Amitriptyline HCL (Elavil®)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

Amitriptyline in Brief
  • Generic name : Amitriptyline hydrochloride
  • Brand names: Elavil®, Amitrol®, Endep®, Levate®, Laroxyl®, Saroten®
  • Therapeutic class: Antidepressant
  • Pharmacologic class: Tricyclic antidepressant (Tertiary amine)
  • FDA Approved: May 1983
  • Chemical Formula: C20H23N
  • Pregnancy Category: C (Teratogenic effects have been observed in animal studies)
  • Habit forming? No
  • Originally discovered: 1950s, Merck Sharp and Dohme

FDA approved indications

  • Depression (endogenous depression is more likely to be alleviated than are other depressive states)

Amitriptyline has been frequently used as an active comparator in clinical trials on newer antidepressants.

Off-label & Investigational uses

  • chronic pain management 7, 9, 10
  • post-herpetic neuralgia 17, 18, 19
  • diabetic peripheral neuropathy 15, 16
  • fibromyalgia 21, 22
  • migraine headaches prophylaxis 25, 26
  • childhood headaches 28
  • chronic tension headache 3, 5, 29, 30
  • drug-induced headache 6
  • irritable bowel syndrome (IBS) with diarrhea 14, 38
  • depressed phase of bipolar affective disorder
  • somatoform pain disorder 32
  • post traumatic stress disorder 33
  • panic/anxiety disorders
  • insomnia 34
  • vulvodynia 35
  • interstitial cystitis (painful bladder syndrome) 36, 37
  • functional dyspepsia26
  • sleep bruxism (teeth grinding) 41
  • burning mouth syndrome 42

Clinical trials demonstrate that amitriptyline achieves at least a good or moderate response in up to 65% of patients with post-herpetic neuralgia and 75% of patients with painful diabetic neuropathy, and other neurogenic pain syndromes that are often unresponsive to narcotic analgesics. Amitriptyline has also demonstrated efficacy in patients with chronic non-malignant pain 7, 9, 10.

In the study a dose of 20 mg/kg of amitriptyline reduced pain in the second phase of the formalin test (an animal model of long-lasting pain in humans). Since the analgesic effect was produced by a single dose, which is insufficient to produce an antidepressant effect, these results indicate that amitriptyline has analgesic properties that are independent of its antidepressant properties 8.

Diabetic neuropathy
Amitriptyline reduces the pain caused by peripheral-nerve disease 16. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of amitriptyline in diabetic neuropathy.

Postherpetic neuralgia
Controlled clinical trials and extensive clinical experience have shown that amitriptyline reduces the severity of post-herpetic neuralgia. It is a reasonable first choice for PHN.

Amitriptyline is useful in treating postherpetic neuralgia. It may provide significant pain relief with the dose 75 mg 18. The alleviant effect of amitriptyline in postherpetic neuralgia appears not to be primarily linked with its serotoninergic effects and is also independent of its effects on depression 19.

Amitriptyline therapy can provide improvements in general health, pain, sleep quality and quantity, and fatigue in the treatment of fibromyalgia 22. Clinical study demonstrated that amitriptyline 25 mg at night is an effective therapeutic regimen for patients with fibromyalgia and is associated with significant improvement in pain, sleep difficulties, and fatigue on awakening. Also, amitriptyline increases blood flow to the affected sites in fibromyalgia patients21.

Interstitial cystitis
Amitriptyline (with maximum dosage 100 mg) appears to be safe and effective for treating interstitial cystitis. Amitriptyline can improve pain, urgency intensity, frequency and functional bladder capacity 37.


Amitriptyline "pros" and "cons"


  • Potent antidepressant effective for various mental disorders
  • Well researched
  • The only documented and most widely used prophylactic therapy for chronic tension-type headache 31
  • Small efficacy advantage over other tricyclic antidepressants
  • Proven analgesic effects 8
  • Relatively early onset of antidepressive effect 12
  • Drug of choice for patients with insomnia, anxiety, or chronic pain syndromes.


