreen on the dressing surface, placing a pan of charcoal briquettes under the bed, and lighting a scented candle by the bedside.

FINISH THE RACE!

Complex nonhealing wounds are encountered across various healthcare settings. Wound malodor is an important component of nonhealing wounds, which adversely affects patients, families, and healthcare providers. Infection, slough, and exudate are the major causes of wound malodor. The essential steps to reduce malodor are to remove necrotic tissue, use antibacterial and odor-absorbing agents, apply appropriate odor “concealers,” educate families, and formulate a patient- and family-centered strategy (Table 1).
 

Acknowledgment: The authors would like to thank Sue Reif, CNP, for her assistance in completing the manuscript.

Wounds that fail to heal become more than mere skin lesions. Pain, malodor, and the accompanying psychological distress often complicate nonhealing wounds and impair quality of life.¹ Management of malodor requires perseverance, sensitivity, and familiarity with tools and procedures that range from surgical debridement to medical-grade honey.

Chronic, nonhealing wounds are defined as persisting for more than 6 months.² These lesions are incapable of undergoing anatomic and functional repair on their own. Commonly encountered nonhealing wounds include pressure ulcers, venous stasis ulcers, arterial insufficiency ulcers, and malignant cutaneous wounds.

Typically, the patient with a nonhealing wound is frail, debilitated, medically complex, and often faced with one or more life-limiting illnesses. Complete wound healing may therefore be unrealistic, and optimal wound management becomes the goal of care.^3,4

Healthcare providers encounter nonhealing wounds in varied settings—acute inpatient, outpatient, long-term, and home care. For instance, in the home care setting, a study of 383 patients enrolled in hospice found that 35% had skin ulcers and wounds.³ Half of those affected had pressure ulcers, 20% had ischemic ulcers, and 30% had other skin disorders such as stasis ulcers, burns, skin tears, and tumors. A larger study, also in hospice patients, found that 26% had pressure ulcers and 10% more developed them within 6 months.⁵

While pressure ulcers are the most common nonhealing wounds, malignant or fungating wounds are found in 5% to 10% of patients with metastatic disease, usually with cancers of the breast, head, and neck.⁶

The three major causes of wound malodor are slough, infection, and exudate

Maximizing wound care provides comfort, relieves suffering, and promotes quality of life.^3,7 To achieve these goals, clinicians must be familiar with strategies to manage complications associated with nonhealing wounds such as pain, malodor, and psychosocial adverse effects. Of these complications, malodor has been pointed out by both patients and caregivers as the most distressing.⁸

This article focuses on wound malodor, discusses the processes that cause wounds to emit an offensive smell, and outlines a comprehensive management approach.

MRS. A., AGE 61, WITH STAGE IV BREAST CANCER

Mrs. A., 61 years old, had a fungating mass in her left breast, which began as a small nodule and progressively enlarged to deform her breast over several months. Her oncologist subsequently staged the extent of her cancer as stage IV after workup revealed lung metastasis. Mrs. A. and her family decided to forgo cancer treatment, including radiotherapy, and to transition to hospice care after discussions with the oncologist.

Mrs. A. lived at home with her husband. Her daughter and three grandchildren all lived nearby.

When her hospice physician arrived at her home to meet her, a strong, pungent, and nauseating smell greeted him as he entered her bedroom. The patient said that for the past few months she had been increasingly distressed by the revolting odor. She rarely left home and had been ashamed to have people visit her, including her family.

On examination, the physician noticed a large fungating mass with yellowish discharge and necrotic tissue in her left breast. In addition to mild pain, she was immensely bothered by the strong odor coming from her breast.

THE IMPACT OF MALODOR

As seen in the case of Mrs. A., malodor has grave effects, both physical and psychological. Patients experience impaired or socially unacceptable body image, social rejection, personal shame, and embarrassment.^9,10 Feelings of fear, anxiety, and depression are common. If left uncontrolled, malodor results in social isolation, reluctance to engage in social activities, diminished appetite, and nausea. In addition, malodor is a constant reminder of patients’ pain and cancer, and it results in further suffering.¹¹

Reactions of family members and caregivers can worsen the situation.^9,12 Expressions of revulsion limit contact and inhibit intimacy, especially near the end of life. Caregivers are often frustrated and distressed over their inability to control the malodor. The environment becomes uninhabitable, and the malodor can permeate clothing, furniture, and living quarters.

