Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy

Abstract

Tricyclic antidepressants have been reported to relieve the paresthesiae associated with peripheral neuropathies of many etiologies. We designed a randomized, double-blind, placebo-controlled, crossover trial to establish the efficacy of nortriptyline in the treatment of cis-diamminedichloroplatinum (CDDP)-induced paresthesiae. The study included 51 evaluable patients with CDDP-induced peripheral neuropathy and painful paresthesiae. The study consisted of two 4 week phases, separated by a 1 week 'wash-out' period, in which patients received escalating dosages of either placebo or nortriptyline. The target maximum dose of nortriptyline was 100 mg/day. Each patient filled out pre-randomization and then weekly questionnaires assessing paresthesiae severity, hours of sleep, quality of life, and adverse effects over the 9 week study. No significant differences in paresthesia were observed in the first treatment period between nortriptyline and placebo (means of 49 and 55 respectively on a 0-100 point scale, P=0.78). Although some evidence of a modest effect in favor of nortriptyline was observed during the second treatment period (about one patient in five got a 10-point reduction in pain from drug above placebo effect), this occurred in the presence of a strong carryover effect. Linear models analysis and Bayes methods confirmed that the effect of nortriptyline on paresthesia was modest at best. Hours of sleep increased in the nortriptyline phase (P=0.02). There was no significant difference in measures of quality of life and the effect of paresthesiae on patients' daily activities between nortriptyline and placebo. There was no major toxicity associated with nortriptyline, but dry mouth, dizziness, and constipation were more common with nortriptyline. In summary, nortriptyline failed to demonstrate strong evidence of any effect on paresthesia or pain. The presence of a potential effect which appeared in the second period of the crossover design is questionable due to the observed carryover effect. Cross-validation sensitivity analysis of results support the conclusion that nortriptyline provides modest improvement at best over placebo in terms of chemotherapy-related neuropathy.

Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update

“…47 Chemotherapy-induced peripheral neuropathy may be another NP condition that is relatively refractory to existing first-line treatments. In 3 RCTs, there was no evidence of efficacy of nortriptyline, 84 amitriptyline, 85 or gabapentin. 86 Finally, recent trials of nortriptyline and morphine and their combination 70 and pregabalin 87 and an equivocal trial of topiramate 88 suggest that lumbosacral radiculopathy might be a third peripheral NP condition that is relatively refractory to existing first-and second-line medications.…”

The Pharmacotherapy of Chronic Pain: A Review

“…Specifically, TCAs have demonstrated analgesia in pain caused by diabetic neuropathy, postherpetic neuralgia (for which there is a solid body of evidence to support efficacy), tension headache, migraine, atypical facial pain, fibromyalgia and low back pain. However, TCAs do not appear to be efficacious in painful HIV sensory neuropathy (48), spinal cord injury (49) and cisplatin-induced neuropathy (50). In neuropathic pain, TCAs relieve brief lancinating pain, constant dysesthetic pain, allodynia and spontaneous pain.…”

Efficacy of lamotrigine in the management of chemotherapy‐induced peripheral neuropathy

“…Tricyclic antidepressants and antiepileptics (eg, gabapentin) are often utilized in clinical practice to treat CIPN; however, clinical trials evaluating the benefits of such therapies for therapy 4,5 or prophylaxis 6 of CIPN do not support such use.…”