Article

An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain

August 2012
Pain 153(10):2073-82

DOI:10.1016/j.pain.2012.06.024

Source
PubMed

Authors:

Shefina Mawani

University of Calgary

Cynthia Chan

Alberta Health Services

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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.

Phytocannabinoids for the Treatment of Neuropathic Pain: A Scoping Review of Randomised Controlled Trials Published Between 2012 and 2023

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Full-text available

Dec 2023
Curr Pain Headache Rep

Purpose of Review Neuropathic pain (NP) remains a challenge to treat, with 50% of patients experiencing limited efficacy from current treatments. Medicinal cannabis, which contains tetrahydrocannabinol (THC), cannabidiol (CBD) and other minor cannabinoids, is garnering attention as an alternative treatment for NP. This paper reviews the clinical evidence for phytocannabinoid treatment of NP. Recent Findings Seventeen randomised controlled trials (RCT) were identified for inclusion in this review. Of these, ten studies using phytocannabinoid preparations containing THC alone had the most evidence for pain relief. Four studies investigating THC/CBD combinations showed some reductions in pain scores, although not all findings were statistically significant, whereas studies investigating CBD (two studies) or cannabidivarin (one study) showed no analgesic effect over placebo. However, CBD studies were of small sample size when compared to other studies in the review and short duration. Results for treatment of diabetic peripheral neuropathy patients with THC showed better improvements over those for NP induced by chemotherapy and multiple sclerosis, with these trials using vaporised whole plant cannabis. This formulation may have trace amounts of other minor cannabinoids, compared with synthetic cannabinoids such as dronabinol or nabilone that were investigated in other studies. Summary This review provides an overview of RCTs that have investigated phytocannabinoid use for the treatment of NP. There appears to be evidence to necessitate further high quality RCTs into novel formulations of phytocannabinoids for the treatment of NP.

Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications

Article

Full-text available

Aug 2022
BMC MED

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.

Study Design Characteristics and Endpoints for Enriched Enrollment Randomized Withdrawal Trials for Chronic Pain Patients: A Systematic Review

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Feb 2022

Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into the randomized phase. There are no recommendations for primary endpoints in such trials. Our objective was to propose recommendations based on assessment of trial characteristics, endpoints and effect sizes in EERW pain trials. We conducted a systematic review by searching electronic databases up to June 2020 for EERW trials comparing an analgesic with a placebo in adults suffering from chronic pain. A total of 28 trials met our criteria, involving 13662 patients in the open or single-blind phase and 7937 patients in the double-blind phase. As primary endpoint 18 trials used pain intensity measured with the visual analogue scale (VAS) or the 11-point numerical rating scale (NRS); 1 trial used a 4-point NRS. Loss of therapeutic response (LTR) was used in 1 trial and time to LTR was used in 8 trials as primary endpoint. Definitions of time to LTR differed considerably between trials. Only 2 out of 8 trials using time to LTR as primary endpoint reported the percentage of patients experiencing a minimum pain relief of 50%, compared to 14 out of 18 trials using NRS or VAS. Due to the complexity and diversity of time to LTR in EERW pain trials, we propose to use the NRS as primary endpoint with conservative imputation methods, and to use time to LTR as secondary endpoint.

The Safety of Medications used to Treat Peripheral Neuropathic Pain, Part 2 (Opioids, Cannabinoids and Other Drugs): review of Double-Blind, Placebo-Controlled, Randomized Clinical Trials

Article

Full-text available

Oct 2020
EXPERT OPIN DRUG SAF

Introduction: Peripheral neuropathic pain is a highly disabling condition for patients and a challenge for physicians. Although many drugs have been assessed in scientific studies, few have demonstrated clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raises the question of the benefit-risk ratio when used in patients experiencing peripheral neuropathies. Areas covered: We conducted a review of double-blind, placebo-controlled, randomized clinical trials to assess the safety of medications used to treat peripheral neuropathic pain. This second review was focused on opioids, cannabinoids, and other medications. The aim was to provide an overview of the treatment-emergent adverse events (TEAEs) (≥10%) and the serious adverse effects described in clinical trials. Expert opinion: Opioids and cannabinoids had significantly more TEAEs than placebos. Locally administered analgesics, such as capsaicin, lidocaine, botulinum toxin A seemed to have the most acceptable safety with only local adverse effects. The results for NMDA antagonists were inconclusive since no safety report was available. Less than half of the studies included presented a good description of adverse effects that included a statistical comparison versus a placebo group. Major methodological improvements must be made to ameliorate the assessment of medication safety in future clinical trials. Keywords: drug-related side effects and adverse reactions; neuropathic pain; peripheral nervous system diseases; randomized controlled trials.

Efficiency of cannabis and cannabidiol in managing chronic pain syndromes: A comprehensive narrative review

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Full-text available

Nov 2024

Chronic pain affects up to 40% of adults, contributing to high medical expenses, the loss of productivity, reduced quality of life (QoL), and disability. Chronic pain requires detailed diagnostic assessment, treatment and rehabilitation, yet approx. 80% of patients report inadequate pain management. As new treatment options are needed, we aimed to explore the effectiveness of medical cannabis-based products in managing chronic pain, with a particular focus on treatment patterns.We searched the PubMed, Scopus and Web of Science databases using keywords related to cannabinoids and chronic pain syndromes. In total, 3,954 articles were identified, and 74 studies involving 12,562 patients were included. The effectiveness of cannabis-based products varied across studies. Cannabinoids were most effective in treating chronic secondary headache and orofacial pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, and chronic neuropathic pain. Properly qualifying patients is the first crucial step in managing chronic pain, considering pain characteristics, comorbidities and other treatment options. Treatment should start with low doses of cannabinoids, which are then increased to achieve the desired therapeutic effect while minimizing adverse effects.This narrative review revealed significant gaps in the evidence regarding precise treatment patterns, particularly for the long-term maintenance treatment needed by patients with chronic pain. Medical cannabis can be considered an option for carefully selected patients with chronic pain syndromes when other treatment options fail to achieve an adequate response, and when the potential benefits outweigh the risks. However, there is still a need for well-designed clinical research to establish the long-term efficacy and safety of cannabinoids.

Evaluating the impact of cannabinoids on sleep health and pain in patients with chronic neuropathic pain: a systematic review and meta-analysis of randomized controlled trials

Article

Full-text available

Dec 2022

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.

Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain: A Systematic Review and Meta-analysis

Article

Full-text available

Nov 2022

Importance Persistent pain is a common and disabling health problem that is often difficult to treat. There is an increasing interest in medicinal cannabis for treatment of persistent pain; however, the limited superiority of cannabinoids over placebo in clinical trials suggests that positive expectations may contribute to the improvements. Objective To evaluate the size of placebo responses in randomized clinical trials in which cannabinoids were compared with placebo in the treatment of pain and to correlate these responses to objective estimates of media attention. Data Sources A systematic literature search was conducted within the MEDLINE and Embase databases. Studies published until September 2021 were considered. Study Selection Cannabinoid studies with a double-blind, placebo-controlled design with participants 18 years or older with clinical pain of any duration were included. Studies were excluded if they treated individuals with HIV/AIDS or severe skin disorders. Data Extraction and Synthesis The study followed the Preferred Reporting Items for Systematic Review and Meta-analyses reporting guideline. Data were extracted by independent reviewers. Quality assessment was performed using the Risk of Bias 2 tool. Attention and dissemination metrics for each trial were extracted from Altmetric and Crossref. Data were pooled and analyzed using a random-effects statistical model. Main Outcomes and Measures Change in pain intensity from before to after treatment, measured as bias-corrected standardized mean difference (Hedges g ). Results Twenty studies, including 1459 individuals (mean [SD] age, 51 [7] years; age range, 33-62 years; 815 female [56%]), were included. Pain intensity was associated with a significant reduction in response to placebo, with a moderate to large effect size (mean [SE] Hedges g , 0.64 [0.13]; P < .001). Trials with low risk of bias had greater placebo responses ( q 1 = 5.47; I ² = 87.08; P = .02). The amount of media attention and dissemination linked to each trial was proportionally high, with a strong positive bias, but was not associated with the clinical outcomes. Conclusions and Relevance Placebo contributes significantly to pain reduction seen in cannabinoid clinical trials. The positive media attention and wide dissemination may uphold high expectations and shape placebo responses in future trials, which has the potential to affect the outcome of clinical trials, regulatory decisions, clinical practice, and ultimately patient access to cannabinoids for pain relief.

Dorsal Column Stimulation and Cannabinoids in the Treatment of Chronic Nociceptive and Neuropathic Pain: a Review of the Clinical and Pre-clinical Data

Article

Full-text available

Feb 2022
Curr Pain Headache Rep

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.

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

Article

Full-text available

Jun 2021

(Appeared originally in Frontiers in Psychiatry 2020 Dec 23; 11:595584).

Recent developments in geriatric psychopharmacology

Article

Jan 2021

Introduction There is a tremendous growing need to address the burden of geriatric psychiatric disorders. Recent developments relevant to geriatric psychiatry have focused on Alzheimer’s disease (AD), severe/refractory depression, and cancer/end of life care. Areas covered This is a non-systematic, narrative review (databases and websites for search: PubMed, Google Scholar, Medscape, ClinicalTrials.gov; focusing on the last 6 years), and covers developments in disease modifying therapies for AD, diagnostic radiotracers for AD, medications for neuropsychiatric symptoms of dementia, ketamine/esketamine, psychedelics, and cannabinoids. Expert opinion Various anti-amyloid agents have failed in phase 3 trials in AD, and the focus of trials in recent years has been on individuals with very early stage AD; several agents are under phase 3 investigation, and aducanumab is under FDA review. Amyloid and tau PET scans have been approved by the FDA to assist in the diagnoses of AD. Promising pharmaceuticals for neuropsychiatric symptoms of dementia include pimavanserin, brexpiprazole, escitalopram, dextromethorphan/quinidine, and lithium. Esketamine, although approved for treatment-resistant depression in general adults, failed to demonstrate efficacy in elderly patients in a phase 3 trial. There is preliminary evidence for benefit of psychedelic-assisted psychotherapy in end-of-life and cancer-related depression/anxiety. Evidence for the use of cannabinoids is currently lacking.

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

Article

Full-text available

Dec 2020

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

The Effect of Medical Cannabis on Anxiety and Depression

Article

Full-text available

Nov 2024

Samer H. Sharkiya

In December 2020, the United Nations removed medical cannabis (MC) from Schedule 4 of the 1961 UN Convention on Narcotic Drugs following a recommendation by the World Health Organization (WHO) on its medical potential to pave the way for the reduction of regulatory barriers for research (United Nations, 2020). Some of the medical indications for MC include but are not limited to rare seizure disorders, symptomatic treatment of nausea and vomiting, insomnia, pain, loss of appetite, anxiety, and post-traumatic stress disorder (PTSD), as well as glaucoma, Huntington’s Disease, dystonia, and Parkinson’s Disease (Klumpers & Thacker, 2019). In countries like the United States, MC prescriptions are on the rise for various medical indications, especially in symptomatic treatment of nausea and vomiting, loss of appetite, and pain among oncology patients (Corroon et al., 2019; Vinette et al., 2022).

