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

Julie E. Hammack, John C. Michalak, Charles Lawrence Loprinzi, Jeff A Sloan, Paul J. Novotny, Gamini S. Soori, Maria Tria Tirona, Kendrith M. Rowland, Philip J. Stella, Joanne A. Johnson

Research output: Contribution to journalArticle

146 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)195-203
Number of pages9
JournalPain
Volume98
Issue number1-2
DOIs
StatePublished - 2002

Fingerprint

Nortriptyline
Peripheral Nervous System Diseases
Cisplatin
Paresthesia
Placebos
Cross-Over Studies
Sleep
Quality of Life
Pain
Placebo Effect
Tricyclic Antidepressive Agents
Dizziness
Constipation
Random Allocation
Mouth
Linear Models

Keywords

  • Cisplatinum
  • Nortriptyline
  • Peripheral neuropathy

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Neurology
  • Neuroscience(all)
  • Pharmacology
  • Clinical Psychology

Cite this

Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. / Hammack, Julie E.; Michalak, John C.; Loprinzi, Charles Lawrence; Sloan, Jeff A; Novotny, Paul J.; Soori, Gamini S.; Tirona, Maria Tria; Rowland, Kendrith M.; Stella, Philip J.; Johnson, Joanne A.

In: Pain, Vol. 98, No. 1-2, 2002, p. 195-203.

Research output: Contribution to journalArticle

Hammack, JE, Michalak, JC, Loprinzi, CL, Sloan, JA, Novotny, PJ, Soori, GS, Tirona, MT, Rowland, KM, Stella, PJ & Johnson, JA 2002, 'Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy', Pain, vol. 98, no. 1-2, pp. 195-203. https://doi.org/10.1016/S0304-3959(02)00047-7
Hammack, Julie E. ; Michalak, John C. ; Loprinzi, Charles Lawrence ; Sloan, Jeff A ; Novotny, Paul J. ; Soori, Gamini S. ; Tirona, Maria Tria ; Rowland, Kendrith M. ; Stella, Philip J. ; Johnson, Joanne A. / Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. In: Pain. 2002 ; Vol. 98, No. 1-2. pp. 195-203.
@article{b43bce8ba74f441883e7e561eea4de63,
title = "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.",
keywords = "Cisplatinum, Nortriptyline, Peripheral neuropathy",
author = "Hammack, {Julie E.} and Michalak, {John C.} and Loprinzi, {Charles Lawrence} and Sloan, {Jeff A} and Novotny, {Paul J.} and Soori, {Gamini S.} and Tirona, {Maria Tria} and Rowland, {Kendrith M.} and Stella, {Philip J.} and Johnson, {Joanne A.}",
year = "2002",
doi = "10.1016/S0304-3959(02)00047-7",
language = "English (US)",
volume = "98",
pages = "195--203",
journal = "Pain",
issn = "0304-3959",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy

AU - Hammack, Julie E.

AU - Michalak, John C.

AU - Loprinzi, Charles Lawrence

AU - Sloan, Jeff A

AU - Novotny, Paul J.

AU - Soori, Gamini S.

AU - Tirona, Maria Tria

AU - Rowland, Kendrith M.

AU - Stella, Philip J.

AU - Johnson, Joanne A.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Cisplatinum

KW - Nortriptyline

KW - Peripheral neuropathy

UR - http://www.scopus.com/inward/record.url?scp=0036299151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036299151&partnerID=8YFLogxK

U2 - 10.1016/S0304-3959(02)00047-7

DO - 10.1016/S0304-3959(02)00047-7

M3 - Article

C2 - 12098632

AN - SCOPUS:0036299151

VL - 98

SP - 195

EP - 203

JO - Pain

JF - Pain

SN - 0304-3959

IS - 1-2

ER -