The Journal of Family Practice

THE CASE

A 49-year-old man with chronic insomnia was referred to the pharmacist authors (LF and DP) to initiate and manage the tapering of nightly zolpidem use. Per chart review, the patient had complaints of insomnia for more than 30 years. His care had been transferred to a Nebraska clinic 5 years earlier, with a medication list that included zolpidem controlled release (CR) 12.5 mg nightly. Since then, multiple interventions to achieve cessation had been tried, including counseling on sleep hygiene, adjunct antidepressant use, and abrupt discontinuation. Each of these methods was unsuccessful. So, his family physician (SS) reached out to the pharmacist authors (LF and DP).

THE APPROACH

Due to the patient’s long history of zolpidem use, a lack of literature on the topic, and worry for withdrawal symptoms, a taper schedule was designed utilizing various benzodiazepine taper resources for guidance. The proposed taper utilized 5-mg immediate release (IR) tablets to ensure ease of tapering. The taper ranged from 20% to 43% weekly reductions based on the ability to split the zolpidem tablet in half.

DISCUSSION

Zolpidem is a sedative-hypnotic medication indicated for the treatment of insomnia when used at therapeutic dosing (ie, 5 to 10 mg nightly). Anecdotal efficacy, accompanied by weak chronic insomnia guideline recommendations, has led prescribers to use zolpidem as a chronic medication to treat insomnia.^1,2 There is evidence of dependence and possible seizures from supratherapeutic zolpidem doses in the hundreds of milligrams, raising safety concerns regarding abuse, dependence, and withdrawal seizures in chronic use.^2,3

Additionally, there is limited evidence regarding the appropriate process of discontinuing zolpidem after chronic use.² Often a taper schedule—similar to those used with benzodiazepine medications—is used as a reference for discontinuation.¹ The hypothetical goal of a taper is to prevent withdrawal effects such as rebound insomnia, anxiety, palpitations, and seizures.³ However, an extended taper may not actually be necessary with chronic zolpidem patients.

Tapering with minimal adverse effects

Pharmacokinetic and pharmacodynamic studies have suggested minimal, if not complete, absence of rebound or withdrawal effects with short-term zolpidem use.⁴ The same appears to be true of patients with long-term use. In a study, Roehrs and colleagues⁵ explored whether long-term treatment (defined as 8 months) caused rebound insomnia upon abrupt withdrawal. The investigators concluded that people with primary insomnia do not experience rebound insomnia or withdrawal symptoms with chronic, therapeutic dosing.

This case documents a successfully accelerated taper for a patient with a chronic history (> 5 years) of zolpidem use.

Another study involving 92 elderly patients on long-term treatment of zolpidem (defined as > 1 month, with average around 9.9 ± 6.2 years) experienced only 1 or 2 nights of rebound insomnia during a month-long taper.^1,6 Following that, they experienced improvements in initiation and staying asleep.

A possible explanation for the lack of dependence or withdrawal symptoms in patients chronically treated with zolpidem is the pharmacokinetic profile. While the selectivity of the binding sites differentiates this medication from benzodiazepines, the additional fact of a short half-life, and no repeated dosing throughout the day, likely limit the risk of experiencing withdrawal symptoms.¹ The daily periods of minimal zolpidem exposure in the body may limit the amount of physical dependence.

Continue to: Discontinuation of zolpidem

Discontinuation of zolpidem

The 49-year-old man had a history of failed abrupt discontinuation of zolpidem in the past (without noted withdrawal symptoms). Thus, various benzodiazepine taper resources were consulted to develop a taper schedule.

We switched our patient from the zolpidem CR 12.5 mg nightly to 10 mg of the IR formulation, and the pharmacists proposed 20% to 43% weekly decreases in dosing based on dosage strengths. At the initial 3-day follow-up (having taken 10 mg nightly for 3 days), the patient reported a quicker onset of sleep but an inability to sleep through the night. The patient denied withdrawal symptoms or any significant impact to his daily routines. These results encouraged a progression to the next step of the taper. For the next 9 days, the patient took 5 mg nightly, rather than the pharmacist-advised dosing of alternating 5 mg and 10 mg nightly, and reported similar outcomes at his next visit.

This success led to the discontinuation of scheduled zolpidem. The patient was also given a prescription of 2.5 mg, as needed, if insomnia rebounded. No adverse effects were noted despite the accelerated taper. Based on patient response and motivation, the taper had progressed more quickly than scheduled, resulting in 3 days of 10 mg, 9 days of 5 mg, and 1 final day of 2.5 mg that was used when the patient had trouble falling asleep. At the 6-month follow-up, the patient informed the physician that he had neither experienced insomnia nor used any further medication.

THE TAKEAWAY

This case documents a successfully accelerated taper for a patient with a chronic history (> 5 years) of zolpidem use. Although withdrawal is often patient specific, this case suggests the risk is low despite the chronic usage. This further adds to the literature suggesting against the need for an extended taper, and possibly a taper at all, when using recommended doses of chronic zolpidem. This is a significant difference compared to past practices that drew from literature-based benzodiazepine tapers.⁶ This case serves as an observational point of reference for clinicians who are assisting patients with chronic zolpidem tapers.

CORRESPONDENCE
Logan Franck, PharmD, 986145 Nebraska Medical Center, Omaha, NE 68198-6145; logan.franck@unmc.edu

THE CASE

A 49-year-old man with chronic insomnia was referred to the pharmacist authors (LF and DP) to initiate and manage the tapering of nightly zolpidem use. Per chart review, the patient had complaints of insomnia for more than 30 years. His care had been transferred to a Nebraska clinic 5 years earlier, with a medication list that included zolpidem controlled release (CR) 12.5 mg nightly. Since then, multiple interventions to achieve cessation had been tried, including counseling on sleep hygiene, adjunct antidepressant use, and abrupt discontinuation. Each of these methods was unsuccessful. So, his family physician (SS) reached out to the pharmacist authors (LF and DP).

THE APPROACH

Due to the patient’s long history of zolpidem use, a lack of literature on the topic, and worry for withdrawal symptoms, a taper schedule was designed utilizing various benzodiazepine taper resources for guidance. The proposed taper utilized 5-mg immediate release (IR) tablets to ensure ease of tapering. The taper ranged from 20% to 43% weekly reductions based on the ability to split the zolpidem tablet in half.

DISCUSSION

Zolpidem is a sedative-hypnotic medication indicated for the treatment of insomnia when used at therapeutic dosing (ie, 5 to 10 mg nightly). Anecdotal efficacy, accompanied by weak chronic insomnia guideline recommendations, has led prescribers to use zolpidem as a chronic medication to treat insomnia.^1,2 There is evidence of dependence and possible seizures from supratherapeutic zolpidem doses in the hundreds of milligrams, raising safety concerns regarding abuse, dependence, and withdrawal seizures in chronic use.^2,3

Additionally, there is limited evidence regarding the appropriate process of discontinuing zolpidem after chronic use.² Often a taper schedule—similar to those used with benzodiazepine medications—is used as a reference for discontinuation.¹ The hypothetical goal of a taper is to prevent withdrawal effects such as rebound insomnia, anxiety, palpitations, and seizures.³ However, an extended taper may not actually be necessary with chronic zolpidem patients.

Tapering with minimal adverse effects

Pharmacokinetic and pharmacodynamic studies have suggested minimal, if not complete, absence of rebound or withdrawal effects with short-term zolpidem use.⁴ The same appears to be true of patients with long-term use. In a study, Roehrs and colleagues⁵ explored whether long-term treatment (defined as 8 months) caused rebound insomnia upon abrupt withdrawal. The investigators concluded that people with primary insomnia do not experience rebound insomnia or withdrawal symptoms with chronic, therapeutic dosing.

