Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Amitriptyline: Difference between pages

{{Short description|Tricyclic antidepressant}}

{{Use American English|date=February 2024}}

{{Use dmy dates|date=February 2024}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 477169407

| image = Amitriptyline2DACS.svg

| width = 200

| alt =

| width2 = 250

| alt2 =

<!-- Clinical data -->

| pronounce = {{IPAc-en|ˌ|æ|m|ᵻ|ˈ|t|ɹ|ɪ|p|t|ᵻ|l|iː|n}}<ref>{{cite web|url=https://www.lexico.com/en/definition/amitriptyline|archive-url=https://web.archive.org/web/20140714140116/http://www.oxforddictionaries.com/us/definition/english/amitriptyline?q=amitriptyline |url-status= dead |title=Amitriptyline |work= Oxford Dictionary |via= Lexico.com |archive-date=14 July 2014 | language= en |access-date=6 January 2021}}</ref>

| tradename = Elavil, others

| DailyMedID = Amitriptyline

| pregnancy_AU = C

| pregnancy_AU_comment =<ref name="Drugs.com pregnancy">{{cite web | title=Amitriptyline Use During Pregnancy | website=Drugs.com | date=2 September 2020 | url=https://www.drugs.com/pregnancy/amitriptyline.html | access-date=13 September 2020 | archive-date=9 November 2020 | archive-url=https://web.archive.org/web/20201109214320/https://www.drugs.com/pregnancy/amitriptyline.html | url-status=live }}</ref>

| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection]]

| class = [[Tricyclic antidepressant]] (TCA)

| ATC_prefix = N06

| ATC_suffix = AA09

| legal_AU = S4

| legal_BR = C1

| legal_BR_comment = <ref>{{cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = 45%<ref name="pmid3893842"/>-53%<ref name = pmid33438398/>

| protein_bound = 96%<ref name = TGA/>

| metabolism = [[Liver]] (CYP2D6, CYP2C19, CYP3A4)<ref name="pmid15554244"/><ref name = pmid33438398/><ref name="pmid11583471"/>

| metabolites = nortriptyline, (''E'')-10-hydroxynortriptyline

| elimination_half-life = 21 hours<ref name="pmid3893842"/>

| excretion = [[Urine]]: 12–80% after 48 hours;<ref name="pmid6667101"/> feces: not studied

<!-- Identifiers -->

| CAS_supplemental = <br />549-18-8 ([[hydrochloride]])<br />17086-03-2 ([[embonate]])

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| synonyms =

<!-- Chemical data -->

| IUPAC_name = 3-(10,11-dihydro-5''H''-dibenzo[''a'',''d'']cycloheptene-5-ylidene)-''N'',''N''-dimethylpropan-1-amine

| C=20 | H=23 | N=1

| SMILES = c3cc2c(/C(c1c(cccc1)CC2)=C\CCN(C)C)cc3

| melting_point = 197.5

| melting_notes =<ref>{{cite journal |vauthors=Blessel KW, Rudy BC, Senkowski BZ |title=Amitriptyline Hydrochloride |journal=Analytical Profiles of Drug Substances |volume=3 |pages=127–148 |date=1974 |doi=10.1016/S0099-5428(08)60066-0|isbn=9780122608032 }}</ref><!-- all melting points for "amitriptyline" in the literature are for the hydrochloride salt -->

<!-- Definition and medical uses -->

'''Amitriptyline''', sold under the brand name '''Elavil''' among others, is a [[tricyclic antidepressant]] primarily used to treat [[major depressive disorder]], a variety of pain syndromes such as [[neuropathic pain]], [[fibromyalgia]], [[migraine]] and [[tension headaches]].<ref name=EMC>{{cite web|title=Amitriptyline Tablets BP 50mg – Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Actavis UK Ltd.|date=24 March 2013|access-date=1 December 2013|url=http://www.medicines.org.uk/emc/medicine/23738/SPC/Amitriptyline+Tablets+BP+50mg/|url-status=live|archive-url=https://web.archive.org/web/20131203015148/http://www.medicines.org.uk/emc/medicine/23738/SPC/Amitriptyline+Tablets+BP+50mg/|archive-date=3 December 2013}}</ref> Due to the frequency and prominence of side effects, amitriptyline is generally considered a

[[Therapy#Lines of therapy|second-line therapy]] for these indications.<ref name=top100drugs/><ref name="pmid32040849"/><ref name="pmid27377815"/><ref name="pmid22529202"/>

<!--Side effects -->

The most common side effects are dry mouth, drowsiness, dizziness, constipation, and weight gain. [[Glaucoma]], liver toxicity and [[arrhythmia|abnormal heart rhythms]] are rare but serious side effects. Blood levels of amitriptyline vary significantly from one person to another,<ref name="pmid28405886">{{cite journal | vauthors = Tfelt-Hansen P, Ågesen FN, Pavbro A, Tfelt-Hansen J | title = Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine | journal = CNS Drugs | volume = 31 | issue = 5 | pages = 389–403 | date = May 2017 | pmid = 28405886 | doi = 10.1007/s40263-017-0430-3 | s2cid = 23560743 }}</ref> and amitriptyline interacts with many other medications potentially aggravating its side effects.

<!-- History, society and culture -->

Amitriptyline was discovered in the late 1950s by scientists at [[Merck & Co.|Merck]] and approved by the US [[Food and Drug Administration]] (FDA) in 1961.<ref name="Half a century of antidepressant dr">{{cite journal | vauthors = Fangmann P, Assion HJ, Juckel G, González CA, López-Muñoz F | title = Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part II: tricyclics and tetracyclics | journal = Journal of Clinical Psychopharmacology | volume = 28 | issue = 1 | pages = 1–4 | date = February 2008 | pmid = 18204333 | doi = 10.1097/jcp.0b013e3181627b60 | s2cid = 31018835 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | author-link = | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free | vauthors = Organization WH }}</ref> It is available as a [[generic medication]].<ref name=AHFS2014>{{cite web| title= Amitriptyline Hydrochloride| url= https://www.drugs.com/monograph/amitriptyline-hydrochloride.html |publisher= The American Society of Health-System Pharmacists| website= Drugs.com| access-date=25 September 2014|url-status=live| archive-url= https://web.archive.org/web/20140924185142/http://www.drugs.com/monograph/amitriptyline-hydrochloride.html|archive-date=24 September 2014}}</ref> In 2021, it was the 107th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Amitriptyline - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Amitriptyline | access-date = 14 January 2024}}</ref>

{{TOC limit}}

==Medical uses==

Amitriptyline is [[indicated]] for the treatment of [[major depressive disorder]] and [[neuropathic pain]] and for the prevention of [[migraine]] and chronic [[tension headache]]. It can be used for the treatment of [[nocturnal enuresis]] in children older than 6 after other treatments have failed.<ref name = EMC/>

===Depression===

Amitriptyline is effective for depression,<ref name="pmid23235671"/> but it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability.<ref name = "AMH">{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | edition = 2013 | place = Adelaide | veditors = Rossi S }}</ref> It can be tried for depression as a second-line therapy, after the failure of other treatments.<ref name= top100drugs>{{cite book | vauthors = Hitchings A, Lonsdale D, Burrage D, Baker E |title=Top 100 drugs : clinical pharmacology and practical prescribing |date=2015 |isbn=978-0-7020-5516-4 |page=50|publisher=Churchill Livingstone }}</ref> For [[treatment-resistant depression|treatment-resistant]] adolescent depression<ref name="pmid25433401">{{cite journal | vauthors = Zhou X, Michael KD, Liu Y, Del Giovane C, Qin B, Cohen D, Gentile S, Xie P | title = Systematic review of management for treatment-resistant depression in adolescents | journal = BMC Psychiatry | volume = 14 | pages = 340 | date = November 2014 | pmid = 25433401 | pmc = 4254264 | doi = 10.1186/s12888-014-0340-6 | doi-access = free }}</ref> or for cancer-related depression<ref name="pmid24950919">{{cite journal | vauthors = Riblet N, Larson R, Watts BV, Holtzheimer P | title = Reevaluating the role of antidepressants in cancer-related depression: a systematic review and meta-analysis | journal = General Hospital Psychiatry | volume = 36 | issue = 5 | pages = 466–473 | date = 2014 | pmid = 24950919 | doi = 10.1016/j.genhosppsych.2014.05.010 }}</ref> amitriptyline is no better than placebo, however the number of treated patients in both studies was small. It is sometimes used for the treatment of depression in [[Parkinson's disease]],<ref>{{cite web | url= http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/movement_disorders/parkinsons_disease.html |title= Parkinson's disease| website= merckmanuals.com| archive-url= https://web.archive.org/web/20131118154550/http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/movement_disorders/parkinsons_disease.html |archive-date=18 November 2013 | publisher= Merck Sharp & Dohme Corp.| date= August 2007| access-date= 22 December 2013}}</ref> but supporting evidence for that is lacking.<ref name="pmid22021174">{{cite journal | vauthors = Seppi K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, Hametner EM, Poewe W, Rascol O, Goetz CG, Sampaio C | title = The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease | journal = Movement Disorders | volume = 26 | issue = Supply 3 | pages = S42–S80 | date = October 2011 | pmid = 22021174 | pmc = 4020145 | doi = 10.1002/mds.23884 }}</ref>

