|
 
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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 19
| Issue : 2 | Page : 110-114 |
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Amitriptyline in irritable bowel syndrome: A clinical review
Mani Rajagopalan1, Ashray Rajagopalan2, Ashwin Rajagopalan3
1 Consultant Psychiatrist, Ballarat, Victoria, Australia
2 Monash Health, Monash University, Clayton, Victoria, Australia
3 Monash School of Medicine, Monash University, Clayton, Victoria, Australia
| Date of Submission | 28-Jan-2021 |
| Date of Decision | 18-Feb-2021 |
| Date of Acceptance | 23-Feb-2021 |
| Date of Web Publication | 15-Apr-2021 |
Correspondence Address:
Dr. Mani Rajagopalan
24 Drummond Street North, Ballarat VIC 3350
Australia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_13_21
Irritable bowel syndrome is the most common functional gastrointestinal disorder in the primary care setting. Symptoms tend to be long lasting and patients have been reported to have a higher prevalence of psychological distress. Antidepressants have been shown to be effective in its management and we review trials involving amitriptyline. Possible mechanisms of action are discussed.
Keywords: Amitriptyline, functional gastrointestinal disorders, irritable bowel syndrome, symptom relief, tricyclic antidepressant
How to cite this article:
Rajagopalan M, Rajagopalan A, Rajagopalan A. Amitriptyline in irritable bowel syndrome: A clinical review. Curr Med Issues 2021;19:110-4 |
| Introduction | |  |
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with complex interactions between the psyche and the digestive tract.[1],[2] Functional gastrointestinal disorders are thought to exist on a spectrum rather than as specific disorders, with significant symptom overlap among the various disorders.[3]
Prominent symptoms of IBS include recurrent abdominal discomfort or pain, bloating, and irregular bowel habits including chronic diarrhea and/or constipation. It is the most common gastrointestinal disorder presenting to both primary care physicians and gastrointestinal clinics.[4] The majority of patients with IBS are diagnosed and treated in primary care.[3]
Concepts surrounding IBS and diagnostic criteria have changed over time. Over many decades, these views have ranged along a spectrum from functional to organic gastrointestinal disease, varying from the belief that the primary disorder is almost entirely psychiatric with anxious, dependent patients, to the view that IBS is a disorder of gut function, with symptoms produced by the abnormal motor activity of the intestinal tract due to an abnormality of intestinal smooth muscle or its control mechanism.[5]
Risk factors for IBS are female sex, younger age, and preceding gastrointestinal infections.[6]
| Diagnostic Criteria | | |
The diagnosis of IBS is based on the symptoms as well as the exclusion of organic disease.[6]
Rome IV Criteria to diagnose IBS are:
“Recurrent abdominal pain, on average, at least 1 day/week in the last 3 months, associated with two or more of the following criteria (Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis).”[7]
- Related to defecation
- Associated with a change in frequency of stool
- Associated with a change in form (appearance) of stool.
Patients with IBS can often be grouped into one of three subtypes: predominant constipation, diarrhea, or those with mixed bowel habits.[3]
However, Drossman writes “The predominant bowel diagnoses of IBS with subtypes of constipation, diarrhea, mixed, and unclassified, are no longer considered distinct disorders. Instead, they exist on a spectrum with linked pathophysiological features that are variably expressed clinically by patient specific differences in the quantity, intensity, and severity of symptoms.”[8] Individual patients can, and often do, move through different points of the spectrum over the long-term course of their illness.
| Psychiatric Aspects | | |
Bockus, Bank, and Willkinson in their article titled “Neurogenic Mucous Colitis” published in 1928 observed that the condition had not achieved its place in gastroenterology because of its “neurotic stigma.”[9] Constipation and a nervous factor were identified as key factors. They reported that almost half of the patients with “neurogenic mucous colitis” had depression and a similar proportion had “marked emotional instability.”
Over the years since, the prevalence of psychological symptoms and psychiatric disorders in patients with IBS has been reported to be above average. Anxiety and depression are more common, and psychological characteristics not only predispose patients to present to their doctors but may also worsen symptoms and interfere with the response to treatment.[4],[10],[11],[12]
| Etiology | | |
A variety of factors have been proposed for the etiology of IBS, but no distinct cause or link between pathologies and IBS symptoms has yet been found.[6],[13] The disease is conceptualized as being “functional”– one where no structural or biochemical abnormalities are detectable with current routine diagnostic tools.[6] Causation is likely to be multifactorial with psychopathology being one among many other contributing factors.[2],[14]
The biopsychosocial conceptual model of functional gastrointestinal disorders includes the role of genetics, developmental factors, sociocultural influences, and environmental factors affecting one's personality, psychological state, and coping skills with these further influencing susceptibility to gut dysfunction. A functional gastrointestinal disorder such as IBS is therefore a result of “interactions of psychosocial factors and altered gut physiology via the brain-gut axis.”[8]
| Treatment Considerations | | |
Not surprisingly, in view of the wide range of proposed multifactorial etiologies, a large number of treatments have been advocated incorporating both psychological and pharmacological approaches. Psychological methods reported to be useful are relaxation training, hypnosis, biofeedback, insight-oriented psychotherapy, cognitive-behavior therapy, and group therapy.[15],[16],[17]
Antidepressants have been used among a broad range of other pharmacological therapies. From initial anecdotal reports[10],[18],[19],[20] antidepressants have been increasingly used in the treatment of IBS. There have been trials with amitriptyline,[21] desipramine,[22],[23],[24] trimipramine,[25],[26],[27],[28] imipramine,[29],[30] amineptine,[31] doxepin,[32] fluoxetine,[33],[34] paroxetine,[35],[36],[37] and citalopram.[29],[38],[39]
We have summarized existing research on amitriptyline as its unique anxiolytic, sedative, antinociceptive, and anticholinergic effects may well have distinct advantages when compared to other antidepressants. In addition, its low cost and widespread availability as compared with some newer antidepressants may be an added advantage particularly in rural settings in developing countries.
