Selective Cannabinoids for Chronic Neuropathic Pain

A Systematic Review and Meta-analysis

Meng, Howard MD; Johnston, Bradley PhD; Englesakis, Marina MLIS; Moulin, Dwight E. MD; Bhatia, Anuj MBBS, MD, FRCPC, FRCA, FFPMRCA, FIPP, EDRA, CIPS

Disclosures

Anesth Analg. 2017;125(5):1638-1652. 

In This Article

Abstract and Introduction

Abstract

Background There is a lack of consensus on the role of selective cannabinoids for the treatment of neuropathic pain (NP). Guidelines from national and international pain societies have provided contradictory recommendations. The primary objective of this systematic review and meta-analysis (SR-MA) was to determine the analgesic efficacy and safety of selective cannabinoids compared to conventional management or placebo for chronic NP.

Methods We reviewed randomized controlled trials that compared selective cannabinoids (dronabinol, nabilone, nabiximols) with conventional treatments (eg, pharmacotherapy, physical therapy, or a combination of these) or placebo in patients with chronic NP because patients with NP may be on any of these therapies or none if all standard treatments have failed to provide analgesia and or if these treatments have been associated with adverse effects. MEDLINE, EMBASE, and other major databases up to March 11, 2016, were searched. Data on scores of numerical rating scale for NP and its subtypes, central and peripheral, were meta-analyzed. The certainty of evidence was classified using the Grade of Recommendations Assessment, Development, and Evaluation approach.

Results Eleven randomized controlled trials including 1219 patients (614 in selective cannabinoid and 605 in comparator groups) were included in this SR-MA. There was variability in the studies in quality of reporting, etiology of NP, type and dose of selective cannabinoids. Patients who received selective cannabinoids reported a significant, but clinically small, reduction in mean numerical rating scale pain scores (0–10 scale) compared with comparator groups (-0.65 points; 95% confidence interval, -1.06 to -0.23 points; P = .002, I 2 = 60%; Grade of Recommendations Assessment, Development, and Evaluation: weak recommendation and moderate-quality evidence). Use of selective cannabinoids was also associated with improvements in quality of life and sleep with no major adverse effects.

Conclusions Selective cannabinoids provide a small analgesic benefit in patients with chronic NP. There was a high degree of heterogeneity among publications included in this SR-MA. Well-designed, large, randomized studies are required to better evaluate specific dosage, duration of intervention, and the effect of this intervention on physical and psychologic function.

Introduction

Neuropathic pain (NP) is common with a prevalence of 7% to 8% of the population.[1] Challenges in management of NP include a high failure rate with available pharmacotherapy.[2] It is acknowledged that, on average, for every 3 patients who receive treatments for NP, only one has analgesic benefit.[3] In the last decade, the use of cannabis and selective cannabinoids (synthetic cannabinoids containing only tetrahydrocannabinol [THC] and cannabis-based medicinal extracts containing a combination of THC and cannabidiol [CBD]) has gained popularity for the treatment of NP.[4] Cannabinoid receptors (CB1 and CB2) have been linked to processes in pain modulation whereby activity at these receptors causes inhibitory effects on pain responses.[5,6] Furthermore, endocannabinoids have been shown to interact with other receptor systems including γ-aminobutyric acid, serotonergic, adrenergic, and opioid receptors, many of which are involved in the analgesic mechanisms of common NP medications.[7]

There is a lack of consensus regarding the role of selective cannabinoids in treating NP that is refractory to recommended first and second-line medications (anticonvulsants, antidepressants, opioids). In its most recent published guidelines, the Canadian Pain Society advocates for the use of selective cannabinoids as the third-line option for NP whereas the Special Interest Group on NP of the International Association for the Study of Pain has provided a weak recommendation against the use of these medications for NP.[8,9] This dichotomy of opinion originates from conflicting results of randomized controlled trials (RCTs) involving the use of small study populations, different types of selective cannabinoids, varying periods of follow-up, a range of dosages, and inclusion of chronic pain syndromes with unclear neuropathic characteristics. There have also been recent attempts to synthesize available evidence on analgesic and adverse-effect profile of selective cannabinoids in patients with NP.[10,11] However, the methodologies and conclusions of these reviews are hampered by inclusion of trials that enrolled participants with heterogeneous phenotypes (neuropathic and non-NP), variability in assessment of domains of pain, and absence of meta-analysis resulting in lack of information on effect size and its confidence limits.

A systematic review and meta-analysis (SR-MA) of this topic, by synthesizing the available evidence, would help arrive at conclusions regarding the benefits and risks of selective cannabinoids as well as dose-response effects. The primary objective of this SR-MA was to determine the analgesic efficacy of selective cannabinoids compared with conventional management or placebo for chronic NP after at least 2 weeks after commencement of treatment. Clinical recommendations based on the guidelines from the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group based on the result of this SR-MA have also been provided.

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