===Pain===

Amitriptyline alleviates painful [[diabetic neuropathy]]. It is recommended by a variety of guidelines as a first or second line treatment.<ref name="pmid32040849">{{cite journal | vauthors = Alam U, Sloan G, Tesfaye S | title = Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs | journal = Drugs | volume = 80 | issue = 4 | pages = 363–384 | date = March 2020 | pmid = 32040849 | doi = 10.1007/s40265-020-01259-2 | s2cid = 211074023 }}</ref> It is as effective for this indication as [[gabapentin]] or [[pregabalin]] but less well tolerated.<ref name="pmid33145709">{{cite journal | vauthors = Liampas A, Rekatsina M, Vadalouca A, Paladini A, Varrassi G, Zis P | title = Pharmacological Management of Painful Peripheral Neuropathies: A Systematic Review | journal = Pain and Therapy | volume = 10 | issue = 1 | pages = 55–68 | date = June 2021 | pmid = 33145709 | pmc = 8119529 | doi = 10.1007/s40122-020-00210-3 | doi-access = free }}</ref> Amitriptyline is as effective at relieving pain as [[duloxetine]]. [[Combination therapy|Combination treatment]] of amitriptyline and pregabalin offers additional pain relief for people whose pain is not adequately controlled with one medication, and is safe.<ref>{{cite journal |date=6 April 2023 |title=Combination therapy for painful diabetic neuropathy is safe and effective |url=https://evidence.nihr.ac.uk/alert/combination-therapy-for-painful-diabetic-neuropathy-is-safe-and-effective/ |journal=NIHR Evidence |language=en |doi=10.3310/nihrevidence_57470|s2cid=258013544 }}</ref><ref>{{cite journal | vauthors = Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Julious S, Rajbhandari S, Sharma S, Rayman G, Gouni R, Alam U, Cooper C, Loban A, Sutherland K, Glover R, Waterhouse S, Turton E, Horspool M, Gandhi R, Maguire D, Jude EB, Ahmed SH, Vas P, Hariman C, McDougall C, Devers M, Tsatlidis V, Johnson M, Rice AS, Bouhassira D, Bennett DL, Selvarajah D | title = Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial | journal = Lancet | volume = 400 | issue = 10353 | pages = 680–690 | date = August 2022 | pmid = 36007534 | pmc = 9418415 | doi = 10.1016/s0140-6736(22)01472-6 }}</ref> Amitriptyline in certain formulations may also induce the level of [[sciatic]]-nerve blockade needed for local [[anesthesia]] therein.<ref name="pmid12749958">{{cite journal | vauthors = Sudoh Y, Cahoon EE, Gerner P, Wang GK | title = Tricyclic antidepressants as long-acting local anesthetics | journal = Pain | volume = 103 | issue = 1–2 | pages = 49–55 | date = May 2003 | pmid = 12749958 | doi = 10.1016/s0304-3959(02)00375-5 | s2cid = 24955042 }}</ref> Here, it has been demonstrated to be of superior potency to [[bupivacaine]], a customary long-acting local anesthetic.

Low doses of amitriptyline moderately improve sleep disturbances and reduce pain and fatigue associated with [[fibromyalgia]].<ref name="pmid28493231" /> It is recommended for fibromyalgia accompanied by depression by [[Association of the Scientific Medical Societies in Germany]]<ref name="pmid28493231">{{cite journal | vauthors = Sommer C, Alten R, Bär KJ, Bernateck M, Brückle W, Friedel E, Henningsen P, Petzke F, Tölle T, Üçeyler N, Winkelmann A, Häuser W | title = [Drug therapy of fibromyalgia syndrome : Updated guidelines 2017 and overview of systematic review articles] | language = de | journal = Schmerz | volume = 31 | issue = 3 | pages = 274–284 | date = June 2017 | pmid = 28493231 | doi = 10.1007/s00482-017-0207-0 | s2cid = 195671256 }}</ref> and as a second-line option for fibromyalgia, with exercise being the first line option, by [[European League Against Rheumatism]].<ref name="pmid27377815">{{cite journal | vauthors = Macfarlane GJ, Kronisch C, Dean LE, Atzeni F, Häuser W, Fluß E, Choy E, Kosek E, Amris K, Branco J, Dincer F, Leino-Arjas P, Longley K, McCarthy GM, Makri S, Perrot S, Sarzi-Puttini P, Taylor A, Jones GT | title = EULAR revised recommendations for the management of fibromyalgia | journal = Annals of the Rheumatic Diseases | volume = 76 | issue = 2 | pages = 318–328 | date = February 2017 | pmid = 27377815 | doi = 10.1136/annrheumdis-2016-209724 | hdl-access = free | doi-access = free | hdl = 2164/8814 }}</ref> Combinations of amitriptyline and [[fluoxetine]] or [[melatonin]] may reduce fibromyalgia pain better than either medication alone.<ref name="pmid29457627">{{cite journal | vauthors = Thorpe J, Shum B, Moore RA, Wiffen PJ, Gilron I | title = Combination pharmacotherapy for the treatment of fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 2 | pages = CD010585 | date = February 2018 | pmid = 29457627 | pmc = 6491103 | doi = 10.1002/14651858.CD010585.pub2 }}</ref>

There is some (low-quality) evidence that amitriptyline may reduce pain in cancer patients. It is recommended only as a second line therapy for non-chemotherapy-induced neuropathic or mixed neuropathic pain, if [[opioid]]s did not provide the desired effect.<ref name="pmid27207115">{{cite journal | vauthors = van den Beuken-van Everdingen MH, de Graeff A, Jongen JL, Dijkstra D, Mostovaya I, Vissers KC | title = Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review | journal = Pain Practice | volume = 17 | issue = 3 | pages = 409–419 | date = March 2017 | pmid = 27207115 | doi = 10.1111/papr.12459 | s2cid = 37418010 }}</ref>

Moderate evidence exists in favor of amitriptyline use for [[atypical facial pain]].<ref name="pmid33037835">{{cite journal | vauthors = Do TM, Unis GD, Kattar N, Ananth A, McCoul ED | title = Neuromodulators for Atypical Facial Pain and Neuralgias: A Systematic Review and Meta-Analysis | journal = The Laryngoscope | volume = 131 | issue = 6 | pages = 1235–1253 | date = June 2021 | pmid = 33037835 | doi = 10.1002/lary.29162 | s2cid = 222256076 }}</ref> Amitriptyline is ineffective for HIV-associated neuropathy.<ref name="pmid33145709"/>

In multiple sclerosis it is frequently used to treat painful paresthesias in the arms and legs (e.g., burning sensations, pins and needles, stabbing pains) caused by damage to the pain regulating pathways of the brain and spinal cord.<ref>{{cite web |title=Elavil for MS |url=https://www.nationalmssociety.org/Treating-MS/Medications/Elavil#:~:text=Amitriptyline%20is%20a%20tricyclic%20antidepressant,the%20brain%20and%20spinal%20cord. |access-date=7 July 2023 |website=nationalmssociety.org}}</ref>

===Headache===

Amitriptyline is probably effective for the prevention of periodic [[migraine]] in adults. Amitriptyline is similar in efficancy to [[venlafaxine]] and [[topiramate]] but carries a higher burden of adverse effects than topiramate.<ref name="pmid22529202">{{cite journal | vauthors = Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E | title = Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society | journal = Neurology | volume = 78 | issue = 17 | pages = 1337–1345 | date = April 2012 | pmid = 22529202 | pmc = 3335452 | doi = 10.1212/WNL.0b013e3182535d20 }}</ref> For many patients, even very small doses of amitriptyline are helpful, which may allow for minimization of side effects.<ref name="pmid30137671">{{cite journal | vauthors = Loder E, Rizzoli P | title = Pharmacologic Prevention of Migraine: A Narrative Review of the State of the Art in 2018 | journal = Headache | volume = 58 | issue = Suppl 3 | pages = 218–229 | date = November 2018 | pmid = 30137671 | doi = 10.1111/head.13375 | s2cid = 52071815 }}</ref> Amitriptyline is not significantly different from placebo when used for the prevention of migraine in children.<ref name="pmid31413170">{{cite journal | vauthors = Oskoui M, Pringsheim T, Billinghurst L, Potrebic S, Gersz EM, Gloss D, Holler-Managan Y, Leininger E, Licking N, Mack K, Powers SW, Sowell M, Victorio MC, Yonker M, Zanitsch H, Hershey AD | title = Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society | journal = Neurology | volume = 93 | issue = 11 | pages = 500–509 | date = September 2019 | pmid = 31413170 | pmc = 6746206 | doi = 10.1212/WNL.0000000000008105 }}</ref>

Amitriptyline may reduce the frequency and duration of chronic [[tension headache]], but it is associated with worse adverse effects than [[mirtazapine]]. Overall, amitriptyline is recommended for tension headache [[prophylaxis]], along with lifestyle advice, which should include avoidance of analgesia and caffeine.<ref name="pmid26859719">{{cite journal | vauthors = Ghadiri-Sani M, Silver N | title = Headache (chronic tension-type) | journal = BMJ Clinical Evidence | volume = 2016 | date = February 2016 | pmid = 26859719 | pmc = 4747324 }}</ref>

===Other indications===

Amitriptyline is effective for the treatment of [[irritable bowel syndrome]]; however, because of its side effects, it should be reserved for select patients for whom other agents do not work.<ref name="pmid24992947">{{cite journal | vauthors = Trinkley KE, Nahata MC | title = Medication management of irritable bowel syndrome | journal = Digestion | volume = 89 | issue = 4 | pages = 253–267 | date = 2014 | pmid = 24992947 | doi = 10.1159/000362405 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ford AC, Wright-Hughes A, Alderson SL, Ow PL, Ridd MJ, Foy R, Bianco G, Bishop FL, Chaddock M, Cook H, Cooper D, Fernandez C, Guthrie EA, Hartley S, Herbert A, Howdon D, Muir DP, Nath T, Newman S, Smith T, Taylor CA, Teasdale EJ, Thornton R, Farrin AJ, Everitt HA | title = Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial | journal = Lancet | volume = 402 | issue = 10414 | pages = 1773–1785 | date = November 2023 | pmid = 37858323 | doi = 10.1016/s0140-6736(23)01523-4 }}</ref><ref>{{Cite journal |date=26 March 2024 |title=Irritable bowel syndrome: low-dose antidepressant improves symptoms |url=https://evidence.nihr.ac.uk/alert/irritable-bowel-syndrome-low-dose-antidepressant-improves-symptoms/ |journal=NIHR Evidence | publisher = National Institute for Health and Care Research (NIHR) | doi = 10.3310/nihrevidence_62555 }}</ref> There is insufficient evidence to support its use for abdominal pain in children with functional gastrointestinal disorders.<ref>{{cite journal | vauthors = de Bruijn CM, Rexwinkel R, Gordon M, Benninga M, Tabbers MM | title = Antidepressants for functional abdominal pain disorders in children and adolescents | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 2 | pages = CD008013 | date = February 2021 | pmid = 33560523 | pmc = 8094232 | doi = 10.1002/14651858.CD008013.pub3 }}</ref>

[[Tricyclic antidepressants]] decrease the frequency, severity, and duration of [[cyclic vomiting syndrome]] episodes. Amitriptyline, as the most commonly used of them, is recommended as a first-line agent for its therapy.<ref name="pmid31241819">{{cite journal | vauthors = Venkatesan T, Levinthal DJ, Tarbell SE, Jaradeh SS, Hasler WL, Issenman RM, Adams KA, Sarosiek I, Stave CD, Sharaf RN, Sultan S, Li BU | title = Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association | journal = Neurogastroenterology and Motility | volume = 31 | issue = Suppl 2 | pages = e13604 | date = June 2019 | pmid = 31241819 | pmc = 6899751 | doi = 10.1111/nmo.13604 }}</ref>