Excessive alcohol intake produces persistent mechanical allodynia and dysregulates the endocannabinoid system in the lumbar dorsal root ganglia of genetically-selected Marchigian Sardinian alcohol-preferring rats

Article

Full-text available

Oct 2024
PHARMACOL RES

Epidemiological data indicate a strong association between alcohol use disorder (AUD) and neuropathic pain. Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a high preference for alcohol compared with their background strain (Wistar rats), but their sensitivity to mechanical allodynia after chronic alcohol exposure is unknown. The present study compared the development of mechanical allodynia between "low, non-pathological drinker" Wistar rats and "high drinker" msP rats using the two-bottle choice (2BC) free-access procedure. Several studies reported the involvement of endocannabinoids (eCBs) in modulating mechanical allodynia, but there are no data on their role in alcohol-related allodynia. Thus, the present study assessed eCBs and their related lipid species in lumbar dorsal root ganglia (DRG) and correlated them with mechanical allodynia in our model. We found that male and female msP rats developed persistent mechanical allodynia during protracted abstinence from alcohol, presenting no sign of recovery, as opposed to Wistar rats. This effect directly correlated with their total alcohol intake. Notably, we found a correlation between lower lumbar DRG 2-arachidonoylglycerol (2-AG) levels and the development of higher mechanical allodynia during abstinence in msP rats of both sexes but not in Wistar rats. Moreover, alcohol-exposed and abstinent msP and Wistar females but not males exhibited significant alterations of thromboxane B2 and prostaglandin E2/prostaglandin D2 compared with naive rats. These findings demonstrate that DRG 2-AG metabolism is altered in msP rats during prolonged abstinence and represents a potentially interesting pharmacological target for the treatment of mechanical allodynia during alcohol abstinence.

Δ9-Tetrahydrocannabinol (THC): A Critical Overview of Recent Clinical Trials and Suggested Guidelines for Future Research

Article

Full-text available

Mar 2024

In this overview, we seek to appraise recent experimental and observational studies investigating THC and its potential role as adjunctive therapy in various medical illnesses. Recent clinical trials are suggestive of the diverse pharmacologic potentials for THC but suffer from small sample sizes, short study duration, failure to address tolerance, little dose variation, ill-defined outcome measures, and failure to identify and/or evaluate confounds, all of which may constitute significant threats to the validity of most trials. However, the existing work underscores the potential therapeutic value of THC and, at the same time, calls attention to the critical need for better-designed protocols to fully explore and demonstrate safety and efficacy. In the most general sense, the present brief review illuminates some intriguing findings about THC, along with the basic threats to the validity of the research that supports those findings. The intent is to highlight existing generic weaknesses in the existing randomized controlled trial literature and, most importantly, provide guidance for improved clinical research.

Cannabis constituents for chronic neuropathic pain; reconciling the clinical and animal evidence

Article

Full-text available

Sep 2023
J NEUROCHEM

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

CANNABIDIOL IN GENERAL MEDICINE PART 1

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Mar 2023

Cannabidiol ve tıp

Endocannabinoid System: Chemical Characteristics and Biological Activity

Article

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Jan 2023

The endocannabinoid system (eCB) has been studied to identify the molecular structures present in Cannabis sativa. eCB consists of cannabinoid receptors, endogenous ligands, and the associated enzymatic apparatus responsible for maintaining energy homeostasis and cognitive processes. Several physiological effects of cannabinoids are exerted through interactions with various receptors, such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered G-protein-coupled receptors (GPR55, GPR3, GPR6, GPR12, and GPR19). Anandamide (AEA) and 2-arachidoylglycerol (2-AG), two small lipids derived from arachidonic acid, showed high-affinity binding to both CB1 and CB2 receptors. eCB plays a critical role in chronic pain and mood disorders and has been extensively studied because of its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities for eCB and are relevant to the treatment of several neurological diseases. This review provides a description of eCB components and discusses how phytocannabinoids and other exogenous compounds may regulate the eCB balance. Furthermore, we show the hypo- or hyperfunctionality of eCB in the body and how eCB is related to chronic pain and mood disorders, even with integrative and complementary health practices (ICHP) harmonizing the eCB.

Guidance in Authorizing Cannabis Products Within Primary Care

Article

Full-text available

Mar 2021

Under the Access to Cannabis for Medical Purposes (ACMPR)1 section of Canada’s cannabis regulations, which came into effect with the Cannabis Act on October 17, 2018, access to medical cannabis is authorized by a physician who signs a medical document. Authorized patients may purchase cannabis from a federally licensed producer, designate another person to produce it for them, or register to produce it themselves.2 Physicians do not prescribe cannabis since it is not a Health Canada–registered medication with a Drug Identification Number. The ACMPR medical document is an authorization for the use of cannabis for medical purposes, and, while the authorizing physician is encouraged to offer guidance on the form, strength, and dose, the dispensed form, dose, and titration are ultimately determined by the licensed producer. Under the Cannabis Act 2018, the use of cannabis for recreational purposes became legal (except for edible cannabis, cannabis extracts, and cannabis topicals, which became lawfully produced and sold as of October 17, 2019; see Table 1). Cannabis for recreational purposes differs from cannabis for medical purposes in that Health Canada does not regulate recreational cannabis production, possession, and distribution in the same way it does for cannabis for medical purposes. The basic facts and advice on safe consumption of recreational cannabis are summarized in the Government of Canada fact sheet.3 Provinces differ in their guidance and regulatory oversight for cannabis use.4 Provincial medical colleges, in the absence of regulatory oversight and approval, issued statements and guidance to comply with federal and provincial regulations (see the list of regulators provided under Recommendation 6). The Cannabis Act legalized recreational cannabis use and proposed a framework for the use of medical cannabis in Canada. However, it remains illegal to carry any cannabis with you when entering or leaving Canada, whether it is for medical or recreational purposes. Before cannabis use legalization, little research had been conducted on its therapeutic use, safety, or efficacy. This situation puts family physicians in a difficult position, as they are asked to authorize their patients’ access to a product with little evidence to support its use. To address this predicament, this document offers family physicians guidance on authorizing cannabis use for some specific conditions. Although the old Access to Cannabis for Medical Purposes regulations spoke only of use for medical purposes without specifying any diagnoses, the writing group chose chronic pain and anxiety as the original clinical areas of focus because they are the most common conditions for which a patient requests authorization. Since the original 2014 version was released, we have updated the document, added content, and broadened the scope of discussion beyond chronic pain and anxiety. Cannabis is the raw plant material, composed of hundreds of different compounds, that serves as the source for non-pharmaceutically produced medical cannabis, including material for smoking and vaping as well as for edibles and concentrates. The two chemicals from the cannabis plant discussed are tetrahydrocannabinol (THC) and cannabidiol (CBD).Research shows that cannabis could be a potent psychoactive substance with a risk of acute and chronic adverse effects of varying severity. Its most common acute effects include perceptual distortions, cognitive impairment, euphoria, and anxiety.5 Chronic use of cannabis may be associated with persistent neuropsychological deficits, even after a period of abstinence.6, 7 The frequency and intensity vary based on the proportional content of psychoactive ingredients and on other factors including extent of use, age of first use, and length of abstinence.8 Medium- and long-term therapeutic and adverse effects of medical and recreational cannabis have not been sufficiently studied. Products containing THC have a known abuse and dependence potential (liability). It is recommended that family physicians consider the anticipated therapeutic benefits versus potential harms for a patient’s health condition before authorizing initial or continuing cannabis use. As with any other therapeutic approach, continuing cannabis use is warranted only if the authorizing physician is satisfied that there has been improvement in the patient’s presenting symptoms (e.g., pain level), function, and/or quality of life; the risk of cannabis use disorder has been reassessed; and the benefits outweigh potential harms.

Medical Cannabis and Cannabinoids for Impaired Sleep: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Article

Full-text available

Sep 2021

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.

Sex Differences in Tolerance to Delta-9-Tetrahydrocannabinol in Mice With Cisplatin-Evoked Chronic Neuropathic Pain

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Full-text available

Jun 2021

Tolerance to the pain-relieving effects of cannabinoids limits the therapeutic potential of these drugs in patients with chronic pain. Recent preclinical research with rodents and clinical studies in humans has suggested important differences between males and females in the development of tolerance to cannabinoids. Our previous work found that male mice expressing a desensitization resistant form (S426A/S430A) of the type 1 cannabinoid receptor (CB1R) show delayed tolerance and increased sensitivity to the antinociceptive effects of delta-9-tetrahydrocannabinol (∆9-THC). Sex differences in tolerance have been reported in rodent models with females acquiring tolerance to ∆9-THC faster than males. However, it remains unknown whether the S426A/S430A mutation alters analgesic tolerance to ∆9-THC in mice with chemotherapy-evoked chronic neuropathic pain, and also whether this tolerance might be different between males and females. Male and female S426A/S430A mutant and wild-type littermates were made neuropathic using four once-weekly injections of 5 mg/kg cisplatin and subsequently assessed for tolerance to the anti-allodynic effects of 6 and/or 10 mg/kg ∆9-THC. Females acquired tolerance to the anti-allodynic effects of both 6 and 10 mg/kg ∆9-THC faster than males. In contrast, the S426A/S430A mutation did not alter tolerance to ∆9-THC in either male or female mice. The anti-allodynic effects of ∆9-THC were blocked following pretreatment with the CB1R antagonist, rimonabant, and partially blocked following pretreatment with the CB2R inverse agonist, SR144528. Our results show that disruption of the GRK/β-arrestin-2 pathway of desensitization did not affect sensitivity and/or tolerance to ∆9-THC in a chronic pain model of neuropathy.

A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products

Article

Full-text available

Mar 2021

Background Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit–safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit–safety balances remain better than those of the noncannabinoid drugs. Interpretation The benefit–safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

The Endocannabinoid System as a Therapeutic Target in Diabetic Peripheral Neuropathic Pain: A Review

Article

Full-text available

May 2021

Amina M Bagher

Diabetic peripheral neuropathy (DPN) is characterized by progressive loss of peripheral nerves, which causes numbness, weakness, and severe pain. The medications available currently provide only modest relief from the pain of DPN and are associated with various side effects, which has generated an enormous demand for research on new therapeutic approaches. Dysregulation of the endocannabinoid system has been reported in DPN. Cannabinoid-based medications have gained increasing attention as a potential therapy to alleviate DPN pain. Endocannabinoids and cannabinoids' actions are mediated primarily by cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). Cannabinoids that activate CB1R have demonstrated a profound antinociceptive effect, although CB1R is associated with undesirable psychoactive effects. Peripherally restricted CB1R agonists help overcome this problem; however, adverse metabolic and cardiovascular effects limit its therapeutic use. In contrast, CB1R antagonists, selective CB2R agonists, and endocannabinoid metabolizing enzymes inhibitors alleviate DPN pain effectively with minimal side effects. This article provides a concise overview of the preclinical and clinical studies that have tested the therapeutic potential of targeting the endocannabinoid system to treat painful DPN.