  • Risk of fatality in overdose
  • Narrow therapeutic index
  • Strong anticholingergic properties, and as a result severe anticholingergic side effects (such as sedation, dry mouth, constipation, urinary hesitancy)
  • Sedation, hypersomnia, and mental/motor impairment. Also, amitriptyline may significantly impair driving performance27. The drug is especially poorly tolerated by those working in jobs demanding intense concentration.
  • Can lower the seizure threshold; contraindicated in persons with epilepsy. Amitriptyline is reputed to be the most proconvulsive TCA40.
  • Cardiotoxicity, which involves the impairment of the cardiac conduction system.
  • Weight gain (greater increase in weight than with nortriptyline, desipramine, zimelidine, and imipramine) 39, 24
  • Possible decreased amount of REM sleep 23

Mechanism of action

Amitriptyline hydrochloride is an antidepressant with sedative effects.

Amitriptyline inhibits the reuptake of noradrenaline at the noradrenergic nerve endings and the reuptake of serotonin (5-hydroxy tryptamine) at the serotoninergic nerve endings in the central nervous system. These two effects are considered to be the likely base of the antidepressant effect. Amitriptyline also has a strong anticholinergic effect 20. In fact, amitriptyline is the most anticholinergic of all antidepressants.

Amitriptyline has ability to antagonize histamine H1 receptors and appears to be a potent antihistamine 11.

Time for Amitriptyline to clear out the system

Elimination half-life varies from 24 to 46 hours. The mean elimination half-life is about 36 hours 2.

Within 24 hours, approximately 25 to 50% of a dose of amitriptyline is excreted in the urine as inactive metabolites; small amounts are excreted in the bile.

Onset of action

  • Antidepressant effect: 4-6 weeks, it is recommended to reduce dosage to lowest effective level. However, antidepressive effect may be noticed as early as after 1 week of therapy 12.
  • Migraine prophylaxis: 6 weeks, higher dosage may be required in heavy smokers because of increased metabolism.

Historical note

The first tricyclic antidepressant discovered was imipramine, which was discovered accidentally in a search for a new antipsychotic in the late 1950s.

The therapeutic and commercial success of N-aminoalkylphenothiazines such as promethazine, promazine, and chlorpromazine, initiated an enormous effort in the molecular modification of the polycyclic phenothiazine ring structure and its N-aminoalkyl side chain.

Hafliger and Schinder, in 1951 US Patent 2,554,736, replaced the sulfur bridge of the phenothiazine ring of promethazine with an ethylene bridge to synthesize imipramine, a weak antihistaminic and mild anticholinergic with sedative properties in normal human volunteers. Kuhn, a clinical psychiatrist in Swiss psychiatric hospital, discovered that of some 500 patients with various psychiatric disorders that were treated, only those with endogenous depression with mental and motor retardation showed a remarkable improvement after about 1 to 6 weeks of daily imipramine therapy.

Thus, the first clinically useful tricyclic antidepressant was discovered. Amitriptyline was synthesized shortly after imipramine discovery and it became another tricyclic antidepressant widely used in clinical practice 4.

