Continuous Intrathecal Infusion of Cannabinoid Receptor Agonists Attenuates Nerve Ligation-Induced Pain in Rats.


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“Cannabinoid receptors (CB1R/CB2R) are known to play important roles in pain transmission.

In this study, we investigated the effects of continuous intrathecal infusion of CB1/2R agonists in the L5/6 spinal nerve ligation pain model.

Continuous intrathecal infusion of CB1/2R agonists elicits antinociception in the pain model.

The mechanisms might involve their actions on neurons and glial cells. CB2R, but not CB1R, seems to play an important role in the regulation of nerve injury-induced neuroinflammation.”

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Combined cannabinoid therapy via an oromucosal spray.

“Extensive basic science research has identified the potential therapeutic benefits of active compounds extracted from the Cannabis sativa L. plant (the cannabinoids). It is recognized that a significant proportion of patients suffering with the debilitating symptoms of pain and spasticity in multiple sclerosis or other conditions smoke cannabis despite the legal implications and stigma associated with this controlled substance. GW Pharmaceuticals have developed Sativex (GW- 1000-02), a combined cannabinoid medicine that delivers and maintains therapeutic levels of two principal cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), via an oromucosal pump spray, that aims to minimize psychotropic side effects.”

“Sativex has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and multiple sclerosis (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome.”

“Sativex(®) (nabiximols, USAN name) oromucosal spray contains the two main active constituents of Cannabis sativa, tetrahydrocannabinol and cannabidiol in a 1:1 molecular ratio, and acts as an endocannabinoid system modulator.”

“Abuse potential and psychoactive effects of δ-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Evidence to date suggests that abuse or dependence on Sativex is likely to occur in only a very small proportion of recipients.”

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Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

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“Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of the antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). However, their use is sometimes limited by the development of a painful sensory neuropathy, which does not respond well to drugs.

Smoked cannabis has been reported in clinical trials to have efficacy in relieving painful HIV-associated sensory neuropathy.

The aim of this study was to evaluate whether the expression of endocannabinoid system molecules is altered during NRTI-induced painful neuropathy, and also whether endocannabinoids can attenuate NRTI-induced painful neuropathy.

Conclusion: These data show that ddC induces thermal hyperalgesia, which is associated with dysregulation of the mRNA expression of some endocannabinoid system molecules. The endocannabinoids AEA and 2-AG have antihyperalgesic activity, which is dependent on cannabinoid receptor and GPR55 activation. Thus, agonists of cannabinoid receptors and GPR55 could be useful therapeutic agents for the management of NRTI-induced painful sensory neuropathy.”

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Compensatory Activation of Cannabinoid CB2 Receptor Inhibition of GABA Release in the Rostral Ventromedial Medulla in Inflammatory Pain.

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“The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain.

Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain.


These studies demonstrate that endocannabinoid signaling to CB1 and CB2 receptors in adult rostral ventromedial medulla is altered in persistent inflammation. The emergence of CB2 receptor function in the rostral ventromedial medulla provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain.”

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Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists.

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“The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability.

We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post-operative, and neuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Co-administration of morphine with JWH015 synergistically inhibited preclinical inflammatory, post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observed for nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP were significantly reduced in the presence of JWH015.

Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects.

The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.”

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Compensatory activation of cannabinoid CB2 receptor inhibition of GABA release in the rostral ventromedial medulla (RVM) in inflammatory pain.

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“The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain.

These studies demonstrate that endocannabinoid signaling to CB1- and CB2-receptors in adult RVM is altered in persistent inflammation.

The emergence of CB2 receptor function in the RVM provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain.”

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The central cannabinoid receptor type-2 (CB2) and chronic pain.

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“Cannabinoid receptor type-2 (CB2, CB2 Receptor, or CB2-R) mediates analgesia, via two mechanisms. CB2 receptors contained in peripheral immune tissue mediates analgesia by altering cytokine profiles, and thus has little adverse effects on central nervous systems. CB2 is also expressed in the neurons and glial cells of the Central Nervous System (CNS). This neuronal expression may also contribute to pain attenuation. The CB2 receptor has been proposed as a potential target in treating chronic pain of several etiologies.”

