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.

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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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Characteristics of Included Studies on Selective Cannabinoids
First Author, Year		Pain Diagnosis	Diagnosis of Neuropathic Pain	Type of Pain	Duration of Pain in Years (Range or SD)	Baseline Pain NRS (Range or SD)		Age in Years (Range), Gender (M/F)	Number of Subjects in Each Group (Can/Com)	Active Rx, Route	Comparator		Duration of Treatment		Remarks
Svendsen, 2004¹⁹		Multiple sclerosis	Clinical and QST	Central	4.5 (0.3–12)	5.5 (3.0–8.0)		50 (20–55); 10/14	24 (24/24)	Dronabinol po—daily dose 2.5–10 mg for 3 wk	Placebo		3 weeks (15–21 d)		Crossover trial (treatments separated by a 3-wk washout period); pre-existing neuropathic pain medication not continued (except paracetamol)
Berman, 2004²²		Neuropathic pain from brachial plexus root avulsion	Clinical	Central	5.0 (0.9–18.6)^a	6.8 ± 1.4		46 (29–63); 46/2	48 (48/48)	THC-CBD^b,c mean number of sprays/d in each group: 8	Placebo		2 wk		Crossover trial (three 2-wk treatments; no washout period between treatments; dpre-existing neuropathic pain medication continued
Rog, 2005¹⁶		Multiple sclerosis	Clinical and NPS	Central	11.6 (1.6–36)	6.5 ± 1.6		49.2 (26.9– 71.4); 14/52	66 (34/32)	THC-CBDb: mean number of sprays/d: 9.6	Placebo		5 weeks		Pre-existing neuropathic pain medication continued
Nurmikko, 2007¹⁵		Neuropathic pain of multiple etiologies	Clinical and NPS	Peripheral	6.4 ± 5.7 (Can) 6.2 ± 6.4 (Com)	7.3 ± 1.4 (Can); 7.2 ± 1.5 (Com)		52.4 ± 15.8 (Can); 54.3 ± 15.2 (Com); 51/74	125 (63/62)	THC-CBD^b: mean number of sprays/d: 10.9 ± 6.8	Placebo		5 wk		Pre-existing neuropathic pain medication continued
Frank, 2008²³		Neuropathic pain of multiple etiologies	Clinical	Central (n = 30) and peripheral (n = 66)	6.4 ± 5.8 years	6.7 ± 1.4		50.1 y (range 23–84); 46/50	96 (96/96)	Nabilone po 2 mg daily	Dihydrocodeine 240 mg daily		6 wk		Crossover trial; all adjuvant analgesics (except dihydrocodeine) allowed
Selvarajah, 2010¹⁷		Neuropathic pain-diabetic neuropathy	Clinical and NTSS-6	Peripheral	>0.5 y	Can: 5.6 ± 2.7 Com: 4.5 ± 2.2		Can: 58.2 ± 8.8 years Com: 54.4 ± 11.6 years; 19/11	30 (15/15)	THC-CBD^b: up to 4 sprays/d	Placebo		12 weeks (titration in first 2 wk and maintenance for 10 wk)		Pre-existing neuropathic pain medication continued
Toth, 2012²⁰	Neuropathic pain-diabetic neuropathy		Clinical and DN4	Peripheral	7.1 ± 7.3 y	5.8 ± 1.8	Can: 60.8 ± 15.3 y Com: 61.6 ± 14.6 y; 14/12e		26 (13/13)	Nabilone 1–4 mg/d		Placebo		5 weeks (after a 4-wk run-in phase to identify responders)	Pre-existing neuropathic pain medication continued; enriched enrollment randomized withdrawal design
Langford, 2013¹³	Multiple sclerosis		Clinical	Central	5.5 ± 5.5 y	6.6 ± 1.4	49.0 ± 10.5 y; 109/230		339 (167/172)	THC-CBD^b: mean daily dose of THC/CBD spray was 8.8 ± 3.9 sprays		Placebo		14 wk	Pre-existing neuropathic pain medication continued
Serpell, 2014¹⁸	Neuropathic pain of multiple etiologies		Clinical	Peripheral	5.5 ± 5.9 y	≥4/10 NRS	57.3 ± 14.2; 96/150		246 (128/118)	THC-CBD^b: mean daily dose of THC/CBD spray was 8.9 sprays		Placebo		15 wk	Pre-existing neuropathic pain medication continued
