SUMMARY OF EVIDENCE

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Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Sep 21.

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Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet].

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SUMMARY OF EVIDENCE

Quantity of Research Available

A total of 416 citations were identified in the literature search. Following screening of titles and abstracts, 385 citations were excluded and 31 potentially relevant reports from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search, and an additional four records were identified through hand searching of reference lists. Of the 36 articles selected for full-text review, 30 articles were excluded for various reasons, and a total of six publications met the selection criteria for inclusion in this report. Appendix 1 presents the PRISMA flow diagram of the study selection process, including reasons for exclusion of full-text publications

Additional studies of potential interest that did not meet the selection criteria are provided in Appendix 6

Summary of Study Characteristics

A brief overview of the studies selected for inclusion can be found in Appendix 2.

Study Design

Five SRs,²^,¹⁴^–¹⁶ including two with meta-analyses,¹⁶^,¹⁷ were identified regarding the clinical effectiveness of cannabinoids in the management of chronic pain among adults; all SRs evaluated the comparative clinical benefits and harms associated with THC:CBD (Sativex^®) in adults experiencing chronic neuropathic or non-cancer pain. There was overlap among the placebo-controlled RCTs relating to THC:CBD in the five published SRs identified for inclusion (Appendix 3). Nine RCTs were common between at least two SRs, while seven RCTs were unique to a single SR. Variation between the studies selected for inclusion across these reviews likely occurred due to differences in the eligible patient populations, in chosen comparators and the search timeframes used; all SRs included data on randomized, placebo-controlled trials.

One evidence-based guideline met the inclusion criteria for this review.¹⁸ This guideline was developed by means of expert consensus and systematic literature searches using an evidence grading approach developed by the American Academy of Neurology. Treatment recommendations were specific to the pharmacological management of chronic neuropathic pain in adult patients.

Country of Origin

Of the five included SRs, two were conducted in the United States,¹⁴^,¹⁷ and one review was conducted in the United Kingdom.¹⁶ One SR was conducted in Canada,² and an updated review was subsequently published by the same primary author.¹⁵

The included evidence-based guideline statement was the product of collaboration between clinicians and researchers from Canada, endorsed by the Canadian Pain Society.¹⁸

Patient Population

All included SRs assessed the clinical benefits and safety of THC:CBD among patients with chronic pain. More specifically, patients with chronic neuropathic pain or chronic non-cancer pain related to fibromyalgia, rheumatoid arthritis, and mixed chronic pain were the focus of the SR published by Lynch et al.²; in their updated review, the authors defined the target population more broadly as patients with chronic non-cancer pain. Conversely, the review by Jawahar et al.¹⁷ focused on patients clinically diagnosed with multiple sclerosis and experiencing non-spastic and non-trigeminal neuralgic pain, while Boychuk et al.¹⁴ included studies relating to patients with chronic non-malignant neuropathic pain. The SR and meta-analysis by Whiting et al.,¹⁶ which included the largest number of primary studies, assessed the effectiveness of cannabinoid products across a wide range of clinical areas, including chronic pain; studies relating to the effect of THC:CBD on chronic pain in this review included patients with cancer and non-cancer pain. None of the included SRs described patients’ prior treatment experience with analgesic medications.

The intended users of the included evidence-based guideline were described as physicians, nurse practitioners and other allied health care professionals involved in the management of neuropathic pain; the guideline is also relevant to patients with chronic neuropathic pain.¹⁸

Interventions and Comparators

Cannabinoid products comprised the main interventions of interest across all included SRs. These products included whole plant cannabinoids such as smoked cannabis, cannabinoid extracts delivered as aerosol spray such as THC:CBD which was of particular interest in this report, as well as synthetic cannabinoids ingested orally such as nabilone or dronabinol. The effectiveness of THC:CBD in RCTs included across all SRs were exclusively compared with placebo. Studies comparing THC:CBD with other active comparators relevant to this review, such as nabilone, opioids, anticonvulsant or antidepressant medications, were not identified.

The included evidence-based guideline focused specifically on pharmacologic treatments for the management of chronic neuropathic pain, including cannabinoid products such as THC:CBD.

