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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.
... The remainder of the 32 studies evaluated insomnia symptoms in patients with cancer, 43 (Table 3). All but two studies 47,50 used subjective self-report questionnaires such as numeric rating scales, 31,32,35,38,39,42,43,46,52,55,56,58 Likert scales, 33 visual analog scales, 34,60,61 purposedeveloped survey questions, 44,49 the Pittsburgh Sleep Quality Index, 36,59 or specific questions within questionnaires such as the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire. 35,40,43,57 Two studies 47,50 utilized polysomnography to objectively measure CBDs impact on sleep outcomes. ...
... Nineteen studies investigated the effects of CBD monotherapy/predominant therapy on insomnia symptoms (seven cross-sectional studies, 22,33,35,37,44,48,49 four cohort studies, 36,38,41,45 four clinical trials, 42,47,51,60 three case series, 40,54,59 and one case report 30 ) ( Table 3). Twenty-one studies investigated the effects of products with nearly equal ratios of CBD to THC (17 clinical trials, 31 Johnson (2010) CBD-containing products were administered through various routes, including oromucosal or sublingual sprays/drops, 31,32,34,[39][40][41]43,44,46,[49][50][51][52][53][54][55][56]58,60,61 oral capsules/ gelatine, 40,44,47,49,59 inhalation, 38,49 or topical application 49 with varying dose and frequency. For studies that reported the quantity of CBD used, doses ranged from 2.5 mg of CBD to 330 mg daily. ...
... All the 34 studies reported some level of improvement in the insomnia symptoms of at least a portion of their participants following the administration of CBD-containing products ( 31,32,42,46,[51][52][53]55,56,58,60,61 ). ...
Background: Cannabidiol (CBD), one of the major cannabinoids derived from the cannabis plant, is available over the counter. CBD is often used by patients for the management of insomnia, yet research supporting CBDs effectiveness as a treatment for insomnia is inadequate. Objective: The objective of this review was to critically evaluate the literature regarding the therapeutic benefits of CBD in the management of insomnia. Methods: A comprehensive search of the following databases from inception to December 29, 2021, was conducted: Ovid MEDLINE® and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search included randomized controlled trials, nonrandomized experimental studies, cross-sectional studies, cohort studies, case series, and case reports. Risk of bias was assessed with the Agency for Healthcare Research and Quality design-specific recommended criteria. Results: Thirty-four studies were eligible for inclusion. All studies reported improvement in the insomnia symptoms of at least a portion of their participants. Of the 34 studies, 19 studies used CBD predominant therapy and 21 studies used nearly equal ratios of CBD to Δ9-tetrahydrocannabinol (THC). Of the studies that performed hypothesis testing, 4 of 7 studies with a CBD predominant arm and 12 of 16 studies with a nearly equal ratio of CBD to THC arm reported significant improvement in insomnia outcomes. However, only 2 of the 34 studies focused on patients with insomnia, of which 1 study was a case report. Additionally, several studies used nonvalidated subjective measures, and most studies failed to include objective measures for symptom assessment. Conclusions: The results of our systematic review suggest that CBD alone or with equal quantities of THC may be beneficial in alleviating the symptoms of insomnia. Nevertheless, future research assessing CBDs effectiveness in population of patients specifically with insomnia utilizing validated subjective and objective measures is necessary before definitive inferences can be made.
... 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.
... 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.
... In this regard, the use of phytocannabinoids is of wide appli-cation7. Dronabinol is used to treat loss of appetite, nausea, vomiting, and in neuropathic pain (NP), mainly in conditions involved with multiple sclerosis 8 . In addition, it has been used in other conditions such as chronic noncancer pain and in other diseases such as fibromyalgia 9 , allodynia 8 and chronic brachial plexus pain 10 , promoting pain relief. ...
... Dronabinol is used to treat loss of appetite, nausea, vomiting, and in neuropathic pain (NP), mainly in conditions involved with multiple sclerosis 8 . In addition, it has been used in other conditions such as chronic noncancer pain and in other diseases such as fibromyalgia 9 , allodynia 8 and chronic brachial plexus pain 10 , promoting pain relief. Despite relevant information on the effects of cannabinoids for pain treatment, little information has been accounted for regarding their actual effect on pain and especially whether they reduce the progression of synthetic opioids. ...
BACKGROUND AND OBJECTIVES
Prevalence of painful neuropathy is around 7%-10% in the entire population, also, it may have different histories and require integrated care. Challenges for patient care are concerning, most of them have not achieved satisfactory results with drugs for pain management, which are often disabling, in addition to associated comorbidities such as sleep disorders and mood swings. Most of the drugs currently being used for neuropathic pain (NP) have several adverse effects, which hinders adherence to treatment and makes it impossible to reach the doses that would be indicated for proper management. Given this scenario, studies are being done aiming at the endocannabinoid system present in the human body with the ability to modulate pain, sleep, and mood disorders, among other benefits. Drugs such as phytocannabinoids, mainly the molecules cannabidiol (CBD) and tetrahydrocannabidiol (THC), have been studied with significant potential for the treatment of painful neuropathy. This review aimed to describe the probable mechanisms of action of cannabinoids in NP and the results obtained so far with the use of these molecules.
CONTENTS
This study is a narrative review of the literature. Data were analyzed using the databases National Library of Medicine (NCBI), Academic Google, Medline and scientific database configurations by LILACS and Web of Science in a temporal search between 2004 and 2022. A total of 45 articles were counted.
CONCLUSION
THC modulates opioid effects in neuropathic pain. This is associated with a pharmacokinetic effect and has also been demonstrated by brain imaging. This significant performance can be associated with specific target sites and primary actors regarding Δ-9-THC and its binding to receptors associated with analgesia. Also, further studies with this component or associated with small cannabinoid variations are necessary to certify its role in neuropathic pain.
