sign in sign up
<<
Home , Fibromyalgia

REVIEW Joanne Schneider, DNP, RN, CNP Mary Patterson, CNP Xavier F. Jimenez, MD, MA Center for Comprehensive 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 : Other uses for tricyclic

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 , especially for for , headache, migraine, gastrointesti- treating pain syndromes. Given the ongoing nal syndromes, fibromyalgia, pelvic pain, , and epidemic of 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 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 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 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 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 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 ,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 , 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 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, , 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 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 , 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 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 (), 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 also offer robust benefits. Of note, the TCAs desipramine14 and nortrip- A meta-analysis of 9 placebo-controlled tyline15 have demonstrated little evidence of ef- TCA trials showed large effect sizes for pain ficacy in neuropathic pain syndromes. reduction, reduction, improved sleep quality, and reduced stiffness and tenderness, Chronic low back pain with the most significant of these improve- Chronic low back pain is a leading cause of ments being for sleep.22 A separate meta- loss of work, excessive healthcare expendi- analysis calculated that the number needed to ture, and disability in the . It treat with amitriptyline for a positive outcome can be due to numerous spinal conditions, is 4.9.23 Recent systematic reviews have sup- including degenerative disk disease, spinal ported these findings, listing TCAs as second- stenosis, lumbar spondylosis, and spinal ar- line agents after pregabalin, , and thropathy. .24

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 12 DECEMBER 2019 809 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. TRICYCLIC ANTIDEPRESSANTS

Of note, TCA monotherapy rarely produc- Based on a randomized, double-blind trial,35 es a complete response in patients with moder- amitriptyline was recommended as a treatment ate to severe fibromyalgia, chronic widespread option for or bladder pain, pain, or significant (depression, with the greatest symptom improvement in pa- ). Supplementation with cognitive-be- tients tolerating a daily dose of 50 mg. havioral therapy, physical therapy, functional Another study36 randomized 56 women restoration, and other modalities is strongly with chronic pelvic pain to amitriptyline or recommended. , or a combination of the drugs for 24 months. Although each regimen resulted Abdominal and gastrointestinal pain in significant reduction in pain, fewer adverse TCAs have been applied to a number of gas- effects occurred with gabapentin than ami- trointestinal syndromes with or without pain. triptyline. Poor compliance and early discon- Patients with have tinuation of amitriptyline were common due long been known to benefit from TCAs; the to anticholinergic effects. number needed to treat for symptomatic ben- 37 25,26 In small uncontrolled studies, about half efit over placebo is 3.5. of women with chronic pelvic pain became Although there is no substantial evidence pain-free after 8 weeks of treatment with nor- that TCAs are useful in reducing active in- triptyline and imipramine. flammation in inflammatory bowel disease, a Randomized controlled studies are need- study involving 81 patients found that resid- ed to confirm potential benefits of TCAs in ual noninflammatory gastrointestinal symp- chronic urologic and pelvic pain. toms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitripty- Insomnia line, with greater benefit for ulcerative colitis Insomnia affects 23% to 56% of people in the than for Crohn disease.27 United States, Europe, and Asia38 and is the TCAs have also shown prophylactic bene- reason for more than 5.5 million primary care fit in cyclic vomiting syndrome, with a clinical visits annually.39 TCAs (especially doxepin, response in over 75% of patients in controlled maprotiline, and amitriptyline40) have been The elimination cohort studies.28 shown to be an effective treatment, with an half-life The efficacy of TCAs in other abdominal or 82% increase in compared with is around gastrointestinal syndromes is unclear or modest placebo, as well as measurably improved total at best.29 However, few alternative treatments sleep time, enhanced sleep efficiency, reduced 24 hours exist for these conditions. Amitriptyline may latency to persistent sleep, and decreased wake for most TCAs, help symptoms of functional dyspepsia,30 but times after sleep onset.38 nortriptyline has proven ineffective in gastro- Dosing should be kept at a minimum to providing paresis.31 Nonetheless, some authors29 suggest minimize harsh anticholinergic effects and a long duration considering TCAs on an individualized basis, avoid daytime sedation. Patients should be of action with proper monitoring, in many if not most advised to take new doses or dose escalations functional gastrointestinal disorders, especially earlier in the night to ensure less hangover se- when paired with behavioral therapies. dation the next morning. For patients with insomnia and comorbid Pelvic and urogynecologic symptoms depression, the American Academy of Sleep Chronic pelvic pain affects up to 24% of 32 33 Medicine suggests the addition of a low dose women and 5% to 10% of men. TCAs (eg, 10–25 mg) of a TCA at nighttime to have shown efficacy in treating chronic pelvic 34 complement preexisting, full-dose, non-TCA pain with or without comorbid depression. antidepressants, while monitoring for sero- Amitriptyline and to a lesser extent nortrip- tonin syndrome and other potential but ex- tyline are the TCAs most often prescribed. ceedingly rare drug-drug interactions.41 Pain relief appears to be independent of anti- depressant effects and may be achieved at low Psychiatric indications doses; initial dosing ranges from 10 to 25 mg other than depression at bedtime, which may be increased to 100 mg Beyond the known benefits in major depres- as tolerated.34 sive disorder, TCAs have been shown to be

