Cannabis for Chronic Pain: Challenges and Considerations.

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy banner

“The National Academies of Sciences, Engineering, and Medicine has found substantial evidence that cannabis (plant) is effective for the treatment of chronic pain in adults, and moderate evidence that oromucosal cannabinoids (extracts, especially nabiximols) improve short-term sleep disturbances in chronic pain. ”

https://www.ncbi.nlm.nih.gov/pubmed/29637590

https://onlinelibrary.wiley.com/doi/abs/10.1002/phar.2115

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Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability.

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“Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals.

Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability.

This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability.

Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis’s abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.”

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Sex differences in antinociceptive response to Δ-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test.

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“Cannabinoids have shown promise for the treatment of intractable pain states and may represent an alternative pharmacotherapy for pain management.

A growing body of clinical evidence suggests a role for sex in pain perception and in cannabinoid response.

We examined cannabinoid sensitivity and tolerance in male and female mice expressing a desensitization-resistant form (S426A/S430A) of the cannabinoid type 1 receptor (CB1R).

Mice were assessed for acute and inflammatory nociceptive behaviors in the formalin test following pretreatment with either vehicle or mixed CB1R/CB2R agonists, Δ-9-tetrahydrocannabinol ([INCREMENT]-THC) (1-6 mg/kg) or CP 55,940 (0.06-0.2 mg/kg). Tolerance to the effects of 6 mg/kg [INCREMENT]-THC or 0.1 mg/kg CP 55,940 was examined by the formalin test following chronic daily dosing.

Female mice showed decreased sensitivity to the effects of [INCREMENT]-THC and CP 55,940 compared with male mice. The S426A/S430A mutation increased the attenuation of nociceptive behaviors for both agonists in both sexes. Female mice displayed delayed tolerance to [INCREMENT]-THC compared with male mice, whereas the S426A/S430A mutation conferred a delay in tolerance to [INCREMENT]-THC in both sexes. Male S426A/S430A mutant mice also display resistance to tolerance to CP 55,940 compared with wild-type controls.

This study demonstrates sex and genotype differences in response for two different cannabinoid agonists. The results underscore the importance of including both male and female mice in preclinical studies of pain and cannabinoid pharmacology.”

https://www.ncbi.nlm.nih.gov/pubmed/29461336

https://insights.ovid.com/crossref?an=00001756-900000000-98413

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The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation

Mary Ann Liebert, Inc. publishers

“Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization.

Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory.

The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB1R) and cannabinoid 2 (CB2R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia.

Topical cannabinoids reduce corneal hyperalgesia and inflammation.

The antinociceptive and anti-inflammatory effects of Δ8THC are mediated primarily via CB1R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT1A receptors and CB2Rs, respectively.

Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.”

https://www.ncbi.nlm.nih.gov/pubmed/29450258

http://online.liebertpub.com/doi/abs/10.1089/can.2017.0041

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Contribution of spinal 5-HT5A receptors to the antinociceptive effects of systemically administered cannabinoid agonist WIN 55,212-2 and morphine.

Canadian Journal of Physiology and Pharmacology

“The antinociceptive effects of cannabinoids and opioids have been known for centuries.

Serotonin and its receptors are also known to play important roles in nociception. However, the contribution of spinal 5-HT5A receptors in antinociceptive effects of cannabinoids and opioids has not been studied.

We conducted this study to clarify spinal mechanisms of the actions of the antinociceptive effects of cannabinoids and opioids.

Our findings show that spinal 5-HT5A receptors are involved in the antinociceptive effects of WIN 55,212-2 and morphine.”

https://www.ncbi.nlm.nih.gov/pubmed/29406831

http://www.nrcresearchpress.com/doi/10.1139/cjpp-2017-0567#.Wnr8P2inHrc

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Medical Cannabis for Neuropathic Pain.

Current Pain and Headache Reports

“Many cultures throughout history have used cannabis to treat a variety of painful ailments. Neuropathic pain is a complicated condition that is challenging to treat with our current medications.

Recent scientific discovery has elucidated the intricate role of the endocannabinoid system in the pathophysiology of neuropathic pain. As societal perceptions change, and legislation on medical cannabis relaxes, there is growing interest in the use of medical cannabis for neuropathic pain.

