Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by Rheumatoid Arthritis

Objectives. To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA).

Methods. We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning.

Efficacy outcomes assessed- were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity.

Results. Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18)
for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the          SF-MPQ pain at present component. There was no effect on morning stiffness but
baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group.

Conclusions. In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population,
they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.nflammatory properties in laboratory studies, as have other plant components, such as terpenoids and flavonoids [3]. Sativex was administered by oromucosal spray, each activation delivering 2.7 mg THC and 2.5 mg CBD. Eligible patients had a diagnosis of RA meeting ACR criteria, with active arthritis not adequately controlled by standard medication. NSAID and prednisolone regimes had to have been stabilized for 1 month and DMARDs for 3 months prior to enrolment, and were maintained constant throughout the study. Exclusion criteria included a history of psychiatric disorders or substance misuse, severe cardiovascular, renal or hepatic disorder, or a history of epilepsy. Dossing was restricted to the evening to minimize possible intoxication-type reactions, with randomized treatment allocation using permuted blocks of four.

Starting dose was one actuation within 0.5 h of retiring, and this was increased by one actuation every 2 days to a maximum of six actuations according to individual response. Stable dosing was then maintained for a further 3 weeks. Patients gave written informed consent to participate, and the study was approved by each local research ethics committee. Primary efficacy variable was pain on movement measured by a 0–10 numerical rating scale (NRS) each morning. Baseline score (obtained as an average of the last 4 days of the 14-day baseline period) was compared with the average of the last 14 days of treatment. Secondary outcomes included NRS measures of pain at rest, sleep quality and morning stiffness, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the 28-joint disease activity score (DAS28). The study plan is shown in Fig. 1. Based on previous results for pain on movement, it was calculated that 23 patients/group would be required to detect 2 units difference with 90% power. A minimum of 54 patients were to be recruited to allow for dropouts. Normally distributed data were to be analysed using one-way analysis of covariance. Change from baseline to endpoint was to be compared between the two treatment groups with the baseline score considered as a covariate. Non-parametric analysis was to be used if there was considerable departure from normality.

Results. The protocol and all study documentation was approved by the Independent Research Ethics Committee representing each of the eight participating centres. Seventy-five patients were screened and 58 met the eligibility criteria. Written informed consent,
as specified by the Declaration of Helsinki (2000), was obtained from all patients prior to screening. Thirty-one of the eligible patients were randomized to CBM and 27 to placebo. One patient withdrew from the active treatment group (unrelated surgery) and three from placebo (adverse events). There were no significant differences in demographics between groups (Table 1). Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for CBM and 5.3 (1.18) for placebo.

Statistically significant improvements in pain on movement, pain at rest, quality of sleep,
DAS28 and the SF-MPQ pain at present component were seen following CBM in comparison with placebo.

Adverse Effects (AE) in CBM group were all of mild or moderate intensity except for two (6%) rated severe (constipation; ‘malaise’) compared with six (22%) in the placebo group. Eight patients (26%) receiving CBM experienced transient dizziness at some point, though in all cases this was rated as mild. The exact timing of these episodes was recorded in six of these patients: four occurred during the initial 2-week titration period, the other two at 16 days. There were no withdrawals due to AE in the CBM group compared with three (11%) for placebo, and no serious AE following the active treatment compared with two (7%) in the placebo group.

For the complete report:  Rheumatology, Volume 45, Issue 1, 1 January 2006, Pages 50–52, D. R. Blake, P. Robson1, M. Ho2, R. W. Jubb3 and C. S. McCabe

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