Further reading


  • 1. U.S. FDA. Amitriptyline HCL Prescribing Information.
  • 2. Ziegler VE, Biggs JT, Ardekani AB, Rosen SH. Contribution to the pharmacokinetics of amitriptyline. J Clin Pharmacol. 1978 Oct;18(10):462-7. PubMed
  • 3. Ashina S, Bendtsen L, Jensen R. Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition. Pain. 2004 Mar;108(1-2):108-14. PubMed
  • 4. Edward F. Domino, MD. History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants. Psychosomatic Medicine 61:591-598 (1999)
  • 5. Couch JR; Amitriptyline Versus Placebo Study Group. Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache. 2011 Jan;51(1):33-51
  • 6. Descombes S, Brefel-Courbon C, Thalamas C, Albucher JF, Rascol O, Montastruc JL, Senard JM. Amitriptyline treatment in chronic drug-induced headache: a double-blind comparative pilot study. Headache. 2001 Feb;41(2):178-82. PubMed
  • 7. Brenne E, van der Hagen K, Maehlum E, Husebo S. Treatment chronic pain with amitriptyline. A double-blind dosage study with determination of serum levels. Tidsskr Nor Laegeforen. 1997 Oct 10;117(24):3491-4. PubMed
  • 8. Acton J, McKenna JE, Melzack R. Amitriptyline produces analgesia in the formalin pain test. Exp Neurol. 1992 Jul;117(1):94-6. PubMed
  • 9. McQuay HJ, Carroll D, Glynn CJ. Dose-response for analgesic effect of amitriptyline in chronic pain. Anaesthesia. 1993 Apr;48(4):281-5. PubMed
  • 10. Bryson HM, Wilde MI. Amitriptyline. A review of its pharmacological properties and therapeutic use. 1996 Jun;8(6):459-76. PubMed
  • 11. Richelson E. Tricyclic antidepressants and histamine H1 receptors. Mayo Clin Proc. 1979 Oct;54(10):669-74.
  • 12. Bech P. Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the Hamilton Depression Scale as evidence of a pure antidepressive effect in the short-term treatment of major depression. Int J Neuropsychopharmacol. 2001 Dec;4(4):337-45. PubMed
  • 14. Morgan V, Pickens D, Gautam S, Kessler R, Mertz H. Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome. Gut. 2005 May;54(5):601-7. PubMed
  • 15. Boyle J, Eriksson ME, Gribble L, Gouni R, Johnsen S, Coppini DV, Kerr D. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care. 2012 Dec PubMed
  • 16. Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindström T, Thorell LH. Amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain. 1997 Dec;13(4):313-23. PubMed
  • 17. Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988 Sep;38(9):1427-32. PubMed
  • 18. Achar A, Chakraborty PP, Bisai S, Biswas A, Guharay T. Comparative study of clinical efficacy of amitriptyline and pregabalin in postherpetic neuralgia. Acta Dermatovenerol Croat. 2012 PubMed
  • 19. Watson CP, Evans RJ. A comparative trial of amitriptyline and zimelidine in post-herpetic neuralgia. Pain. 1985 Dec;23(4):387-94. PubMed
  • 20. Hyttel J, Christensen AV, Fjalland B. Neuropharmacological properties of amitriptyline, nortriptyline and their metabolites. Acta Pharmacol Toxicol (Copenh). 1980 Jul;47(1):53-7. PubMed
  • 21. Kulshreshtha P, Gupta R, Yadav RK, Bijlani RL, Deepak KK. Effect of low-dose amitriptyline on autonomic functions and peripheral blood flow in fibromyalgia: a pilot study. Pain Med. 2012 Jan PubMed
  • 22. Hannonen P, Malminiemi K, Yli-Kerttula U, Isomeri R, Roponen P. A randomized, double-blind, placebo-controlled study of moclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder. Rheumatology. 1998 Dec;37(12):1279-86.
  • 23. Riemann D, Velthaus S, Laubenthal S, Müller WE, Berger M. REM-suppressing effects of amitriptyline and amitriptyline-N-oxide: results of two uncontrolled pilot trials. Pharmacopsychiatry. 1990 Nov;23(6):253-8.
  • 24. Berken GH, Weinstein DO, Stern WC. Weight gain. A side-effect of tricyclic antidepressants. J Affect Disord. 1984 Oct;7(2):133-8. PubMed