Outcomes

The primary clinical outcome across all SRs was patient-reported pain relief measured using validated pain scales (i.e. Numerical Rating Scale [NmRS],²^,¹⁴^–¹⁷ Visual Analogue Scale [VAS],²^,¹⁶^,¹⁷ Neuropathic Pain Scale [NPS],²^,¹⁴^–¹⁶ Pain Disability Index [PDI],²^,¹⁴ Brief Pain Inventory [BPI],¹⁵^–¹⁷ and McGill Pain Questionnaire – Short Form [SF-MPQ]²). The rate of adverse events, including serious adverse events, drug-related withdrawals, and frequently reported side effects, was the secondary outcome among all SRs. One SR also attempted to quantify patients’ activities of daily living and quality of life,¹⁶ and another SR measured patients’ level of function as a secondary outcome measure.² The length of follow-up across studies included across all reviews spanned the period from one week to 15 weeks.

The included evidence-based guideline provided recommendations of the differential diagnosis of neuropathic pain, therapeutic options, and presented a clinical practice algorithm. The evidence for different pharmacological pain management options was rated using a grading system developed by the American Academy of Neurology (AAN).¹⁸ Specific criteria were developed based on the type of clinical question (e.g. diagnostic, prognostic, therapeutic) and are used to guide the rating of published evidence into one of four categories based on methodological rigour (Class I to Class IV, with Class I representing the highest quality studies).

Summary of Critical Appraisal

A detailed overview of the strengths and limitations of each included study is presented in Appendix 4.

Systematic Reviews

The included SRs were generally well designed. Namely, all review authors utilized a comprehensive literature search across several electronic databases, and four out of five reviews enforced duplicate article screening and duplicate extraction of data with a consensus procedure in case of disagreements.¹⁴^–¹⁷ A list of included studies and individual study characteristics was provided by four review authors in tabular format,²^,¹⁵^–¹⁷ while the authors of one review described the study characteristics narratively.¹⁴ In addition, the methodological rigour and scientific quality of included studies was assessed across all reviews and were considered appropriately in the analysis and formulation of conclusions in four SRs.²^,¹⁴^,¹⁶^,¹⁷

Despite the application of best practices in the conduct of SRs, there were also some concerns relating to these studies. Namely, while one SR clearly stated that the research questions posed and inclusion criteria used were established a priori and referenced a study protocol,¹⁶ it was unclear whether the authors of four SRs²^,¹⁴^,¹⁵^,¹⁷ pre-defined the published research objectives or developed a review protocol in order to avoid bias in selecting studies during the review process. Furthermore, in three SRs where data were not statistically combined in a meta-analysis,²^,¹⁴^,¹⁵ one of three reviews justified the decision to not statistically pool the results.² While the authors of one review calculated pooled effect sizes when data from three or more studies were available, the appropriateness of combining results based on consideration for between- and within-study variation (statistical and clinical heterogeneity) was not described.¹⁷ Finally, while the review authors’ potential conflicts of interest were clearly acknowledged in all SRs, sources of funding of included studies were not described in four of five reviews.²^,¹⁴^–¹⁶ The likelihood of publication bias was not assessed in any of the included SRs.

Guidelines

Methodological quality of the included evidence-based guideline was evaluated using the AGREE-II instrument.¹³ The quality of this guideline document is strengthened by the inclusion of a clear description of the objective and its intended users, the use of a systematic search in identifying published evidence to support recommendations, as well as consideration for health benefits, adverse effects, and risks in formulating recommendations, and guidance on how the recommendations can be put into practice. Nevertheless, reporting regarding the process of guideline development was unclear; namely, while a systematic search of the literature was conducted, the use of systematic methods in reviewing the published evidence was not clearly reported, and it was unclear whether stakeholder involvement considered the views and preferences of patient representatives. In addition, it was unclear whether the guideline was externally reviewed by experts prior to publication, and the guideline does not describe facilitators and barriers to its application. Finally, while the competing interests of the guideline authors were disclosed, it remains unclear whether the views of the funding body influenced the content of the guideline.

Summary of Findings

What is the clinical effectiveness and safety of delta-9-tetrahydrocannabinol/cannabidiol for the treatment of adult patients with chronic non-cancer pain or neuropathic pain?

The clinical effectiveness and safety of THC:CBD (Sativex^®) for the treatment of chronic neuropathic or non-cancer pain in adults is summarized below based on outcomes relating to patient-related benefits and harms, as reported by the original study authors. A detailed synthesis of the results of each included study is presented in Appendix 5.

