The study was approved by the McGill University Health Centre Research Ethics Committee, and all participants gave written informed consent. Participants were recruited at the McGill University Health Centre.
Those eligible were men and women aged 18 years or older with neuropathic pain of at least three months in duration caused by trauma or surgery, with allodynia or hyperalgesia, and with an average weekly pain intensity score greater than 4 on a 10-cm visual analogue scale. Participants had a stable analgesic regimen and reported not having used cannabis during the year before the study (Appendix 1, available at www.cmaj.ca/cgi/content/full/cmaj.091414/DC1
). Potential participants had to have normal liver function (defined as aspartate aminogransferase less than three times normal), normal renal function (defined as a serum creatinine level < 133 μmol/L), normal hematocrit (> 38%) and a negative result on β human chorionic gonadotropin pregnancy test (if applicable). Women of child-bearing potential consented to use adequate contraception during the study and for three months afterward.
Exclusion criteria were pain due to cancer or nociceptive causes, presence of significant cardiac or pulmonary disease, current substance abuse or dependence (including abuse of or dependence on cannabis), history of psychotic disorder, current suicidal ideation, pregnancy or breastfeeding, participation in another clinical trial within 30 days of enrolment in our trial, and ongoing insurance claims.
We used a randomized, double-blind, placebo-controlled, four-period crossover design. Each period was 14 days in duration, beginning with five days on the study drug followed by a nine-day washout period. Eligible participants were randomized to a sequence of treatment periods based on a Latin square design.
Cannabis was obtained from Prairie Plant Systems Inc. (Saskatoon, Sask.) and the United States National Institute of Drug Abuse. Prairie Plant Systems Inc. blended cannabis flowers and leaves to prepare three different potencies of active drug (2.5%, 6.0% and 9.4% tetrahydrocannabinol). The US National Institute of Drug Abuse used ethanolic extraction of cannabinoids to prepare the 0% tetrahydrocannabinol product. Intermediate doses (2.5% and 6.0% tetrahydrocannabinol) were used to increase the likelihood of successful blinding. Doses of 25 mg (± 1 mg) were prepared in opaque gelatin capsules by the study pharmacist. A panel of nine independent personnel examined the appearance of the four cannabis preparations and found no association between estimated and true potency (data not shown).
Cannabis doses were delivered as single smoked inhalations using a titanium pipe (RayDiaTor, Mori Designs, Auburn, WA, USA). The first dose of each period was self-administered under observation in a ventilated room. For dose delivery, one capsule of the assigned potency was opened and the cannabis tipped into the bowl of the pipe. Participants were instructed to inhale for five seconds while the cannabis was lit, hold the smoke in their lungs for ten seconds, and then exhale. The beginning of inhalation was recorded as the onset of the exposure. Subsequent doses were self-administered in the same manner three times daily at home for the first five days of each period.
Routine medications were continued throughout the trial. Use of breakthrough analgesia (acetaminophen) was allowed.
The study nurse explained the study to each participant, sought signed informed consent, obtained a medical history and performed a chart review. The study physician conducted a physical examination. Urinary drug screening was performed. Participants were contacted by telephone on three occasions during the first five days of the screening phase to calculate a baseline average pain score. A psychological evaluation was conducted by a clinical psychologist.
On the first day of each period, participants were followed for three hours. Vital signs and ratings of pain, “high,” relaxation, stress, happiness and heart rate were recorded, and blood was collected for tetrahydrocannabinol assays. On days one and five of each study period, blood was collected for hematologic and biochemical analyses. At the end of their first visit, participants were given four labelled containers for urine collection and 13 cannabis doses for the five days of treatment.
During the first five days of each period, participants were contacted daily by telephone to administer questionnaires on pain intensity, sleep, medication and adverse effects. Participants collected early morning urine samples daily. They returned on day five to return the urine samples, to undergo urinary and blood tests, and to complete questionnaires on pain quality, mood, quality of life and assessments of potency. At the end of the study, participants completed final adverse event reports and potency assessments. Participants were advised not to drive a vehicle or operate heavy machinery while under the influence of the study drug.
Outcome measures were selected following published recommendations for clinical trials of chronic pain.18
Pain intensity was measured using an 11-item numeric rating scale, with “no pain” and “worst pain possible” as anchors. The numeric rating scale was administered once daily for present, worst, least and average pain intensity during the previous 24 hours. As per protocol, the average pain intensity score over the five days on study drug constituted the primary outcome. Acute effects on pain intensity were measured using a 100-mm visual analogue scale. Pain quality was assessed using the McGill Pain Questionnaire.19
Sleep was assessed using the Leeds Sleep Evaluation Questionnaire.20
The short-form Profile of Mood States was used to examine mood effects.21
Quality of life was assessed using the EQ-5D health outcome instrument.22
The items “high,” “relaxed,” “stressed,” and “happy” were measured using a 100-mm visual analogue scale (0 = not at all, 10 = extremely).23–25
Potency assessments were conducted by asking participants on the fifth day of each period to guess which potency they had received. At the end of the trial, participants were asked to guess the order in which they received the treatments. Standard assays for plasma tetrahydrocannabinol assays were used (Appendix 1).
Our primary hypothesis was that smoked cannabis containing 9.4% tetrahydrocannabinol is superior to 0% tetrahydrocannabinol in reducing average pain intensity. The comparison of within-patient average weekly pain intensity when assigned 9.4% tetrahydrocannabinol cannabis compared with placebo was the contrast of primary interest. A sample size of 32 patients was targeted assuming a within-patient difference of 10 mm26
in the primary outcome between active and placebo drug, on a 100 mm scale, with a standard deviation of 20 mm, and with 80% power and 5% significance.
A generalized linear model including drug, period and first-order carryover effects was fitted. If the carryover effect or period effect was not significant, then a reduced model was refitted. Nine-five per cent confidence intervals were generated. Significance tests were performed at a 5% level. An identical procedure to that described above for the primary outcome was performed to assess the secondary outcomes, including the McGill Pain Questionnaire, the Leeds Sleep Evaluation Questionnaire, the Profile of Mood States, and EQ-5D. Statistical procedures for day one assessments and EQ-5D analyses are shown in Appendix 1. Data from all randomized participants were included in all safety and efficacy analyses.
All reported adverse events were classified according to severity, seriousness and relationship to the study drug. An independent data-monitoring committee monitored the safety-related aspects of the trial.
In conducting the study, we followed the Good Clinical Practice guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.27
The trial was registered with the International Standard for Randomised Controlled Trials Register (ISRCTN683140063).