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'''| [[Amitriptyline hydrochloride labels and packages|Labels and Packages]]'''
'''| [[Amitriptyline hydrochloride labels and packages|Labels and Packages]]'''


==Mechanism of Action==
==Medical uses==
 
===Widely accepted medical uses===
 
Amitriptyline is used for a number of medical conditions including [[major depressive disorder]] (MDD) which is its only [[Food and Drug Administration|FDA]]-labelled indication.<ref name = DM/> This is also a [[Therapeutic Goods Administration|TGA]]- and [[Medicines and Healthcare Products Regulatory Agency|MHRA]]-labelled indication.<ref name = AMH/><ref name = BNF/> Some evidence suggests that amitriptyline may have superior efficacy compared to other antidepressants,<ref name="pmid11157426">{{cite journal |author = Barbui, C; Hotopf, M | title = Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials | journal = The British Journal of Psychiatry : the Journal of Mental Science | volume = 178 | issue = 2| pages = 129–144 |date=February 2001 | pmid = 11157426 | doi = 10.1192/bjp.178.2.129| url = http://bjp.rcpsych.org/cgi/pmidlookup?view=long&pmid=11157426}}</ref> including the [[Selective serotonin reuptake inhibitors|SSRIs]].<ref>{{cite journal|title=Selective serotonin reuptake inhibitors versus tricyclic
antidepressants: a meta-analysis of efficacy and tolerability|journal=Journal of Affective Disorders|date=April 2000|volume=58|issue=1|pages=19-36|doi=10.1016/S0165-0327(99)00092-0|pmid=10760555|author=Anderson, IM}}</ref> Although it is rarely used as a first-line antidepressant nowadays due to its high degree of toxicity in overdose and generally poorer tolerability than the newer antidepressants such as the [[selective serotonin reuptake inhibitors]] (SSRIs) and [[serotonin-norepinephrine reuptake inhibitors]] (SNRIs).<ref name = AMH/>
 
It is TGA-labelled for [[migraine]] prophylaxis, as it is also is in cases of [[neuropathic pain]] disorders,<ref name = AMH/> [[fibromyalgia]]<ref name = "Coch">{{cite journal | author = Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ | title = Amitriptyline for neuropathic pain and fibromyalgia in adults | journal = Cochrane Database of Systematic Reviews | volume = 12 | issue = | pages = CD008242 | year = 2012 | pmid = 23235657 | doi = 10.1002/14651858.CD008242.pub2 | editor1-last = Moore | editor1-first = RA }}</ref> and [[nocturnal enuresis]].<ref name = "AMH">{{cite isbn|9780980579093}}</ref><ref>{{cite journal|title=Drug Treatment of Nocturnal Enuresis|journal=Paediatric and Perinatal Drug Therapy|date=June 2000|volume=4|issue=1|pages=12-18|publisher=Informa Healthcare|url=http://group.bmj.com/docs/pdf/4_1_s3.pdf|format=PDF|author=Kennea, NL; Evans, JHC}}</ref> Amitriptyline is a popular [[off-label use|off-label]] treatment for [[irritable bowel syndrome]].<ref name = IBS>{{cite journal|title=Management of Irritable Bowel Syndrome|journal=American Family Physician|date=November 2002|volume=66|issue=10|pages=1867-1874|author=Viera, AJ; Hoag, S; Shaughnessy, J|url=http://www.aafp.org/afp/2002/1115/p1867.pdf|format=PDF}}</ref> Although it is most frequently reserved for severe cases of abdominal pain in patients with IBS due to the fact that it needs to be taken regularly to work and has a generally poor tolerability profile, although a firm evidence base supports its efficacy in this indication.<ref name = IBS/> Amitriptyline can also be used as an anticholinergic drug in the treatment of early stage Parkinson disease if depression also needs to be treated.<ref>[http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/movement_disorders/parkinsons_disease.html Parkinson's Disease]. Merck Sharp & Dohme Corp. August 2007. Retrieved on 2013-12-22.</ref>
 