Lynch, 2014¹⁴	Neuropathic pain- chemotherapy- induced		Clinical	Central and peripheral	1.4 years (range not provided)	6.8 ± 1.2	56.0 ± 10.8; 3/15		18 (18/18)	THC-CBD^b: mean daily dose of THC/CBD spray was 8 sprays		Placebo		4 wk	Crossover trial (treatments separated by a 2-wk washout period); pre-existing neuropathic pain medication continued
Turcotte, 2015²¹	Multiple sclerosis		Clinical and DN4	Central	4.5 y (2.3–5.8 y)	7.7 ± 1.4	45.5 ± 10.8; 2/13		15 (8/7)	Nabilone: 2 mg/d		Placebo		9 wk (initial 4 wk for titration)	Pre-existing neuropathic pain medication continued

Abbreviations: Can, cannabinoid; CBD, cannabidiol; Com, comparator; DN4, Douleur Neuropathique 4 questionnaire; NP, neuropathic pain; NRS, Numerical Rating Scale; NTSS-6, Neuropathy Total Symptom Score-6; QST, quantitative sensory testing; THC-CBD, δ-9-tetrahydrocannabinol (27 mg/mL) and cannabidiol (25 mg/mL).
^aTime since last surgical intervention.
^bEach 100 μL spray delivers 2.7 mg of THC and 2.5 mg of CBD.
^cTwo active treatment groups (THC-CBD and THC) but data extracted only for THC-CBD group.
^dMaximum 24-h dose allowed was 48 sprays: 129.6 mg/120 mg of THC-CBD or 129.6 mg of THC.
^eGreater proportion of women randomized to the nabilone group than placebo.

Table 2. Outcomes Reported in Included Studies on Selective Cannabinoids
First Author, Year	Primary Outcome	Secondary Outcome(s)		Adverse Events	Remarks
Svendsen, 2004¹⁹	Median pain intensity score in the last (third) week of treatment Dronabinol: 4 (IQR 2.3–6) Placebo: 5 (IQR 4–6.4)	Improvements in Dronabinol group (versus placebo) in: • Median radiating pain intensity and pain relief score • QoL (SF-36: bodily pain and mental health domains) • QST No difference between groups in: • Rescue analgesia • Physical functioning (EDSS)		More patients had AE (dizziness, headache, tiredness, myalgia) during active treatment, especially in the first week of treatment; 17% of patients in dronabinol group could not tolerate 10 mg od	Diagnosis of central pain established by history, examination, QST
Berman, 2004²²	Mean pain intensity score in the last (second) week of treatment THC-CBD: 6.1 ± 1.4 Placebo: 6.6 ± 1.4	Improvements in THC-CBD group (versus placebo) in: • Sleep quality • SF-MPQ PRI and VAS • PDI: similar in 3 groups • GHQ-12 score		Common adverse effects in active groups: dizziness, somnolence, dysgeusia, nausea, euphoria	3 withdrawals during the study: Placebo: 1—N&V during placebo administration; 1—anxiety and paranoia, experienced while taking placebo THC-CBD: 1—feeling faint
Rog, 2005¹⁶	Mean pain intensity score in the last (fifth) wk of treatment THC-CBD: 3.85 ± 2.1 Placebo: 4.96 ± 2.15	Improvements in THC-CBD group (versus placebo) in: • NPS score • PGIC • Sleep quality No difference between groups in: • Neuropsychologic outcomes		More patients on THC-CBD than placebo reported dizziness, dry mouth, and somnolence; cognitive side effects were limited to long-term memory storage
Nurmikko, 2007¹⁵	Mean pain intensity score in the last (fifth) wk of treatment: THC-CBD: 5.8 ± 1.4 Placebo: 6.7 ± 1.5	Improvements in THC-CBD group (versus placebo) in: • NPS composite score • Sleep quality • QST (dynamic and punctate allodynia) • Physical function (PDI) • PGIC		Sedative and gastrointestinal side effects were reported more commonly by patients on THC-CBD	Withdrawals due to AE: -THC-CBD: 11 (19%) patients Placebo: 2 (3%) patients
