Cannabinoids in the management of chronic pain: a front line clinical perspective

AbstractChronic pain is an escalating public health problem. Currently available treatments are inadequate to control chronic pain conditions, and there is a critical need for novel treatments. Over a half century of elegant preclinical research has identified the presence of a sophisticated endocannabinoid system that is part of our natural pain and immune defense network. Convergent work has supported the significant potential to exploit this system to decrease pain and inflammation. Although the clinical research remains in its infancy, recent systematic reviews have found that 25 of 30 randomized controlled trials have demonstrated a significant analgesic effect. The authors concluded that cannabinoids currently available for clinical use demonstrate a modest analgesic effect and are safe for the management of chronic pain. There is a critical need for more translational research so that the excellent work of Dr. Itai Bab and our basic science colleagues around the world can move forward in providing novel cannabinoid-based medicines. This should include more potent analgesics that are limited in side effects with several routes of delivery. Our patients deserve additional agents for pain control with a novel mechanism of action, and cannabinoids are the new frontier.

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Inherent Sex Differences in the Expression of the Endocannabinoid System within V1M Cortex and PAG of Sprague Dawley Rats

10.21203/rs.3.rs-606890/v1 ◽

2021 ◽

Author(s):

Aidan Levine ◽

Erika Liktor-Busa ◽

Austin A Lipinski ◽

Sarah Couture ◽

Shreya Balasubramanian ◽

...

Keyword(s):

Mass Spectrometry ◽

Chronic Pain ◽

Sex Differences ◽

Cannabinoid Receptors ◽

Endocannabinoid System ◽

Brain Regions ◽

Sprague Dawley ◽

Female Population ◽

Sprague Dawley Rats ◽

Chronic Pain Conditions

Abstract Background: Several chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system is comprised of the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands. Methods: Brain tissue from naïve male and female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unbiased proteomic analysis, and immunohistochemistry. Results: Mass spectrometry revealed cortical AEA levels were significantly higher in males compared to females (p<0.001), whereas 2-AG levels in periaqueductal grey were significantly higher in females compared to males (p<0.0001). Immunohistochemistry followed by unbiased proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG.Conclusions: Our results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

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Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats

Biology of Sex Differences ◽

10.1186/s13293-021-00402-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Aidan Levine ◽

Erika Liktor-Busa ◽

Austin A. Lipinski ◽

Sarah Couture ◽

Shreya Balasubramanian ◽

...

Keyword(s):

Mass Spectrometry ◽

Chronic Pain ◽

Sex Differences ◽

Cannabinoid Receptors ◽

Endocannabinoid System ◽

Brain Regions ◽

Sprague Dawley ◽

Female Population ◽

Sprague Dawley Rats ◽

Chronic Pain Conditions

Abstract Background Several chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands. Methods Brain tissue from naïve male and estrous staged female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unlabeled quantitative proteomic analysis, and immunohistochemistry. Results Mass spectrometry revealed significant differences in 2-AG and AEA concentrations between males and females, as well as between female estrous cycle stages. Specifically, 2-AG concentration was lower within female PAG as compared to male PAG (*p = 0.0077); female 2-AG concentration within the PAG did not demonstrate estrous stage dependence. Immunohistochemistry followed by proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG. Conclusions Our results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

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Medical cannabis for orthopaedic patients with chronic musculoskeletal pain: does evidence support its use?

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x20937968 ◽

2020 ◽

Vol 12 ◽

pp. 1759720X2093796

Author(s):

Herman Johal ◽

Christopher Vannabouathong ◽

Yaping Chang ◽

Meng Zhu ◽

Mohit Bhandari

Keyword(s):

Chronic Pain ◽

Musculoskeletal Pain ◽

Endocannabinoid System ◽

Current Evidence ◽

Therapeutic Effects ◽

Current Guideline ◽

Medical Cannabis ◽

Orthopaedic Patients ◽

Effectiveness Factors ◽

Chronic Pain Conditions

The treatment of chronic, non-cancer musculoskeletal pain has become a topic growing interest as it is believed to be one of the reasons for the current opioid epidemic. The medicinal use of cannabis has a long history as a number of active compounds in cannabis have been shown to interact with the body’s endocannabinoid system to reduce pain. This position paper provides a history on the evolution of cannabis, the science behind its therapeutic effects, and review of the evidence and current guideline recommendations on its use as a treatment for patients with chronic, non-cancer musculoskeletal pain. Results from systematic reviews have demonstrated a statistically significant reduction in chronic pain conditions with cannabinoids, compared with placebo, although the effects might be considered small and did not reach the minimally important difference. More adverse events were reported in the cannabinoid group than in the placebo group with longer than 2 weeks of treatment. There is a lack of evidence on dependence. With changes to policies, patients’ perception has changed to be more positive toward the use of medical cannabis. Current recommendations from North America, Latin America, Europe, Australia and Iran support the use of medical cannabis for chronic, non-cancer pain. Based on the current evidence, it is our position that cannabinoids may be considered as an adjunctive therapy after recommended first- and second-line therapies have failed to provide sufficient efficacy or tolerability. Patients should consider the balance between the desirable and undesirable effects of taking cannabis for chronic pain, and comprehensively consider their own values and preferences, as well as cost-effectiveness factors, based on the information provided by their physician.

