Importance Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. Objective To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. Data Sources Twenty-eight databases from inception to April 2015. Study Selection Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. Data Extraction and Synthesis Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. Main Outcomes and Measures Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. Results A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. Conclusions and Relevance There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

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Cannabinoids for Medical Use: A Systematic Review and Meta-analysis.

Background and objectives:  This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005.

Methods:  Studies were identified using the Cochrane Database and Medline. Trials were classified according to the aetiological condition. All class I and II randomized controlled trials (RCTs) were assessed; lower class studies were considered only in conditions that had no top-level studies. Treatments administered using repeated or single administrations were considered, provided they are feasible in an outpatient setting.

Results:  Most large RCTs included patients with diabetic polyneuropathies and post-herpetic neuralgia, while an increasing number of smaller studies explored other conditions. Drugs generally have similar efficacy in various conditions, except in trigeminal neuralgia, chronic radiculopathy and HIV neuropathy, with level A evidence in support of tricyclic antidepressants (TCA), pregabalin, gabapentin, tramadol and opioids (in various conditions), duloxetine, venlafaxine, topical lidocaine and capsaicin patches (in restricted conditions). Combination therapy appears useful for TCA-gabapentin and gabapentin-opioids (level A).

Conclusions:  There are still too few large-scale comparative studies. For future trials, we recommend to assess comorbidities, quality of life, symptoms and signs with standardized tools and attempt to better define responder profiles to specific drug treatments.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1468-1331.2010.02999.x

EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision

Background and objectives: This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005. Methods: Studies were identified using the Cochrane Database and Medline. Trials were classified according to the aetiological condition. All class I and II randomized controlled trials (RCTs) were assessed; lower class studies were considered only in conditions that had no top-level studies. Treatments administered using repeated or single administrations were considered, provided they are feasible in an outpatient setting. Results: Most large RCTs included patients with diabetic polyneuropathies and postherpetic neuralgia, while an increasing number of smaller studies explored other conditions. Drugs generally have similar e!cacy in various conditions, except in trigeminal neuralgia, chronic radiculopathy and HIV neuropathy, with level A evidence in support of tricyclic antidepressants (TCA), pregabalin, gabapentin, tramadol and opioids (in various conditions), duloxetine, venlafaxine, topical lidocaine and capsaicin patches (in restricted conditions). Combination therapy appears useful for TCAgabapentin and gabapentin-opioids (level A). Conclusions: There are still too few large-scale comparative studies. For future trials, we recommend to assess comorbidities, quality of life, symptoms and signs with standardized tools and attempt to better define responder profiles to specific drug treatments.

EFNS guidelines on the pharmacological treatment of neuropathic pain: 2009 revision

Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.

The evidence for pharmacological treatment of neuropathic pain

Recent years have seen a rapid rise in the medical and recreational use of cannabis: a broad term that can be used to describe the various products and chemical compounds (e.g., marijuana, cannabinoids) derived from different species of the cannabis plant. Despite increased cannabis use and a changing state-level policy landscape, conclusive evidence regarding the shortand long-term health effects—both harms and benefits—of cannabis use remains elusive.

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The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

Objective: To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model. Methods: Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV- associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving 30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model. Results: Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR 71, 16) vs 17% (IQR 29, 8) with placebo (p 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported. Conclusion: Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.

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Cannabis in painful HIV-associated sensory neuropathy A randomized placebo-controlled trial

Although cannabis may have potential therapeutic value, inhalation of a combustion product is an undesirable delivery system. The aim of the study was to investigate vaporization using the Volcano® device as an alternative means of delivery of inhaled Cannabis sativa. Eighteen healthy inpatient subjects enrolled to compare the delivery of cannabinoids by vaporization to marijuana smoked in a standard cigarette. One strength (1.7, 3.4, or 6.8% tetrahydrocannabinol (THC)) and delivery system was randomly assigned for each of the 6 study days. Plasma concentrations of Δ-9-THC, expired carbon monoxide (CO), physiologic and neuropsychologic effects were the main outcome measures. Peak plasma concentrations and 6-h area under the plasma concentration–time curve of THC were similar. CO levels were reduced with vaporization. No adverse events occurred. Vaporization of cannabis is a safe and effective mode of delivery of THC. Further trials of clinical effectiveness of cannabis could utilize vaporization as a smokeless delivery system.

Clinical Pharmacology & Therapeutics (2007) 82, 572–578; doi:10.1038/sj.clpt.6100200; published online 11 April 2007

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C. A. Jay

Papers

Cannabis in painful HIV-associated sensory neuropathy A randomized placebo-controlled trial

Vaporization as a smokeless cannabis delivery system: a pilot study.

Cannabis in painful HIV-associated sensory neuropathy