  • 25. Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol. 1979 Nov;36(11):695-9. PubMed
  • 26. Talley NJ, Locke GR, Saito YA, et al.Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study. Gastroenterology. 2015 Aug;149(2):340-9.e2. PubMed
  • 27. Iwamoto K, Takahashi M, Nakamura Y, Kawamura Y, Ishihara R, Uchiyama Y, Ebe K, Noda A, Noda Y, Yoshida K, Iidaka T, Ozaki N. The effects of acute treatment with paroxetine, amitriptyline, and placebo on driving performance and cognitive function in healthy Japanese subjects: a double-blind crossover trial. Hum Psychopharmacol. 2008 Jul;23(5):399-407
  • 28. Hershey AD, Powers SW, Bentti AL, Degrauw TJ. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache. 2000 Jul-Aug;40(7):539-49. PubMed
  • 29. Boline PD, Kassak K, Bronfort G, Nelson C, Anderson AV. Spinal manipulation vs. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial. J Manipulative Physiol Ther. 1995 Mar-Apr;18(3):148-54. PubMed
  • 30. Cerbo R, Barbanti P, Fabbrini G, Pascali MP, Catarci T. Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogenetic implications. Headache. 1998 Jun;38(6):453-7. PubMed
  • 31. Ashina S, Bendtsen L, Jensen R. Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition. Pain. 2004 Mar;108(1-2):108-14. PubMed
  • 32. Ikawa M, Yamada K, Ikeuchi S. Efficacy of amitriptyline for treatment of somatoform pain disorder in the orofacial region: A case series. J Orofac Pain. 2006 Summer;20(3):234-40. PubMed
  • 33. Davidson J, Kudler H, Smith R, Mahorney SL, Lipper S, Hammett E, Saunders WB, Cavenar JO. Treatment of posttraumatic stress disorder with amitriptyline and placebo. JAMA Psychiatry. 1990 Mar;47(3):259-66.
  • 34. Srisurapanont M, Jarusuraisin N. Amitriptyline vs. lorazepam in the treatment of opiate-withdrawal insomnia: a randomized double-blind study. Acta Psychiatr Scand. 1998 Mar;97(3):233-5.
  • 35. Reed BD, Caron AM, Gorenflo DW, Haefner HK. Treatment of vulvodynia with tricyclic antidepressants: efficacy and associated factors. J Low Genit Tract Dis. 2006 Oct;10(4):245-51. PubMed
  • 36. van Ophoven A, Hertle L. Long-term results of amitriptyline treatment for interstitial cystitis. J Urol. 2005 Nov;174(5):1837-40. PubMed
  • 37. van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol. 2004 Aug;172(2):533-6. PubMed
  • 38. Rajagopalan M, Kurian G, John J. Symptom relief with amitriptyline in the irritable bowel syndrome. J Gastroenterol Hepatol. 1998 Jul;13(7):738-41. PubMed
  • 39. Fernstrom MH, Kupfer DJ. Antidepressant-induced weight gain. Psychiatry Res. PubMed
  • 40. What is the most appropriate antidepressant to use in epileptics? by UK Medicines Information pharmacists for NHS healthcare professionals.
  • 41. Lino PA, de Castro Martins C, Miranda GFPC, et al. Use of antidepressants in dentistry: a systematic review. Oral Dis. 2017 Aug 24
  • 42. Fenelon M, Quinque E, Arrive E, Catros S, Fricain JC. Pain-relieving effects of clonazepam and amitriptyline in burning mouth syndrome: a retrospective study. Int J Oral Maxillofac Surg. 2017 May 1.

Published: August 26, 2008
Last updated: September 01, 2017

Interesting facts

Amitriptyline facts
  • Nortriptyline (marketed under brand name Pamelor) is an intermediate active metabolite of amitriptyline.
  • Amitriptyline is the only documented and most widely used antidepressant for tension headache prophylaxis.
  • The first tricyclic antidepressant discovered was imipramine, which was discovered accidentally in a search for a new antipsychotic medicine in the late 1950s.

More Facts
Home | Contact Us | Cookies Policy

This website is certified by Health On the Net Foundation. Click to verify. This site complies with the HONcode standard for trustworthy health information: verify here

Copyright 2007-2020 All rights reserved.
All information is for educational purposes only.