Keywords:
Cannabidiol; Cannabinoids; Cannabis; Pain
... Evidence summaries and clinical guideline recommendations 1. CBM use for people with chronic pain Forty-seven studies relevant to pain management were reviewed, including 22 RCT, 46-67 11 pre-post studies or uncontrolled trials, 68-78 11 cross-sectional or observational cohort studies, 79-89 and 3 case series. [90][91][92] Most studies (38/47) reported at least moderate benefits of CBM for chronic pain, [46][47][48]50,51,54,55,57,[59][60][61][62][63][64][65][66][67][68][69][70][73][74][75][76][77][78][79][80][82][83][84][86][87][88][89][90][91][92] seven were inconclusive or found insufficient evidence, 49,53,56,58,71,72,85 and two reported mixed results. 52,81 Associated improvements in secondary outcomes, including QoL, functionality, and mood, have also been observed with the use of medical cannabis in addition to reductions in pain severity, intensity, and interference. ...
... Although these five studies found improvements in nausea with cannabis use, other studies found nausea to be an adverse event associated with cannabis use among some participants. [46][47][48][49][50]54,[57][58][59]71,72,74,77,78 These studies were limited by study design (case series or cross-sectional surveys), small numbers of patients, unknown duration or dosing of cannabis, and the possibility of selection and recall bias. It is also unclear which cannabis formulation or route of administration is optimal (smoked vs. oral, THC vs. CBD vs. Practical tip. ...
Background: One in five individuals live with chronic pain globally, which often co-occurs with sleep problems, anxiety, depression, and substance use disorders. Although these conditions are commonly managed with cannabinoid-based medicines (CBM), health care providers report lack of information on the risks, benefits, and appropriate use of CBM for therapeutic purposes. Aims: We present these clinical practice guidelines to help clinicians and patients navigate appropriate CBM use in the management of chronic pain and co-occurring conditions. Materials and Methods: We conducted a systematic review of studies investigating the use of CBM for the treatment of chronic pain. Articles were dually reviewed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Clinical recommendations were developed based on available evidence from the review. Values and preferences and practical tips have also been provided to support clinical application. The GRADE system was used to rate the strength of recommendations and quality of evidence. Results: From our literature search, 70 articles met inclusion criteria and were utilized in guideline development, including 19 systematic reviews and 51 original research studies. Research typically demonstrates moderate benefit of CBM in chronic pain management. There is also evidence for efficacy of CBM in the management of comorbidities, including sleep problems, anxiety, appetite suppression, and for managing symptoms in some chronic conditions associated with pain including HIV, multiple sclerosis, fibromyalgia, and arthritis. Conclusions: All patients considering CBM should be educated on risks and adverse events. Patients and clinicians should work collaboratively to identify appropriate dosing, titration, and administration routes for each individual. Systematic Review Registration: PROSPERO no. 135886.
... Highly purified THC:CBD combination and CBD-only capsules demonstrated acceptable safety and tolerability profiles in clinical trials for persons with epilepsy, chronic pain, and symptoms associated with multiple sclerosis and cancers [40,[45][46][47][48][49][50][51][52][53][54][55][56]. In these trials, the common cannabinoid-related AEs were mostly somnolence, diarrhea, abdominal pain, fatigue, nausea, dry mouth, or dizziness, which occurred mainly during the up-titration and were considered mild or moderate in severity and resolved without discontinuation of the cannabinoid [40,[45][46][47][48][49][50][51][52][53][54][55][56]. ...
... Highly purified THC:CBD combination and CBD-only capsules demonstrated acceptable safety and tolerability profiles in clinical trials for persons with epilepsy, chronic pain, and symptoms associated with multiple sclerosis and cancers [40,[45][46][47][48][49][50][51][52][53][54][55][56]. In these trials, the common cannabinoid-related AEs were mostly somnolence, diarrhea, abdominal pain, fatigue, nausea, dry mouth, or dizziness, which occurred mainly during the up-titration and were considered mild or moderate in severity and resolved without discontinuation of the cannabinoid [40,[45][46][47][48][49][50][51][52][53][54][55][56]. Similar to these studies, our participants also experienced somnolence and diarrhea as common AEs regardless of study arm. ...
Background:
With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed.
Methods:
We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0-2 scores).
Results:
Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate.
Conclusions:
In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.
... In recent years, numerous clinical studies and meta-analyses have shown that medicinal cannabis and cannabinoids-by acting on the cannabinoid receptors (CBs) of the endocannabinoid system-are effective in alleviating neuropathic pain [7][8][9][10][11]. Evidence suggests this alternative treatment approach may be suitable also for trigeminal neuralgia [12,13]. ...
Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment of neuropathic pain. Here, we investigated the effect of URB937, a blood–brain barrier impermeant FAAH inhibitor, on experimentally induced mechanical allodynia in an animal model of trigeminal neuralgia. Male Sprague-Dawley rats were subjected to chronic constriction injury of the infraorbital nerve (IoN-CCI); operated animals were treated sub-chronically with URB937 (1 mg/kg, i.p.) or vehicle before or after trigeminal mechanical allodynia establishment. We also assayed mRNA expression levels of the pain neuropeptide calcitonin gene-related peptide (CGRP) and cytokines in the medulla, cervical spinal cord, and trigeminal ganglion ipsilateral to IoN-CCI using rt-PCR. URB937 treatment prevented the development of mechanical allodynia and IoN-CCI-induced changes in mRNA expression levels of CGRP and cytokines in the evaluated areas. When administered after allodynia development, URB937 prevented IoN-CCI-induced changes in CGRP and cytokine gene expression; this was not associated with a significant abrogation of the mechanical allodynia. These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms.
... For example, CBD is hypothesised to control self-perpetuating inflammatory pathways that ultimately dictate the depth and duration of mucosal injury to deliver clinically meaningful benefits [62,[131][132][133]. In parallel, THC has the capacity to provide complementary effects to control anxiety, promote food intake/appetite and sleep quality [134][135][136][137]. However, it cannot be ignored that while THC provides potential benefits for the patient, it certainly introduces additional medicolegal complexity, with many countries enforcing strict no-tolerance laws with respect to operating heavy machinery or driving motor vehicles. ...
The side effects of cancer therapy continue to cause significant health and cost burden to the patient, their friends and family, and governments. A major barrier in the way in which these side effects are managed is the highly siloed mentality that results in a fragmented approach to symptom control. Increasingly, it is appreciated that many symptoms are manifestations of common underlying pathobiology, with changes in the gastrointestinal environment a key driver for many symptom sequelae. Breakdown of the mucosal barrier (mucositis) is a common and early side effect of many anti-cancer agents, known to contribute (in part) to a range of highly burdensome symptoms such as diarrhoea, nausea, vomiting, infection, malnutrition, fatigue, depression, and insomnia. Here, we outline a rationale for how, based on its already documented effects on the gastrointestinal microenvironment, medicinal cannabis could be used to control mucositis and prevent the constellation of symptoms with which it is associated. We will provide a brief update on the current state of evidence on medicinal cannabis in cancer care and outline the potential benefits (and challenges) of using medicinal cannabis during active cancer therapy.
