Category Archives: Chronic Pain

The endocannabinoid system as a therapeutic target in neuropathic pain: a review

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“Introduction: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes.

Areas covered: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain.

Expert opinion: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39317147/

“Research on the modulation of the endocannabinoid system in nervous tissue related to neuropathic pain reveals complex mechanisms of pain modulation. Dysregulation of the endocannabinoid system, microglial activation, and interactions between various signaling pathways contribute to the onset and persistence of neuropathic pain. Understanding these molecular and cellular processes is crucial for developing targeted therapies that leverage the endocannabinoid system to alleviate neuropathic pain.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2024.2407824

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain”

https://www.sciencedaily.com/releases/2007/10/071024141745.htm

Cannabidiol for the Treatment of Cervical Spondyloarthritis-Related Pain: A Case Report

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“Spondyloarthritis (SA) is a chronic inflammatory disease that predominantly affects the spinal column. SA-related pain can be intense, persistent, and disabling. Studies with cannabis have been conducted involving patients with refractory epilepsy, multiple sclerosis, Parkinson’s disease, sleep disorders, and chronic pain.

Cannabidiol is the major non-psychotropic component of cannabis, has anti-inflammatory and analgesic properties, and exerts anxiolytic and mood-stabilizing effects. This paper reports a case of a 72-year-old male with SA, with mild stenoses of the spinal canal at C4-C5 and C5-C6 and stenoses of the left neural foramina at C3-C4, C4-C5, C5-C6, and C6-C7.

The use of cannabidiol in our patient achieved satisfactory results in the control of pain related to cervical spondyloarthritis.”

https://pubmed.ncbi.nlm.nih.gov/39295690/

https://www.cureus.com/articles/278440-cannabidiol-for-the-treatment-of-cervical-spondyloarthritis-related-pain-a-case-report#!/

Effectiveness of Cannabinoids Treatment in Pain Management and Other Fibromyalgia-Associated Symptoms: A Case Series

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“Pharmacological therapies for FM are still ineffective in many patients, involving adverse effects that hinder their long-term use.

We aimed to assess the effectiveness of cannabinoids (Tilray Dried Flower THC18) in the management of chronic pain and other FM-associated symptoms according to patient-reported outcomes, in a series of three FM patients. 

We observed improvements after one and three months of cannabinoids treatment in Brief Pain Inventory (BPI), Visual Analogue Scale (VAS), Insomnia Severity Index (ISI), SF-36 Health Survey, and Fibromyalgia Impact Questionnaire (FIQ) allowing pain relief, and improvements in sleep quality, performance of daily life activities, and quality of life.

In conclusion, although more studies are needed, in our series of FM patients, cannabinoids treatment showed promising results in the management of chronic pain and other FM-associated symptoms, improving the quality of life of these patients.”

https://www.heraldopenaccess.us/openaccess/effectiveness-of-cannabinoids-treatment-in-pain-management-and-other-fibromyalgia-associated-symptoms-a-case-series

THC vapor inhalation attenuates hyperalgesia in rats using a chronic inflammatory pain model

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“Humans use cannabinoid drugs to alleviate pain.

As cannabis and cannabinoids are legalized in the U.S. for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain.

Here, we tested the effects of repeated THC vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (i.e., treated with Complete Freund’s Adjuvant [CFA]).

We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA, and also reduces mechanical hypersensitivity in CFA males but not females. Many of the anti-hyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure.

We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor (CB1) agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the CB1 inverse agonist AM251 (1mg/kg; i.p.) blocks the anti-hyperalgesic effects of THC vapor in males and females.

These data provide a foundation for future work that will explore the cells and circuits underlying the anti-hyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain.

PERSPECTIVE: Cannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals.”

https://pubmed.ncbi.nlm.nih.gov/39121915/

https://www.jpain.org/article/S1526-5900(24)00599-6/abstract

Analgesic properties of next generation modulators of endocannabinoid signaling: leveraging modern tools for the development of novel therapeutics

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“Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored.

In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and a/b-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action (MOA) and without intoxication.

We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG) hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor, GRABeCB2.0, may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level. 

