REVIEW Joanne Schneider, DNP, RN, CNP Mary Patterson, CNP Xavier F. Jimenez, MD, MA Center for Comprehensive Pain Recovery, Center for Comprehensive Pain Recovery, Center for Comprehensive Pain Recovery, Neurological Institute, Cleveland Clinic Neurological Institute, Cleveland Clinic Neurological Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH Beyond depression: Other uses for tricyclic antidepressants ABSTRACT ost tricyclic antidepressants (TCAs) M have US Food and Drug Administration Tricyclic antidepressants (TCAs) were originally designed approval for treatment of depression and anxi- and marketed for treating depression, but over time they ety disorders, but they are also a viable off-label have been applied to a variety of conditions, mostly off- option that should be considered by clinicians label. TCAs can serve as first-line or augmenting drugs in specialties beyond psychiatry, especially for for neuropathic pain, headache, migraine, gastrointesti- treating pain syndromes. Given the ongoing nal syndromes, fibromyalgia, pelvic pain, insomnia, and epidemic of opioid use disorder, increasing atten- psychiatric conditions other than depression. This article tion has been drawn to alternative strategies for reviews pharmacology, dosing, and safety considerations chronic pain management, renewing an interest for these uses. in the use of TCAs. This review summarizes the pharmacologic KEY POINTS properties of TCAs, their potential indications Amitriptyline is the most useful TCA for many painful in conditions other than depression, and safety conditions. considerations. ■ BRIEF HISTORY OF TRICYCLICS TCAs can be especially helpful for patients with a pain syndrome or insomnia with comorbid depression, al- TCAs were originally designed in the 1950s and marketed later for treating depression. though their benefits appear to be independent of anti- Due to their adverse effects and lethality in depressant effects. overdose quantities, over time they have been largely replaced by selective serotonin reup- TCAs have long half-lives and so can be taken once a day. take inhibitors (SSRIs) and serotonin-norepi- nephrine reuptake inhibitors (SNRIs) in de- Effective dosages for symptom control in many conditions pression management. However, TCAs have are lower than for severe depression; dosage should start been applied to conditions other than depres- low and be gradually increased while monitoring efficacy sion with varying degrees of efficacy and safety. and adverse effects. ■ TCA PHARMACOLOGY TCAs should not be used concurrently with a monoamine Named for their chemical structure, TCAs oxidase inhibitor and by certain patient groups: the el- contain 3 rings with 1 side chain. They are derly, pregnant women, and patients with certain cardiac grouped into tertiary and secondary amine 1 conduction abnormalities, epilepsy, or risk of suicide. subtypes (Table 1). TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. doi:10.3949/ccjm.86a.19005 They are widely distributed throughout the CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 12 DECEMBER 2019 807 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. TRICYCLIC ANTIDEPRESSANTS TABLE 1 Dosing and adverse effects of commonly prescribed tricyclic antidepressants Adverse effectsa Reuptake Hypoten- Weight Initial/maximum mechanismb Sedation sion Seizures gain Cardiac dosing (for MDD) Tertiary amine tricyclic antidepressants (TCAs) Amitriptyline 5-HT > NE +++ +++ ++ ++ +++ 25–75 mg/ 200 mg daily Clomipramine 5-HT > NE ++ ++ +++ + ++ 25 mg/ 250 mg daily Doxepin 5-HT = NE ++++ + ++ ++ + 50–75 mg/ 300 mg nightly Imipramine 5-HT = NE ++ +++ ++ ++ +++ 50–100 mg/ 200 mg daily Secondary amine TCAs Despiramine NE > 5-HT + + + + ++ 100–200 mg/ 300 mg daily Maprotiline NE > 5-HT ++ + + ++ + 25–50 mg/ 225 mg nightly Nortriptyline NE > 5-HT + + + + ++ 25–50 mg/ 150 mg daily a Plus sign indicates potential severity of adverse effects. b Tertiary amine TCAs tend to preferentially inhibit serotonin reuptake, resulting in greater synaptic serotonin levels, whereas secondary amine TCAs tend to preferentially inhibit norepinephrine reuptake, resulting in greater synaptic norepinephrine levels. MDD = major depressive disorder; NE = norepinephrine; 5-HT = serotonin systemic circulation because they are highly vision, urinary retention, drowsiness, and se- lipophilic, resulting in systemic effects includ- dation.1 ing central nervous system manifestations. Research suggests that TCAs relieve pain Peak plasma concentration is at about 2 to centrally through a descending pathway that 6 hours, and elimination