===Investigational uses===
 
* [[Eating disorders]]<ref name = MSR/> Although the few randomised controlled trials investigating its efficacy in eating disorders have been discouraging.<ref>{{cite journal|title=Evidence-based pharmacotherapy of eating disorders|journal=International Journal of Neuropsychopharmacology|date=March 2012|volume=15|issue=2|pages=189-207|doi=10.1017/S1461145711000381|pmid=21414249|author=Flament, MF; Bissada, H; Spettigue, W}}</ref>
* [[Pseudobulbar affect]]<ref>{{cite journal|title=Dextromethorphan/quinidine sulfate (Zenvia) for Pseudobulbar Affect|journal=Drugs Today (Barc)|date=May 2010|volume=44|issue=9|pages=661-668|doi=10.1358/dot.2008.44.9.1258664|pmid=19137121|pmc=2872986|author=Rosen, H|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872986/pdf/nihms173379.pdf|format=PDF}}</ref>
* [[Insomnia]]. Its use in the elderly for this indication is recommended against due to the development of tolerance and the potential for adverse effects such as constipation.<ref name = AMH/>
* Urinary urge incontinence. This is an accepted use for amitriptyline in Australia.<ref name = "AMH" />
* [[Cyclic vomiting syndrome]]<ref>{{cite journal | title = Clinical experience with amitriptyline for management of children with cyclic vomiting syndrome | year = 2009 | author = Sim Y-J, Kim J-M, Kwon S, Choe B-H  |journal=Korean Journal of Pediatrics | volume = 52 |issue = 5 | pages = 538–43 | doi = 10.3345/kjp.2009.52.5.538 }}</ref><ref name="pmid20109231">{{cite journal | author = Boles RG, Lovett-Barr MR, Preston A, Li BU, Adams K | title = Treatment of cyclic vomiting syndrome with co-enzyme Q10 and amitriptyline, a retrospective study| journal = BMC Neurol | volume = 10| pages = 10 | year = 2010 | pmid = 20109231 | pmc = 2825193 | doi = 10.1186/1471-2377-10-10 }}</ref>
* [[Tinnitus]]<ref name="pmid11771024">{{cite journal | author = Bayar N, Böke B, Turan E, Belgin E | title = Efficacy of amitriptyline in the treatment of subjective tinnitus | journal = J Otolaryngol | volume = 30 | issue = 5 | pages = 300–3 |date=October 2001 | pmid = 11771024 | doi = 10.2310/7070.2001.19597 }}</ref>
* [[Chronic cough]]<ref name="pmid17146380">{{cite journal | author = Jeyakumar A, Brickman TM, Haben M | title = Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy | journal = Laryngoscope | volume = 116 | issue = 12 | pages = 2108–12 |date=December 2006 | pmid = 17146380 | doi = 10.1097/01.mlg.0000244377.60334.e3 }}</ref>
* [[Vulvodynia]]<ref name="pmid19183087">{{cite journal | author = Brown CS, Wan J, Bachmann G, Rosen R | title = Self-management, amitriptyline, and amitripyline plus triamcinolone in the management of vulvodynia | journal = J Womens Health (Larchmt) | volume = 18|issue = 2 | pages = 163–9 |date=February 2009 | pmid = 19183087 | pmc = 2945720 | doi = 10.1089/jwh.2007.0676 }}</ref>
* [[Interstitial cystitis]]<ref name="pmid15247722">{{cite journal | author = van Ophoven A, Pokupic S, Heinecke A, Hertle L | title = A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis | journal = J. Urol. | volume = 172 | issue = 2 | pages = 533–6 |date=August 2004 | pmid = 15247722 |doi=10.1097/01.ju.0000132388.54703.4d }}</ref>
* Preventive treatment for patients with recurring [[biliary dyskinesia]] ([[sphincter of Oddi]] dysfunction)<ref name="Hubscher">{{cite book |first1=Arnold |last1=Wald |year=2006 |chapter=Functional biliary type pain syndrome |editor1-first=Pankaj Jay |editor1-last=Pasricha |editor2-first=William D. |editor2-last=Willis |editor3-first=G. F. |editor3-last=Gebhart |title=Chronic Abdominal and Visceral Pain |location=London |publisher=Informa Healthcare |pages=453–62 |isbn=978-0-8493-2897-8}}</ref>
* [[Functional dyspepsia]] that has failed to respond to a first-line treatment ([[famotidine]] or [[mosapride]]).<ref name="pmid15943846">{{cite journal | author = Otaka M, Jin M, Odashima M, Matsuhashi T, Wada I, Horikawa Y, Komatsu K, Ohba R, Oyake J, Hatakeyama N, Watanabe S | title = New strategy of therapy for functional dyspepsia using famotidine, mosapride and amitriptyline |journal = Aliment. Pharmacol. Ther. | volume = 21 Suppl 2 | issue =| pages = 42–6 |date=June 2005 | pmid = 15943846 | doi = 10.1111/j.1365-2036.2005.02473.x }}</ref>
* [[Attention deficit/hyperactivity disorder]] (in addition to, or sometimes in place of ADHD stimulant drugs){{citation needed|date=December 2013}}
 
==Adverse effects==
 
===Adverse effects by frequency===
 
Adverse effects include the following:<ref name = DM>{{cite web|title=AMITRIPTYLINE HYDROCHLORIDE tablet, film coated [Dispensing Solutions, Inc.]|work=DailyMed|publisher=Dispensing Solutions, Inc.|date=September 2013|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5f95829b-4040-49a8-bac4-a845c227c81a|accessdate=1 December 2013}}</ref><ref name = MSR>{{cite web|title=Levate (amitriptyline), dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|accessdate=1 December 2013|url=http://reference.medscape.com/drug/levate-amitriptyline-342936#showall}}</ref><ref name = TGA>{{cite web|title=Endep Amitriptyline hydrochloride|date=10 December 2012|accessdate=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}}</ref><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|accessdate=1 December 2013|url=http://www.medicines.org.uk/emc/medicine/23738/SPC/Amitriptyline+Tablets+BP+50mg/}}</ref><ref name = AMH/><ref name = BNF>{{cite isbn|9780857110848}}</ref>
 
====Common (≥1% frequency)====
 
{{colbegin|2}}
* Weight gain
* [[Anticholinergic]] side effects (it tends to produce more anticholinergic effects than the other TCAs) such as:
** Constipation
** [[Xerostomia]] (dry mouth)
** [[Mydriasis]] (dilated pupils)
** Blurred vision
** Urinary hesitancy
** Reduced GI motility
** Anticholinergic delirium (particularly in the elderly and in Parkinson's disease)
* Dizziness
* Headache
* [[Somnolence]] (drowsiness) it tends to be a more sedating TCA.<ref>{{cite isbn|9780470979488}}</ref><ref name = GG/>
* Decreased [[lacrimation]] (that is, decreased ability to cry)
* [[Orthostatic hypotension]]
* Sinus tachycardia
* Impotence
* Loss of libido
* Other sexual adverse effects
* Tremor
* Dizziness
* Sweating
* Agitation
* Insomnia
* Anxiety
* Confusion
{{colend}}
 
====Uncommon (0.1–1% frequency)====
 
{{colbegin|2}}
* Slowed cardiac conduction
* T wave inversion or flattening (particularly at high doses)
* Arrhythmias
* Sinus tachycardia
* Nausea
* Hyperglycaemia
* Gynaecomastia (breast enlargement in men)
* Breast enlargement and galactorrhoea in females
* Allergic skin reactions
* Mania
* Hypomania
{{colend}}
 
