PEP Topic 
Peripheral Neuropathy

Nortriptyline is a tricyclic antidepressant that blocks the reuptake of neurotransmitters at neuronal membranes. Researchers have found that this action increases available serotonin and norepinephrine in the central nervous system, potentiating their effects.

Effectiveness Not Established

Research Evidence Summaries

Hammack, J.E., Michalak, J.C., Loprinzi, C.L., Sloan, J.A., Novotny, P.J., Soori, G.S., . . . Johnson, J.A. (2002). Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum–induced peripheral neuropathy. Pain, 98(1–2), 195–203.

doi: 10.1016/S0304-3959(02)00047-7

Intervention Characteristics/Basic Study Process:

Fifty-one patients with preexisting cisplatin-induced peripheral neuropathy and painful paresthesias were randomly assigned to arm 1, in which they received active drug (nortriptyline) in the first four-week phase followed by placebo in the second phase; or arm 2, whereby the order was reversed. Patients were started on 1 25 mg tablet of nortriptyline or placebo. At weekly intervals during each of the phases, patients received an additional tablet of either nortriptyline (25 mg) or placebo as tolerated. The target maximum dose at the end of each drug phase was 100 mg of nortriptyline or placebo (four tablets).

Sample Characteristics:

  • A total of 51 patients treated with cisplatin who received escalating doses of nortriptyline during a four-week period were studied.
  • Exclusion criteria included diabetes, glaucoma, prostatism, dementia, HIV infection, major psychiatric disease, significant cardiac disease, or postural hypotension.
  • Study participants had evidence on sensory examination of chemotherapy-induced peripheral neuropathy (CIPN).

Study Design:

The study had a randomized, double-blind, placebo-controlled, crossover design

Measurement Instruments/Methods:

Each patient filled out pre-randomization and weekly questionnaires assessing paresthesia severity, hours of sleep, quality of life, and adverse effects during the nine-week study period.


A modest effect was noted with nortriptyline regarding relief of cisplatin-induced paresthesia and improved sleep.


Based on results from this one small pilot study, and the lack of objective measurements of neuropathy, the effectiveness of nortriptyline in reducing neuropathy-associated paraesthesia has not been established.


The primary endpoint did not separate pain from paresthesia in cisplatin-induced paraesthesia over the placebo group.