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A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment
Abstract
Peripheral neuropathic pain (PNP) associated with allodynia poses a significant clinical challenge. The efficacy of Δ(9) -tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray, a novel cannabinoid formulation, was investigated in this 15-week randomized, double-blind, placebo-controlled parallel group study.
In total, 303 patients with PNP associated with allodynia were screened; 128 were randomized to THC/CBD spray and 118 to placebo, in addition to their current analgesic therapy. The co-primary efficacy endpoints were the 30% responder rate in PNP 0-10 numerical rating scale (NRS) score and the mean change from baseline to the end of treatment in this score. Various key secondary measures of pain and functioning were also investigated.
At the 30% responder level, there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis (intention-to-treat) dataset [p = 0.034; 95% confidence interval (CI): 1.05-3.70]. There was also a reduction in mean PNP 0-10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group, but which failed to reach statistical significance. Secondary measures of sleep quality 0-10 NRS score (p = 0.0072) and Subject Global Impression of Change (SGIC) (p = 0.023) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment.
These findings demonstrate that, in a meaningful proportion of otherwise treatment-resistant patients, clinically important improvements in pain, sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray. THC/CBD spray was well tolerated and no new safety concerns were identified.
... High certainty evidence from 12 RCTs (1777 patients) [24,26,28,30,35,37,38,45,50,55,57,60] shows that cannabinoids probably slightly increase the risk of diarrhea, compared with placebo ...
... Moderate certainty evidence from 7 RCTs (1086 patients) [24,26,30,37,38,55,60] indicates that cannabinoids, compared to placebo, probably slightly increases the risk of disturbance in attention (RD, 2% [95% CI, 0% to 7%]) ( Table 1, Supplementary Figure S6 in Appendix C). ...
... Moderate certainty evidence from 9 RCTs (1538 patients) [24,26,30,32,33,38,43,45,55] showed that medical cannabis or cannabinoids may slightly increase the risk of vomiting (RD, 2% [95% CI, 0% to 6%]) ( Table 1, SupplementaryFigure S7 in Appendix C). ...
Study Objectives
We conducted a systematic review to explore the effectiveness of medical cannabis for impaired sleep.
Methods
We searched MEDLINE, EMBASE, CENTRAL and PsychINFO to January 2021 for randomized trials of medical cannabis or cannabinoids for impaired sleep vs. any non-cannabis control. When possible, we pooled effect estimates for all patient-important sleep-related outcomes and used the GRADE approach to appraise the certainty of evidence.
Results
Thirty-nine trials (5,100 patients) were eligible for review, of which 38 evaluated oral cannabinoids and 1 administered inhaled cannabis. The median follow-up was 35 days, and most trials (33 of 39) enrolled patients living with chronic cancer or noncancer chronic pain. Among patients with chronic pain, moderate certainty evidence found that medical cannabis probably results in a small improvement in sleep quality versus placebo (modeled risk difference [RD] for achieving the minimally important difference [MID], 8% [95% CI, 3 to 12]). Moderate to high certainty evidence shows that medical cannabis vs. placebo results in a small improvement in sleep disturbance for chronic non-cancer pain (modeled RD for achieving the MID, 19% [95% CI, 11 to 28]) and a very small improvement in sleep disturbance for chronic cancer pain (WMD of -0.19cm [95%CI, -0.36 to -0.03cm]; interaction p=0.03). Moderate to high certainty evidence shows medical cannabis, versus placebo, results in a substantial increase in the risk of dizziness (RD 29% [95%CI, 16 to 50], for trials with ≥3 months follow-up), and a small increase in the risk of somnolence, dry mouth, fatigue, and nausea (RDs ranged from 6% to 10%).
Conclusion
Medical cannabis and cannabinoids may improve impaired sleep among people living with chronic pain, but the magnitude of benefit is likely small.
... With the advent of novel cannabinoid formulations, randomized controlled studies of cannabinoids in chronic pain syndromes have been crucial in exploring efficacy of these medications as a therapeutic option for chronic pain. Serpell et al. recently conducted a double-blinded randomized placebo-controlled study of a tetrahydrocannabinol and cannabidiol oromucosal spray in peripheral neuropathic pain associated with allodynia [65]. The study used a pump action oromucosal spray that delivered 2.7 mg of THC and 2.5 mg of CBD with each 100-µL spray. ...
... The median duration of treatment with THC/CBD spray was 78.2 days, vs. 86.4 days with placebo [65]. ...
... With respect to the primary endpoint, a total of 34 patients (28%) in the THC/CBD spray group were classified as responders at the 30% preset level compared with 19 patients (16%) in the placebo group, which was statistically significant with an odds ratio of 1.97 (p = 0.034 95% CI: 1.05-3.70). The co-primary endpoint of change in the PNP 0-10 NRS score was notable for a non-statistically significant mean reduction of −0.34 points (p = 0.14; 95% CI: −0.79 to 0.11 points) and −0.48 points (p = 0.12; 95% CI: −1.08 to 0.12) in favor of the THC/CBD spray treatment [65]. ...
Purpose of Review
The main objective of this review is to appraise the literature on the role of spinal cord stimulation (SCS), cannabinoid therapy, as well as SCS and cannabinoid combination therapy for the management of chronic neuropathic and nociceptive pain. Current research suggests that SCS reduces pain and increases functional status in carefully selected patients with minimal side effects.
Recent Findings
As cannabinoid-based medications become a topic of increasing interest in pain management, data remains limited regarding the clinical efficacy of cannabinoids for pain relief. Furthermore, from a mechanistic perspective, although various pain treatment modalities utilize overlapping pain-signaling pathways, clarifying whether cannabinoids work synergistically with SCS via shared mechanisms remains to be determined. In considering secondary outcomes, the current literature suggests cannabinoids improve quality of life, specifically sleep quality, and that SCS decreases opioid consumption, increases functional capacity, and decreases long-term healthcare costs.
Summary
These findings, along with the high safety profiles of SCS and cannabinoids overall, incentivize further exploration of cannabinoids as an adjunctive therapy to SCS in the treatment of neuropathic and nociceptive pain.
... 14 NBX has also been investigated for treatment of neuropathic pain. Superior analgesic effects compared with placebo were demonstrated in randomized clinical trials (RCTs) [15][16][17][18][19] and in a large observational study. 20 A recent meta-analysis of nine RCTs involving 1289 participants concluded that NBX was superior to placebo in reducing chronic neuropathic pain, with a small but significant effect size. ...
... 25 Elsewhere, a 16-week placebo-controlled RCT in 240 MS patients with central neuropathic pain found no significant difference in pain intensity reduction from baseline between DRO (-1.92 points) and placebo (-1.81 points). 26 Our findings suggest that THC has a role in neuropathic pain as previously [15][16][17][18][19] Formulation appears to be key to patients benefitting from the synergy between THC and CBD, and possibly other phytotherapeutic substances (eg terpenoids) found in the Cannabis sativa plant. 42 A higher proportion of patients discontinued treatment with DRO than NBX (39.8% vs 23.7%), mainly due to TRAEs (14.8% vs 5.9%), which occurred most frequently in the SOCs of general disorders and administration site conditions, nervous system disorders and psychiatric disorders. ...
... Common AEs in RCTs of NBX in neuropathic pain were dizziness, dysgeusia, nausea, fatigue, dry mouth and somnolence, especially during the first few weeks of treatment. [15][16][17][18][19] The current European approved label lists dizziness (nervous system disorder) and fatigue (general disorder) as very common adverse drug reactions (ADRs; frequency ≥ 1/10) with possible causality to NBX. 14 In a RCT of DRO in 240 patients with neuropathic pain, common ADRs were dizziness, vertigo, fatigue, and dry mouth, occurring most often in the initial 4 weeks of treatment during up-titration to the maximum tolerable dose. 26 The FDA's Prescribing Information for DRO lists dizziness, euphoria, paranoid reaction, somnolence, thinking abnormal, abdominal pain, nausea and vomiting as the most common ADRs. ...
Purpose:
To compare the effectiveness and tolerability of add-on treatment with nabiximols (NBX: delta-9-tetrahydrocannabinol: cannabidiol) oromucosal spray or oral dronabinol (DRO: synthetic tetrahydrocannabinol) in patients with severe neuropathic pain poorly responsive to established treatments.
Methods:
An analysis was conducted of anonymized, propensity score-matched real-world data from the German Pain e-Registry, using a sequential non-inferiority superiority approach, for adult outpatients with neuropathic pain who had initiated treatment with NBX or DRO between 10 March 2017 and 31 December 2019. The primary effectiveness variable was percent change from baseline in a 9-factor aggregated symptom relief (ASR-9) score, a composite index of nine distinct pain- and health-related parameters assessed using validated patient-reported instruments. Safety was assessed by the incidence of physician-confirmed treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation.
Results:
Propensity score-matched data were analyzed for 337 patients treated with NBX and 337 patients treated with DRO. Mean (standard deviation) THC dose over the 24-week evaluation period was 16.6 (6.5) mg for NBX and 17.2 (7.6) mg for DRO (p<0.001). Median (standard error) improvement relative to baseline in the ASR-9 composite score was 55.4% (0.5) for NBX and 40.5% (0.5) for DRO (least squares mean difference, 14.0 (0.7), 95% confidence interval 12.6-15.4; p<0.001), and incidences of TRAEs (21.1 vs 35%) and TRAE-related discontinuations (5.9 vs 14.8%) were significantly lower with NBX than DRO (p<0.001 for both), collectively indicating pre-specified non-inferiority and superiority of NBX. More NBX- than DRO-treated patients discontinued non-cannabinoid background pain medications and rescue analgesics, especially opioid analgesics (p<0.001 for both).
Conclusion:
Add-on treatment with cannabinoids is effective for treatment of severe neuropathic pain with inadequate response to established treatments. In daily practice, NBX had superior effectiveness and tolerability compared to DRO. The results emphasize the importance of combining CBD with THC in this patient population.
... Seventeen references were included in the qualitative analysis [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63], as shown in Table 2. Four studies followed an RCT parallel design [50,58,61,63], and 13 studies followed a crossover design [47,48,59,60,62,49,51 -57]. ...
... Seventeen references were included in the qualitative analysis [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63], as shown in Table 2. Four studies followed an RCT parallel design [50,58,61,63], and 13 studies followed a crossover design [47,48,59,60,62,49,51 -57]. ...
... • Two studies reported mechanical allodynia and at least one of the following: radiculopathy, complex regional pain syndrome (CRPS) type 2, post-herpetic neuralgia (PHN), and peripheral neuropathy [47,61]. ...
Background:
Chronic neuropathic pain (NP) presents therapeutic challenges. Interest in the use of cannabis-based medications has outpaced the knowledge of its efficacy and safety in treating NP. The objective of this review was to evaluate the effectiveness of cannabis-based medications in individuals with chronic NP.
Methods:
Randomized placebo-controlled trials using tetrahydrocannabinol (THC), cannabidiol (CBD), cannabidivarin (CBDV), or synthetic cannabinoids for NP treatment were included. The MEDLINE, Cochrane Library, EMBASE, and Web of Science databases were examined. The primary outcome was the NP intensity. The risk of bias analysis was based on the Cochrane handbook.
Results:
The search of databases up to 2/1/2021 yielded 379 records with 17 RCTs included (861 patients with NP). Meta-analysis showed that there was a significant reduction in pain intensity for THC/CBD by -6.624 units (P < .001), THC by -8.681 units (P < .001), and dronabinol by -6.0 units (P = .008) compared to placebo on a 0-100 scale. CBD, CBDV, and CT-3 showed no significant differences. Patients taking THC/CBD were 1.756 times more likely to achieve a 30% reduction in pain (P = .008) and 1.422 times more likely to achieve a 50% reduction (P = .37) than placebo. Patients receiving THC had a 21% higher improvement in pain intensity (P = .005) and were 1.855 times more likely to achieve a 30% reduction in pain than placebo (P < .001).
Conclusion:
Although THC and THC/CBD interventions provided a significant improvement in pain intensity and were more likely to provide a 30% reduction in pain, the evidence was of moderate-to-low quality. Further research is needed for CBD, dronabinol, CT-3, and CBDV.