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The Metabolomics of Chronic Pain Conditions: A Systematic Review

Biological Research For Nursing ◽

10.1177/1099800420941105 ◽

2020 ◽

Vol 22 (4) ◽

pp. 458-471

Author(s):

Edwin N. Aroke ◽

Keesha L. Powell-Roach

Keyword(s):

Systematic Review ◽

Chronic Pain ◽

Public Health Problem ◽

The United States ◽

High Quality Research ◽

Downstream Effects ◽

Significant Public Health Problem ◽

Significant Public Health ◽

Chronic Pain Conditions ◽

Metabolomic Approach

Background: Chronic pain is a significant public health problem in the United States, affecting approximately 100 million people. Yet there is a lack of robust biomarkers for clinical use in chronic pain conditions. Downstream effects of environmental, genomic, and proteomic variations in individuals with chronic pain conditions can be identified and quantified using a metabolomic approach. Aim/Design: The purpose of this systematic review was to examine the literature for reports of potential metabolomic signatures associated with chronic pain conditions. Methods: We searched relevant electronic databases for published studies that used various metabolomic approaches to investigate chronic pain conditions among subjects of all ages. Results: Our search identified a total of 586 articles, 18 of which are included in this review. The reviewed studies used metabolomics to investigate fibromyalgia ( n = 5), osteoarthritis ( n = 4), migraine ( n = 3), musculoskeletal pain ( n = 2), and other chronic pain conditions ( n = 1/condition). Results show that several known and newly identified metabolites differ in individuals with chronic pain conditions compared to those without these conditions. These include amino acids (e.g., glutamine, serine, and phenylalanine) and intermediate products (e.g., succinate, citrate, acetylcarnitine, and N-acetylornithine) of pathways that metabolize various macromolecules. Conclusion: Though more high-quality research is needed, this review provides insights into potential biomarkers for future metabolomics studies in people with chronic pain conditions.

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Monoclonal Antibodies for Chronic Pain Treatment: Present and Future

International Journal of Molecular Sciences ◽

10.3390/ijms221910325 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10325

Author(s):

Eva M. Sánchez-Robles ◽

Rocío Girón ◽

Nancy Paniagua ◽

Carmen Rodríguez-Rivera ◽

David Pascual ◽

...

Keyword(s):

Chronic Pain ◽

Monoclonal Antibodies ◽

Pain Treatment ◽

Treatment Options ◽

Chronic Lower Back Pain ◽

Preclinical Research ◽

Novel Therapy ◽

Calcitonin Gene ◽

Processing Pathways ◽

Chronic Pain Conditions

Chronic pain remains a major problem worldwide, despite the availability of various non-pharmacological and pharmacological treatment options. Therefore, new analgesics with novel mechanisms of action are needed. Monoclonal antibodies (mAbs) are directed against specific, targeted molecules involved in pain signaling and processing pathways that look to be very effective and promising as a novel therapy in pain management. Thus, there are mAbs against tumor necrosis factor (TNF), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), or interleukin-6 (IL-6), among others, which are already recommended in the treatment of chronic pain conditions such as osteoarthritis, chronic lower back pain, migraine, or rheumatoid arthritis that are under preclinical research. This narrative review summarizes the preclinical and clinical evidence supporting the use of these agents in the treatment of chronic pain.

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Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

Neuronal Signaling ◽

10.1042/ns20170144 ◽

2018 ◽

Vol 2 (4) ◽

Cited By ~ 2

Author(s):

J. Daniel Lafreniere ◽

Melanie E.M. Kelly

Keyword(s):

Chronic Pain ◽

Current Knowledge ◽

Endocannabinoid System ◽

Ocular Pain ◽

Physiological Basis ◽

Future Directions ◽

Anti Inflammatory ◽

Neuroprotective Actions ◽

Chronic Pain Conditions ◽

Ocular Safety

Challenges in the management of ocular pain are an underappreciated topic. Currently available therapeutics lack both efficacy and clear guidelines for their use, with many also possessing unacceptable side effects. Promising novel agents would offer analgesic, anti-inflammatory, and possibly neuroprotective actions; have favorable ocular safety profiles; and show potential in managing neuropathic pain. Growing evidence supports a link between the endocannabinoid system (ECS) and a range of physiological and disease processes, notably those involving inflammation and pain. Both preclinical and clinical data suggest analgesic and anti-inflammatory actions of cannabinoids and ECS-modifying drugs in chronic pain conditions, including those of neuropathic origin. This review will examine existing evidence for the anatomical and physiological basis of ocular pain, specifically, ocular surface disease and the development of chronic ocular pain. The mechanism of action, efficacy, and limitations of currently available treatments will be discussed, and current knowledge related to ECS-modulation of ocular pain and inflammatory disease will be summarized. A perspective will be provided on the future directions of ECS research in terms of developing cannabinoid therapeutics for ocular pain.