====Rare (<0.1% frequency)====
 
{{colbegin|2}}
* [[Cardiomyopathy]]
* [[Hepatitis]]
* [[Liver failure]]
* [[Jaundice]]
* [[Systemic lupus erythematosus|Lupus]]-like syndrome (migratory arthritis, positive ANA and rheumatoid factor)
* [[Hypotension]] (low blood pressure)
* Syncope (fainting)
* Hypertension
* Tachycardia
* Palpitations
* Myocardial infarction
* Heart block
* Stroke
* [[Agranulocytosis]]
* [[Leukopenia|Leukopaenia]]
* [[Thrombocytopaenia]]
* [[Purpura]]
* [[Eosinophilia]]
* [[Neuroleptic malignant syndrome]]
{{colend}}
 
====Unknown frequency adverse effects====
 
{{colbegin|2}}
* [[Hyperglycaemia]]
* [[Hypoglycaemia]]
* Skin rash
* Urticaria (hives)
* Photosensitization
* Oedema
* Seizures
* Testicular swelling
* Increased or decreased libido
* [[Urinary retention]]
* Dilatation of the urinary tract
* Disturbance of accommodation
* Increased ocular pressure
* Paralytic [[ileus]]
* Epigastric distress
* [[Stomatitis]]
* Peculiar taste
* Parotid swelling
* Black tongue
* [[Alopecia]] (hair loss)
* Urinary frequency
* [[Diaphoresis]]
* [[Myocardial infarction]]
* Coma
* Hallucinations
* Delusions
* Weight loss
* Weakness
* Fatigue
* Headache
* Increased perspiration
* Urinary frequency
* Confusional states
* Disorientation
* Incoordination
* Ataxia
* Tremors
* Peripheral neuropathy
* Numbness
* Tingling
* Paraesthesias
* [[Extrapyramidal symptoms]]
* [[Tardive dyskinesia]]
* Dysarthria
* Disturbed concentration
* [[Syndrome of inappropriate antidiuretic hormone secretion]] (SIADH)
* [[Hyponatraemia]]
* Tinnitus (ringing in the ears)
* Alteration in EEG patterns
{{colend}}
 
===Contraindications===
 
The following are the known contraindications of amitriptyline.<ref name = EMC/>
{{colbegin|2}}
* Hypersensitivity to tricyclic antidepressants or to any of its excipients
* History of [[myocardial infarction]]
* History of arrhythmias, particularly heart block to any degree
* [[congestive heart failure]]
* Coronary artery insufficiency
* [[Mania]]
* Severe liver disease
* Children under 7 years
* Breast feeding
* Patients who are taking [[monoamine oxidase inhibitors]] (MAOIs) or have taken them within the last 14 days.
{{colend}}
 
===Interactions===
 
Amitriptyline is known to interact with:<ref name = TGA/>
* [[Monoamine oxidase inhibitors]] as it can potentially induce a [[serotonin syndrome]]
* [[CYP2D6]] inhibitors and substrates such as [[fluoxetine]] due to the potential for an increase in plasma concentrations of the drug to be seen.
* [[Guanethidine]] — as it can reduce the antihypertensive effects of this drug.
* [[Anticholinergic]] agents such as [[benztropine]], [[hyoscine]] (scopolamine) and [[atropine]]. Due to the fact that the two might exacerbate each other's anticholinergic effects, including paralytic ileus and tachycardia.
* [[Antipsychotics]] due to the potential for them to exacerbate the sedative, anticholinergic, epileptogenic and pyrexic (fever-promoting) effects. Also increases the risk of [[neuroleptic malignant syndrome]]
* [[Cimetidine]] due to the potential for it to interfere with hepatic metabolism of amitriptyline and hence increasing steady-state concentrations of the drug.
* [[Disulfiram]] due to the potential for the development of delirium
* [[Electroconvulsive therapy|ECT]] may increase the risks associated with this treatment
* Antithyroid medications — may increase the risk of [[agranulocytosis]]
* Thyroid hormones — potential for increased adverse effects such as CNS stimulation and arrhythmias.
* [[Analgesics]], such as [[tramadol]] due to the potential for an increase in seizure risk.
* Medications that are subject to gastric inactivation (e.g. levodopa) due to the potential for amitriptyline to delay gastric emptying and reduce intestinal motility
* Medications that may be subject to increased absorption given more time in the small intestine (e.g. anticoagulants)
* Serotoninergic agents such as the [[Selective serotonin reuptake inhibitor|SSRIs]] and [[triptans]] due to the potential for [[serotonin syndrome]].
 
===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/> thus it and other tricyclic antidepressants are no longer recommended as first line therapy for depression. Alternative agents, SSRIs and SNRIs are safer in overdose, though they are no more efficacious than TCAs. English folk singer, [[Nick Drake]], died from an overdose of Tryptizol in 1974.
 
The possible symptoms of amitriptyline overdose include:<ref name = TGA/>
{{colbegin|2}}
* Drowsiness
* Hypothermia (low body temperature)
* Tachycardia (high heart rate)
* Other arrhythmic abnormalities, such as [[bundle branch block]]
* ECG evidence of impaired conduction
* [[Congestive heart failure]]
* Dilated pupils
* Convulsions (e.g. seizures, [[myoclonus]])
* Severe hypotension (very low blood pressure)
* [[Stupor]]
* Coma
* [[Polyradiculoneuropathy]]
* Changes in the [[electrocardiogram]], particularly in QRS axis or width
* Agitation
* Hyperactive reflexes
* Muscle rigidity
* Vomiting
{{colend}}
 
