Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
TL;DR: A systematic review and meta-analysis of all randomized controlled trials of Cannabis-based medicines suggests that CBMs might be effective for chronic pain treatment, based on limited evidence, primarily for neuropathic pain patients.
Abstract: BACKGROUND The management of chronic pain is a complex challenge worldwide. Cannabis-based medicines (CBMs) have proven to be efficient in reducing chronic pain, although the topic remains highly controversial in this field. OBJECTIVES This study's aim is to conduct a conclusive review and meta-analysis, which incorporates all randomized controlled trials (RCTs) in order to update clinicians' and researchers' knowledge regarding the efficacy and adverse events (AEs) of CBMs for chronic and postoperative pain treatment. STUDY DESIGN A systematic review and meta-analysis. METHODS An electronic search was conducted using Medline/Pubmed and Google Scholar with the use of Medical Subject Heading (MeSH) terms on all literature published up to July 2015. A follow-up manual search was conducted and included a complete cross-check of the relevant studies. The included studies were RCTs which compared the analgesic effects of CBMs to placebo. Hedges's g scores were calculated for each of the studies. A study quality assessment was performed utilizing the Jadad scale. A meta-analysis was performed utilizing random-effects models and heterogeneity between studies was statistically computed using I² statistic and tau² test. RESULTS The results of 43 RCTs (a total of 2,437 patients) were included in this review, of which 24 RCTs (a total of 1,334 patients) were eligible for meta-analysis. This analysis showed limited evidence showing more pain reduction in chronic pain -0.61 (-0.78 to -0.43, P < 0.0001), especially by inhalation -0.93 (-1.51 to -0.35, P = 0.001) compared to placebo. Moreover, even though this review consisted of some RCTs that showed a clinically significant improvement with a decrease of pain scores of 2 points or more, 30% or 50% or more, the majority of the studies did not show an effect. Consequently, although the primary analysis showed that the results were favorable to CBMs over placebo, the clinical significance of these findings is uncertain. The most prominent AEs were related to the central nervous and the gastrointestinal (GI) systems. LIMITATIONS Publication limitation could have been present due to the inclusion of English-only published studies. Additionally, the included studies were extremely heterogeneous. Only 7 studies reported on the patients' history of prior consumption of CBMs. Furthermore, since cannabinoids are surrounded by considerable controversy in the media and society, cannabinoids have marked effects, so that inadequate blinding of the placebo could constitute an important source of limitation in these types of studies. CONCLUSIONS The current systematic review suggests that CBMs might be effective for chronic pain treatment, based on limited evidence, primarily for neuropathic pain (NP) patients. Additionally, GI AEs occurred more frequently when CBMs were administered via oral/oromucosal routes than by inhalation.Key words: Cannabis, CBMs, chronic pain, postoperative pain, review, meta-analysis.
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TL;DR: It seems unlikely that cannabinoids are highly effective medicines for CNCP, as effects suggest that number needed to treat to benefit is high, and number neededto treat to harm is low, with limited impact on other domains.
Abstract: This review examines evidence for the effectiveness of cannabinoids in chronic noncancer pain (CNCP) and addresses gaps in the literature by: considering differences in outcomes based on cannabinoid type and specific CNCP condition; including all study designs; and following IMMPACT guidelines. MEDLINE, Embase, PsycINFO, CENTRAL, and clinicaltrials.gov were searched in July 2017. Analyses were conducted using Revman 5.3 and Stata 15.0. A total of 91 publications containing 104 studies were eligible (n = 9958 participants), including 47 randomised controlled trials (RCTs) and 57 observational studies. Forty-eight studies examined neuropathic pain, 7 studies examined fibromyalgia, 1 rheumatoid arthritis, and 48 other CNCP (13 multiple sclerosis-related pain, 6 visceral pain, and 29 samples with mixed or undefined CNCP). Across RCTs, pooled event rates (PERs) for 30% reduction in pain were 29.0% (cannabinoids) vs 25.9% (placebo); significant effect for cannabinoids was found; number needed to treat to benefit was 24 (95% confidence interval [CI] 15-61); for 50% reduction in pain, PERs were 18.2% vs 14.4%; no significant difference was observed. Pooled change in pain intensity (standardised mean difference: -0.14, 95% CI -0.20 to -0.08) was equivalent to a 3 mm reduction on a 100 mm visual analogue scale greater than placebo groups. In RCTs, PERs for all-cause adverse events were 81.2% vs 66.2%; number needed to treat to harm: 6 (95% CI 5-8). There were no significant impacts on physical or emotional functioning, and low-quality evidence of improved sleep and patient global impression of change. Evidence for effectiveness of cannabinoids in CNCP is limited. Effects suggest that number needed to treat to benefit is high, and number needed to treat to harm is low, with limited impact on other domains. It seems unlikely that cannabinoids are highly effective medicines for CNCP.