810 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

TABLE 2 Dosing guide for tricyclic antidepressants in conditions other than depression Initial/ Adverse effect Indication maximum dosing Dose escalation management Headache or Amitriptyline 10–25 mg/ Individualized: Dry mouth and secretions: migraine 100 mg nightly Increase by 10–25 mg Pilocarpine 5 mg 2–3/day every 5–14 days, Neuropathic pain Amitriptyline 25–50 mg/ assess for tolerability Constipation: 150 mg nightly and adverse effects Stool softeners, eg, (or divided into twice-daily docusate sodium, senna doses if frequent pain or Amitriptyline side glycoside symptom flares) effects (dry mouth, orthostasis) often limit Weight gain: Chronic low back Amitriptyline, 25–50 mg/ dose escalation above Consider augmenting with pain maprotiline 150 mg nightly 100 mg; metformin 500–1,000 nortriptyline or mg/day or topiramate Fibromyalgia or Amitriptyline, 25–50 mg/ maprotiline may be 50–100 mg/day chronic widespread nortriptyline, 150 mg nightly considered (better Seizures, QT interval pain maprotiline (or divided into twice-daily tolerated at higher prolongation, active doses if frequent pain or doses) suicidal risk, orthostasis, or symptom flares) falls: Discontinue the agent Irritable bowel Amitriptyline, 10–25 mg/ syndrome nortriptyline 100 mg nightly Cyclic vomiting Amitriptyline, 25–50 mg/ syndrome nortriptyline 100 mg nightly Chronic pelvic pain, Amitriptyline, 10–25 mg/ interstitial cystitis, nortriptyline, 100 mg nightly nocturia imipramine Insomnia Amitriptyline, 25–50 mg/ maprotiline, 150 mg nightly doxepin effective for obsessive-compulsive disorder, Tolerance to some effects may develop over panic disorder, posttraumatic disorder, time. If adverse effects prove to be a problem, bulimia nervosa, and childhood enuresis.42 therapy may need to be stopped or doses ad- Given the shortage of mental health clini- justed. Alternatively, adjunctive medications cians and the high prevalence of these condi- to address adverse effects may be considered tions, nonpsychiatrist physicians should be fa- (eg, pilocarpine for dry mucous membranes, miliar with the therapeutic potential of TCAs tamsulosin for urinary retention) (Table 2). for these indications. Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, ■■ ADVERSE EFFECTS studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs Adverse effects vary among TCAs. Com- and SNRIs, although SSRIs have a greater mon ones include blurred vision, dry mouth, tendency to produce nausea, whereas TCAs constipation, urinary retention, hypotension, are more likely to cause constipation.44 tachycardia, tremor, weight gain, and sexual dysfunction.43 Tertiary amines are generally Discontinuation syndrome more sedating than secondary amines and Abrupt discontinuation or unintentionally cause more anticholinergic effects (Table 1). missed doses of TCAs have been associated

