The State of Synthetic Cannabinoid Medications for the Treatment of Pain.

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.

Medical Cannabis Use Among Canadian Veterans and Non-Veterans: A National Survey.

Background: Medical cannabis (MC) is used by Canadian Veterans to manage a wide range of health issues. However, there is little information comparing the reasons for MC use and its perceived effectiveness between Veterans and non-Veterans. Objects: We compared MC use among a convenience sample of Canadian Veterans and with non-Veteran controls, including demographics, reasons and patterns of use, and perceived effectiveness. Methods: Between November and December 2021, Canadian Veterans using cannabis were invited to participate in a survey using a national press release, social media, and announcements on online platform dedicated to promoting health among Canadian Veterans and non-Veterans during the pandemic (www.MissionVav.com). The survey was also mentioned in a monthly newsletter from Veteran Affairs Canada. Self-reported effectiveness was evaluated using a 0 to 10 visual analogue scale (0 being not all effective, 10 being the most effective). Results: The survey was completed by 157 people, including 108 (69%) males and 49 (31%) females. The mean age was 57 years (range 19 to 84). Among responders, 90 (63%) identified as Veterans. The most common reasons for MC use among Veterans included: insomnia (80%), anxiety (73%), and depression (52%). Veterans reported medical conditions such as chronic pain (88%) and arthritis (51%). Compared with non-Veterans, Veterans were significantly more likely to be male (83% vs. 49%), have a higher BMI (35.2 vs. 30.9), to report problems with sleep, anxiety, depression, and PTSD, and to use cannabis in edible form (51% vs. 22%). Self-reported mean effectiveness scores for MC were highest for PTSD (8.4), insomnia (8.2), anxiety (8.1), depression (8.0), and chronic pain (7.6). Conclusions: We found important differences in user characteristics and cannabis use patterns between Canadian Veterans and non-Veterans. Further controlled studies are required to validate these findings, but these data suggest that orally administered cannabis products may be worth further study.

COVID-19 Vaccine in Immunosuppressed Adults with Autoimmune rheumatic Diseases (COVIAAD): safety, immunogenicity and antibody persistence at 12 months following Moderna Spikevax primary series.

OBJECTIVE: To assess the safety, immunogenicity and cellular responses following the Moderna Spikevax primary series in rheumatic disease. METHODS: We conducted a 12-month, prospective, non-randomised, open-label, comparative trial of adults with either rheumatoid arthritis (RA, n=131) on stable treatment; systemic lupus erythematosus (SLE, n=23) on mycophenolate mofetil (MMF); other rheumatic diseases on prednisone ≥10 mg/day (n=8) or age-matched/sex-matched controls (healthy control, HC, n=58). Adverse events (AEs), humoral immune responses (immunogenicity: IgG positivity for anti-SARS-CoV-2 spike protein and its receptor binding domain, neutralising antibodies (NAbs)), cellular responses (ELISpot) and COVID-19 infection rates were assessed. RESULTS: Frequency of solicited self-reported AEs following vaccination was similar across groups (HC 90%, RA 86%, SLE 90%); among them, musculoskeletal AEs were more frequent in RA (HC 48% vs RA 66% (Δ95% CI CI 3 to 32.6)). Disease activity scores did not increase postvaccination. No vaccine-related serious AEs were reported. Postvaccination immunogenicity was reduced in RA and SLE (RA 90.2%, SLE 86.4%; for both, ΔCIs compared with HC excluded the null). Similarly, NAbs were reduced among patients (RA 82.6%, SLE 81.8%). In RA, age >65 (OR 0.3, 95% CI 0.1 to 0.8) and rituximab treatment (OR 0.003, 95% CI 0.001 to 0.02) were negative predictors of immunogenicity. ELISpot was positive in 16/52 tested RA and 17/26 HC (ΔCI 11.2-53.3). During the study, 11 HC, 19 RA and 3 SLE patients self-reported COVID-infection. CONCLUSION: In COVID-19 Vaccine in Immunosuppressed Adults with Autoimmune Diseases, the Moderna Spikevax primary series was safe. MMF, RA age >65 and rituximab were associated with reduced vaccine-induced protection.