This case documents a successfully accelerated taper for a patient with a chronic history (> 5 years) of zolpidem use.

Another study involving 92 elderly patients on long-term treatment of zolpidem (defined as > 1 month, with average around 9.9 ± 6.2 years) experienced only 1 or 2 nights of rebound insomnia during a month-long taper.^1,6 Following that, they experienced improvements in initiation and staying asleep.

A possible explanation for the lack of dependence or withdrawal symptoms in patients chronically treated with zolpidem is the pharmacokinetic profile. While the selectivity of the binding sites differentiates this medication from benzodiazepines, the additional fact of a short half-life, and no repeated dosing throughout the day, likely limit the risk of experiencing withdrawal symptoms.¹ The daily periods of minimal zolpidem exposure in the body may limit the amount of physical dependence.

Continue to: Discontinuation of zolpidem

Discontinuation of zolpidem

The 49-year-old man had a history of failed abrupt discontinuation of zolpidem in the past (without noted withdrawal symptoms). Thus, various benzodiazepine taper resources were consulted to develop a taper schedule.

We switched our patient from the zolpidem CR 12.5 mg nightly to 10 mg of the IR formulation, and the pharmacists proposed 20% to 43% weekly decreases in dosing based on dosage strengths. At the initial 3-day follow-up (having taken 10 mg nightly for 3 days), the patient reported a quicker onset of sleep but an inability to sleep through the night. The patient denied withdrawal symptoms or any significant impact to his daily routines. These results encouraged a progression to the next step of the taper. For the next 9 days, the patient took 5 mg nightly, rather than the pharmacist-advised dosing of alternating 5 mg and 10 mg nightly, and reported similar outcomes at his next visit.

This success led to the discontinuation of scheduled zolpidem. The patient was also given a prescription of 2.5 mg, as needed, if insomnia rebounded. No adverse effects were noted despite the accelerated taper. Based on patient response and motivation, the taper had progressed more quickly than scheduled, resulting in 3 days of 10 mg, 9 days of 5 mg, and 1 final day of 2.5 mg that was used when the patient had trouble falling asleep. At the 6-month follow-up, the patient informed the physician that he had neither experienced insomnia nor used any further medication.

THE TAKEAWAY

This case documents a successfully accelerated taper for a patient with a chronic history (> 5 years) of zolpidem use. Although withdrawal is often patient specific, this case suggests the risk is low despite the chronic usage. This further adds to the literature suggesting against the need for an extended taper, and possibly a taper at all, when using recommended doses of chronic zolpidem. This is a significant difference compared to past practices that drew from literature-based benzodiazepine tapers.⁶ This case serves as an observational point of reference for clinicians who are assisting patients with chronic zolpidem tapers.

CORRESPONDENCE
Logan Franck, PharmD, 986145 Nebraska Medical Center, Omaha, NE 68198-6145; logan.franck@unmc.edu

THE CASE

A 49-year-old man with chronic insomnia was referred to the pharmacist authors (LF and DP) to initiate and manage the tapering of nightly zolpidem use. Per chart review, the patient had complaints of insomnia for more than 30 years. His care had been transferred to a Nebraska clinic 5 years earlier, with a medication list that included zolpidem controlled release (CR) 12.5 mg nightly. Since then, multiple interventions to achieve cessation had been tried, including counseling on sleep hygiene, adjunct antidepressant use, and abrupt discontinuation. Each of these methods was unsuccessful. So, his family physician (SS) reached out to the pharmacist authors (LF and DP).

THE APPROACH

Due to the patient’s long history of zolpidem use, a lack of literature on the topic, and worry for withdrawal symptoms, a taper schedule was designed utilizing various benzodiazepine taper resources for guidance. The proposed taper utilized 5-mg immediate release (IR) tablets to ensure ease of tapering. The taper ranged from 20% to 43% weekly reductions based on the ability to split the zolpidem tablet in half.

DISCUSSION

Zolpidem is a sedative-hypnotic medication indicated for the treatment of insomnia when used at therapeutic dosing (ie, 5 to 10 mg nightly). Anecdotal efficacy, accompanied by weak chronic insomnia guideline recommendations, has led prescribers to use zolpidem as a chronic medication to treat insomnia.^1,2 There is evidence of dependence and possible seizures from supratherapeutic zolpidem doses in the hundreds of milligrams, raising safety concerns regarding abuse, dependence, and withdrawal seizures in chronic use.^2,3

Additionally, there is limited evidence regarding the appropriate process of discontinuing zolpidem after chronic use.² Often a taper schedule—similar to those used with benzodiazepine medications—is used as a reference for discontinuation.¹ The hypothetical goal of a taper is to prevent withdrawal effects such as rebound insomnia, anxiety, palpitations, and seizures.³ However, an extended taper may not actually be necessary with chronic zolpidem patients.

Tapering with minimal adverse effects

Pharmacokinetic and pharmacodynamic studies have suggested minimal, if not complete, absence of rebound or withdrawal effects with short-term zolpidem use.⁴ The same appears to be true of patients with long-term use. In a study, Roehrs and colleagues⁵ explored whether long-term treatment (defined as 8 months) caused rebound insomnia upon abrupt withdrawal. The investigators concluded that people with primary insomnia do not experience rebound insomnia or withdrawal symptoms with chronic, therapeutic dosing.

This case documents a successfully accelerated taper for a patient with a chronic history (> 5 years) of zolpidem use.

Another study involving 92 elderly patients on long-term treatment of zolpidem (defined as > 1 month, with average around 9.9 ± 6.2 years) experienced only 1 or 2 nights of rebound insomnia during a month-long taper.^1,6 Following that, they experienced improvements in initiation and staying asleep.

A possible explanation for the lack of dependence or withdrawal symptoms in patients chronically treated with zolpidem is the pharmacokinetic profile. While the selectivity of the binding sites differentiates this medication from benzodiazepines, the additional fact of a short half-life, and no repeated dosing throughout the day, likely limit the risk of experiencing withdrawal symptoms.¹ The daily periods of minimal zolpidem exposure in the body may limit the amount of physical dependence.

Continue to: Discontinuation of zolpidem

Discontinuation of zolpidem

The 49-year-old man had a history of failed abrupt discontinuation of zolpidem in the past (without noted withdrawal symptoms). Thus, various benzodiazepine taper resources were consulted to develop a taper schedule.

We switched our patient from the zolpidem CR 12.5 mg nightly to 10 mg of the IR formulation, and the pharmacists proposed 20% to 43% weekly decreases in dosing based on dosage strengths. At the initial 3-day follow-up (having taken 10 mg nightly for 3 days), the patient reported a quicker onset of sleep but an inability to sleep through the night. The patient denied withdrawal symptoms or any significant impact to his daily routines. These results encouraged a progression to the next step of the taper. For the next 9 days, the patient took 5 mg nightly, rather than the pharmacist-advised dosing of alternating 5 mg and 10 mg nightly, and reported similar outcomes at his next visit.

This success led to the discontinuation of scheduled zolpidem. The patient was also given a prescription of 2.5 mg, as needed, if insomnia rebounded. No adverse effects were noted despite the accelerated taper. Based on patient response and motivation, the taper had progressed more quickly than scheduled, resulting in 3 days of 10 mg, 9 days of 5 mg, and 1 final day of 2.5 mg that was used when the patient had trouble falling asleep. At the 6-month follow-up, the patient informed the physician that he had neither experienced insomnia nor used any further medication.