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 12 DECEMBER 2019 811 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. TRICYCLIC ANTIDEPRESSANTS

with a discontinuation syndrome in about Concomitant monoamine oxidase inhibitor 40% of users.45 Patients should be warned treatment about this possibility and the syndrome’s po- Giving TCAs together with monoamine tential effects: dizziness, insomnia, headaches, oxidase inhibitor antidepressants should be nausea, vomiting, flulike achiness, and rest- avoided, given the risk of hypertensive crisis. lessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also oc- Suicide risk cur. Symptoms generally present within 2 to TCAs are dangerous and potentially lethal in 5 days after dose discontinuation and last 7 to overdose and so should not be prescribed to 14 days.45 suicidal or otherwise impulsive patients. However, all TCAs have a long half-life, Pregnancy allowing for sufficient coverage with once- TCAs are in pregnancy risk category C (ani- daily dosing and thus carry a lower risk of dis- mal studies show adverse effects on fetus; no continuation syndrome than many other anti- adequate or well-controlled studies in hu- depressants (78% with venlafaxine; 55% with mans; potential benefits may warrant use de- 45 paroxetine). spite risks). Using TCAs during pregnancy has To discontinue therapy safely, the dosage very rarely led to neonatal withdrawal such as should be reduced gradually. As is pharmaco- irritability, jitteriness, and convulsions, as well logically expected, the greatest likelihood of as fetal QTc interval prolongation.49 discontinuation syndrome is associated with The American College of Obstetricians longer duration of continuous treatment. and Gynecologists recommends that therapy for depression during pregnancy be individu- ■■ CONTRAINDICATIONS alized, incorporating the expertise of the pa- Cardiac conduction abnormalities tient’s mental health clinician, obstetrician, TCAs should not be prescribed to patients primary healthcare provider, and pediatri- who have right bundle branch block, a severe cian. In general, they recommend that TCAs TCAs may electrolyte disturbance, or other cardiac con- should be avoided if possible and that alterna- duction deficit or arrhythmia that can prolong tives such as SSRIs or SNRIs should be con- have a role the QTc interval and elevate the risk of lethal sidered.50 as first-line arrhythmia.46,47 Cardiac effects from TCAs TCAs are excreted in breast milk, but they have not been detected in the serum of nurs- agents are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained ing infants, and no adverse events have been for neuropathic to assess cardiac risk, and dose escalation can reported. pain syndromes proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms). ■■ OVERDOSE IS HIGHLY DANGEROUS Severe morbidity and death are associated Advanced age For elderly patients, TCAs should be pre- with TCA overdose, characterized by convul- scribed with caution and sometimes not at sions, cardiac arrest, and coma (the “3 Cs”). 48 These dangers occur at much higher rates all, because anticholinergic effects may wors- 43 en preexisting urinary retention (including with TCAs than with other antidepressants. benign prostatic hyperplasia), narrow-angle of toxicity develop rap- glaucoma, imbalance and gait issues, and cog- idly, usually within the first hour of overdose. nitive impairment and dementia. Dehydra- Manifestations of overdose include prolonged tion and orthostatic hypotension are contra- QTc, cardiac arrhythmias, tachycardia, hyper- indications for TCAs, as they may precipitate tension, severe hypotension, agitation, sei- falls or hypotensive shock. zures, depression, hal- lucinations, seizures, and coma. Epilepsy Overdose management includes activated TCAs should also be used with caution in pa- charcoal, seizure control, cardioversion, hy- tients with epilepsy, as they lower the seizure dration, electrolyte stabilization, and other threshold. intensive care.