Amitriptyline may improve pain and urgency intensity associated with [[bladder pain syndrome]] and can be used in the management of this syndrome.<ref name="pmid29972328">{{cite journal | vauthors = Giusto LL, Zahner PM, Shoskes DA | title = An evaluation of the pharmacotherapy for interstitial cystitis | journal = Expert Opinion on Pharmacotherapy | volume = 19 | issue = 10 | pages = 1097–1108 | date = July 2018 | pmid = 29972328 | doi = 10.1080/14656566.2018.1491968 | s2cid = 49674883 }}</ref><ref name="pmid32904438">{{cite journal | vauthors = Colemeadow J, Sahai A, Malde S | title = Clinical Management of Bladder Pain Syndrome/Interstitial Cystitis: A Review on Current Recommendations and Emerging Treatment Options | journal = Research and Reports in Urology | volume = 12 | pages = 331–343 | date = 2020 | pmid = 32904438 | pmc = 7455607 | doi = 10.2147/RRU.S238746 | doi-access = free }}</ref> Amitriptyline can be used in the treatment of nocturnal [[enuresis]] in children. However, its effect is not sustained after the treatment ends. Alarm therapy gives better short- and long-term results.<ref name="pmid26789925">{{cite journal | vauthors = Caldwell PH, Sureshkumar P, Wong WC | title = Tricyclic and related drugs for nocturnal enuresis in children | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 1 | pages = CD002117 | date = January 2016 | pmid = 26789925 | pmc = 8741207 | doi = 10.1002/14651858.CD002117.pub2 }}</ref>

In the US, amitriptyline is commonly used in children with [[ADHD]] as an adjunct to stimulant medications without any evidence or guideline supporting this practice.<ref name="pmid30630642">{{cite journal | vauthors = Klein T, Woo TM, Panther S, Odom-Maryon T, Daratha K | title = Somnolence-Producing Agents: A 5-Year Study of Prescribing for Medicaid-Insured Children With Attention Deficit Hyperactivity Disorder | journal = Journal of Pediatric Health Care | volume = 33 | issue = 3 | pages = e1–e8 | date = 2019 | pmid = 30630642 | doi = 10.1016/j.pedhc.2018.10.002 | s2cid = 58577978 }}</ref> Many physicians in the UK (and the US also) commonly prescribe amitriptyline for [[insomnia]];<ref name="pmid24567616">{{cite journal | vauthors = Everitt H, McDermott L, Leydon G, Yules H, Baldwin D, Little P | title = GPs' management strategies for patients with insomnia: a survey and qualitative interview study | journal = The British Journal of General Practice | volume = 64 | issue = 619 | pages = e112–e119 | date = February 2014 | pmid = 24567616 | pmc = 3905408 | doi = 10.3399/bjgp14X677176 }}</ref> however, [[Cochrane (organization)|Cochrane]] reviewers were not able to find any randomized controlled studies that would support or refute this practice.<ref name="pmid29761479">{{cite journal | vauthors = Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, Manson CC, Wilson S | title = Antidepressants for insomnia in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 5 | pages = CD010753 | date = May 2018 | pmid = 29761479 | pmc = 6494576 | doi = 10.1002/14651858.CD010753.pub2 }}</ref> Similarly, a major [[systematic review]] and [[network meta-analysis]] of medications for the treatment of insomnia published in 2022 found little evidence to inform the use of amitriptyline for insomnia.<ref name="pmid35843245">{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | hdl-access = free | s2cid = 250536370 | doi-access = free | hdl = 11380/1288245 }}</ref> The well-known sedating effects of amitriptyline, however, bear understanding on and arguable justification for this practice. It may function similarly to [[doxepin]] in this regard, although the evidence for [[doxepin]] is more robust.<ref name="pmid29487083">{{cite journal | vauthors = Atkin T, Comai S, Gobbi G | title = Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery | journal = Pharmacological Reviews | volume = 70 | issue = 2 | pages = 197–245 | date = April 2018 | pmid = 29487083 | doi = 10.1124/pr.117.014381 }}</ref> [[Trimipramine]] may be a more novel alternative, especially given its tendency to not suppress; indeed, rather, brighten; R.E.M. sleep.<ref name="pmid2693052">{{cite journal | vauthors = Pecknold JC, Luthe L | title = Trimipramine, anxiety, depression and sleep | journal = Drugs | volume = 38 | issue = Suppl 1 | pages = 25–31; discussion 49–50 | date = 1989 | pmid = 2693052 | doi = 10.2165/00003495-198900381-00007 }}</ref><ref name="pmid12237787">{{cite journal | vauthors = Riemann D, Voderholzer U, Cohrs S, Rodenbeck A, Hajak G, Rüther E, Wiegand MH, Laakmann G, Baghai T, Fischer W, Hoffmann M, Hohagen F, Mayer G, Berger M | title = Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study | journal = Pharmacopsychiatry | volume = 35 | issue = 5 | pages = 165–74 | date = September 2002 | pmid = 12237787 | doi = 10.1055/s-2002-34119 }}</ref><ref name="pmid8863001">{{cite journal | vauthors = Berger M, Gastpar M | title = Trimipramine: a challenge to current concepts on antidepressives | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 246 | issue = 5 | pages = 235–9 | date = 1996 | pmid = 8863001 | doi = 10.1007/BF02190274 }}</ref>

==Contraindications and precautions==

The known contraindications of amitriptyline are:<ref name = EMC/>

{{Div col|colwidth=30em}}

* History of [[myocardial infarction]]

* History of arrhythmias, particularly any degree of [[heart block]]

* [[Coronary artery disease]]

* [[Porphyria]]

* Severe liver disease (such as [[cirrhosis]])

* Being under six years of age

* Patients who are taking [[monoamine oxidase inhibitors]] (MAOIs) or have taken them within the last 14 days

{{colend}}

Amitriptyline should be used with caution in patients with [[epilepsy]], impaired liver function, [[pheochromocytoma]], [[urinary retention]], [[benign prostatic hyperplasia|prostate enlargement]], [[hyperthyroidism]], and [[pyloric stenosis]].<ref name = EMC/>

In patients with the rare condition of shallow [[anterior chamber of eyeball]] and narrow [[anterior chamber angle]], amitriptyline may provoke attacks of acute [[glaucoma]] due to dilation of the pupil. It may aggravate [[psychosis]], if used for depression with [[schizophrenia]], or precipitate the switch to [[mania]] in those with [[bipolar disorder]].<ref name = EMC/>

[[CYP2D6#Genotype/phenotype variability|CYP2D6 poor metabolizers]] should avoid amitriptyline due to increased side effects. If it is necessary to use it, half dose is recommended.<ref name="pmid23486447">{{cite journal | vauthors = Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Müller DJ, Gaedigk A, Stingl JC | title = Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants | journal = Clinical Pharmacology and Therapeutics | volume = 93 | issue = 5 | pages = 402–408 | date = May 2013 | pmid = 23486447 | pmc = 3689226 | doi = 10.1038/clpt.2013.2 }}</ref> Amitriptyline can be used during pregnancy and lactation when SSRIs have been shown not to work.<ref name="pmid22283766">{{cite journal | vauthors = Nielsen RE, Damkier P | title = Pharmacological treatment of unipolar depression during pregnancy and breast-feeding--a clinical overview | journal = Nordic Journal of Psychiatry | volume = 66 | issue = 3 | pages = 159–166 | date = June 2012 | pmid = 22283766 | doi = 10.3109/08039488.2011.650198 | s2cid = 11327135 }}</ref>

==Side effects==

The most frequent side effects, occurring in 20% or more of users, are dry mouth, drowsiness, dizziness, constipation, and weight gain (on average 1.8&nbsp;kg<ref name="pmid25590213">{{cite journal | vauthors = Domecq JP, Prutsky G, Leppin A, Sonbol MB, Altayar O, Undavalli C, Wang Z, Elraiyah T, Brito JP, Mauck KF, Lababidi MH, Prokop LJ, Asi N, Wei J, Fidahussein S, Montori VM, Murad MH | title = Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 2 | pages = 363–370 | date = February 2015 | pmid = 25590213 | pmc = 5393509 | doi = 10.1210/jc.2014-3421 }}</ref>).<ref name="pmid23235671">{{cite journal | vauthors = Leucht C, Huhn M, Leucht S | title = Amitriptyline versus placebo for major depressive disorder | journal = The Cochrane Database of Systematic Reviews | volume = 12 | issue = | pages = CD009138 | date = December 2012 | pmid = 23235671 | doi = 10.1002/14651858.CD009138.pub2 }}</ref> Other common side effects are headache problems ([[amblyopia]], blurred vision), [[tachycardia]], increased appetite, [[tremor]], fatigue/[[asthenia]]/feeling slowed down, and [[indigestion|dyspepsia]].<ref name="pmid23235671"/>

A less common side effect of amitriptyline is urination problems (8.7%).<ref name="pmid23235671"/>

Amitriptyline can increase suicidal thoughts and behavior in people under the age of 24 and was black boxed by the FDA for these qualifiers due to this potential side effect.<ref>{{cite book | vauthors = Thour A, Marwaha R | chapter = Amitriptyline | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing|date=July 18, 2023 | pmid = 30725910 | chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK537225/#:~:text=Amitriptyline%20can%20also%20cause%20heart,glaucoma%2C%20confusion%2C%20and%20delirium. |access-date=March 18, 2024}}</ref>

Amitriptyline-associated [[sexual dysfunction]] (occurring at a frequency of 6.9%) seems to be mostly confined to males with depression and is expressed predominantly as [[erectile dysfunction]] and low [[libido]] disorder, with lesser frequency of ejaculatory and orgasmic problems. The rate of sexual dysfunction in males treated for indications other than depression and in females is not significantly different from placebo.<ref name="pmid29019272">{{cite journal | vauthors = Chen LW, Chen MY, Lian ZP, Lin HS, Chien CC, Yin HL, Chu YH, Chen KY | title = Amitriptyline and Sexual Function: A Systematic Review Updated for Sexual Health Practice | journal = American Journal of Men's Health | volume = 12 | issue = 2 | pages = 370–379 | date = March 2018 | pmid = 29019272 | pmc = 5818113 | doi = 10.1177/1557988317734519 }}</ref>

