Category Archives: Pain

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice.

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“Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects.

Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class.

Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects.

Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin.

In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.”

https://www.ncbi.nlm.nih.gov/pubmed/27890602

State of the evidence: Cannabinoids and cancer pain-A systematic review.

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“Cannabinoids are widely used to alleviate intractable symptoms such as pain, nausea, and muscle spasticity. The purpose of this review was to ascertain the current state of the science regarding use of cannabinoids for cancer pain.

CONCLUSIONS:

Eight randomized control trials met the inclusion criteria for review. Most trials found analgesic effects from cannabinoids when compared to placebo, although not all associations reached statistical significance. The analgesic effects of cannabinoids were also limited by dose-dependent side effects. Side effects most commonly reported were changes in cognition, sedation, and dizziness.

IMPLICATIONS FOR PRACTICE:

There is evidence that cannabinoids are effective adjuvants for cancer pain not completely relieved by opioid therapy, but there is a dearth of high-quality studies to support a stronger conclusion. Cannabinoids appear to be safe in low and medium doses. Methodological limitations of the trials limited the ability to make sound conclusions. Further research is warranted before efficacy, safety, and utility of cannabinoids for cancer pain can be determined.”

https://www.ncbi.nlm.nih.gov/pubmed/27863159

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.”

https://www.ncbi.nlm.nih.gov/pubmed/27842450

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.”

https://www.ncbi.nlm.nih.gov/pubmed/27831665

Descending serotonergic and noradrenergic systems do not regulate the antipruritic effects of cannabinoids.

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“For centuries, cannabinoids have been known to be effective in pain states. Itch and pain are two sensations sharing a lot in common.

OBJECTIVE:

The goal of this research was to observe whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behaviour and whether neurotoxic destruction of descending serotonergic and noradrenergic pathways mediate the antipruritic effect of WIN 55,212-2.

CONCLUSION:

Our findings indicate that cannabinoids dose-dependently reduce serotonin-induced scratching behaviour and neurotoxic destruction of descending inhibitory pathways does not mediate this antipruritic effect.”

https://www.ncbi.nlm.nih.gov/pubmed/27805543

 

Opioids Out, Cannabis In

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“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.”

http://jamanetwork.com/journals/jama/article-abstract/2576617

Crystal Structure of the Human Cannabinoid Receptor CB1.

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“Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use.

CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders.

Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study.

The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding.

In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids.

This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.”

https://www.ncbi.nlm.nih.gov/pubmed/27768894

Effect of medical cannabis on thermal quantitative measurements of pain in patients with Parkinson’s disease.

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“Cannabis can alleviate pain of various etiologies.

This study assessed the effect of cannabis on motor symptoms and pain parameters in patients with Parkinson’s disease (PD).

CONCLUSIONS:

Cannabis improved motor scores and pain symptoms in PD patients, together with a dissociate effect on heat and cold pain thresholds. Peripheral and central pathways are probably modulated by cannabis.

SIGNIFICANCE:

Quantitative sensory test results are significantly altered following cannabis consumption in patients with PD. Cannabis probably acts on pain in PD via peripheral and central pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/27723182

The Role of Cannabinoid Receptors in the Descending Modulation of Pain.

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“The endogenous antinociceptive descending pathway represents a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes the periaqueductal grey (PAG)-rostral ventromedial medulla (RVM)-dorsal horn (DH) axis, which is the best characterized pain modulation system through which pain is endogenously inhibited. Thus, an alternative rational strategy for silencing pain is the activation of this anatomical substrate.

Evidence of the involvement of cannabinoid receptors (CB) in the supraspinal modulation of pain can be found in several studies in which intra-cerebral microinjections of cannabinoid ligands or positive modulators have proved to be analgesic in different pain models, whereas cannabinoid receptor antagonists or antisense nucleotides towards CB1 receptors have facilitated pain.

Like opioids, cannabinoids produce centrally-mediated analgesia by activating a descending pathway which includes PAG and its projection to downstream RVM neurons, which in turn send inhibitory projections to the dorsal horn of the spinal cord.

Indeed, several studies underline a supraspinal regulation of cannabinoids on g-aminobutyric acid (GABA) and glutamate release which inhibit and enhance the antinociceptive descending pathway, respectively. Cannabinoid receptor activation expressed on presynaptic GABAergic terminals reduces the probability of neurotransmitter release thus dis-inhibiting the PAG-RVM-dorsal horn antinociceptive pathway.

Cannabinoids seem to increase glutamate release (maybe as consequence of GABA decrease) and to require glutamate receptor activation to induce antinociception. The consequent outcome is behavioral analgesia, which is reproduced in several pain conditions, from acute to chronic pain models such as inflammatory and neuropathic pain.

Taken together these findings would suggest that supraspinal cannabinoid receptors have broad applications, from pain control to closely related central nervous system diseases such as anxiety and depression.”

https://www.ncbi.nlm.nih.gov/pubmed/27713370

NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System.

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“Nonsteroidal anti-inflammatory drugs (NSAIDs) act upon peripheral tissues and upon the central nervous system to produce analgesia. A major central target of NSAIDs is the descending pain control system. The rostral structures of the descending pain control system send impulses towards the spinal cord and regulate the transmission of pain messages. Key structures of the descending pain control system are the periaqueductal gray matter (PAG) and the rostral ventromedial region of the medulla (RVM), both of which are critical targets for endogenous opioids and opiate pharmaceuticals. NSAIDs also act upon PAG and RVM to produce analgesia and, if repeatedly administered, induce tolerance to themselves and cross-tolerance to opioids. Experimental evidence shows that this is due to an interaction of NSAIDs with endogenous opioids along the descending pain control system. Analgesia by NSAIDs along the descending pain control system also requires an activation of the CB1 endocannabinoid receptor. Several experimental approaches suggest that opioids, NSAIDs and cannabinoids in PAG and RVM cooperate to decrease GABAergic inhibition and thus enhance the descending flow of impulses that inhibit pain.”

 https://www.ncbi.nlm.nih.gov/pubmed/27713305