Pain relief

Patient-reported pain relief following treatment with THC:CBD in comparison with placebo therapy was reported across all included reviews. In general, the review authors’ conclusions regarding the direction and magnitude of the analgesic effect related to THC:CBD, as compared with placebo, are conflicting. Disagreements between the published reviews are summarized below.

In the SR by Lynch et al.² which evaluated the effect of THC:CBD against placebo in patients with chronic non-cancer pain, the authors reported that findings from five RCTs revealed a statistically significant reduction in pain on validated patient-reported pain measures (i.e. NmRS, VAS, NPS, PDI, SF-MPQ) when comparing THC:CBD with placebo; however, Lynch et al. also found evidence from two RCTs which did not support a statistically significant difference in pain scores between the active treatment and placebo. Nevertheless, the authors concluded that cannabinoids, including THC:CBD, are modestly effective in reducing pain among patients with chronic non-cancer pain. Furthermore, in their updated review,¹⁵ Lynch et al. identified an additional two placebo-controlled RCTs concerning the effect of THC:CBD on chronic non-cancer pain. Despite the lack of a statistically significant reduction in pain observed at the last follow-up in a 14-week RCT cited by the review authors, it was suggested that the updated review adds further support to the available evidence showing that cannabinoids (including THC:CBD) are modestly effective analgesic products for the management of chronic non-cancer pain.

In contrast to the reviews by Lynch et al.,²^,¹⁵ Jawahar et al.¹⁷ drew the conclusion that nabiximols, the main drug class to which THC:CBD belongs, are not effective agents for relieving chronic pain. However, this finding relates specifically to the management of multiple sclerosis patients who are experiencing non-spastic and non-trigeminal neuralgic pain, and the conclusion elicited in this review is based on a pooled effect size derived using data from three placebo-controlled RCTs which did not reach statistical significance for pain reduction.

In the SR by Boychuk et al.¹⁴ which assessed the therapeutic effect of THC:CBD among patients with chronic non-malignant neuropathic pain, the authors identified three 3 placebo-controlled RCTs which found a statistically significant reduction in mean pain intensity following treatment with THC:CBD. However, the review authors also found evidence from two other placebo-controlled RCTs which found no significant difference in pain at the last follow-up between patients treated with THC:CBD and placebo. As a result, Boychuk et al. concluded that THC:CBD may provide an effective analgesic effect in chronic neuropathic pain conditions that are unresponsive to other treatments.

Whiting et al.¹⁶ statistically combined the results from a number of placebo-controlled RCTs relating to the effect of THC:CBD in alleviating chronic pain resulting from malignant and non-malignant causes. While the authors found that the average number of patients reporting a 30% or greater reduction in pain was greater with cannabinoids (THC and THC:CBD), the results of the pooled analyses were not statistically significant. Given that the pooled analysis was conducted using one RCT evaluating the effectiveness of THC alone and two RCTs conducted among cancer patients in addition to five RCTs relating to the use of THC:CBD for non-cancer pain, the pooled analgesic effect of THC:CBD for non-cancer pain was not reported. The authors concluded that there was moderate quality evidence supporting the use of cannabinoids in the management of chronic pain.

Adverse events

The rate of adverse events following treatment with THC:CBD, as compared with placebo, was reported across all included SRs. Similarly to findings regarding the effect of THC:CBD in alleviating chronic neuropathic and non-cancer pain, evidence regarding the comparative safety of THC:CBD in patients experiencing chronic pain is not consistent across all included SRs. Inconsistencies in the published literature are summarized below.

Based on the SR and updated review by Lynch et al.,²^,¹⁵ the authors drew the conclusion that cannabinoids, and THC:CBD in particular, are a safe treatment option for chronic non-cancer (mainly neuropathic) pain. This conclusion was made on the basis of no serious (life-threatening) adverse events observed across all RCTs included in the initial SR,² and two serious adverse events noted in patients who received THC:CBD in one RCT identified in the updated review.¹⁵ While the authors listed a number of common drug-related adverse events reported in the published RCTs, these adverse events were considered to be minor in nature and did not impact the authors’ conclusions regarding the safety of THC:CBD. Similarly to the conclusions made by Lynch et al., Boychuk et al.¹⁴ found that very few risks were associated with the use of cannabinoid products such as THC:CBD in the treatment of chronic neuropathic pain. The authors drew this conclusion based on a review of five placebo-controlled RCTs relating to THC:CBD, three of which suggested an increased incidence of mouth ulcers, dysgeusia (alteration in taste), and sore throat following use of THC:CBD oromucosal spray. Much like Lynch et al., Boychuk et al. did not consider the observed adverse event to be major.

