Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems-A Novel Treatment Option for Chronic Pain Management.

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“Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time, and is often resistant to medical treatment.

Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments.

The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects.

Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target.

A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain.

Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme.

Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors) that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins.

The plasticity of the endocannabinoid system (ECS) and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated.

Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively.

Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.”

http://www.ncbi.nlm.nih.gov/pubmed/27582708

Medical Marijuana-Opportunities and Challenges

“Over the recent years, public and political opinions have demonstrated increasing support for the legalization of medical marijuana.

To date, 24 states as well as the District of Columbia have legalized cannabis for medical use, 4 states have legalized the recreational use of Marijuana.

Marijuana is derived from the hemp plant Cannabis sativa. Δ-9-tetrahydrocannabinol (THC) is the major psychoactive constituent of cannabis, while cannabidiol (CBD) is the major non-psychoactive constituent. THC is a partial agonist at CB1 and CB2 receptors, while CBD at high levels is an antagonist CB1 and CB2.

CB1 is abundantly expressed in the brain, and CB2 is expressed on immune cells (expression of CB2 on neurons remains controversial). The brain also produces endogenous cannabis-like substances (endocannabinoids) that bind and activate the CB1/CB2 receptors.

There is tremendous interest in harnessing the therapeutic potential of plant-derived and synthetic cannabinoids.

This Editorial provides an overview of diseases that may be treated by cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948749/

The Effect of Muscarinic Receptor Modulators on the Antinociception Induced by CB2 Receptor Agonist, JWH133 in Mice.

“There is no published study regarding the interaction between muscarinic receptor modulators and antinociception induced by cannabinoidreceptor (CB2) agonist. The effect of pilocarpine (a muscarinic agonist) and atropine (a muscarinic antagonist) on JWH-133 (a CB2 agonist) induced analgesia in mice was studied. First the analgesic effect of JWH-133 (0.001-1 mg/Kg) or pilocarpine (2.5-20 mg/kg) or atropine (0.2-5 mg/kg) was evaluated. Subsequently, the effect of co-administration of pilocarpine (2.5 mg/kg) or atropine (5 mg/kg) and JWH-133 (0.001-1 mg/Kg) were studied too. JWH-133 and pilocarpine provoked antinociception in mice but atropine did not. Pilocarpine potentiated the analgesic effect of JWH-133 but atropine antagonized that. It can be concluded that JWH-133 induced antinociception is affected by muscarinic receptor modulators in mice.”

http://www.ncbi.nlm.nih.gov/pubmed/27504865

Cannabinoids in pain and inflammation.

“Cannabinoids exhibit medicinal properties including analgesic, anti-inflammatory and immunosuppressive properties. This paper reviews some of the recent findings in the study of cannabinoids in pain and inflammation. Some of the effects of cannabinoids are receptor mediated and others are receptor independent. Endocannabinoids naturally reduce pain and are cerebroprotective. Natural and synthetic cannabinoids have the potential to reduce nociception, reverse the development of allodynia and hyperalgesia, reduce inflammation and inflammatory pain and protect from secondary tissue damage in traumatic head injury.”

http://www.ncbi.nlm.nih.gov/pubmed/15265314

The future of cannabinoids as analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic overview.

 

“For thousands of years, physicians and their patients employed cannabis as a therapeutic agent.

Despite this extensive historical usage, in the Western world, cannabis fell into disfavor among medical professionals because the technology available in the 1800s and early 1900s did not permit reliable, standardized preparations to be developed.

However, since the discovery and cloning of cannabinoid receptors (CB1 and CB2) in the 1990s, scientific interest in the area has burgeoned, and the complexities of this fascinating receptor system, and its endogenous ligands, have been actively explored.

Recent studies reveal that cannabinoids have a rich pharmacology and may interact with a number of other receptor systems-as well as with other cannabinoids-to produce potential synergies.

Cannabinoids-endocannabinoids, phytocannabinoids, and synthetic cannabinoids-affect numerous bodily functions and have indicated efficacy of varying degrees in a number of serious medical conditions.

Cannabinoid receptor agonists and/or molecules that affect the modulation of endocannabinoid synthesis, metabolism, and transport may, in the future, offer extremely valuable tools for the treatment of a number of currently intractable disorders.”

 http://www.ncbi.nlm.nih.gov/pubmed/17890938

Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia.

“Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia.

In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness.

Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate mechanical hyperalgesia when administered individually, but exert opposing effects when administered together.

The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined drug treatments in chronic pain conditions can be optimized.”

http://www.ncbi.nlm.nih.gov/pubmed/27450703

Cannabinoid Modulation of Cutaneous Aδ Nociceptors During Inflammation

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“Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB1 and CB2).

These results suggest that attenuation of mechanically evoked responses of Aδ nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB1 receptors during inflammation.

Several studies have demonstrated that locally administered cannabinoids produce antinociception in animal models of both acute and persistent pain through peripheral mechanisms.

Taken together, our data suggest that peripherally acting cannabinoids could be a potential therapeutic treatment for chronic inflammatory pain.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585399/

 

Pharmacologic and non-pharmacologic treatments for chronic pain in individuals with HIV: a systematic review.

“Chronic pain occurs in as many as 85% of individuals with HIV and is associated with substantial functional impairment. Little guidance is available for HIV providers seeking to address their patients’ chronic pain. We conducted a systematic review to identify clinical trials and observational studies that examined the impact of pharmacologic or non-pharmacologic interventions on pain and/or functional outcomes among HIV-infected individuals with chronic pain in high-development countries. Eleven studies met inclusion criteria and were mostly low or very low quality. Seven examined pharmacologic interventions (gabapentin, pregabalin, capsaicin, analgesics including opioids) and four examined non-pharmacologic interventions (cognitive behavioral therapy, self-hypnosis, smoked cannabis). The only controlled studies with positive results were of capsaicin and cannabis, and had short-term follow-up (≤12 weeks). Among the seven studies of pharmacologic interventions, five had substantial pharmaceutical industry sponsorship. These findings highlight several important gaps in the HIV/chronic pain literature that require further research.”

http://www.ncbi.nlm.nih.gov/pubmed/27267445

Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain

“Cannabis use was associated with 64% lower opioid use in patients with chronic pain.

Cannabis use was associated with better quality of life in patients with chronic pain.

Cannabis use was associated with fewer medication side effects and medications used.”

  • Journal of Pain Home

“Opioids are commonly used to treat patients with chronic pain (CP), though there is little evidence that they are effective for long term CP treatment. Previous studies reported strong associations between passage of medical cannabis laws and decrease in opioid overdose statewide. Our aim was to examine whether using medical cannabis for CP changed individual patterns of opioid use.

Using an online questionnaire, we conducted a cross-sectional retrospective survey of 244 medical cannabis patients with CP who patronized a medical cannabis dispensary in Michigan between November 2013 and February 2015. Data collected included demographic information, changes in opioid use, quality of life, medication classes used, and medication side effects before and after initiation of cannabis usage. Among study participants, medical cannabis use was associated with a 64% decrease in opioid use (n = 118), decreased number and side effects of medications, and an improved quality of life (45%).

This study suggests that many CP patients are essentially substituting medical cannabis for opioids and other medications for CP treatment, and finding the benefit and side effect profile of cannabis to be greater than these other classes of medications. More research is needed to validate this finding.

Perspective

This article suggests that using medical cannabis for CP treatment may benefit some CP patients. The reported improvement in quality of life, better side effect profile, and decreased opioid use should be confirmed by rigorous, longitudinal studies that also assess how CP patients use medical cannabis for pain management.”

http://www.jpain.org/article/S1526-5900(16)00567-8/abstract

[MEDICAL CANNABIS].

“The cannabis plant has been known to humanity for centuries as a remedy for pain, diarrhea and inflammation.

Current research is inspecting the use of cannabis for many diseases, including multiple sclerosis, epilepsy, dystonia, and chronic pain.

In inflammatory conditions cannabinoids improve pain in rheumatoid arthritis and: pain and diarrhea in Crohn’s disease.

Despite their therapeutic potential, cannabinoids are not free of side effects including psychosis, anxiety, paranoia, dependence and abuse.

Controlled clinical studies investigating the therapeutic potential of cannabis are few and small, whereas pressure for expanding cannabis use is increasing.

Currently, as long as cannabis is classified as an illicit drug and until further controlled studies are performed, the use of medical cannabis should be limited to patients who failed conventional better established treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/27215115