Targeting the endocannabinoid system for management of HIV-associated neuropathic pain: A systematic review

Article

Full-text available

Feb 2021

Human immunodeficiency virus (HIV) infection and antiretroviral therapy can independently induce HIV-associated neuropathic pain (HIV-NP). There is a dearth of drugs or therapeutic modalities that can alleviate HIV-NP. Smoked cannabis has been reported to improve pain measures in patients with neuropathic pain. Cannabis, phytocannabinoids, and the endocannabinoids such N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), produce some of their effects via cannabinoid receptors (CBRs). Endocannabinoids are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase. We searched PubMed, Google Scholar, clinicaltrials.gov and clinicaltrialsregister.eu using various key words and their combinations for published papers that studied HIV-NP and cannabis, cannabinoids, or endocannabinoids up to 27th December 2020. All original research articles that evaluated the efficacy of molecules that modulate the endocannabinoid system (ECS) for the prevention and/or treatment of pain in HIV-NP animal models and patients with HIV-NP were included. The PubMed search produced a total of 117 articles, whereas the Google Scholar search produced a total of 9467 articles. Amongst the 13 articles that fulfilled the inclusion criteria 11 articles were found in both searches whereas 2 articles were found in Google Scholar only. The clinicaltrials.gov and clinicaltrialsregister.eu searches produced five registered trials of which three were completed and with results. Ten preclinical studies found that the endocannabinoids (2-AG and AEA), synthetic mixed CB1R/CB2R agonist WIN 55,212-2, a CB2R-selective phytocannabinoid β-caryophyllene, synthetic CB2R-selective agonists (AM1710, JWH015, JWH133 and Gp1a, but not HU308); FAAH inhibitors (palmitoylallylamide, URB597 and PF-3845) and a drug combination of indomethacin plus minocycline, which produces its effects in a CBR-dependent manner, either prevented the development of and/or attenuated established HIV-NP. Two clinical trials demonstrated greater efficacy of smoked cannabis over placebo in alleviating HIV-NP, whereas another clinical trial demonstrated that cannabidivarin, a cannabinoid that does not activate CBRs, did not reduce HIV-NP. The available preclinical results suggest that targeting the ECS for prevention and treatment of HIV-NP is a plausible therapeutic option. Clinical evidence shows that smoked cannabis alleviates HIV-NP. Further research is needed to find out if non-psychoactive drugs that target the ECS and are delivered by other routes than smoking could be useful as treatment options for HIV-NP.

Veränderung der Ranvier’schen Schnürringarchitektur bei Patienten mit diabetischer Neuropathie

Thesis

Jan 2021

Franziska Frank

In der Krankheitsentstehung der diabetischen Neuropathie wird die paranodale Demyelinisierung als ein möglicher Pathomechanismus diskutiert, wobei Studien mit Gewebeproben von Patienten aufgrund der Invasivität limitiert sind. In der vorliegenden Studie wurden periphere Nervenfasern in Hautbiopsien von Patienten mit diabetischer Neuropathie und in Patienten mit Diabetes mellitus ohne Neuropathie untersucht. Ziel war es, nodale und paranodale Veränderungen, wie eine Dispersion der paranodalen Proteine Caspr und Neurofascin oder der nodalen Na-Kanäle, zu detektieren und die Proben auf verlängerte Ranvier`sche Schnürringe zu untersuchen. Es wurde die Hypothese überprüft, dass paranodale Demyelinisierungen bei Patienten mit diabetischer Neuropathie in Hautbiopsien, als minimal-invasive Methode, nachweisbar sind. Hautproben von Patienten mit Diabetes mellitus ohne Neuropathie sollten zudem in einem frühen Krankheitsstadium untersucht werden. Für die Untersuchung konnten 35 Patienten mit einer diabetischen Neuropathie, 17 Patienten mit Diabetes mellitus und 31 Kontrollen eingeschlossen werden. Immunfluoreszenzfärbungen mit Antikörpern gegen Caspr, Neurofascin und Natrium-Kanälen wurden zur Analyse der Ranvier`schen Schnürringarchitektur durchgeführt und ausgewertet. Eine erhöhte Anzahl an verlängerten Schnürringen, als Zeichen einer segmentalen Demyelinisierung, konnte in den Patienten mit diabetischer Neuropathie aber auch in Patienten mit Diabetes mellitus nachgewiesen werden. Weiterhin waren vermehrt Veränderungen der paranodalen Proteine, wie eine Dispersion von Caspr und Neurofascin in den Proben des Fingers der Patienten mit diabetischer Neuropathie sowie eine Dispersion von Neurofascin im Unterschenkel in beiden Patientengruppen nachweisbar. Interessanterweise waren einzelne Veränderungen auch in den gesunden Kontrollen auffindbar. Veränderungen der Schnürringarchitektur lassen sich mithilfe der Hautbiopsie nachweisen und quantifizieren. Nodale und paranodale Veränderungen weisen auf demyelinisierende Prozesse in Patienten mit diabetischer Neuropathie hin und finden sich auch bereits in einem frühen Krankheitsstadium.

Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference

Article

Nov 2024
AGE AGEING

Background Cannabinoid-based medicines (CBMs) are being used widely in older people. However, information on the incidence of adverse events (AEs) is limited. Objective To quantify the incidence rate difference (IRD) of AEs in middle aged and older adults of age ≥50 years receiving CBMs and also examine associations with weekly doses. Design Systematic review and meta-analysis. Data sources MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library and ClinicalTrials.gov (1st Jan 1990–12th June 2023). Methods We included randomised clinical trials (RCTs) using CBMs with mean participant age ≥50 years for medicinal purposes for all clinical indications. Paired reviewers independently screened studies, extracted data and appraised risk of bias. We estimated pooled effect-sizes IRD under the random-effects model. Results Data from 58 RCTs (37 moderate-high quality studies, pooled n = 6611, mean age range 50–87 years, 50% male, n = 3450 receiving CBMs) showed that compared with controls, the incidence of all-cause and treatment-related AEs attributable to delta-9-tetrahydrocannabinol (THC)-containing CBMs were: THC alone [IRD:18.83(95% Confidence Interval [CI], 1.47–55.79) and 16.35(95% CI, 1.25–48.56)] respectively; THC:cannabidiol (CBD) combination [IRD:19.37(95% CI, 4.24–45.47) and 11.36(95% CI, 2.55–26.48)] respectively. IRDs of serious AEs, withdrawals and deaths were not significantly greater for CBMs containing THC with or without CBD. THC dose-dependently increased the incidence of dry mouth, dizziness/lightheadedness, mobility/balance/coordination difficulties, dissociative/thinking/perception problems and somnolence/drowsiness. The interaction of weekly THC:CBD doses played a role in mostly neurological, psychiatric and cardiac side-effects. Conclusions Although CBMs in general are safe and acceptable in middle aged and older adults, one needs to be mindful of certain common dose-dependent side-effects of THC-containing CBMs.

Cannabiskonsum und CannabiskonsumstörungenCannabis use and cannabis use disorders

Article

Aug 2024

Cannabis use and cannabis use disorders have taken on a new social significance as a result of partial legalization. In 2021 a total of 4.5 million adults (8.8%) in Germany used the drug. The number of users as well as problematic use have risen in the last decade. Cannabis products with a high delta-9-tetrahydrocannabinol (THC) content and their regular use lead to changes in cannabinoid receptor distribution in the brain and to modifications in the structure and functionality of relevant neuronal networks. The consequences of cannabinoid use are particularly in the psychological functioning and can include intoxication, harmful use, dependence with withdrawal symptoms and cannabis-induced mental disorders. Changes in the diagnostics between ICD-10 and ICD-11 are presented. Interdisciplinary S3 guidelines on cannabis-related disorders are currently being developed and will be finalized shortly.

The State of Synthetic Cannabinoid Medications for the Treatment of Pain

Article

Jul 2024

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.

Cannabis for medical use versus opioids for chronic non-cancer pain: a systematic review and network meta-analysis of randomised clinical trials

Article

Full-text available

Jan 2024

Objective The objective of this study is to evaluate the comparative benefits and harms of opioids and cannabis for medical use for chronic non-cancer pain. Design Systematic review and network meta-analysis. Data sources EMBASE, MEDLINE, CINAHL, AMED, PsycINFO, PubMed, Web of Science, Cannabis-Med, Epistemonikos and the Cochrane Library (CENTRAL) from inception to March 2021. Study selection Randomised trials comparing any type of cannabis for medical use or opioids, against each other or placebo, with patient follow-up ≥4 weeks. Data extraction and synthesis Paired reviewers independently extracted data. We used Bayesian random-effects network meta-analyses to summarise the evidence and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to evaluate the certainty of evidence and communicate our findings. Results Ninety trials involving 22 028 patients were eligible for review, among which the length of follow-up ranged from 28 to 180 days. Moderate certainty evidence showed that opioids provide small improvements in pain, physical functioning and sleep quality versus placebo; low to moderate certainty evidence supported similar effects for cannabis versus placebo. Neither was more effective than placebo for role, social or emotional functioning (all high to moderate certainty evidence). Moderate certainty evidence showed there is probably little to no difference between cannabis for medical use and opioids for physical functioning (weighted mean difference (WMD) 0.47 on the 100-point 36-item Short Form Survey physical component summary score, 95% credible interval (CrI) −1.97 to 2.99), and cannabis resulted in fewer discontinuations due to adverse events versus opioids (OR 0.55, 95% CrI 0.36 to 0.83). Low certainty evidence suggested little to no difference between cannabis and opioids for pain relief (WMD 0.23 cm on a 10 cm Visual Analogue Scale (VAS), 95% CrI −0.06 to 0.53) or sleep quality (WMD 0.49 mm on a 100 mm VAS, 95% CrI −4.72 to 5.59). Conclusions Cannabis for medical use may be similarly effective and result in fewer discontinuations than opioids for chronic non-cancer pain. PROSPERO registration number CRD42020185184.

Medicinal Plants for the Treatment of Neuropathic Pain: A Review of Randomized Controlled Trials

Article

Jul 2023
CURR PHARM BIOTECHNO

Neuropathic pain is a disabling condition caused by various diseases and can profoundly impact the quality of life. Unfortunately, current treatments often do not produce complete amelioration and can be associated with potential side effects. Recently, herbal drugs have garnered more attention as an alternative or a complementary treatment. In this article, we summarized the results of randomized clinical trials to evaluate the effects of various phytomedicines on neuropathic pain. In addition, we discussed their main bioactive components and potential mechanisms of action to provide a better view of the application of herbal drugs for treating neuropathic pain.

Terapie XXI w

Book

Full-text available

Jul 2022

Cannabis and Anxiety

Chapter

Jun 2023

An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.