In contrast to these SRs, Whiting et al.¹⁶ combined data on adverse events in a meta-analysis and drew the conclusion that cannabinoids were associated with an increased risk of short-term adverse events. However, this conclusion was made based on the pooling of studies on different types of cannabinoid products across several clinical conditions. Pooled effect size estimates relating to adverse events among patients receiving THC:CBD in the treatment of chronic neuropathic or non-cancer pain were not reported separately; therefore, the pooled effect of THC:CBD on the rate of adverse events in not clear. Nevertheless, when examining the individual effect sizes of RCTs evaluating the safety of THC:CBD in patients with chronic non-cancer pain, more adverse events were associated with the use of THC:CBD than placebo. The findings from this meta-analysis warrant further study.

While the review by Jawahar et al.¹⁷ made no specific conclusion regarding the comparative safety of THC:CBD observed across the included studies in the review, the most frequently reported adverse event in patients treated with THC:CBD was dizziness, followed by drowsiness or fatigue, vertigo, and headaches. This finding was reflected in across the other four SRs selected for inclusion in this report.

What are the evidence-based guidelines relating to the use of delta-9-tetrahydrocannabinol/cannabidiol for adult patients with chronic non-cancer pain or neuropathic pain?

The evidence-based guideline by Moulin et al.,¹⁸ produced in support with the Canadian Pain Society, recommends that cannabinoids, including THC:CBD, be used as third-line agents in the management of chronic neuropathic pain, following non-response to antidepressant or anticonvulsant agents (first-line therapy), or opioid products (second-line therapy). This recommendation was made based on the SR by Lynch et al.², which assessed the effectiveness of smoked cannabis, THC:CBD buccal spray, and synthetic cannabinoids in comparison with placebo.

Evidence-based guidelines for the management of patients with other chronic non-cancer pain in the Canadian context were not identified in the published literature.

Limitations

The SRs and meta-analysis included in this report appeared well designed and addressed the research questions posted. However, certain factors related to these reviews, as well as the published literature which informed the study conclusions, may limit a clear interpretation of the results and their applicability to the Canadian setting. Most notably, variation in the number, quality, and types of RCTs, as well as the different pain conditions assessed, reduces the comparability of findings across the published reviews in order to inform the true analgesic effect and safety of THC:CBD buccal spray for the pain conditions of interest in this report. Furthermore, reliance on placebo-controlled RCTs across all included reviews may be of limited utility to clinical practice given that the effectiveness of THC:CBD buccal spray is likely to be routinely used alongside other active pharmacotherapies. Although all review authors performed an assessment of the scientific quality of clinical studies selected for inclusion, the use of simplistic (4-item) quality assessment scales in two included SRs may be problematic as this tool may not permit a thorough evaluation of all relevant aspects related to a study’s scientific quality; in addition, too much emphasis may be placed on items such as blinding, and this tool may be susceptive to poor consistency between different raters. This may subsequently impact the formulation of study conclusions.

The selected guideline recommendations were supported by published clinical evidence; however, there is uncertainty relating to the methodological rigour and stakeholder involvement in the guideline development process. The applicability of this guideline to clinical practice may be limited owing to the lack of high-quality evidence supporting the specified recommendations, particularly relating to the use of THC:CBD buccal spray for alleviating chronic non-cancer pain.

Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner.

Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

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Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Sep 21. SUMMARY OF EVIDENCE.
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Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet].

SUMMARY OF EVIDENCE

Quantity of Research Available

Summary of Study Characteristics

Study Design

Country of Origin

Patient Population

Interventions and Comparators

Outcomes

Summary of Critical Appraisal

Systematic Reviews

Guidelines

Summary of Findings

What is the clinical effectiveness and safety of delta-9-tetrahydrocannabinol/cannabidiol for the treatment of adult patients with chronic non-cancer pain or neuropathic pain?

Pain relief

Adverse events

What are the evidence-based guidelines relating to the use of delta-9-tetrahydrocannabinol/cannabidiol for adult patients with chronic non-cancer pain or neuropathic pain?

Limitations

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