Managing malodor can be emotionally draining, physically daunting, and frustrating for healthcare professionals, as several methods are usually employed, often in a trial-and-error approach, to achieve an acceptable degree of odor control. In addition, clinicians must face the challenge of treating malodorous wounds at very close distance without reacting in a way that offends or alarms patients and family members.¹³

MALODOR PRODUCTION: WHERE IS THAT SMELL COMING FROM?

All wounds can produce an odor.¹⁴ Wounds that are expected to heal typically emit a faint but not unpleasant odor, akin to fresh blood. Wounds colonized by Pseudomonas aeruginosa produce a fruity or grapelike odor that is tolerable. Malodor occurs with wounds infected by other gram-negative organisms or anaerobic bacteria.¹⁵ Similarly, wounds covered by necrotic tissue smell like decaying flesh.

Three major causes

The three major causes of wound malodor are slough, infection, and exudate (Figure 1).

Slough is dead or necrotic tissue, usually resulting from vascular compromise. Arterial ulcers, pressure ulcers, and malignant wounds all form slough from capillary occlusion, subsequent ischemia, and tissue necrosis.

Infection. Devitalized tissue, an ideal medium in which bacteria thrive, becomes the source of infection. Anaerobic bacteria are usually implicated in malodor. These include Bacteroides fragilis, Bacteroides prevotella, Clostridium perfringens, and Fusobacterium nucleatum.^16,17 Anaerobic organisms produce putrescine and cadaverine, which are largely responsible for the offensive odor.^16,18 Volatile fatty acids such as propionic, butyric, isovaleric, and valeric acid are formed from lipid catabolism by anaerobes and add to malodor.¹⁷ Aerobic bacteria such as Proteus, Klebsiella, and Pseudomonas species supercolonize necrotic tissue as well and contribute to malodor.^17,18

Exudate. Since nonhealing wounds undergo repeated cycles of inflammation, infection, and necrosis, accumulation of exudate becomes inevitable. Exudate typically is a pus-like fluid containing serum, fibrin, and white blood cells, which leak from blood vessels. In addition, bacteria that colonize chronic wounds filled with necrotic tissue activate proteases that degrade and liquefy dead tissue, thereby forming extensive amounts of exudate.¹⁹

Apart from slough, infection, and exudate, poor general hygiene and dressings left on for too long may contribute to malodor.¹⁶ Moisture-retentive dressings such as hydrocolloids leave an odor after removal. Dressings that liquefy upon contact with the wound surface leave a pus-like, potentially malodorous material.

MALODOR ASSESSMENT: DO YOU SMELL SOMETHING?

Various ways to document wound malodor can prove useful in guiding assessment and treatment. Descriptions such as “foul,” “putrid,” “fishy,” or “filled the room” vividly portray the initial presentation. A 10-point numerical scale similar to a numerical pain scale or a visual analogue scale can be used as a subjective measure.

Other grading methods, which to the authors’ knowledge are not validated, may be helpful. In a study that focused on patients suffering from malodorous gynecologic malignancies, von Gruenigen et al²⁰ used a 0-to-3 scale:

• 0 Absent
• 1 Not offensive
• 2 Offensive but tolerable
• 3 Offensive and intolerable.

A scale often adapted by other authors was devised by Baker and Haig,²¹ which clearly defines four classes:

• 1 Strong—odor is evident upon entering the room (6 to 10 feet from the patient) with the dressing intact
• 2 Moderate—odor is evident upon entering the room with dressing removed
• 3 Slight—odor is evident at close proximity to the patient when the dressing is removed
• 4 No odor—no odor is evident, even at the patient’s bedside with the dressing removed.

COMPREHENSIVE MANAGEMENT: HOW DO WE WIN THE ‘RACE’?

The acronym RACE outlines an approach to dealing with malodor. It stands for removal of necrotic tissue; antibacterials; odor concealers; and education and support (Table 1).

Remove necrotic tissue

An important step in eliminating malodor is to remove necrotic tissue. This starts with debridement, which decreases the incidence of infection and hastens wound closure.^22,23 Table 2 compares the different types of debridement.

