A recent brief trial of smoked cannabis (% THC cigarettes 3 times daily). Author manuscript; available in PMC Jul preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. .. These studies suggest that different cannabinoids may offer pain relief in cancer by both In addition, the combination was shown to circumvent the development of tolerance . Read chapter 5 Development of Cannabinoid Drugs: The medical use of marijuana is Those early activities are collectively referred to as the preclinical phase. . tMarijuana cigarettes were available under a special FDA-sponsored .. that six of the nine cannabinoids under development for analgesia were discontinued.
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As the clock ticks down to the July 1 deadline when recreational marijuana will be legalized in Canada, governments are scrambling and the controversy is mounting among those who want a say in how it will be grown, sold and regulated. Meanwhile, tens of thousands of Canadians—people who are living with chronic pain—are wondering when their needs will be met.
They are desperate for safe and effective pain treatments that will not turn them into drug addicts. Pain specialists and scientists at Dalhousie Medical School are on the brink of answering that call.
They've launched a company, Panag Pharma Inc. The first of these products is a topical analgesic cream that targets aches and pains in muscles and joints close to the surface, making it ideal for such common afflictions as osteoarthritis. Known simply as Topical A OTC at this stage, the cream uses cannabinoids derived from clover and cloves—rather than cannabis—to target pathways involved in inflammation and pain.
It also uses capsaicin—the compound that gives that spicy zing to chili peppers—to target other pain pathways. The trial, led by anesthesiologist and assistant professor, Dr. Karim Mukhida, will test the cream's ability to relieve pain in patients with osteoarthritis of the knee. A referral is not needed to join the trial; patients who want to learn more can contact Joan Falkenham joan.
Just a few years ago, the evidence supporting cannabinoid products for pain relief in humans was mostly anecdotal. Lynch, who's been interested in cannabinoid research for two decades—since patients began telling her that cannabis was giving them relief from chronic pain, without the side effects and addictive qualities of many pharmaceutical treatments they had tried. Cannabinoids were proving profoundly analgesic in animal models of acute and especially chronic pain, both neuropathic and inflammatory.
Lynch wanted to learn more about the potential benefits for people, but there were relatively few clinical trials underway at the time because cannabis was and still is a controlled substance. Despite the regulatory challenges, Drs. Lynch and Kelly and other Dalhousie researchers began exploring how cannabinoids do the job. Among this dedicated group were Dr. Orlando Hung, an anesthesiologist with a bent for inventing new drug delivery methods, and Dr.
Christian Lehmann, an anesthesiologist with a particular interest in pre-clinical models of inflammation. They co-founded Panag Pharma Inc. Lynch and Kelly and together they incorporated the company in January Dalhousie University The science behind cannabinoids and pain.
THC was isolated in by Israeli chemist Dr. A longtime mentor to Dr. Lynch and her colleagues—and now an advisor to Panag Pharma—he has been on the forefront of medical marijuana research for more than 50 years. In fact, they adopted the name Panag Pharma for their company because "panag" is an ancient Hebrew word for cannabis. Lynch knows from talking to her patients, most people who are in pain don't want the psychotropic effects of THC—they just want to function normally, without pain.
American scientists took the first step to solving that conundrum in the s, when they cloned the two main receptors in the human endocannabinoid system. The endocannabinoid system is the body's web of cannabinoid receptors, which are targets for cannabinoids found naturally in humans and other animals. When a compound acts on these receptors, it can activate the system and trigger a release of pain-relieving chemicals. THC is just one phyto plant cannabinoid that can trigger the body's endocannabinoid receptors to provide this pain relief.
One of the non-THC compounds the researchers have studied intensely triggers cannabinoid 2 CB2 receptors, the non-psychoactive endocannabinoid receptor found in the immune system.
This is the compound the researchers have included in Panag's over-the-counter topical pain cream. They're utilizing its anti-inflammatory properties in another product patent pending for treating interstitial cystitis, a painful condition of the bladder.
Panag's researchers are also developing topical medications that target painful eye diseases. One of their patented medications contains a synthetic cannabinoid that activates another internal cannabinoid receptor to treat inflammation of the front of the eye.
At the same time, they're developing an eye treatment using the non-addictive phytocannabinoid known as CBD cannabidiol , to help people suffering from conditions such as dry eye.
Smoking results in rapid absorption and onset of psychoactive effects, and is the preferred mode of recreational use. Marijuana use is followed by a disruption of short-term memory, cognitive impairment, a sense of slowing of time, mood alterations, enhanced body awareness, reduced ability to focus, incoordination, and sleepiness [ 9 ]. Ingestion of hashish leads to delayed onset and longer duration of actions.
THC can also be inhaled in a vaporized form without smoking, that avoids the inhalation of combustion by-products, while providing higher bioavailability.
In animal studies, both intraperitoneal and localized administration of cannabinoids have been used [ 29 ][ 30 ][ 31 ][ 32 ], [ 33 ]. Cannabinoids have been studied in various types of neuropathic pain including nerve injury, chemotherapy-induced, diabetic neuropathy, etc.