301 citations
TL;DR: Different clinical aspects of fibromyalgia are outlined, including the burden, diagnosis and treatment of this condition, and various hypotheses of fibroitalgia etiopathogenesis are discussed.
Abstract: Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia are still debated and, consequently, so are the strategies for treating this condition. Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome. Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional-cognitive factors, the mind-body relationship and a biopsychological ability to cope with stress. The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals.
213 citations
TL;DR: This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment.
Abstract: There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.
171 citations
05 Sep 2018
TL;DR: This guide to treatments for low back pain, fibromyalgia, and tension headache can be helpful in finding the right treatment for individual patients.
Abstract: Objectives Many interventions are available to manage chronic pain; understanding the durability of treatment effects may assist with treatment selection. We sought to assess which noninvasive nonpharmacological treatments for selected chronic pain conditions are associated with persistent improvement in function and pain outcomes at least 1 month after the completion of treatment. Data sources Electronic databases (Ovid MEDLINE®, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews) through November 2017, reference lists, and ClinicalTrials.gov . Review methods Using predefined criteria, we selected randomized controlled trials of noninvasive nonpharmacological treatments for five common chronic pain conditions (chronic low back pain; chronic neck pain; osteoarthritis of the knee, hip, or hand; fibromyalgia; and tension headache) that addressed efficacy or harms compared with usual care, no treatment, waitlist, placebo, or sham intervention; compared with pharmacological therapy; or compared with exercise. Study quality was assessed, data extracted, and results summarized for function and pain. Only trials reporting results for at least 1 month post-intervention were included. We focused on the persistence of effects at short term (1 to Results Two hundred eighteen publications (202 trials) were included. Many included trials were small. Evidence on outcomes beyond 1 year after treatment completion was sparse. Most trials enrolled patients with moderate baseline pain intensity (e.g., >5 on a 0 to 10 point numeric rating scale) and duration of symptoms ranging from 3 months to >15 years. The most common comparison was against usual care. Chronic low back pain : At short term, massage, yoga, and psychological therapies (primarily CBT) (strength of evidence [SOE]: moderate) and exercise, acupuncture, spinal manipulation, and multidisciplinary rehabilitation (SOE: low) were associated with slight improvements in function compared with usual care or inactive controls. Except for spinal manipulation, these interventions also improved pain. Effects on intermediate-term function were sustained for yoga, spinal manipulation, multidisciplinary rehabilitation (SOE: low), and psychological therapies (SOE: moderate). Improvements in pain continued into intermediate term for exercise, massage, and yoga (moderate effect, SOE: low); mindfulness-based stress reduction (small effect, SOE: low); spinal manipulation, psychological therapies, and multidisciplinary rehabilitation (small effects, SOE: moderate). For acupuncture, there was no difference in pain at intermediate term, but a slight improvement at long term (SOE: low). Psychological therapies were associated with slightly greater improvement than usual care or an attention control on both function and pain at short-term, intermediate-term, and long-term followup (SOE: moderate). At short and intermediate term, multidisciplinary rehabilitation slightly improved pain compared with exercise (SOE: moderate). High-intensity multidisciplinary rehabilitation (≥20 hours/week or >80 hours total) was not clearly better than non–high-intensity programs. Chronic neck pain : At short and intermediate terms, acupuncture and Alexander Technique were associated with slightly improved function compared with usual care (both interventions), sham acupuncture, or sham laser (SOE: low), but no improvement in pain was seen at any time (SOE: llow). Short-term low-level laser therapy was associated with moderate improvement in function and pain (SOE: moderate). Combination exercise (any 3 of the following: muscle performance, mobility, muscle re-education, aerobic) demonstrated a slight improvement in pain and function short and long term (SOE: low). Osteoarthritis : For knee osteoarthritis, exercise and ultrasound demonstrated small short-term improvements in function compared with usual care, an attention