Cannabis products: medical use

Article

Full-text available

Mar 2023

Cannabinoids versus placebo for pain: A systematic review with meta-analysis and Trial Sequential Analysis

Article

Full-text available

Jan 2023
PLOS ONE

Objectives To assess the benefits and harms of cannabinoids in participants with pain. Design Systematic review of randomised clinical trials with meta-analysis, Trial Sequential Analysis, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Data sources The Cochrane Library, MEDLINE, Embase, Science Citation Index, and BIOSIS. Eligibility criteria for selecting studies Published and unpublished randomised clinical trials comparing cannabinoids versus placebo in participants with any type of pain. Main outcome measures All-cause mortality, pain, adverse events, quality of life, cannabinoid dependence, psychosis, and quality of sleep. Results We included 65 randomised placebo-controlled clinical trials enrolling 7017 participants. Fifty-nine of the trials and all outcome results were at high risk of bias. Meta-analysis and Trial Sequential Analysis showed no evidence of a difference between cannabinoids versus placebo on all-cause mortality (RR 1.20; 98% CI 0.85 to 1.67; P = 0.22). Meta-analyses and Trial Sequential Analysis showed that cannabinoids neither reduced acute pain (mean difference numerical rating scale (NRS) 0.52; 98% CI -0.40 to 1.43; P = 0.19) or cancer pain (mean difference NRS -0.13; 98% CI -0.33 to 0.06; P = 0.1) nor improved quality of life (mean difference -1.38; 98% CI -11.81 to 9.04; P = 0.33). Meta-analyses and Trial Sequential Analysis showed that cannabinoids reduced chronic pain (mean difference NRS -0.43; 98% CI -0.72 to -0.15; P = 0.0004) and improved quality of sleep (mean difference -0.42; 95% CI -0.65 to -0.20; P = 0.0003). However, both effect sizes were below our predefined minimal important differences. Meta-analysis and Trial Sequential Analysis indicated that cannabinoids increased the risk of non-serious adverse events (RR 1.20; 95% CI 1.15 to 1.25; P < 0.001) but not serious adverse events (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07). None of the included trials reported on cannabinoid dependence or psychosis. Conclusions Cannabinoids reduced chronic pain and improved quality of sleep, but the effect sizes are of questionable importance. Cannabinoids had no effects on acute pain or cancer pain and increased the risks of non-serious adverse events. The harmful effects of cannabinoids for pain seem to outweigh the potential benefits.

Therapeutic uses of Cannabis sativa L. Current state and future perspectives

Chapter

Jan 2023

Cannabis sativa L. was used for medicinal purposes for millennia, being useful for the treatment of several conditions such as pain, convulsions, insomnia, and lack of appetite, among others. However, due to its psychotropic side effects and the impossibility to prepare standardized formulations it was banned in the late 1930s and removed from therapeutics, being considered as a drug that was solely used for recreational purposes. In the last two decades, this situation has changed, and the therapeutic use of cannabis has resurged again, demonstrating that standardized cannabis preparations can be safe and useful for the treatment of a broad range of pathologies. In fact, several cannabis-based formulations have been approved with medicinal purposes. This chapter analyzes the medicinal use of cannabis, describing their benefits, risks, and current and future perspectives.

Cannabis Dosing and Administration for Sleep: A Systematic Review

Article

Sep 2022

Study objectives As cannabis is increasingly used to treat sleep disorders, we performed a systematic review to examine the effects of cannabis on sleep and to guide cannabis prescribers in their recommendations to patients, specifically focusing on dosing. Methods We searched EMBASE, Medline, and Web of Science and identified 4,550 studies for screening. 568 studies were selected for full-text review and 31 were included for analysis. Study results were considered positive based on improvements in sleep architecture or subjective sleep quality. Bias in randomised controlled trials was assessed using Cochrane Risk of Bias tool 2.0. Results Sleep improvements were seen in 7 out of 19 randomised studies and in 7 out of 12 uncontrolled trials. There were no significant differences between the effects of tetrahydrocannabinol and cannabidiol. Cannabis showed most promise at improving sleep in patients with pain-related disorders, as compared to those with neurologic, psychiatric, or sleep disorders, and showed no significant effects on healthy participants’ sleep. While subjective improvements in sleep quality were often observed, diagnostic testing showed no improvements in sleep architecture. Adverse events included headaches, sedation, and dizziness, and occurred more frequently at higher doses, though no serious adverse events were observed. Conclusion High-quality evidence to support cannabis use for sleep remains limited. Heterogeneity in cannabis types, doses, timing of administration, and sleep outcome measures limit the ability to make specific dosing recommendations.

Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: a systematic review of non-randomised studies

Article

Full-text available

Aug 2022

Objective To establish the prevalence of long-term and serious harms of medical cannabis for chronic pain. Design Systematic review and meta-analysis. Data sources MEDLINE, EMBASE, PsycINFO and CENTRAL from inception to 1 April 2020. Study selection Non-randomised studies reporting on harms of medical cannabis or cannabinoids in adults or children living with chronic pain with ≥4 weeks of follow-up. Data extraction and synthesis A parallel guideline panel provided input on the design and interpretation of the systematic review, including selection of adverse events for consideration. Two reviewers, working independently and in duplicate, screened the search results, extracted data and assessed risk of bias. We used random-effects models for all meta-analyses and the Grades of Recommendations, Assessment, Development and Evaluation approach to evaluate the certainty of evidence. Results We identified 39 eligible studies that enrolled 12 143 adult patients with chronic pain. Very low certainty evidence suggests that adverse events are common (prevalence: 26.0%; 95% CI 13.2% to 41.2%) among users of medical cannabis for chronic pain, particularly any psychiatric adverse events (prevalence: 13.5%; 95% CI 2.6% to 30.6%). Very low certainty evidence, however, indicates serious adverse events, adverse events leading to discontinuation, cognitive adverse events, accidents and injuries, and dependence and withdrawal syndrome are less common and each typically occur in fewer than 1 in 20 patients. We compared studies with <24 weeks and ≥24 weeks of cannabis use and found more adverse events reported among studies with longer follow-up (test for interaction p<0.01). Palmitoylethanolamide was usually associated with few to no adverse events. We found insufficient evidence addressing the harms of medical cannabis compared with other pain management options, such as opioids. Conclusions There is very low certainty evidence that adverse events are common among people living with chronic pain who use medical cannabis or cannabinoids, but that few patients experience serious adverse events.

Overcoming clinical challenges of refractory neuropathic pain

Article

Jul 2022

Introduction: : Refractory neuropathic pain (ReNP), and its definition, is widely disputed amongst clinicians due in part to unclear categorical diagnosing guidelines, overall time duration of neuropathic pain, and the exhaustiveness of treatment options. Usually ReNP is defined as chronic, intractable, and unresponsive neuropathic pain that have otherwise been untreatable. Areas covered: : In this narrative review, we discuss and summarize the effectiveness of prospective ReNP research conducted over the past 10 years. This research looks at pharmacological and interventional therapies in clinical trial settings. The pharmacological therapies discussed include the use of adjuvant treatments to improve the safety and efficacy of conventional approaches. Different modalities of administration, such as injection therapy and intrathecal drug delivery systems, provide targeted drug delivery. Interventional therapies such as neuromodulation, pulse radiofrequency, and nerve lesioning are more invasive, however, they are increasingly utilized in the field, as reflected in ongoing clinical trials. Expert opinion: : Based on the current data from RCTs and systematic reviews, it is clear that single drug therapy cannot be effective and has significant limitations. Transitioning to interventional modalities that showed more promising results sooner rather than later may be even more cost-efficient than attempting different conservative treatments with a high failure rate.

Cannabis-Based Products for Chronic Pain : A Systematic Review

Article

Jun 2022
ANN INTERN MED

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).

Efficacy of Cannabis and its Constituents in Disease Management: Insights from Clinical Studies

Article

Full-text available

May 2022

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.

Atypical Analgesics

Chapter

Jan 2021

Yuri Chaves Martins

Chronic pain has been one of the most important public health problems of the 21st century. Due to the impact of the opioid prescribing epidemic and the challenges of helping those affected, the interest in non-opioid analgesics has been growing over the past decade. Hence non-opioid medications use is increasing, despite a weak evidence base and, at times, known harms of some drugs on these categories. The present chapter will focus on the role of antidepressants, antiepileptics, antipsychotics, cannabinoids, anesthetics, muscle relaxants, and other atypical analgesics in the treatment of chronic pain. We will review the evidence supporting the use of each class of drug and discuss its hypothesized or theorized mechanisms of action in chronic pain conditions. The use of typical analgesics such as opioids, non-steroid anti-inflammatory drugs, corticosteroids, and acetaminophen will not be discussed.

Different Drugs for the Treatment of Painful Diabetic Peripheral Neuropathy: A Meta-Analysis

Article

Full-text available

Oct 2021

Objective: To systematically evaluate the effects of different drugs for the treatment of painful diabetic peripheral neuropathy. Methods: All literature from PubMed, Embase, and Cochrane Central Register of Controlled Trials published over the past 12 years (from January 1, 2008 to June 1, 2020) was searched, and two reviewers independently assessed study eligibility, continuous data extraction, independent assessment of bias risk, and graded strength of evidence. The pain score was used as the main result, and 30 and 50% pain reduction and adverse events were used as secondary results. Results: A total of 37 studies were included. Pregabalin, duloxetine, tapentadol, lacosamide, mirogabalin, and capsaicin were all more effective than placebo in alleviating the pain associated with diabetic peripheral neuropathy, while ABT-894 and gabapentin showed no significant effect. In addition, the efficacy of buprenorphine, tanezumab, fulranumab and others could not be concluded due to insufficient studies. Conclusion: Pregabalin and duloxetine showed good therapeutic effects on painful DPN, but adverse events were also significant. The analgesic effects of ABT-894 and gabapentin need to be further studied with longer and larger RCTs. As an opioid drug, tapentadol has a good analgesic effect, but due to its addiction, it needs to be very cautious in clinical use. Although lacosamide, mirogabalin, and capsaicin are more effective than placebo, the therapeutic effect is weaker than pregabalin. For the results of our meta-analysis, long-term studies are still needed to verify their efficacy and safety in the future. Systematic Review Registration: PROSPERO, identifier: CRD42020197397.

Medical cannabis or cannabinoids for chronic pain: A clinical practice guideline

Article

Full-text available

Sep 2021
Br Med J

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.

Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: A systematic review and meta-analysis of randomised clinical trials

Article

Full-text available

Sep 2021
Br Med J

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

The PATCH trial: Efficacy and safety of 5% lidocaine-medicated plaster for the treatment of patients with trigeminal neuralgia: A study protocol for a multicentric, double-blind, enriched enrolment randomised withdrawal, vehicle-controlled study

Article

Full-text available

Aug 2021

Introduction Trigeminal neuralgia (TN) is characterised by a sudden, severe, electric shock like paroxysmal pain, which is almost always associated with triggers. Carbamazepine is the first-line medical management of TN. However, side effects are common. Currently, there is no ideal treatment for TN. Since there is a known abnormality of Na ⁺ channels in the trigger zone, 5% lidocaine-medicated plaster (LMP), which can block the Na ⁺ channels on Aδ and C fibres, is an effective treatment method in many chronic pain conditions. A case report has found the benefit of LMP for the treatment of TN without any side effects. Whether LMP is an option for the treatment of TN is worth exploring. Methods and analysis The PATCH trial is a double-blind, enriched enrolment with randomised withdrawal, vehicle-controlled trial, aiming to explore the effects and safety of LMP in patients with TN. There is a 3-week initial open-label phase, followed by a 4-week double-blind treatment phase for responders. In the double-blind phase, patients will have to withdraw from this PATCH study if they meet one of the following criteria for treatment failure such as: >50% increase in pain intensity or paroxysms, lack of efficacy or side effects. The primary outcome will be the number of treatment failures. Adverse events will also be monitored throughout the study. Ethics and dissemination This study protocol has been approved by the Institutional Review Board of Beijing Tiantan Hospital (approval number: KY 2020-102-02). The results will be disseminated in international academic meetings and published in peer-reviewed journals. Trial registration number NCT04570293 .

The Treatment of Painful Diabetic Neuropathy

Article

Jul 2021

Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact, resulting in a low quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, there are currently no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful-DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful-DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. Weak opioids (e.g., tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants, such as amitriptyline and α2δ ligand gabapentin, are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol) should be prescribed with caution in view of the lack of definitive data surrounding efficacy and concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g., botulinum toxin, intravenous lidocaine,, and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practice. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy, and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies, such as novel compounds and stratification of patients according to individual characteristics, (e.g., pain phenotype, neuroimaging, and genotype) to improve treatment responses.

Safety and Tolerability of Natural and Synthetic Cannabinoids in Older Adults: A Systematic Review and Meta-Analysis of Open-Label Trials and Observational Studies

Article

Jul 2021

Background and objective: Although cannabinoid-based medications are increasingly used by older adults, their safety and tolerability in this age group remain unclear. The purpose of this systematic review was to examine the safety and tolerability of cannabinoid-based medications by conducting a meta-analysis of open-label observational studies of cannabinoid-based medications for all indications in individuals with a mean age of ≥50 years. Methods: A systematic search was conducted on PubMed, PsycINFO, MEDLINE, EMBASE and CINHAL. Study quality was assessed using an adapted version of the Grading of Recommendations Assessment, Development and Evaluation criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. We included studies that (a) were published from 1990 onwards; (b) included older adults (mean age ≥50 years); and (c) provided data on the safety and tolerability of medical cannabinoids. Data were pooled using a random-effects approach. Risk of adverse events, serious adverse events and withdrawals was computed as the incidence rate (IR). Separate analyses were conducted by the cannabinoid-based medication used, for delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and a combination of THC and CBD (THC:CBD). Results: Thirty-eight studies were identified (THC = 23; CBD = 6; THC:CBD = 9; N = 2341, mean age: 63.19 ± 8.08 years, men: 53.86%). THC had a very low incidence of all-cause and treatment-related adverse events (IR: 122.18, 95% confidence interval [CI] 38.23-253.56; IR: 84.76, 95% CI 0.13-326.01, respectively) and negligible serious adverse events (IR = 0). Similar IRs for CBD (all cause, IR: 111.91, 95% CI 1.24-495.93; treatment related, IR: 1.76, 95% CI 4.63-23.05) and no serious adverse events (IR = 0). CBD was not associated with a risk of treatment-related withdrawals. THC had a low risk of all-cause and treatment-related withdrawals (IR: 25.18, 95% CI 12.35-42.52; IR: 7.83, 95% CI 3.26-14.38, respectively). The THC:CBD treatment had a low risk of all-cause and treatment-related adverse events (IR: 100.72, 95% CI 0.25-383.00; IR: 55.38, 95% CI 8.61-142.80, respectively), but reported a risk of all-cause and treatment-related serious adverse events (IR: 21.32, 95% CI 0.18-93.26; IR: 3.71, 95% CI 0.21-11.56, respectively), and all-cause and treatment-related withdrawals (IR: 78.63, 95% CI 17.43-183.90; IR: 34.31, 95% CI 6.09-85.52, respectively). Significant heterogeneity (I2 >55%) was present in most analyses. Conclusions: Although cannabinoid-based medications were generally safe and acceptable to adults aged over 50 years, these estimates are limited by the lack of a control condition and considerable heterogeneity. Nevertheless, they complement and are consistent with comparable evidence from randomised controlled trials.

Nabilone (Cesamet)

Chapter

Jul 2021

Use of smoked marijuana medicinally has been documented for centuries, including its use as an antiemetic. Academic- and industry-sponsored research in cannabinoids and synthetic analogues led to the development of nabilone, a Δ9-tetrahydrocannabinol (Δ9-THC) analogue. Numerous studies demonstrated nabilone’s superiority over older antiemetics, and while it was initially set for FDA approval in 1985 by Eli Lilly and Company, it was not until 2006 that Valeant Pharmaceuticals secured final FDA approval for nabilone and marketed under the name Cesamet, for the treatment of chemotherapy-induced nausea and vomiting. The emergence of newer, more efficacious antiemetics such as serotonin antagonists has led to nabilone being reserved for breakthrough nausea and vomiting not controlled by standard antiemetics. Additionally, since nabilone is a Δ9-THC analogue, researchers have conducted studies exploring its possible use in the treatment of chronic pain; however results have been mixed. Therefore, chronic pain is not an FDA-approved use of nabilone.

Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis

Article

Full-text available

Mar 2021
PLOS MED

Background Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years. Methods and findings A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those <50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies. Conclusions This pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.

Perioperative Pain and Addiction Interdisciplinary Network (PAIN): consensus recommendations for perioperative management of cannabis and cannabinoid-based medicine users by a modified Delphi process

Article

Oct 2020

In many countries, liberalisation of the legislation regulating the use of cannabis has outpaced rigorous scientific studies, and a growing number of patients presenting for surgery consume cannabis regularly. Research to date suggests that cannabis can impact perioperative outcomes. We present recommendations obtained using a modified Delphi method for the perioperative care of cannabis-using patients. A steering committee was formed and a review of medical literature with respect to perioperative cannabis use was conducted. This was followed by the recruitment of a panel of 17 experts on the care of cannabis-consuming patients. Panellists were blinded to each other's participation and were provided with rater forms exploring the appropriateness of specific perioperative care elements. The completed rater forms were analysed for consensus. The expert panel was then unblinded and met to discuss the rater form analyses. Draft recommendations were then created and returned to the expert panel for further comment. The draft recommendations were also sent to four independent reviewers (a surgeon, a nurse practitioner, and two patients). The collected feedback was used to finalise the recommendations. The major recommendations obtained included emphasising the importance of eliciting a history of cannabis use, quantifying it, and ensuring contact with a cannabis authoriser (if one exists). Recommendations also included the consideration of perioperative cannabis weaning, additional postoperative nausea and vomiting prophylaxis, and additional attention to monitoring and maintaining anaesthetic depth. Postoperative recommendations included anticipating increased postoperative analgesic requirements and maintaining vigilance for cannabis withdrawal syndrome.

Chapter 6 - Cannabinoids and Pain

Chapter

Oct 2020

Steven James

Medical marijuana and the promise of medical advances with cannabinoids is a controversial topic. This book provides clinicians with credible, peer-reviewed science to advise patients on the use of cannabinoids in practice. From the history of cannabis to the recent discoveries, chapters include the science of cannabinoids, changes in the legal and regulatory landscape, and the emerging area of endocannabinoids. The book differentiates approved cannabinoids from cannabis and medical marijuana and stimulates clinicians to think about the risks and benefits of these two drugs. It provides the factual background for clinicians to lead the discussion on the continued use of marijuana, ongoing areas of research and future advances and development of new medications for treatment. An invaluable guide for all specialists in the pharmaceutical sciences, toxicologists, biochemists, neurologists, psychiatrists, addiction specialists, as well as primary care physicians, nurse practitioners, and regulators and policymakers.

Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review

Article

Full-text available

Jul 2001

Fiona A Campbell

Objective To establish whether cannabis is an effective and safe treatment option in the management of pain. Design Systematic review of randomised controlled trials. Data sources Electronic databases Medline, Embase, Oxford Pain Database, and Cochrane Library; references from identified papers; hand searches. Study selection Trials of cannabis given by any route of administration (experimental intervention) with any analgesic or placebo (control intervention) in patients with acute, chronic non-malignant, or cancer pain. Outcomes examined were pain intensity scores, pain relief scores, and adverse effects. Validity of trials was assessed independently with the Oxford score. Data extraction Independent data extraction; discrepancies resolved by consensus. Data synthesis 20 randomised controlled trials were identified, 11 of which were excluded. Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. No randomised controlled trials evaluated cannabis; all tested active substances were cannabinoids. Oral delta-9-tetrahydrocannabinol (THC) 5-20 mg, an oral synthetic nitrogen analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg were about as effective as codeine 50-120 mg, and oral benzopyranoperidine 2-4 mg was less effective than codeine 60-120 mg and no better than placebo. Adverse effects, most often psychotropic, were common.

A Comparison between Enriched and Nonenriched Enrollment Randomized Withdrawal Trials of Opioids for Chronic Noncancer Pain

Article

Full-text available

Sep 2011

An enriched enrollment randomized withdrawal (EERW) design excludes potential participants who are nonresponders or who cannot tolerate the experimental drug before random assignment. It is unclear whether EERW design has an influence on the efficacy and safety of opioids for chronic noncancer pain (CNCP). The primary objective was to compare the results from EERW and non-EERW trials of opioids for CNCP. Secondary objectives were to compare weak versus strong opioids, subgroups of patients with different types of pain, and the efficacy of opiods compared with placebo versus other drugs. MEDLINE, EMBASE and CENTRAL were searched up to July 2009, for randomized controlled trials of any opioid for CNCP. Metaanalyses and meta-regressions were conducted to compare the results. Treatment efficacy was assessed by effect sizes (small, medium and large) and the incidence of adverse effects was assessed by a clinically relevant mean difference of 10% or greater. Sixty-two randomized trials were included. In 61 trials, the duration was less than 16 weeks. There was no difference in efficacy between EERW and non-EERW trials for both pain (P=0.6) and function (P=0.3). However, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness and dry skin⁄itching compared with non-EERW. Opioids were more effective than placebo in patients with nociceptive pain (effect size=0.60, 95% CI 0.49 to 0.72) and neuropathic pain (effect size=0.56, 95% CI 0.38 to 0.73). EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta- analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin.

Cannabinoid-Mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain

Article

Full-text available

Mar 2010
MOL PAIN

Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state. Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists. The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state.