THE TAKEAWAY

This case documents a successfully accelerated taper for a patient with a chronic history (> 5 years) of zolpidem use. Although withdrawal is often patient specific, this case suggests the risk is low despite the chronic usage. This further adds to the literature suggesting against the need for an extended taper, and possibly a taper at all, when using recommended doses of chronic zolpidem. This is a significant difference compared to past practices that drew from literature-based benzodiazepine tapers.⁶ This case serves as an observational point of reference for clinicians who are assisting patients with chronic zolpidem tapers.

CORRESPONDENCE
Logan Franck, PharmD, 986145 Nebraska Medical Center, Omaha, NE 68198-6145; logan.franck@unmc.edu

REFERENCES

1. Weng MK. Universal adult hepatitis B vaccinations: work group considerations. Presented to the Advisory Committee on Immunization Practices on November 3, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/02-HepWG-weng-508.pdf
2. Kovayashi M. Considerations for age-based and risk-based use of PCV15 and PCV20 among US adults and proposed policy options. Presented to the Advisory Committee on Immunization Practices on October 20, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-10-20-21/02-Pneumococcal-Kobayashi-508.pdf
3. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67:1-31.
4. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morbid Mortal Wkly Rep. 2019;68:1069-1075.

REFERENCES

1. Weng MK. Universal adult hepatitis B vaccinations: work group considerations. Presented to the Advisory Committee on Immunization Practices on November 3, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/02-HepWG-weng-508.pdf
2. Kovayashi M. Considerations for age-based and risk-based use of PCV15 and PCV20 among US adults and proposed policy options. Presented to the Advisory Committee on Immunization Practices on October 20, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-10-20-21/02-Pneumococcal-Kobayashi-508.pdf
3. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67:1-31.
4. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morbid Mortal Wkly Rep. 2019;68:1069-1075.

REFERENCES

1. Weng MK. Universal adult hepatitis B vaccinations: work group considerations. Presented to the Advisory Committee on Immunization Practices on November 3, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/02-HepWG-weng-508.pdf
2. Kovayashi M. Considerations for age-based and risk-based use of PCV15 and PCV20 among US adults and proposed policy options. Presented to the Advisory Committee on Immunization Practices on October 20, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-10-20-21/02-Pneumococcal-Kobayashi-508.pdf
3. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67:1-31.
4. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morbid Mortal Wkly Rep. 2019;68:1069-1075.

Botulinum toxin (BoNT) was first approved by the US Food and Drug Administration (FDA) for the treatment of strabismus and blepharospasm in 1989. Since then, approved indications have expanded to include spasticity, cervical dystonia, severe axillary hyperhidrosis, bladder dysfunction, and chronic migraine headache, as well as multiple cosmetic uses.^1,2 Over the course of 30 years of clinical use, BoNT has proven to be effective and safe.^3,4 This has led to the expanded use of BoNT for additional medical conditions.^1,2

In the review that follows, we will discuss the utility of BoNT in the treatment of headaches, spasticity, and cervical dystonia. We will then explore the evidence for emerging indications that include chronic joint pain, trigeminal neuralgia, and plantar fasciitis. But first, a brief word about how BoNT works and its safety profile.

Seven toxins, but only 2 are used for medical purposes

BoNT is naturally produced by Clostridium botulinum, an anaerobic, spore-forming bacteria.¹ BoNT inhibits acetylcholine release from presynaptic vesicles at the neuromuscular junctions, which results in flaccid paralysis in peripheral skeletal musculature and autonomic nerve terminals.^1,5 These effects from BoNT can last up to 3 to 6 months.¹

Seven different toxins have been identified (A, B, C, D, E, F, and G), but only toxins A and B are currently used for medical purposes.⁵ Both have similar effects, although there are slight differences in mechanism of action. Toxin B injections are also reported to be slightly more painful. There are also differences in preparation, with some requiring reconstitution, which vary by brand. Certain types of BoNT require refrigeration, and an in-depth review of the manufacturer’s guidelines is recommended before use.

Safety and adverse effects

Although BoNT is 1 of the most lethal toxins known to humans, it has been used in clinical medicine for more than 30 years and has proven to be safe if used properly.³ Adverse effects are rare and are often location and dose dependent (200 U and higher). Immediate or acute adverse effects are usually mild and can include bruising, headache, allergic reactions, edema, skin conditions, infection, or pain at the injection site.⁴ Delayed adverse effects can include muscle weakness that persists throughout the 3 to 6 months of duration and is usually related to incorrect placement or unintentional spread.⁴

Serious adverse events are rare: there are reports of the development of botulism, generalized paralysis, dysphagia, respiratory effects, and even death in patients who had received BoNT injections.³ In a majority of cases, a direct relationship with BoNT was never established, and in most incidents reported, there were significant comorbidities that could have contributed to the adverse event.³ These events appear to be related to higher doses of BoNT, as well as possible incorrect injection placement.³

Knowledge of anatomy and correct placement of BoNT are vitally important, as they have a significant impact on the effectiveness of treatment and adverse events.³ In preventing adverse events, those administering BoNT need to be familiar with the BoNT brand being used, verify proper storage consistent with the manufacturer’s recommendations, and confirm correct dosages with proper reconstitution process.³

Continue to: BoNT is contraindicated

BoNT is contraindicated in those with a history of a previous anaphylactic reaction to BoNT. Patients with known hypersensitivity to BoNT, including those with neuromuscular junction diseases and anterior horn disorders, should be considered for other forms of treatment due to the risk of an exaggerated response. No adverse events have been recorded in regard to pregnancy and lactation, although these remain a potential contraindication.^3,4,6

Taking a closer look at current indications

Headaches

Chronic migraine (CM) is defined by the International Headache Society as at least 15 days per month with headaches and 8 of those days with migraine features. BoNT has been FDA approved for treatment of CM since 2011. This was based on 2 large, double-blind, randomized, placebo-controlled trials that showed a significant reduction from baseline for headaches and migraine days, total time, and frequency of migraines.^7,8

Knowledge of anatomy and correct placement of BoNT are vitally important, as they have a significant impact on the effectiveness of treatment and adverse events.

Subsequent studies have continued to show benefit for CM treatment. In a recent Cochrane systematic review and meta-­analysis, it was determined that BoNT can decrease frequency of CM by 2 days per month, and it is recommended by several organizations as a treatment option for CM.⁹

Low-quality evidence has not shown benefit for tension-type headaches. However, further research is warranted, especially for chronic tension-type headache, which is defined as daily tension headaches.¹⁰

Spasticity

Spasticity is caused by an insult to the brain or spinal cord and can often occur after a stroke, brain or spinal cord injury, cerebral palsy, or other neurologic condition.¹¹ BoNT was initially FDA approved in 2010 for treatment of upper limb spasticity in adults, although it had been used for treatment for spasticity for more than 20 years prior to that. It currently is approved for upper and lower spasticity in adults and recently was expanded to include pediatrics.¹²

Continue to: A small case series...

A small case series conducted soon after BoNT was introduced showed promising results, and subsequent meta-analyses and systematic reviews have shown positive results for use of BoNT for the management of spasticity.¹³ Studies have begun to focus on specific regions of the upper and lower limbs to identify optimal sites for injections.

Cervical dystonia

Cervical dystonia (CD) is the most common form of dystonia and is defined as impairment of activities of daily living due to abnormal postures of the head and neck. BoNT was approved for CD in 1999 after several pivotal randomized placebo-controlled ­double-blind studies showed improvement of symptoms.¹⁴ Several BoNT formulations have been given Level A classification, and can be considered a potential first-line treatment for CD.^15,16 The most common adverse effects reported have been dry mouth, dysphagia, muscle weakness, and neck pain.^14-16

Recent metaanalyses evaluating knee and shoulder pain have shown BoNT is safe and effective for joint pain.