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Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet].


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“Chronic pain is a complex, severe and debilitating condition which can lead to a considerable reduction in function and quality of life. Patients may present with different forms of chronic pain resulting from a number of identifiable causes, including pain due to lesion or dysfunction of the nerves, spinal cord or brain (neuropathic pain), or persistent pain caused by other non-malignant conditions, such as low-back pain or pain due to inflammation of various arthritic conditions. The prevalence of chronic non-cancer pain or neuropathic pain among Canadian adults is not well known. However, prevalence estimates using large, population-based questionnaires have shown that 4% to 8% of the general population in the developed world experiences neuropathic pain, suggesting that approximately two million Canadians may be affected by this disabling condition. Chronic pain is of particular concern among Canadians aged 65 years and older; based on cross-sectional data from the 1996/1997 National Population Health Survey and the 2005 Canadian Community Health Survey, chronic pain was estimated to affect 27% and 38% of seniors living in households and health care institutions, respectively. A number of treatments are available for the management of neuropathic pain or chronic non-cancer pain. These include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (duloxetine, venlafaxine), anticonvulsants (pregabalin, gabapentin, carbamazepine, phenytoin), topical lidocaine, and opioid analgesics. However, these medications are associated with limited pain relief and numerous adverse effects. The therapeutic use of several synthetic cannabinoid products for the symptomatic relief of chronic pain has also been studied. In particular, a combination of two products, delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) marketed under the name Sativex® is available for use as a buccal spray. This cannabis-based agent is approved for use in Canada as an add-on therapy for adult patients experiencing muscle spasticity caused by multiple sclerosis (MS), and it has received a Notice of Compliance with conditions for MS-related central neuropathic pain and the treatment of cancer pain unresponsive to opioids. The purpose of this review is to examine the available published literature relating to THC:CBD buccal spray for the treatment of chronic non-cancer or neuropathic pain in adults.”

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Opioids Out, Cannabis In

“Negotiating the Unknowns in Patient Care for Chronic Pain”

“With the current nationwide epidemic of opioid abuse, dependence, and fatalities, clinicians are being asked by federal agencies and professional societies to control their prescribing of narcotic medications for pain. Federal guidelines emphasize tapering, discontinuing, and limiting initiation of these drugs except in provision of end-of-life care. Reducing reliance on opioids, however, is a massive task. According to one estimate, more than 650 000 opioid prescriptions are dispensed each day in the United States. Unless the nation develops an increased tolerance to chronic pain, reduction in opioid prescribing leaves a vacuum that will be filled with other therapies.”

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Medical Marijuana: Just the Beginning of a Long, Strange Trip?

Physical Therapy Journal

“Medical marijuana continues to gain acceptance and become legalized in many states. Various species of the marijuana plant have been cultivated, and this plant can contain up to 100 active compounds known as cannabinoids.

Two cannabinoids seem the most clinically relevant: Δ9-tetrahydrocannabinol (THC), which tends to produce the psychotropic effects commonly associated with marijuana, and cannabidiol (CBD), which may produce therapeutic effects without appreciable psychoactive properties.

Smoking marijuana, or ingesting extracts from the whole plant orally (in baked goods, teas, and so forth), introduces variable amounts of THC, CBD, and other minor cannabinoids into the systemic circulation where they ultimately reach the central and peripheral nervous systems.

Alternatively, products containing THC, CBD, or a combination of both compounds, can also be ingested as oral tablets, or via sprays applied to the oral mucosal membranes. These products may provide a more predictable method for delivering a known amount of specific cannabinoids into the body.

Although there is still a need for randomized controlled clinical trials, preliminary studies have suggested that medical marijuana and related cannabinoids may be beneficial in treating chronic pain, inflammation, spasticity, and other conditions seen commonly in physical therapist practice.

Physical therapists should therefore be aware of the options that are available for patients considering medical marijuana, and be ready to provide information for these patients.”

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