Liver tests abnormalities occur in 10–12% of patients on amitriptyline, but are usually mild, asymptomatic and transient,<ref name="LiverTox"/> with consistently elevated [[alanine transaminase]] in 3% of all patients.<ref name="pmid24362450">{{cite journal | vauthors = Voican CS, Corruble E, Naveau S, Perlemuter G | title = Antidepressant-induced liver injury: a review for clinicians | journal = The American Journal of Psychiatry | volume = 171 | issue = 4 | pages = 404–415 | date = April 2014 | pmid = 24362450 | doi = 10.1176/appi.ajp.2013.13050709 }}</ref><ref name="pmid13961401">{{cite journal | vauthors = Holmberg MB | title = A study of blood count and serum transaminase in prolonged treatment with amitriptyline | journal = The Journal of New Drugs | volume = 2 | issue = 6 | pages = 361–365 | date = 1962 | pmid = 13961401 | doi = 10.1177/009127006200200606 }}</ref> The increases of the enzymes above the 3-fold threshold of liver toxicity are uncommon, and cases of clinically apparent liver toxicity are rare;<ref name="LiverTox">{{cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK548410/|title=Amitriptyline|date=6 January 2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|access-date=6 January 2021|via=PubMed|pmid=31643729|archive-date=21 January 2022|archive-url=https://web.archive.org/web/20220121040521/https://www.ncbi.nlm.nih.gov/books/NBK548410/|url-status=live}}</ref> nevertheless, amitriptyline is placed in the group of antidepressants with greater risks of hepatic toxicity.<ref name="pmid24362450"/>

Amitriptyline [[QT-interval prolongation|prolongs the QT interval]].<ref name=AmitryptilineQT>{{cite journal | vauthors = Zemrak WR, Kenna GA | title = Association of antipsychotic and antidepressant drugs with Q-T interval prolongation | journal = American Journal of Health-System Pharmacy | volume = 65 | issue = 11 | pages = 1029–1038 | date = June 2008 | pmid = 18499875 | doi = 10.2146/ajhp070279 | url = http://www.medscape.com/viewarticle/575632_5 | url-status = live | archive-url = https://web.archive.org/web/20161221095718/http://www.medscape.com/viewarticle/575632_5 | archive-date = 21 December 2016 }}</ref> This prolongation is relatively small at therapeutic doses<ref name="pmid29466824">{{cite journal | vauthors = Hefner G, Hahn M, Hohner M, Roll SC, Klimke A, Hiemke C | title = QTc Time Correlates with Amitriptyline and Venlafaxine Serum Levels in Elderly Psychiatric Inpatients | journal = Pharmacopsychiatry | volume = 52 | issue = 1 | pages = 38–43 | date = January 2019 | pmid = 29466824 | doi = 10.1055/s-0044-102009 | s2cid = 3447931 }}</ref> but becomes severe in overdose.<ref name="pmid32252558">{{cite journal | vauthors = Campleman SL, Brent J, Pizon AF, Shulman J, Wax P, Manini AF | title = Drug-specific risk of severe QT prolongation following acute drug overdose | journal = Clinical Toxicology | volume = 58 | issue = 12 | pages = 1326–1334 | date = December 2020 | pmid = 32252558 | pmc = 7541562 | doi = 10.1080/15563650.2020.1746330 }}</ref>

==Overdose==

{{Main|Tricyclic antidepressant overdose}}

The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of [[serotonin syndrome]] and adverse cardiac effects. The [[British National Formulary]] notes that amitriptyline can be particularly dangerous in overdose,<ref name = BNF>{{cite book | author = Joint Formulary Committee | title = British National Formulary (BNF) | year = 2013 | url = https://archive.org/details/bnf65britishnati0000unse | isbn = 978-0-85711-084-8 | edition = 65th | location = London, UK | publisher = Pharmaceutical Press | url-access = registration }}</ref> thus it and other TCAs are no longer recommended as first-line therapy for depression.

The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available. Activated charcoal may reduce absorption if given within 1–2 hours of ingestion. If the affected person is unconscious or has an impaired gag reflex, a nasogastric tube may be used to deliver the activated charcoal into the stomach. ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised. Body temperature should be regulated with measures such as heating blankets if necessary. Cardiac monitoring is advised for at least five days after the overdose. [[Benzodiazepines]] are recommended to control seizures. [[Haemodialysis|Dialysis]] is of no use due to the high degree of [[Plasma protein binding|protein binding]] with amitriptyline.<ref name=TGA>{{cite web|title=Endep Amitriptyline hydrochloride|date=10 December 2012|access-date=1 December 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04558-3|format=PDF|work=TGA eBusiness Services|publisher=Alphapharm Pty Limited|url-status=live|archive-url=https://web.archive.org/web/20170813145944/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04558-3|archive-date=13 August 2017}}</ref>

== Interactions ==

Since amitriptyline and its active metabolite nortriptyline are primarily metabolized by cytochromes [[CYP2D6]] and [[CYP2C19]] (see [[Amitriptyline#Pharmacology]]), the inhibitors of these enzymes are expected to exhibit pharmacokinetic interactions with amitriptyline. According to the prescribing information, the interaction with [[CYP2D6]] inhibitors may increase the plasma level of amitriptyline.<ref name = EMC/> However, the results in the other literature are inconsistent:<ref name="pmid15554244">{{cite journal | vauthors = Breyer-Pfaff U | title = The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man | journal = Drug Metabolism Reviews | volume = 36 | issue = 3–4 | pages = 723–746 | date = October 2004 | pmid = 15554244 | doi = 10.1081/dmr-200033482 | s2cid = 25565048 }}</ref> the co-administration of amitriptyline with a potent CYP2D6 inhibitor [[paroxetine]] does increase the plasma levels of amitriptyline two-fold and of the main active metabolite nortriptyline 1.5-fold,<ref name="pmid10672631">{{cite journal | vauthors = Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R | title = Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients | journal = Psychopharmacology | volume = 147 | issue = 4 | pages = 378–383 | date = January 2000 | pmid = 10672631 | doi = 10.1007/s002130050006 | s2cid = 22476829 }}</ref> but combination with less potent CYP2D6 inhibitors [[thioridazine]] or [[levomepromazine]] does not affect the levels of amitriptyline and increases nortriptyline by about 1.5-fold;<ref name="pmid7909176">{{cite journal | vauthors = Jerling M, Bertilsson L, Sjöqvist F | title = The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline | journal = Therapeutic Drug Monitoring | volume = 16 | issue = 1 | pages = 1–12 | date = February 1994 | pmid = 7909176 | doi = 10.1097/00007691-199402000-00001 | s2cid = 1428027 }}</ref> a moderate CYP2D6 inhibitor fluoxetine does not seem to have a significant effect on the levels of amitriptyline or nortriptyline.<ref name="pmid8685072">{{cite journal | vauthors = Vandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T, Sechter D, Bizouard P | title = Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients | journal = Pharmacological Research | volume = 31 | issue = 6 | pages = 347–353 | date = June 1995 | pmid = 8685072 | doi = 10.1016/1043-6618(95)80088-3 }}</ref><ref name="pmid1454161">{{cite journal | vauthors = Vandel S, Bertschy G, Bonin B, Nezelof S, François TH, Vandel B, Sechter D, Bizouard P | title = Tricyclic antidepressant plasma levels after fluoxetine addition | journal = Neuropsychobiology | volume = 25 | issue = 4 | pages = 202–207 | date = 1992 | pmid = 1454161 | doi = 10.1159/000118838 }}</ref> A case of clinically significant interaction with potent CYP2D6 inhibitor [[terbinafine]] has been reported.<ref name="pmid16175144">{{cite journal | vauthors = Castberg I, Helle J, Aamo TO | title = Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline | journal = Therapeutic Drug Monitoring | volume = 27 | issue = 5 | pages = 680–682 | date = October 2005 | pmid = 16175144 | doi = 10.1097/01.ftd.0000175910.68539.33 }}</ref>

A potent inhibitor of [[CYP2C19]] and other cytochromes [[fluvoxamine]] increases the level of amitriptyline two-fold while slightly decreasing the level of nortriptyline.<ref name="pmid8685072"/> Similar changes occur with a moderate inhibitor of CYP2C19 and other cytochromes [[cimetidine]]: amitriptyline level increases by about 70%, while nortriptyline decreases by 50%.<ref name="pmid3912187">{{cite journal | vauthors = Curry SH, DeVane CL, Wolfe MM | title = Cimetidine interaction with amitriptyline | journal = European Journal of Clinical Pharmacology | volume = 29 | issue = 4 | pages = 429–433 | date = 1985 | pmid = 3912187 | doi = 10.1007/BF00613457 | s2cid = 25430195 }}</ref> [[CYP3A4]] inhibitor [[ketoconazole]] elevates amitriptyline level by about a quarter.<ref name="pmid11583471">{{cite journal | vauthors = Venkatakrishnan K, Schmider J, Harmatz JS, Ehrenberg BL, von Moltke LL, Graf JA, Mertzanis P, Corbett KE, Rodriguez MC, Shader RI, Greenblatt DJ | title = Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies | journal = Journal of Clinical Pharmacology | volume = 41 | issue = 10 | pages = 1043–1054 | date = October 2001 | pmid = 11583471 | doi = 10.1177/00912700122012634 | s2cid = 27146286 }}</ref> On the other hand, [[cytochrome P450]] inducers such as [[carbamazepine]] and [[St. John's Wort]] decrease the levels of both amitriptyline and nortriptyline<ref name="pmid7909176"/><ref name="pmid11799342">{{cite journal | vauthors = Johne A, Schmider J, Brockmöller J, Stadelmann AM, Störmer E, Bauer S, Scholler G, Langheinrich M, Roots I | title = Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ) | journal = Journal of Clinical Psychopharmacology | volume = 22 | issue = 1 | pages = 46–54 | date = February 2002 | pmid = 11799342 | doi = 10.1097/00004714-200202000-00008 | s2cid = 25670895 }}</ref>

Oral contraceptives may increase the blood level of amitriptyline by as high as 90%.<ref name="pmid27444984">{{cite journal | vauthors = Berry-Bibee EN, Kim MJ, Simmons KB, Tepper NK, Riley HE, Pagano HP, Curtis KM | title = Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review | journal = Contraception | volume = 94 | issue = 6 | pages = 650–667 | date = December 2016 | pmid = 27444984 | doi = 10.1016/j.contraception.2016.07.011 }}</ref> Valproate moderately increases the levels of amitriptyline and nortriptyline through an unclear mechanism.<ref name="pmid8689811">{{cite journal | vauthors = Wong SL, Cavanaugh J, Shi H, Awni WM, Granneman GR | title = Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics | journal = Clinical Pharmacology and Therapeutics | volume = 60 | issue = 1 | pages = 48–53 | date = July 1996 | pmid = 8689811 | doi = 10.1016/S0009-9236(96)90166-6 | s2cid = 37720622 }}</ref>