BoNT is currently being used off-label for management of multiple types of dystonia with reported success, as research on its use for noncervical dystonia (including limb, laryngeal, oromandibular, and truncal) continues. Although there are case series and some randomized trials exploring BoNT for certain types of dystonia, most are lacking high-­quality evidence from double-blind, randomized controlled trials.^14-16

Exploring the evidence for emerging indications

There has been significant interest in using BoNT for management for both nociceptive and neuropathic pain symptoms.⁵

Nociceptive pain is the irritation and painful response to actual or potential tissue damage. It is a major component of chronic pain and is difficult to treat, with limited effective options.^5,17

Continue to: Neuropathic pain

Neuropathic pain is related to abnormalities that disrupt the normal function of the nervous system. Abnormalities could be related to anatomic or structural changes that cause compression, trauma, scar tissue, or a number of other conditions that affect nerve function. These can be either central or peripheral and can be caused by multiple etiologies.

The following discussion explores the evidence for potential emerging indications for BoNT. The TABLE^1,5,18-40 summarizes what we know to date.

Chronic joint pain

Refractory joint pain is difficult to treat and can be debilitating for patients. It can have multiple causes but is most commonly related to arthritic changes. Due to the difficulty with treatment, there have been attempts to use BoNT as an intra-articular treatment for refractory joint pain. Results vary and are related to several factors, including the initial degree of pain, the BoNT dosage, and the formulation used, as well as the joint injected.

There appears to be a potentially significant improvement in short-term pain with BoNT compared to conventional therapies, such as physical therapy, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and hyaluronic acid injections. In studies evaluating long-term benefits, it was noted that after 6 months, there was no significant difference between BoNT and control groups.^19-21

The knee joint has been the focus of most research, but BoNT has also been used for shoulder and ankle pain, with success. Recent meta-analyses evaluating knee and shoulder pain have shown BoNT is safe and effective for joint pain.^20,21 There has been no significant difference noted in adverse events with BoNT compared to controls. Currently, more long-term data and research are needed, but BoNT is safe and a potentially effective treatment option for short-term relief of refractory joint pain.^19-21

Continue to: Chronic exertional compartment sydrome

Chronic exertional compartment syndrome (CECS) is defined subjectively as pain in a specific compartment that develops during exercise and resolves upon stopping, as well as objectively with an increase in intra-­muscular pressure.²² It is most common in the lower leg and is a difficult condition to manage. Nonsurgical and surgical options are only successful at returning the patient to full activity 40% to 80% of the time.²³

An initial study done in 2013 of BoNT injected into the anterior and lateral compartments of the lower extremity showed that symptoms resolved completely in 94% of patients treated.²² The actual mechanism of benefit is not clearly understood but is potentially related to muscle atrophy and loss of contractile tissue. However, it has not been reported that these changes have affected the strength or performance of patients who receive BoNT for CECS.²³

Thoracic outlet syndrome

Thoracic outlet syndrome (TOS) is a compression of neurovascular structures within the thoracic outlet. There are several locations of potential compression, as well as possible neurogenic, vascular, or nonspecific manifestations.²⁴ Compression can be from a structural variant, such as a cervical rib, or due to soft tissue from the scalene or pectoralis musculature. TOS is difficult to diagnose and treat. Physical therapy is the mainstay of treatment, but failure is common and treatment options are otherwise limited. Decompression surgery is an option if conservative management fails, but it has a high recurrence rate.²⁴

In an effort to harness the therapeutic value of muscle atrophy, denervation, and relaxation afforded by BoNT, clinicians have injected the agent into the anterior and middle scalenes and the pectoralis minor to provide patients with relief from TOS.²⁴ This treatment requires advanced imaging with either fluoroscopy or ultrasound guidance for correct placement and knowledge of surrounding anatomy. Small case reports and case series have demonstrated success, but a small double-blind randomized controlled study of 37 individuals with neurogenic TOS in 2011 did not show a reduction in symptoms.²⁵ Multiple subsequent case reports and case series have continued to show positive results.^24,25 A recent retrospective study showed that patients with TOS who had positive results with BoNT had better surgical outcomes.²⁶

Trigeminal neuralgia and peripheral nerve pain

A meta-analysis in 2019 reviewed evidence for trigeminal neuralgia as well as other types of peripheral neuropathies, including diabetic neuropathy and postherpetic neuropathy. It showed that BoNT injections are safe, as well as effective, for short-term relief at 3 months. However, overall study sizes were small and long-term data are still lacking; larger high-quality studies are needed for further substantiation.²⁷

Continue to: Plantar fascitis

BoNT has been used for treatment of plantar fasciitis. Small randomized controlled studies have compared BoNT to both placebo and corticosteroids, showing that BoNT has better long-term outcomes at 3, 6, and 12 months.^28,29 BoNT is currently being used when standard treatments have failed; however, larger randomized controlled studies are still needed prior to BoNT being accepted as standard treatment.²⁹

Lateral epicondylitis

A systematic review and meta-analysis done in 2017 showed that BoNT is superior to placebo at 16 weeks. No significant difference was noted between BoNT and corticosteroids at 8 weeks, although corticosteroids did demonstrate better improvement at the short-term interval of 2 to 4 weeks.³⁰ As expected, BoNT was associated with grip-strength weakness compared to placebo and corticosteroids at 12 weeks. Subsequent small randomized controlled studies have continued to show benefit with BoNT, but all studies noted grip weakness (which resolved) and duration of effect was dose dependent.^30,31

Temporomandibular joint pain

BoNT has been studied in the treatment of temporomandibular joint (TMJ) pain and dislocations since 1998, and was shown to improve quality of life.³² BoNT has been injected into the musculature surrounding the TMJ, as well as into the joint, and has proven to be effective in these areas.³³ There are limited treatment options for TMJ pain and dislocations, and although research is still ongoing, BoNT is considered a potential treatment option.^32,33

Myofascial, neck, and back chronic pain

Chronic back pain is common and can be due to multiple conditions. BoNT has been studied for treatment focusing on myofascial pain in the neck and back region. Case series have shown improvement with targeted BoNT injections.³⁴ However, in randomized controlled double-blind studies comparing BoNT to placebo, local anesthetics, and steroids, there were no significant differences in pain scores.^35,36 The majority of studies have been landmark based or used the site of maximal tenderness as guidance for injections, but there is some evidence that targeted injections focusing on specific muscle groups may improve benefit.⁵ This usually requires the use of imaging for guidance.

Chronic pelvic pain

Chronic pelvic pain is common and has been reported to affect 1 in 7 women.³⁷ It is often difficult to diagnose the exact source of the pain, and it can be very difficult to treat. In a 2020 systematic review (including 12 observational studies and 5 randomized controlled trials) of BoNT for treatment of chronic pelvic pain, the quality of evidence varied widely.³⁸ Observational studies showed good benefit, but only 1 randomized trial showed statistical difference with the use of BoNT for pelvic pain. No serious adverse events were reported in any of the studies.³⁸ Chronic pelvic pain can be caused by a number of different conditions, and more high-quality research for BoNT is needed, focusing on specific causes.^5,38

Continue to: Complex regional pain

Complex regional pain

Complex regional pain syndrome (CRPS) can be a debilitating condition that causes pain, sympathetic dysregulation, and central nervous system sensitization, often related to a traumatic event. Incidence is reported as 5 to 26 per 100,000, although it most likely is severely underdiagnosed.³⁹ Treatment options are limited, and often patients continue to struggle with pain.

Due to the mechanism of action of BoNT, it has a high potential benefit for treatment of the allodynia and hyperalgesia associated with CRPS. BoNT injections have been used for the treatment of CRPS with limited success.⁴⁰

Although research is ongoing, BoNT is considered a potential treatment option for TMJ pain.