... A previous clinical study described the therapeutic efficacy of CBD and Δ9-THC co-administration, in doses of 2.5 mg CBD and 2.7 mg Δ9-THC in an oral mucosa spray. After treatment sessions ranging from one to several weeks, patients reported improved sleep, reduced pain, and reduced fatigue (Serpell et al. 2014). ...
Abstract Introduction Cannabidiol (CBD) is a potential therapeutic for pain management. Yet, there exists a dearth of studies of its tolerability and efficacy, especially in special populations. Former elite athletes are a special population both susceptible to chronic pain and also highly trained and attuned to assess medication tolerability concerns. The purpose of the present open-label pilot study was to assess the tolerability of CBD in this population. Materials and methods Retrospective analysis was conducted in deidentified data from 20 individuals who were all previously professional athletes in US/American football, track and field, or basketball, with careers ranging from 4 to 10 years. Participants received topical CBD (10 mg twice daily by controlled dispenser) for chronic pain resulting from acute lower extremity injuries. Assessments of tolerability and secondary analyses of pain, pain-related disability, and activities of daily living were collected by self-report over the 6-week study period. Data were analyzed by descriptive statistics, pairwise t-test, and linear regression. Results Seventy percent of participants completed the study. Of the individuals who completed the study, 50% reported minor adverse effects, none of which required medical attention, and 50% did not report any adverse effects. The mostly commonly reported effects were skin dryness (43% of study completers) and skin rash (21% of study completers), which rapidly resolved. There was a significant improvement in self-reported pain levels (intake mean 3.5 ± 0.29; exit mean 1.7 ± 0.23; P
... The most common conditions for which individuals obtain medical cannabis cards are pain, insomnia, anxiety and depressed mood (8-10), but evidence for the efficacy of cannabis to treat these symptoms has been mixed (7,(11)(12)(13)(14)(15)(16)(17)(18). Studies examining the effects of cannabis on chronic pain have generally had small sample sizes and null results (19), except for some evidence of efficacy for neuropathic pain (19)(20)(21). While patients using opioid medications for chronic pain have reported preliminary success in substituting cannabis for these medications (22, 23), electronic health records, including prescription drug monitoring program data from a large multisite medical cannabis program, demonstrated minimal to no change in either opioids or sedative hypnotics over the 6 months of medical cannabis use (24). ...
Background
Evidence for long-term effectiveness of commercial cannabis products used to treat medical symptoms is inconsistent, despite increasingly widespread use.Objective
To prospectively evaluate the effects of using cannabis on self-reported symptoms of pain, insomnia, anxiety, depression, and cannabis use disorder (CUD) after 12 months of use.Methods
This observational cohort study describes outcomes over 9 months following a 12-week randomized, waitlist-controlled trial (RCT: NCT03224468) in which adults (N = 163) who wished to use cannabis to alleviate insomnia, pain, depression, or anxiety symptoms were randomly assigned to obtain a medical marijuana card immediately (immediate card acquisition group) or to delay obtaining a card for 12 weeks delay (delayed card acquisition group). During the 9-month post-randomization period, all participants could use cannabis as they wished and choose their cannabis products, doses, and frequency of use. Insomnia, pain, depression, anxiety, and CUD symptoms were assessed over the 9-month post-randomization period.ResultsAfter 12 months of using cannabis for medical symptoms, 11.7% of all participants (n = 19), and 17.1% of those using cannabis daily or near-daily (n = 6) developed CUD. Frequency of cannabis use was positively correlated with pain severity and number of CUD symptoms, but not significantly associated with severity of self-reported insomnia, depression, or anxiety symptoms. Depression scores improved throughout the 9 months in all participants, regardless of cannabis use frequency.Conclusions
Frequency of cannabis use was not associated with improved pain, anxiety, or depression symptoms but was associated with new-onset cannabis use disorder in a significant minority of participants. Daily or near-daily cannabis use appears to have little benefit for these symptoms after 12 months of use.
... The search term "cannabis" AND "pain" was used in PubMed and results filtered for clinical trials; papers that were not relevant to pain were removed from the search. Of the 27 clinical trials described in Table 2, two-thirds of the trials reported a clear significant beneficial effect in the majority of their patients [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. Four of the trials found no significant benefit in comparison with placebo [80][81][82][83]; therefore, overall owing to a clear majority significant benefit in the use of CBPM to treat pain. ...
Dysmenorrhoea effects up to 90% of women of reproductive age, with medical management options including over-the-counter analgesia or hormonal contraception. There has been a recent surge in medicinal cannabis research and its analgesic properties. This paper aims to critically investigate the current research of medicinal cannabis for pain relief and to discuss its potential application to treat dysmenorrhoea. Relevant keywords, including medicinal cannabis, pain, cannabinoids, tetrahydrocannabinol, dysmenorrhoea, and clinical trial, have been searched in the PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library (Wiley) databases and a clinical trial website (clinicaltrials.gov). To identify the relevant studies for this paper, 84 papers were reviewed and 20 were discarded as irrelevant. This review critically evaluated cannabis-based medicines and their mechanism and properties in relation to pain relief. It also tabulated all clinical trials carried out investigating medicinal cannabis for pain relief and highlighted the side effects. In addition, the safety and toxicology of medicinal cannabis and barriers to use are highlighted. Two-thirds of the clinical trials summarised confirmed positive analgesic outcomes, with major side effects reported as nausea, drowsiness, and dry mouth. In conclusion, medicinal cannabis has promising applications in the management of dysmenorrhoea. The global medical cannabis market size was valued at USD 11.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 21.06% from 2022 to 2030. This will encourage academic as well as the pharmaceutical and medical device industries to study the application of medical cannabis in unmet clinical disorders.