The prescribing information warns that the combination of amitriptyline with [[monoamine oxidase inhibitor]]s may cause potentially lethal [[serotonin syndrome]];<ref name = EMC/> however, this has been disputed.<ref name="pmid16460699">{{cite journal | vauthors = Gillman PK | title = A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action | journal = Biological Psychiatry | volume = 59 | issue = 11 | pages = 1046–1051 | date = June 2006 | pmid = 16460699 | doi = 10.1016/j.biopsych.2005.11.016 | s2cid = 12179122 }}</ref> The prescribing information cautions that some patients may experience a large increase in amitriptyline concentration in the presence of topiramate.<ref name=DailyMed/> However, other literature states that there is little or no interaction: in a pharmacokinetic study topiramate only increased the level of amitriptyline by 20% and nortriptyline by 33%.<ref name="pmid15355124">{{cite journal | vauthors = Bialer M, Doose DR, Murthy B, Curtin C, Wang SS, Twyman RE, Schwabe S | title = Pharmacokinetic interactions of topiramate | journal = Clinical Pharmacokinetics | volume = 43 | issue = 12 | pages = 763–780 | date = 2004 | pmid = 15355124 | doi = 10.2165/00003088-200443120-00001 | s2cid = 10427097 }}</ref>

Amitriptiline counteracts the antihypertensive action of [[guanethidine]].<ref name = TGA/><ref name="pmid5468457">{{cite journal | vauthors = Meyer JF, McAllister CK, Goldberg LI | title = Insidious and prolonged antagonism of guanethidine by amitriptyline | journal = JAMA | volume = 213 | issue = 9 | pages = 1487–1488 | date = August 1970 | pmid = 5468457 | doi = 10.1001/jama.1970.03170350053016 }}</ref> When given with amitriptyline, other [[anticholinergic]] agents may result in [[hyperpyrexia]] or [[paralytic ileus]].<ref name=DailyMed>{{cite web |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61d2da8d-b435-4ada-a013-401786f7cace |title=DailyMed – AMITRIPTYLINE HYDROCHLORIDE tablet, film coated |format= |access-date=2 February 2021 |archive-date=25 January 2021 |archive-url=https://web.archive.org/web/20210125110607/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61d2da8d-b435-4ada-a013-401786f7cace |url-status=live }}</ref> Co-administration of amitriptyline and [[disulfiram]] is not recommended due to the potential for the development of toxic delirium.<ref name = TGA/><ref name="pmid7092508">{{cite journal | vauthors = Maany I, Hayashida M, Pfeffer SL, Kron RE | title = Possible toxic interaction between disulfiram and amitriptyline | journal = Archives of General Psychiatry | volume = 39 | issue = 6 | pages = 743–744 | date = June 1982 | pmid = 7092508 | doi = 10.1001/archpsyc.1982.04290060083018 }}</ref> Amitriptyline causes an unusual type of interaction with the [[anticoagulant]] [[phenprocoumon]] during which great fluctuations of the [[prothrombin time]] have been observed.<ref name="urlCHAPTER 132 ORAL ANTICOAGULATION | Free Medical Textbook">{{cite web |url=https://medtextfree.wordpress.com/2012/02/09/chapter-132-oral-anticoagulation/ |title=CHAPTER 132 ORAL ANTICOAGULATION &#124; Free Medical Textbook |date=9 February 2012 |format= |access-date=2 February 2021 |archive-date=27 September 2020 |archive-url=https://web.archive.org/web/20200927103658/https://medtextfree.wordpress.com/2012/02/09/chapter-132-oral-anticoagulation/ |url-status=live }}</ref>

==Pharmacology==

===Pharmacodynamics===

{{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}}

{| class="wikitable floatright" style="font-size:small;"

|+ Molecular targets of amitriptyline (AMI) and main active metabolite nortriptyline (NTI)<ref name="PDSP">{{cite web | title = PDSP K_i Database | work = Psychoactive Drug Screening Program (PDSP) | author1-link = Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=amitriptyline&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | archive-date = 27 August 2021 | archive-url = https://web.archive.org/web/20210827213623/https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=amitriptyline&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | url-status = live }}</ref>

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! Site !! {{abbr|AMI|Amitriptyline}} !! {{abbrlink|NTI|Nortriptyline}} !! Species !! Ref

|-

| {{abbrlink|SERT|Serotonin transporter}} || 2.8–36 || 15–279 || Human ||<ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–258 | date = December 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9 }}</ref><ref name="pmid9400006">{{cite journal | vauthors = Owens MJ, Morgan WN, Plott SJ, Nemeroff CB | title = Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 283 | issue = 3 | pages = 1305–1322 | date = December 1997 | pmid = 9400006 }}</ref>

|-

| {{abbrlink|NET|Norepinephrine transporter}} || 19–102 || 1.8–21 || Human ||<ref name="pmid9537821" /><ref name="pmid9400006" />

|-

| {{abbrlink|DAT|Dopamine transporter}} || 3,250 || 1,140 || Human ||<ref name="pmid9537821" />

|-

| [[5-HT1A receptor|5-HT_1A]] || 450–1,800 || 294 || Human ||<ref name="pmid7855217">{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 559–565 | date = May 1994 | pmid = 7855217 | doi = 10.1007/bf02244985 | s2cid = 21236268 }}</ref><ref name="pmid2898916">{{cite journal | vauthors = Peroutka SJ | title = Antimigraine drug interactions with serotonin receptor subtypes in human brain | journal = Annals of Neurology | volume = 23 | issue = 5 | pages = 500–504 | date = May 1988 | pmid = 2898916 | doi = 10.1002/ana.410230512 | s2cid = 41570165 }}</ref>

|-

| [[5-HT1B receptor|5-HT_1B]] || 840 || {{abbr|ND|No data}} || Rat ||<ref name="pmid2942638">{{cite journal | vauthors = Peroutka SJ | title = Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex | journal = Journal of Neurochemistry | volume = 47 | issue = 2 | pages = 529–540 | date = August 1986 | pmid = 2942638 | doi = 10.1111/j.1471-4159.1986.tb04532.x | s2cid = 25108290 }}</ref>

|-

| [[5-HT2A receptor|5-HT_2A]] || 18–23 || 41 || Human ||<ref name="pmid7855217" /><ref name="pmid2898916" />

|-

| [[5-HT2B receptor|5-HT_2B]] || 174 || {{abbr|ND|No data}} || Human ||<ref name="pmid8743744">{{cite journal | vauthors = Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H | title = Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? | journal = The European Journal of Neuroscience | volume = 8 | issue = 5 | pages = 959–967 | date = May 1996 | pmid = 8743744 | doi = 10.1111/j.1460-9568.1996.tb01583.x | s2cid = 19578349 }}</ref>

|-

| [[5-HT2C receptor|5-HT_2C]] || 4-8 || 8.5 || Rat ||<ref name="pmid8876023">{{cite journal | vauthors = Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J | title = Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor | journal = Psychopharmacology | volume = 126 | issue = 3 | pages = 234–240 | date = August 1996 | pmid = 8876023 | doi = 10.1007/bf02246453 | s2cid = 24889381 }}</ref><ref name="pmid10379421">{{cite journal | vauthors = Sánchez C, Hyttel J | title = Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 4 | pages = 467–489 | date = August 1999 | pmid = 10379421 | doi = 10.1023/a:1006986824213 | s2cid = 19490821 }}</ref>

|-

| [[5-HT3 receptor|5-HT₃]] || 430 || 1,400 || Rat ||<ref name="pmid2533080">{{cite journal | vauthors = Schmidt AW, Hurt SD, Peroutka SJ | title = '[3H]quipazine' degradation products label 5-HT uptake sites | journal = European Journal of Pharmacology | volume = 171 | issue = 1 | pages = 141–143 | date = November 1989 | pmid = 2533080 | doi = 10.1016/0014-2999(89)90439-1 }}</ref>

|-

| [[5-HT6 receptor|5-HT₆]] || 65–141 || 148 || Human/rat ||<ref name="pmid8522988">{{cite journal | vauthors = Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW | title = Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor | journal = Journal of Neurochemistry | volume = 66 | issue = 1 | pages = 47–56 | date = January 1996 | pmid = 8522988 | doi = 10.1046/j.1471-4159.1996.66010047.x | s2cid = 35874409 }}</ref><ref name="pmid14645659">{{cite journal | vauthors = Hirst WD, Abrahamsen B, Blaney FE, Calver AR, Aloj L, Price GW, Medhurst AD | title = Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling | journal = Molecular Pharmacology | volume = 64 | issue = 6 | pages = 1295–1308 | date = December 2003 | pmid = 14645659 | doi = 10.1124/mol.64.6.1295 | s2cid = 33743899 }}</ref><ref name="pmid7680751">{{cite journal | vauthors = Monsma FJ, Shen Y, Ward RP, Hamblin MW, Sibley DR | title = Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs | journal = Molecular Pharmacology | volume = 43 | issue = 3 | pages = 320–327 | date = March 1993 | pmid = 7680751 }}</ref>

|-

| [[5-HT7 receptor|5-HT₇]] || 92.8–123 || {{abbr|ND|No data}} || Rat ||<ref name="pmid8394362">{{cite journal | vauthors = Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Sibley DR | title = Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype | journal = The Journal of Biological Chemistry | volume = 268 | issue = 24 | pages = 18200–18204 | date = August 1993 | pmid = 8394362 | doi = 10.1016/S0021-9258(17)46830-X | doi-access = free }}</ref>

|-

| [[Alpha-1A adrenergic receptor|α_1A]] || 6.5–25 || 18–37 || Human ||<ref name="pmid20363235">{{cite journal | vauthors = Nojimoto FD, Mueller A, Hebeler-Barbosa F, Akinaga J, Lima V, Kiguti LR, Pupo AS | title = The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha1B-adrenoceptors | journal = Neuropharmacology | volume = 59 | issue = 1–2 | pages = 49–57 | date = 2010 | pmid = 20363235 | doi = 10.1016/j.neuropharm.2010.03.015 | s2cid = 207225294 }}</ref><ref name="pmid32608144">{{cite journal | vauthors = Proudman RG, Pupo AS, Baker JG | title = The affinity and selectivity of α-adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-adrenoceptors | journal = Pharmacology Research & Perspectives | volume = 8 | issue = 4 | pages = e00602 | date = August 2020 | pmid = 32608144 | pmc = 7327383 | doi = 10.1002/prp2.602 }}</ref>

