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.

81 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: An updated systematic review of randomized controlled trials examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to PRISMA guidelines for systematic reviews reporting on health care outcomes. Eleven trials published since our last review met inclusion criteria. The quality of the trials was excellent. Seven of the trials demonstrated a significant analgesic effect. Several trials also demonstrated improvement in secondary outcomes (e.g., sleep, muscle stiffness and spasticity). Adverse effects most frequently reported such as fatigue and dizziness were mild to moderate in severity and generally well tolerated. This review adds further support that currently available cannabinoids are safe, modestly effective analgesics that provide a reasonable therapeutic option in the management of chronic non-cancer pain.
    Journal of Neuroimmune Pharmacology 03/2015; 10(2). DOI:10.1007/s11481-015-9600-6 · 4.11 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.
    Journal of Neuroimmune Pharmacology 12/2014; 10(2). DOI:10.1007/s11481-014-9575-8 · 4.11 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3-gallate, curcumin and the mustard oil glycoside from e.g. broccoli, sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF-κB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.015 · 9.72 Impact Factor
Show more