Ratcliffe. 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

Pain and Anaesthesia Research Centre, St Bartholomew's Hospital, London, UK.
Journal of Neurology (Impact Factor: 3.38). 11/2012; 260(4). DOI: 10.1007/s00415-012-6739-4
Source: PubMed


Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we 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. Patients 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 patients 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. 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 patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients 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 patients 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. 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 patients.

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    • "Regarding serious adverse events (SAEs); in a study of oral cannabis extract in 279 patients with MS there were 3 adverse events described as serious and medication related, these included urinary tract infection, head injury and interstitial lung disease (Zajicek et al. 2012). In a study examining nabilone in treatment of 37 patients with diabetic neuropathy one patient was seen in the emergency room for assessment of delirium which resolved when the medication was discontinued (Toth et al. 2012) and in a study of the oral mucosal cannabis spray in 339 patients with neuropathic pain associated with MS there were 2 SAEs in the treatment group (suicidal ideation and disorientation) (Langford et al. 2013). "
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    Journal of Neuroimmune Pharmacology 03/2015; 10(2). DOI:10.1007/s11481-015-9600-6 · 4.11 Impact Factor
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    • "This could suggest that Δ9-THC is the major therapeutic chemical within cannabis, based on the reports that cannabis in North America may have a low CBD content (ElSohly et al. 2000; Wilkinson et al. 2003; EMCDD 2008). However, pharmaceutical, medical cannabis extracts being developed (Sativex & Cannador) contain essentially equal proportions of Δ9-THC and CBD (Novotna et al. 2011; Zajicek et al. 2012; Langford et al. 2013). Although it has been reported that CBD may limit the side-effect potential of Δ9-THC within cannabis (Dalton et al. 1976; Russo and Guy 2006), little direct evidence has been provided for such a specific ratio and contrasts with the low CBD:Δ9-THC ratio (1:10–1:200) in many recreational cannabis extracts (Burgdorf et al. 2011). "
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    Journal of Neuroimmune Pharmacology 12/2014; 10(2). DOI:10.1007/s11481-014-9575-8 · 4.11 Impact Factor
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    • "Among Sativex® responders (72%), the mean spasticity score on a 0–10 numeric rating scale decreased from 7 before treatment to 3 within 10 days of starting Sativex® spray (Koehler et al., 2014). The results were confirmed in multiple further studies (Collin et al., 2007; Rog et al., 2007; Wade et al., 2010; Sastre-Garriga et al., 2011; Langford et al., 2013; Serpell et al., 2013) but so far none has systematically evaluated the effects of Sativex® on active MRI lesions and relapse rates. 3.3. "
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