... Most of the trials included in the meta-analysis were conducted in the United Kingdom (16 out of 36, 44%), [23][24][25][26][27]34,[38][39][40][41]43,44,50,51,56,57 followed by Canada (7 out of 36, 19%), 34,44,45,47,48,52,55 the Czech Republic (5 out of 36, 14%), 27,34,37,39,44 the United States (4 out of 36, 11%), 22,28,30,36 the Netherlands (3 out of 36, 8%), 29,33,49 Austria (2 out of 36, 6%), 37,54 Belgium (2 out of 36, 6%), 30,44 Spain (2 out of 36, 6%), 34,39 Switzerland (2 out of 36, 6%), 31,53 Italy (2 out of 36, 6%), 35,39 and Germany (2 out of 36, 6%), 32,42 with the remaining countries (Denmark, 46 France, 34 Poland, 39 and Romania) 44 contributing participants to 1 study each. Of the included studies, 6 trials recruited patients from more than 1 country (range: 2-5 countries). ...
... Most of the trials included in the meta-analysis were conducted in the United Kingdom (16 out of 36, 44%), [23][24][25][26][27]34,[38][39][40][41]43,44,50,51,56,57 followed by Canada (7 out of 36, 19%), 34,44,45,47,48,52,55 the Czech Republic (5 out of 36, 14%), 27,34,37,39,44 the United States (4 out of 36, 11%), 22,28,30,36 the Netherlands (3 out of 36, 8%), 29,33,49 Austria (2 out of 36, 6%), 37,54 Belgium (2 out of 36, 6%), 30,44 Spain (2 out of 36, 6%), 34,39 Switzerland (2 out of 36, 6%), 31,53 Italy (2 out of 36, 6%), 35,39 and Germany (2 out of 36, 6%), 32,42 with the remaining countries (Denmark, 46 France, 34 Poland, 39 and Romania) 44 contributing participants to 1 study each. Of the included studies, 6 trials recruited patients from more than 1 country (range: 2-5 countries). ...
... Most of the trials included in the meta-analysis were conducted in the United Kingdom (16 out of 36, 44%), [23][24][25][26][27]34,[38][39][40][41]43,44,50,51,56,57 followed by Canada (7 out of 36, 19%), 34,44,45,47,48,52,55 the Czech Republic (5 out of 36, 14%), 27,34,37,39,44 the United States (4 out of 36, 11%), 22,28,30,36 the Netherlands (3 out of 36, 8%), 29,33,49 Austria (2 out of 36, 6%), 37,54 Belgium (2 out of 36, 6%), 30,44 Spain (2 out of 36, 6%), 34,39 Switzerland (2 out of 36, 6%), 31,53 Italy (2 out of 36, 6%), 35,39 and Germany (2 out of 36, 6%), 32,42 with the remaining countries (Denmark, 46 France, 34 Poland, 39 and Romania) 44 contributing participants to 1 study each. Of the included studies, 6 trials recruited patients from more than 1 country (range: 2-5 countries). ...
Background
For patients with chronic, non-cancer pain, traditional pain-relieving medications include opioids, which have shown benefits but are associated with increased risks of addiction and adverse effects. Medical cannabis has emerged as a treatment alternative for managing these patients and there has been a rise in the number of randomized clinical trials in recent years; therefore, a systematic review of the evidence was warranted.
Objective
To analyze the evidence surrounding the benefits and harms of medical cannabinoids in the treatment of chronic, non-cancer-related pain.
Design
Systematic review with meta-analysis.
Data sources
Medline, Embase, CINAHL, SCOPUS, Google Scholar, and Cochrane Databases.
Eligibility criteria
English language randomized clinical trials of cannabinoids for the treatment of chronic, non-cancer-related pain.
Data extraction and synthesis
Study quality was assessed using the Cochrane risk of bias tool. All stages were conducted independently by a team of 6 reviewers. Data were pooled through meta-analysis with different durations of treatment (2 weeks, 2 months, 6 months) and stratified by route of administration (smoked, oromucosal, oral), conditions, and type of cannabinoids.
Main outcomes and measures
Patient-reported pain and adverse events (AEs).
Results
Thirty-six trials (4006 participants) were included, examining smoked cannabis (4 trials), oromucosal cannabis sprays (14 trials), and oral cannabinoids (18 trials). Compared with placebo, cannabinoids showed a significant reduction in pain which was greatest with treatment duration of 2 to 8 weeks (weighted mean difference on a 0-10 pain visual analogue scale −0.68, 95% confidence interval [CI], −0.96 to −0.40, I ² = 8%, P < .00001; n = 16 trials). When stratified by route of administration, pain condition, and type of cannabinoids, oral cannabinoids had a larger reduction in pain compared with placebo relative to oromucosal and smoked formulations but the difference was not significant ( P[interaction] > .05 in all the 3 durations of treatment); cannabinoids had a smaller reduction in pain due to multiple sclerosis compared with placebo relative to other neuropathic pain ( P[interaction] = .05) within 2 weeks and the difference was not significant relative to pain due to rheumatic arthritis; nabilone had a greater reduction in pain compared with placebo relative to other types of cannabinoids longer than 2 weeks of treatment but the difference was not significant ( P[interaction] > .05). Serious AEs were rare, and similar across the cannabinoid (74 out of 2176, 3.4%) and placebo groups (53 out of 1640, 3.2%). There was an increased risk of non-serious AEs with cannabinoids compared with placebo.
Conclusions
There was moderate evidence to support cannabinoids in treating chronic, non-cancer pain at 2 weeks. Similar results were observed at later time points, but the confidence in effect is low. There is little evidence that cannabinoids increase the risk of experiencing serious AEs, although non-serious AEs may be common in the short-term period following use.
... 3 Six trials (1484 patients) have reported results for at least 30% pain relief compared with placebo in any pain condition. 33,35,53,57,59,64 The combined effect was a small beneficial effect (RD 0.06, 95% CI 0.01 to 0.12, very low-quality evidence, Analysis 4.1.1). This would be equivalent to an NNTB of 17; the number of patients in nil effect trials required to reduce the effect to a clinically irrelevant NNTB of 20 would be 262. ...
... 59 Twelve studies (2497 patients) reported mean pain change, showing a small benefit (mean difference [MD] 20.34, 95% CI 20.54 to 20.14; very low-quality of evidence, Analysis 4.3.1). 3,17,27,33,35,39,48,49,53,57,59,64 We downgraded this outcome twice for limitations in the design and implementation of available studies and once for unexplained heterogeneity (50%). ...
... We found no difference between treatment and placebo groups (RD 0.03, 95% CI 20.07 to 0.12, low-quality, Analysis 6.1.5). 1,27,53,64 We downgraded once for limitations in the design and implementation of included studies and once for unexplained heterogeneity. Similarly, in 2 trials (193 participants) that reported 50% reduction in pain intensity, we found no difference between treatment and control groups (RD 0.05, 95% CI 20.11 to 0.21, very low-quality, Analysis 5.2.5). ...
Cannabinoids, cannabis, and cannabis-based medicines (CBM) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We assessed methodological quality, scope, and results of systematic reviews of randomised controlled trials of these treatments. Several search strategies sought self-declared systematic reviews. Methodological quality was assessed using both AMSTAR-2 and techniques important for bias reduction in pain studies. Of the 106 articles read, 57 were self-declared systematic reviews, most published since 2010. They included any type of cannabinoid, cannabis, or CBM, at any dose, however administered, in a broad range of pain conditions. No review examined the effects of a particular cannabinoid, at a particular dose, using a particular route of administration, for a particular pain condition, reporting a particular analgesic outcome. Confidence in the results in the systematic reviews using AMSTAR-2 definitions was critically low (41), low (8), moderate (6), or high (2). Few used criteria important for bias reduction in pain. Cochrane reviews typically provided higher confidence; all industry-conflicted reviews provided critically low confidence. Meta-analyses typically pooled widely disparate studies, and, where assessable, were subject to potential publication bias. Systematic reviews with positive or negative recommendation for use of cannabinoids, cannabis, or CBM in pain typically rated critically low or low (24/25 [96%] positive; 10/12 [83%] negative). Current reviews are mostly lacking in quality and cannot provide a basis for decision-making. A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain.
... 59 Twelve studies (2497 patients) reported mean pain change, showing a small benefit (mean difference [MD] 20.34, 95% CI 20.54 to 20.14; very low-quality of evidence, Analysis 4.3.1). 3,17,27,33,35,39,48,49,53,57,59,64 We downgraded this outcome twice for limitations in the design and implementation of available studies and once for unexplained heterogeneity (50%). ...
... We found no difference between treatment and placebo groups (RD 0.03, 95% CI 20.07 to 0.12, low-quality, Analysis 6.1.5). 1,27,53,64 We downgraded once for limitations in the design and implementation of included studies and once for unexplained heterogeneity. Similarly, in 2 trials (193 participants) that reported 50% reduction in pain intensity, we found no difference between treatment and control groups (RD 0.05, 95% ...
... We found no significant change in pain between treatment groups (MD 20.31, 95% CI 20.65 to 0.03, low-quality, Analysis 6.3.3). 1,27,49,53,64 We downgraded this outcome once for limitations in the design and implementation of included studies and once for selective reporting bias. ...
Cannabinoids, cannabis, and cannabis-based medicines (CBMs) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We summarised efficacy and adverse events (AEs) of these types of drugs for treating pain using randomised controlled trials: in people of any age, with any type of pain, and for any treatment duration. Primary outcomes were 30% and 50% reduction in pain intensity, and AEs. We assessed risk of bias of included studies, and the overall quality of evidence using GRADE. Studies of <7 and >7 days treatment duration were analysed separately. We included 36 studies (7217 participants) delivering cannabinoids (8 studies), cannabis (6 studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Evidence of benefit was found for cannabis <7 days (risk difference 0.33, 95% confidence interval 0.20-0.46; 2 trials, 231 patients, very low-quality evidence) and nabiximols >7 days (risk difference 0.06, 95% confidence interval 0.01-0.12; 6 trials, 1484 patients, very low-quality evidence). No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in our primary analyses; 81% of subgroup analyses were negative. Cannabis, nabiximols, and delta-9-tetrahydrocannabinol had more AEs than control. Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.
... Currently, the use of cannabinoids to treat neuropathic pain, and more broadly chronic pain, remains controversial and their medical use remains limited to a few countries in the world, mainly in cancer support care. Among the studies selected in this review, eight studies, involving a total of 537 patients, evaluated tetrahydrocannabidiol (THC)/cannabidiol (CBD) [31][32][33][34], nabilone [35], Cannabis cigarette [36,37] and CT-3 1ʹ,1ʹdimethylheptyl-Δ8-tetrahydrocannabinol-11-oic acid [38] ( Table 2). ...
... Four studies with 222 patients treated with inhaled THC/CBD (2-12 inhalations/day; 27 mg/ml/25 mg/ml, spray of 100 µL; 2.7 mg/2.5 mg, 11 inhalations/day) were conducted over 4 weeks until 15 weeks [31][32][33][34]. They showed that the main TEAEs observed were fatigue (15-43.8%), ...
... However, none of these TEAEs were statistically compared to a placebo. The drop-out rate due to TEAEs was about 18 and 19% in 2 [31,34] of the 4 studies. THC/CBD association was effective (primary endpoint) in two studies [31,34] and not in the two other studies [32,33]. ...
Introduction: Peripheral neuropathic pain is a highly disabling condition for patients and a challenge for physicians. Although many drugs have been assessed in scientific studies, few have demonstrated clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raises the question of the benefit-risk ratio when used in patients experiencing peripheral neuropathies.
Areas covered: We conducted a review of double-blind, placebo-controlled, randomized clinical trials to assess the safety of medications used to treat peripheral neuropathic pain. This second review was focused on opioids, cannabinoids, and other medications. The aim was to provide an overview of the treatment-emergent adverse events (TEAEs) (≥10%) and the serious adverse effects described in clinical trials.
Expert opinion: Opioids and cannabinoids had significantly more TEAEs than placebos. Locally administered analgesics, such as capsaicin, lidocaine, botulinum toxin A seemed to have the most acceptable safety with only local adverse effects. The results for NMDA antagonists were inconclusive since no safety report was available. Less than half of the studies included presented a good description of adverse effects that included a statistical comparison versus a placebo group. Major methodological improvements must be made to ameliorate the assessment of medication safety in future clinical trials.