... Three studies included high-dose THC groups, [17][18][19] whereas five studies included low-dose THC groups. [20][21][22][23][24] Five studies included CBD. 17-20 23 Compared with placebo, cannabinoid use was associated with a significant reduction in pain intensity scores (SMD: −0.55, 95% CI:−0.69 to −0.19, 95% PI: −1.51 to 0.39, p=0.003, I 2 =82.49, τ 2 =0.20, ...
Background
Chronic neuropathic pain is often debilitating and can have a significant impact on sleep health and quality of life. There is limited information on the impact of cannabinoids on sleep health when treating neuropathic pain.
Objective
The objectives of this systematic review and meta-analysis were to determine the effect of cannabinoids on sleep quality, pain intensity, and patient impression of treatment efficacy in patients with neuropathic pain.
Evidence review
Nine available medical literature databases were searched for randomized controlled trials comparing synthetic and natural cannabinoids to placebo in patients with neuropathic pain syndromes. Data on validated tools for sleep quality, pain intensity, patients’ global impression of change (PGIC), and incidence of adverse effects of cannabinoids were extracted and synthesized.
Findings
Of the 3491 studies screened, eight randomized controlled trials satisfied the inclusion criteria for this review. Analyses were performed using R -4.1.2. using the metafor package and are interpreted using alpha=0.05 as the threshold for statistical significance. Validated measures for sleep health were not used in most studies. Meta-analysis of data from six studies showed that cannabinoids were associated with a significant improvement in sleep quality (standardized mean difference (SMD): 0.40; 95% CI: 0.19 to −0.61, 95% prediction interval (PI): −0.12 to 0.88, p-value=0.002, I ² =55.26, τ ² =0.05, Q-statistic=16.72, GRADE: moderate certainty). Meta-analysis of data from eight studies showed a significant reduction in daily pain scores in the cannabinoid (CB) group (SMD: −0.55, 95% CI:−0.69 to −0.19, 95% PI: −1.51 to 0.39, p=0.003, I ² =82.49, τ ² =0.20, Q-statistic=47.69, GRADE: moderate certainty). However, sleep health and analgesic benefits were associated with a higher likelihood of experiencing daytime somnolence, nausea, and dizziness.
Conclusions
Cannabinoids have a role in treating chronic neuropathic pain as evidenced by significant improvements in sleep quality, pain intensity, and PGIC. More research is needed to comprehensively evaluate the impact of cannabinoids on sleep health and analgesic efficacy.
PROSPERO registration number
CRD42017074255.
... Scientifically, they are termed "cannabinoids", reflecting their distinctive chemotype and their interactions with the human endogenous cannabinoid system [3,4]. THC is renowned for its intoxicating and euphorigenic effects but has also demonstrated efficacy in treating conditions such as chronic pain, chemotherapy-induced nausea and vomiting, and spasticity in multiple sclerosis [2,[5][6][7][8][9][10]. CBD is a non-intoxicating cannabinoid with a well-established safety profile at therapeutic doses [11][12][13][14][15]. Clinical trials have demonstrated efficacy of CBD in treating epilepsy, anxiety, and psychosis [16][17][18]. ...
Background
Australian pharmacists currently dispense a wide range of prescription-only cannabis-based medicines. Recent regulatory changes will expand the role of pharmacists, allowing certain low-dose cannabidiol products to be supplied without a prescription in pharmacies. This harmonises Australia with many other countries where cannabidiol products are readily available to consumers.
Aim
To examine Australian pharmacists’ experience, knowledge and attitudes towards medicinal cannabis and their preparedness to supply over-the-counter low-dose cannabidiol products.
Method
We conducted a cross-sectional study using a 51-item on-line questionnaire that was informed by previous surveys of health professionals and assessed for face validity. Australian pharmacists were recruited to complete the survey between May and December 2021, primarily through professional pharmacy organisations. Pharmacists were included in the final dataset if they completed the demographic characteristics section and at least one additional section of the questionnaire. Data were analysed using descriptive and relational statistical tests.
Results
There were 272 attempts to complete this survey and 217 responses included in the final dataset. Over half of the respondents (60.0%, 130/217) had dispensed at least one medicinal cannabis prescription during their career and 58.5% (127/217) had received at least one medicinal cannabis enquiry in the last fortnight. Only around half (53.9%, 117/217) felt comfortable supplying medicinal cannabis products and fewer (39.3%, 79/201) were confident discussing cannabis-related enquiries. More than half of the respondents (58.7%, 118/201) supported the provision of low-dose cannabidiol products through pharmacies. Two-thirds (67.8%, 80/118) of respondents achieved relatively low scores (< 60%) in the knowledge component of the survey. Most respondents (94.2%, 178/189) endorsed a need for further training in this area.
Conclusion
Australian pharmacists tended to support medicinal cannabis availability and improved access to low-dose cannabidiol products via pharmacies. However, results highlight a need for improved training and education of pharmacists around cannabis-based medicines.
... The clinical use of cannabinoid preparations such as Sativex ® , containing Δ9-THC and CBD has been shown to be successful in the alleviation of chronic pain (Bilbao and Spanagel, 2022). Despite pitfalls in reaching primary endpoints in clinical investigation (Berman et al., 2004;Serpell et al., 2014;Lichtman et al., 2018), secondary endpoints were reached improving the overall quality of life of patients. Furthermore, both compounds display individual and overlapping routes of action in pain alleviation, studied respectively (Russo, 2008). ...
Endocannabinoids (eCBS) are endogenously derived lipid signaling molecules that serve as tissue hormones and interact with multiple targets, mostly within the endocannabinoid system (ECS). The ECS is a highly conserved regulatory system involved in homeostatic regulation, organ formation, and immunomodulation of chordates. The term “cannabinoid” evolved from the distinctive class of plant compounds found in Cannabis sativa, an ancient herb, due to their action on CB1 and CB2 receptors. CB1/2 receptors are the primary targets for eCBs, but their effects are not limited to the ECS. Due to the high interest and extensive research on the ECS, knowledge on its constituents and physiological role is substantial and still growing. Crosstalk and multiple targeting of molecules are common features of endogenous and plant compounds. Cannabimimetic molecules can be divided according to their origin, natural or synthetic, including phytocannabinoids (pCB’s) or synthetic cannabinoids (sCB’s). The endocannabinoid system (ECS) consists of receptors, transporters, enzymes, and signaling molecules. In this review, we focus on the effects of cannabinoids on Cys-loop receptors. Cys-loop receptors belong to the class of membrane-bound pentameric ligand gated ion channels, each family comprising multiple subunits. Mammalians possess GABA type A receptors (GABAAR), glycine receptors (GlyR), serotonin receptors type 3 (5-HT3R), and nicotinic acetylcholine receptors (nAChR). Several studies have shown different modulatory effects of CBs on multiple members of the Cys-loop receptor family. We highlight the existing knowledge, especially on subunits and protein domains with conserved binding sites for CBs and their possible pharmacological and physiological role in epilepsy and in chronic pain. We further discuss the potential for cannabinoids as first line treatments in epilepsy, chronic pain and other neuropsychiatric conditions, indicated by their polypharmacology and therapeutic profile.