Sharp or surgical debridement involves the use of a scalpel or scissors. This type of debridement may increase the risk of bleeding, pain, and malignant cell seeding in fungating wounds.^4,24

Enzymatic debridement employs chemicals with proteolytic action (eg, collagenase) to digest extracellular proteins in wounds.^18,25

Mechanical debridement involves aggressive therapies such as forceful irrigation and hydrotherapy, which may fail to discriminate between necrotic and viable tissues.^18,26

Biological debridement using maggots, which ingest bacteria and devitalized tissue, may cause increased wound bleeding and may be unacceptable for patients and families.^24,27

Autolytic debridement is often recommended, particularly if complete healing is not the primary goal.^17,24,28,29 Autolysis uses proteolytic enzymes and phagocytic cells present in the wound bed and wound fluid to clear devitalized tissue. It is easy, inexpensive, noninvasive, and painless,⁴ and it requires less frequent dressing changes relative to standard dressing or wet-to-dry dressing.

Autolytic debridement is commonly accomplished using hydrocolloid and hydrogel dressings.^15,29 Hydrocolloids are adhesive, occlusive, and conformable dressings that are suitable for wounds with low to moderate amounts of exudate. Upon contact with the wound surface, the dressing absorbs the exudate, forms a gel layer, and maintains a moist environment. Hydrocolloids are not recommended for infected wounds or for those with copious exudate as they may lead to maceration around the wound. A disadvantage of hydrocolloid dressings is their tendency to generate brown, often malodorous exudate when removed.

On the other hand, hydrogels in amorphous gel, dressing, sheet, or impregnated gauze form are water-based products that create a moist environment similar to hydrocolloids. Aside from causing minimal trauma to the wound bed when removed, the dressing’s cooling effect may bring some pain relief. Hydrogels are appropriate for dry wounds and for those with minimal exudate.

After debridement, the wound is cleansed and irrigated. A number of cleansers and solutions are available, but normal saline is a cheap alternative. To irrigate, experts recommend an 18- or 20-gauge intravenous catheter attached to a 30- or 60-mL syringe.¹⁵ This technique provides 8 to 15 psi of pressure, enough to cleanse the wound without causing tissue trauma.

Antibacterials and absorption

Antibacterials. Topical antibiotics have several advantages over systemic antibiotics in treating chronic wounds.^30,31 These include a high and sustained concentration of the antimicrobial at the site of infection, limited potential for systemic absorption and toxicity, reduced potential for antibiotic resistance, and drawing of the patient’s and caregiver’s attention to the wound.

Metronidazole is the most widely used topical antibacterial for malodor management. Its efficacy is likely due to the predominant involvement of anaerobic bacteria in foul-smelling wounds. Topical metronidazole is available as a gel and as a cream. A systematic review showed that on average, topical metronidazole was used once daily for 14 consecutive days.¹⁹ The layer of topical metronidazole is typically covered with a nonadherent primary dressing followed by an absorbent secondary dressing.

The best clinical evidence for topical metronidazole consists of case reports and series.^32–35 The largest of these studies was done by Finlay et al, who treated 47 patients with malodorous benign and malignant cutaneous wounds with 0.75% metronidazole gel daily.³² Forty-five (96%) of the patients reported significantly decreased odor by 14 days, as well as decreased pain, discharge, and surrounding cellulitis.

A randomized, placebo-controlled trial conducted by Bale et al had equivocal findings.⁹ All 41 patients who received metronidazole gel reported a decrease in malodor within 3 days of starting it. However, 76% of patients who received placebo also reported malodor control; in the final analysis, no significant difference was noted in the success rate between the two groups.

Metronidazole tablets can be crushed and sprinkled over the wound. As with metronidazole gel or cream, the crushed tablets are applied daily and covered by a primary nonadherent dressing and an absorbent secondary dressing. This off-label use of metronidazole serves as a cheaper alternative to commercially available topical preparations. To our knowledge, there has been no head-to-head trial comparing the two topical strategies.

Systemic metronidazole, often given orally, has been recommended if evidence of deep tissue or systemic infection is noted¹⁵ and in cases of fungating wounds with fistulas invading either the gastrointestinal or genitourinary tracts.¹⁸ Side effects such as nausea, neuropathy, and alcohol intolerance (ie, disulfiram reaction) may occur, which are not seen with topical metronidazole.