812 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

■■ OFF-LABEL TCA MANAGEMENT monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailor- Dosing recommendations for off-label use ing the approach to the patient, and routinely of TCAs vary based on the condition, the assessing for adverse effects and other safety medication, and the suggestions of individual considerations. authors and researchers. In general, dosing In addition, we strongly recommend sup- ranges for pain and other nondepression indi- plementing TCA therapy with nonpharmaco- cations may be lower than for severe depres- logic strategies such as lifestyle changes, dietary sion (Table 2).1 modifications, exercise, physical therapy, and As with any pharmacologic titration, mental health optimization. ■ ■■ REFERENCES doi:10.1097/01.BRS.0000092372.73527.BA 18. Atkinson JH, Slater MA, Wahlgren DR, et al. Effects of noradren- 1. Obata H. mechanisms of antidepressants for neuropathic ergic and antidepressants on chronic low back pain pain. Int J Mol Sci 2017; 18(11). doi:10.3390/ijms18112483 intensity. Pain 1999; 83(2):137–145. 2. Kremer M, Yalcin I, Goumon Y, et al. A dual noradrenergic mecha- doi:10.1016/s0304-3959(99)00082-2 nism for the relief of neuropathic by the 19. Urquhart DM, Hoving JL, Assendelft WW, Roland M, van Tulder drugs duloxetine and amitriptyline. J Neurosci 2018; 38(46):9934– MW. Antidepressants for non-specific back pain. Cochrane Database 9954. doi:10.1523/JNEUROSCI.1004-18.2018 Syst Rev 2008; (1):CD001703. doi:10.1002/14651858.CD001703.pub3 3. Tomkins GE, Jackson JL, O’Malley PG, Balden E, Santoro JE. Treat- 20. Urquhart DM, Wluka AE, van Tulder M, et al. Efficacy of low-dose ment of chronic headache with antidepressants: a meta-analysis. amitriptyline for chronic low back pain: a randomized . Am J Med 2001; 111(1):54–63. doi:10.1016/s0002-9343(01)00762-8 JAMA Intern Med 2018; 178(11):1474–1481. 4. Jackson JL, Cogbill E, Santana-Davila R, et al. A comparative ef- doi:10.1001/jamainternmed.2018.4222 fectiveness meta-analysis of drugs for the prophylaxis of migraine 21. Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014; 311(15):1547– headache. PLoS One 2015; 10(7):e0130733. 1555. doi:10.1001/jama.2014.3266 doi:10.1371/journal.pone.0130733 22. Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatment of 5. International Association for the Study of Pain (IASP). IASP Termi- fibromyalgia. A meta-analysis and review. Psychosomatics 2000; nology. www.iasp-pain.org/Education/Content.aspx?ItemNumber=1 41(2):104–113. pmid:10749947 698&navItemNumber=576. Accessed November 20, 2019. 23. Hauser W, Wolfe F, Tolle T, Uceyler N, Sommer C. The role of anti- 6. Feller L, Khammissa RAG, Fourie J, Bouckaert M, Lemmer J. Posther- depressants in the management of fibromyalgia syndrome: a sys- pectic neuralgia and trigeminal neuralgia. Pain Res Treat 2017; tematic review and meta-analysis. CNS Drugs 2012; 26(4):297–307. 2017:1681765. doi:10.1155/2017/1681765 doi:10.2165/11598970-000000000-00000 7. Shillo P, Sloan G, Greig M, et al. Painful and painless diabetic 24. Calandre EP, Rico-Villademoros F, Slim M. An update on pharmaco- neuropathies: what is the difference? Curr Diab Rep 2019; 19(6):32. therapy for the treatment of fibromyalgia. Expert Opin Pharmaco- doi:10.1007/s11892-019-1150-5 ther 2015; 16(9):1347–1368. doi:10.1517/14656566.2015.1047343 8. Schwartzman RJ, Maleki J. Postinjury neuropathic pain syndromes. 