The treatment of overdose is mostly supportive as there is no specific antidote for amitriptyline overdose.<ref name = TGA/> Activated charcoal may reduce absorption if given within 1-2 hours of ingestion.<ref name = TGA/> If the affected person is unconscious or have an impaired gag reflex a nasograstic tube may be used to deliver the activated charcoal in the stomach.<ref name = TGA/> ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised.<ref name = TGA/> Body temperature should be regulated with measures such as heating blankets if necessary.<ref name = TGA/> Likewise cardiac arrhythmias can be treated with [[propanolol]] and should heart failure occur digitalis may be used.<ref name = TGA/> Cardiac monitoring is advised for at least five days after the overdose.<ref name = TGA/> Other measures include the use of inhalation anaesthetics or [[diazepam]] for convulsions and barbiturates should be avoided if possible due to the potential for additive CNS depression (that is, on top of the CNS depression caused by the amitriptyline).<ref name = TGA/> [[Haemodialysis|Dialysis]] is of no use due to the high degree of [[Plasma protein binding|protein binding]] with amitriptyline.<ref name = TGA/>
 
==Mechanism of action==
 
{| class="wikitable sortable" style = "float: right; margin-left:15px; text-align:center"
|-
! Receptor !! K<sub>i</sub> [nM]<ref group = Note>These K<sub>i</sub> values are averaged binding affinities towards cloned human receptors when available.</ref> <br>(amitriptyline)<ref name = PDSP>{{cite web | title = PDSP K<sub>i</sub> Database |work = Psychoactive Drug Screening Program (PDSP)|author =  Roth, BL; Driscol, J | url =http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | accessdate = 1 December 2013 |date = 12 January 2011}}</ref><ref name = GG>{{cite isbn|9780071624428}}</ref>!! K<sub>i</sub> [nM]<ref group = Note>As with amitriptyline, these K<sub>i</sub>values are averaged binding affinities towards cloned human receptors when available.</ref> <br>([[nortriptyline]])<ref name = PDSP/><ref name = GG/>
|-
| [[Serotonin transporter|SERT]] || 3.13 || 16.5
|-
| [[Norepinephrine transporter|NET]] || 22.4 || 4.37
|-
| [[Dopamine transporter|DAT]] || 5380 || 3100
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 450 || 294
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 840 || -
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 4.3 || 5
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 6.15 || 8.5
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 103 || 148
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 114 || -
|-
| [[Histamine H1 receptor|H<sub>1</sub>]] || 1.1 || 15.1
|-
| [[Histamine H3 receptor|H<sub>3</sub>]] || 1000 || -
|-
| [[Histamine H4 receptor|H<sub>4</sub>]] || 33.6 || -
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 12.9 || 40
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || 11.8 || 110
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] || 25.9 || 50
|-
| [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] || 7.2 || 84
|-
| [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]] || 19.9 || 97
|-
| [[alpha-1 adrenergic receptor|α<sub>1</sub>]] || 24 || 55
|-
| [[alpha-2 adrenergic receptor|α<sub>2</sub>]] || 690 || 2030
|-
| [[Dopamine D1 receptor|D<sub>1</sub>]] || 89 || -
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 1460 || 2570
|-
| [[Dopamine D3 receptor|D<sub>3</sub>]] || 206 || -
|-
| [[Dopamine D5 receptor|D<sub>5</sub>]] || 170 || -
|-
| [[Sigma receptor|σ]] || 300 || 2000
|}
 
Amitriptyline acts primarily as a [[serotonin-norepinephrine reuptake inhibitor]], with strong actions on the [[serotonin transporter]] and moderate effects on the [[norepinephrine transporter]].<ref>{{cite web|url=http://www.cnsforum.com/content/pictures/imagebank/hirespng/antidep_uptake_specific.png |title=Potency of antidepressants to block noradrenaline reuptake |publisher=CNS Forum |date= |accessdate=2013-02-16}}</ref><ref name="pmid9537821">{{cite journal | author = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = Eur. J. Pharmacol. | volume = 340 | issue = 2–3 | pages = 249–58 |date=December 1997|pmid = 9537821 | doi =10.1016/S0014-2999(97)01393-9  }}</ref> It has negligible influence on the [[dopamine transporter]] and therefore does not affect [[dopamine]] [[reuptake]], being nearly 1,000 times weaker on it than on [[serotonin]].<ref name="pmid9537821" /> It is metabolised to [[nortriptyline]] — a more potent and selective [[norepinephrine reuptake inhibitor]] — which may hence compliment its effects on norepinephrine reuptake.<ref name = TGA/>
 