Randomized Placebo-Controlled Double-Blind Clinical Trial of Cannabis-Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy

Article

Full-text available

Oct 2009

To assess the efficacy of Sativex, a cannabis-based medicinal extract, as adjuvant treatment in painful diabetic peripheral neuropathy (DPN). In this randomized controlled trial, 30 subjects with painful DPN received daily Sativex or placebo. The primary outcome measure was change in mean daily pain scores, and secondary outcome measures included quality-of-life assessments. There was significant improvement in pain scores in both groups, but mean change between groups was not significant. There were no significant differences in secondary outcome measures. Patients with depression had significantly greater baseline pain scores that improved regardless of intervention. This first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN. Depression was a major confounder and may have important implications for future trials on painful DPN.

Cannabinoid CB(1) receptor activation stimulates neurite outgrowth and inhibits capsaicin-induced Ca(2+) influx in an in vitro model of diabetic neuropathy

Article

Full-text available

Jun 2009

Cannabinoid CB(1) receptors mediate, in part, the neuroprotectant properties of endocannabinoids, and altered signalling via the CB(1) receptor may contribute to the pathogenesis of diabetic neuropathy. We investigated CB(1) receptor function in PC12 cells differentiated into a neuronal phenotype with nerve growth factor (NGF, 50 ng/ml) in 5.5 and 50 mM concentrations of glucose. High glucose was associated with impaired NGF-induced neurite outgrowth (P < 0.01; n = 185-218) and reduced expression of CB(1) receptor mRNA (P < 0.01; n = 6) on day 6 of culture. Whilst treatment of hyperglycemic cells with HU210 (0.03-3 microM) increased neurite length in a concentration-dependent manner (P < 0.01; n = 136-218), CB(1) receptor expression was not significantly altered by chronic agonist stimulation (P = 0.32; n = 6 per group). Application of the CB(1) agonist HU210 (1 microM) inhibited capsaicin-induced calcium transients to a similar degree in cells cultured in high glucose (40%) versus normal (43%) (P < 0.05; n = 33-50). HU210-mediated rescue of neurite outgrowth and inhibition of calcium influx was blocked by the selective CB(1) antagonist AM251 (1 microM), but not by the selective CB(2) antagonist AM630 (1 microM), confirming the role of CB(1) receptors. High glucose treatment did not significantly elevate endocannabinoid levels. These results suggest that high glucose concentrations are associated with decreased expression, but preserved function of CB(1) receptors in nerve cells.

Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review

Article

Full-text available

Aug 2001

To establish whether cannabis is an effective and safe treatment option in the management of pain. Systematic review of randomised controlled trials. Electronic databases Medline, Embase, Oxford Pain Database, and Cochrane Library; references from identified papers; hand searches. Trials of cannabis given by any route of administration (experimental intervention) with any analgesic or placebo (control intervention) in patients with acute, chronic non-malignant, or cancer pain. Outcomes examined were pain intensity scores, pain relief scores, and adverse effects. Validity of trials was assessed independently with the Oxford score. Independent data extraction; discrepancies resolved by consensus. 20 randomised controlled trials were identified, 11 of which were excluded. Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. No randomised controlled trials evaluated cannabis; all tested active substances were cannabinoids. Oral delta-9-tetrahydrocannabinol (THC) 5-20 mg, an oral synthetic nitrogen analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg were about as effective as codeine 50-120 mg, and oral benzopyranoperidine 2-4 mg was less effective than codeine 60-120 mg and no better than placebo. Adverse effects, most often psychotropic, were common. Cannabinoids are no more effective than codeine in controlling pain and have depressant effects on the central nervous system that limit their use. Their widespread introduction into clinical practice for pain management is therefore undesirable. In acute postoperative pain they should not be used. Before cannabinoids can be considered for treating spasticity and neuropathic pain, further valid randomised controlled studies are needed.

Development and validation of the Neuropathic Pain Symptom Inventory

Article

Full-text available

May 2004

This study describes the development and validation of the Neuropathic Pain Symptom Inventory (NPSI), a new self-questionnaire specifically designed to evaluate the different symptoms of neuropathic pain. Following a development phase and a pilot study, we generated a list of descriptors reflecting spontaneous ongoing or paroxysmal pain, evoked pain (i.e. mechanical and thermal allodynia/hyperalgesia) and dysesthesia/paresthesia. Each of these items was quantified on a (0-10) numerical scale. The validation procedure was performed in 176 consecutive patients with neuropathic pain of peripheral (n = 120) or central (n = 56) origin, recruited in five pain centers in France and Belgium. It included: (i) assessment of the test-retest reliability of each item, (ii) determination of the factorial structure of the questionnaire and analysis of convergent and divergent validities (i.e. construct validity), and (iii) evaluation of the ability of the NPSI to detect the effects of treatment (i.e. sensitivity to change). The final version of the NPSI includes 10 descriptors (plus two temporal items) that allow discrimination and quantification of five distinct clinically relevant dimensions of neuropathic pain syndromes and that are sensitive to treatment. The psychometric properties of the NPSI suggest that it might be used to characterize subgroups of neuropathic pain patients and verify whether they respond differentially to various pharmacological agents or other therapeutic interventions.

Validation of a Modified Version of the Brief Pain Inventory for Painful Diabetic Peripheral Neuropathy

Article

Full-text available

Sep 2005
J Vasc Nurs

Neuropathic pain is the focus of current clinical research, clinical identification, and treatment. It is unique from nociceptive pain and requires evaluation of the relevance and utility of common pain measures created for other painful conditions. This study evaluated the psychometric properties of a modified Brief Pain Inventory (BPI) for patients with painful diabetic peripheral neuropathy (BPI-DPN). Participants were patients with painful DPN (n = 255) enrolled in a DPN Burden of Illness survey referred through 17 outpatient settings (primary care physicians, endocrinologists, neurologists, and anesthesiologists). Patients completed the BPI-DPN and self-report measures of health-related quality of life, mood sleep, and health care use. Construct, criterion and discriminant validity, and internal consistency reliability were evaluated. Principal axis factoring with oblimin rotation revealed two interpretable factors (eigenvalues > 1.0), consistent with most published BPI validation studies: a severity scale comprising the four BPI Severity items and an interference scale comprising the seven Interference items, which satisfied criteria for interpretability and model fit. Cronbach's alpha was high (0.94) for both scales. Mean pain Severity was highly correlated with Bodily Pain from the Medical Outcomes Study Short Form-12, version 2 (r(s) = 0.63, P < .001), the Pain/Discomfort item in the Euro-QoL (r(s) = 0.58, P < .001), and a verbal rating scale measure of pain severity (r(s) = 0.74, P < .001). Individual BPI-DPN Interference domains were moderately correlated (r(s)'s > 0.5, P < .001) with analogous measures, and the Sleep Interference item had a high, significant association with the three primary Medical Outcome Study-Sleep scale subscales (r(s)'s = 0.66-71, P < .001). Worst Pain and Interference ratings were significantly associated with hospital use and outpatient visits because of DPN. These results replicate, in a pure peripheral neuropathic pain condition, the BPI psychometric characteristics documented in populations with nociceptive or mixed pain conditions. The BPI-DPN is a promising instrument in the evaluation of painful DPN.

The Prevalence, Severity, and Impact of Painful Diabetic Peripheral Neuropathy in Type 2 Diabetes

Article

Full-text available

Aug 2006
DIABETES CARE

To determine the prevalence of painful diabetic peripheral neuropathy (PDPN) in a population-based sample and to estimate its severity and impact. A cross-sectional descriptive study consisting of two phases: phase 1, a postal survey to patients with type 2 diabetes (an initial screening questionnaire including one question about pain); phase 2, neurological history and examination using the Toronto Clinical Scoring System. Subjects with PDPN or mixed (PDPN and nonneuropathic) pain completed the Neuropathic Pain Scale and Neuroqol to assess severity and nature of the pain and impact on quality of life. Those without PDPN completed the Neuroqol only. In phase 1, there was a 92.7% response (n = 326), with 208 (63.8%) subjects reporting pain. In phase 2, 269 (82.5%) subjects attended and 51 (19.0%) were found to have PDPN: 99 (36.8%) nonneuropathic pain, 20 (7.4%) mixed pain, and 99 (36.8%) no pain (PDPN prevalence 26.4%). Of those with PDPN, 80% stated that their pain was moderate or severe. Those affected had poorer quality of life than those with no pain (difference in mean scores 3.6 [95% CI 2.5-4.6%]) compared with those with nonneuropathic pain (1.7 [0.4-2.9%]). Both pain and neuropathy score were independently associated with quality of life, and subjects with PDPN had significantly higher neuropathy scores. Our study showed a prevalence of PDPN of 26.4%. Having PDPN has a significant negative effect on quality of life, and increasing neuropathy is associated with an increasing risk of developing PDPN.

Effects of nabilone, a synthetic cannabinoid, on postoperative pain

Article

Full-text available

Sep 2006

Pierre Beaulieu

Cannabinoids have been shown to have analgesic properties in animal studies, but a potential role for these drugs in acute pain management has not been established. It was hypothesized that nabilone, an oral cannabinoid synthetic tetrahydrocannabinol analogue, decreases morphine consumption, pain scores, nausea and vomiting following major surgery. A double-blind, randomized, placebo-controlled, parallel-group pilot trial compared the effects of two different doses, 1 mg (n = 11) and 2 mg (n = 9) of nabilone, ketoprofen 50 mg (n = 11) or placebo (n = 10), given at eight-hour intervals for 24 hr. Outcomes included morphine consumption, pain scores and emesis after major surgery. Secondary outcomes included patient tolerability of the study medication. Forty-one patients (mean age 52 +/- 2 yr) undergoing gynecologic (46%), orthopedic (44%), or other (10%) surgery were recruited. Cumulative 24-hr morphine consumption was not different between the four groups, but pain scores at rest and on movement were significantly higher in the 2 mg nabilone group compared to the other groups. There were no significant differences between groups with respect to episodes of nausea and vomiting, quality of sleep, sedation, euphoria, pruritus, or the number and severity of adverse events. No serious adverse event was recorded. Contrary to the main hypothesis, high dose nabilone in the presence of morphine patient controlled analgesia is associated with an increase in pain scores in patients undergoing major surgery.

Expression of Cannabinoid CB1 Receptors in Models of Diabetic Neuropathy

Article

Full-text available

Nov 2007

A clearer understanding of the mechanisms underlying the development and progression of diabetic neuropathy is likely to indicate new directions for the treatment of this complication of diabetes. In the present study we investigated the expression of cannabinoid CB(1) receptors in models of diabetic neuropathy. PC12 cells were differentiated into a neuronal phenotype with nerve growth factor (NGF) (50 ng/ml) in varying concentrations of glucose (5.5-50 mM). CB(1) receptor expression was studied at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR) and at the protein level via immunohistochemical and Western blot analysis. CB(1) expression was also compared in dorsal root ganglia (DRG) removed from streptozotocin-induced diabetic rats versus control animals. Total neurite length induced by NGF was reduced in cells cultured in 20 to 50 mM glucose at day 6 (P < 0.01 versus 5.5 mM; n = 6). Cell viability assays conducted in parallel on day 6 confirmed that the total cell numbers were not significantly different among the various glucose concentrations (P = 0.86; n = 12). RT-PCR, immunohistochemical, and Western blot analysis all revealed down-regulation of the CB(1) receptor in cells treated with high glucose (P < 0.05; n = 4-5 for each), and in DRG removed from diabetic rats compared with controls (P < 0.01; n = 5 for immunohistochemistry, and n = 3 for Western blot). These results suggest that high glucose concentrations are associated with decreased expression of CB(1) receptors in nerve cells. Given the neuroprotective effect of cannabinoids, a decline in CB(1) receptor expression may contribute to the neurodegenerative process observed in diabetes.