|-

| [[Alpha-1B adrenergic receptor|α_1B]] || 600–1700|| 850–1300|| Human ||<ref name="pmid20363235"/><ref name="pmid32608144"/>

|-

| [[Alpha-1D adrenergic receptor|α_1D]] || 560 || 1500 || Human ||<ref name="pmid32608144"/>

|-

| [[alpha-2 adrenergic receptor|α₂]] || 114–690 || 2,030 || Human ||<ref name="pmid9400006" /><ref name="pmid7855217" />

|-

| [[Alpha-2A adrenergic receptor|α_2A]] || 88 || {{abbr|ND|No data}} || Human ||<ref name="pmid22982401">{{cite journal | vauthors = Fallarero A, Pohjanoksa K, Wissel G, Parkkisenniemi-Kinnunen UM, Xhaard H, Scheinin M, Vuorela P | title = High-throughput screening with a miniaturized radioligand competition assay identifies new modulators of human α2-adrenoceptors | journal = European Journal of Pharmaceutical Sciences | volume = 47 | issue = 5 | pages = 941–951 | date = December 2012 | pmid = 22982401 | doi = 10.1016/j.ejps.2012.08.021 }}</ref>

|-

| [[Alpha-2B adrenergic receptor|α_2B]] || >1000 || {{abbr|ND|No data}} || Human ||<ref name="pmid22982401"/>

|-

| [[Alpha-2C adrenergic receptor|α_2C]] || 120 || {{abbr|ND|No data}} || Human ||<ref name="pmid22982401"/>

|-

| [[Beta adrenergic receptor|β]] || >10,000 || >10,000 || Rat ||<ref name="pmid8699">{{cite journal | vauthors = Bylund DB, Snyder SH | title = Beta adrenergic receptor binding in membrane preparations from mammalian brain | journal = Molecular Pharmacology | volume = 12 | issue = 4 | pages = 568–580 | date = July 1976 | pmid = 8699 }}</ref><ref name="pmid10379421" />

|-

| [[Dopamine D1 receptor|D₁]] || 89 || 210 (rat) || Human/rat ||<ref name="pmid19091563" /><ref name="pmid10379421"/>

|-

| [[Dopamine D2 receptor|D₂]] || 196–1,460 || 2,570 || Human ||<ref name="pmid7855217" /><ref name="pmid19091563" />

|-

| [[Dopamine D3 receptor|D₃]] || 206 || {{abbr|ND|No data}} || Human ||<ref name="pmid19091563" />

|-

| [[Dopamine D4 receptor|D₄]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}

|-

| [[Dopamine D5 receptor|D₅]] || 170 || {{abbr|ND|No data}} || Human ||<ref name="pmid19091563" />

|-

| [[Histamine H1 receptor|H₁]] || 0.5–1.1 || 3.0–15 || Human ||<ref name="pmid19091563">{{cite journal | vauthors = von Coburg Y, Kottke T, Weizel L, Ligneau X, Stark H | title = Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics | journal = Bioorganic & Medicinal Chemistry Letters | volume = 19 | issue = 2 | pages = 538–542 | date = January 2009 | pmid = 19091563 | doi = 10.1016/j.bmcl.2008.09.012 }}</ref><ref name="pmid22033803">{{cite journal | vauthors = Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R | title = Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 385 | issue = 2 | pages = 145–170 | date = February 2012 | pmid = 22033803 | doi = 10.1007/s00210-011-0704-0 | s2cid = 14274150 }}</ref><ref name="pmid16782354">{{cite journal | vauthors = Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG | title = Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes | journal = Bioorganic & Medicinal Chemistry | volume = 14 | issue = 19 | pages = 6640–6658 | date = October 2006 | pmid = 16782354 | doi = 10.1016/j.bmc.2006.05.077 }}</ref>

|-

| [[Histamine H2 receptor|H₂]] || 66 || 646 || Human ||<ref name="pmid22033803" />

|-

| [[Histamine H3 receptor|H₃]] || 75,900;>1000 || 45,700 || Human ||<ref name="pmid19091563" /><ref name="pmid22033803" />

|-

| [[Histamine H4 receptor|H₄]] || 34–26,300 || 6,920 || Human ||<ref name="pmid22033803" /><ref name="pmid11179435">{{cite journal | vauthors = Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF | title = Discovery of a novel member of the histamine receptor family | journal = Molecular Pharmacology | volume = 59 | issue = 3 | pages = 427–433 | date = March 2001 | pmid = 11179435 | doi = 10.1124/mol.59.3.427 | url = https://cdr.lib.unc.edu/record/uuid:d42d8e6e-1a6d-40fc-9371-e4a7ab63f3ea | access-date = 11 December 2019 | url-status = live | archive-url = https://web.archive.org/web/20210827213636/https://cdr.lib.unc.edu/concern/articles/b2773x653 | archive-date = 27 August 2021 }}</ref>

|-

| [[Muscarinic acetylcholine receptor M1|M₁]] || 11.0–14.7 || 40 || Human ||<ref name="pmid8100134">{{cite journal | vauthors = Stanton T, Bolden-Watson C, Cusack B, Richelson E | title = Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics | journal = Biochemical Pharmacology | volume = 45 | issue = 11 | pages = 2352–2354 | date = June 1993 | pmid = 8100134 | doi = 10.1016/0006-2952(93)90211-e }}</ref><ref name="pmid10227113">{{cite journal | vauthors = Bymaster FP, Nelson DL, DeLapp NW, Falcone JF, Eckols K, Truex LL, Foreman MM, Lucaites VL, Calligaro DO | title = Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro | journal = Schizophrenia Research | volume = 37 | issue = 1 | pages = 107–122 | date = May 1999 | pmid = 10227113 | doi = 10.1016/s0920-9964(98)00146-7 | s2cid = 19891653 }}</ref>

|-

| [[Muscarinic acetylcholine receptor M2|M₂]] || 11.8 || 110 || Human ||<ref name="pmid8100134" />

|-

| [[Muscarinic acetylcholine receptor M3|M₃]] || 12.8–39 || 50 || Human ||<ref name="pmid8100134" /><ref name="pmid10227113" />

|-

| [[Muscarinic acetylcholine receptor M4|M₄]] || 7.2 || 84 || Human ||<ref name="pmid8100134" />

|-

| [[Muscarinic acetylcholine receptor M5|M₅]] || 15.7–24 || 97 || Human ||<ref name="pmid8100134" /><ref name="pmid10227113" />

|-

| [[Sigma-1 receptor|σ₁]] || 287–300 || 2,000 || Guinea pig/rat ||<ref name="pmid2877462">{{cite journal | vauthors = Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JF | title = 1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 22 | pages = 8784–8788 | date = November 1986 | pmid = 2877462 | pmc = 387016 | doi = 10.1073/pnas.83.22.8784 | doi-access = free | bibcode = 1986PNAS...83.8784W }}</ref><ref name="pmid17689532">{{cite journal | vauthors = Werling LL, Keller A, Frank JG, Nuwayhid SJ | title = A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder | journal = Experimental Neurology | volume = 207 | issue = 2 | pages = 248–257 | date = October 2007 | pmid = 17689532 | doi = 10.1016/j.expneurol.2007.06.013 | s2cid = 38476281 }}</ref>

|-

| {{abbrlink|hERG|human Ether-à-go-go-Related Gene}} || 3,260 || 31,600 || Human ||<ref name="pmid10742304">{{cite journal | vauthors = Jo SH, Youm JB, Lee CO, Earm YE, Ho WK | title = Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline | journal = British Journal of Pharmacology | volume = 129 | issue = 7 | pages = 1474–1480 | date = April 2000 | pmid = 10742304 | pmc = 1571977 | doi = 10.1038/sj.bjp.0703222 }}</ref><ref name="pmid22244872">{{cite journal | vauthors = Yamakawa Y, Furutani K, Inanobe A, Ohno Y, Kurachi Y | title = Pharmacophore modeling for hERG channel facilitation | journal = Biochemical and Biophysical Research Communications | volume = 418 | issue = 1 | pages = 161–166 | date = February 2012 | pmid = 22244872 | doi = 10.1016/j.bbrc.2011.12.153 }}</ref>

|-

| [[PARP1]] || 1650 || {{abbr|ND|No data}} || Human ||<ref>{{cite journal | vauthors = Fu L, Wang S, Wang X, Wang P, Zheng Y, Yao D, Guo M, Zhang L, Ouyang L | title = Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 3 | date = December 2016 | pmid = 28442756 | pmc = 5431371 | doi = 10.1038/s41598-016-0007-2 }}</ref>

|-

| [[TrkA]] || 3,000<br />(agonist) || {{abbr|ND|No data}} || Human ||<ref name="pmid19549602">{{cite journal | vauthors = Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K | title = Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity | journal = Chemistry & Biology | volume = 16 | issue = 6 | pages = 644–656 | date = June 2009 | pmid = 19549602 | pmc = 2844702 | doi = 10.1016/j.chembiol.2009.05.010 }}</ref>

|-

| [[TrkB]] || 14,000<br />(agonist) || {{abbr|ND|No data}} || Human ||<ref name="pmid19549602"/>

|- class="sortbottom"

| colspan="5" style="width: 1px;" | Values are K_i (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

|}

Amitriptyline inhibits [[serotonin transporter]] (SERT) and [[norepinephrine transporter]] (NET). It is metabolized to [[nortriptyline]], a stronger [[norepinephrine reuptake inhibitor]], further augmenting amitriptyline's effects on norepinephrine reuptake (see table in this section).

Amitriptyline additionally acts as a potent inhibitor of the [[serotonin receptor|serotonin]] [[5-HT2A receptor|5-HT_2A]], [[5-HT2C receptor|5-HT_2C]], the [[alpha-1A adrenergic receptor|α_1A-adrenergic]], the [[histamine receptor|histamine]] [[H1 receptor|H₁]] and the M₁-M₅ [[muscarinic acetylcholine receptor]]s (see table in this section).