Medicinal Cannabis Use for Rheumatic Conditions in the US Versus Canada: Rationale for Use and Patient-Health Care Provider Interactions.

OBJECTIVE: Understanding how medical cannabis (MC) use is integrated into medical practice for rheumatic disease management is essential. We characterized rationale for MC use, patient-physician interactions around MC, and MC use patterns among people with rheumatic conditions in the US and Canada. METHODS: We surveyed 3406 participants with rheumatic conditions in the US and Canada, with 1727 completing the survey (50.7% response rate). We assessed disclosure of MC use to health care providers, MC authorization by health care providers, and MC use patterns and investigated factors associated with MC disclosure to health care providers in the US versus Canada. RESULTS: Overall, 54.9% of US respondents and 78.0% of Canadians reported past or current MC use, typically because of inadequate symptom relief from other medications. Compared to those in Canada, fewer US participants obtained MC licenses, disclosed MC use to their health care providers, or asked advice on how to use MC (all P values <0.001). Overall, 47.4% of Canadian versus 28.2% of US participants rated their medical professionals as their most trusted information source. MC legality in state of residence was associated with 2.49 greater odds of disclosing MC use to health care providers (95% confidence interval: 1.49-4.16, P < 0.001) in the US, whereas there were no factors associated with MC disclosure in Canada. Our study is limited by our convenience sampling strategy and cross-sectional design. CONCLUSION: Despite widespread availability, MC is poorly integrated into rheumatic disease care, with most patients self-directing use with minimal or no clinical oversight. Concerted efforts to integrate MC into education and clinical policy is critical.

Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Face validity of the ICD-10 criteria of substance abuse and dependence for patients prescribed cannabis-based medicines for chronic pain-A survey of pain medicine physicians in Canada, Germany and Israel.

BACKGROUND AND OBJECTIVE: A major concern with cannabis-based medicines (CbM) and medical cannabis (MC) is the risk of abuse and dependence. The face validity of the International Classification of Diseases (ICD-10) criteria for cannabis dependence in patients prescribed CbM for chronic pain has not been assessed. DATABASES AND DATA TREATMENT: Physicians from Canada, Germany and Israel were recruited via the mailing lists of national pain societies. To be eligible, physicians had to have prescribed CbM for chronic pain treatment in the past 12 months. Participants were asked to rate the appropriateness of items adapted from the substance use module of the Composite International Diagnostic Interview Version 3.0 to assess dependence in the context of chronic pain treatment with CbM and the appropriateness of two additional items. In case of disagreement, participants were asked to give reasons. Furthermore, they were asked to suggest potential additional criteria. RESULTS: On average 69.0% of 178 participating physicians indicated agreement with the appropriateness of the ICD-10 criteria, while 20.6% indicated disagreement. The highest disagreement rate was observed for the item on repeated use despite legal problems (35.4% disagreement or strong disagreement). Reasons for disagreement were summarized into six content categories using qualitative methods of analysis. Additional criteria suggested by participants were summarized into 10 content categories. CONCLUSIONS: A collaboration of psychiatrists and pain physicians is required to define criteria and develop instruments to capture abuse and dependence of CbM in chronic pain patients. SIGNIFICANCE: Sixty-nine per cent of 178 pain medicine physicians in Canada, Germany and Israel who participated in a survey on the appropriateness of the ICD-10 criteria for cannabis abuse and dependence for patients prescribed cannabis-derived products for chronic pain assessed the criteria as appropriate, whereas 20.6% deemed the criteria as not appropriate.

Cautious Hope for Cannabidiol (CBD) in Rheumatology Care.

