Adjunctive Agents in the Management of Chronic Pain

David R. P. Guay, PharmD, FCP, FCCP, FASCP


Pharmacotherapy. 2001;21(9) 

In This Article

Tricyclic Antidepressants

Tricyclic antidepressants are considered first-line systemic therapy for many neuropathic pain syndromes, including diabetic neuropathy.[23,24] In a literature review, 6 of 13 controlled trials evaluating antidepressants for diabetic neuropathy showed clinically significant pain relief with use of tricyclic antidepressants.[25,26] Electrotherapy may enhance the response of patients with a partial response to tricyclic antidepressants in diabetic neuropathy.[27] However, no differences in the effectiveness of different tricyclic antidepressants were shown.[28,29] Thus, the appropriate choice of tricyclic antidepressant depends on each agent's adverse-effect profile.

Current literature supports the use of tricyclic antidepressants for the management of postherpetic neuralgia,[26,30,31] and up to 67% of patients respond to tricyclic antidepressant treatment.[31,32,33,34,35]

Central poststroke pain is pain that occurs in body areas that have lost part of their sensory innervation due to a stroke. Tricyclic anti-depressants have been considered first-line systemic therapy for central poststroke pain,[26,36,37,38] although their use for central poststroke pain relief is supported only by isolated case reports[32] and one placebo-controlled trial in which amitriptyline demonstrated superior relief compared with that of placebo in 10 (67%) of 15 patients.[38] Some evidence exists that early onset of antidepressant therapy (< 1 yr after stroke) can positively affect treatment success in central poststroke pain.[37]

Tricyclic antidepressants may be useful as adjunctive therapy for cancer-related neuropathic pain syndromes.[39] Tricyclic antidepressants provide pain relief by independently providing analgesia specific for neuropathic pain, potentiating the effect of opioids, and improving underlying depression and insomnia.[39,40] Although controlled trials using tricyclic anti-depressants in patients with cancer are limited and most data about tricyclic antidepressant analgesic effectiveness have been obtained with other chronic pain syndromes, these agents are accepted as adjunctive analgesics for cancer pain.[32,39]

Amitriptyline, nortriptyline, and desipramine have been established as analgesics independent of their antidepressant effects.[23] Although their mechanism of analgesic action has not been clearly defined, tricyclic antidepressants are thought to have an inhibitory effect on nociceptive pathways by blocking the reuptake of serotonin and norepinephrine.[41] Originally, the major mechanism of the analgesic effect of tricyclic antidepressants was believed to be related to serotonin reuptake inhibition. However, the selective serotonin reuptake inhibitor antidepressants have not demonstrated substantial effectiveness in neuropathic pain.[23,26,28] Animal models of peripheral neuropathic pain have shown that tricyclic antidepressants act as sodium channel blockers, similar to local anesthetic and antiarrhythmic agents.[42]

Tricyclic antidepressants should be administered cautiously in patients with angle-closure glaucoma, benign prostatic hypertrophy, urinary retention, constipation, cardiovascular disease, or impaired liver function. The agents should be avoided in patients with second- or third-degree heart block, arrhythmias, prolonged QT interval on the electrocardiogram, or severe liver disease and in patients who have had a recent acute myocardial infarction.[32]

The adverse effects of tricyclic antidepressants are well known, but their prevalence rates vary by agent and patient group. In general, elderly patients experience a higher frequency of adverse effects, and slow dosage titration is recommended.[43,44] The most common adverse effects of tricyclic antidepressants (constipation, dry mouth, blurred vision, cognitive changes, tachycardia, urinary hesitation) are associated with their anticholinergic activity. Other common adverse effects are orthostatic hypotension, falls, weight gain, and sedation. In general, the secondary amines (e.g., desipramine, nortriptyline) exhibit fewer anticholinergic and sedative effects than do the tertiary amines (e.g., amitriptyline, imipramine, doxepin); therefore, the secondary amines may be more desirable in the elderly population.[28]

Neuropathic pain generally responds more quickly than depression to tricyclic antidepres-sants (i.e., 3-10 days vs 2-4 wks) and often with one-third to one-half the dosage administered for depression.[28,45] Owing to their improved adverse-effect profiles, therapy with one of the secondary amine tricyclic antidepressants should be considered in elderly patients. For desipramine, nortriptyline, amitriptyline, and imipramine, a starting dosage of 10 mg at bedtime is recommended, with dosage increments of 10-25 mg made no more frequently than every 5-7 days.[24] Although the timing of administration will not affect a tricyclic antidepressant's analgesic activity, bedtime administration is recommended to take advantage of the sedative activity. The tricyclic antidepressant dosage should depend on the degree of pain relief and emergence of adverse effects. A daily dose of 50-100 mg of the above agents is usually effective.[23,28,46] If a patient reaches a dosage of 75-100 mg/day without sufficient pain relief, determination of the serum drug concentration may be reasonable to evaluate whether presum-ably adequate drug concentrations have been achieved. Remember, no accepted therapeutic drug concentration range exists for analgesia.

Not all patients respond to tricyclic anti-depressant therapy within 10 days of initiation or with lower dosages. Some patients may require higher dosages and several weeks of treatment before efficacy is evident. Patients are often referred to specialty pain clinics because the tricyclic antidepressant dosage was not adequate. In addition, these drugs may be discontinued unnecessarily because of adverse effects caused by starting them at inappropriately high dosages, titrating the dosage upward too rapidly, or starting several drugs at one time.[23] An adequate trial must be given before failure of a tricyclic antidepressant is determined.[28] Failure of one tricyclic antidepressant does not preclude success with a different agent, and the practitioner should consider trying two or, perhaps, three agents sequentially before substituting another therapeutic option.

Patients abruptly withdrawn from a tricyclic antidepressant may experience withdrawal that manifests as any of a variety of clinical symptoms (e.g., malaise, insomnia, drowsiness, anorexia, muscle aches, apathy, headache, mania, profuse sweating, irritability, abdominal pains, diarrhea, nausea, vivid and terrifying dreams, movement disorders). To avoid a withdrawal syndrome, a slow taper over 2-4 weeks (depending on the dosage) is recommended.[47]


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