Frank, 2008²³	Mean VAS over the last 2 (fifth and sixth) wk of treatment period Nabilone: 6 ± 2.4 Dihydrocodeine: 5.9 ± 2.4	Improvements in nabilone group (versus placebo) in: • QoL (nabilone superior to dihydrocodeine for physical function but dihydrocodeine superior for bodily pain domain) No difference between groups in: • Mental functioning • Sleep quality • Psychometric function		More N&V with nabilone and more tiredness and nightmares with dihydrocodeine	33 patients failed to complete the trial and the cohort studied had a variety of neuropathic pain syndromes
Selvarajah, 2010¹⁷	Mean total pain scores in the last (12th) wk of treatment: Can: 4 ± 2.9 Com: 2.5 ± 2.9	No difference between groups in: • MPQ • QoL (SF-36, EQ-5D)			• Six patients (group not specified) withdrew because of adverse effects • Patients with severe depression in both groups had significant analgesic benefit in response to the interventions
Toth, 2012²⁰	Mean daily pain score in the last (5th) wk of treatment Can: 3.5 ± 1.3 Com: 5.4 ± 1.7	Improvements in nabilone group (versus placebo) in: • Anxiety (HADS-A) • Sleep quality (MOSSSPI) • QoL (EQ-5D) • PGIC and PTSS		Mild-to-moderate: dizziness and drowsiness most common	Potential unmasking occurred in 6 patients
Langford, 2013¹³	Patients with >30% reduction in pain NRS compared to baseline: Can: 50% Com: 45% Mean daily pain score in the last (14th) wk of treatment Can: 4.5 ± 2.2 Com: 4.7 ± 2.3	No difference between groups in: • Sleep quality • QoL (BPI-SF) • PGIC		Mild-to-moderate: dizziness, vertigo, drowsiness, fatigue, nausea, and dry mouth most common	Large placebo effect
Serpell, 2014¹⁸	Patients with >30% reduction in pain NRS compared to baseline: Can: 28% Com: 16%	Improvements in THC-CBD group (versus placebo) in: • Sleep quality (NRS) • PGIC • NPS • BPI-SF • QoL (EQ-5D) • QST (dynamic allodynia) No difference between groups in: • QST (punctate allodynia)	Mild-to-moderate: dissociation and disorientation most common
Lynch, 2014¹⁴	Mean daily pain score in the last (fourth) wk of treatment Can: 6.0 ± 1.2 Com: 6.4 ± 1.2	No difference between groups in: • QoL (SF-36) • QST (dynamic and punctate allodynia)	Mild: fatigue, dizziness, dry mouth, nausea		Study was significantly underpowered
Turcotte, 2015²¹	VAS for pain intensity Can: 3.5 ± 1.4 Com: 5.6 ± 1.4	Improvements in nabilone group (versus placebo) in: • PGIC	Mild: dizziness, drowsiness, dry mouth		Combination of gabapentin and nabilone evaluated

Abbreviations: BPI-SF, Brief Pain Inventory—Short Form; EDSS, expanded disability status scale score; EQ-5D, European Quality-of-Life 5 Domains; GHQ-12, General Health Questionnaire-12; HADS-A, Anxiety subscale of the Hospital Anxiety and Depression Scale; IQR, interquartile range; MOSSSPI, Medical Outcomes Study sleep scale problems index; N&V, nausea and vomiting; ND, no difference; NPS, neuropathic pain score; NRS, numerical rating score; PPT, pressure pain threshold; PRI, pain rating index; PTSS, pain treatment satisfaction scale; QoL, quality of life; QST, quantitative sensory testing; SF-MPQ, short form McGill questionnaire; PDI, pain disability index; PGIC, patient's global impression of change; VAS, Visual Analog Scale.