Significance Statement Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, non-intoxicating, mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/39060165/

https://jpet.aspetjournals.org/content/early/2024/07/26/jpet.124.002119

Cannabidiol and Beta-Caryophyllene Combination Attenuates Diabetic Neuropathy by Inhibiting NLRP3 Inflammasome/NFκB through the AMPK/sirT3/Nrf2 Axis

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“Background: In this study, we investigated in detail the role of cannabidiol (CBD), beta-caryophyllene (BC), or their combinations in diabetic peripheral neuropathy (DN). The key factors that contribute to DN include mitochondrial dysfunction, inflammation, and oxidative stress.

Methods: Briefly, streptozotocin (STZ) (55 mg/kg) was injected intraperitoneally to induce DN in Sprague-Dawley rats, and we performed procedures involving Randall Sellito calipers, a Von Frey aesthesiometer, a hot plate, and cold plate methods to determine mechanical and thermal hyperalgesia in vivo. The blood flow to the nerves was assessed using a laser Doppler device. Schwann cells were exposed to high glucose (HG) at a dose of 30 mM to induce hyperglycemia and DCFDA, and JC1 and Mitosox staining were performed to determine mitochondrial membrane potential, reactive oxygen species, and mitochondrial superoxides in vitro. The rats were administered BC (30 mg/kg), CBD (15 mg/kg), or combination via i.p. injections, while Schwann cells were treated with 3.65 µM CBD, 75 µM BC, or combination to assess their role in DN amelioration.

Results: Our results revealed that exposure to BC and CBD diminished HG-induced hyperglycemia in Schwann cells, in part by reducing mitochondrial membrane potential, reactive oxygen species, and mitochondrial superoxides. Furthermore, the BC and CBD combination treatment in vivo could prevent the deterioration of the mitochondrial quality control system by promoting autophagy and mitochondrial biogenesis while improving blood flow. CBD and BC treatments also reduced pain hypersensitivity to hyperalgesia and allodynia, with increased antioxidant and anti-inflammatory action in diabetic rats. These in vivo effects were attributed to significant upregulation of AMPK, sirT3, Nrf2, PINK1, PARKIN, LC3B, Beclin1, and TFAM functions, while downregulation of NLRP3 inflammasome, NFκB, COX2, and p62 activity was noted using Western blotting.

Conclusions: the present study demonstrated that STZ and HG-induced oxidative and nitrosative stress play a crucial role in the pathogenesis of diabetic neuropathy. We find, for the first time, that a CBD and BC combination ameliorates DN by modulating the mitochondrial quality control system.”

https://www.mdpi.com/2227-9059/12/7/1442

“In summary, the present studies demonstrated that STZ- and HG-induced oxidative and nitrosative stress play a crucial role in the pathogenesis of diabetic neuropathy. The functional, behavioral, and molecular deficits were due to oxidant-induced damage, neuroinflammation, and bioenergetic deficits. These pathological consequences of nerve injury have been attenuated by the combination of CBD and BC in vitro and in vivo.

Our findings suggest that the enhanced neuroprotective effects of combination therapy may be attributable to simultaneous inhibition of oxidative stress, neuroinflammation, and NLRP3, as well as activation of Nrf2. Hence, the combination therapy could be suggested as a potential strategy that can be further pursued for the management of STZ- and HG-induced diabetic neuropathy.”

https://pubmed.ncbi.nlm.nih.gov/39062016/

Cannabidiol and pain

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“Chronic pain presents significant personal, psychological, and socioeconomic hurdles, impacting over 30% of adults worldwide and substantially contributing to disability. Unfortunately, current pharmacotherapy often proves inadequate, leaving fewer than 70% of patients with relief. This shortfall has sparked a drive to seek alternative treatments offering superior safety and efficacy profiles.

Cannabinoid-based pharmaceuticals, notably cannabidiol (CBD), hold promise in pain management, driven by their natural origins, versatility, and reduced risk of addiction. As we navigate the opioid crisis, ongoing research plunges into CBD’s therapeutic potential, buoyed by animal studies revealing its pain-relieving prowess through various system tweaks. However, the efficacy of cannabis in chronic pain management remains a contentious and stigmatized issue.

