Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial

Abstract

Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN.

Conflict of interest statement

DISCLOSURE

Heather Bentley and Ben Gouaux are employees of the Center for Medicinal Cannabis Research at the University of California, San Diego, the study sponsor. Ms Bentley is Project Manager for the CMCR and assisted the investigator with regulatory issues, oversight/monitoring, and preparation of the manuscript. Mr. Gouaux is a Research Associate with the CMCR and assisted the investigator with regulatory issues, oversight/monitoring, data preparation and analysis, and preparation and submission of the article. The authors declare that over the past 3 years Dr. Atkinson has received compensation from Eli Lilly Pharmaceuticals. The authors declare that they have not received other financial support or compensation in the past 3 years or have any personal financial holdings that could be perceived as constituting a conflict of interest.

Figures

Figure 1

Study Schema. After screening, eligible subjects were randomized to receive cannabis or placebo first (treatment week 1; Rx 1), followed by the alternative treatment (treatment week 2; Rx 2). The principal measure of pain, the Descriptor Differential Scale (DDS), was measured at five time points (DDS1–5; arrowheads). The primary outcome was the difference in DDS change from baseline (DDS1) to the end of each treatment (active or placebo) week (DDS2/4). Remaining DDS assessments (3, 5) were used in secondary analyses. During each day of the 5-day treatment week, subjects smoked cannabis or placebo cigarettes four times daily. On day 1 of each week, cannabis dose was titrated to efficacy and tolerability as described in the text. On the remaining days (2–4), subjects smoked the maximum tolerated dose achieved on day 1.

Figure 2

Dose escalation schedule for day 1 of the study treatment weeks. See text for details. The objective of the dose escalation was to find, for each study subject, a dose of smoked cannabis that optimized pain relief, while minimizing unwanted adverse effects.

Figure 3

CONSORT Flow Diagram. Disposition of subjects screened, randomized, and completing both treatment periods. Placebo 1, subjects randomized to receive placebo cannabis during the first treatment week; Active 1, subjects randomized to receive active cannabis during the first treatment week. DSPN, distal sensory polyneuropathy; + Utox, positive urine toxicology for substances of abuse, including cannabis.

Figure 4

Plot of treatment effect. DDS pain severity scores (mean, 95% CI) for participants in the cannabis (CNB) and placebo (PCB) arms before study treatment (W/I), during each of the 2 treatment weeks (1, 2) and during the Washout (W/O) between treatment weeks. Cannabis was superior to placebo in this crossover trial whether subjects were treated with cannabis during the first or second treatment week. The median difference in DDS pain severity change was 3.3 points (p = 0.016, WRT).