A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain

Clin J Pain. Sep-Oct 2003;19(5):323-8. doi: 10.1097/00002508-200309000-00007.


Objective: The involvement of ongoing peripheral activity in the generation of nociceptive input in neuropathic pain suggests that topical drug delivery may be useful as a treatment strategy. This is a pilot study providing initial information regarding the use of novel topical preparations containing amitriptyline (AMI), ketamine (KET), and a combination of both in the treatment of neuropathic pain.

Methods: The study design included a 2 day randomized, double blind, placebo controlled, 4 way cross-over trial of all treatments, followed by an open label treatment phase using the combination cream for 7 days. Twenty volunteers with chronic neuropathic pain were randomly assigned to treatment order and applied 5 mls of each topical treatment (1% AMI, 0.5% KET, combination AMI 1%/KET 0.5%, and placebo) for 2 days. Measures of pain at the end of each block included the short form McGill Pain Questionnaire (MPQ) and visual analog scales (VAS) for present pain intensity and pain relief. Eleven subjects who judged subjective improvement from any treatment in the initial trial entered the open-label trial and used the combination cream for 7 days. Pain levels were recorded daily using the same measures. Blood levels for amitriptyline and ketamine were performed at 7 days to determine whether systemic absorption had occurred.

Results: There was no statistically significant difference from placebo after 2 days for any treatment during the double blind component of the trial. In the 11 subjects who used the combination cream, there was a statistically significant effect, with subjects reporting significantly greater analgesia by days 3 to 7 according to measures of pain and pain relief. Blood levels revealed that there was no significant systemic absorption of amitriptyline or ketamine. Only 2 subjects experienced side effects; these were minor and did not lead to discontinuation of the cream.

Conclusion: This pilot study demonstrated a lack of effect for all treatments in the 2 day double blind placebo controlled trial, followed by analgesia in an open label trial in a subgroup of subjects who chose to use the combination cream for 7 days. Blood analysis revealed no significant systemic absorption of either agent after 7 days of treatment, and creams were well tolerated. A larger scale randomized trial over a longer interval is warranted to examine further effects observed in the open label trial.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Adult
  • Aged
  • Aged, 80 and over
  • Amitriptyline / administration & dosage*
  • Chronic Disease
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Humans
  • Ketamine / administration & dosage*
  • Male
  • Middle Aged
  • Nervous System Diseases / complications*
  • Nervous System Diseases / drug therapy
  • Pain / drug therapy*
  • Pain / etiology*
  • Pain Measurement / methods
  • Pilot Projects
  • Placebos
  • Treatment Outcome


  • Drug Combinations
  • Placebos
  • Amitriptyline
  • Ketamine