half-life is around 24 inhibits transmission of pain signals in the spi- hours for most agents, providing a long dura- nal cord, as well as peripherally through com- tion of action. Clearance depends on cyto- plex anti-neuroimmune actions.2 Norepineph- chrome P450 oxidative enzymes.1 rine appears to play a more important role in ■ MECHANISMS OF ACTION this process than serotonin, although both are deemed necessary for the “dual action” often TCAs inhibit reuptake of norepinephrine and cited in pain management,1 which is also the serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. rationale for widespread use of SNRIs to con- They also block postsynaptic histamine, al- trol pain. pha-adrenergic, and muscarinic-acetylcholine Table 1 compares neurotransmitter reup- receptors, causing a variety of adverse effects, take mechanisms, adverse effect profiles, and including dry mouth, confusion, cognitive typical dosages for depression for commonly impairment, hypotension, orthostasis, blurred prescribed TCAs. 808 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 12 DECEMBER 2019 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. SCHNEIDER AND COLLEAGUES ■ POTENTIAL USES TCAs have been used to treat chronic low back pain for decades and have been repeatedly Headache and migraine shown to be more effective than placebo in re- TCAs have been shown to be effective for ducing pain severity.16,17 A double-blind con- managing and preventing chronic headache 18 3,4 trolled trial from 1999 compared the effects syndromes. Amitriptyline has been the most of the TCA maprotiline (up to 150 mg daily), studied of the TCAs for both chronic daily and the SSRI paroxetine (up to 30 mg daily), and episodic migraine headache, showing the most placebo and found a statistically significant efficacy among diverse drug classes (angio- reduction in back pain with maprotiline com- tensin II receptor blockers, anticonvulsants, pared with paroxetine and placebo. However, beta-blockers, SSRIs) compared with placebo. a 2008 meta-analysis suggested little evidence However, in head-to-head trials, amitriptyline that TCAs were superior to placebo.19 was no more effective than SSRIs, venlafax- 4 4 Evidence of TCA efficacy for back pain ine, topiramate, or propranolol. Jackson et al was reported in 2018 with a well-designed suggested that prophylactic medication choic- 6-month double-blind randomized controlled es should be tailored to patient characteristics trial20 comparing low-dose amitriptyline (25 and expected adverse effects, and specifically mg) with an active comparator (benztropine recommended that TCAs—particularly ami- 1 mg). The authors reported that amitripty- triptyline—be reserved for patients who have line was effective in reducing pain and pain- both migraine and depression. related disability without incurring serious ad- Neuropathic pain verse effects. They suggested continued use of Neuropathic pain is defined as pain second- TCAs for chronic low back pain if complicat- ary to a lesion or disease of the somatosensory ed with pain-related disability, insomnia, de- nervous system5 and is the pathomechanistic pression, or other comorbidity, although they component of a number of conditions, in- called for further large-scale studies. They also cluding postherpetic neuralgia,6 diabetic and cautioned that patients started the trial with nondiabetic painful polyneuropathy,7 post- symptoms similar to the adverse effects of traumatic or postsurgical neuropathic pain8 TCAs themselves; this has implications for Increasing (including plexus avulsion and complex re- monitoring of symptoms as well as TCA ad- attention 9 gional pain syndrome ), central poststroke verse effects while using these drugs. has been drawn pain,10 spinal cord injury pain,11 and multiple Fibromyalgia and chronic widespread pain sclerosis-associated pain.12 to alternative Fibromyalgia is a common, frustrating, non- As a group, TCAs appear to have a role as inflammatory pain syndrome characterized strategies first-line agents for managing these varied neu- by diffuse hyperalgesia and multiple comor- ropathic pain syndromes. In a recent meta-anal- for chronic pain bidities.21 Although sleep hygiene, exercise, ysis,13 16 (89%) of 18 placebo-controlled trials management of TCAs (mainly amitriptyline at 25–150 mg/ cognitive-behavioral therapy, some gabapen- day) for these pain conditions were positive, tinoids (pregabalin), and a combination of with a combined number needed to treat of 3.6, these therapies have demonstrated efficacy, suggesting a role for TCAs in these conditions. TCAs