The following double-blind placebo-controlled trials were published in peer-reviewed journals. These studies were done over the last four decades, in different clinical settings, and used varying diagnostic criteria for IBS.
| Trials with Amitriptyline | | |
Steinhart et al. reported on the therapeutic usefulness of amitriptyline in “spastic colon syndrome” in a 4-week crossover study in New York, USA.[40] The spastic colon syndrome was defined as a variant of IBS where the predominant symptom is recurrent abdominal pain associated most commonly with constipation and occasionally diarrhea. Fourteen patients (3 males, 11 females), all of whom had an adequate trial of antispasmodic medication were prescribed either 50 mg amitriptyline or placebo for 4 weeks. After a 2-week washout period, patients crossed over to the other agent. The average duration of symptoms was 5.1 years. Improvement with amitriptyline was highly significant comparing predrug (baseline) and postdrug periods; direct comparison with placebo bordered on but did not reach significance. The authors postulated that the high placebo response may have been due to urgent desire to obtain relief, and the patients possibly seeing participation in the study as the last chance for symptom improvement. Those who responded to amitriptyline had higher depression and anxiety scores compared to the normal population.
Rajagopalan et al. conducted a randomized double-blind placebo-controlled trial of 40 patients, recruited from a gastroenterology clinic at a tertiary hospital in Vellore, India.[41] Patients were diagnosed with IBS by a gastroenterologist using the Rome I criteria. Twenty-two patients completed the trial. Patients were assessed by a psychiatrist to rate anxiety and depressive symptoms as well as administer a personality questionnaire.
Patients received either amitriptyline or placebo, with tablets identical in appearance. Each amitriptyline tablet was of 25 mg strength and patients took 1 tablet per night for 1 week, 2 tablets per night for the second week, and three tablets each night until 12 weeks had passed. Subsequently, the gastroenterologist reviewed each patient, and changes in symptoms were noted. Sixty-four percent global improvement was seen in the amitriptyline group, compared to 26% in the control group. Patients on amitriptyline had significantly improved abdominal pain, bowel movement satisfaction, and feelings of wellbeing, with younger and more extroverted patients responding better. The authors suggest that while this finding should be interpreted with caution due to the small sample size, personality characteristics as a predictor of outcome could be an area for future research. Levels of anxiety and depression and nature as well as severity of gastrointestinal symptoms did not predict response to treatment, but these may well determine which patients with IBS seek help in the first place.
Vahedi et al. performed a double-blind randomized controlled trial completed by 50 out of 54 patients fulfilling the Rome II criteria for diarrhea-predominant IBS.[42] Patients were recruited from a gastroenterology clinic in Tehran, Iran, and received either 10 mg amitriptyline daily or placebo for 2 months. The degree of improvement was not significantly different between the two groups at the end of the 1st month. Patients receiving amitriptyline showed 68% complete response (loss of all symptoms) after two months; whereas, those receiving placebo showed only 28% complete response. There was a greater reduction in the incidence of loose stools and feeling of incomplete defecation in the amitriptyline group. Anxiety and depression did not correlate with reduction in pain with amitriptyline therapy, suggesting that the effect of amitriptyline in IBS is independent of its antidepressant effects.
Bahar et al. performed a double-blind placebo-controlled study of 33 adolescents (24 female) aged 12–18, with newly diagnosed IBS recruited from a private outpatient pediatric gastroenterology clinic in California, USA.[43] Patients were surveyed initially, and after 2, 6, 10, and 13 weeks. Amitriptyline or placebo was administered for weeks 3–10 of the study, with dosage varying according to patient body mass. Patients between 30 and 50 kg received one 10 mg capsule, those between 50 and 80 kg received two, and those at 80 kg received three (30 mg in total). Those who received amitriptyline were more likely to experience improvement from baseline in overall quality of life and reduction in right lower quadrant pain, periumbilical pain as well as a reduction in IBS-associated diarrhea. More than half of the adolescents eligible to participate in the study refused to do so because their parents were uncomfortable with the use of an antidepressant in children, due to negative press reports. This study was carried out in the years around the time the United States Food and Drug Administration issued formal “black box” warnings regarding the increased potential for “suicidality” in children consuming antidepressant medications. Of the 16 patients who received amitriptyline, 14 elected to continue the medication after cessation of the trial.