control, or sham procedure (SOE: moderate for exercise, low for ultrasound), which persisted into the intermediate term only for exercise (SOE: low). Exercise was also associated with moderate improvement in pain (SOE: low). Long term, the small improvement in function seen with exercise persisted, but there was no clear effect on pain (SOE: low). Evidence was sparse on interventions for hip and hand osteoarthritis. Exercise for hip osteoarthritis was associated with slightly greater function and pain improvement than usual care short term (SOE: low). The effect on function was sustained intermediate term (SOE: low). Fibromyalgia : In the short term, acupuncture (SOE: moderate), CBT, tai chi, qigong, and exercise (SOE: low) were associated with slight improvements in function compared with an attention control, sham, no treatment, or usual care. Exercise (SOE: moderate) and CBT improved pain slightly, and tai chi and qigong (SOE: low) improved pain moderately in the short term. At intermediate term for exercise (SOE: moderate), acupuncture, and CBT (SOE: low), slight functional improvements persisted; they were also seen for myofascial release massage and multidisciplinary rehabilitation (SOE: low); pain was improved slightly with multidisciplinary rehabilitation in the intermediate term (SOE: low). In the long term, small improvements in function continued for multidisciplinary rehabilitation but not for exercise or massage (SOE: low for all); massage (SOE: low) improved long-term pain slightly, but no clear impact on pain for exercise (SOE: moderate) or multidisciplinary rehabilitation (SOE: low) was seen. Short-term CBT was associated with a slight improvement in function but not pain compared with pregabalin. Chronic tension headache : Evidence was sparse and the majority of trials were of poor quality. Spinal manipulation slightly improved function and moderately improved pain short term versus usual care, and laser acupuncture was associated with slight pain improvement short term compared with sham (SOE: low). There was no evidence suggesting increased risk for serious treatment-related harms for any of the interventions, although data on harms were limited. Conclusions Exercise, multidisciplinary rehabilitation, acupuncture, CBT, and mind-body practices were most consistently associated with durable slight to moderate improvements in function and pain for specific chronic pain conditions. Our findings provided some support for clinical strategies that focused on use of nonpharmacological therapies for specific chronic pain conditions. Additional comparative research on sustainability of effects beyond the immediate post-treatment period is needed, particularly for conditions other than low back pain.
160 citations
TL;DR: The quantity and quality of evidence are such that cannabis‐based medicines may be reasonably considered for chronic neuropathic pain and all other chronic pain conditions (cancer, non‐neuropathic noncancer pain).
156 citations
References
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TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
45,105 citations
"Efficacy of Cannabis-Based Medicine..." refers methods in this paper
...Heterogeneity between studies was statistically studied using the I2 statistic and Tau2 tests (98)....
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TL;DR: A structured summary is provided including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings.
31,379 citations
"Efficacy of Cannabis-Based Medicine..." refers methods in this paper
...METHODS Information Sources The study was conducted according to the PRISMA statement (83)....
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Journal Article•
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TL;DR: An instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research is described and its use to determine the effect of rater blinding on the assessments of quality is described.
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"Efficacy of Cannabis-Based Medicine..." refers background or result in this paper
...Even though the studies were not required to have a quality threshold level other than the preexisting inclusion criteria, their validity was assessed by the Jadad scale (84)....
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...To conclude our findings, according to the Jadad scale (84), 10 studies received a “5” score, showing high quality evidence....
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TL;DR: In this article, a large-scale computer-assisted telephone survey was conducted to explore the prevalence, severity, treatment and impact of chronic pain in 15 European countries and Israel and found that chronic pain is a major health care problem in Europe that needs to be taken more seriously.
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