Amitriptyline additionally functions as a [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT3 receptor|5-HT<sub>3</sub>]], [[5-HT6 receptor|5-HT<sub>6</sub>]], [[5-HT7 receptor|5-HT<sub>7</sub>]], [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic]], [[H1 receptor|H<sub>1</sub>]], [[H2 receptor|H<sub>2</sub>]],<ref name="EllisEllis1987">{{cite book | author1 = Albert Ellis | author2 = Gwynn Pennant Ellis | title = Progress in Medicinal Chemistry | url = http://books.google.com/books?id=jr0u58hFDhEC&pg=PA56 | accessdate = 27 November 2011 | date = 1 January 1987 | publisher = Elsevier | isbn = 978-0-444-80876-9 | page = 56}}</ref> [[H4 receptor|H<sub>4</sub>]],<ref name="pmid11179435">{{cite journal | author = Nguyen T, Shapiro DA, George SR, ''et al.''| title = Discovery of a novel member of the histamine receptor family | journal = Molecular Pharmacology | volume = 59 | issue = 3|pages = 427–33 |date=March 2001 | pmid = 11179435 | doi = | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11179435}}</ref><ref name="Yogeeswari2010">{{cite book | author = D. Sriram & P. Yogeeswari | title = Medicinal Chemistry|url = http://books.google.com/books?id=tUSLclf_NoQC&pg=PA299 | accessdate = 27 November 2011 | date = 1 September 2010 | publisher = Pearson Education India | isbn = 978-81-317-3144-4 | page = 299}}</ref> and [[muscarinic acetylcholine receptor|mACh receptor]][[receptor antagonist|antagonist]], and [[sigma-1 receptor|σ<sub>1</sub> receptor]] [[agonist]].<ref name="pmid9400006">{{cite journal |author = Owens MJ, Morgan WN, Plott SJ, Nemeroff CB | title = Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites | journal = J. Pharmacol. Exp. Ther. | volume = 283 | issue = 3 | pages = 1305–22 |date=December 1997 |pmid = 9400006 | doi = }}</ref><ref name="bookEssentials of clinical psychopharmacology">{{cite book | author = Alan F. Schatzberg, Charles B. | title = Essentials of clinical psychopharmacology | publisher = American Psychiatric Pub | year = 2006 | page = 7 |isbn=978-1-58562-243-6 }}</ref><ref name="pmid11561066">{{cite journal | author = Rauser L, Savage JE, Meltzer HY, Roth BL | title = Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor | journal = J. Pharmacol. Exp. Ther. | volume = 299 | issue = 1 | pages = 83–9 |date=October 2001 | pmid = 11561066 | doi =  }}</ref><ref name="pmid17689532">{{cite journal | author = 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 = Exp. Neurol. | volume = 207 | issue = 2 | pages = 248–57 |date=October 2007 | pmid = 17689532 | doi = 10.1016/j.expneurol.2007.06.013  }}</ref> It has also been shown to be a relatively weak [[NMDA receptor]] [[NMDA receptor antagonist|negative allosteric modulator]] at the same [[binding site]] as [[phencyclidine]].<ref name="pmid2568580">{{cite journal|author = Sills MA, Loo PS | title = Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate | journal = Mol. Pharmacol. | volume = 36 | issue = 1 | pages = 160–5 |date=July 1989 | pmid = 2568580 | doi = }}</ref> Amitriptyline inhibits [[sodium channel]]s, [[L-type calcium channel|<small>L</small>-type calcium channel]]s, and [[Kv1.1|K<sub>v</sub>1.1]], [[Kv7.2|K<sub>v</sub>7.2]], and [[Kv7.3|K<sub>v</sub>7.3]] [[voltage-gated potassium channel]]s, and therefore acts as a [[sodium channel blocker|sodium]], [[calcium channel blocker|calcium]], and [[potassium channel blocker|potassium]] [[channel blocker]] as well.<ref name="pmid9435180">{{cite journal | author = Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C | title = Inhibition of neuronal Na+ channels by antidepressant drugs | journal = J. Pharmacol. Exp. Ther. | volume = 284 | issue = 1 | pages = 208–14 |date=January 1998 | pmid = 9435180 | doi = }}</ref><ref name="pmid17456683">{{cite journal| author = 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 = 1256–1264 |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}}</ref>
 
Recently, amitriptyline has been demonstrated to act as an [[agonist]] of the [[TrkA]] and [[TrkB|TrkB receptor]]s.<ref name="pmid19549602">{{cite journal | author = 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 = Chem. Biol.|volume = 16 | issue = 6 | pages = 644–56 |date=June 2009 | pmid = 19549602 | pmc = 2844702 | doi = 10.1016/j.chembiol.2009.05.010 }}</ref> It promotes the [[heterodimerization]] of these [[protein]]s in the absence of [[Nerve Growth Factor|NGF]] and has potent [[neurotrophic]] activity both ''in-vivo'' and ''in-vitro'' in mouse models.<ref name="pmid19549602" /><ref>{{cite web|url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20A)/AMITRIPTYLINE.html |title=Pharmaceutical Information - AMITRIPTYLINE |publisher=RxMed |date= |accessdate=2013-02-16}}</ref> These are the same receptors [[brain-derived neurotrophic factor|BDNF]] activates, an [[endogenous]] [[neurotrophin]] with powerful antidepressant effects, and as such this property may contribute significantly to its therapeutic efficacy against depression. Amitriptyline also acts as [[FIASMA]] (functional inhibitor of [[Sphingomyelin phosphodiesterase|acid sphingomyelinase]]).<ref name="pmid18504571">{{cite journal |author=Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P|title=Identification of novel functional inhibitors of acid sphingomyelinase|journal=PLoS ONE|volume=6|issue=8|pages=e23852|year=2011|doi=10.1371/journal.pone.0023852 |editor1-last=Riezman|editor1-first=Howard |pmid=21909365 |pmc=3166082}}</ref>
 
==Pharmacokinetics==
 
[[File:Nortriptyline2DACS.svg|thumb|200|left|[[Nortriptyline]], amitriptyline's chief active metabolite]]
Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolised on first-pass through the liver.<ref name = TGA/> It is metabolised mostly via [[CYP2D6]], [[CYP3A4]], [[CYP2C9]]-mediated N-demethylation into nortriptyline,<ref name =TGA/> which is another [[tricyclic antidepressant]] in its own right.<ref name = MD/> It is 96% bound to plasma proteins, nortriptyline is 93-95% bound to plasma proteins.<ref name = TGA/><ref name = MSRN>{{cite web|title=Pamelor, Aventyl (nortriptyline) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|accessdate=2 December 2013|url=http://reference.medscape.com/drug/pamelor-nortriptyline-342944#showall}}</ref>It is mostly excreted in the urine (around 30-50%) as metabolites either free or as glucuronide and sulfate conjugates.<ref name = TGA/>Small amounts are also excreted in faeces.<ref name = MSR/><br clear="all" />
 