Keywords: drug-related side effects and adverse reactions; neuropathic pain; peripheral nervous system diseases; randomized controlled trials.
... After screening, de-duplication and exclusion, nine RCTs involving 1,289 patients in total (633 treated with nabiximols, 656 treated with placebo) were included in the meta-analysis, six from the PubMed search and three from the ClinicalTrials.gov search [24][25][26][27][28][29][30][31][32]. ...
... Minor data-set corrections were required for five [25,[28][29][30]32] of the nine included studies, with most revisions identified and applied from ClinicalTrials.gov [41][42][43][44] (Supplementary Table S1). ...
Objective. Pooled analysis of nabiximols and placebo in randomized controlled studies (RCTs) of chronic neuropathic pain.
Design. Systematic review and meta-analysis.
Methods. A systematic literature search was conducted to identify double-blind placebo-controlled RCTs of nabiximols for chronic neuropathic pain. The clinical endpoint of interest was change from baseline in mean pain score on 11-point numerical rating scales. Mean difference (MD) and standardized mean difference (SMD, Hedges’ g) were calculated using fixed effect (FE) and random effects (RE) models. Strength of evidence was assessed using the Cochrane Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. Risk of bias was assessed using the revised Cochrane risk-of-bias tool (RoB 2).
Results. Nine RCTs with 1289 participants were included. Quality of evidence (GRADE) was moderate. One study had a high risk of bias (RoB 2) and five had some concerns. For the pooled endpoint of change from baseline in mean pain score, nabiximols was superior to placebo, with a MD of -0.40 (95% confidence interval [CI]: -0.59 to -0.21; FE, p<0.0001) or -0.44 (95% CI: -0.70 to -0.19; RE, p = 0.0006). A SMD of -0.21 (95% CI: -0.32 to -0.10; FE) or -0.26 (95% CI: -0.42 to -0.10; RE) indicated an incremental benefit over background analgesia. Results in favor of nabiximols were maintained in sensitivity analyses.
Conclusions. Nabiximols was superior to placebo for reduction of chronic neuropathic pain, with a small effect size. Larger RCTs designed to assess the effect of nabiximols in neuropathic pain are required to reach more definitive conclusions.
... However, no change in symptomatic pain via behavioral measures was detected with CB2 agonist treatment. Preclinical studies targeting the cannabinoid system for neuropathic pain relief have since translated to clinical trials with favorable outcomes, as described below [23][24][25]. ...
... Treatment of chronic neuropathic pain has also been studied in a randomized controlled trial, in which 303 patients were randomized to either Sativex (a combination THC/ CBD oromucosal spray) treatment or placebo spray. The treatment arm demonstrated a significant number of patients reporting 30% reduction in pain level as well as improvements in sleep quality over 15 weeks [23]. Similar relief of SN Compr. ...
Cannabis use has increased dramatically in America with recent regulatory policy changes. Despite growing access and prevalence of use of cannabinoids both medically and recreationally, scientific evidence describing its safety and efficacy are limited, especially in the context of treating musculoskeletal pathology. The purpose of this review is to present data evaluating the role of cannabinoids as an adjunct in multimodal pain management, as a modulator in bone metabolism, and as a potential agent in combating the opioid epidemic.
... In contrast, Sativex was effective at providing sustained relief of central neuropathic pain in patients with multiple sclerosis on fixed and self-titrating schedules compared to patients receiving placebo [102,103]. Moreover, Sativex improved pain at targeted responder levels and significantly improved sleep in difficult-to-treat neuropathic pain arising from brachial plexus avulsion and allodynia-characterized neuropathic pain [104,105]. The latter study was followed-up with a 52-week open-label trial in which pain relief was maintained without dose increase or toxicity [106]. ...
Pain in Sickle Cell Disease (SCD) is a major comorbidity and unique with acute pain due to recurrent and episodic vaso-occlusive crises as well as chronic pain, which can span an individual’s entire life. Opioids are the mainstay treatment for pain in SCD. Due to recent health crises raised by adverse effects including deaths from opioid use, pain management in SCD is adversely affected. Cannabis and its products are most widely used for pain in multiple conditions and also by patients with SCD on their own. With the availability of “Medical Cannabis” and approval to use cannabis as medicine across majority of States in the United States as well as over-the-counter preparations, cannabis products are being used increasingly for SCD. The reliability of many of these products remains questionable, which poses a major health risk to the vulnerable individuals seeking pain relief. Therefore, this review provides up to date insights into available categories of cannabis-based treatment strategies, their mechanism of action and pre-clinical and clinical outcomes in SCD. It provides evidence for the benefits and risks of cannabis use in SCD and cautions about the unreliable and unvalidated products that may be adulterated with life-threatening non-cannabis compounds.
... In a study of 125 patients with PNP, Sativex oral mucosal spray produced significant pain relief compared to placebo (Nurmikko et al., 2007). In another study of 303 PNP patients, Sativex oral mucosal spray produced clinically important improvements in pain (Serpell et al., 2014). An oral formulation of THC was found to alleviate pain due to multiple sclerosis (van Amerongen et al., 2018). ...
Human immunodeficiency virus (HIV) infection and antiretroviral therapy can independently induce HIV-associated neuropathic pain (HIV-NP). There is a dearth of drugs or therapeutic modalities that can alleviate HIV-NP. Smoked cannabis has been reported to improve pain measures in patients with neuropathic pain. Cannabis, phytocannabinoids, and the endocannabinoids such N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), produce some of their effects via cannabinoid receptors (CBRs). Endocannabinoids are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase. We searched PubMed, Google Scholar, clinicaltrials.gov and clinicaltrialsregister.eu using various key words and their combinations for published papers that studied HIV-NP and cannabis, cannabinoids, or endocannabinoids up to 27th December 2020. All original research articles that evaluated the efficacy of molecules that modulate the endocannabinoid system (ECS) for the prevention and/or treatment of pain in HIV-NP animal models and patients with HIV-NP were included. The PubMed search produced a total of 117 articles, whereas the Google Scholar search produced a total of 9467 articles. Amongst the 13 articles that fulfilled the inclusion criteria 11 articles were found in both searches whereas 2 articles were found in Google Scholar only. The clinicaltrials.gov and clinicaltrialsregister.eu searches produced five registered trials of which three were completed and with results. Ten preclinical studies found that the endocannabinoids (2-AG and AEA), synthetic mixed CB1R/CB2R agonist WIN 55,212-2, a CB2R-selective phytocannabinoid β-caryophyllene, synthetic CB2R-selective agonists (AM1710, JWH015, JWH133 and Gp1a, but not HU308); FAAH inhibitors (palmitoylallylamide, URB597 and PF-3845) and a drug combination of indomethacin plus minocycline, which produces its effects in a CBR-dependent manner, either prevented the development of and/or attenuated established HIV-NP. Two clinical trials demonstrated greater efficacy of smoked cannabis over placebo in alleviating HIV-NP, whereas another clinical trial demonstrated that cannabidivarin, a cannabinoid that does not activate CBRs, did not reduce HIV-NP. The available preclinical results suggest that targeting the ECS for prevention and treatment of HIV-NP is a plausible therapeutic option. Clinical evidence shows that smoked cannabis alleviates HIV-NP. Further research is needed to find out if non-psychoactive drugs that target the ECS and are delivered by other routes than smoking could be useful as treatment options for HIV-NP.
... Nugent et al. (2017) conducted a systematic review to investigate current research into the application of cannabis as a treatment for chronic pain. It was found that although many studies suggest the efficacy of cannabis as a treatment for neuropathic pain (Lynch et al. 2014;Serpell et al. 2014;Wallace et al. 2015;Wilsey et al. 2013;Wilsey et al. 2016), there is insufficient evidence to definitively suggest its efficacy as a treatment for other chronic pain conditions, such as arthritis and fibromyalgia (Nugent et al. 2017). ...
Background:
Cannabis refers to a plant in the family Cannabaceae, which has been used medically, recreationally, and industrially. The last two decades, in particular, have seen a large increase in the volume of literature on this topic. The present bibliometric analysis aims to capture the characteristics of scholarly journal publications on the topic of cannabis and cannabinoid research.
Methods:
Searches were run on the Scopus database on April 02, 2021, as follows "(TITLE (cannabi* OR hashish OR marijuana OR marihuana)) AND ( LIMIT-TO ( DOCTYPE,"ar" ) OR LIMIT-TO ( DOCTYPE,"re" ) )". Results were exported on the same day to prevent discrepancies between daily database updates. Only "article" and "review" publication types were included; no further search limits were applied. The "article" publication type includes publications featuring original research, whereas "review" includes reviews and conference papers. The following data were collected: number of publications (in total and per year), authors, and journals; open access status; publications per journal; journals publishing the highest volume of literature and their impact factors, language of publication; document type; publication country; author affiliations; funding sponsors; most highly cited publications; and most highly published authors. Trends in this subset of publications were identified and presented. Bibliometric networks were constructed using the software tool VOSviewer.
Results:
A total of 29 802 publications (10 214 open access), published by 65 109 authors, were published in 5474 journals from 1829 to 2021. The greatest number of publications was published over the last 20 years. The journal that published the largest number of publications was Drug and Alcohol Dependence (n = 705). The most productive countries included the USA (n = 12 420), the UK (n = 2236), and Canada (n = 2062); many of the most common institutional affiliations and funding sponsors originated from these countries.
Conclusions:
The number of publications published on the topic of cannabis follows an upward trend. Over the past 20 years, the volume of cannabis research has grown steeply, which can be attributed to a large amount of funding dedicated to researching this topic. Future research should continue to investigate changes in the publication characteristics of emerging research, as the volume of publications on this topic is expected to rapidly grow.
... Cannabis sativa possa vir a ser utilizada como adjuvante para o tratamento da dor crônica (particularmente aquela de origem neuropática), concluímos que é razoável considerar o uso de canabinóides como uma opção no tratamento na gestão da dor crônica. É importante salientar o fato de que dois dos ensaios examinandos [14,15] ...
This book brings together studies and views from different areas and researchers in Brazil on the contribution of science to the development of society. In this way, we provide quality scientific information to everyone, in addition to stimulating the production of scientific texts by students and professionals. Organizer: Guilherme Antônio Lopes de Oliveira. ISBN: 978-65-86212-55-6.
... The majority of clinical studies describe the efficacy of CBD and ∆9-THC co-administration, generally in doses of 2.5 mg CBD and 2.7 mg ∆9-THC in an oral mucosa spray, with treatment periods varying from one to several weeks. After treatment sessions, patients reported reduced pain, improved sleep quality, and reduced insomnia and fatigue [112][113][114][115]. One of the best studied CBD-containing registered products is Sativex ® (Nabiximols), containing the abovementioned doses of CBD and ∆9-THC. ...
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD’s mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD’s action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD’s action and future perspectives for research.
... Entre los compuestos psicoactivos se encuentran: el tetrahidrocannabinol (THC) y el cannabinol (CBN), siendo el primero el más estudiado. 6 Al THC se le han descrito múltiples propiedades beneficiosas para la salud como, por ejemplo, en el control del dolor en: accidentes cerebrovasculares, 7 neuropatía periférica, 8 y en cáncer, 9 entre otros. Sin embargo, su uso se ha visto limitado por las propiedades psicoactivas que presenta este compuesto dado que puede alterar la función de la memoria y generar algunos síntomas psicóticos. ...