25. Jackson JL, O’Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Med Clin North Am 1999; 83(3):597–626. Treatment of functional gastrointestinal disorders with antidepres- doi:10.1016/s0025-7125(05)70126-7 sant medications: a meta-analysis. Am J Med 2000; 108(1):65–72. 9. Oaklander AL, Horowitz SH. The complex regional pain syndrome. doi:10.1016/s0002-9343(99)00299-5 Handb Clin Neurol 2015; 131:481–503. 26. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Efficacy of tricyclic anti- doi:10.1016/B978-0-444-62627-1.00026-3 depressants in irritable bowel syndrome: a meta-analysis. World J 10. Akyuz G, Kuru P. Systematic review of central post stroke pain: Gastroenterol 2009; 15(13):1548–1553. doi:10.3748/wjg.15.1548 what is happening in the central nervous system? Am J Phys Med 27. Iskandar HN, Cassell B, Kanuri N, et al. Tricyclic antidepressants for Rehabil 2016; 95(8):618–627. doi:10.1097/PHM.0000000000000542 management of residual symptoms in inflammatory bowel disease. 11. Shiao R, Lee-Kubli CA. Neuropathic pain after spinal cord injury: J Clin Gastroenterol 2014; 48(5):423–429. challenges and research perspectives. Neurotherapeutics 2018; doi:10.1097/MCG.0000000000000049 15(3):635–653. doi:10.1007/s13311-018-0633-4 28. Lee LY, Abbott L, Mahlangu B, Moodie SJ, Anderson S. The man- 12. Ceruti S. What role does play in the development agement of cyclic vomiting syndrome: a systematic review. Eur J of untreatable painful conditions? Pain Manag 2018; 8(1):37–44. Gastroenterol Hepatol 2012; 24(9):1001–1006. doi:10.2217/pmt-2017-0038 doi:10.1097/MEG.0b013e328355638f 13. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for 29. Thorkelson G, Bielefeldt K, Szigethy E. Empirically supported use of neuropathic pain in adults: a systematic review and meta-analysis. psychiatric medications in adolescents and adults with IBD. Inflamm Lancet Neurol 2015; 14(2):162–173. Bowel Dis 2016; 22(6):1509–1522. doi:10.1016/S1474-4422(14)70251-0 doi:10.1097/MIB.0000000000000734 14. Hearn L, Moore RA, Derry S, Wiffen PJ, Phillips T. 30. Braak B, Klooker TK, Wouters MM, et al. Randomised clinical trial: for neuropathic pain in adults. Cochrane Database Syst Rev 2014; the effects of amitriptyline on drinking capacity and symptoms (9):CD011003. doi:10.1002/14651858.CD011003.pub2 in patients with functional dyspepsia, a double-blind placebo- 15. Derry S, Whiffen PJ, Aldington D, Moore RA. Nortriptyline for controlled study. Aliment Pharmacol Ther 2011; 34(6):638–648. neuropathic pain in adults. Cochrane Database Syst Rev 2015; doi:10.1111/j.1365-2036.2011.04775.x 1:CD011209. doi:10.1002/14651858.CD011209.pub2 31. Parkman HP, Van Natta ML, Abell TL, et al. Effect of nortriptyline on 16. Salerno SM, Browning R, Jackson JL. The effect of antidepressant symptoms of idiopathic gastroparesis: the NORIG randomized clini- treatment on chronic back pain: a meta-analysis. Arch Intern Med cal trial. JAMA 2013; 310(24):2640–2649. 2002; 162(1):19–24. doi:10.1001/archinte.162.1.19 doi:10.1001/jama.2013.282833 17. Staiger TO, Gaster B, Sullivan MD, Deyo RA. Systematic review of 32. Latthe P, Latthe M, Say L, Gulmezoglu M, Khan KS. WHO sys- antidepressants in the treatment of chronic low back pain. Spine tematic review of prevalence of chronic pelvic pain: a neglected (Phila Pa 1976) 2003; 28(22):2540–2545. reproductive health morbidity. BMC Public Health 2006; 6:177.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 12 DECEMBER 2019 813 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. TRICYCLIC ANTIDEPRESSANTS