Cannabidiol (CBD), a major metabolite of Cannabis sativa, is popularized as a medicinal product, with potential for analgesic, antiinflammatory, and antioxidant effects. CBD may hold promise as a treatment in rheumatic diseases, but evidence to date remains preclinical. Preclinical effects on pain and inflammation is encouraging, but clinical study is lacking, with only a single study in knee osteoarthritis reporting a promising effect on symptoms. CBD products are freely available over the counter and marketed as food supplements or wellness products. The World Health Organization has identified pure CBD as safe and without abuse potential, but products are not subject to drug regulatory standards, leading to inconsistency in manufacturing practices and quality of products. Not only have molecular concentrations of CBD been identified as inaccurate, but concerns exist regarding contaminants, including heavy metals, pesticides, microbes, and mycotoxins, as well as added tetrahydrocannabinol. Drug-drug interactions pose a potential risk due to metabolism via the cytochrome P450 enzyme pathway. Patients wishing to use CBD should obtain a product with certification of Good Manufacturing Practices, initiate treatment with a nighttime low dose, and have defined outcome goals within a reasonable time frame. Treatments should not be managed by nonmedical dispensary personnel. The hope that CBD may be a useful therapy must be substantiated by sound scientific study.

Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity.

ABSTRACT: Alterations in the composition and function of the gut microbiome in women with fibromyalgia have recently been demonstrated, including changes in the relative abundance of certain bile acid-metabolizing bacteria. Bile acids can affect multiple physiological processes, including visceral pain, but have yet to be explored for association to the fibromyalgia gut microbiome. In this study, 16S rRNA sequencing and targeted metabolomic approaches were used to characterize the gut microbiome and circulating bile acids in a cohort of 42 women with fibromyalgia and 42 healthy controls. Alterations in the relative abundance of several bacterial species known to metabolize bile acids were observed in women with fibromyalgia, accompanied by significant alterations in the serum concentration of secondary bile acids, including a marked depletion of α-muricholic acid. Statistical learning algorithms could accurately detect individuals with fibromyalgia using the concentration of these serum bile acids. Serum α-muricholic acid was highly correlated with symptom severity, including pain intensity and fatigue. Taken together, these findings suggest serum bile acid alterations are implicated in nociplastic pain. The changes observed in the composition of the gut microbiota and the concentration of circulating secondary bile acids seem congruent with the phenotype of increased nociception and are quantitatively correlated with symptom severity. This is a first demonstration of circulating bile acid alteration in individuals with fibromyalgia, potentially secondary to upstream gut microbiome alterations. If corroborated in independent studies, these observations may allow for the development of molecular diagnostic aids for fibromyalgia as well as mechanistic insights into the syndrome.

Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.

Predictors of Pain Reduction Among Fibromyalgia Patients Using Medical Cannabis: A Long-Term Prospective Cohort Study.

OBJECTIVE: Many patients with fibromyalgia (FM) report using cannabis as a strategy to improve pain. Given that pain often co-occurs with symptoms of anxiety and depression (i.e., negative affect) and sleep problems among patients with FM, improvements in these symptoms might indirectly contribute to reductions in pain intensity following cannabis use. The main objective of the study was to examine whether changes in pain intensity following initiation of medical cannabis among patients with FM could be attributed to concurrent changes (i.e., reductions) in negative affect and sleep problems. METHODS: This was a 12-month prospective cohort study among patients with FM (n = 323) initiating medical cannabis under the care of physicians. Patients were assessed at baseline, and follow-up assessment visits occurred every 3 months after initiation of medical cannabis. Patients' levels of pain intensity, negative affect, and sleep problems were assessed across all visits. RESULTS: Multilevel mediation analyses indicated that reductions in patients' levels of pain intensity were partly explained by concurrent reductions in sleep problems and negative affect (both P < 0.001). This remained significant even when accounting for patients' baseline characteristics or changes in medical cannabis directives over time (all P > 0.05). CONCLUSION: Our findings provide preliminary insight into the potential mechanisms of action underlying pain reductions among patients with FM who are using medical cannabis. Given the high attrition rate (i.e., 75%) observed in the present study at 12 months, our findings cannot be generalized to all patients with FM who are using medical cannabis.

Cannabis use disorder in patients with chronic pain: overestimation and underestimation in a cross-sectional observational study in 3 German pain management centres.

