Amitriptyline in Brief
- Active ingredient: Amitriptyline hydrochloride
- Brand names: Elavil, Amitrol, Endep, Levate, Laroxyl, Saroten
- Drug 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
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
Thus, the first clinically useful tricyclic antidepressant was discovered.
It did not take long for the diamine structure of an additional N-CH2
group in imipramine to be substituted with a C=CH group in amitriptyline.
Amitriptyline was another tricyclic antidepressant which soon became
widely used clinically 4.
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 36, 37
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, 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.
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.
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 and may not
act as an antidepressant. 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.
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
Amitriptyline "pros" and "cons"
- Potent antidepressant
- 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
- Risk of fatality in overdose
- Narrow therapeutic index
- Strong anticholingergic properties, and as a result severe anticholingergic side effects
- Sedation, hypersomnia, and mental/motor impairment. Also, amitriptyline may significantly impaire 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.
- 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
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.
- 1. U.S. FDA. Amitriptyline HCL Prescribing Information.
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in chronic tension-type headache is not directly related to serotonin
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- 4. Edward F. Domino, MD. History of Modern Psychopharmacology:
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pain with amitriptyline. A double-blind dosage study with determination
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- 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