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Amitriptyline

A Review of its Pharmacological Properties and Therapeutic Use in Chronic Pain States

Summary

Synopsis

Amitriptyline is a tricyclic antidepressant agent which also has analgesic properties. Whether its analgesic effects are linked to its mood-altering activity or attributable to a discrete pharmacological action (or a combination of both) is unknown.

Clinical trials demonstrate that oral amitriptyline achieves at least a good or moderate response in up to two-thirds of patients with post-herpetic neuralgia and three-quarters of patients with painful diabetic neuropathy, neurogenic pain syndromes that are often unresponsive to narcotic analgesics. Amitriptyline has also demonstrated efficacy in heterogeneous groups of patients with chronic non-malignant pain. Other possible areas of use for amitriptyline are in patients with fibromyalgia or as an adjuvant for uncontrolled cancer pain, although evidence for the latter application is limited.

Adverse events resulting from the antimuscarinic activity of amitriptyline (primarily dry mouth and sedation) are commonly reported, even at the low dosages used for the control of pain. Low starting doses and careful dosage titration may help to minimise these effects. Orthostatic hypotension and tachycardia, sometimes associated with tricyclic antidepressant agents, may also pose a problem in the elderly.

In summary, amitriptyline has a valuable place in the treatment of chronic pain conditions that affect the elderly provided that the drug is used judiciously to minimise adverse effects. Importantly, amitriptyline remains the best studied of the antidepressant agents in post- herpetic neuralgia and diabetic neuropathy and is an important and effective treatment option in these syndromes.

Pharmacological Properties

Two theories have been proposed to explain the analgesic activity of tricyclic antidepressant agents: firstly, that any analgesic activity is secondary to their antidepressant effects; and secondly, that they have an independent analgesic effect. Clinical data suggest that analgesia may be produced independently of the antidepressant effects of these agents; however, the precise mechanism by which this is achieved is unknown.

The analgesic effects of amitriptyline have been documented in several animal models after either single or multiple doses, but the relevance of these models to chronic pain states in humans is unknown. Amitriptyline produced dose-dependent analgesia to each of 3 different noxious stimuli in 2 studies.

Amitriptyline is rapidly absorbed after oral administration, but has a low oral bioavailability because of a large first-pass effect. The pharmacokinetics of amitriptyline (like those of other tricyclic antidepressants) are characterised by large interpatient variability. The drug is widely distributed throughout the body and is highly protein bound. Amitriptyline is extensively metabolised in the liver; the major metabolite, nortriptyline, is pharmacologically active. The terminal elimination half-life of amitriptyline ranges from 12.9 to 36.1 hours. No clear effect of older age on the pharmacokinetics of amitriptyline has been defined, although clearance may be decreased. There is no clear relationship between amitriptyline plasma concentrations and analgesic effect, although concentrations of amitriptyline plus nortriptyline needed to produce a significant analgesic effect appear to be lower than those required for an antidepressant effect.

Therapeutic Use

In patients with post-herpetic neuralgia of at least 3 months’ duration, oral amitriptyline achieved a 21 to 46% reduction in pain intensity from baseline as assessed by a visual analogue scale after 3 to 6 weeks’ treatment. 47 to 67% of patients reported a good or excellent response to therapy. When subjective assessment parameters were used, amitriptyline achieved significantly better pain relief than placebo or comparator agents (lorazepam, zimeldine and maprotiline).

Up to 74% of patients with painful diabetic neuropathy reported at least good or moderate pain relief after 6 to 8 weeks’ treatment with amitriptyline. Amitriptyline achieved a significantly greater reduction in pain intensity (29 to 51%) than placebo (15%) but had a similar effect to topical capsaicin (42%) or desipramine (28%). Limited clinical data in central post-stroke pain suggest that amitriptyline may be useful in these patients.

36% of patients with fibromyalgia showed clinical improvement after 6 months’ treatment with amitriptyline compared with 19% of placebo recipients. According to 2 patient surveys, amitriptyline was as effective as other agents and treatment modalities commonly used in this patient group. Results obtained with amitriptyline in patients with rheumatoid arthritis are conflicting.

Even in a heterogeneous group of patients, namely those presenting at a pain clinic with chronic nonmalignant pain, amitriptyline demonstrated small but significant analgesic effects compared with placebo in 2 of 3 studies. These results are supported by a meta-analysis which demonstrated an overall mean analgesic effect size of 0.73 for amitriptyline.

Antidepressant agents, including amitriptyline, are widely recommended and used as adjuvant agents in patients with cancer pain. However, few clinical trials have prospectively investigated the efficacy of amitriptyline in this patient group.

Tolerability

The adverse events most commonly reported with amitriptyline, even at the relatively low dosages used in pain syndromes, result from its antimuscarinic activity. 27 to 80% of patients with pain syndromes in clinical trials reported dry mouth and 17 to 62% reported tiredness/drowsiness. Since tolerance to these effects often develops, low starting doses and careful dosage titration may help to minimise toxicity. Up to 18% of patients withdrew from amitriptyline therapy as a result of adverse events.

Orthostatic hypotension and tachycardia can pose a problem in elderly patients receiving tricyclic agents at dosages in the antidepressant range; there is evidence that these effects may occur, albeit infrequently, at the lower dosages used in the treatment of pain. As with other tricyclic antidepressant agents, raised glucose levels can occur with amitriptyline.

Dosage and Administration

For the treatment of chronic pain states, amitriptyline should be started at a dosage of 10 to 25 mg/day and increased by 10 to 25 mg/week to the maximum suggested or tolerated dosage. To minimise the risk of adverse events in the elderly, amitriptyline should be started at a low dosage (10 mg/day) and titrated gradually in 10mg increments. The suggested maximum dosage for the treatment of neurogenic pain is 75 mg/day.

Amitriptyline, like other tricyclic antidepressant agents, should be administered with caution in patients with urinary retention, prostatic hypertrophy, glaucoma, constipation, impaired liver function or cardiovascular disease. It should be avoided in those with heart block or arrhythmias or immediately after myocardial infarction and in patients with severe liver disease.

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Correspondence to Harriet M. Bryson.

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Various sections of the manuscript reviewed by: S. Carette, Department of Medicine, Centre Hospitalier de l’Université Laval, Sainte Foy, Québec, Canada; B.M. Fusco, Department of Clinical Medicine, University ‘La Sapienza’ of Rome, Rome, Italy; K. Ghose, Department of Pharmacology, University of Otago, Dunedin, New Zealand; J.J. Lee, Pain Relief Clinic, Worcester Royal Infirmary, Ronkswood Branch, Worcester, England; F.H. McDowell, Winifred Masterton Burke Rehabilitation Hospital, White Plains, New York, USA; G. Olive, Service de Pharmacologie Clinique, Service de Biochimie, Hôpital Saint-Vincent de Paul, Paris, France; P. Onghena, Department of Educational Sciences, Katholieke Universiteit Leuven, Leuven, Belguim; I. Pilowsky, Department of Psychiatry, University of Adelaide, Adelaide, Australia; C.P.N. Watson, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

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Bryson, H.M., Wilde, M.I. Amitriptyline. Drugs & Aging 8, 459–476 (1996). https://doi.org/10.2165/00002512-199608060-00008

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Keywords

  • Adis International Limited
  • Fibromyalgia
  • Amitriptyline
  • Herpes Zoster
  • Diabetic Neuropathy