Category Archives: Pain

Complex Regional Pain Syndrome Type I: Evidence for the CB1 and CB2 Receptors Immunocontent and Beneficial Effect of Local Administration of Cannabidiol in Mice

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“Introduction: Complex regional pain syndrome type I (CRPS-I) is a debilitating neuropathic painful condition associated with allodynia, hyperalgesia, sudomotor and/or vasomotor dysfunctions, turning investigation of its pathophysiology and new therapeutic strategies into an essential topic. We aim to investigate the impact of ischemia/reperfusion injury on the immunocontent of CB1 and CB2 cannabinoid receptor isoforms in the paws of mice submitted to a chronic postischemia pain (CPIP) model and the effects of local administration of cannabidiol (CBD) on mechanical hyperalgesia. 

Methods: Female Swiss mice, 30-35 g, were submitted to the CPIP model on the right hind paw. Skin and muscle samples were removed at different periods for western blot analysis. 

Results: No changes in the immunocontent of CB1 and CB2 receptors in paw muscle tissues after ischemia-reperfusion were observed. CBD promoted an antihyperalgesic effect in both phases. AM281 reversed the effect of CBD, whereas ruthenium red abolished the late phase. 

Conclusion: Our results point to the possible beneficial effects of local administration of CBD in modulating CRPS-I in humans. As possible targets for CBD antihyperalgesia in this model, the contribution of cannabinoid receptor CB1, in addition to TRPM8 is suggested.”

https://pubmed.ncbi.nlm.nih.gov/37903029/

https://www.liebertpub.com/doi/10.1089/can.2023.0093

Chronic Cannabigerol as an Effective Therapeutic for Cisplatin-Induced Neuropathic Pain

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“Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60-70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females.”

https://pubmed.ncbi.nlm.nih.gov/37895913/

https://www.mdpi.com/1424-8247/16/10/1442

Medical Cannabis Alleviates Chronic Neuropathic Pain Effectively and Sustainably without Severe Adverse Effect: A Retrospective Study on 99 Cases

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“Introduction: Medical cannabis may provide a treatment option for chronic neuropathic pain. However, empirical disease-specific data are scarce.

Methods: This is a retrospective observational study including 99 patients with chronic neuropathic pain. These patients received medical cannabis by means of inhaling dried flowers with tetrahydrocannabinol content of <12-22% at a maximal daily dose of 0.15-1 g. Up to six follow-ups were carried out at intervals of 4-6 weeks. Pain severity, sleep disturbance, general improvement, side effects, and therapy tolerance at the follow-up consultations were assessed in interviews and compared with the baseline data using non-parametric Wilcoxon signed-rank test.

Results: Within 6 weeks on the therapy, median of the pain scores decreased significantly from 7.5 to 4.0 (p < 0.001). The proportion of patients with severe pain (score >6) decreased from 96% to 16% (p < 0.001). Sleep disturbance was significantly improved with the median of the scores decreased from 8.0 to 2.0 (p < 0.001). These improvements were sustained over a period of up to 6 months. There were no severe adverse events reported. Mild side effects reported were dryness in mucous tissue (5.4%), fatigue (4.8%), and increased appetite (2.7%). Therapy tolerance was reported in 91% of the interviews.

Conclusion: Medical cannabis is safe and highly effective for treating neuropathic pain and concomitant sleep disturbance.”

https://pubmed.ncbi.nlm.nih.gov/37900896/

https://karger.com/mca/article/6/1/89/860557/Medical-Cannabis-Alleviates-Chronic-Neuropathic

Chronic wound-related pain, wound healing and the therapeutic potential of cannabinoids and endocannabinoid system modulation

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“Chronic wounds represent a significant burden on the individual, and the healthcare system. Individuals with chronic wounds report pain to be the most challenging aspect of living with a chronic wound, with current therapeutic options deemed insufficient. The cutaneous endocannabinoid system is an important regulator of skin homeostasis, with evidence of system dysregulation in several cutaneous disorders. Herein, we describe the cutaneous endocannabinoid system, chronic wound-related pain, and comorbidities, and review preclinical and clinical evidence investigating endocannabinoid system modulation for wound-related pain and wound healing. Based on the current literature, there is some evidence to suggest efficacy of endocannabinoid system modulation for promotion of wound healing, attenuation of cutaneous disorder-related inflammation, and for the management of chronic wound-related pain. However, there is 1) a paucity of preclinical studies using validated models, specific for the study of chronic wound-related pain and 2) a lack of randomised control trials and strong clinical evidence relating to endocannabinoid system modulation for wound-related pain. In conclusion, while there is some limited evidence of benefit of endocannabinoid system modulation in wound healing and wound-related pain management, further research is required to better realise the potential of targeting the endocannabinoid system for these therapeutic applications.”

https://pubmed.ncbi.nlm.nih.gov/37865988/

“Modulation of the endocannabinoid system may be beneficial for wound-related pain. Cannabinoid-based therapeutics may promote wound healing and reduce inflammation.”