We examined current basic scientific research and data from recent randomized controlled trials (RCTs) evaluating medical cannabis for the treatment of neuropathic pain.

These studies involved patients with diverse etiologies of neuropathic pain and included medical cannabis with different THC concentrations and routes of administration. Multiple RCTs demonstrated efficacy of medical cannabis for treating neuropathic pain, with number needed to treat (NNT) values similar to current pharmacotherapies.

Although limited by small sample sizes and short duration of study, the evidence appears to support the safety and efficacy of short-term, low-dose cannabis vaporization and oral mucosal delivery for the treatment of neuropathic pain.

The results suggest medical cannabis may be as tolerable and effective as current neuropathic agents; however, more studies are needed to determine the long-term effects of medical cannabis use. Furthermore, continued research to optimize dosing, cannabinoidratios, and alternate routes of administration may help to refine the therapeutic role of medical cannabis for neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/29388063

https://link.springer.com/article/10.1007%2Fs11916-018-0658-8

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Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain.

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“Chronic pain is common in the United States and prescribed opioid analgesics use for noncancer pain has increased dramatically in the past two decades, possibly accounting for the current opioid addiction epidemic. Co-morbid drug use in those prescribed opioid analgesics is common, but there are few data on polysubstance use patterns.

We explored patterns of use of cigarette, alcohol, and illicit drugs in HIV-infected people with chronic pain who were prescribed opioid analgesics.

Almost half of the sample of people with HIV and chronic pain reported current prescribed opioid analgesic use (N = 372, 47.1%). Illicit drug use was common (N = 505, 63.9%), and cannabis was the most commonly used illicit substance (N = 311, 39.4%).

In multivariate analyses, only cannabis use was significantly associated with lower odds of prescribed opioid analgesic use (adjusted odds ratio = 0.57; 95% confidence interval: 0.38-0.87).

Conclusions/Importance: Our data suggest that new medical cannabis legislation might reduce the need for opioid analgesics for pain management, which could help to address adverse events associated with opioid analgesic use.”

https://www.ncbi.nlm.nih.gov/pubmed/29338578

http://www.tandfonline.com/doi/abs/10.1080/10826084.2017.1416408?journalCode=isum20

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Anti-Inflammatory Drugs and Herbs with Special Emphasis on Herbal Medicines for Countering Inflammatory Diseases and Disorders – A Review.

“Diseases with inflammatory etiopathology have increased in incidence in recent times. Drugs used for therapeutic management of such inflammatory diseases are relieving the ailment but at the same time also countering serious life-threatening consequences. Moreover, they are costly and rarely available at all places. In this context, research and development on medicinal herbs have opened a new era in the prophylactic and therapeutic management of inflammatory diseases.

OBJECTIVE:

To highlight the importance of anti-inflammatory medicine-synthetic drugs and natural herbs, their constituents, mechanism of action, benefits, side effects and future prospects. The overall aim is to provide better health services to patiens regardless of their background on equality basis.

RESULTS:

Anti-inflammatory herbs have proven beneficial by combating inflammatory responses that lead to severe abnormality in body systems. Inflammation though a protective response to infection or injury and may result in pathological outcome when aggravated or of severe degree thus needs an early intervention for proper resolution. Medicinal plants or their constituents are considered beneficial due to the properties i.e., satisfactory potency, ease of availability, cheapness, less or no side effects, safer and efficient as compared to the synthetic counterparts. These medicinal herbs contain phytoconstituents that can prevent undesirable inflammatory processes and also posses anti-inflammatory activity. Steroids, glycosides, phenolics, flavonoids, alkaloids, polysaccharides, terpenoids, cannabinoids, fatty acids are common phytoconstituents present in these plants. Different mechanisms have been explored for the anti-inflammatory action of these active ingredients. They may synergize the anti-inflammatory pathway enzymes, factors, proteins or interfere with these in the inflammatory pathway like lipooxygenases, cyclooxygenases, tumor necrosis factors, interleukins, prostaglandin, nitric oxide, mitogen-activated protein, nuclear factor, etc. Considering all the above-mentioned factors, further research from molecular to cellular level will enable a better understanding of the mechanisms. Common anti-inflammatory herbal plants are Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis, Urtica dioica, Uncaria tomentosa, Vaccinium myrtillus, Olea europaea and much more. They are believed to be without side effects unlike the chemical counterparts or synthetic anti-inflammatory agents e.g. steroids, nonsteroid anti-inflammatory drugs, and immunosuppressant used for controlling and suppressing inflammatory crisis. A proper phytochemical, pharmacological and physiological evaluation will enable their safe and effective use in inflammatory conditions. Many of these anti-inflammatory drugs and herbal preparations have been patented with some under consideration.