ABSTRACT: There are concerns that cannabis use disorder (CUD) may develop in patients with chronic pain prescribed medical cannabis (MC). The criteria for CUD according to the Statistical Manual for Mental Disorders Version 5 (DSM-5) were not developed for the identification of patients using cannabis for therapeutic reasons. In addition, some items of CUD might be attributed to the desire of the patient to relieve the pain. Therefore, alternative strategies are needed to identify the true prevalence of CUD in persons with chronic pain being treated with MC. The prevalence of CUD in patients with chronic pain according to the DSM-5 criteria was assessed using an anonymous questionnaire in 187 consecutive patients attending 3 German pain centres in 2021. Questionnaires were rated as follows: (1) all criteria included, (2) removal of items addressing tolerance and withdrawal, and (3) removal of positive items if associated with the desire to relieve pain. Abuse was assessed by self-report (use of illegal drugs and diversion and illegal acquisition of MC) and urine tests for illegal drugs. Physicians recorded any observation of abuse. Cannabis use disorder according to the DSM-5 criteria was present in 29.9%, in 13.9% when items of tolerance and withdrawal were removed, and in 2.1% when positive behaviour items were removed. In 10.7%, at least 1 signal of abuse was noted. Urine tests were positive for nonprescribed drugs (amphetamines and tranquilizer) in 4.8% of subjects. Physicians identified abuse in 1 patient. In this study, the DSM-5 criteria overestimated and physicians underestimated the prevalence of CUD in patients prescribed MC for chronic pain.

International, multidisciplinary Delphi consensus recommendations on non-pharmacological interventions for fibromyalgia.

OBJECTIVES: To develop evidence-based expert recommendations for non-pharmacological treatments for pain, fatigue, sleep problems, and depression in fibromyalgia. METHODS: An international, multidisciplinary Delphi exercise was conducted. Authors of EULAR and the Canadian Fibromyalgia Guidelines Group, members of the American Pain Society and clinicians with expertise in fibromyalgia were invited. Participants were asked to select non-pharmacological interventions that could be offered for specific fibromyalgia symptoms and to classify them as either core or adjunctive treatments. An evidence summary was provided to aid the decision making. Items receiving >70% votes were accepted, those receiving <30% votes were rejected and those obtaining 30-70% votes were recirculated for up to two additional rounds. RESULTS: Seventeen experts participated (Europe (n = 10), North America (n = 6), and Israel (n = 1)) in the Delphi exercise and completed all three rounds. Aerobic exercise, education, sleep hygiene and cognitive behavioural therapy were recommended as core treatments for all symptoms. Mind-body exercises were recommended as core interventions for pain, fatigue and sleep problems. Mindfulness was voted core treatment for depression, and adjunctive treatment for other symptoms. Other interventions, namely music, relaxation, hot bath, and local heat were voted as adjunctive treatments, varying between symptoms. CONCLUSIONS: This study provided evidence-based expert consensus recommendations on non-pharmacological treatments for fibromyalgia that may be used to individualise treatments in clinical practice targeting the diverse symptoms associated with fibromyalgia.

"It feels like an endless fight": a qualitative study exploring healthcare utilization of persons with rheumatic conditions waiting for pain clinic admission.

BACKGROUND: Individuals living with a rheumatic pain condition can face delays in accessing pain clinics, which prevents them from receiving timely treatment. Little is known regarding their specific healthcare utilization in order to alleviate pain while waiting to obtain services in pain clinics. Hence, the aim of this study was to explore the perceptions and experiences of persons living with rheumatic conditions regarding healthcare utilization while waiting to access a pain clinic. METHODS: In this qualitative descriptive study, semi-structured interviews were conducted with adults living with a painful rheumatic condition that reported either being waiting for admission in a pain clinic, having been referred but then denied pain clinic services, or having received services during the previous six months, in the province of Quebec, Canada. The interviews were transcribed verbatim, and an inductive thematic analysis was performed. RESULTS: Twenty-six individuals were interviewed (22 women and 4 men; mean age 54 ± 10 years). Three themes were identified: 1) lacking guidance in identifying solutions to their complex and multidimensional needs, 2) struggling to obtain and maintain services due to systemic access barriers, and 3) displaying resilience through a search for accessible and sustainable self-management strategies. CONCLUSIONS: The current approaches and structures of health services fail to adequately answer the service needs of individuals experiencing painful rheumatic conditions. Important shifts are required in pain education, in increasing access to multidisciplinary approaches at the primary care level and in breaking down barriers individuals with chronic pain face to receive appropriate and timely care.