Li et al. conducted a randomized controlled trial completed by 139 out of 170 enrolled patients with refractory diarrhea-predominant IBS per the Rome III criteria.[44] Patients were aged between 18 and 65 and recruited from the gastroenterology outpatient clinic of Guangzhou Nansha Central Hospital, China as well as the surrounding region. Over 4 weeks, 0.5 g Lactobacillus acidophilus was administered three times daily to all patients; the amitriptyline group also received 25 mg amitriptyline at bedtime.
Abdominal pain, distension, degree of satisfaction with bowel habits, quality of life including dysphoria and health worries, and IBS symptom severity scores of the amitriptyline group had improved significantly both on day 10 and week 4. Amitriptyline was ceased after week four and patients were observed for the next year. Ten patients out of sixty-three from the amitriptyline group experienced a recurrence of symptoms a year later and eight of these responded to the reinstitution of amitriptyline. Prolongation of the whole gut transit time with amitriptyline was seen as being a distinct advantage in diarrhea-predominant IBS.
| Mechanism of Action | | |
Amitriptyline is a tricyclic antidepressant and acts by blocking the uptake of serotonin and norepinephrine. It has strong binding affinities for alpha-adrenergic, histamine (H1), and muscarinic (M1) receptors. It is more sedating and has increased anticholinergic properties compared to other tricyclic antidepressants. Amitriptyline's well-established anxiolytic effects can often be seen at low doses. Analgesic effects and pain tolerance are improved through peripheral or central antinociceptive properties, probably related to norepinephrine more than serotonin.[43],[45],[46] Alteration of visceral sensitivity as a potential mechanism has also been reported.[42]
In an interesting study, Morgan et al. conducted a randomized placebo-controlled double-blind crossover study of 22 women aged 24–57 with painful IBS, of whom 19 completed the study.[47] Patients took at bedtime either placebo or amitriptyline, 25 mg for 1 week, and then 50 mg for weeks 2–4. Following three weeks' washout, patients swapped to the alternate treatment. Before beginning treatment, patients rated their symptoms over the last week. Patients also rated their symptoms over the last 2 weeks of each treatment, following each phase of treatment. A 0–10 visual analog scale (0 being none and 10 being very severe) was used to separately rate abdominal pain, diarrhea, constipation, bowel movement distress, and bloating.
Following each period of treatment, functional magnetic resonance imaging was used during rectal distension to measure cerebral activation associated with rectal pain. Three distensions were issued at each of 15 mmHg, 30 mmHg, and 50 mmHg. This procedure occurred while the patient either listened to relaxing music or a recording of crying babies, which had previously been shown to be stressful to female volunteers. Thirteen of the 19 patients reported improved symptoms with amitriptyline, 5 with placebo, and 1 reported no change on either. Patients rated their pain during the last 2 weeks of treatment to be on average 4.2 on amitriptyline but 5.3 on placebo. Morgan et al. determined that amitriptyline caused a reduction in brain activation during rectal distension when IBS patients were subjected to mental stress, and postulated that the improvement in IBS symptoms seen with amitriptyline is due to a central, rather than peripheral nervous system effect, with the mechanism likely to be through the reduction in the affective component of pain or a reduction in stress-related symptom exacerbation.
We have not emphasized the antidepressant effect of amitriptyline as this is unlikely to be a significant factor given the doses used in various trials, apart from Rajagopalan et al. where patients were on 75 mg of amitriptyline daily for 10 weeks.[41] Most doses in these trials (often below 50 mg daily) would be considered subtherapeutic for the management of any underlying depression and it is, therefore, unlikely that a significant antidepressant effect could lead to clinical improvement. In addition, patients with significant depression had been excluded in at least three studies.[41],[44],[47]
However, it is possible that even at low doses, amitriptyline decreases some of the accompanying psychological symptoms in IBS, especially anxiety, which can otherwise intensify digestive complaints. In addition, the analgesic and sedative effects of amitriptyline occur at doses lower than their traditional effective antidepressant doses. Anticholinergic effects are an added benefit in diarrhea-predominant IBS.
Pain affects behavior and it has been postulated that antidepressants have a greater effect on the behavior of pain patients than on their experience of pain intensity.[48]
Bahar et al. suggest that when used at lower doses, perhaps amitriptyline “should no longer be termed an “antidepressant” or “psychotropic” medication, but rather one to treat neuropathic pain associated with chronic pain syndromes.”[43]
| Conclusion | | |
Amitriptyline in varying doses from 10 mg to 75 mg has been found to be effective in alleviating symptoms of IBS. Research suggests that improvement is more likely to occur if treatment continues for at least 8 weeks. It is the first author's clinical experience that amitriptyline at doses of 50–75 mg at night, used in conjunction with psychological strategies over 8–12 weeks, further improves outcome.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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