There is currently limited evidence on BoNT for CRPS, and uncertainty regarding the best injection location remains. Studies have looked at lumbar sympathetic blocks, intra-­articular, and grid-like BoNT injections over the area affected by CRPS.^39-41 Case studies/series and observational studies have shown success with minimal adverse reactions, but larger high-quality, randomized controlled double-blind studies are still lacking.^39-41

Concluding thoughts

Most chronic pain conditions have very limited treatment options, making the exploration of BoNT as a potential addition to those treatments an appealing possibility. Since it was first introduced in 1989, it has been proven to be safe, with limited adverse events, for the treatment of chronic pain.

Due to the mechanism of action of BoNT, it has a high potential benefit for treatment of the allodynia and hyperalgesia associated with complex regional pain syndrome.

However, providers need to be familiar with the type and formulation of BoNT product being used. Extensive knowledge of surrounding anatomy and ability to place BoNT in an exact location (which may require either fluoroscopy or ultrasound guidance) is essential.

Continue to: Adequate research and evidence...

Adequate research and evidence for most of the applications discussed in this article are still lacking; some limitations include small sample size, bias, lower quality, and poor methodology. There is also a lack of standardization, including which BoNT product is used, dosage, and location of BoNT placement. All of these issues will need to be addressed in further research.

CORRESPONDENCE
Caleb Dickison, DO, CAQSM, 36065 Darnall Loop, Fort Hood, TX 76544; cal.dickison23@gmail.com

Botulinum toxin (BoNT) was first approved by the US Food and Drug Administration (FDA) for the treatment of strabismus and blepharospasm in 1989. Since then, approved indications have expanded to include spasticity, cervical dystonia, severe axillary hyperhidrosis, bladder dysfunction, and chronic migraine headache, as well as multiple cosmetic uses.^1,2 Over the course of 30 years of clinical use, BoNT has proven to be effective and safe.^3,4 This has led to the expanded use of BoNT for additional medical conditions.^1,2

In the review that follows, we will discuss the utility of BoNT in the treatment of headaches, spasticity, and cervical dystonia. We will then explore the evidence for emerging indications that include chronic joint pain, trigeminal neuralgia, and plantar fasciitis. But first, a brief word about how BoNT works and its safety profile.

Seven toxins, but only 2 are used for medical purposes

BoNT is naturally produced by Clostridium botulinum, an anaerobic, spore-forming bacteria.¹ BoNT inhibits acetylcholine release from presynaptic vesicles at the neuromuscular junctions, which results in flaccid paralysis in peripheral skeletal musculature and autonomic nerve terminals.^1,5 These effects from BoNT can last up to 3 to 6 months.¹

Seven different toxins have been identified (A, B, C, D, E, F, and G), but only toxins A and B are currently used for medical purposes.⁵ Both have similar effects, although there are slight differences in mechanism of action. Toxin B injections are also reported to be slightly more painful. There are also differences in preparation, with some requiring reconstitution, which vary by brand. Certain types of BoNT require refrigeration, and an in-depth review of the manufacturer’s guidelines is recommended before use.

Safety and adverse effects

Although BoNT is 1 of the most lethal toxins known to humans, it has been used in clinical medicine for more than 30 years and has proven to be safe if used properly.³ Adverse effects are rare and are often location and dose dependent (200 U and higher). Immediate or acute adverse effects are usually mild and can include bruising, headache, allergic reactions, edema, skin conditions, infection, or pain at the injection site.⁴ Delayed adverse effects can include muscle weakness that persists throughout the 3 to 6 months of duration and is usually related to incorrect placement or unintentional spread.⁴

Serious adverse events are rare: there are reports of the development of botulism, generalized paralysis, dysphagia, respiratory effects, and even death in patients who had received BoNT injections.³ In a majority of cases, a direct relationship with BoNT was never established, and in most incidents reported, there were significant comorbidities that could have contributed to the adverse event.³ These events appear to be related to higher doses of BoNT, as well as possible incorrect injection placement.³

Knowledge of anatomy and correct placement of BoNT are vitally important, as they have a significant impact on the effectiveness of treatment and adverse events.³ In preventing adverse events, those administering BoNT need to be familiar with the BoNT brand being used, verify proper storage consistent with the manufacturer’s recommendations, and confirm correct dosages with proper reconstitution process.³

Continue to: BoNT is contraindicated

BoNT is contraindicated in those with a history of a previous anaphylactic reaction to BoNT. Patients with known hypersensitivity to BoNT, including those with neuromuscular junction diseases and anterior horn disorders, should be considered for other forms of treatment due to the risk of an exaggerated response. No adverse events have been recorded in regard to pregnancy and lactation, although these remain a potential contraindication.^3,4,6

Taking a closer look at current indications

Headaches

Chronic migraine (CM) is defined by the International Headache Society as at least 15 days per month with headaches and 8 of those days with migraine features. BoNT has been FDA approved for treatment of CM since 2011. This was based on 2 large, double-blind, randomized, placebo-controlled trials that showed a significant reduction from baseline for headaches and migraine days, total time, and frequency of migraines.^7,8

Knowledge of anatomy and correct placement of BoNT are vitally important, as they have a significant impact on the effectiveness of treatment and adverse events.

Subsequent studies have continued to show benefit for CM treatment. In a recent Cochrane systematic review and meta-­analysis, it was determined that BoNT can decrease frequency of CM by 2 days per month, and it is recommended by several organizations as a treatment option for CM.⁹

Low-quality evidence has not shown benefit for tension-type headaches. However, further research is warranted, especially for chronic tension-type headache, which is defined as daily tension headaches.¹⁰

Spasticity

Spasticity is caused by an insult to the brain or spinal cord and can often occur after a stroke, brain or spinal cord injury, cerebral palsy, or other neurologic condition.¹¹ BoNT was initially FDA approved in 2010 for treatment of upper limb spasticity in adults, although it had been used for treatment for spasticity for more than 20 years prior to that. It currently is approved for upper and lower spasticity in adults and recently was expanded to include pediatrics.¹²

Continue to: A small case series...

A small case series conducted soon after BoNT was introduced showed promising results, and subsequent meta-analyses and systematic reviews have shown positive results for use of BoNT for the management of spasticity.¹³ Studies have begun to focus on specific regions of the upper and lower limbs to identify optimal sites for injections.

Cervical dystonia

Cervical dystonia (CD) is the most common form of dystonia and is defined as impairment of activities of daily living due to abnormal postures of the head and neck. BoNT was approved for CD in 1999 after several pivotal randomized placebo-controlled ­double-blind studies showed improvement of symptoms.¹⁴ Several BoNT formulations have been given Level A classification, and can be considered a potential first-line treatment for CD.^15,16 The most common adverse effects reported have been dry mouth, dysphagia, muscle weakness, and neck pain.^14-16

Recent metaanalyses evaluating knee and shoulder pain have shown BoNT is safe and effective for joint pain.

BoNT is currently being used off-label for management of multiple types of dystonia with reported success, as research on its use for noncervical dystonia (including limb, laryngeal, oromandibular, and truncal) continues. Although there are case series and some randomized trials exploring BoNT for certain types of dystonia, most are lacking high-­quality evidence from double-blind, randomized controlled trials.^14-16

Exploring the evidence for emerging indications

There has been significant interest in using BoNT for management for both nociceptive and neuropathic pain symptoms.⁵

Nociceptive pain is the irritation and painful response to actual or potential tissue damage. It is a major component of chronic pain and is difficult to treat, with limited effective options.^5,17

Continue to: Neuropathic pain

Neuropathic pain is related to abnormalities that disrupt the normal function of the nervous system. Abnormalities could be related to anatomic or structural changes that cause compression, trauma, scar tissue, or a number of other conditions that affect nerve function. These can be either central or peripheral and can be caused by multiple etiologies.