The International Association for the Study of Pain (IASP) presently refrains from endorsing cannabinoid use for pain relief. Nevertheless, evidence indicates their potential in alleviating cancer-related, neuropathic, arthritis, and musculoskeletal pain, necessitating further investigation. Crucially, our comprehension of CBD’s role in pain management is a journey still unfolding, with animal studies illustrating its analgesic effects through interactions with the endocannabinoid, inflammatory, and nociceptive systems.

As the plot thickens, it’s clear: the saga of chronic pain and CBD’s potential offers a compelling narrative ripe for further exploration and understanding.”

https://pubmed.ncbi.nlm.nih.gov/39029988/

https://www.sciencedirect.com/science/article/abs/pii/S0074774224000680?via%3Dihub

Understanding the epidemiology and perceived efficacy of cannabis use in patients with chronic musculoskeletal pain

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“Background: The belief that cannabis has analgesic and anti-inflammatory properties continues to attract patients with chronic musculoskeletal (MSK) pain towards its use. However, the role that cannabis will play in the management of chronic MSK pain remains to be determined. This study examined 1) the rate, patterns of use, and self-reported efficacy of cannabis use among patients with chronic MSK pain and 2) the interest and potential barriers to cannabis use among patients with chronic MSK pain not currently using cannabis.

Methods: Self-reported cannabis use and perceived efficacy were prospectively collected from chronic MSK pain patients presenting to the Orthopaedic Clinic at the University Health Network, Toronto, Canada. The primary dependent variable was current or past use of cannabis to manage chronic MSK pain; bivariate and multivariable logistic regression were used to identify patient characteristics independently associated with this outcome. Secondary outcomes were summarized descriptively, including self-perceived efficacy among cannabis users, and interest as well as barriers to cannabis use among cannabis non-users.

Results: The sample included 629 patients presenting with chronic MSK pain (mean age: 56±15.7 years; 56% female). Overall, 144 (23%) reported past or present cannabis use to manage their MSK pain, with 63.7% perceiving cannabis as very or somewhat effective and 26.6% considering it as slightly effective. The strongest predictor of cannabis use in this study population was a history of recreational cannabis use (OR 12.7, p<0.001). Among cannabis non-users (N=489), 65% expressed interest in using cannabis to manage their chronic MSK pain, but common barriers to use included lack of knowledge regarding access, use and evidence, and stigma.

Conclusions: One in five patients presenting to an orthopaedic surgeon with chronic MSK pain are using or have used cannabis with the specific intent to manage their pain, and most report it to be effective. Among non-users, two-thirds reported an interest in using cannabis to manage their MSK pain, but common barriers to use existed. Future double-blind placebo-controlled trials are required to understand if this reported efficacy is accurate, and what role, if any, cannabis may play in the management of chronic MSK pain.”

https://pubmed.ncbi.nlm.nih.gov/38961506/

“One in five patients presenting to an orthopaedic surgeon with chronic MSK pain are using or have used cannabis with the specific intent to manage their pain, and most report it to be effective. Among non-users, two-thirds reported an interest in using cannabis to manage their MSK pain, but common barriers to use existed. Future double-blind placebo-controlled trials are required to understand if this reported efficacy is accurate, and what role, if any, cannabis may play in the management of chronic MSK pain.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00231-1

Δ 9 -Tetrahydrocannabinol alleviates hyperalgesia in a humanized mouse model of sickle cell disease

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“People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects.

Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of Δ9-tetrahydrocannabinol (THC), cannabis’ intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control.

Acute THC administration (0.1-3 mg-kg-1, intraperitoneal, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in HbSS, but not HbAA mice. In the tail-flick assay, THC (1 and 3 mg-kg-1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg-kg-1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-h novel object recognition). Subchronic THC treatment (1 and 3 mg-kg-1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice.

Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. 

Significance Statement The study explores THC’s efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC’s potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.”

https://pubmed.ncbi.nlm.nih.gov/38955494/

https://jpet.aspetjournals.org/content/early/2024/07/02/jpet.124.002285

Select Minor Cannabinoids from Cannabis sativa are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain

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“Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. 

Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between labs or parse out potential sex differences that could be present.

We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice.

We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. 

Significance Statement Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study we evaluated 5 minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that 4 of the 5 minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.”

https://pubmed.ncbi.nlm.nih.gov/38834356/

https://jpet.aspetjournals.org/content/early/2024/06/04/jpet.124.002212