Cannabis trial on pain does not meet endpoint

C
#MSBlog: Cannabis extract just misses out on central pain effect in MS!


EpubLangford et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol. 2012 Nov 21.

Background: Central neuropathic pain (CNP) occurs in MSer. The provision of adequate pain relief to these MSers can very difficult. 


Objective: To report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. 


Methods: MSers who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 MSers were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. 

Results: The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of MSers on THC/CBD spray classed as responders at the 30 % level compared to 45 % of MSers on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of MSers receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically significant compared to placebo, with estimated treatment differences of -0.79 and 0.99 points, respectively, in favor of THC/CBD spray treatment. 

Conclusion: The results of the current investigation were equivocal, with conflicting findings in the two phases of the study. While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period, the primary endpoint was not met due to a similarly large number of placebo responders. In contrast, there was a marked effect in phase B of the study, with an increased time to treatment failure in the THC/CBD spray group compared to placebo. These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these MSers.

“This study shows how hard it can be to do symptomatic trials. The aim of this study was to try and find a responder group of MSers and to then test the drug to see if it reduced pain. MSers with chronic myelopathic pain will find these results disappointing  a large number of MSers use street cannabis for pain were hoping to be able to access a legal medicinal product for their pain.”

CoI: Multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

7 comments

    • Re: "Do you think the street cannabis users experience a placebo effect?"

      Almost certainly; this happens with all symptomatic treatments. Please read the posts on this blog concerning the placebo effect! The issue is how large is the effect over and above the placebo effect?

    • Yes, too many people find cannabis or nabilone effective and it is backed up by animal studies. I suspect the problem lies in the trial design.

    • Re: "is GOD placebo?"

      I don't know this is an interesting question. I suspect the psychologists who design experiments with functional MRI could answer this question.

    • Dean ME. A homeopathic origin for placebo controls: 'an invaluable gift of God'. Altern Ther Health Med. 2000 Mar;6(2):58-66.

      The acknowledged early adoption of placebo controls in drug trials by homeopaths is currently thought to have been derived from prior external attempts to discredit the system. This claim is reexamined in the light of a comprehensive literature search for 19th-century homeopathic therapeutic trials and provings using placebo. Single-blind placebo controls, still used today, are shown to have originated independently within homeopathy's own disciplinary matrix before the first external evaluations. They are the most likely source for later placebo-controlled crossover and parallel group experiments by homeopaths.

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