The following discussion explores the evidence for potential emerging indications for BoNT. The TABLE^1,5,18-40 summarizes what we know to date.

Chronic joint pain

Refractory joint pain is difficult to treat and can be debilitating for patients. It can have multiple causes but is most commonly related to arthritic changes. Due to the difficulty with treatment, there have been attempts to use BoNT as an intra-articular treatment for refractory joint pain. Results vary and are related to several factors, including the initial degree of pain, the BoNT dosage, and the formulation used, as well as the joint injected.

There appears to be a potentially significant improvement in short-term pain with BoNT compared to conventional therapies, such as physical therapy, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and hyaluronic acid injections. In studies evaluating long-term benefits, it was noted that after 6 months, there was no significant difference between BoNT and control groups.^19-21

The knee joint has been the focus of most research, but BoNT has also been used for shoulder and ankle pain, with success. Recent meta-analyses evaluating knee and shoulder pain have shown BoNT is safe and effective for joint pain.^20,21 There has been no significant difference noted in adverse events with BoNT compared to controls. Currently, more long-term data and research are needed, but BoNT is safe and a potentially effective treatment option for short-term relief of refractory joint pain.^19-21

Continue to: Chronic exertional compartment sydrome

Chronic exertional compartment syndrome (CECS) is defined subjectively as pain in a specific compartment that develops during exercise and resolves upon stopping, as well as objectively with an increase in intra-­muscular pressure.²² It is most common in the lower leg and is a difficult condition to manage. Nonsurgical and surgical options are only successful at returning the patient to full activity 40% to 80% of the time.²³

An initial study done in 2013 of BoNT injected into the anterior and lateral compartments of the lower extremity showed that symptoms resolved completely in 94% of patients treated.²² The actual mechanism of benefit is not clearly understood but is potentially related to muscle atrophy and loss of contractile tissue. However, it has not been reported that these changes have affected the strength or performance of patients who receive BoNT for CECS.²³

Thoracic outlet syndrome

Thoracic outlet syndrome (TOS) is a compression of neurovascular structures within the thoracic outlet. There are several locations of potential compression, as well as possible neurogenic, vascular, or nonspecific manifestations.²⁴ Compression can be from a structural variant, such as a cervical rib, or due to soft tissue from the scalene or pectoralis musculature. TOS is difficult to diagnose and treat. Physical therapy is the mainstay of treatment, but failure is common and treatment options are otherwise limited. Decompression surgery is an option if conservative management fails, but it has a high recurrence rate.²⁴

In an effort to harness the therapeutic value of muscle atrophy, denervation, and relaxation afforded by BoNT, clinicians have injected the agent into the anterior and middle scalenes and the pectoralis minor to provide patients with relief from TOS.²⁴ This treatment requires advanced imaging with either fluoroscopy or ultrasound guidance for correct placement and knowledge of surrounding anatomy. Small case reports and case series have demonstrated success, but a small double-blind randomized controlled study of 37 individuals with neurogenic TOS in 2011 did not show a reduction in symptoms.²⁵ Multiple subsequent case reports and case series have continued to show positive results.^24,25 A recent retrospective study showed that patients with TOS who had positive results with BoNT had better surgical outcomes.²⁶

Trigeminal neuralgia and peripheral nerve pain

A meta-analysis in 2019 reviewed evidence for trigeminal neuralgia as well as other types of peripheral neuropathies, including diabetic neuropathy and postherpetic neuropathy. It showed that BoNT injections are safe, as well as effective, for short-term relief at 3 months. However, overall study sizes were small and long-term data are still lacking; larger high-quality studies are needed for further substantiation.²⁷

Continue to: Plantar fascitis

BoNT has been used for treatment of plantar fasciitis. Small randomized controlled studies have compared BoNT to both placebo and corticosteroids, showing that BoNT has better long-term outcomes at 3, 6, and 12 months.^28,29 BoNT is currently being used when standard treatments have failed; however, larger randomized controlled studies are still needed prior to BoNT being accepted as standard treatment.²⁹

Lateral epicondylitis

A systematic review and meta-analysis done in 2017 showed that BoNT is superior to placebo at 16 weeks. No significant difference was noted between BoNT and corticosteroids at 8 weeks, although corticosteroids did demonstrate better improvement at the short-term interval of 2 to 4 weeks.³⁰ As expected, BoNT was associated with grip-strength weakness compared to placebo and corticosteroids at 12 weeks. Subsequent small randomized controlled studies have continued to show benefit with BoNT, but all studies noted grip weakness (which resolved) and duration of effect was dose dependent.^30,31

Temporomandibular joint pain

BoNT has been studied in the treatment of temporomandibular joint (TMJ) pain and dislocations since 1998, and was shown to improve quality of life.³² BoNT has been injected into the musculature surrounding the TMJ, as well as into the joint, and has proven to be effective in these areas.³³ There are limited treatment options for TMJ pain and dislocations, and although research is still ongoing, BoNT is considered a potential treatment option.^32,33

Myofascial, neck, and back chronic pain

Chronic back pain is common and can be due to multiple conditions. BoNT has been studied for treatment focusing on myofascial pain in the neck and back region. Case series have shown improvement with targeted BoNT injections.³⁴ However, in randomized controlled double-blind studies comparing BoNT to placebo, local anesthetics, and steroids, there were no significant differences in pain scores.^35,36 The majority of studies have been landmark based or used the site of maximal tenderness as guidance for injections, but there is some evidence that targeted injections focusing on specific muscle groups may improve benefit.⁵ This usually requires the use of imaging for guidance.

Chronic pelvic pain

Chronic pelvic pain is common and has been reported to affect 1 in 7 women.³⁷ It is often difficult to diagnose the exact source of the pain, and it can be very difficult to treat. In a 2020 systematic review (including 12 observational studies and 5 randomized controlled trials) of BoNT for treatment of chronic pelvic pain, the quality of evidence varied widely.³⁸ Observational studies showed good benefit, but only 1 randomized trial showed statistical difference with the use of BoNT for pelvic pain. No serious adverse events were reported in any of the studies.³⁸ Chronic pelvic pain can be caused by a number of different conditions, and more high-quality research for BoNT is needed, focusing on specific causes.^5,38

Continue to: Complex regional pain

Complex regional pain

Complex regional pain syndrome (CRPS) can be a debilitating condition that causes pain, sympathetic dysregulation, and central nervous system sensitization, often related to a traumatic event. Incidence is reported as 5 to 26 per 100,000, although it most likely is severely underdiagnosed.³⁹ Treatment options are limited, and often patients continue to struggle with pain.

Due to the mechanism of action of BoNT, it has a high potential benefit for treatment of the allodynia and hyperalgesia associated with CRPS. BoNT injections have been used for the treatment of CRPS with limited success.⁴⁰

Although research is ongoing, BoNT is considered a potential treatment option for TMJ pain.

There is currently limited evidence on BoNT for CRPS, and uncertainty regarding the best injection location remains. Studies have looked at lumbar sympathetic blocks, intra-­articular, and grid-like BoNT injections over the area affected by CRPS.^39-41 Case studies/series and observational studies have shown success with minimal adverse reactions, but larger high-quality, randomized controlled double-blind studies are still lacking.^39-41

Concluding thoughts

Most chronic pain conditions have very limited treatment options, making the exploration of BoNT as a potential addition to those treatments an appealing possibility. Since it was first introduced in 1989, it has been proven to be safe, with limited adverse events, for the treatment of chronic pain.

Due to the mechanism of action of BoNT, it has a high potential benefit for treatment of the allodynia and hyperalgesia associated with complex regional pain syndrome.