CONCLUSION:

Natural herbs are safe, effective and better options as anti-inflammatory agents than synthetic ones. The phytoconstituents are as effective with the comparable mechanism of action as synthetic molecules. Future research should focus on molecular mechanisms of different beneficial applications of these herbal plants in various diseases. Recent patents on anti-inflammatory drugs and herbal plants have been covered which provide insight into the current status and future prospects in this field.”

https://www.ncbi.nlm.nih.gov/pubmed/29336271  http://www.eurekaselect.com/159064/article

“Cannabinoids as novel anti-inflammatory drugs”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

“Cannabinoids for the treatment of inflammation.” http://www.ncbi.nlm.nih.gov/pubmed/17520866

“Cannabis-based drugs have been shown to be effective in inflammatory diseases.” https://www.ncbi.nlm.nih.gov/pubmed/29110674

http://www.thctotalhealthcare.com/tag/anti-inflammatory/

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WWL70 protects against chronic constriction injury-induced neuropathic pain in mice by cannabinoid receptor-independent mechanisms.

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“Targeting the endocannabinoid system has emerged as an effective strategy for the treatment of inflammatory and neurological diseases.

Unlike the inhibition of the principal 2-arachidonyl glycerol (2-AG) hydrolytic enzyme monoacylglycerol lipase (MAGL), which leads to 2-AG overload and cannabinoid receptor desensitization, selective inhibition of the minor 2-AG hydrolytic enzyme alpha, beta-hydrolase domain 6 (ABHD6) can provide therapeutic benefits without producing cannabimimetic side effects. We have shown that inhibition of ABHD6 significantly reduces neuroinflammation and exerts neuroprotection in animal models of traumatic brain injury and multiple sclerosis. However, the role of ABHD6 inhibition on neuropathic pain has not been explored.

CONCLUSIONS:

This study reveals a novel mechanism for the antinociceptive effect of the 2-AG catabolic enzyme ABHD6 inhibitor WWL70. Understanding the interaction between endocannabinoid and eicosanoid pathways might provide a new avenue for the treatment of inflammatory and neuropathic pain.”

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Antinociceptive effects of mixtures of mu opioid receptor agonists and cannabinoid receptor agonists in rats: impact of drug and fixed-dose ratio.

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“Pain is a significant clinical problem, and there is a need for effective pharmacotherapies with fewer adverse effects than currently available drugs (e.g., mu opioid receptor agonists).

Cannabinoid receptor agonists enhance the antinociceptive effects of mu opioid receptor agonists, but it remains unclear which drugs and in what proportion will yield the most effective and safest treatments.

The antinociceptive effects of the mu opioid receptor agonists etorphine and morphine alone and in combination with the cannabinoid receptor agonists Δ9-THC and CP55940 were studied in male Sprague-Dawley rats (n=16) using a warm water tail withdrawal procedure.

The ratio of opioid to cannabinoid (3:1, 1:1, and 1:3) varied for each mixture. Drugs administered alone or as pairwise mixtures of an opioid and a cannabinoid dose-dependently increased tail withdrawal latency. Mixtures with morphine produced supra-additive (CP55940) and additive (Δ9-THC) effects, whereas mixtures with etorphine and either cannabinoid were sub-additive. The interactions were not different among ratios for a particular mixture.

The nature of the interaction between opioids and cannabinoids with regard to antinociceptive effects varies with the particular drugs in the mixture, which can have implications for designing combination therapies for pain.”

https://www.ncbi.nlm.nih.gov/pubmed/29183835

http://www.sciencedirect.com/science/article/pii/S0014299917307719

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