Category Archives: Chronic Pain

Cannabis-Based Products for Chronic Pain : A Systematic Review

Posted on by
Reply
Annals of Internal Medicine

“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.”

https://pubmed.ncbi.nlm.nih.gov/35667066/

https://www.acpjournals.org/doi/10.7326/M21-4520


The Role of Cannabidiol (CBD) in a Cisplatin-Induced Model of Chronic Neuropathic Pain

Posted on by
Reply

“Cannabinoid-based therapies offer a safer, non-opioid alternative for the management of chronic pain. While most studies focus on the analgesic potential of the main psychoactive component of marijuana, Δ9-tetrahydrocannabinol, fewer studies have investigated the role of the non-psychoactive component, cannabidiol (CBD). CBD has been purported to have analgesic, anti-inflammatory, anticonvulsant, and anxiolytic effects. In addition to having actions at both cannabinoid receptors (CB1 and CB2 ), CBD has been shown to interact with both the transient receptor potential vanilloid-1 (TRPV1) and serotonergic (5-HT) receptors. Clinically, CBD’s lack of psychoactivity and decreased abuse liability make it an appealing pharmacotherapeutic for the management of chronic pain. Therefore, the purpose of the current study was to determine whether CBD sex- or dose-dependently reverses antinociception in an acute model of thermal pain and/or mechanical allodynia in a model of cisplatin-induced chronic neuropathic pain. Furthermore, we observed the degree to which CB1 , CB2 , 5-HT, and TRPV1 receptors may be mediating these anti-allodynic responses. Male and female wild-type mice were assessed for either the anti-allodynic effects of 0, 1, 3, 10, and 30 mg/kg CBD in a cisplatin-induced model of neuropathic pain or the antinociceptive effects of 0, 1, 3, 10, 30, and 100 mg/kg CBD in a model of acute thermal (tail-flick) pain 60 minutes following CBD administration. To determine the relative contributions of each receptor subtype in mediating the anti-allodynic effects of CBD, male and female mice were pretreated with either: vehicle, the CB1 inverse agonist SR141716A (10 mg/kg), the CB2 antagonist SR144528 (10 mg/kg), the TRPV1 antagonist capsazepine (10 mg/kg), or the 5-HT2 antagonist methysergide (4 mg/kg) 30 minutes prior to treatment with CBD. Mice were assessed for the effects of the pretreatment alone and in combination with CBD. CBD at a dose of 3 mg/kg was able to partially reverse cisplatin-induced allodynia in male and female mice, while doses of 10 and 30 mg/kg resulted in nearly complete reversal. Our preliminary findings showed that the anti-allodynic effects of 30 mg/kg CBD were completely blocked following pretreatment with SR141716A and SR144528, and partially blocked by capsazepine in both male and female mice. Interestingly, pretreatment with methysergide partially attenuated the anti-allodynic effects of CBD in females alone. In contrast, CBD (0-100 mg/kg) failed to induce antinociception on the tail-flick assay. CBD did induce mild hypothermia with males showing a greater degree of CBD-mediated hypothermia than female mice. Taken together, these findings suggest that CBD may be a more effective treatment option for the management of chronic pain. This study highlights the therapeutic potential of CBD in a model of neuropathic pain and suggests that these effects may have clinical implications for the use of cannabinoids in chronic pain management.”

https://pubmed.ncbi.nlm.nih.gov/35560789/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R5197

The Effects of ß-caryophyllene on Pain-Evoked and Pain-Depressed Behaviors in Rats with Chronic Inflammatory Pain

Posted on by
Reply

“The antinociceptive effects of major cannabinoids such as ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been extensively studied in rats. These studies have led to formulations of THC and CBD for human use; however, humans use different strains of Cannabis that contain several hundred different compounds. The contribution of these compounds to pain relief produced by Cannabis is unclear. ß-caryophyllene (BCP) is one compound found in the essential oils of Cannabis. Despite some early studies, the extent to which these compounds produce pain relief in assays of pain-evoked behaviors (i.e., von Frey and Hargreaves tests) and pain-depressed behaviors (i.e., home cage wheel running) is unclear. We hypothesized that BCP would inhibit mechanical allodynia and thermal hyperalgesia as well as restore depressed wheel running activity in male Sprague-Dawley rats with inflammatory pain. Three different doses of BCP (10, 30, and 100 mg/kg) or vehicle were administered to rats via an intraperitoneal injection after hindpaw inflammation induced by an intraplantar injection of Complete Freund’s Adjuvant (CFA). Neither the low dose (10 mg/kg) nor the medium dose (30 mg/kg) of BCP reversed mechanical allodynia of the inflamed hindpaw after intraperitoneal injection. However, a high dose of BCP (100 mg/kg) reversed mechanical allodynia on the von Frey test; however, this dose did not reverse thermal hyperalgesia. A hindpaw injection of 0.1 mL CFA decreased wheel running activity as is consistent with a painful stimulus. However, neither 30 mg/kg BCP nor 100 mg/kg BCP restored pain-depressed wheel running in injured rats. These same doses of BCP did not affect wheel running in uninjured control rats. Therefore, a high dose BCP produces pain relief, although it only does so against mechanical allodynia. BCP does not restore normal activity. This suggests that although pain may be eliminated following BCP administration, a return to normal levels of activity may not be possible which raises questions about the utility of BCP to treat pain. Future studies of the pain-relieving effects of Cannabis constituents must include tests of many pain-related behaviors to understand dose-response relationships and their therapeutic potential.”