https://www.sciencedirect.com/science/article/pii/S0753332223015123?via%3Dihub

The Place of Cannabinoids in the Treatment of Gynecological Pain

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“Cannabis sativa (L), a plant with an extensive history of medicinal usage across numerous cultures, has received increased attention over recent years for its therapeutic potential for gynecological disorders such as endometriosis, chronic pelvic pain, and primary dysmenorrhea, due at least in part to shortcomings with current management options. Despite this growing interest, cannabis inhabits an unusual position in the modern medical pharmacopoeia, being a legal medicine, legal recreational drug, and an illicit drug, depending on jurisdiction. To date, the majority of studies investigating cannabis use have found that most people are using illicit cannabis, with numerous obstacles to medical cannabis adoption having been identified, including outdated drug-driving laws, workplace drug testing policies, the cost of quality-assured medical cannabis products, a lack of cannabis education for healthcare professionals, and significant and persistent stigma. Although currently lacking robust clinical trial data, a growing evidence base of retrospective data, cohort studies, and surveys does support potential use in gynecological pain conditions, with most evidence focusing on endometriosis. Cannabis consumers report substantial reductions in pelvic pain, as well as common comorbid symptoms such as gastrointestinal disturbances, mood disorders such as anxiety and depression, and poor sleep. Substitution effects were reported, with >50% reduction or cessation in opioid and/or non-opioid analgesics being the most common. However, a substantial minority report not disclosing cannabis consumption to their health professional. Therefore, while such deprescribing trends are potentially beneficial, the importance of medical supervision during this process is paramount given the possibility for withdrawal symptoms.”

https://pubmed.ncbi.nlm.nih.gov/37831340/

“Cannabis, whether purchased illicitly, or obtained through legal means, is commonly used by those with chronic pelvic pain, especially people with endometriosis. People report several benefits from using cannabis, including being able to reduce their normal medications including opioid based painkillers, but often don’t tell their health professional about this. This could lead to issues with withdrawal symptoms, so clinicians should be aware of the high prevalence of use of cannabis in this population.”

https://link.springer.com/article/10.1007/s40265-023-01951-z

Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies

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“Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.

Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.

Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/37843213/

https://journals.lww.com/nrronline/fulltext/2024/04000/cannabinoids_and_endocannabinoids_as_therapeutics.22.aspx

Applications of Cannabinoids in Neuropathic Pain: An Updated Review

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“Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need.

Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain.

Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids.

Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/37824417/

https://www.dl.begellhouse.com/journals/3667c4ae6e8fd136,7ec6441519bff684,786cb61f3f1ec955.html

Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study

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“The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.”

https://pubmed.ncbi.nlm.nih.gov/37644897/

https://onlinelibrary.wiley.com/doi/10.1111/adb.13317

An answered call for aid? Cannabinoid clinical framework for the opioid epidemic

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“Background: The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools.

Main body: The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids.

Conclusion: Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.”

https://pubmed.ncbi.nlm.nih.gov/37587466/

“Resistance to cannabis-based medicines for the opioid epidemic may have many origins, particularly the stigma associated with recreational cannabis use. That said, the evidence to date suggests that it is time for a sea change in the clinical approach to cannabis for pain management and OUD. Throughout the history of science and clinical medicine, there have been transformative changes that were initially considered heretical: hand hygiene as a means to prevent infection prior to germ theory, therapy for H. pylori to combat peptic ulcer disease, and even the genetic basis of cancer were all dismissed by their era’s established medical communities. Similarly, we face great resistance to the implementation of CBD and other cannabinoids for treatment-resistant chronic illnesses, despite the compelling evidence, strong overall safety profile, and urgent need. Many of our patients have already begun their own self-guided journey into pain management with cannabinoids and the burden is now on providers to consolidate the information available, conduct more rigorous research, form best practices, and implement guidelines that will inform both the field and those we care for without stigma.”

https://harmreductionjournal.biomedcentral.com/articles/10.1186/s12954-023-00842-6

Cannabis Versus Opioids for Pain

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“In the human body, pain is an inherent alarm system that activates when there is actual or potential damage, directing an individual’s attention toward the issue. Pain is a frequently cited reason for seeking healthcare or medical assistance. Pain encompasses various elements, including nociception, the perception of pain, suffering, and pain behaviors. Although pain is a fundamental mechanism, it can become burdensome when it persists for an extended period, leading to suffering and pain-related behaviors. Chronic and unrelenting pain can cause psychological, physical, and emotional distress, adding further strain to individuals.

The search for an ideal pain relief medication has been an ongoing endeavor since ancient times, as certain types of pain still lack definitive treatment options. Several strategies have been developed to address intractable pain that does not respond to nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids being the mainstay in many pain management protocols. In recent years, there has been growing and promising evidence suggesting the potential effectiveness of cannabinoids in the management of chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/34424653/