However, providers need to be familiar with the type and formulation of BoNT product being used. Extensive knowledge of surrounding anatomy and ability to place BoNT in an exact location (which may require either fluoroscopy or ultrasound guidance) is essential.

Continue to: Adequate research and evidence...

Adequate research and evidence for most of the applications discussed in this article are still lacking; some limitations include small sample size, bias, lower quality, and poor methodology. There is also a lack of standardization, including which BoNT product is used, dosage, and location of BoNT placement. All of these issues will need to be addressed in further research.

CORRESPONDENCE
Caleb Dickison, DO, CAQSM, 36065 Darnall Loop, Fort Hood, TX 76544; cal.dickison23@gmail.com

Botulinum toxin (BoNT) was first approved by the US Food and Drug Administration (FDA) for the treatment of strabismus and blepharospasm in 1989. Since then, approved indications have expanded to include spasticity, cervical dystonia, severe axillary hyperhidrosis, bladder dysfunction, and chronic migraine headache, as well as multiple cosmetic uses.^1,2 Over the course of 30 years of clinical use, BoNT has proven to be effective and safe.^3,4 This has led to the expanded use of BoNT for additional medical conditions.^1,2

In the review that follows, we will discuss the utility of BoNT in the treatment of headaches, spasticity, and cervical dystonia. We will then explore the evidence for emerging indications that include chronic joint pain, trigeminal neuralgia, and plantar fasciitis. But first, a brief word about how BoNT works and its safety profile.

Seven toxins, but only 2 are used for medical purposes

BoNT is naturally produced by Clostridium botulinum, an anaerobic, spore-forming bacteria.¹ BoNT inhibits acetylcholine release from presynaptic vesicles at the neuromuscular junctions, which results in flaccid paralysis in peripheral skeletal musculature and autonomic nerve terminals.^1,5 These effects from BoNT can last up to 3 to 6 months.¹

Seven different toxins have been identified (A, B, C, D, E, F, and G), but only toxins A and B are currently used for medical purposes.⁵ Both have similar effects, although there are slight differences in mechanism of action. Toxin B injections are also reported to be slightly more painful. There are also differences in preparation, with some requiring reconstitution, which vary by brand. Certain types of BoNT require refrigeration, and an in-depth review of the manufacturer’s guidelines is recommended before use.

Safety and adverse effects

Although BoNT is 1 of the most lethal toxins known to humans, it has been used in clinical medicine for more than 30 years and has proven to be safe if used properly.³ Adverse effects are rare and are often location and dose dependent (200 U and higher). Immediate or acute adverse effects are usually mild and can include bruising, headache, allergic reactions, edema, skin conditions, infection, or pain at the injection site.⁴ Delayed adverse effects can include muscle weakness that persists throughout the 3 to 6 months of duration and is usually related to incorrect placement or unintentional spread.⁴

Serious adverse events are rare: there are reports of the development of botulism, generalized paralysis, dysphagia, respiratory effects, and even death in patients who had received BoNT injections.³ In a majority of cases, a direct relationship with BoNT was never established, and in most incidents reported, there were significant comorbidities that could have contributed to the adverse event.³ These events appear to be related to higher doses of BoNT, as well as possible incorrect injection placement.³

Knowledge of anatomy and correct placement of BoNT are vitally important, as they have a significant impact on the effectiveness of treatment and adverse events.³ In preventing adverse events, those administering BoNT need to be familiar with the BoNT brand being used, verify proper storage consistent with the manufacturer’s recommendations, and confirm correct dosages with proper reconstitution process.³

Continue to: BoNT is contraindicated

BoNT is contraindicated in those with a history of a previous anaphylactic reaction to BoNT. Patients with known hypersensitivity to BoNT, including those with neuromuscular junction diseases and anterior horn disorders, should be considered for other forms of treatment due to the risk of an exaggerated response. No adverse events have been recorded in regard to pregnancy and lactation, although these remain a potential contraindication.^3,4,6

Taking a closer look at current indications

Headaches

Chronic migraine (CM) is defined by the International Headache Society as at least 15 days per month with headaches and 8 of those days with migraine features. BoNT has been FDA approved for treatment of CM since 2011. This was based on 2 large, double-blind, randomized, placebo-controlled trials that showed a significant reduction from baseline for headaches and migraine days, total time, and frequency of migraines.^7,8

Knowledge of anatomy and correct placement of BoNT are vitally important, as they have a significant impact on the effectiveness of treatment and adverse events.

Subsequent studies have continued to show benefit for CM treatment. In a recent Cochrane systematic review and meta-­analysis, it was determined that BoNT can decrease frequency of CM by 2 days per month, and it is recommended by several organizations as a treatment option for CM.⁹

Low-quality evidence has not shown benefit for tension-type headaches. However, further research is warranted, especially for chronic tension-type headache, which is defined as daily tension headaches.¹⁰

Spasticity

Spasticity is caused by an insult to the brain or spinal cord and can often occur after a stroke, brain or spinal cord injury, cerebral palsy, or other neurologic condition.¹¹ BoNT was initially FDA approved in 2010 for treatment of upper limb spasticity in adults, although it had been used for treatment for spasticity for more than 20 years prior to that. It currently is approved for upper and lower spasticity in adults and recently was expanded to include pediatrics.¹²

Continue to: A small case series...

A small case series conducted soon after BoNT was introduced showed promising results, and subsequent meta-analyses and systematic reviews have shown positive results for use of BoNT for the management of spasticity.¹³ Studies have begun to focus on specific regions of the upper and lower limbs to identify optimal sites for injections.

Cervical dystonia

Cervical dystonia (CD) is the most common form of dystonia and is defined as impairment of activities of daily living due to abnormal postures of the head and neck. BoNT was approved for CD in 1999 after several pivotal randomized placebo-controlled ­double-blind studies showed improvement of symptoms.¹⁴ Several BoNT formulations have been given Level A classification, and can be considered a potential first-line treatment for CD.^15,16 The most common adverse effects reported have been dry mouth, dysphagia, muscle weakness, and neck pain.^14-16

Recent metaanalyses evaluating knee and shoulder pain have shown BoNT is safe and effective for joint pain.

BoNT is currently being used off-label for management of multiple types of dystonia with reported success, as research on its use for noncervical dystonia (including limb, laryngeal, oromandibular, and truncal) continues. Although there are case series and some randomized trials exploring BoNT for certain types of dystonia, most are lacking high-­quality evidence from double-blind, randomized controlled trials.^14-16

Exploring the evidence for emerging indications

There has been significant interest in using BoNT for management for both nociceptive and neuropathic pain symptoms.⁵

Nociceptive pain is the irritation and painful response to actual or potential tissue damage. It is a major component of chronic pain and is difficult to treat, with limited effective options.^5,17

Continue to: Neuropathic pain

Neuropathic pain is related to abnormalities that disrupt the normal function of the nervous system. Abnormalities could be related to anatomic or structural changes that cause compression, trauma, scar tissue, or a number of other conditions that affect nerve function. These can be either central or peripheral and can be caused by multiple etiologies.

The following discussion explores the evidence for potential emerging indications for BoNT. The TABLE^1,5,18-40 summarizes what we know to date.

Chronic joint pain

Refractory joint pain is difficult to treat and can be debilitating for patients. It can have multiple causes but is most commonly related to arthritic changes. Due to the difficulty with treatment, there have been attempts to use BoNT as an intra-articular treatment for refractory joint pain. Results vary and are related to several factors, including the initial degree of pain, the BoNT dosage, and the formulation used, as well as the joint injected.