https://pubmed.ncbi.nlm.nih.gov/35556755/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3008

Cannabis, cannabinoids, and cannabis-based medicines: future research directions for analgesia

Posted on by
Reply

“The use of cannabis spans thousands of years and encompasses almost all dimensions of the human experience, including consumption for recreational, religious, social, and medicinal purposes. Its use in the management of pain has been anecdotally described for millennia. However, an evidence base has only developed over the last 100 years, with an explosion in research occurring in the last 20-30 years, as more states in the USA as well as countries worldwide have legalized and encouraged its use in pain management. Pain remains one of the most common reasons for individuals deciding to use cannabis medicinally. However, cannabis remains illegal at the federal level in the USA and in most countries of the world, making it difficult to advance quality research on its efficacy for pain treatment. Nonetheless, new products derived both from the cannabis plant and the chemistry laboratory are being developed for use as analgesics. This review examines the current landscape of cannabinoids research and future research directions in the management of pain.”

https://pubmed.ncbi.nlm.nih.gov/35534020/

https://rapm.bmj.com/content/early/2022/05/08/rapm-2021-103109


Cannabinoid Therapeutics in Chronic Neuropathic Pain: From Animal Research to Human Treatment

Posted on by
Reply
Frontiers Logo

“Despite the importance of pain as a warning physiological system, chronic neuropathic pain is frequently caused by damage in the nervous system, followed by persistence over a long period, even in the absence of dangerous stimuli or after healing of injuries. Chronic neuropathic pain affects hundreds of millions of adults worldwide, creating a direct impact on quality of life. This pathology has been extensively characterized concerning its cellular and molecular mechanisms, and the endocannabinoid system (eCS) is widely recognized as pivotal in the development of chronic neuropathic pain. Scientific evidence has supported that phyto-, synthetic and endocannabinoids are efficient for pain management, while strong data arise from the therapeutic use of Cannabis-derived products. The use of medicinal Cannabis products is directed toward not only relieving symptoms of chronic pain, but also improving several aspects of patients’ welfare. Here, we review the involvement of eCS, along with other cellular and molecular elements, in chronic neuropathic pain pathology and how this system can be targeted for pain management.”

https://pubmed.ncbi.nlm.nih.gov/34916962/

“The role of eCS as a pharmacological target and the advantages of using medicinal Cannabis sp. to treat pain is remarkable, as described in this review.”

https://www.frontiersin.org/articles/10.3389/fphys.2021.785176/full


Synthesis of the Cannabimovone and Cannabifuran Class of Minor Phytocannabinoids and Their Anti-inflammatory Activity

Posted on by
Reply

“Despite centuries-long use of Cannabis in human culture and the now ubiquitous claims of its medicinal value, only a small handful of phytocannabinoids have been rigorously evaluated for pharmacological properties. While more than 100 distinct minor cannabinoids have been documented to date, a paucity of studies on their biological activities have been conducted due to a lack of routine access to sufficient quantities for testing. Herein, we report a strategy to prepare several structurally diverse minor cannabinoids deriving synthetically from readily available cannabidiol. Furthermore, we examined their ability to polarize activated microglia toward an anti-inflammatory phenotype using LPS-stimulated BV2 microglial cells. The minor cannabinoids studied, especially cannabielsoin, dehydrocannabielsoin, cannabimovone, and 3′-epicannabimovone, inhibited the production of prototypical pro-inflammatory biomarkers. This study represents the beginning of a systematic mapping of the roles minor cannabinoids may play in the medicinal properties of cannabis used for the treatment of pain and inflammation. “

https://pubmed.ncbi.nlm.nih.gov/35476908/             

Long-term observational studies with cannabis-based medicines for chronic non-cancer pain: A systematic review and meta-analysis of effectiveness and safety

Posted on by
Reply

“Background and objective: This systematic review evaluated the effectiveness, tolerability and safety of cannabis-based medicines (CbMs) for chronic non-cancer pain (CNCP) in long-term observational studies.

Databases and data treatment: CENTRAL, EMBASE and MEDLINE were searched to December 2021. We included prospective observational studies with a study duration ≥ 26 weeks. Pooled estimates of event rates of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model.