==Brand names==
 
Brand names include (just including those used in English-speaking countries with † to indicate discontinued brands):<ref name = MD>{{cite book|title=Amitriptyline|work=Martindale: The Complete Drug Reference|date=30 January 2013|accessdate=2 December 2013|url=http://www.medicinescomplete.com.elibrary.jcu.edu.au/mc/martindale/current/ms-12293-g.htm|publisher=Pharmaceutical Press|location=London, UK}}</ref><ref>{{cite web|title=Amitriptyline|accessdate=2 December 2013|url=http://www.drugs.com/international/amitriptyline.html|work=Drugs.com}}</ref>
{{colbegin|4}}
* Amirol <small>([[New Zealand|NZ]])</small>
* Amit <small>([[India|IN]])</small>
* Amitone <small>([[India|IN]])</small>
* Amitor <small>([[India|IN]])</small>
* Amitrip <small>([[Australia|AU]],† [[India|IN]], [[New Zealand|NZ]])</small>
* Amitriptyline <small>([[United Kingdom|UK]])</small>
* Amitriptyline Hydrochloride Caraco <small>([[United States of America|US]])</small>
* Amitriptyline Hydrochloride Mutual <small>([[United States of America|US]])</small>
* Amitriptyline Hydrochloride Mylan <small>([[United States of America|US]])</small>
* Amitriptyline Hydrochloride Sandoz <small>([[United States of America|US]])</small>
* Amitriptyline Hydrochloride Vintage <small>([[United States of America|US]])</small>
* Amitriptyline Hydrochloride <small>([[United Kingdom|UK]])</small>
* Amitrol† <small>([[Australia|AU]])</small>
* Amrea <small>([[India|IN]])</small>
* Amypres <small>([[India|IN]])</small>
* Apo-Amitriptyline <small>([[Canada|CA]], [[Hong Kong|HK]], [[Singapore|SG]])</small>
* Crypton <small>([[India|IN]])</small>
* Elavil <small>([[Canada|CA]], [[United Kingdom|UK]],† [[United States of America|US]]†)</small>
* Eliwel <small>([[India|IN]])</small>
* Endep <small>([[Australia|AU]], [[Hong Kong|HK]],† [[South Africa|ZA]],† [[United States of America|US]]†)</small>
* Enovil† <small>([[United States of America|US]])</small>
* Gentrip <small>([[India|IN]])</small>
* Kamitrin <small>([[India|IN]])</small>
* Latilin <small>([[India|IN]])</small>
* Levate <small>([[United States of America|US]])</small>
* Maxitrip <small>([[India|IN]])</small>
* Mitryp <small>([[India|IN]])</small>
* Mitryp-10 <small>([[India|IN]])</small>
* Odep <small>([[India|IN]])</small>
* Qualitriptine <small>([[Hong Kong|HK]])</small>
* Sandoz Amitriptyline <small>([[South Africa|ZA]])</small>
* Sarotena <small>([[India|IN]])</small>
* Tadamit <small>([[India|IN]])</small>
* Trepiline <small>([[South Africa|ZA]])</small>
* Tripta <small>([[Singapore|SG]])</small>
* Tryptanol <small>([[South Africa|ZA]])</small>
* Tryptomer <small>([[India|IN]])</small>
{{colend}}
 
==See also==
* [[Nortriptyline]]
* [[Tricyclic antidepressant]]


==References==
==References==

Revision as of 01:37, 10 February 2014

Amitriptyline
AMITRIPTYLINE HYDROCHLORIDE®
FDA Package Insert
Indications and Usage
Dosage and Administration
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
How Supplied/Storage and Handling
Patient Counseling Information
Labels and Packages
Clinical Trials on Amitriptyline
ClinicalTrials.gov

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

For patient information about Amitriptyline, click here.

Synonyms / Brand Names: Amitriptyline Hydrochloride, Amitriptyline HCL, Amitriprolidine, Amitriptylin, Amitryptiline, Amitryptyline, Amytriptiline, Adepress, Adepril, Amitid, Amitril, Damilan, Damilen, dAmitriptyline, Elanil, Elavil, Endep, Flavyl, Hexathane, Horizon, Lantron, Laroxil, Laroxyl, Lentizol, Proheptadiene, Redomex, Saroten, Sarotex, Seroten, Sylvemid, Triptanol, Triptilin, Triptisol, Tryptanol, Tryptizol

Overview

Amitriptyline (Elavil, Endep, Levate and many others) is a tricyclic antidepressant (TCA). It is the most widely used TCA and is an efficacious treatment for major depressive disorder (clinical depression). It was originally developed by Merck and was initially approved by the United States Food and Drug Administration (FDA) on 7 April 1961.[1]

Category

Antidepressants

FDA Package Insert

AMITRIPTYLINE HYDROCHLORIDE tablet, film coated

Indications and Usage | Dosage and Administration | Dosage Forms and Strengths | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Use in Specific Populations | Overdosage | Description | Clinical Pharmacology | Nonclinical Toxicology | Clinical Studies | How Supplied/Storage and Handling | Patient Counseling Information | Labels and Packages

Medical uses

Widely accepted medical uses

Amitriptyline is used for a number of medical conditions including major depressive disorder (MDD) which is its only FDA-labelled indication.[2] This is also a TGA- and MHRA-labelled indication.[3][4] Some evidence suggests that amitriptyline may have superior efficacy compared to other antidepressants,[5] including the SSRIs.[6] Although it is rarely used as a first-line antidepressant nowadays due to its high degree of toxicity in overdose and generally poorer tolerability than the newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).[3]

It is TGA-labelled for migraine prophylaxis, as it is also is in cases of neuropathic pain disorders,[3] fibromyalgia[7] and nocturnal enuresis.[3][8] Amitriptyline is a popular off-label treatment for irritable bowel syndrome.[9] Although it is most frequently reserved for severe cases of abdominal pain in patients with IBS due to the fact that it needs to be taken regularly to work and has a generally poor tolerability profile, although a firm evidence base supports its efficacy in this indication.[9] Amitriptyline can also be used as an anticholinergic drug in the treatment of early stage Parkinson disease if depression also needs to be treated.[10]