There appears to be a potentially significant improvement in short-term pain with BoNT compared to conventional therapies, such as physical therapy, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and hyaluronic acid injections. In studies evaluating long-term benefits, it was noted that after 6 months, there was no significant difference between BoNT and control groups.^19-21

The knee joint has been the focus of most research, but BoNT has also been used for shoulder and ankle pain, with success. Recent meta-analyses evaluating knee and shoulder pain have shown BoNT is safe and effective for joint pain.^20,21 There has been no significant difference noted in adverse events with BoNT compared to controls. Currently, more long-term data and research are needed, but BoNT is safe and a potentially effective treatment option for short-term relief of refractory joint pain.^19-21

Continue to: Chronic exertional compartment sydrome

Chronic exertional compartment syndrome (CECS) is defined subjectively as pain in a specific compartment that develops during exercise and resolves upon stopping, as well as objectively with an increase in intra-­muscular pressure.²² It is most common in the lower leg and is a difficult condition to manage. Nonsurgical and surgical options are only successful at returning the patient to full activity 40% to 80% of the time.²³

An initial study done in 2013 of BoNT injected into the anterior and lateral compartments of the lower extremity showed that symptoms resolved completely in 94% of patients treated.²² The actual mechanism of benefit is not clearly understood but is potentially related to muscle atrophy and loss of contractile tissue. However, it has not been reported that these changes have affected the strength or performance of patients who receive BoNT for CECS.²³

Thoracic outlet syndrome

Thoracic outlet syndrome (TOS) is a compression of neurovascular structures within the thoracic outlet. There are several locations of potential compression, as well as possible neurogenic, vascular, or nonspecific manifestations.²⁴ Compression can be from a structural variant, such as a cervical rib, or due to soft tissue from the scalene or pectoralis musculature. TOS is difficult to diagnose and treat. Physical therapy is the mainstay of treatment, but failure is common and treatment options are otherwise limited. Decompression surgery is an option if conservative management fails, but it has a high recurrence rate.²⁴

In an effort to harness the therapeutic value of muscle atrophy, denervation, and relaxation afforded by BoNT, clinicians have injected the agent into the anterior and middle scalenes and the pectoralis minor to provide patients with relief from TOS.²⁴ This treatment requires advanced imaging with either fluoroscopy or ultrasound guidance for correct placement and knowledge of surrounding anatomy. Small case reports and case series have demonstrated success, but a small double-blind randomized controlled study of 37 individuals with neurogenic TOS in 2011 did not show a reduction in symptoms.²⁵ Multiple subsequent case reports and case series have continued to show positive results.^24,25 A recent retrospective study showed that patients with TOS who had positive results with BoNT had better surgical outcomes.²⁶

Trigeminal neuralgia and peripheral nerve pain

A meta-analysis in 2019 reviewed evidence for trigeminal neuralgia as well as other types of peripheral neuropathies, including diabetic neuropathy and postherpetic neuropathy. It showed that BoNT injections are safe, as well as effective, for short-term relief at 3 months. However, overall study sizes were small and long-term data are still lacking; larger high-quality studies are needed for further substantiation.²⁷

Continue to: Plantar fascitis

BoNT has been used for treatment of plantar fasciitis. Small randomized controlled studies have compared BoNT to both placebo and corticosteroids, showing that BoNT has better long-term outcomes at 3, 6, and 12 months.^28,29 BoNT is currently being used when standard treatments have failed; however, larger randomized controlled studies are still needed prior to BoNT being accepted as standard treatment.²⁹

Lateral epicondylitis

A systematic review and meta-analysis done in 2017 showed that BoNT is superior to placebo at 16 weeks. No significant difference was noted between BoNT and corticosteroids at 8 weeks, although corticosteroids did demonstrate better improvement at the short-term interval of 2 to 4 weeks.³⁰ As expected, BoNT was associated with grip-strength weakness compared to placebo and corticosteroids at 12 weeks. Subsequent small randomized controlled studies have continued to show benefit with BoNT, but all studies noted grip weakness (which resolved) and duration of effect was dose dependent.^30,31

Temporomandibular joint pain

BoNT has been studied in the treatment of temporomandibular joint (TMJ) pain and dislocations since 1998, and was shown to improve quality of life.³² BoNT has been injected into the musculature surrounding the TMJ, as well as into the joint, and has proven to be effective in these areas.³³ There are limited treatment options for TMJ pain and dislocations, and although research is still ongoing, BoNT is considered a potential treatment option.^32,33

Myofascial, neck, and back chronic pain

Chronic back pain is common and can be due to multiple conditions. BoNT has been studied for treatment focusing on myofascial pain in the neck and back region. Case series have shown improvement with targeted BoNT injections.³⁴ However, in randomized controlled double-blind studies comparing BoNT to placebo, local anesthetics, and steroids, there were no significant differences in pain scores.^35,36 The majority of studies have been landmark based or used the site of maximal tenderness as guidance for injections, but there is some evidence that targeted injections focusing on specific muscle groups may improve benefit.⁵ This usually requires the use of imaging for guidance.

Chronic pelvic pain

Chronic pelvic pain is common and has been reported to affect 1 in 7 women.³⁷ It is often difficult to diagnose the exact source of the pain, and it can be very difficult to treat. In a 2020 systematic review (including 12 observational studies and 5 randomized controlled trials) of BoNT for treatment of chronic pelvic pain, the quality of evidence varied widely.³⁸ Observational studies showed good benefit, but only 1 randomized trial showed statistical difference with the use of BoNT for pelvic pain. No serious adverse events were reported in any of the studies.³⁸ Chronic pelvic pain can be caused by a number of different conditions, and more high-quality research for BoNT is needed, focusing on specific causes.^5,38

Continue to: Complex regional pain

Complex regional pain

Complex regional pain syndrome (CRPS) can be a debilitating condition that causes pain, sympathetic dysregulation, and central nervous system sensitization, often related to a traumatic event. Incidence is reported as 5 to 26 per 100,000, although it most likely is severely underdiagnosed.³⁹ Treatment options are limited, and often patients continue to struggle with pain.

Due to the mechanism of action of BoNT, it has a high potential benefit for treatment of the allodynia and hyperalgesia associated with CRPS. BoNT injections have been used for the treatment of CRPS with limited success.⁴⁰

Although research is ongoing, BoNT is considered a potential treatment option for TMJ pain.

There is currently limited evidence on BoNT for CRPS, and uncertainty regarding the best injection location remains. Studies have looked at lumbar sympathetic blocks, intra-­articular, and grid-like BoNT injections over the area affected by CRPS.^39-41 Case studies/series and observational studies have shown success with minimal adverse reactions, but larger high-quality, randomized controlled double-blind studies are still lacking.^39-41

Concluding thoughts

Most chronic pain conditions have very limited treatment options, making the exploration of BoNT as a potential addition to those treatments an appealing possibility. Since it was first introduced in 1989, it has been proven to be safe, with limited adverse events, for the treatment of chronic pain.

Due to the mechanism of action of BoNT, it has a high potential benefit for treatment of the allodynia and hyperalgesia associated with complex regional pain syndrome.

However, providers need to be familiar with the type and formulation of BoNT product being used. Extensive knowledge of surrounding anatomy and ability to place BoNT in an exact location (which may require either fluoroscopy or ultrasound guidance) is essential.

Continue to: Adequate research and evidence...

Adequate research and evidence for most of the applications discussed in this article are still lacking; some limitations include small sample size, bias, lower quality, and poor methodology. There is also a lack of standardization, including which BoNT product is used, dosage, and location of BoNT placement. All of these issues will need to be addressed in further research.

CORRESPONDENCE
Caleb Dickison, DO, CAQSM, 36065 Darnall Loop, Fort Hood, TX 76544; cal.dickison23@gmail.com

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; jose.villalon-gomez@emory.edu

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; jose.villalon-gomez@emory.edu

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; jose.villalon-gomez@emory.edu