Cannabis, Pain, and Sleep: Lessons from Therapeutic Clinical Trials of Sativex®, a Cannabis-Based Medicine

Article

Full-text available

Nov 2007
CHEM BIODIVERS

Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times. This review examines modern studies on effects of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex). Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients' quality of life.

Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: Randomised, crossover, double blind study

Article

Full-text available

Feb 2008
Br Med J

To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain. Randomised, double blind, crossover trial of 14 weeks' duration comparing dihydrocodeine and nabilone. Outpatient units of three hospitals in the United Kingdom. 96 patients with chronic neuropathic pain, aged 23-84 years. The primary outcome was difference between nabilone and dihydrocodeine in pain, as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period. Secondary outcomes were changes in mood, quality of life, sleep, and psychometric function. Side effects were measured by a questionnaire. Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks. Treatment periods were separated by a 2 week washout period. Results Mean baseline visual analogue score was 69.6 mm (range 29.4-95.2) on a 0-100 mm scale. 73 patients were included in the available case analysis and 64 patients in the per protocol analysis. The mean score was 6.0 mm longer for nabilone than for dihydrocodeine (95% confidence interval 1.4 to 10.5) in the available case analysis and 5.6 mm (10.3 to 0.8) in the per protocol analysis. Side effects were more frequent with nabilone. Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects, although no major adverse events occurred for either drug. Current Controlled Trials ISRCTN15330757 controlled-trials.com] .

The role of central and peripheral Cannabinoid 1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain

Article

May 2001
PAIN

We have examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cannabinoid activity. WIN55,212-2 (0.3–10 mg kg−1), CP-55,940 (0.03–1 mg kg−1) and HU-210 (0.001–0.03 mg kg−1) were all active in a ‘tetrad’ of tests consisting of tail-flick, catalepsy, rotarod and hypothermia following subcutaneous administration, with a rank order of potency in each of HU-210>CP-55,940>WIN55,212-2. The effects of WIN55,212-2 in each assay were blocked by the Cannabinoid1 (CB1) antagonist SR141716A. In the partial sciatic ligation model of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h of subcutaneous administration with D50 values of 0.52, 0.08 and 0.005 mg kg−1, respectively. In this model WIN55,212-2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB1 antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. These data show that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.

The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain

Article

Jun 2001
BRIT J PHARMACOL

The analgesic properties of the synthetic cannabinoid WIN55,212-2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. Seven days later, sensory thresholds were reassessed and the development of allodynia to cold and mechanical stimuli and hyperalgesia to a noxious thermal stimulus confirmed. The effect of WIN55,212-2 (0.1 – 5.0 mg kg−1, i.p.) on the signs of neuropathy was then determined; there was a dose related reversal of all three signs of painful neuropathy at doses which did not generally alter sensory thresholds in the contralateral unligated limb. This effect was prevented by co-administration of the CB1 receptor antagonist SR141716a, but not by co-administration of the CB2 receptor antagonist SR144528, suggesting this action of WIN55,212-2 is mediated via the CB1 receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone. These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB1 receptor. British Journal of Pharmacology (2001) 133, 586–594; doi:10.1038/sj.bjp.0704110

The Hospital Anxiety And Depression Scale

Article

Jun 1983
ACTA PSYCHIAT SCAND

ABSTRACT– A self-assessment scale has been developed and found to be a reliable instrument for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. The anxiety and depressive subscales are also valid measures of severity of the emotional disorder. It is suggested that the introduction of the scales into general hospital practice would facilitate the large task of detection and management of emotional disorder in patients under investigation and treatment in medical and surgical departments.

Threats to the Validity of Clinical Trials Employing Enrichment Strategies for Sample Selection

Article

Apr 1998
Contr Clin Trials

Subject selection and exclusion criteria employed in typical clinical effectiveness trials of investigational new drugs have two fundamental aims: (1) to ensure that patients entering a study are truly suffering from the condition the drug is intended to treat and (2) to maximize the likelihood that the study will detect an effect of the drug if, in fact, one exists. Typical protocol selection criteria not only specify exacting procedures for establishing and documenting the diagnosis of those recruited for a study but also seek to increase, relative to the prevalence in the general population, the proportion of individuals in the sample likely to respond to pharmacological treatment. Because it is ordinarily impossible to learn prior to extensive clinical experience with a new drug which, if any, patient characteristics reliably predict a consistent treatment response, strategies for sample “enrichment” typically operate by excluding patients (for example, those with very advanced and/or complicated illness, those with serious concomitant illness, those at the extremes of age, those with very mild illness, and so forth) in whom a dependable response to treatment seems unlikely on logical and/or generic grounds.

The impact of pain in patients with polyneuropathy

Article

May 2011
EUR J PAIN

Peripheral neuropathy (PN) is a common impairment which may impact upon quality of life (QoL). Neuropathic pain (NeP) occurs in up to 50% of patients with PN. We hypothesized that disability and impaired quality of life resulting from PN is primarily associated with presence of NeP. Our aim was to determine using prospectively identified PN patients presenting to a tertiary care neuromuscular clinic if presence of NeP (PN+NeP) had greater impact upon QoL than with absence of NeP (PN-NeP). A second aim was to identify if QoL varied based upon etiology of PN. We analyzed neuropathy severity (Toronto Clinical Neuropathy Score (TCSS)), pain quantity and quality (Visual Analogue Scale (VAS) pain score, Brief Pain Inventory (BPI)), QoL and health status measures (EuroQol Instrument 5 Domains (EQ-5D), Medical Outcomes Sleep Study Scale (MOSSS), Hospital Anxiety and Depression Scale (HADS), Short Form 36 Health Survey (SF-36)) and Health Assessment Questionnaire (HAQ) to determine impact of NeP. Although both cohorts were epidemiologically similar and had similar severity of PN, PN+NeP patients had considerably greater impairment for QoL, sleep efficacy, and features of anxiety and depression, leading to substantially greater health care resources utilization when compared to PN-NeP patients. The magnitude of NeP severity was the only explaining variable for increased impact upon QoL measures and diminishing overall wellbeing. Our results confirm that NeP is a primary indicator for worsening QoL and diminished overall wellbeing in PN patients. The etiology of PN did not influence levels of NeP-related compromise of QoL. Further studies are needed to determine optimal methods for management of PN+NeP patients subjected to a significant physiological, psychological and functional burden.

Abuse potential and psychoactive effects of δ-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine

Article

May 2011
EXPERT OPIN DRUG SAF

Philip J Robson

Introduction: There is a growing consensus that cannabis dependence is a substantial and underappreciated problem. The key component responsible for the euphoric effects of cannabis and its dependence potential is δ-9-tetrahydrocannabinol (THC). THC-containing cannabinoid medicines theoretically pose a risk of abuse and dependence. Areas covered: In order to evaluate the potential of Sativex to cause cannabis-like psychoactivity, abuse or dependence relevant data from all published papers have been reviewed along with the integrated safety analysis for Sativex use in multiple sclerosis (MS) patients on file at GW Pharmaceuticals. Expert opinion: In clinical trials, intoxication scores have been low and euphoria reported by only 2.2% of patients. Tolerance has not occurred, abrupt withdrawal has not resulted in a formal withdrawal syndrome, and no cases of abuse or diversion have been reported to date. A formal abuse liability study of Sativex in experienced cannabis smokers showed some abuse potential in comparison with placebo at higher doses, but scores were consistently lower than equivalent doses of THC. Evidence to date suggests that abuse or dependence on Sativex is likely to occur in only a very small proportion of recipients.

Impact of responder definition on the enriched enrollment randomized withdrawal trial design for establishing proof of concept in neuropathic pain

Article

Mar 2011
PAIN

The objective of this study was to evaluate how enrichment for responders increases assay sensitivity in an enriched enrollment randomized withdrawal (EERW) proof-of-concept (POC) study in neuropathic pain. Adults with moderate to severe peripheral neuropathic pain entered a 3- to 4-day screening period, followed by a 12-day titration to the highest tolerated dose that provided pain control (pregabalin 50200 mg t.i.d.), and then a 9-day maintenance period. Subjects were stratified as primary responders (>= 30%), secondary responders (>= 10% to <30%), or nonresponders (<10%) based on decrease in pain intensity and were randomized to placebo or pregabalin during the randomized withdrawal period. The primary endpoint was mean of average 24-h pain intensity during the last 3 days of treatment period relative to the 3 days before randomization. Time-to-efficacy-failure was the key secondary endpoint. Other features included not requiring discontinuation of current analgesic therapies and blinding investigators to study design elements that could contribute to non-treatment-related responses. Effect size (ES) (mean treatment difference/SD) was used to measure assay sensitivity. Pregabalin-treated subjects (n = 52) had significantly less pain than those receiving placebo (n = 51) (P <= .003). Effect size of the primary endpoint was 0.72 for primary responders and decreased if secondary and nonresponders were included in the analysis. The highest ES (1.68) was demonstrated for the endpoint time-to-efficacy-failure seen in primary responders with painful diabetic neuropathy. The EERW trial design using time-to-efficacy-failure may provide a sensitive and efficient method to conduct POC studies of novel therapies in patients with neuropathic pain.

An Open-Label Comparison of Nabilone and Gabapentin as Adjuvant Therapy or Monotherapy in the Management of Neuropathic Pain in Patients with Peripheral Neuropathy

Article

Nov 2010
Pain Pract

Neuropathic pain (NeP) is prevalent in patients with peripheral neuropathy (PN), regardless of etiology. We sought to compare the efficacy of the cannabinoid nabilone as either monotherapy or adjuvant therapy with a first-line medication for NeP, gabapentin, in a patient population with PN-NeP. Patients diagnosed with PN-NeP were permitted to initiate monotherapy (nabilone or gabapentin) or add one of these two medications (adjuvant therapy) to their existing NeP treatment regimen in a non-randomized open-label nature. Baseline data collected included a primary outcome (visual analog scores [VAS] of pain) and secondary outcomes (quality of life [EuroQol 5 Domains and Short-Form 36] assessments and assessments of sleep [Medical Outcomes Sleep Study Scale {MOSSS}], anxiety and depression [Hospital Anxiety and Depression Scale], and pain [Brief Pain Inventory]). Reassessment and modulation of dosing and/or medications occurred at 3- and 6-month intervals. Medication adverse effects and drug efficacy, as well as questionnaires, were assessed at 6 months. Matched analysis of variance testing was performed to compare 3- and 6-month scores with baseline, as well as to compare therapies at equal time points. Significant improvements in pain VAS were seen in all treatment groups at 6 months. Numerous sleep parameters within MOSSS, Brief Pain Inventory, and Short-Form 36 improved in patients receiving nabilone or gabapentin either as monotherapy or adjuvant treatment. Hospital Anxiety and Depression Scale-A scores were significantly improved in all treatment groups. Sleep adequacy and the sleep problems index within the MOSSS improved in nabilone monotherapy patients in particular. The benefits of monotherapy or adjuvant therapy with nabilone appear comparable to gabapentin for management of NeP. We advocate for head-to-head randomized, double-blind studies for current therapies for NeP in order to determine potential advantages beneficial in this patient population.

