Topical administration of ketamine and related compounds in neuropathic pain
In our clinic we develop prototypes of transdermal creams to treat neuropathic pain. Currently we work on simple creams containing amitriptyline (5-10%) and ketamine (10%).
Here we quote from a clinical source and a patent analysis on various cream compositions for neuropathic pain, published in the VS.
Relief of pain associated with neuralgia due to diabetes (DPN), chemotherapy (CPN) or shingles in adults (PHN) by ketamine and amitriptyline cream
A topical analgesic cream consisting of 4% amitriptyline and 2% ketamine cream as a patented formulationhas been tested in four-week, Phase IIb 200- patient trial in diabetic peripheral neuropathy (DPN).
It was a double blind, placebo-controlled study of this compounded cream in 215 DPN patients. For the primary endpoint, the difference in changes in pain intensity between the compounded cream and placebo over the four week duration of the trial, nearly reached statistical significance (p=0.0715).
Key secondary endpoints measured in the trial indicate that 60% of patients in the active treatment arm achieved a reduction of pain scores of at least 30% compared with 48% of patients in the placebo arm (p=0.076).
33% of patients in the active treatment arm achieved a reduction in pain scores of at least 50% compared with 21% of patients in the placebo arm (p=0.078).
In a second clinical trial.
(four-week, 360- patients) in post-herpetic neuralgia (PHN) comparing the efficacy and safety of the compounded cream against both gabapentin and placebo. These data demonstrated that the cream achieved statistically significant superior efficacy compared with placebo (p=0.024) and it wa comparable to gabapentine.
63% of patients in the cream treatment arm achieved a reduction in pain scores of at least 30%, significantly higher than that of patients in the placebo arm (p=0.033).
Data results further indicate that the cream achieved a superior safety profile when compared with gabapentin, especially with regard to dizziness and somnolence, as evaluated by the reporting of adverse events.
The use of ketamine transdermally in an organogel has shown some promise in the treatment of neuropathy. Ketamine is an N-methyl-D-aspartate receptor antagonist and thus blocks a cascade of intracellular events that inhibit the hyper excitability of spinal cord neurons. Animal data show that certain spontaneous pains and allodynia have been treated successfully with Ketamine. Also, in humans, phantom limb pain has been treated with success (Nadine & Bouhassira, Acta. Neurol. Scand 1999 (Supp 173):12-24). Ketamine has been used experimentally to treat neuropathic pain by a variety of routes including the intravenous and subcutaneous. The topical form of Ketamine is effective in treating painful neuropathy when other traditional medicines have failed. (Crowley et al., International Journal of Pharmaceutical Compounding 1998; 2:122-1273).
Other compositions have been employed, including combinations of individual compounds. U.S. Pat. No. 6,387,957 B1 (Frome) relates to the treatment of Sympathetically Mediated Pain (SMP), which include various neuropathies, employing the compounds ketamine (NMDA receptor antagonist), amitriptyline (anticholinergic antidepressant), and guanethidine (sympathetic blocking agent), in combination or independently. However, the compounds employed by Frome act independently of each other as illustrated by the effectiveness of individual compounds. Frome’s invention lacks any synergism of the compounds as the compounds merely complement the other compounds, but does not synergize, or supplement, the activities of the other compounds. For example, ketamine a very potent antineuropathic agents was used in limited concentrations. Whether alone or in combination, small concentrations of ketamine were likely used due to ketamine’s known neurotoxic effects. Frome’s invention also suffers from limitations in the preparation, dosage, application or administration methods and potential side effects. The effectiveness of Frome’s compounds depends on the volume of the preparation and whether the compounds are alone or in combination. The side effects of amitriptyline and guanethidine are well known. These are disruptive to a person’s quality of life and are not addressed by Frome in his patent.
Ketamine is an N-methyl-D-aspartate (NMDA) calcium channel antagonist that can be admixed in the compositions described herein in concentrations ranging from 10-50%, preferably 10 to 30%, and most preferably from 15% to 20% safely. Topical ketamine is effective for treating painful neuropathy when other traditional medicines have failed. See Crowley K L, Flores J A, Hughes C N et al. Clinical application of ketamine ointment in the treatment of sympathetically maintained pain, International Journal of Pharmaceutical Compounding 1998; 2:122-127.
Title:Treatment of neuropathyDocument Type and Number:United States Patent 7687080Abstract:Methods and compositions for the topical or transdermal treatment of neuropathy. More particularly, transdermal or topical compositions including a combination of ingredients that provide a surprising degree of effective relief from the symptoms of peripheral neuropathy and methods for administering the compositions to treat various neuropathies.
April 2010, Jan M. Keppel Hesselink, MD, PhD