Results: Six studies were included with 2686 participants, with study duration ranging between 26 and 52 weeks. Pain conditions included were nociceptive, nociplastic, neuropathic and mixed pain. The certainty of evidence for every outcome was very low. The weighted mean difference of mean pain reduction was 1.75 (95% Confidence interval [CI] 0.72 to 2.78) on a 0-10 scale. 20.8 % (95% CI 10.2 % to 34.0 %) of patients reported pain relief of 50% or greater. The effect size for sleep problems was moderate and for depression and anxiety was low. Study completions was reported for 53.3% (95% CI 26.8% to 79.9%) of patients, with dropouts of 6.8 % (95% CI 4.3% to 9.7%) due to adverse events. Serious adverse events occurred in 3.0% (95 CI 0.02 % to 12.8%) and 0.3 % (95% CI 0.1% to 0.6%) of patients died.

Conclusions: Information included in observational studies should be regarded with caution.Within the context of observational studies, CbMs had positive effects on multiple symptoms for some CNCP patients and were generally well tolerated and safe.”

https://pubmed.ncbi.nlm.nih.gov/35467781/

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies

Posted on by
Reply

“Cannabinoid co-administration may enable reduced opioid doses for analgesia. This updated systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements. We searched Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase (2016 onwards). Ninety-two studies met the search criteria including 15 ongoing trials. Meta-analysis of seven preclinical studies found the median effective dose (ED50) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED50 of morphine alone. Six preclinical studies found no evidence of increased opioid abuse liability with cannabinoid administration. Of five healthy-volunteer experimental pain studies, two found increased pain, two found decreased pain and one found reduced pain bothersomeness with cannabinoid administration; three demonstrated that cannabinoid co-administration may increase opioid abuse liability. Three randomized controlled trials (RCTs) found no evidence of opioid-sparing effects of cannabinoids in acute pain. Meta-analysis of four RCTs in patients with cancer pain found no effect of cannabinoid administration on opioid dose (mean difference -3.8 mg, 95% CI -10.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI -2.05, 5.72); five studies found more adverse events with cannabinoids compared with placebo (risk ratio 1.13, 95% CI 1.03, 1.24). Of five controlled chronic non-cancer pain trials; one low-quality study with no control arm, and one single-dose study reported reduced pain scores with cannabinoids. Three RCTs found no treatment effect of dronabinol. Meta-analyses of observational studies found 39% reported opioid cessation (95% CI 0.15, 0.64, I2 95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99, I2 92.8%, seven studies). In summary, preclinical and observational studies demonstrate the potential opioid-sparing effects of cannabinoids in the context of analgesia, in contrast to higher-quality RCTs that did not provide evidence of opioid-sparing effects.”

https://pubmed.ncbi.nlm.nih.gov/35459926/

Recreational cannabis legalizations associated with reductions in prescription drug utilization among Medicaid enrollees

Posted on by
Reply

“The potential substitution of cannabis for prescription medication has attracted a substantial amount of attention within the context of medical cannabis laws (MCLs). However, much less is known about the association between recreational cannabis laws (RCLs) and prescription drug use. With recent evidence supporting substitution of cannabis for prescription drugs following MCLs, it is reasonable to ask what effect RCLs may have on those outcomes. We use quarterly data for all Medicaid prescriptions from 2011 to 2019 to investigate the effect of state-level RCLs on prescription drug utilization. We estimate this effect with a series of two-way fixed effects event study models. We find significant reductions in the volume of prescriptions within the drug classes that align with the medical indications for pain, depression, anxiety, sleep, psychosis, and seizures. Our results suggest substitution away from prescription drugs and potential cost savings for state Medicaid programs.”

https://pubmed.ncbi.nlm.nih.gov/35429072/

Measuring the Change in Health-Related Quality of Life in Patients Using Marijuana for Pain Relief

Posted on by
Reply

“Current evidence suggests that cannabinoids are safe with minimal side effects and are effective in managing chronic pain. Data also show that medical marijuana (MM) may improve quality of life (QoL) among patients. However, there are little data showing the health-related QoL (HRQoL) benefit in MM patients using it for pain. The purpose of this study was to determine if there is a relationship between HRQol and MM use in patients using it to relieve pain.

Results

1,762 people responded to the screening request, and 1,393 (79%) met screening criteria. Of those, 353 (25.3%) agreed to participate and 51% completed all 4 surveys, for a final sample of 181 with 85 male and 95 female and one nonbinary subject. The average age was 41.21 (SD = 12.9) years, with no difference between genders. The adjusted HRQoL score improved from 0.722 to 0.747 (p = 0.011) from survey 2 to survey 4, as did the self-reported pain and health scores. The EQ-5D subscales revealed no change in mobility or usual activities, significant improvement in anxiety and pain, and a significant worsening in self-care.

Conclusion

The results show a significant improvement in HRQoL among patients using MM for pain. The EQ-5D subscales validated the pain improvement and also showed an improvement in anxiety. However, the decline in the self-care subscale may have tempered the overall improvement in HRQoL, and further research into which aspects of self-care are impacted by MM use in this population is warranted. Overall, there is a positive relationship between MM use and HRQoL in patients using it for pain.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832252/