... Although, as far as we know, there were no studies based on pure CBD intraoral administration. 27,28,29 Scientists are still trying to find the best way of CBD application, to improve it's absorption. Wong et al. 30 found that the trigeminal ganglion had both CB1 and CB2 receptors that innervate the rat masseter muscles and prooved that intramuscular injection of CBD alone (5mg/ml) decreased mechanical sensitization and increased the mechanical threshold of masseter muscle mechanoreceptors. ...
Introduction: Temporomandibular disorders (TMD) and orofacial pain present therapeutic challenges. Interest in the use of CBD-based medications has outpaced the knowledge of its efficacy and safety in treating TMD. The objective of this review was to evaluate the effectiveness of CBD-based medications in individuals with TMD.
Materials and Methods: The PubMed, Embase, Scopus databases were examined. The search was filtered to include only papers published from 2007 to 2022. The main question was asked: Can CBD/Cannabis play an important role in the therapy of orofacial pain and TMD?
Results: After applying the inclusion and exclusion criteria and analyzing the abstracts, 31 articles were finally selected.
Conclusions: CBD should be taken into consideration in the therapy of masticatory muscles in patients with TMD and orofacial pain. Further research is needed for CBD administration.
... Several clinical trials have shown inconclusive results on the use of selective cannabinoid products containing THC for the treatment of chronic neuropathic pain in adults. [14][15][16] In other studies, treatment with THC containing cannabinoids decreased pain in patients with rheumatoid arthritis and neuropathic radiculopathy. 17,18 The THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingular cortex and sensorimotor cortex in functional MRI imaging. ...
Background
The prevalence of chronic pain in children and adolescents is high. In some patients, it can be severe and refractory to conventional treatment options. There is increasing interest in the use of cannabinoids for therapeutic purposes in children and adolescents. Nabilone, a synthetic cannabinoid, is approved in Canada for the treatment of nausea and vomiting associated with chemotherapy. It can also be used off label for treatment of chronic pain.
Aims
This study aims to characterize the use of nabilone for severe chronic pain in a pediatric population.
Methods
This is a retrospective cohort study of patients 18 years or younger who were prescribed nabilone for chronic pain in a tertiary multidisciplinary pediatric chronic pain clinic between July 1, 2013 and June 30, 2017.
Results
During the four-year study period, we screened the charts of 507 patients and identified a total of 28 patients (5.5%) who were treated with nabilone as part of their chronic pain treatment. Common indications for nabilone treatment include mixed neuropathic/nociceptive pain, abdominal pain, neuropathic pain, and spasticity. In all patients, nabilone was prescribed as an adjunctive treatment. 7 patients (25%) reported a slight improvement in pain symptoms. Side effects were reported by 21.4% of patients. The most common reported side effects were sedation and cognitive slowing.
Conclusions
Adjunctive treatment with nabilone may improve pain symptoms in a subset of pediatric chronic pain patients. Further research investigating the long-term safety and efficacy of nabilone in the treatment of chronic pain in children is needed.
... In patients with treatment-resistant peripheral neuropathic pain, oromucosal CBD spray improved pain control and increased sleep quality. 12 Transdermal application of CBD oils also have been shown to significantly improve pain and reduce other disturbing sensations in patients experiencing diabetic peripheral neuropathy. 13 CONCLUSIONS Future research is needed to determine the usefulness of CBD oils after dental procedures and in the management of various orofacial pain conditions. ...
... This finding is in line with the published literature demonstrating the positive effect of THC on sleep, in the context of different medical indications, both in controlled (87)(88)(89) and uncontrolled studies (45,(90)(91)(92). Similar results were found in controlled studies on a combination of THC and CBD (93)(94)(95). As for the effect of CBD on sleep, one study showed that CBD does not impair sleep (96), and several uncontrolled studies have shown that CBD improves sleep (69,97). ...
Background
Almost 90% of patients with dementia suffer from some type of neurobehavioral symptom, and there are no approved medications to address these symptoms.
Objective
To evaluate the safety and efficacy of the medical cannabis oil “Avidekel” for the reduction of behavioral disturbances among patients with dementia.
Materials and methods
In this randomized, double-blind, single-cite, placebo-controlled trial conducted in Israel ( ClinicalTrials.gov : NCT03328676), patients aged at least 60, with a diagnosis of major neurocognitive disorder and associated behavioral disturbances were randomized 2:1 to receive either “Avidekel,” a broad-spectrum cannabis oil (30% cannabidiol and 1% tetrahydrocannabinol: 295 mg and 12.5 mg per ml, respectively; n = 40) or a placebo oil ( n = 20) three times a day for 16 weeks. The primary outcome was a decrease, as compared to baseline, of four or more points on the Cohen-Mansfield Agitation Inventory score by week 16.
Results
From 60 randomized patients [mean age, 79.4 years; 36 women (60.0%)], 52 (86.7%) completed the trial (all eight patients who discontinued treatment were from the investigational group). There was a statistically significant difference in the proportion of subjects who had a Cohen-Mansfield Agitation Inventory score reduction of ≥ 4 points at week 16: 24/40 (60.0%) and 6/20 (30.0%) for investigational and control groups, respectively (χ ² = 4.80, P = 0.03). There was a statistically significant difference in the proportion of subjects who had a Cohen-Mansfield Agitation Inventory score reduction of ≥ 8 points at week 16: 20/40 (50%) and 3/20 (15%), respectively (χ ² = 6.42, P = 0.011). The ANOVA repeated measures analysis demonstrated significantly more improvement in the investigational group compared to the control group at weeks 14 and 16 ( F = 3.18, P = 0.02). Treatment was mostly safe, with no significant differences in the occurrence of adverse events between the two groups.