Both topical and systemic metronidazole can be used together on a time-limited basis for extensive malodorous wounds, such as fungating malignant wounds or stage IV sacral pressure ulcers.

Other antimicrobial agents used to treat malodor include silver-containing products, iodine-containing topical agents, mupirocin, bacitracin, neomycin, and polymyxin B.

Honey has been used for wound care since the era of the ancient Egyptians

Honey was used for wound care by the ancient Egyptians, and it is still used.³⁶ Its beneficial effects include antimicrobial, debriding, deodorizing, anti-inflammatory, and granulation tissue-stimulating. Honey has even been shown to significantly decrease skin colonization with various kinds of bacteria, including methicillin-resistant Staphylococcus aureus.³⁷ Medical-grade honey is preferred over table honey, as the latter is nonsterile and can contain Clostridium spores, which contaminate the wound.³⁸

Yogurt and buttermilk lower the pH of the wound and control bacterial proliferation to control malodor.^39,40 Either is applied for 10 to 15 minutes after the wound is cleansed and is then washed off thoroughly.

Absorbent dressings are used either over a layer of topical metronidazole and a nonadherent primary dressing or as a primary dressing itself. An absorbent dressing containing activated charcoal is used for rapid improvement, although cost may be prohibitive, especially in developing countries.^13,19 Another type of absorbent dressing, composed of polyester impregnated with sodium chloride, has been found to be useful in malodor control.⁴¹ An important pointer is to maintain a tight seal around the absorbent dressing to prevent leakage of exudate.

Concealers

Aromatics used to conceal malodor include scented candles, incense, fragrant flowers and plants, and air-freshener sprays. When circumstances allow, candles are good options since they conceal malodor by emitting fragrance, and the flame burns off foul-smelling chemicals. Aromatics such as coffee beans, vanilla beans, and cider vinegar can be placed in a pan and left under the patient’s bed or close to it. Drops of peppermint oil or oil of wintergreen can be placed on wound dressings.

Other odor concealers are adsorbent materials that attract and cause ions and molecules to adhere to their surface. Examples are charcoal, baking soda, and cat litter. As with other aromatics, these materials are placed in pans and left under the bed or near the patient.

Aromatics can have disadvantages, as certain scents, especially strong ones, can be nauseating for patients. Some fragrances trigger asthma or skin irritation. Patients and caregivers can be left with an unpleasant association of certain fragrances with malodor by conditioning.^15,17,18

Education and support

Concerns of the patient and family members need to be heard, addressed promptly, and reassessed with each visit, since uncontrolled malodor can be a chief source of caregiver fatigue.

Foremost in formulating a patient- and family-centered malodor management strategy is to commit to controlling malodor as much as possible. Regular follow-up appointments should be made, whether in the office or at home, to check on the patient’s progress and address new and ongoing concerns. Symptoms accompanying malodor, such as pain, bleeding, and sleep disturbance, need to be addressed, as they all affect quality of life.¹ Audience-appropriate educational materials should be made available.²⁶ Online resources that patients and families can explore include the websites of the Wound Ostomy and Continence Nurses Society (www.wocn.org) and the Association for the Advancement of Wound Care (aawconline.org).

Avoid expressing distress at odors in front of or within hearing of patients and families

Healthcare professionals need to be prepared to deal with problems and complications involving patients and family members that may arise in the course of treatment.¹² Problems include the cost and local unavailability of dressing supplies, insurance coverage for dressings and topical agents, lack of assistance at home, and fear of changing dressings. A cardinal rule for healthcare providers is to avoid expressing distress at odors in front of or within hearing of patients and families.

OTHER STRATEGIES: WHAT ELSE CAN WE DO?

Curcumin, the main biologically active compound in the herb turmeric, applied directly to wounds three times daily as an ointment, has been shown to have odor-controlling properties.⁴²

Sugar paste has been reported to control malodor by drawing out exudative and tissue fluid osmotically, and inhibiting bacterial growth.^16,17 Water is mixed with sugar (ie, granulated, caster, or powdered) to form a paste, with additives like glycerin and polyethylene glycol used to alter the consistency. Thick clay-like paste is good for wounds with large cavities, while thin paste is useful for wounds with small or superficial openings. The paste is applied twice daily and is covered by an absorbent dressing.