Amitriptyline is a non-selective blocker of multiple ion channels, in particular, [[voltage-gated sodium channel]]s [[Nav1.3|Na_v1.3]], [[Nav1.5|Na_v1.5]], [[Nav1.6|Na_v1.6]], [[Nav1.7|Na_v1.7]], and [[Nav1.8|Na_v1.8]],<ref name="pmid28905186">{{cite journal | vauthors = Horishita T, Yanagihara N, Ueno S, Okura D, Horishita R, Minami T, Ogata Y, Sudo Y, Uezono Y, Sata T, Kawasaki T | title = Antidepressants inhibit Na_v1.3, Na_v1.7, and Na_v1.8 neuronal voltage-gated sodium channels more potently than Na_v1.2 and Na_v1.6 channels expressed in Xenopus oocytes | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 390 | issue = 12 | pages = 1255–1270 | date = December 2017 | pmid = 28905186 | doi = 10.1007/s00210-017-1424-x | s2cid = 23385313 }}</ref><ref name="pmid29574705">{{cite journal | vauthors = Atkin TA, Maher CM, Gerlach AC, Gay BC, Antonio BM, Santos SC, Padilla KM, Rader J, Krafte DS, Fox MA, Stewart GR, Petrovski S, Devinsky O, Might M, Petrou S, Goldstein DB | title = A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy | journal = Epilepsia | volume = 59 | issue = 4 | pages = 802–813 | date = April 2018 | pmid = 29574705 | doi = 10.1111/epi.14037 | s2cid = 4478321 | doi-access = free }}</ref><ref name="pmid10688618">{{cite journal | vauthors = Nau C, Seaver M, Wang SY, Wang GK | title = Block of human heart hH1 sodium channels by amitriptyline | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 292 | issue = 3 | pages = 1015–1023 | date = March 2000 | pmid = 10688618 | doi = }}</ref> [[voltage-gated potassium channel]]s [[Kv7.2|K_v7.2]]/ [[Kv7.3|K_v7.3]],<ref name="pmid17456683">{{cite journal | vauthors = Punke MA, Friederich P | title = Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels | journal = Anesthesia and Analgesia | volume = 104 | issue = 5 | pages = 1256–64, tables of contents | date = May 2007 | pmid = 17456683 | doi = 10.1213/01.ane.0000260310.63117.a2 | url = http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=17456683 | access-date = 15 October 2009 | url-status = live | s2cid = 21924741 | doi-access = free | archive-url = https://web.archive.org/web/20210827213624/https://journals.lww.com/anesthesia-analgesia/pages/default.aspx | archive-date = 27 August 2021 }}</ref> [[Kv7.1|K_v7.1]], [[Kv7.1|K_v7.1]]/[[KCNE1]],<ref name="pmid29621539">{{cite journal | vauthors = Villatoro-Gómez K, Pacheco-Rojas DO, Moreno-Galindo EG, Navarro-Polanco RA, Tristani-Firouzi M, Gazgalis D, Cui M, Sánchez-Chapula JA, Ferrer T | title = Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline | journal = Biochemical Pharmacology | volume = 152 | issue = | pages = 264–271 | date = June 2018 | pmid = 29621539 | doi = 10.1016/j.bcp.2018.03.016 | s2cid = 4929937 }}</ref> and [[hERG]].<ref name="pmid10742304"/>

===Mechanism of action===

Inhibition of serotonin and norepinephrine transporters by amitriptyline results in interference with neuronal reuptake of [[serotonin]] and [[norepinephrine]]. Since the reuptake process is important physiologically in terminating transmitting activity, this action may potentiate or prolong activity of serotonergic and adrenergic neurons and is believed to underlie the antidepressant activity of amitriptyline.<ref name=DailyMed/>

Inhibition of norepinephrine reuptake leading to increased concentration of norepinephrine in the

[[posterior gray column]] of the spinal cord appears to be mostly responsible for the analgesic action of amitriptyline. Increased level of norepinephrine increases the basal activity of [[alpha-2 adrenergic receptor]]s, which mediate an analgesic effect by increasing [[gamma-aminobutyric acid]] transmission among [[spinal interneuron]]s. The blocking effect of amitriptyline on sodium channels may also contribute to its efficacy in pain conditions.<ref name="pmid33438398">{{cite journal | vauthors = McClure EW, Daniels RN | title = Classics in Chemical Neuroscience: Amitriptyline | journal = ACS Chemical Neuroscience | volume = 12 | issue = 3 | pages = 354–362 | date = February 2021 | pmid = 33438398 | doi = 10.1021/acschemneuro.0c00467 | s2cid = 231596860 }}</ref>

===Pharmacokinetics===

Amitriptyline is readily absorbed from the gastrointestinal tract (90–95%).<ref name = pmid33438398/> Absorption is gradual with the peak concentration in blood plasma reached after about 4 hours.<ref name="pmid3893842">{{cite journal | vauthors = Schulz P, Dick P, Blaschke TF, Hollister L | title = Discrepancies between pharmacokinetic studies of amitriptyline | journal = Clinical Pharmacokinetics | volume = 10 | issue = 3 | pages = 257–268 | date = 1985 | pmid = 3893842 | doi = 10.2165/00003088-198510030-00005 | s2cid = 41881790 }}</ref> Extensive metabolism on the [[First pass effect|first pass through the liver]] leads to average [[bioavailability]] of about 50% (45%<ref name="pmid3893842"/>-53%<ref name = pmid33438398/>). Amitriptyline is metabolized mostly by [[CYP2C19]] into [[nortriptyline]] and by [[CYP2D6]] leading to a variety of [[Hydroxylation|hydroxylated]] metabolites, with the principal one among them being (''E'')-10-hydroxynortriptyline<ref name="pmid15554244" /> (see metabolism scheme),<ref name = pmid33438398/> and to a lesser degree, by [[CYP3A4]].<ref name="pmid11583471" /> [[File:Amitriptyline metabolism.png|thumb|left|upright=1.5|Metabolism of amitriptyline to major active metabolites.]]

[[Nortriptyline]], the main active metabolite of amitriptyline, is an antidepressant on its own right. Nortriptyline reaches 10% higher level in the [[blood plasma]] than the parent drug amitriptyline and 40% greater [[Area under the curve (pharmacokinetics)|area under the curve]], and its action is an important part of the overall action of amitriptyline.<ref name="pmid3893842"/><ref name="pmid15554244"/>

Another active metabolite is (''E'')-10-hydroxynortriptyline, which is a norepinephrine uptake inhibitor four times weaker than nortriptyline. (''E'')-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its [[cerebrospinal fluid]] level, which is a close proxy of the brain concentration of a drug, is twice higher than nortriptyline's. Based on this, (''E'')-10-hydroxynortriptyline was suggested to significantly contribute to antidepressant effects of amitriptyline.<ref name="pmid7712660">{{cite journal | vauthors = Nordin C, Bertilsson L | title = Active hydroxymetabolites of antidepressants. Emphasis on E-10-hydroxy-nortriptyline | journal = Clinical Pharmacokinetics | volume = 28 | issue = 1 | pages = 26–40 | date = January 1995 | pmid = 7712660 | doi = 10.2165/00003088-199528010-00004 | s2cid = 38046048 }}</ref>

Blood levels of amitriptyline and nortriptyline and pharmacokinetics of amitriptyline in general, with [[Clearance (pharmacology)|clearance]] difference of up to 10-fold, vary widely between individuals.<ref name="pmid8736630">{{cite journal | vauthors = Bryson HM, Wilde MI | title = Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states | journal = Drugs & Aging | volume = 8 | issue = 6 | pages = 459–476 | date = June 1996 | pmid = 8736630 | doi = 10.2165/00002512-199608060-00008 | s2cid = 22923577 }}</ref> Variability of the area under the curve [[Pharmacokinetics#Metrics|in steady state]] is also high, which makes a slow upward [[drug titration|titration]] of the dose necessary.<ref name="pmid28405886"/>

In the blood, amitriptyline is 96% bound to plasma proteins; nortriptyline is 93–95% bound, and (''E'')-10-hydroxynortiptyline is about 60% bound.<ref name = TGA/><ref name=MSRN>{{cite web|title=Pamelor, Aventyl (nortriptyline) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=2 December 2013|url=http://reference.medscape.com/drug/pamelor-nortriptyline-342944#showall|url-status=live|archive-url=https://web.archive.org/web/20131203024651/http://reference.medscape.com/drug/pamelor-nortriptyline-342944#showall|archive-date=3 December 2013}}</ref><ref name="pmid7712660"/>

Amitriptyline has an elimination half life of 21 hours,<ref name="pmid3893842"/> nortriptyline – 23–31 hours,<ref name="pmid7248140">{{cite journal | vauthors = Dawlilng S, Lynn K, Rosser R, Braithwaite R | title = The pharmacokinetics of nortriptyline in patients with chronic renal failure | journal = British Journal of Clinical Pharmacology | volume = 12 | issue = 1 | pages = 39–45 | date = July 1981 | pmid = 7248140 | pmc = 1401753 | doi = 10.1111/j.1365-2125.1981.tb01852.x }}</ref> and (''E'')-10-hydroxynortiptyline - 8–10 hours.<ref name="pmid7712660"/> Within 48 hours, 12-80% of amitriptyline is eliminated in the urine, mostly as metabolites.<ref name="pmid6667101">{{cite journal | vauthors = Schulz P, Balant-Gorgia AE, Kubli A, Gertsch-Genet C, Garrone G | title = Elimination and pharmacological effects following single oral doses of 50 and 75 mg of amitriptyline in man | journal = Archiv Fur Psychiatrie und Nervenkrankheiten | volume = 233 | issue = 6 | pages = 449–455 | date = 1983 | pmid = 6667101 | doi = 10.1007/BF00342785 | s2cid = 20844722 }}</ref> 2% of the unchanged drug is excreted in the urine.<ref name=drugbank>{{cite web |title=Amitriptyline |url=https://www.drugbank.ca/drugs/DB00321 |website=drugbank.ca |access-date=29 January 2019 |archive-date=30 January 2019 |archive-url=https://web.archive.org/web/20190130053200/https://www.drugbank.ca/drugs/DB00321 |url-status=live }}</ref> Elimination in the feces, apparently, have not been studied.