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INTRAVENOUS LIDOCIANE INFUSION FOR PATIENTS WITH CHRONIC PAIN CONDITIONS. HOW ARE WE DOING?

10.26226/morressier.5ab3c87fa874c60026558c66 ◽

2018 ◽

Author(s):

Husham Al-shather

Keyword(s):

Chronic Pain ◽

Chronic Pain Conditions

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Retrospective analysis on the effect of spinal cord stimulation on opioid consumption

Pain Management ◽

10.2217/pmt-2020-0016 ◽

2020 ◽

Author(s):

Awinita Barpujari ◽

Michael A Erdek

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Retrospective Analysis ◽

Spinal Cord Stimulation ◽

Alternative Therapy ◽

Opioid Consumption ◽

Opioid Use ◽

Number Of Patients ◽

Chronic Pain Conditions ◽

Post Trial

Aim: Spinal cord stimulation (SCS) is used to clinically manage and/or treat several chronic pain etiologies. A limited amount is known about the influence on patients' use of opioid pain medication. This retrospective analysis evaluated SCS effect on opioid consumption in patients presenting with chronic pain conditions. Materials & methods: Sixty-seven patients underwent a temporary trial device, permanent implant or both. Patients were divided for assessment based on the nature of their procedure(s). Primary outcome was change in morphine equivalent dose (MED), ascertained from preoperative and postoperative medication reports. Results: Postoperative MED was significantly lower in patients who received some form of neuromodulation therapy. Pretrial patients reported an average MED of 41.01 ± 10.23 mg per day while post-trial patients reported an average of 13.30 ± 5.34 mg per day (p < 0.001). Pre-implant patients reported an average MED of 39.14 ± 13.52 mg per day while post-implant patients reported an average MED of 20.23 ± 9.01 mg per day (p < 0.001). There were no significant differences between pre-trial and pre-implant MED, nor between post-trial and post-implant MED. Of the 42 study subjects who reported some amount of pre-intervention opioid use, 78.57% indicated a lower MED (n = 33; p < 0.001), 16.67% indicated no change (n = 7) and 4.76% (n = 2) indicated a higher MED, following intervention. Moreover, SCS therapy resulted in a 26.83% reduction (p < 0.001) in the number of patients with MED >50 mg per day. Conclusion: Spinal cord stimulation may reduce opioid use when implemented appropriately. Neuromodulation may represent alternative therapy for alleviating chronic pain which may avoid a number of deleterious side effects commonly associated with opioid consumption.

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Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund’s adjuvant-induced mouse model

Molecular Pain ◽

10.1177/1744806921990934 ◽

2021 ◽

Vol 17 ◽

pp. 174480692199093

Author(s):

Dan-jie Su ◽

Long-fei Li ◽

Sai-ying Wang ◽

Qi Yang ◽

Yu-jing Wu ◽

...

Keyword(s):

Chronic Pain ◽

Mouse Model ◽

Anterior Cingulate Cortex ◽

Analgesic Effect ◽

Microglial Activation ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant

Chronic pain is highly prevalent worldwide and severely affects daily lives of patients and family members. Praeruptorin C (Pra-C) is a main active ingredient derived from Peucedanum praeruptorum Dunn, traditionally used as antibechic, anti-bronchitis and anti-hypertension drug. Here, we evaluated the effects of Pra-C in a chronic inflammatory pain mouse model induced by complete Freund’s adjuvant (CFA) injection. Pra-C (3 mg/kg) treatment for just 3 days after CFA challenge relieved CFA-induced mechanical allodynia and hindpaw edema in mice. In the anterior cingulate cortex (ACC), Pra-C treatment inhibited microglia activation and reduced levels of proinflammatory cytokines, TNF-α and IL-1β, and suppressed upregulation of glutamate receptors caused by CFA injection. In addition, Pra-C attenuated neuronal hyperexcitability in ACC of CFA-injected mice. In vitro studies confirmed the analgesic effect of Pra-C was due to its inhibitory ability on microglial activation. In conclusion, Pra-C administration had a certain effect on relieving chronic pain by inhibiting microglial activation, attenuating proinflammatory cytokine releasing and regulating excitatory synaptic proteins in the ACC of the CFA-injected mice.

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