El cannabis alberga gran cantidad de compuestos con características de importancia en diversos procesos que incluyen los industriales, recreativos y medicinales. Los compuestos más abundantes en estas plantas son los cannabinoides, siendo los más importantes y estudiados el tetrahidrocannabinol (THC), un compuesto que a pesar de que se le han descrito múltiples propiedades medicinales y potencial terapéutico, su uso se ha visto limitado debido a sus efectos psicoactivos; y el cannabidiol (CBD) que se diferencia del anterior porque no presenta esta propiedad. Este último ha cobrado importancia por sus propiedades para tratar algunas enfermedades como el cáncer gracias a su efecto pro-apotótico, anti-proliferativo y anti-angiogénico. Esta revisión tiene como objetivo describir los mecanismos inmunomoduladores asociados a los cannabinoides no psicoactivos en modelos in vivo de diferentes tipos de cáncer como: glioblastoma, cáncer de seno, cáncer de pulmón, cáncer colorrectal y melanoma. Entre los hallazgos obtenidos en diferentes trabajos se destaca la capacidad de este compuesto, en combinación con otros fármacos antineoplásicos, de inducir apoptosis e inhibir la metástasis mediante la regulación de ciertas moléculas como CD31, Id-1, caspasas 3 y 9, y metaloproteinasas, entre otras. A pesar de que estos compuestos son vistos como prometedores fármacos, hacen falta más estudios que evalúen los mecanismos inmunomoduladores de los cannabinoides no psicoactivos, debido a que evidencias previas solo han descrito sus propiedades in vitro, por lo tanto, hace falta ahondar un poco más en el estudio de modelos in vivo, para un posible uso posterior en ensayos clínicos, y de esta forma ser considerados como verdaderos agentes terapéuticos.
... A total of 4 (9%) studies reported cardiac disorder as an adverse event, but they did not specify which cardiovascular disease they were referring to. [19][20][21][22] Tachycardia Tachycardia events were reported in 12 studies. [23][24][25][26][27][28][29][30][31][32][33][34] The pooled relative risk for tachycardia was 1.94 (95% CI 0.81e4.64) ...
Aim: The objective of this study was to evaluate the cardiovascular toxicity associated with medical use of cannabinoids. Methods: A two-stage systematic review (SR) approach was undertaken to assess current evidence on cannabinoid-associated cardiovascular events reported among randomized controlled trials (RCT). First, we searched for SRs in multiple sources until June 2019. Second, RCTs identified from SRs were included if they assessed medical cannabis and reported cardiovascular events. The outcomes of interest were all types of cardiovascular events. Data were extracted by two independent reviewers. Study quality was assessed using the Cochrane risk of bias. A statistical test of heterogeneity was performed. The summary risk ratios and 95% Confidence Intervals (CIs) were calculated using a random-effects model. Results:
A total of 47 studies involving 2,800 patients were included. The median duration of cannabinoid use was 15.8 days (range 1 to 322) and 45% of studies excluded patients with underlying cardiovascular diseases. Cannabinoid use was significantly associated with increased risks of orthostatic hypotension (RR 3.16; 95% CI 2.27 – 4.40; I2 = 2.3%), and hypotension (RR 3.55; 95% CI 1.45 – 8.71; I2 = 31.8%) with a trend of increased risk of tachycardia (RR 1.94; 95% CI 0.81 – 4.64; I2 = 48.6%). No study reported serious cardiovascular events. Conclusions: Cannabinoid use was associated with tachycardia, hypotension, and orthostatic hypotension. There is a paucity of data for other cardiovascular events among medical cannabis users. More data especially long-term effects among patients with existing cardiovascular diseases are needed.
... Cannabinoids: A fast-growing field of therapeutic intervention in different brain disorders is to modulate the endocannabinoid (eCB) system to harness favorable outcomes [205,284]. Cannabis-based research has come a long way from its introduction in 1838 by William O'Shaughnessy [285] for the treatment of migraines [286,287] and neuropathic pain [285,288,289]. The current cannabis preparations available clinically are Cesamet (nabilone), Marinol (dronabinol: ∆9-tetrahydrocannabinol [∆9-THC]), and Sativex also branded as Nabiximols (∆9-THC with cannabidiol) [290]. ...
Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.
... Cannabinoid receptors such as CB1 and CB2 are predominantly expressed in the brain and on immune cells indicating they may play a useful role in regulating inflammation [143]. There have been a few clinical studies that investigated the effectiveness of THC/CBD sprays as a treatment method for neuropathic pain within cancer patients and have observed measurable reductions in pain of patients [144][145][146]. Although the clinical efficacy of these treatments is still to be determined they are all certainly great candidates as therapeutic strategies, neuroprotectants, and anti-inflammatory agents for chemotherapy-induced inflammatory organ damage. ...
Breast Cancer is still one of the most common cancers today; however, with advancements in diagnostic and treatment methods, the mortality and survivorship of patients continues to decrease and increase, respectively. Commonly used treatments today consist of drug combinations, such as doxorubicin and cyclophosphamide; docetaxel, doxorubicin, and cyclophosphamide; or doxorubicin, cyclophosphamide, and paclitaxel. Although these combinations are effective at destroying cancer cells, there is still much to be understood about the effects that chemotherapy can have on normal organ systems such as the nervous system, gastrointestinal tract, and the liver. Patients can experience symptoms of cognitive impairments or “chemobrain”, such as difficulty in concentrating, memory recollection, and processing speed. They may also experience gastrointestinal (GI) distress symptoms such as diarrhea and vomiting, as well as hepatotoxicity and long term liver damage. Chemotherapy treatment has also been shown to induce peripheral neuropathy resulting in numbing, pain, and tingling sensations in the extremities of patients. Interestingly, researchers have discovered that this array of symptoms that cancer patients experience are interconnected and mediated by the inflammatory response.
... Clinical trials investigating the combined effects of Δ 9 -THC and CBD (e.g. Sativex®) on chronic neuropathic pain have yielded promising initial results [87,114,151,156]. However, the therapeutic effects of CBD administered alone have received limited clinical attention. ...
Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.
... S1 Text for additional details) from 21 articles[42,46,48,49,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84] reported on 1,965 patients [analysed 1,940; Total person-years of THC:CBD exposure: 394.29 person-years; Mean person-years of THC exposure (mean ± SD): 15.17 ± 28.20 person-years] on active and 1,887 (analysed 1,863) on placebo, ranging from 50 to 67 years in age (males: 0% to 80%). All studies used placebo as control. ...
Background
Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years.
Methods and findings
A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those <50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies.
Conclusions
This pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.
... A combination of THC:CBD significantly alleviated their pain intensity compared to the placebo group (23 [43%] vs. 12 [21%]) and also showed weak positive effects with respect to the avoidance of avoiding nausea and vomiting, while the effects in the THCmonotherapy group were non-significant [139]. Some other cannabinoids including ∆-9 tetrahydrocannabinol, cannabidiol and a THC-11-oic acid analog have also been tested for their capacity to reduce the neuropathic pain caused by chemotherapy, and have shown favorable analgesic properties [140][141][142][143]. A phase II clinical trial investigated the curative effects of THC:CBD when combined with dose-intensified TMZ, as versus TMZ mono-chemotherapy, in patients with glioblastoma multiforme (GBM) (clinical trial NCT01812603). ...
In recent years, evidence has accumulated that cannabinoids—especially the non-psychoactive compound, cannabidiol (CBD)—possess promising medical and pharmacological activities that might qualify them as potential anti-tumor drugs. This review is based on multiple studies summarizing different mechanisms for how CBD can target tumor cells including cannabinoid receptors or other constituents of the endocannabinoid system, and their complex activation of biological systems that results in the inhibition of tumor growth. CBD also participates in anti-inflammatory activities which are related to tumor progression, as demonstrated in preclinical models. Although the numbers of clinical trials and tested tumor entities are limited, there is clear evidence that CBD has anti-tumor efficacy and is well tolerated in human cancer patients. In summary, it appears that CBD has potential as a neoadjuvant and/or adjuvant drug in therapy for cancer.
... Nabiximol's effect on neuropathic pain in a 15-week randomized, double-blind, placebo-controlled, parallel-group study showed an effect of active treatment measured as the 30% responder level in favor of active treatment compared to placebo. The other outcome-measure, the reduction in mean of NRS scores did not reach statistical significance [21]. A similar study assessed the effect of nabiximols in 125 patients with peripheral neuropathic pain. ...
Indications of cannabis use are numerous although the indication to relief pain remains a major research interest and clinical application. Studies investigating the effect of herbal cannabis and cannabis-based medicine on neuropathic, non-neuropathic pain, acute pain and experimentally induced pain were reviewed. A search was performed in PubMed and Cochrane library for articles published in English between January 1, 2000 and May 8, 2020. The search terms used were related to cannabis and pain in adults. We identified 34 studies, of which 30 were randomized controlled clinical trials (RCTs). Varying effects were identified from the RCTs, and as expected more promising effects from non-RCTs. Cannabis-based medications were found most effective as an adjuvant therapy in refractory multiple sclerosis, and weak evidence was found to support the treatment of cancer pain especially in advanced stages. Chronic rheumatic pain showed promising results. Adverse events of cannabis-based treatment were found to be more frequent with tetrahydrocannabinol herbal strains compared to other cannabis-derived products.
... We identified nine placebo-controlled studies on cannabinoids (mostly transmucosal nabiximols and oral THC, only two yielding positive results) published before June 2013, with a moderate final quality of evidence against their use. We identified two additional more recent high-quality RCTs of cannabinoids in neuropathic pain: one study of nabiximols (Sativex, 128 patients treated) yielded positive results for peripheral neuropathic pain, albeit with a modest effect size (NNT = 8.3); another study of oral dronabinol (tetrahydrocannabinol or THC, 124 patients treated) yielded negative results for neuropathic pain due to multiple sclerosis [62,63]. The final quality of evidence was high. ...
Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.
... The alteration of neurotransmitter release from the brain by cannabinoids, could result in pain reduction and muscle relaxation, as well as antioxidant and anti-inflammatory action ( Serpell et al., 2014 ;Atalay et al., 2020 ). Cannabinoid receptors have been verified in the sensory neurons and satellite glial cells of the dorsal root ganglia in the equine brain ( Chiocchetti et al., 2020 ). ...
The potential use of cannabidiol (CBD) as a nutraceutical to support improved health and welfare has been of increasing interest. In particular, CBD has been shown to decrease anxiety in humans and small animals. While there is little research published on the effects of CBD supplementation in horses, its use is increasing rapidly. The objective of this study was to determine the effect of feeding a pelleted CBD supplement on equine reactivity and heart rate (HR). Seventeen stock-type geldings were divided into control (CON) or treatment (TRT) groups. The TRT group received 100 mg of CBD once daily. Control horses were maintained on their standard diet without supplementation. A novel object test was used to evaluate changes in HR and reactivity before and after 6 weeks of supplementation. Heart rate was recorded before, at, and after exposure to the novel object. Reactivity when the horse was exposed to the novel object was scored live and through video review. There was no difference in starting, stimulus, or final HR, but TRT horses exhibited less reactivity after 6 weeks of supplementation. Results suggest that CBD supplementation may lower reactivity in horses.
... As detailed in Table 1, patients could also be educated about products with a 1:1 ratio of THC:CBD such as nabiximol and those with oral or topical delivery methods [7,48]. Several studies have demonstrated the tolerability of oromucosal nabiximol sprays [49][50][51]. ...
The goal of this systematic review was to define a consensus within the current literature regarding the impact/effect of cannabis or cannabinoids on the treatment of patients with head and neck cancer. We conducted a review of PubMed, Embase, and Web of Science databases, using a comprehensive search strategy, focusing on articles relating to head & neck cancer and cannabis/cannabinoids without a time limit for publication. Two, independent reviewers screened articles based on title/abstract and included the ones selected by both. We then conducted a full-text review and excluded all articles which did not meet inclusion criteria. A single reviewer then assessed studies for methodological quality and extracted relevant data using a premade data collection tool. We identified five studies that met inclusion criteria. Studies were of varying quality and the majority investigated recreational cannabis use with only one study reporting dosing across participants. Lack of standardized cannabis exposure presents a wide array of potential confounding variables across the remaining studies. Meta-analysis was not attempted due to variability in reported outcomes. It is impossible to draw any conclusions regarding the benefit or adverse effects of current medical cannabis products in this patient population. The literature regarding the effect of cannabis/cannabinoids on head & neck cancer patients is limited. However, the current lack of evidence does not definitively disprove the efficacy of cannabis. High-quality studies are necessary for physicians to provide advice to patients who are either using or interested in cannabis as an adjunctive treatment.