doi:10.1186/1471-2458-6-177 43. Wang SM, Han C, Bahk WM, et al. Addressing the side effects of 33. Moise G, Capodice J, Winfree CJ. Treatment of chronic pelvic pain contemporary antidepressant drugs: a comprehensive review. Chon- in men and women. Expert Rev Neurother 2007; 7(5):507–520. nam Med J 2018; 54(2):101–112. doi:10.4068/cmj.2018.54.2.101. doi:10.1586/14737175.7.5.507 44. Trindade E, Menon D, Topfer LA, Coloma C. Adverse effects as- 34. Lai HH. Management of interstitial cystitis/bladder pain syndrome sociated with selective serotonin reuptake inhibitors and tricyclic with tricyclic antidepressants. In: Moldwin RM, ed. Urological and antidepressants: a meta-analysis. CMAJ 1998; 159(10):1245–1252. Gynaecological Chronic Pelvic Pain. Cham, Switzerland: Springer; pmid:9861221 2017:107–118. 45. Fava M. Prospective studies of adverse events related to antide- 35. American Urological Association. Diagnosis and treatment inter- pressant discontinuation. J Clin Psychiatry 2006; 67(suppl 4):14–21. stitial cystitis/bladder pain syndrome (2014). www.auanet.org/ pmid:16683858 guidelines/interstitial-cystitis/bladder-pain-syndrome-(2011-amend- 46. Gintant G. An evaluation of hERG current assay performance: trans- ed-2014). Accessed November 19, 2019. lating preclinical safety studies to clinical QT prolongation. Pharma- 36. Carey ET, As-Sanie S. New developments in the pharmacotherapy col Ther 2011; 129(2):109–119. doi:0.1016/j.pharmthera.2010.08.008. of neuropathic chronic pelvic pain. Future Sci OA 2016; 2(4):FSO148. 47. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc doi:10.4155/fsoa-2016-0048 prolongation, torsades de pointes, and psychotropic medications. 37. Papandreou C, Skapinakis P, Giannakis D, Sofikitis N, Mavreas V. Psychosomatics 2013; 54(1):1–13. doi:10.1016/j.psym.2012.11.001 Antidepressant drugs for chronic urological pelvic pain: an evidence- 48. American Geriatrics Society 2015 Beers Criteria Update Expert based review. Adv Urol 2009; 2009:797031. doi:10.1155/2009/797031 Panel. American Geriatrics Society 2015 updated Beers Criteria for 38. Liu Y, Xu X, Dong M, Jia S, Wei Y. Treatment of insomnia with tricy- potentially inappropriate medication use in older adults. J Am Geri- clic antidepressants: a meta-analysis of polysomnographic random- atr Soc 2015; 63(11):2227–2246. doi:10.1111/jgs.13702 ized controlled trials. Sleep Med 2017; 34:126–133. 49. Fukushima N, Nanao K, Fukushima H, Namera A, Miura M. A neo- doi:10.1016/j.sleep.2017.03.007 natal prolonged QT syndrome due to maternal use of oral tricyclic 39. Matheson E, Hainer BL. Insomnia: pharmacologic therapy. Am Fam antidepressants. Eur J Pediatr 2016; 175(8):1129–1132. Physician 2017; 96(1):29–35. pmid:28671376 doi:10.1007/s00431-016-2722-x 40. McCall C, McCall WV. What is the role of sedating antidepressants, 50. ACOG Committee on Practice Bulletins—Obstetrics. ACOG Practice antipsychotics, and anticonvulsants in the management of insom- Bulletin: Clinical management guidelines for obstetrician-gynecol- nia? Curr Psychiatry Rep 2012; 14(5):494–502. ogists number 92, April 2008 (replaces practice bulletin number 87, doi:10.1007/s11920-012-0302-y November 2007). Use of psychiatric medications during pregnancy 41. Clark MS, Smith PO, Jamieson B. FPIN’s clinical inquiries: antidepres- and lactation. Obstet Gynecol 2008; 111(4):1001–1020. sants for the treatment of insomnia in patients with depression. Am doi:10.1097/AOG.0b013e31816fd910 Fam Physician 2011; 84(9):1–2. pmid:22164891 42. Sadock BJ, Sadock VA, Ruiz P. Kaplan and Sadock’s Synopsis of Address: Xavier F. Jimenez, MD, MA, Neurological Institute, C15, Cleve- Psychiatry. New York, NY: Lippincott Williams & Wilkins; 2014. land Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

8th Annual Basic and Clinical Immunology for the Busy Clinician:

What Is New and Hot in Immunology

February 28-29, 2020 Saguaro Scottsdale, Scottsdale, AZ Register now! ccfcme.org/clinical20 Never has a conference been so specifically tailored to bridge the bench to the bedside and beyond! Register to attend a one-of-a-kind symposium with a unique array of educational offerings in the field of clinical immunology. This is designed for busy clinicians who desire to increase their declarative and procedural knowledge in the field as it applies to patient care. This activity has been approved for AMA PRA Category 1 Credit™.

814 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.