Conclusion
In this randomized controlled trial, ‘Avidekel’ oil significantly reduced agitation over placebo in patients suffering from behavioral disturbances related to dementia, with non-serious side-effects. Further research is required with a larger sample size.
... Current clinical data indicate that vaporized cannabis flower can reduce chronic pain (Wallace et al., 2015;Wilsey et al., 2016); and that oral cannabinoids are effective in reducing chemotherapy-induced nausea and vomiting (Meiri et al., 2007), and patient-reported spasticity in multiple sclerosis (Zajicek et al., 2003). Other studies suggest potential sleep improvement associated primarily with oral cannabinoids in patient populations (Serpell et al., 2014;Whiting et al., 2015). Though a comprehensive account of clinical research with cannabis and cannabinoids falls outside the scope of the present manuscript, interested readers can refer to reviews by Whiting et al. (2015), National Academies of Sciences, Engineering, and Medicine (2017), and Pratt et al. (2019). ...
Aim: To characterize perceived benefits and challenges experienced by medicinal cannabis users.
Methods: An anonymous online survey collected demographics, health information, and open-ended responses from medicinal cannabis users regarding perceptions, motivations, and experience of treatment. Qualitative open-ended responses were thematically analyzed.
Results: Respondents ( N = 808) were predominantly White (79%), female (63%), with a mean (SD) age of 38 (20). Two hundred eighty-four (35%) respondents provided data on a dependent family member (e.g., child; 22% of total sample). Most used cannabidiol (CBD)-dominant products (58%), primarily for neurological disorders (38%) or pain (25%). Primary motivations for medicinal cannabis use were based on beliefs that traditional treatments were ineffective and/or had intolerable side effects (51%), positive scientific or media portrayals of the safety/efficacy of cannabis as a therapeutic (29%), or preference for “natural” treatments over pharmaceuticals (21%). A majority of respondents (77%) attributed positive effects to the medicinal use of cannabis/cannabinoids. These included physical symptom improvements such as reduced pain (28%), improved sleep (18%), and seizure reduction (18%), and mental health improvements including reduced anxiety (22%) and improved mood (11%). Additionally, respondents reported reduced use of other medications (e.g., opioids) (12%), and improved quality of life (14%). Problems associated with use were cited by 41% of respondents, and included unwanted side effects (16%), lack of information or medical support (16%), prohibitive costs (12%), and legal concerns (10%).
Conclusion: Most participants reported benefits from cannabis use for a variety of conditions where traditional treatments were ineffective or unacceptable. Concerns regarding cannabis side effects, legality, lack of information, and cost were raised. Data indicate greater research and education on the safety and efficacy of medicinal cannabis/cannabinoid use is warranted.
... He contended that CBD works to enhance THC's therapeutic effects [4]. As evidence, he cited a 2010 clinical trial of Sativex, a botanical compound comprised of THC and CBD, to treat neuropathic pain in people with multiple sclerosis [5]. The study consisted of 177 participants and had three arms. ...
The following disquisition investigates interpretations, insights, and inconsistencies causing conflicts, controversies, and consternation within the segment of the scientific community that studies the viability of treating physiological and psychological conditions through the administration of botanic cannabinoids. The intrinsic constructs and theories involved in this aspect of scientific inquiry are complex and convoluted, with deep-rooted biases dependent on the paradigm to which the researcher subscribes. This paper aims to examine two constructs of controversy, each related to competing paradigms inherent within the study of biomolecular psychology.
... The meta-analysis (Fig. 3) showed the beneficial effect of cannabinoids on chronic pain (SMD − 0.26, 95% CI − 0.35 to − 0.17; P < 0.00001). Further subgroup analyses indicated that compared to placebo, dronabinol [10,11,95,106,139,150,161,12,23,34,45,56,72,73,84] and nabiximols [10,[33][34][35][36][37][38][39][40][41][42][43][44][46][47][48][49][50][51][52] were associated with significant improvements and moderate evidence ( Fig. 2B) in conditions causing chronic pain (dronabinol SMD − 0.31; nabiximols SMD − 0.25, P < 0.0001). Trials using nabilone vs placebo [114,115,118,119,122,[124][125][126]162] (but not vs active [120,121,123]) also reported a significant effect (SMD − 0.41, P = 0.02), but the evidence on this effect was low (Fig. 2B). ...
Background
Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events.
Methods
We systematically reviewed (registered at PROSPERO: CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea /vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevant/disease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools.
Results
In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD − 0.5[CI − 0.62, − 0.38] high grade) and Parkinsonism (− 0.41[CI − 0.75, − 0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (− 0.31[CI − 0.46, − 0.15]), appetite (− 0.51[CI − 0.87, − 0.15]) and Tourette (− 1.01[CI − 1.58, − 0.44]) and moderate evidence for nabiximols on chronic pain (− 0.25[− 0.37, − 0.14]), spasticity (− 0.36[CI − 0.54, − 0.19]), sleep (− 0.24[CI − 0.35, − 0.14]) and SUDs (− 0.48[CI − 0.92, − 0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid.
Conclusions
Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.
... 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.
... 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.
... 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.
Introduction: This review aims to provide an overview of the advancements and status of clinical studies and potential permeation-enhancing strategies in the transdermal delivery of cannabinoids. Methods: A systematic and comprehensive literature search across academic databases, search engines, and online sources to identify relevant literature on the transdermal administration of cannabinoids. Results: Cannabinoids have proven beneficial in the treatment of wide-ranging physical and psychological disorders. A shift toward legalized cannabinoid products has increased both interests in cannabinoid research and the development of novel medicinal exploitations of cannabinoids in recent years. Oral and pulmonary delivery of cannabinoids has several limitations, including poor bioavailability, low solubility, and potential side effects. This has diverted scientific attention toward the transdermal route, successfully overcoming these hurdles by providing higher bioavailability, safety, and patient compliance. Yet, due to the barrier properties of the skin and the lipophilic nature of cannabinoids, there is a need to increase the permeation of the drugs to the underneath layers of skin to reach desired therapeutic plasma levels. Literature describing detailed clinical trials on cannabinoid transdermal delivery, either with or without permeation-enhancing strategies, is limited. Conclusion: The limited number of reports indicates that increased attention is needed on developing and examining efficient transdermal delivery systems for cannabinoids, including patch design and composition, drug-patch interaction, clinical effectiveness and safety in vivo, and permeation-enhancing strategies.
Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta‐9‐tetrahydrocannabinol (THC). While there have been some positive findings, meta‐analyses of this clinical work indicates that this effectiveness is limited and hampered by side‐effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC‐containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side‐effects of cannabis. image
Objective:
Nabiximols is used for treating various symptoms associated with multiple sclerosis (MS). Nabiximols is also being investigated as a potential treatment medication for individuals with cannabis use disorder (CUD). A variety of investigations have shown that, at low doses, nabiximols is overall well tolerated for MS treatment. However, due to tolerance, the management of CUD would likely require much higher doses of nabiximols to be effective. The effects of high doses of nabiximols on clinical laboratory tests remain unclear. Therefore, we investigated the sub-chronic effects of high doses of nabiximols on liver function, renal function, and other routine blood tests in this prospective study.
Methods:
We performed a secondary analysis of various blood markers results collected during a double-blind, placebo-controlled randomized clinical trial (Sativex and Behavioral-relapse Prevention Strategy in Cannabis Dependence, NCT01747850, https://clinicaltrials.gov/ct2/show/record/NCT01747850). This trial tested the impact of the 12-week administration of nabiximols with a maximum daily dose of up to 113.4 mg THC/105 mg CBD.
Results:
The measurements of the various biomarkers were in the normal range during the 12-week time frame. The results indicate an overall good tolerability of high-dose nabiximols on the blood markers measured.
Conclusion:
Our preliminary results suggest that high doses of nabiximols might be well tolerated by individuals with CUD.
Introduction:
Medical cannabis has been used to relieve the symptoms of people with various chronic diseases. Despite of this, it has been stigmatized, even after its legalization in many countries.
Aim:
The purpose of this study was to investigate the quality of life of patients receiving medical cannabis.
Material and method:
One hundred patients receiving medical cannabis were given (a) a socio-demographic and clinical questionnaire, and (b) the SF-36 Health Survey scale for assessing quality of life.
Results:
The majority of our patients who received medical cannabis to treat their neurological disorders (58%) reported decrease in their symptoms (96%), better energy and vitality (68%), ability to perform their professional duties (88%), and an improvement in sleeping and appetite (79% and 71%, respectively) after receiving medical cannabis. Our participants exhibited very few restrictions in activities due to emotional difficulties, a moderate general health status as well as moderate vitality and energy. Participants, who reported a longer period of receiving medical cannabis, reported statistically significant more energy and vitality (p = 0.000), but also better mental (p = 0.000) and general health status (p = 0.001). Furthermore, the majority of patients have disclosed medical cannabis use to their family members (85%) and enjoyed their support (93%), but they haven't revealed their medication treatment to their social environment (81%).
Conclusions:
Appropriate knowledge could significantly help health professionals in the field of planning and implementation of personalized nursing care in order to achieve optimal therapeutic outcomes.
Health care providers face a tremendous difficulty in dealing with the widespread, substantial, and disabling condition of chronic neuropathic pain. Although there are several pharmaceutical options, no standard treatment currently exists for neuropathic pain that is effective in the long
Health care providers face a tremendous difficulty in dealing with the widespread, substantial, and disabling condition of chronic neuropathic pain. Although there are several pharmaceutical options, no standard treatment currently exists for neuropathic pain that is effective in the long
Le domaine des neurosciences a connu des avancées considérables ces dernières années grâce au développement de technologies d'imagerie de plus en plus performantes. Depuis 10 ans, l’imagerie fonctionnelle ultrasonore (fUS) participe activement à la progression de la compréhension de l’activité cérébrale. Elle permet l’imagerie du couplage neurovasculaire (CNV) par lequel l’activité neuronale induit une augmentation du débit sanguin cérébral. Or, la dégradation de ce couplage semble être un point commun à de nombreuses pathologies. Ces travaux de thèse portent sur l’application de l’imagerie fUS à la détection de biomarqueurs neurovasculaires précoces de maladies de notre temps. Le caractère portable des ultrasons laisse présager le développement de sondes simples d’utilisation et faciles d’accès en clinique permettant l’évaluation du CNV. En particulier, l’objectif final est de développer un outil permettant le diagnostic simple, rapide et précoce de maladies neurodégénératives ou cardiovasculaires. Pour cela, dans un premier temps, nous avons caractérisé l’altération du CNV dans deux modèles représentatifs de syndromes chroniques directement liés à nos modes de vie actuels : un modèle d’altération pharmacologique par le cannabis et un modèle pathologique d’obésité. Nous montrons que l’imagerie fUS permet de mesurer l’altération du CNV simplement, par la mesure des fluctuations spontanées du débit sanguin cérébral ou bien par la mesure de la réponse hémodynamique induite par une stimulation. Cependant, ce type d’exploration n’est pas encore possible chez l’humain adulte car la boite crânienne est peu perméable aux ultrasons. C’est le frein majeur à l’utilisation du fUS cérébral en clinique. Nous nous sommes donc tournés vers l’œil, au fond duquel se trouve la rétine. C’est le seul tissu du système nerveux central qui n’est pas soigneusement protégé à l’intérieur d’une coque osseuse. Sur un modèle de rat, nous avons développé une méthodologie permettant de mesurer la réponse fonctionnelle hémodynamique de la rétine à une stimulation lumineuse brève répétée. Cette méthodologie d’imagerie fUS oculaire a été optimisée afin d’être assez courte pour, à terme, être applicable en routine clinique. Enfin, nous avons appliqué ce nouvel outil à l’étude de la Maladie d’Alzheimer (MA), autre fléau du XXIème siècle. Sur un modèle de rat de la MA, nous avons pu discriminer les animaux sains des animaux malades grâce à la mesure de la réponse fonctionnelle hémodynamique rétinienne par l’imagerie fUS oculaire. Nous avons également pu mettre en évidence la différence de temporalité dans le traitement de l’information visuelle de la rétine au cortex visuel entre les animaux sains et les animaux malades. Finalement, nous avons démontré la faisabilité d’un outil diagnostic utilisant l’imagerie fUS pour mesurer le couplage neurovasculaire via la rétine. Par ces travaux, nous espérons participer au transfert de l’imagerie fUS vers une utilisation de routine en clinique.