Therapeutic levels of amitriptyline range from 75 to 175&nbsp;ng/mL (270–631&nbsp;nM),<ref name="SadockSadock2008">{{cite book| vauthors = Sadock BJ, Sadock VA |url=https://books.google.com/books?id=ubG51n2NgfwC&pg=PA18|title=Kaplan & Sadock's Concise Textbook of Clinical Psychiatry|publisher=Lippincott Williams & Wilkins|year=2008|isbn=978-0-7817-8746-8|pages=18–|archive-url=https://web.archive.org/web/20170708005933/https://books.google.com/books?id=ubG51n2NgfwC|archive-date=8 July 2017|url-status=live}}</ref> or 80–250&nbsp;ng/mL of both amitriptyline and its metabolite nortriptyline.<ref name="Orsulak Review TDM">{{cite journal | vauthors = Orsulak PJ | title = Therapeutic monitoring of antidepressant drugs: guidelines updated | journal = Therapeutic Drug Monitoring | volume = 11 | issue = 5 | pages = 497–507 | date = September 1989 | pmid = 2683251 | doi = 10.1097/00007691-198909000-00002 }}</ref>

===Pharmacogenetics===

Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body.<ref name="pmid10319193">{{cite journal | vauthors = Rudorfer MV, Potter WZ | title = Metabolism of tricyclic antidepressants | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 3 | pages = 373–409 | date = June 1999 | pmid = 10319193 | doi = 10.1023/A:1006949816036 | s2cid = 7940406 }}</ref> Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.<ref name="pmid 22565785">{{cite journal | vauthors = Stingl JC, Brockmöller J, Viviani R | title = Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function | journal = Molecular Psychiatry | volume = 18 | issue = 3 | pages = 273–287 | date = March 2013 | pmid = 22565785 | doi = 10.1038/mp.2012.42 | s2cid = 20888081 }}</ref><ref name="pmid 17113714">{{cite journal | vauthors = Kirchheiner J, Seeringer A | title = Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1770 | issue = 3 | pages = 489–494 | date = March 2007 | pmid = 17113714 | doi = 10.1016/j.bbagen.2006.09.019 }}</ref><ref>{{cite journal | vauthors = Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Müller DJ, Gaedigk A, Stingl JC | title = Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants | journal = Clinical Pharmacology and Therapeutics | volume = 93 | issue = 5 | pages = 402–408 | date = May 2013 | pmid = 23486447 | pmc = 3689226 | doi = 10.1038/clpt.2013.2 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/109971/1/cptclpt20132.pdf | access-date = 4 November 2018 | url-status = live | archive-url = https://web.archive.org/web/20210827213631/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/109971/cptclpt20132.pdf;jsessionid=2C1238337B5AD4C28DEA9617A364BC2D?sequence=1 | archive-date = 27 August 2021 }}</ref><ref name=":0">{{cite book | title=Medical Genetics Summaries | chapter=Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK425165/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=6 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2017 | pmid=28520380 | id=Bookshelf ID: NBK425165 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=6 February 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }}</ref>

Individuals can be categorized into different types of CYP2D6 or CYP2C19 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers,<ref name="pmid23486447"/> and have "normal" metabolism of amitriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use amitriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.<ref name="pmid 22565785"/><ref name="pmid 17113714"/><ref name="pmid23486447"/><ref name=":0" />

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively. The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.<ref name="pmid23486447"/> The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are [[CYP2D6]] poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are [[CYP2D6]] intermediate metabolizers.<ref name="pmid21412232">{{cite journal | vauthors = Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ | title = Pharmacogenetics: from bench to byte--an update of guidelines | journal = Clinical Pharmacology and Therapeutics | volume = 89 | issue = 5 | pages = 662–673 | date = May 2011 | pmid = 21412232 | doi = 10.1038/clpt.2011.34 | s2cid = 2475005 | doi-access = }}</ref>

{{clear}}

==Chemistry==

[[File:Synthesis of amitriptyline.png|thumb|right|upright=1.5|Chemical synthesis of amitriptyline.]]

Amitriptyline is a highly lipophilic molecule having an [[octanol-water partition coefficient]] (pH 7.4) of 3.0,<ref>The Pharmaceutical Codex. 1994. Principles and practice of pharmaceutics, 12th edn. Pharmaceutical press</ref> while the [[Partition coefficient|log P]] of the free base was reported as 4.92.<ref>Hansch C, Leo A, Hoekman D. 1995. Exploring QSAR.Hydrophobic, electronic and steric constants. Washington, DC: American Chemical Society.</ref> Solubility of the free base amitriptyline in water is 14&nbsp;mg/L.<ref name="pmid16552741">{{cite journal | vauthors = Box KJ, Völgyi G, Baka E, Stuart M, Takács-Novák K, Comer JE | title = Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution--a validation study | journal = Journal of Pharmaceutical Sciences | volume = 95 | issue = 6 | pages = 1298–1307 | date = June 2006 | pmid = 16552741 | doi = 10.1002/jps.20613 }}</ref> Amitriptyline is prepared by reacting [[dibenzosuberane]] with 3-(dimethylamino)propylmagnesium chloride and then heating the resulting intermediate product with [[hydrochloric acid]] to [[Elimination reaction|eliminate]] water.<ref name="pmid33438398"/>

==History==

Amitriptyline was first developed by the American pharmaceutical company [[Merck & Co.|Merck]] in the late 1950s. In 1958, Merck approached a number of clinical investigators proposing to conduct clinical trials of amitriptyline for schizophrenia. One of these researchers, [[Frank Ayd]], instead, suggested using amitriptyline for depression. Ayd treated 130 patients and, in 1960, reported that amitriptyline had antidepressant properties similar to another, and the only known at the time, tricyclic antidepressant [[imipramine]].<ref name=Era>{{cite book | vauthors = Healy D |date=1997 |title= The Antidepressant Era |url= |location= |publisher=Harvard University Press |pages= 74–76 |isbn=0674039572 }}</ref> Following this, the US [[Food and Drug Administration]] approved amitriptyline for depression in 1961.<ref name="Half a century of antidepressant dr"/>

In Europe, due to a quirk of the patent law at the time allowing patents only on the chemical synthesis but not on the drug itself, [[Hoffmann-La Roche|Roche]] and [[Lundbeck]] were able to independently develop and market amitriptyline in the early 1960s.<ref name=Psychopharmacologists>{{cite book | vauthors = Healy D |date=1999 |title=The Psychopharmacologists II |url=https://www.researchgate.net/publication/24904879 |location= |publisher=Arnold |pages= 565–566 |isbn=1860360106 }}</ref>

According to research by the historian of psychopharmacology [[David Healy (psychiatrist)|David Healy]], amitriptyline became a much bigger selling drug than its precursor imipramine because of two factors. First, amitriptyline has much stronger anxiolytic effect. Second, Merck conducted a marketing campaign raising clinicians' awareness of depression as a clinical entity.<ref name=Psychopharmacologists/><ref name=Era/>

==Society and culture==

[[File:EndepBoxes.JPG|thumb|Two boxes of amitriptyline (Endep; produced by [[Alphapharm]], Australian market) in 10 and 25 mg doses]]

In the 2021 film ''[[The Many Saints of Newark]]'', amitriptyline (referred to by the brand name Elavil) is part of the plot line of the movie.<ref>{{cite web|url=https://www.vanityfair.com/hollywood/2021/10/many-saints-of-newark-the-sopranos-easter-eggs|title=The Sopranos Fan's Guide to The Many Saints of Newark|vauthors=Press J|work=[[Vanity Fair (magazine)|Vanity Fair]]|quote=Livia is already troubled enough in the yesteryear of Many Saints that her doctor wants to prescribe her the antidepressant Elavil, but she rejects it. "I'm not a drug addict!" she sneers. Tony pores over the Elavil pamphlet with great interest and even schemes with Dickie Moltisanti to get his suffering mother to take it: "It could make her happy."|date=10 January 2021|access-date=10 January 2021|archive-date=1 October 2021|archive-url=https://web.archive.org/web/20211001210620/https://www.vanityfair.com/hollywood/2021/10/many-saints-of-newark-the-sopranos-easter-eggs|url-status=live}}</ref>

===Names===

Amitriptyline is the English and French [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}, while amitriptyline hydrochloride is its {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |url= https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA889|date=14 November 2014| publisher=Springer|isbn=978-1-4757-2085-3| pages= 889– | url-status=live|archive-url=https://web.archive.org/web/20170908171129/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA889 |archive-date=8 September 2017}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA48|year=2000|publisher=Taylor & Francis |isbn= 978-3-88763-075-1| pages= 48–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM | title= Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA15|date=6 December 2012| publisher= Springer Science & Business Media|isbn=978-94-011-4439-1|pages=15–|url-status=live| archive-url= https://web.archive.org/web/20170215043620/https://books.google.com/books?id=tsjrCAAAQBAJ| archive-date=15 February 2017}}</ref><ref name="Drugs.com">{{cite web |url=https://www.drugs.com/international/amitriptyline.html |title= Amitriptyline |website= Drugs.com| publisher= | access-date=13 August 2017 |url-status=live |archive-url= https://web.archive.org/web/20170813151219/https://www.drugs.com/international/amitriptyline.html |archive-date=13 August 2017 }}</ref> Its generic name in Spanish and Italian and its {{abbrlink|DCIT|Denominazione Comune Italiana}} are {{lang|es|amitriptilina}}, in German is {{lang|de|Amitriptylin}}, and in [[Latin language|Latin]] is {{lang|la|amitriptylinum}}.<ref name="IndexNominum2000" /><ref name="Drugs.com" /> The [[embonate]] salt is known as amitriptyline embonate, which is its BANM, or as amitriptyline pamoate unofficially.<ref name="IndexNominum2000" />

=== Prescription trends ===

Between 1998 and 2017, along with [[imipramine]], amitriptyline was the most commonly prescribed first antidepressant for children aged 5–11 years in England. It was also the most prescribed antidepressant (along with [[fluoxetine]]) for 12 to 17-year olds.<ref>{{cite journal | vauthors = Jack RH, Hollis C, Coupland C, Morriss R, Knaggs RD, Butler D, Cipriani A, Cortese S, Hippisley-Cox J | title = Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998-2017: A population-based cohort study | journal = PLOS Medicine | volume = 17 | issue = 7 | pages = e1003215 | date = July 2020 | pmid = 32697803 | pmc = 7375537 | doi = 10.1371/journal.pmed.1003215 | veditors = Hellner C | doi-access = free }}</ref>

==Research==

The few randomized controlled trials investigating amitriptyline efficacy in [[eating disorder]] have been discouraging.<ref>{{cite journal | vauthors = Flament MF, Bissada H, Spettigue W | title = Evidence-based pharmacotherapy of eating disorders | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 2 | pages = 189–207 | date = March 2012 | pmid = 21414249 | doi = 10.1017/S1461145711000381 | doi-access = free }}</ref>

== See also ==

* [[List of antidepressants]]

== References ==

{{Reflist}}

== Further reading ==

* {{cite book | title=Medical Genetics Summaries | chapter=Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK425165/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=6 | publisher=[[National Center for Biotechnology Information]] (NCBI) | date=March 2017 | pmid=28520380 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

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