... Along with AEA, FAAH can also degrade other Nacylethanolamines (e.g., N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA)), Nacyl-amides (e.g., N-acyl-taurines, N-acylglycines) and primary amides (e.g., oleamide), which can activate non-cannabinoid receptors (e.g., TRP channels, PPARα) [212,[290][291][292][293]. Studies have reported that treatment with FAAH inhibitors increases the levels of AEA as well as OEA and PEA [212,290]. MAGL can also degrade other 2-acylglycerols (e.g., 2-linoleoyl glycerol, 2-oleoyl glycerol, 2-palmitoyl glycerol), which can activate non-CB1/-CB2 receptors [164,296,297]. Therefore, manipulation of FAAH and MAGL may also affect other lipids and may exert undesirable effects [164]. ...
Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.
The treatment of chronic, non-cancer musculoskeletal pain has become a topic growing interest as it is believed to be one of the reasons for the current opioid epidemic. The medicinal use of cannabis has a long history as a number of active compounds in cannabis have been shown to interact with the body’s endocannabinoid system to reduce pain. This position paper provides a history on the evolution of cannabis, the science behind its therapeutic effects, and review of the evidence and current guideline recommendations on its use as a treatment for patients with chronic, non-cancer musculoskeletal pain. Results from systematic reviews have demonstrated a statistically significant reduction in chronic pain conditions with cannabinoids, compared with placebo, although the effects might be considered small and did not reach the minimally important difference. More adverse events were reported in the cannabinoid group than in the placebo group with longer than 2 weeks of treatment. There is a lack of evidence on dependence. With changes to policies, patients’ perception has changed to be more positive toward the use of medical cannabis. Current recommendations from North America, Latin America, Europe, Australia and Iran support the use of medical cannabis for chronic, non-cancer pain. Based on the current evidence, it is our position that cannabinoids may be considered as an adjunctive therapy after recommended first- and second-line therapies have failed to provide sufficient efficacy or tolerability. Patients should consider the balance between the desirable and undesirable effects of taking cannabis for chronic pain, and comprehensively consider their own values and preferences, as well as cost-effectiveness factors, based on the information provided by their physician.
Palliative care is a specialized medical care that focuses on quality of life for patients with serious illnesses. In the realm of palliative care and symptom management, there is growing interest in the role for cannabis-based medicine. There is some evidence to support the use of cannabinoids for the palliation of some symptoms and quality of life issues. Most notably, research supports the efficacy of cannabinoids for the treatment of chemotherapy-induced nausea and vomiting, though the evidence for phytocannabinoids is lacking. Moreover, cannabis use in the treatment of neuropathic pain is supported by several small high-quality studies. There is great interest in cannabis-based medicine to aid in the management of other symptoms such as anorexia, cachexia, insomnia, fatigue, anxiety, and delirium, among others that are prevalent in palliative care patients. Though there are limited studies for these various applications of cannabis, the data is not conclusive, and patients’ treatment goals must be carefully considered prior to the administration of medical cannabis. Further research is needed to better understand the possible benefits of medical cannabis as well as the safety, side effects, and drug interactions.
Objective:
To compile and synthesize the available literature describing medical cannabis use across various disease states.
Data sources:
PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords.
Study selection and data extraction:
Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019.
Data synthesis:
Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care.
Relevance to patient care and clinical practice:
Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria.
Conclusions:
As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.
The purpose of this article is to present evidence on the efficacy and safety of medical cannabis as a therapy for symptom management in palliative care. This article provides an overview of the evidence on the risks and benefits of using medical cannabis for the indications of chronic pain, cancer-related pain, cancer cachexia, dementia, and Alzheimer's disease. Currently, there is insufficient evidence to determine the effectiveness and safety of cannabinoids for most reviewed indications, with the exception of chronic pain. Future research is required before palliative care clinicians can make evidence-based decisions on the integration of medical cannabis as adjunct therapies.
There is growing interest in using cannabinoids for chronic pain. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the analgesic efficacy and adverse effects of cannabinoids for chronic non-cancer pain. PubMed, EMBASE, Web of Science, Cochrane CENTRAL and clinicaltrials.gov were searched up to December 2018. Information on the type, dosage, route of administration, pain conditions, pain scores, and adverse events were extracted for qualitative analysis. Meta-analysis of analgesic efficacy was performed. Meta-regression was performed to compare the analgesic efficacy for different pain conditions (neuropathic versus non-neuropathic pain). Risk of bias was assessed by The Cochrane Risk of Bias tool, and the strength of the evidence was assessed using the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Forty-three randomized controlled trials were included. Meta-analysis was performed for 33 studies that compared cannabinoids to placebo, and showed a mean pain score (scale 0–10) reduction of −0.70 (p < 0.001, random effect). Meta-regression showed that analgesic efficacy was similar for neuropathic and non-neuropathic pain (Difference = −0.14, p = 0.262). Inhaled, oral, and oromucosal administration all provided statistically significant, but small reduction in mean pain score (−0.97, −0.85, −0.45, all p < 0.001). Incidence of serious adverse events was rare, and non-serious adverse events were usually mild to moderate. Heterogeneity was moderate. The GRADE level of evidence was low to moderate. Pain intensity of chronic non-cancer patients was reduced by cannabinoids consumption, but effect sizes were small. Efficacy for neuropathic and non-neuropathic pain was similar.
The 20% prevalence of chronic pain in the general population is a major health concern given the often profound associated impairment of daily activities, employment status, and health-related quality of life in sufferers. Resource utilization associated with chronic pain represents an enormous burden for healthcare systems. Although analgesia based on the World Health Organization's pain ladder continues to be the mainstay of chronic pain management, aside from chronic cancer pain or end-of-life care, prolonged use of non-steroidal anti-inflammatory drugs or opioids to manage chronic pain is rarely sustainable. As the endocannabinoid system is known to control pain at peripheral, spinal, and supraspinal levels, interest in medical use of cannabis is growing. A proprietary blend of cannabis plant extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the principal cannabinoids is formulated as an oromucosal spray (USAN name: nabiximols) and standardized to ensure quality, consistency and stability. This review examines evidence for THC:CBD oromucosal spray (nabiximols) in the management of chronic pain conditions. Cumulative evidence from clinical trials and an exploratory analysis of the German Pain e-Registry suggests that add-on THC:CBD oromucosal spray (nabiximols) may have a role in managing chronic neuropathic pain, although further precise clinical trials are required to draw definitive conclusions.
Burning mouth syndrome (BMS) is a neuropathic pain disorder associated with a burning sensation on oral mucosal surfaces with frequently reported xerostomia, dysgeusia and tingling or paraesthetic sensations. However, patients present no clinically evident causative lesions. The poor classification of the disorder has resulted in a diagnostic challenge, particularly for the clinician/dentist evaluating these individuals. Major research developments have been made in the BMS field in recent years to address this concern, principally in terms of the pathophysiological mechanisms underlying the disorder, in addition to therapeutic advancements. For the purpose of this review, an update on the pathophysiological mechanisms will be discussed from a neuropathic, immunological, hormonal and psychological perspective. This review will also focus on the many therapeutic strategies that have been explored for BMS, including antidepressants/antipsychotics, nonsteroidal anti-inflammatories, hormone replacement therapies, phytotherapeutic compounds and non-pharmacological interventions, overall highlighting the lack of controlled clinical studies to support the effectiveness of such therapeutic avenues. Particular focus is given to the cannabinoid system, and the potential of cannabis-based therapeutics in managing BMS patients.
Multicenter, randomized, double-blind, placebo controlled, clinical trial.
The objective of this paper is to evaluate the effectiveness of cannabinoids and an anti-inflammatory diet, alone and in combination, for the management of neuropathic pain (NP) after spinal cord injury (SCI).
Two Canadian SCI rehabilitation centers.
A sample of 144 individuals with SCI will receive either an anti-inflammatory diet, cannabinoids or a placebo for 6 weeks. Following this, a combined effect of these treatments will be evaluated for a further 6 weeks. The primary outcome measure will be the change in NP as assessed by the numeric rating scale (NRS). Secondary outcomes will include changes in inflammation, mood, sleep, spasticity, cost-effectiveness, and function.
This study will assess the efficacy of an anti-inflammatory diet and cannabinoids (individually and in combination) for the treatment of NP following SCI. Results may reveal a cost-effective, side-effect free intervention strategy which could be utilized for the long-term management of NP following SCI.
This chapter will cover some key aspects of how the psychoactive constituents of cannabis interact with our brains to produce the characteristic experiences associated with the drug's “high.” It also explores the body's complex and naturally occurring neurochemical internal cannabinoid signaling system that interacts with plant-produced chemicals found inside the cannabis flower. This chapter summarizes the discovery of the ECS, our realization of its growing medical and behavioral importance, and our changing view of its many functions. This whole area of cannabinoid-related research is of intense interest not only to scientists of various stripes, but also pharmaceutical companies, who glimpse the possibilities of designing drugs to manipulate the system in order to help treat a wide variety of illnesses.
This chapter reviews the historical use of cannabis as a pharmaceutical; examine some of the arguments for the use of medical marijuana and of CBD as well as the numerous conceptual, practical, and legal difficulties that stand in the way of the necessary, definitive clinical trials. Such investigations would tell us whether or not cannabis and/or its many constituents have the utility for particular medical conditions. We will review existing data that medical marijuana may be effective in treating a variety of illnesses and try to gauge the strength of the supporting evidence for a handful of the most studied of them.
Introduction
: Nabiximols, a cannabinoid-based oromucosal spray, is indicated as add-on therapy for symptomatic relief of spasticity in persons with multiple sclerosis (MS). This review compiles tolerability and safety data from clinical trials that investigated nabiximols for spasticity and/or chronic pain.
Areas covered
: Systematic searches identified 38 placebo-controlled randomised controlled trials (RCTs) or post-RCT open-label studies reporting safety data: 15 in (mainly MS) spasticity; 16 in neuropathic pain; six in chronic cancer pain; and one in rheumatoid arthritis pain. In RCTs, discontinuation rates due to adverse events (AEs) for nabiximols and placebo were lower in spasticity studies (5.4% and 2.8%, respectively) than in neuropathic pain (12.9% and 5.3%) or cancer pain (19.5% and 16.6%) studies. The most consistently identified AEs were dizziness, nausea and fatigue in spasticity or neuropathic pain studies; and dizziness, nausea, vomiting and somnolence in cancer pain studies. Serious AE (SAE) rates for nabiximols and placebo were higher in cancer pain studies (21.8% and 16.9%) than in MS spasticity (4.7% vs. 0.8%) and neuropathic pain (4.1% vs. 3.1%) studies despite similar dose ranges. Treatment-related SAEs showed no particular pattern.
Expert opinion
: More than 15 years’ investigation of nabiximols oromucosal spray in spasticity and chronic pain conditions indicates an acceptable overall safety profile.
Legalization of cannabidiol (CBD) products has ignited interest in clinical practice and research. One desired indication includes possible pain-relieving effects of CBD. The purposes of the current article are to (1) clarify terminology relevant to cannabinoids; (2) explain and understand the pharmacotherapeutics of CBD; (3) examine research of the current use of CBD by older adults for treating pain; (4) discuss safety considerations with using CBD products; and (5) provide best practice recommendations for clinicians as they advise their older adult patients. A review of the literature demonstrated mixed results on the efficacy of CBD in relieving pain in older adults. There is inconsistency in the labeling of over-the-counter CBD products that can result in safety issues and will require more federal quality control. Likewise, gaps in knowledge regarding safety and efficacy of CBD use in older adults are vast and require further research. [Journal of Gerontological Nursing, 47(7), 6-15.].
In this chapter, we have summarized systematic reviews of randomized controlled trials using cannabis-based medicine for pain, including, but not limited to, chronic pain (non-cancer pain, neuropathic pain, centralized pain disorders such as fibromyalgia, rheumatic inflammatory pain, cancer pain) and acute pain. It appears that more consistent methodology is needed among future research designs with regard to cannabis product, dosing, method of intake, timing of administration, pain scale measurements, and how pain is subjectively measured and reported. Without this, it is challenging to compare the breadth of data that now exists on cannabis and its effect on pain.
Nabiximols is a whole-plant prescription cannabinoid approved in many regions of the world. It meets the same regulatory requirements of other pharmaceutical products in terms of efficacy, safety, and consistency. Most of the current evidence for nabiximols is in the management of patients with MS, cancer-related pain, and chronic neuropathic pain. The treatment is generally well tolerated with adverse effects similar to other orally administered cannabinoid products. Storage and administration of nabiximols are different than other cannabinoids and are important to counsel patients on its appropriate use.
