Beyond depression: Other uses for tricyclic antidepressants

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Fibromyalgia and chronic widespread pain

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.21 Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.22 A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.23 Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.24

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.27

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.28

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.29 However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,30 but nortriptyline has proven ineffective in gastroparesis.31 Nonetheless, some authors29 suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women32 and 5% to 10% of men.33 TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.34 Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.34

Based on a randomized, double-blind trial,35 amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study36 randomized 56 women with chronic pelvic pain to amitriptyline or gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,37 about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.


Insomnia affects 23% to 56% of people in the United States, Europe, and Asia38 and is the reason for more than 5.5 million primary care visits annually.39 TCAs (especially doxepin, maprotiline, and amitriptyline40) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.38

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.41

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.42 Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

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Gabapentin for alcohol use disorder: A good option, or cause for concern?

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