Pressure relief is vital in managing pressure ulcers.^18,43 Repositioning every 2 hours and using special devices, such as mattress overlays, alternating pressure mattresses, and low air loss mattresses, are frequently employed techniques.

If circumstances permit and when congruent with the patient’s goals of care, intra-arterial chemotherapy and radiotherapy can be contemplated for malignant fungating wounds.^44,45

Other strategies include opening the windows during dressing changes, increasing the frequency of dressing changes, promptly removing used dressings from the house, and ensuring good general hygiene.

CASE RESOLUTION

After telling her that he was committed to control the malodor or, if possible, eliminate it, Mrs. A.’s doctor prepared two lists of materials—one for himself and one for Mrs. A.’s husband. He returned the next day, brought out his supplies, asked Mrs. A. to lie in bed, and invited her husband to assist him.

He cleansed and irrigated the breast lesion with normal saline, making sure to remove as much dead tissue as he could. He applied a layer of metronidazole cream to the wound cavity, then covered it with a nonadherent dressing. He then covered the wound with gauze, sealed the edges with medical adhesive tape, and applied a few drops of oil of wintergreen to the surface. A pan of charcoal briquettes was put under the bed, and a candle with Mrs. A.’s favorite scent was lit by the bedside. The physician then instructed Mrs. A.’s husband to repeat the procedure once daily for 1 week.

After 2 weeks, Mrs. A. and her husband said the foul odor had greatly decreased. She appeared more cheerful and energetic, especially after her grandchildren visited a few days earlier. The physician then instructed the husband to stop using metronidazole cream and to apply a hydrocolloid dressing every 3 days instead. He advised them to continue the rest of the process of applying a few drops of oil of wintergreen on the dressing surface, placing a pan of charcoal briquettes under the bed, and lighting a scented candle by the bedside.

FINISH THE RACE!

Complex nonhealing wounds are encountered across various healthcare settings. Wound malodor is an important component of nonhealing wounds, which adversely affects patients, families, and healthcare providers. Infection, slough, and exudate are the major causes of wound malodor. The essential steps to reduce malodor are to remove necrotic tissue, use antibacterial and odor-absorbing agents, apply appropriate odor “concealers,” educate families, and formulate a patient- and family-centered strategy (Table 1).
 

Acknowledgment: The authors would like to thank Sue Reif, CNP, for her assistance in completing the manuscript.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Insulin therapy is one of the most effective tools clinicians can use to help patients reach their individualized hemoglobin A_1c target. However, decisions about when and how to start insulin therapy have to be individualized to the needs and goals of each patient. Many insulin options are available, one of the most common being the addition of basal insulin to oral antidiabetic drugs. Although patients are often reluctant to start insulin, this reluctance can be overcome through patient education and hands-on training.

Here, we review hemoglobin A_1c targets, factors that determine when to start insulin therapy, and the different regimens that can be used.

MOST PATIENTS EVENTUALLY NEED INSULIN

Type 2 diabetes mellitus is a chronic progressive disease associated with insulin resistance, beta-cell dysfunction, and decreased insulin secretion. Consequently, most patients eventually require insulin therapy to reduce the risk of long-term complications.

The efficacy of therapy can be assessed by measuring hemoglobin A_1c, an important marker of the chronic hyperglycemic state. The hemoglobin A_1c value can be reported as a ratio (%) standardized against the results of the Diabetes Control and Complications Trial,¹ or as International Federation of Clinical Chemistry units (mmol/mol).² Table 1 shows the relationship between hemoglobin A_1c and average glucose values.³

WHAT IS AN APPROPRIATE HEMOGLOBIN A_1c TARGET?

The short answer is, “It depends.”

Currently, the American Association of Clinical Endocrinologists (AACE) supports a hemoglobin A_1c goal of less than 6.5% for otherwise healthy patients but states that the goal should be individualized for patients with concurrent illnesses or at risk of hypoglycemia.⁴

On the other hand, the American Diabetes Association (ADA) recommends a higher hemoglobin A_1c target of less than 7% for most adults with type 2 diabetes mellitus.⁵ This value was shown to be associated with a reduction in the microvascular and macrovascular complications of diabetes.