Riassunto
Il dolore neuropatico è difficile da alleviare. I trattamenti farmacologici di prima o di seconda intenzione per questo dolore comprendono gli antidepressivi triciclici (in particolare, amitriptilina), gli antidepressivi inibitori del reuptake della serotonina e della noradrenalina (in particolare, duloxetina), gli antiepilettici (gabapentin e pregabalina), il tramadolo, trattamenti topici (cerotti alla lidocaina, capsaicina ad alta concentrazione e tossina botulinica A per il dolore neuropatico periferico). Questi trattamenti possono essere associati tra di loro in caso di risposta parziale alla monoterapia. Gli oppiacei forti costituiscono un trattamento di ripiego, da soli o in associazione con uno dei trattamenti precedenti. Gli studi recenti e una migliore metodologia degli studi clinici, che ora tengono maggiormente conto della natura dei sintomi neuropatici, dovrebbero permettere di prevedere meglio i profili dei responder ai trattamenti. I nuovi trattamenti in fase di sviluppo includono in particolare gli antagonisti dei recettori di alcuni canali del sodio.
Objective
To compare the effectiveness, safety, and tolerability of add-on nabiximols (NBX) oromucosal spray vs typical oral long-acting opioid (LAO) analgesics in patients with severe (± chronic) peripheral neuropathic back pain poorly responsive to other treatments.
Methods
Retrospective analysis of anonymized, propensity score–matched data from the German Pain e-Registry of adult outpatients who initiated NBX or LAO between March 2017 and March 2020.
Results
Data were analyzed from propensity score–matched patients treated with NBX (n = 655) or LAO (n = 655): mean age ≈51 years; 57% female; mean pain duration ≈2.6 years; chronic pain 61%; severe dysfunctional pain 93%. At 6 months, NBX was noninferior to LAO for overall symptom relief, based on the least-squares mean difference between cohorts in change from baseline in patient-reported, pain-related aggregated nine-item scale scores (−27.84%; 95% confidence interval [CI] −29.71 to −25.96; P < 0.001) and individual pain-related scale scores. Subsequent prespecified superiority analysis of the primary endpoint showed that NBX was superior to LAO: all secondary endpoints measuring symptoms of pain and physical function improved significantly with NBX and LAO, with between-group differences favoring NBX (all P < 0.001). Fewer patients treated with NBX than LAO experienced treatment-related adverse events (25.5% vs 76.0%; P < 0.001) or discontinued treatment because of treatment-related adverse events (7.9% vs 29.3%; P < 0.001).
Conclusion
Within study limitations (e.g., observational design, all potential biases), add-on NBX was superior to and better tolerated than add-on treatment with typical oral LAO analgesics in patients with neuropathic back pain inadequately controlled by recommended/established systemic therapies.
Objective
To determine the benefits and harms of medical cannabis and cannabinoids for chronic pain.
Design
Systematic review and meta-analysis.
Data sources
MEDLINE, EMBASE, AMED, PsycInfo, CENTRAL, CINAHL, PubMed, Web of Science, Cannabis-Med, Epistemonikos, and trial registries up to January 2021.
Study selection
Randomised clinical trials of medical cannabis or cannabinoids versus any non-cannabis control for chronic pain at ≥1 month follow-up.
Data extraction and synthesis
Paired reviewers independently assessed risk of bias and extracted data. We performed random-effects models meta-analyses and used GRADE to assess the certainty of evidence.
Results
A total of 32 trials with 5174 adult patients were included, 29 of which compared medical cannabis or cannabinoids with placebo. Medical cannabis was administered orally (n=30) or topically (n=2). Clinical populations included chronic non-cancer pain (n=28) and cancer related pain (n=4). Length of follow-up ranged from 1 to 5.5 months. Compared with placebo, non-inhaled medical cannabis probably results in a small increase in the proportion of patients experiencing at least the minimally important difference (MID) of 1 cm (on a 10 cm visual analogue scale (VAS)) in pain relief (modelled risk difference (RD) of 10% (95% confidence interval 5% to 15%), based on a weighted mean difference (WMD) of −0.50 cm (95% CI −0.75 to −0.25 cm, moderate certainty)). Medical cannabis taken orally results in a very small improvement in physical functioning (4% modelled RD (0.1% to 8%) for achieving at least the MID of 10 points on the 100-point SF-36 physical functioning scale, WMD of 1.67 points (0.03 to 3.31, high certainty)), and a small improvement in sleep quality (6% modelled RD (2% to 9%) for achieving at least the MID of 1 cm on a 10 cm VAS, WMD of −0.35 cm (−0.55 to −0.14 cm, high certainty)). Medical cannabis taken orally does not improve emotional, role, or social functioning (high certainty). Moderate certainty evidence shows that medical cannabis taken orally probably results in a small increased risk of transient cognitive impairment (RD 2% (0.1% to 6%)), vomiting (RD 3% (0.4% to 6%)), drowsiness (RD 5% (2% to 8%)), impaired attention (RD 3% (1% to 8%)), and nausea (RD 5% (2% to 8%)), but not diarrhoea; while high certainty evidence shows greater increased risk of dizziness (RD 9% (5% to 14%)) for trials with <3 months follow-up versus RD 28% (18% to 43%) for trials with ≥3 months follow-up; interaction test P=0.003; moderate credibility of subgroup effect).
Conclusions
Moderate to high certainty evidence shows that non-inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain, along with several transient adverse side effects, compared with placebo. The accompanying BMJ Rapid Recommendation provides contextualised guidance based on this body of evidence.
Systematic review registration
https://osf.io/3pwn2
Clinical question
What is the role of medical cannabis or cannabinoids for people living with chronic pain due to cancer or non-cancer causes?
Current practice
Chronic pain is common and distressing and associated with considerable socioeconomic burden globally. Medical cannabis is increasingly used to manage chronic pain, particularly in jurisdictions that have enacted policies to reduce use of opioids; however, existing guideline recommendations are inconsistent, and cannabis remains illegal for therapeutic use in many countries.
Recommendation
The guideline expert panel issued a weak recommendation to offer a trial of non-inhaled medical cannabis or cannabinoids, in addition to standard care and management (if not sufficient), for people living with chronic cancer or non-cancer pain.
How this guideline was created
An international guideline development panel including patients, clinicians with content expertise, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. The MAGIC Evidence Ecosystem Foundation (MAGIC) provided methodological support. The panel applied an individual patient perspective.
The evidence
This recommendation is informed by a linked series of four systematic reviews summarising the current body of evidence for benefits and harms, as well as patient values and preferences, regarding medical cannabis or cannabinoids for chronic pain.
Understanding the recommendation
The recommendation is weak because of the close balance between benefits and harms of medical cannabis for chronic pain. It reflects a high value placed on small to very small improvements in self reported pain intensity, physical functioning, and sleep quality, and willingness to accept a small to modest risk of mostly self limited and transient harms. Shared decision making is required to ensure patients make choices that reflect their values and personal context. Further research is warranted and may alter this recommendation.
Neuropathic pain represents a broad category of pain syndromes that include a wide variety of peripheral and central disorders. The overall prevalence of neuropathic pain in the general population is reported to be between 7 and 10%. Management of neuropathic pain presents an unmet clinical need, with less than 50% of patients achieving substantial pain relief with medications currently recommended such as pregabalin, gabapentin, duloxetine and various tricyclic antidepressants. It has been suggested that cannabis-based medicines (CbMs) and medical cannabis (MC) may be a treatment option for those with chronic neuropathic pain. CbMs/MC are available in different forms: licensed medications or medical products (plant-derived and/or synthetic products such as tetrahydrocannabinol or cannabidiol); magistral preparations of cannabis plant derivatives with defined molecular content such as dronabinol (tetrahydrocannabinol); and herbal cannabis with a defined content of tetrahydrocannabinol and/or cannabidiol, together with other active ingredients (phytocannabinoids other than cannabidiol/tetrahydrocannabinol, terpenes and flavonoids). The availability of different types of CbMs/MC varies between countries worldwide. Systematic reviews of available randomised controlled trials have stated low-quality evidence for CbMs and MC for chronic neuropathic pain. Depending on the studies included in the various quantitative syntheses, authors have reached divergent conclusions on the efficacy of CbMs/MC for chronic neuropathic pain (from not effective to a clinically meaningful benefit). Clinically relevant side effects of CbMs/MC, especially for central nervous system and psychiatric disorders, have been reported by some systematic reviews. Recommendations for the use of CbMs/MC for chronic neuropathic pain by various medical associations also differ, from negative recommendations, no recommendation possible, recommended as third-line therapy, or recommended as an alternative in selected cases failing standard therapies within a multimodal concept. After reading this paper, readers are invited to formulate their own conclusions regarding the potential benefits and harms of CbMs/MC for the treatment of chronic neuropathic pain.
Objective:
Current treatments for chronic pain have limited effectiveness and tolerability. With growing interest in the potential of cannabinoids, there is a need to inform risk-benefit considerations. Thus, this focused systematic review assesses the quality of safety assessment and reporting in chronic noncancer pain cannabinoid trials.
Methods:
The protocol for this review has been published, and, registered in PROSPERO. We searched MEDLINE, EMBASE, The Cochrane Library, Scopus and PsychINFO for double-blind, placebo-controlled, randomized controlled trials of cannabinoids for chronic pain, with a primary outcome related to pain. The primary review outcome is adherence to the 2004 CONSORT Harms extension. Secondary outcomes included type, reporting method, frequency and severity of AEs, trial participant withdrawals, and reasons for withdrawals.
Results:
In total, 43 studies (4,436 participants) were included. Type of cannabinoid (number of studies) included nabiximols (12), dronabinol (8), nabilone (7), oral cannabis extract preparations (5), smoked THC (5), vaporised THC (3), novel synthetic cannabinoids (2), sublingual cannabis extract preparations (1). The median CONSORT score was 7. On average, 3-4 recommendations of the CONSORT guidelines were not being met in trials. Seventeen trials did not provide their method of adverse event (AE) assessment, fourteen trials did not report on serious adverse events (SAEs) and, seven trials provided no quantitative data about AEs.
Discussion:
Better harms assessment and reporting are needed in chronic pain cannabinoid trials. Improvements may be achieved through: expanded education/knowledge translation, increased research regulation by ethics boards, funding agencies and journals, and greater emphasis on safety assessment and reporting throughout research training.
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL -1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.
Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design.
A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase.
Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols.
The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.
Background:
Chronic neuropathic pain affects 1%-2% of the adult population and is often refractory to standard pharmacologic treatment. Patients with chronic pain have reported using smoked cannabis to relieve pain, improve sleep and improve mood.
Methods:
Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial. Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events.
Results:
We recruited 23 participants (mean age 45.4 [standard deviation 12.3] years, 12 women [52%]), of whom 21 completed the trial. The average daily pain intensity, measured on the 11-point numeric rating scale, was lower on the prespecified primary contrast of 9.4% v. 0% tetrahydrocannabinol (5.4 v. 6.1, respectively; difference = 0.7, 95% confidence interval [CI] 0.02-1.4). Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief. Participants receiving 9.4% tetrahydrocannabinol reported improved ability to fall asleep (easier, p = 0.001; faster, p < 0.001; more drowsy, p = 0.003) and improved quality of sleep (less wakefulness, p = 0.01) relative to 0% tetrahydrocannabinol. We found no differences in mood or quality of life. The most common drug-related adverse events during the period when participants received 9.4% tetrahydrocannabinol were headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness and cough.
Conclusion:
A single inhalation of 25 mg of 9.4% tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated. Further long-term safety and efficacy studies are indicated. (International Standard Randomised Controlled Trial Register no. ISRCTN68314063).
To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spasticity in people with multiple sclerosis.
The results from three randomized, placebo-controlled, double-blind parallel group studies were combined for analysis.
666 patients with multiple sclerosis and spasticity.
A 0-100 mm Visual Analogue Scale (VAS, transformed to a 0-10 scale) or a 0-10 Numerical Rating Scale (0-10 NRS) was used to measure spasticity. Patients achieving a > or =30% improvement from baseline in their spasticity score were defined as 'responders'. Global impression of change (GIC) at the end of treatment was also recorded.