Background:
Cannabinoids are often prescribed for neuropathic pain, but the evidence-based recommendation is "weak against."
Objectives:
The aim was to examine the effect of two cannabinoids and their combination in peripheral neuropathic pain.
Methods:
This was a randomized, double-blind, trial with treatment arms for cannabidiol (CBD), tetra-hydro-cannabinol (THC), CBD and THC combination (CBD/THC), and placebo in a 1:1:1:1 ratio and flexible drug doses (CBD 5 to 50 mg, THC 2.5 mg to 25 mg, and CBD/THC 5 mg/2.5 mg to 50 mg/25 mg). Treatment periods of 8-week duration were proceeded by 1 week for baseline observations. Patients with painful polyneuropathy, post-herpetic neuralgia and peripheral nerve injury (traumatic or surgical) failing at least one previous evidence-based pharmacological treatment were eligible for inclusion. The primary outcome was the change in weekly average of daily pain measured with a numeric rating scale (NRS). Trail Making Test (TMT) was used as one of the tests of mental functioning.
Results:
One hundred and forty-five patients were included in the study of which 118 were randomized and 115 included in the intention-to-treat analysis. None of the treatments reduced pain compared to placebo (p = 0.04 - 0.60). Effect sizes as estimated in week 8 (positive values worse and negative better than placebo) were CBD mean 1.14 NRS points (95% CI 0.11 - 2.19), THC 0.38 (CI -0.65 - 1.4), and CBD/THC -0.12 (-1.13 - 0.89).
Conclusions:
CBD, THC and their combination did not relieve peripheral neuropathic pain in patients failing at least one previous evidence-based treatment for neuropathic pain.
Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use.
Although humans have used the hemp Cannabis sativa plant for thousands of years, recently there has been a shift in the availability of hemp products that are high in secondary metabolites while maintaining low levels of the intoxicating phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Historically, there have been many therapeutic applications of hemp in ethnobotanical formulations for a range of conditions. The primary compound of interest is cannabidiol (CBD), which demonstrates powerful antiepileptic properties and is the rationale behind the change in legal status enabling further production and research of hemp. The plant also contains additional phytocannabinoids, as well as other bioactive molecules including terpenes and flavonoids. There is sufficient preliminary evidence for a molecular mechanism through both the endocannabinoid system and the serotonin system; additionally, there may be non-specific interactions that occur when combinations of complex formulations are administered. The interconnected nature of the endocannabinoid system with other signaling systems in the central nervous system, immune system, and other essential peripheral functions complicates the discrete identification of specific molecular mechanisms. When evaluating the potential pharmaceutical applications of the hemp Cannabis sativa plant as a whole, it is found to be well-tolerated in human clinical settings and have vast therapeutic applications across a wide range of symptoms.KeywordsEndocannabinoid systemCannabidiol (CBD)TerpenesFlavonoidsPhytocannabinoidsCannabigerol (CBG)Pharmacology
Background:
Contemporary data are needed about the utility of cannabinoids in chronic pain.
Purpose:
To evaluate the benefits and harms of cannabinoids for chronic pain.
Data sources:
Ovid MEDLINE, PsycINFO, EMBASE, the Cochrane Library, and Scopus to January 2022.
Study selection:
English-language, randomized, placebo-controlled trials and cohort studies (≥1 month duration) of cannabinoids for chronic pain.
Data extraction:
Data abstraction, risk of bias, and strength of evidence assessments were dually reviewed. Cannabinoids were categorized by THC-to-CBD ratio (high, comparable, or low) and source (synthetic, extract or purified, or whole plant).
Data synthesis:
Eighteen randomized, placebo-controlled trials (n = 1740) and 7 cohort studies (n = 13 095) assessed cannabinoids. Studies were primarily short term (1 to 6 months); 56% enrolled patients with neuropathic pain, with 3% to 89% female patients. Synthetic products with high THC-to-CBD ratios (>98% THC) may be associated with moderate improvement in pain severity and response (≥30% improvement) and an increased risk for sedation and are probably associated with a large increased risk for dizziness. Extracted products with high THC-to-CBD ratios (range, 3:1 to 47:1) may be associated with large increased risk for study withdrawal due to adverse events and dizziness. Sublingual spray with comparable THC-to-CBD ratio (1.1:1) probably is associated with small improvement in pain severity and overall function and may be associated with large increased risk for dizziness and sedation and moderate increased risk for nausea. Evidence for other products and outcomes, including longer-term harms, were not reported or were insufficient.
Limitation:
Variation in interventions; lack of study details, including unclear availability in the United States; and inadequate evidence for some products.
Conclusion:
Oral, synthetic cannabis products with high THC-to-CBD ratios and sublingual, extracted cannabis products with comparable THC-to-CBD ratios may be associated with short-term improvements in chronic pain and increased risk for dizziness and sedation. Studies are needed on long-term outcomes and further evaluation of product formulation effects.
Primary funding source:
Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. (PROSPERO: CRD42021229579).
There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers' attention to discover the scientific evidence of cannabis’s beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents such as megestrol acetate in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. As high as 572 patients and as low as nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.
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.
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.
Objective: To review the safety and efficacy of cannabis use for chronic pain in older people. Setting: The case took place in a geriatric primary-care clinic in Colorado. Practice Description: The clinic serves adults 75 years of age and older where clinical pharmacists are used for medication consults and follow-up. Practice Innovation: Older people are using cannabis to treat a variety of conditions, with use increasing as more states legalize cannabis medically and recreationally. The primary reason for use is pain. Pharmacists in Colorado can assist with education regarding cannabis use and evaluate if cannabis may be safe for older people. Main Outcome Measurement: This case evaluates the use of a combination CBD:THC cannabis product in a 78-year-old female patient who was previously using opioids for degenerative disc disease and osteoarthritis. Results: The patient found improvement in her pain when using the combination cannabis product without any adverse effects. Conclusion: Further safety and efficacy evidence is needed for using combination cannabis products for pain management in older people.
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
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.
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.
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.
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.
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.