Effect of rimonabant, the cannabinoid CB1 receptor antagonist, on peripheral nerve in streptozotocin-induced diabetic rat

Article

Jul 2010

The aim of this study is to investigate the effect of rimonabant, which has antiatherosclerotic and antiinflammatory properties, on peripheral neuropathy in a diabetic rat. Diabetic rat models were induced by treatment with streptozotocin and then either normal or diabetic rats were treated with an oral dose of 10mg/kg/day rimonabant or placebo for 24 weeks. We quantified the densities of intraepidermal (PGP9.5+) nerve fiber and total skin (RECA-1+) capillary length. We also measured the current perception threshold, as defined by the intensity of sine-wave stimulus, skin blood flow after treadmill running and TNF-alpha level in spinal cord tissue or plasma. After 24 weeks, rimonabant reduced the body weight and food intake in both diabetic and normal rats, but it had no effect on blood sugar levels. In addition, rimonabant treatment significantly improved the decreased intraepidermal nerve fiber density (5.53+/-0.12 vs. 4.36+/-0.27/mm, P<0.05) and alleviated the increased current perception threshold in rimonabant-treated versus control diabetic rats. These responses were closely associated with the attenuation of skin capillary loss (1.98+/-0.07 vs. 1.67+/-0.10 mm/mm(2), P<0.05), increase in skin blood flow (14.93+/-1.08 vs. 12.07+/-0.87 TPU, P<0.05) and reduction in TNF-alpha level in tissue (70.10+/-4.99 vs. 91.18+/-3.34 pg/mg, P<0.05) in rimonabant-treated diabetic rats compared with placebo. These findings suggest that rimonabant can be beneficial for treatment of diabetic peripheral neuropathy, possibly due to its potential role in micro- and macrovessel protection and its anti-inflammatory properties.

Rimonabant, a cannabinoid CB1 receptor antagonist, attenuates mechanical allodynia and counteracts oxidative stress and nerve growth factor deficit in diabetic mice

Article

Jul 2010

Diabetes is one of the leading causes of painful neuropathy and to date, besides a tight glycemic control, a viable treatment for this complication is not available. Rimonabant is a selective cannabinoid CB(1) receptor antagonist that produces a significant increase in insulin sensitivity and a reduction of HbA(1c) in diabetic patients. This study aimed to investigate the therapeutic potential of rimonabant in relieving diabetes-induced neuropathic pain. The repeated treatment with rimonabant evoked a significant attenuation of mechanical allodynia in diabetic mice that was dose- and time-dependent. This effect occurred without alteration of hyperglycemia, but it was associated with significant effects on many key players in the pathogenesis of diabetic neuropathy. Metabolic changes induced by hyperglycemia lead to oxidative stress, deregulation of cytokine control and reduced production and transport of nerve growth factor (NGF), and all these factors contribute to neuropathic pain. Rimonabant treatment reduced oxidative stress in peripheral nerve, as revealed by the ability of the compound to counteract the reduced glutathione (GSH) depletion. The same repeated treatment inhibited tumor necrosis factor (TNFalpha) overproduction in the spinal cord and increased the NGF support. This rimonabant-induced improvement might favour the nerve regeneration; accordingly, the histological analysis of sciatic nerves showed a marked degeneration of myelinated fibers in diabetic mice, that was substantially reduced after rimonabant administration. These findings support the hypothesis that CB(1) antagonists would represent a new opportunity for diabetic patients, since currently there are no treatments for painful diabetic neuropathy other than treating the diabetic condition per se.

The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial

Article

Dec 2009

Sleep disorders affect many patients with chronic pain conditions. Cannabis has been reported by several patient populations to help sleep. We evaluated the safety and efficacy of nabilone, a synthetic cannabinoid, on sleep disturbance in fibromyalgia (FM), a disease characterized by widespread chronic pain and insomnia. We conducted a randomized, double-blind, active-control, equivalency crossover trial to compare nabilone (0.5-1.0 mg before bedtime) to amitriptyline (10-20 mg before bedtime) in patients with FM with chronic insomnia. Subjects received each drug for 2 wk with a 2-wk washout period. The primary outcome was sleep quality, measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Questionnaire. Secondary outcomes included pain, mood, quality of life, and adverse events (AEs). Thirty-one subjects were enrolled and 29 completed the trial (26 women, mean age 49.5 yr). Although sleep was improved by both amitriptyline and nabilone, nabilone was superior to amitriptyline (Insomnia Severity Index difference = 3.2; 95% confidence interval = 1.2-5.3). Nabilone was marginally better on the restfulness (Leeds Sleep Evaluation Questionnaire difference = 0.5 [0.0-1.0]) but not on wakefulness (difference = 0.3 [-0.2 to 0.8]). No effects on pain, mood, or quality of life were observed. AEs were mostly mild to moderate and were more frequent with nabilone. The most common AEs for nabilone were dizziness, nausea, and dry mouth. Nabilone is effective in improving sleep in patients with FM and is well tolerated. Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline. Longer trials are needed to determine the duration of effect and to characterize long-term safety.

Enriched Enrollment Randomized Withdrawal Trial Designs of Analgesics

Article

Nov 2009
CLIN J PAIN

Nathaniel Katz

To systematically identify and critically assess clinical trials that use enriched enrollment randomized withdrawal (EERW) trial design as a methodology for assessing the effect of analgesics pain. A comprehensive literature search was conducted through April 2007 in Medline and Embase to identify all randomized controlled trials that use EERW trial designs. Data were collected from relevant trials and tabulated. Results were categorized on the basis of study designs, preenrichment and postenrichment disposition, discontinuation rates, primary and secondary efficacy results, and respective P values. The literature search identified 2875 unique citations, most of which were deemed inappropriate for this analysis. The primary reasons for exclusion included inappropriate study design, no available abstract, not a clinical study, and therapeutic area not related to chronic pain. Eight EERW clinical trials of analgesics were identified. Half of the trials were in chronic low back pain, and 5 of 8 trials used an opioid as the active drug. Of the 8 trials, 5 used a parallel design and 3 used crossover designs. The primary efficacy parameter used was pain scores or time to discontinuation, and statistically and clinically significant effects in active treatments relative to placebo were observed after randomization in all trials. The median magnitude of effect was 1.7 on a 10-point scale. Time to exit was a more statistically powerful endpoint than mean pain intensity. EERW trials are an emerging type of study design that in certain settings may offer advantages over traditional trial designs in characterizing the effects of analgesic medications.

Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D and Hogestatt EDVanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400: 452-457

Article

Aug 1999

The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.

The Prevalence and Impact of Chronic Pain with Neuropathic Pain Symptoms in the General Population

Article

Aug 2009
PAIN MED

We performed a prevalence estimate of chronic pain with neuropathic pain (NeP) symptoms to determine its frequency and associations with morbidity. We conducted a telephone-based survey based upon a random sampling of both urban and rural households of the general population in one Canadian province to determine NeP prevalence and its impact upon financial well-being and quality of life. Telephonic use of the DN4 questionnaire (DN4Q), used to identify NeP symptoms in those patients with chronic pain, was validated within selected clinical populations of chronic pain. Epidemiological data was obtained for all subjects. EuroQoL (EQ)-5D data estimating quality of life was measured. Chronic pain was present in 35.0% of the surveyed population of 1,207 subjects, with NeP symptoms present in 17.9%. The NeP group had significantly more pain, was female predominant, had a greater belief of being economically disadvantaged, suffered from more restrictions in mobility and in usual activities, and had overall lower EQ-5D utility scores compared with subjects with non-NeP. DN4Q validation demonstrated that pain entities not normally defined as NeP are recorded as such using the DN4Q, and that a spectrum of NeP features may occur across a host of painful conditions. Despite limitations of the DN4Q, symptoms of NeP may be more prevalent in the general population than expected and has a greater impact upon patients' lives than non-NeP. Limitations of the DN4Q may relate to the concept of a spectrum of NeP existent amongst heterogenous NeP and non-NeP syndromes.

Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy

Article

Oct 2008
PHARMACOLOGY

Magdalena Bujalska-Zadrozny

The effect of CB-1 and CB-2 receptor agonists, as well as an influence of a non-selective inhibitor of nitric oxide synthase (NOS), L-NOArg, and an inhibitor acting preferentially on cyclooxygenase-1 (COX-1), indomethacin, on the action of cannabinoid receptor agonists in a streptozotocin (STZ)-induced neuropathic model was investigated. When administered alone, a non-selective cannabinoid receptor agonist, WIN 55,212-2, a potentially selective CB-1 cannabinoid receptor agonist, Met-F-AEA, and a selective CB-2 cannabinoid receptor agonist, AM1241, dose-dependently reduced STZ-induced hyperalgesia. The results of the present study also demonstrated that inhibitors of COX and NOS increase antihyperalgesic activity of low doses of CB-1 and CB-2 receptor agonists. Hypothetical consequences of this phenomenon are discussed.

A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy

Article

Oct 2008
PAIN

Although many pharmacological agents are used in the therapy of neuropathic pain (NeP) due to polyneuropathy (PN), there are limited comparison studies comparing these agents. We evaluated patients with PN and related NeP in a tertiary care neuromuscular clinic with prospective follow-up after 3 and 6 months for degree of NeP using a Visual Analog Score (VAS). Clinical response to specific open-label pharmacotherapies was measured and compared for those patients not receiving pharmacotherapy. The severity of PN was quantified by the Toronto Clinical Scoring System (TCSS), with patients classified according to etiology of PN. Of a total of 408 patients referred for diagnosis and/or management of PN, NeP was identified in 182 patients (45%). NeP was most prevalent in patients with alcohol-associated PN. Pharmacotherapy management was provided in 91% of cases at first visit, and for 87% of cases after 6 months of follow-up. There were no serious adverse events for patients related to any medications, which included gabapentinoids, tricyclic antidepressants, anticonvulsants, cannabinoids and topical agents. Prevalence of intolerable side effects was similar amongst groups of medications. Approximated numbers needed to treat were similar between different individual oral pharmacotherapies, trending towards greater treatment efficacy with combination therapy. NeP is common in patients with PN and frequently requires pharmacotherapy management, which may be more effective with combination therapy. Future studies assessing longer duration of follow-up and quality of life changes with the use of various pharmacotherapies for management of NeP due to PN will be important.

An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain

Abstract

No full-text available