The patient populations were similar. The adjusted mean change of the numerical rating scale from baseline in the treated group was -1.30 compared with -0.97 for placebo. Using a linear model, the treatment difference was -0.32 (95% CI -0.61, -0.04, p = 0.026). A statistically significant greater proportion of treated patients were responders (odds ratio (OR) = 1.62, 95% CI 1.15, 2.28; p = 0.0073) and treated patients also reported greater improvement: odds ratio 1.67 (95% CI 1.05, 2.65; p = 0.030). High numbers of subjects experienced at least one adverse event, but most were mild to moderate in severity and all drug-related serious adverse events resolved.
The meta-analysis demonstrates that nabiximols is well tolerated and reduces spasticity.
Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied.
Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent mu-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels.
Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit.
The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.
1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3), a potent analog of THC-11-oic acid, produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids. Therefore, CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain.
To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans.
Randomized, placebo-controlled, double-blind crossover trial conducted in Germany from May-September 2002.
Twenty-one patients (8 women and 13 men) aged 29 to 65 years (mean, 51 years) who had a clinical presentation and examination consistent with chronic neuropathic pain (for at least 6 months) with hyperalgesia (n = 21) and allodynia (n = 7).
Patients were randomized to two 7-day treatment orders in a crossover design. Two daily doses of CT-3 (four 10-mg capsules per day) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days. After a washout and baseline period of 1 week each, patients crossed over to the second 7-day treatment period.
Visual analog scale (VAS) and verbal rating scale scores for pain; vital sign, hematologic and blood chemistry, and electrocardiogram measurements; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale; and adverse effects.
The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence (mean [SD], -11.54 [14.16] vs 9.86 [21.43]; P =.02). Eight hours after intake of the drug, the pain scale differences between groups were less marked. No dose response was observed. Adverse effects, mainly transient dry mouth and tiredness, were reported significantly more often during CT-3 treatment (mean [SD] difference, -0.67 [0.50] for CT-3-placebo sequence vs 0.10 [0.74] for placebo-CT-3 sequence; P =.02). There were no significant differences with respect to vital signs, blood tests, electrocardiogram, Trail-Making Test, and Addiction Research Center Inventory-Marijuana scale. No carryover or period effects were observed except on the Trail-Making Test.
In this preliminary study, CT-3 was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed.
To evaluate the effect of the oral synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis.
Randomised double blind placebo controlled crossover trial.
Outpatient clinic, University Hospital of Aarhus, Denmark.
24 patients aged between 23 and 55 years with multiple sclerosis and central pain.
Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period.
Median spontaneous pain intensity (numerical rating scale) in the last week of treatment.
Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change.
Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.
Progress in the understanding of chronic pain with neuropathic features has been hindered by a lack of epidemiologic research in the general population. The Leeds Assessment of Neuropathic Symptoms and Signs score (S-LANSS) was recently validated for use in postal surveys, making the identification of pain of predominantly neuropathic origin possible. Six family practices in 3 UK cities (Aberdeen, Leeds, and London) generated a total random sample of 6,000 adults. The mailed questionnaire included demographic items, chronic pain identification, and intensity questions, the S-LANSS, the Level of Expressed Needs questionnaire, and the Neuropathic Pain Scale. With a corrected response rate of 52%, the prevalence of any chronic pain was 48% and the prevalence of pain of predominantly neuropathic origin was 8%. Respondents with this chronic neuropathic pain were significantly more likely to be female, slightly older, no longer married, living in council rented accommodation, unable to work, have no educational qualifications, and be smokers than all other respondents. Multiple logistic regression modeling found that pain of predominantly neuropathic origin was independently associated with older age, gender, employment (being unable to work), and lower educational attainment. Respondents with this pain type also reported significantly greater pain intensity, higher scores on the NPS, higher levels of expressed need, and longer duration of pain. This is the first estimate of the prevalence and distribution of pain of predominantly neuropathic origin in the general population, using a previously validated and reliable data collection instrument. PERSPECTIVE: Chronic pain with neuropathic features appears to be more common in the general population than previously suggested. This type of pain is more severe than other chronic pain but distributed similarly throughout sociodemographic groups.
In the course of developing a standardised, non-disease-specific instrument for describing and valuing health states (based on the items in Table 1), the EuroQol Group (whose members are listed In the Appendix) conducted postal surveys in England, The Netherlands and Sweden which indicate a striking similarity in the relative valuations attached to 14 different health states (see Table 3). The data were collected using a visual analogue scale similar to a thermometer (see Table 2). The EuroQol Instrument Is Intended to complement other quality-of-life measures and to facilitate the collection of a common data set for reference purposes. Others interested in participating in the extension of this work are invited to contact the EuroQol Group.
Unlabelled:
We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain.
Perspective:
The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning.
Background:
Patients with neuropathic pain present with various pain-related sensory abnormalities. These sensory features form different patterns or mosaics-the sensory profile-in individual patients. One hypothesis for the development of sensory profiles is that distinct pathophysiological mechanisms of pain generation produce specific sensory abnormalities. Several controlled trials of promising new drugs have produced negative results, but these findings could have been a result of heterogeneity in the patient population. Subgrouping patients on the basis of individual sensory profiles could reduce this heterogeneity and improve trial design.
Recent developments:
A statistical categorisation of patients with neuropathic pain showed that subgroups of patients with distinct sensory profiles who perceive their pain differently do exist across a range of neuropathic disorders, although some distinct disorder-specific profiles were also detected. Results of the first clinical trials to use the subgroup approach at baseline could show a superior effect of the study drugs in specific subgroups, rather than in the entire cohort of patients. WHERE NEXT?: A new classification of neuropathic pain should take into account subgroups of patients with different sensory profiles. Sensory phenotyping has the potential to improve clinical trial design by enriching the study population with potential treatment responders, and might lead to a stratified treatment approach and ultimately to personalised treatment.
Cannabinoids are emerging as potential options for neuropathic pain treatment. This study evaluated an oral cannabinoid, nabilone, in the treatment of refractory human diabetic peripheral neuropathic pain (DPN). We performed a single-center, randomized, double-blind, placebo-controlled, flexible-dose study with an enriched enrolment randomized withdrawal design. DPN subjects with a pain score ⩾4 (0-10 scale) continued regular pain medications and were administered single-blinded adjuvant nabilone for 4weeks. Subjects achieving ⩾30% pain relief (26/37) were then randomized and treated with either flexible-dose nabilone 1-4mg/day (n=13) or placebo (n=13) in a further 5-week double-blind treatment period, with 30% (11/37) of subjects deemed run-in-phase nabilone nonresponders. For nabilone run-in-phase responders, there was an improvement in the change in mean end-point neuropathic pain vs placebo (mean treatment reduction of 1.27; 95% confidence interval 2.29-0.25, P=0.02), with an average nabilone dose at end point of 2.9±1.1mg/day, and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale, the Medical Outcomes Study sleep scale problems index, and the European Quality of Life-5-Domains index score (each P<0.05). Nabilone run-in-phase responders reported greater global end-point improvement with nabilone than with placebo (100% vs 31%; P<0.05). Medication-related confusion led to discontinuation in 2/37 subjects during single-blind nabilone treatment. Potential unmasking occurred in 62% of both groups. Flexible-dose nabilone 1-4mg/day was effective in relieving DPN symptoms, improving disturbed sleep, quality of life, and overall patient status. Nabilone was well tolerated and successful as adjuvant in patients with DPN.
The adoption of new drug therapies involves an assessment of risk:benefit based upon the best clinical evidence, including clinical trials but also everyday clinical practice data collection. However, in the case of Sativex, a cannabinoid medicine containing the two main active ingredients of cannabis, δ-9-tetrahydrocannabinol and cannabidiol, the picture is somewhat clouded by preconceived views regarding the world's most widely used illicit drug, herbal cannabis. In this review, I aim to look beyond these preconceptions and evaluate the body of published data concerning this medicine currently approved in different countries for the management of one of the most frequent and disabling symptoms associated with multiple sclerosis, spasticity. In particular, data relevant to areas of concern such as tolerability, safety, psychoactivity, effects on withdrawal (including possible drug tolerance) and finally the potential for abuse/dependence are evaluated. Balancing these risk factors, the main positive clinical data published over the years by the Oxford Centre for Enablement, following on from the first pilot study in 2004, are presented. Based upon our experience, the benefits that are seen initially with Sativex when treating multiple sclerosis spasticity patients are generally maintained during long-term treatment. Furthermore, following withdrawal of Sativex, symptoms often return, but, beyond this, sudden cessation is generally safe with no evidence of physiological or psychological dependence. Dose escalation has not usually been observed in clinical trials or clinical practice after the first titration weeks. Adverse effects occur relatively frequently, but they are usually mild to moderate in intensity and rarely require drug discontinuation. Overall, Sativex appears to be well-tolerated and a useful addition for patients who have failed treatment with traditional antispastic agents.
Objectives. The goals of this study were to define the endpoints of pain research that are important to patients with chronic pain and to identify clinical and demographic variables that are associated with patients' choices of endpoints.
Patients & Setting. Interviews were completed with 40 patients seen at the anesthesia pain clinic of an urban tertiary care medical center.
Design. Each patient was presented with 4 brief (3–4 sentences) fixed information vignettes describing studies in which new medications would be evaluated. For each, patients were asked to describe how the medication being studied might offer an improvement over their current therapy.
Outcome measures. Measures included structured qualitative analysis of responses, the Brief Pain Inventory, and Global Distress Index of the Memorial Symptom Assessment Scale.
Results. Patients described a total of 20 endpoints. Individually, patients cited between 2 and 9 endpoints each (mean 4.9, standard deviation 1.7). Of these, the most commonly cited were decrease pain, decrease opioid dose, decrease frequency of scheduled dose, increased ability to function, decrease frequency of breakthrough dose, and improve sleep. Patients with severe pain cited more endpoints than did those with mild or moderate pain (mean 5.5 vs. 4.3; Rank sum test p = 0.01).
Conclusions. These data suggest that empirical research can provide data to guide the choice of endpoints in clinical studies of pain interventions.
A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.
Muscle spasticity is common in multiple sclerosis (MS), occurring in more than 60% of patients.
To compare Sativex with placebo in relieving symptoms of spasticity due to MS.
A 15-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy.
The primary endpoint was a spasticity 0-10 numeric rating scale (NRS). Intention-to-treat (ITT) analysis showed a non-significant improvement in NRS score, in favor of Sativex. The per protocol (PP) population (79% of subjects) change in NRS score and responder analyses (> or =30% improvement from baseline) were both significantly superior for Sativex, compared with placebo: -1.3 versus -0.8 points (change from baseline, p=0.035); and 36% versus 24% (responders, p=0.040). These were supported by the time to response (ITT: p=0.068; PP: p=0.025) analyses, carer global impression of change assessment (p=0.013) and timed 10-meter walk (p=0.042). Among the subjects who achieved a > or =30% response in spasticity with Sativex, 98, 94 and 73% reported improvements of 10, 20 and 30%, respectively, at least once during the first 4 weeks of treatment. Sativex was generally well tolerated, with most adverse events reported being mild-to-moderate in severity.
The 0-10 NRS and responder PP analyses demonstrated that Sativex treatment resulted in a significant reduction in treatment-resistant spasticity, in subjects with advanced MS and severe spasticity. The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status.
Pregabalin is effective in several neuropathic pain syndromes. This trial evaluated its efficacy, safety, and tolerability for treatment of painful HIV-associated neuropathy.
This randomized, double-blind, placebo-controlled, parallel-group trial included a 2-week double-blind dose-adjustment (150-600 mg/day BID) phase, a 12-week double-blind maintenance phase, and an optional 3-month open label extension phase. The primary efficacy measure was the mean Numeric Pain Rating Scale (NPRS) score, an 11-point numeric rating scale. Secondary measures included Patient Global Impression of Change (PGIC) and sleep measurements.