Investigational uses

Adverse effects

Adverse effects by frequency

Adverse effects include the following:[2][11][22][23][3][4]

Common (≥1% frequency)

  • Weight gain
  • Anticholinergic side effects (it tends to produce more anticholinergic effects than the other TCAs) such as:
    • Constipation
    • Xerostomia (dry mouth)
    • Mydriasis (dilated pupils)
    • Blurred vision
    • Urinary hesitancy
    • Reduced GI motility
    • Anticholinergic delirium (particularly in the elderly and in Parkinson's disease)
  • Dizziness
  • Headache
  • Somnolence (drowsiness) it tends to be a more sedating TCA.[24][25]
  • Decreased lacrimation (that is, decreased ability to cry)
  • Orthostatic hypotension
  • Sinus tachycardia
  • Impotence
  • Loss of libido
  • Other sexual adverse effects
  • Tremor
  • Dizziness
  • Sweating
  • Agitation
  • Insomnia
  • Anxiety
  • Confusion

Uncommon (0.1–1% frequency)

  • Slowed cardiac conduction
  • T wave inversion or flattening (particularly at high doses)
  • Arrhythmias
  • Sinus tachycardia
  • Nausea
  • Hyperglycaemia
  • Gynaecomastia (breast enlargement in men)
  • Breast enlargement and galactorrhoea in females
  • Allergic skin reactions
  • Mania
  • Hypomania

Rare (<0.1% frequency)

Unknown frequency adverse effects

Contraindications

The following are the known contraindications of amitriptyline.[23]

  • Hypersensitivity to tricyclic antidepressants or to any of its excipients
  • History of myocardial infarction
  • History of arrhythmias, particularly heart block to any degree
  • congestive heart failure
  • Coronary artery insufficiency
  • Mania
  • Severe liver disease
  • Children under 7 years
  • Breast feeding
  • Patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days.

Interactions

Amitriptyline is known to interact with:[22]

  • Monoamine oxidase inhibitors as it can potentially induce a serotonin syndrome
  • CYP2D6 inhibitors and substrates such as fluoxetine due to the potential for an increase in plasma concentrations of the drug to be seen.
  • Guanethidine — as it can reduce the antihypertensive effects of this drug.
  • Anticholinergic agents such as benztropine, hyoscine (scopolamine) and atropine. Due to the fact that the two might exacerbate each other's anticholinergic effects, including paralytic ileus and tachycardia.
  • Antipsychotics due to the potential for them to exacerbate the sedative, anticholinergic, epileptogenic and pyrexic (fever-promoting) effects. Also increases the risk of neuroleptic malignant syndrome
  • Cimetidine due to the potential for it to interfere with hepatic metabolism of amitriptyline and hence increasing steady-state concentrations of the drug.
  • Disulfiram due to the potential for the development of delirium
  • ECT may increase the risks associated with this treatment
  • Antithyroid medications — may increase the risk of agranulocytosis
  • Thyroid hormones — potential for increased adverse effects such as CNS stimulation and arrhythmias.
  • Analgesics, such as tramadol due to the potential for an increase in seizure risk.
  • Medications that are subject to gastric inactivation (e.g. levodopa) due to the potential for amitriptyline to delay gastric emptying and reduce intestinal motility
  • Medications that may be subject to increased absorption given more time in the small intestine (e.g. anticoagulants)
  • Serotoninergic agents such as the SSRIs and triptans due to the potential for serotonin syndrome.

Overdose

Main article: 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,[4] thus it and other tricyclic antidepressants are no longer recommended as first line therapy for depression. Alternative agents, SSRIs and SNRIs are safer in overdose, though they are no more efficacious than TCAs. English folk singer, Nick Drake, died from an overdose of Tryptizol in 1974.

The possible symptoms of amitriptyline overdose include:[22]

The treatment of overdose is mostly supportive as there is no specific antidote for amitriptyline overdose.[22] Activated charcoal may reduce absorption if given within 1-2 hours of ingestion.[22] If the affected person is unconscious or have an impaired gag reflex a nasograstic tube may be used to deliver the activated charcoal in the stomach.[22] ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised.[22] Body temperature should be regulated with measures such as heating blankets if necessary.[22] Likewise cardiac arrhythmias can be treated with propanolol and should heart failure occur digitalis may be used.[22] Cardiac monitoring is advised for at least five days after the overdose.[22] Other measures include the use of inhalation anaesthetics or diazepam for convulsions and barbiturates should be avoided if possible due to the potential for additive CNS depression (that is, on top of the CNS depression caused by the amitriptyline).[22] Dialysis is of no use due to the high degree of protein binding with amitriptyline.[22]

Mechanism of action

Receptor Ki [nM][Note 1]
(amitriptyline)[26][25]		 Ki [nM][Note 2]
(nortriptyline)[26][25]
SERT 3.13 16.5
NET 22.4 4.37
DAT 5380 3100
5-HT1A 450 294
5-HT1B 840 -
5-HT2A 4.3 5
5-HT2C 6.15 8.5
5-HT6 103 148
5-HT7 114 -
H1 1.1 15.1
H3 1000 -
H4 33.6 -
M1 12.9 40
M2 11.8 110
M3 25.9 50
M4 7.2 84
M5 19.9 97
α1 24 55
α2 690 2030
D1 89 -
D2 1460 2570
D3 206 -
D5 170 -
σ 300 2000

Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the serotonin transporter and moderate effects on the norepinephrine transporter.[27][28] It has negligible influence on the dopamine transporter and therefore does not affect dopamine reuptake, being nearly 1,000 times weaker on it than on serotonin.[28] It is metabolised to nortriptyline — a more potent and selective norepinephrine reuptake inhibitor — which may hence compliment its effects on norepinephrine reuptake.[22]

Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2,[29] H4,[30][31] and mACh receptorantagonist, and σ1 receptor agonist.[32][33][34][35] It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine.[36] Amitriptyline inhibits sodium channels, L-type calcium channels, and Kv1.1, Kv7.2, and Kv7.3 voltage-gated potassium channels, and therefore acts as a sodium, calcium, and potassium channel blocker as well.[37][38]

Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[39] It promotes the heterodimerization of these proteins in the absence of NGF and has potent neurotrophic activity both in-vivo and in-vitro in mouse models.[39][40] These are the same receptors BDNF activates, an endogenous neurotrophin with powerful antidepressant effects, and as such this property may contribute significantly to its therapeutic efficacy against depression. Amitriptyline also acts as FIASMA (functional inhibitor of acid sphingomyelinase).[41]

Pharmacokinetics

File:Nortriptyline2DACS.svg
Nortriptyline, amitriptyline's chief active metabolite

Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolised on first-pass through the liver.[22] It is metabolised mostly via CYP2D6, CYP3A4, CYP2C9-mediated N-demethylation into nortriptyline,[22] which is another tricyclic antidepressant in its own right.[42] It is 96% bound to plasma proteins, nortriptyline is 93-95% bound to plasma proteins.[22][43]It is mostly excreted in the urine (around 30-50%) as metabolites either free or as glucuronide and sulfate conjugates.[22]Small amounts are also excreted in faeces.[11]

Brand names

Brand names include (just including those used in English-speaking countries with † to indicate discontinued brands):[42][44]

  • Amirol (NZ)
  • Amit (IN)
  • Amitone (IN)
  • Amitor (IN)
  • Amitrip (AU,† IN, NZ)
  • Amitriptyline (UK)
  • Amitriptyline Hydrochloride Caraco (US)
  • Amitriptyline Hydrochloride Mutual (US)
  • Amitriptyline Hydrochloride Mylan (US)
  • Amitriptyline Hydrochloride Sandoz (US)
  • Amitriptyline Hydrochloride Vintage (US)
  • Amitriptyline Hydrochloride (UK)
  • Amitrol† (AU)
  • Amrea (IN)
  • Amypres (IN)
  • Apo-Amitriptyline (CA, HK, SG)
  • Crypton (IN)
  • Elavil (CA, UK,† US†)
  • Eliwel (IN)
  • Endep (AU, HK,† ZA,† US†)
  • Enovil† (US)
  • Gentrip (IN)
  • Kamitrin (IN)
  • Latilin (IN)
  • Levate (US)
  • Maxitrip (IN)
  • Mitryp (IN)
  • Mitryp-10 (IN)
  • Odep (IN)
  • Qualitriptine (HK)
  • Sandoz Amitriptyline (ZA)
  • Sarotena (IN)
  • Tadamit (IN)
  • Trepiline (ZA)
  • Tripta (SG)
  • Tryptanol (ZA)
  • Tryptomer (IN)

See also

References

  1. ↑ Fangmann P, Assion HJ, Juckel G, González CA, López-Muñoz F (February 2008). "Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part II: tricyclics and tetracyclics". Journal of Clinical Psychopharmacology. 28 (1): 1–4. doi:10.1097/jcp.0b013e3181627b60. PMID 18204333.
  2. ↑ 2.0 2.1 "AMITRIPTYLINE HYDROCHLORIDE tablet, film coated [Dispensing Solutions, Inc.]". DailyMed. Dispensing Solutions, Inc. September 2013. Retrieved 1 December 2013.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Template:Cite isbn
  4. ↑ 4.0 4.1 4.2 Template:Cite isbn
  5. ↑ Barbui, C; Hotopf, M (February 2001). "Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials". The British Journal of Psychiatry : the Journal of Mental Science. 178 (2): 129–144. doi:10.1192/bjp.178.2.129. PMID 11157426.
  6. ↑ Anderson, IM (April 2000). "Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability". Journal of Affective Disorders. 58 (1): 19–36. doi:10.1016/S0165-0327(99)00092-0. PMID 10760555. line feed character in |title= at position 57 (help)
  7. ↑ Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ (2012). Moore, RA, ed. "Amitriptyline for neuropathic pain and fibromyalgia in adults". Cochrane Database of Systematic Reviews. 12: CD008242. doi:10.1002/14651858.CD008242.pub2. PMID 23235657.
  8. ↑ Kennea, NL; Evans, JHC (June 2000). "Drug Treatment of Nocturnal Enuresis" (PDF). Paediatric and Perinatal Drug Therapy. Informa Healthcare. 4 (1): 12–18.
  9. ↑ 9.0 9.1 Viera, AJ; Hoag, S; Shaughnessy, J (November 2002). "Management of Irritable Bowel Syndrome" (PDF). American Family Physician. 66 (10): 1867–1874.
  10. ↑ Parkinson's Disease. Merck Sharp & Dohme Corp. August 2007. Retrieved on 2013-12-22.
  11. ↑ 11.0 11.1 11.2 "Levate (amitriptyline), dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 1 December 2013.
  12. ↑ Flament, MF; Bissada, H; Spettigue, W (March 2012). "Evidence-based pharmacotherapy of eating disorders". International Journal of Neuropsychopharmacology. 15 (2): 189–207. doi:10.1017/S1461145711000381. PMID 21414249.
  13. ↑ Rosen, H (May 2010). "Dextromethorphan/quinidine sulfate (Zenvia) for Pseudobulbar Affect" (PDF). Drugs Today (Barc). 44 (9): 661–668. doi:10.1358/dot.2008.44.9.1258664. PMC 2872986. PMID 19137121.
  14. ↑ Sim Y-J, Kim J-M, Kwon S, Choe B-H (2009). "Clinical experience with amitriptyline for management of children with cyclic vomiting syndrome". Korean Journal of Pediatrics. 52 (5): 538–43. doi:10.3345/kjp.2009.52.5.538.
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