Baseline mean NPRS score was 6.93 for patients randomized to pregabalin (n = 151) and 6.72 for those to placebo (n = 151). Pregabalin average daily dosage (SD) was 385.7 (160.3) mg/d. At endpoint, pregabalin and placebo showed substantial reductions in mean NPRS score from baseline: -2.88 vs -2.63, p = 0.3941. Pregabalin had greater improvements in NPRS score relative to placebo at weeks 1 (-1.14 vs -0.69, p = 0.0131) and 2 (-1.92 vs -1.43, p = 0.0393), and at weeks 7 (-3.22 vs -2.53 p = 0.0307) and 8 (-3.33 vs -2.53, p = 0.0156). At all other time points, differences between groups were not significant. Sleep measurements and 7-item PGIC did not differ among treatment groups; however, collapsed PGIC scores showed 82.8% of pregabalin and 66.7% of placebo patients rated themselves in 1 of the 3 "improved" categories (p = 0.0077). Somnolence and dizziness were the most common adverse events with pregabalin.
Pregabalin was well-tolerated, but not superior to placebo in the treatment of painful HIV neuropathy. Factors predicting analgesic response in HIV neuropathy warrant additional research. Classification of Evidence: This Class II trial showed that pregabalin is not more effective than placebo in treatment of painful HIV neuropathy.
Poorly controlled cancer pain is a significant public health problem throughout the world. There are many barriers that lead to undertreatment of cancer pain. One important barrier is inadequate measurement and assessment of pain. To address this problem, the Pain Research Group of the WHO Collaborating Centre for Symptom Evaluation in Cancer Care has developed the Brief Pain Inventory (BPI), a pain assessment tool for use with cancer patients. The BPI measures both the intensity of pain (sensory dimension) and interference of pain in the patient's life (reactive dimension). It also queries the patient about pain relief, pain quality, and patient perception of the cause of pain. This paper describes the development of the Brief Pain Inventory and the various applications to which the BPI is suited. The BPI is a powerful tool and, having demonstrated both reliability and validity across cultures and languages, is being adopted in many countries for clinical pain assessment, epidemiological studies, and in studies of the effectiveness of pain treatment.
Postherpetic neuralgia (PHN) is a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients.
To determine the efficacy and safety of the anticonvulsant drug gabapentin in reducing PHN pain.
Multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996 through July 1997.
Sixteen US outpatient clinical centers.
A total of 229 subjects were randomized.
A 4-week titration period to a maximum dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants and/or narcotics were continued if therapy was stabilized prior to study entry and remained constant throughout the study.
The primary efficacy measure was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. Secondary measures included average daily sleep scores, Short-Form McGill Pain Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire, and Profile of Mood States (POMS). Safety measures included the frequency and severity of adverse events.
One hundred thirteen patients received gabapentin, and 89 (78.8%) completed the study; 116 received placebo, and 95 (81.9%) completed the study. By intent-to-treat analysis, subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary measures of pain as well as changes in pain and sleep interference showed improvement with gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the 2 groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group).
Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy.
A multicentre double blind, randomised, placebo controlled 7-week study evaluated the efficacy and safety of gabapentin 1800 or 2400 mg/day in treating postherpetic neuralgia. Three hundred and thirty-four men and women aged at least 18 years (mean 73) received gabapentin 1800 or 2400 mg daily or placebo in three divided doses with a forced titration schedule. The primary outcome measure was change in average daily pain diary score (baseline week v final week). Secondary outcomes included mean weekly sleep interference score; Short Form-McGill Pain Questionnaire (SF-MPQ); Clinician and Patient Global Impression of Change (CGIC/PGIC); Short Form-36 Health Survey (SF-36). From week 1, pain scores showed a significantly greater improvement with gabapentin: the final difference v baseline was -34.5% for the 1800 mg dose, -34.4% for the 2400 mg dose compared with -15.7% for the placebo group. The difference vs. placebo was 18.8% for the 1800 mg dose (95% confidence interval 10.9-26.8%; P<0.01) and 18.7% for the 2400 mg dose (10.7-26.7%; P<0.01). Sleep interference diaries showed a similar pattern. There were significant differences in favour of gabapentin for number of patients reporting >50% reduction in their pain intensity, in the CGIC and PGIC, in the sensory and total scores of the SF-MPQ (both doses), in the visual analogue scale of pain of the SF-MPQ (2400 mg only) and in the vitality, bodily pain and mental health domains of the SF-36. Overall gabapentin was well tolerated. The most common adverse events were dizziness and somnolence, particularly during the titration phase. Thus, this study confirms the role of gabapentin as an efficacious and well-tolerated treatment for postherpetic neuralgia.
Neuropathic pains refer to a heterogeneous group of pain conditions characterised by lesion or dysfunction of the normal sensory pathways. Clinical characteristics include: delayed onset of pain after nervous system lesion, pain in area of sensory loss, spontaneous and different evoked types of pains. It has so far only been possible to classify these pains on basis of underlying cause or on anatomical location. The mechanisms underlying neuropathic pain are not yet clear, but neuronal hyperexcitability in those neurons that have lost their normal patterned input seems to be a common denominator for many, if not all types, of neuropathic pains. Along these lines, a mechanism-based classification has recently been proposed, which is an attractive approach because it provides a frame for a rationally based therapy of neuropathic pains. The clinical manifestations of neuronal hyperexcitability due to nervous system lesions is described.
A double-blind, randomised, placebo-controlled 8-week study was conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain, using doses up to 2400 mg/day. The study used a novel design that was symptom- rather than syndrome-based; an approach that aimed to reflect the realities of clinical practice. Participants had a wide range of neuropathic pain syndromes, with at least two of the following symptoms: allodynia, burning pain, shooting pain, or hyperalgesia. Patients were randomised to gabapentin (n=153) or placebo (n=152). Gabapentin was given in three divided doses, initially titrated to 900 mg/day over 3 days, followed by two further increases, to a maximum of 2400 mg/day if required by the end of week 5. The primary outcome measure was changed in average daily pain diary score (baseline versus final week). Over the 8 week study, this score decreased (i.e. improved) by 1.5 (21%) in gabapentin treated patients and by 1.0 (14%) in placebo treated patients (P=0.048, rank-based analysis of covariance). Significant differences were shown in favour of gabapentin (P<0.05) for the Clinician and Patient Global Impression of Change, and some domains of the Short Form-McGill Pain Questionnaire. Improvements were also shown in patient-reported outcomes in quality of life, as seen by significant differences in favour of gabapentin in several domains of the Short-Form-36 Health Survey. Gabapentin was well tolerated and the majority of patients completed the study (79 versus 73% for placebo). The most common adverse events were mild to moderate dizziness and somnolence, most of which were transient and occurred during the titration phase. This study shows that gabapentin reduces pain and improves some quality-of-life measures in patients with a wide range of neuropathic pain syndromes.
The efficacy and safety of sustained-release tramadol compared to placebo in the treatment of post-herpetic neuralgia were evaluated in a multicenter, randomized, double-blind, parallel-group study in 127 outpatients. Treatment was administrated for 6 weeks. The dose of tramadol could be increased from 100 mg/day to 400 mg/day (300 mg/day in patients more than 75 years old). Groups were compared on changes in pain intensity on a Visual Analogue Scale (VAS) between inclusion and the 6th week of treatment (covariance analysis as main analysis and repeated measures analysis as complementary analysis) in the per protocol (PP) population. The randomized population comprised 127 patients aged 35-85 years, mostly females (72.4%). Groups were comparable at inclusion both in the intent to treat (ITT) population (63 patients in the tramadol group and 62 patients in the placebo group) and in the PP population (53 patients in the tramadol group and 55 patients in the placebo group). Mean pain intensity on day 43 adjusted on day 1 (covariance analysis) was significantly lower in the tramadol group than in the placebo group in both the PP (P=0.0499), and the ITT (P=0.031) populations. The two groups significantly differed on change in pain intensity over time (repeated measures analysis) in the ITT population (P=0.012). The percentage of pain relief over the 6th week was significantly higher in the tramadol group than in the placebo group (P=0.017). During the 6th week, patients in the tramadol group required less rescue medication than patients in the placebo group (P=0.022). No significant difference was found between groups either in pain intensity on a 5-point Verbal Scale (VRS) or in quality of life measurements. Tramadol was administered at an average dosage of 275.5 (89.7) mg/day after a 1-week dose-adaptation period. Tramadol was well tolerated. No notable difference appeared between groups either in the percentage of patients with treatment-associated adverse events (TAAE) (29.7% in the tramadol group and 31.8% in the placebo group) or in the total number of TAAE (31 in the tramadol group and 28 in the placebo group).
Peripheral neuropathic pain, that clinical pain syndrome associated with lesions to the peripheral nervous system, is characterized by positive and negative symptoms. Positive symptoms include spontaneous pain, paresthesia and dysthesia, as well as a pain evoked by normally innocuous stimuli (allodynia) and an exaggerated or prolonged pain to noxious stimuli (hyperalgesia/hyperpathia). The negative symptoms essentially reflect loss of sensation due to axon/neuron loss, the positive symptoms reflect abnormal excitability of the nervous system. Diverse disease conditions can result in neuropathic pain but the disease diagnosis by itself is not helpful in selecting the optimal pain therapy. Identification of the neurobiological mechanisms responsible for neuropathic pain is leading to a mechanism-based approach to this condition, which offers the possibility of greater diagnostic sensitivity and a more rational basis for therapy. We are beginning to move from an empirical symptom control approach to the treatment of pain to one targeting the specific mechanisms responsible. This review highlights some of the mechanisms underlying neuropathic pain and the novel targets they reveal for future putative analgesics.
A consensus conference with representatives from academia, governmental agencies, and the pharmaceutical industry met and concluded that clinical trials designed to assess the efficacy and effectiveness of treatments for chronic pain should consider outcomes in six core domains: pain, physical functioning, emotional functioning, patient global ratings of satisfaction, negative health states and adverse events, and patient disposition. In addition, it was acknowledged that there are many secondary domains that might be of importance and should be included in trials depending on the nature of the treatment and population to whom the treatment is targeted.
Treatment outcome in patients with neuropathic pain (NP) is often variable and disappointing. We tested the hypothesis that patients with clear evidence of nervous system lesion respond better to pharmacological treatment with documented effect on NP than patients with poor or no evidence of nervous system lesion. Furthermore, we examined whether specific symptoms or signs were associated with treatment outcome. A total of 214 patients with suspected non-cancer NP were divided into four groups with graded evidence of nervous system lesion based on medical history, bedside sensory examination, quantitative sensory tests, electrophysiology, and neuroimaging. Patients were treated with imipramine guided by plasma-drug concentrations. Gabapentin 2400 mg/day was given in case of treatment failure or if imipramine treatment was not possible. Two hundred patients completed the study. Global pain relief was similar in the four groups. There was no association between evidence of nervous system lesion and treatment outcome. Classical NP signs: abnormal temporal summation, cold and brush allodynia, and abnormal sensibility to temperature were also unrelated to outcome. Treatment outcome was similar in peripheral and central definite NP. Neither definite evidence of nervous system lesion nor abnormal sensory phenomena seems to predict for good outcome of therapy with imipramine or gabapentin in patients with suspected neuropathic pain.
The objective was to investigate the effectiveness of cannabis-based medicines for treatment of chronic pain associated with brachial plexus root avulsion. This condition is an excellent human model of central neuropathic pain as it represents an unusually homogenous group in terms of anatomical location of injury, pain descriptions and patient demographics. Forty-eight patients with at least one avulsed root and baseline pain score of four or more on an 11-point ordinate scale participated in a randomised, double-blind, placebo-controlled, three period crossover study. All patients had intractable symptoms regardless of current analgesic therapy. Patients entered a baseline period of 2 weeks, followed by three, 2-week treatment periods during each of which they received one of three oromucosal spray preparations. These were placebo and two whole plant extracts of Cannabis sativa L.: GW-1000-02 (Sativex), containing Delta(9)tetrahydrocannabinol (THC):cannabidiol (CBD) in an approximate 1:1 ratio and GW-2000-02, containing primarily THC. The primary outcome measure was the mean pain severity score during the last 7 days of treatment. Secondary outcome measures included pain related quality of life assessments. The primary outcome measure failed to fall by the two points defined in our hypothesis. However, both this measure and measures of sleep showed statistically significant improvements. The study medications were generally well tolerated with the majority of adverse events, including intoxication type reactions, being mild to moderate in severity and resolving spontaneously. Studies of longer duration in neuropathic pain are required to confirm a clinically relevant, improvement in the treatment of this condition.
Objective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. Methods. Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. Conclusions. There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and