CB-1 receptors have been found to be upregulated in the thalamus [ 34 ] and the spinal cord [ 35 ] after nerve injury in rat models of neuropathic pain. Another study showed CB-2 receptors were induced in a localized area of spinal cord consistent with the location of nerve injury [ 36 ]. Systemic administration of both WIN, and HU suppressed mechanical allodynia and thermal hyperalgesia in a rat model of trigeminal neuralgia [ 37 ]. WIN, also provided antinociception in a model of sciatic nerve injury, with enhanced action if administered pre-emptively [ 38 ].
Intrathecal JWH, a CB-2 agonist, also significantly improved mechanical allodynia after sciatic nerve injury [ 39 ]. Mechanical allodynia developing in diabetic rats also responds to WIN administration [ 40 ], as does thermal hyperalgesia and tactile allodynia induced in rats by the chemotherapeutic agent paclitaxel [ 41 ]. Mechanical allodynia induced by vincristine [ 42 ] and cisplatin [ 43 ] administration in rats is suppressed through both CB-1 and CB-2 receptor agonism.
Pure CB-2 agonists also decrease chemotherapy induced neuropathic pain [ 44 ]. These studies demonstrate that cannabinoids can be potentially used as analgesics in treating neuropathic pain accompanying diverse pathologies. Both CB1 and CB2 receptors are involved in the mediation of inflammatory pain [ 46 ]. WIN, has been shown to attenuate the delayed phase of oro-facial pain induced by formalin injection in rats [ 47 ]. Systemic HU, a novel CB-2 agonist also attenuated inflammatory pain during hot plate test in mice [ 49 ].
Inflammatory pain and swelling in mouse hindpaw were relieved by systemic administration of both non-selective HU and CB-2 selective JWH [ 31 ], and also by local injection of CB-2 agonist AM [ 32 ], [ 33 ]. Since, inflammatory pain is a hallmark of several chronic diseases including sickle cell disease and cancer, cannabinoids appear to be a promising therapy to treat severe pain in these diseases.
Both endogenous and exogenous cannabinoids are being investigated for a role in cancer pain management. Cannabinoids have been found effective in increasing the threshold at which pain is perceived in tumor-afflicted mice [ 50 ].
Mechanical hyperalgesia in a murine model of bone cancer pain is associated with decreased anandamide levels in the affected area and was alleviated by local injection of anandamide.
Hyperalgesia in this model was tested by measuring the paw withdrawal frequency in mice injected with fibrosarcoma cells into the calcaneum [ 29 ]. The cannabinoid agonist WIN, has also been shown to attenuate tumor induced hyeralgesia in mice, through peripheral action on CB-1 and CB-2 receptors, rather than by central action [ 51 ], [ 50 ].
Another study suggested that the antinociceptive action of WIN, in a mouse tumor model is solely via CB-1 receptors [ 48 ]. Systemic administration of CP, also attenuates tumor-induced hyperalgesia [ 30 ]. These studies suggest that different cannabinoids may offer pain relief in cancer by both systemic and peripheral routes, primarily via CB-1 receptors, and the route of administration may be tailored to the specific need. The preclinical studies described above provide a rationale for further evaluation of cannabinoid receptor agonists in different types of pain.
Both CB-1 and CB-2 receptors appear to be involved in pain modulation, and selective agonists may be useful when the specific role of each receptor is fully characterized in each type of pain. Especially in cases of pain attributable wholly or partly to inflammation, it may be worthwhile to explore a local route of administering the cannabinoid and thus avoid systemic side effects.
Opioids and cannabinoids both provide antinociception through G-protein coupled mechanisms, and many studies have explored synergistic interactions between them. A study using subcutaneous morphine and intraperitoneal THC in rats showed equivalent antinociception using high dose morphine or high dose THC or a low dose combination of both.
In addition, the combination was shown to circumvent the development of tolerance when compared to either drug alone [ 52 ]. Pretreatment with HU also increased the antinociceptive effect of morphine injected into the periaqueductal gray and prevented the development of tolerance [ 53 ].
Synergistic effect with an opioid-cannabinoid combination has been shown in other studies as well, using systemic [ 54 , 55 , 52 , 56 , 57 ] or topical agonists [ 58 ]. THC also enhances the analgesic action of fentanyl and buprenorphine patches [ 59 ]. However, ultra-low dose naltrexone has also been shown to enhance the anti-nociceptive action of WIN 55,, while high dose naltrexone does not [ 60 ]. This is similar to enhancement of the antinociceptive action of morphine by ultra-low concentrations of naloxone or naltrexone [ 61 ], [ 62 ].
Also, CB1 receptor knockout mice appear to have lesser opioid addiction and withdrawal [ 65 ], suggesting a role for cannabinoid receptors in opioid signaling pathways. These data support the harmonious and even supportive use of cannabinoids in conjunction with opioids.
Most studies evaluating synergism between opioids and cannabinoids have been in healthy subjects, and the subject needs to be studied further in specific disease models. A slightly additive analgesic action was observed with the THC-morphine combination when testing sensitivity to electric stimulation [ 67 ].
Thus, adjunct use of cannabinoids may permit the use of lower doses of opioids than otherwise required, thus acting as an opioid sparing agent in similar situations. However, in other conditions, the addition of a cannabinoid may confer no additional benefit, so the optimal therapy for pain management in specific conditions remains an area for future research.
Table 4 compares certain features of cannabinoids and opioids relevant to their use as antinociceptive agents. While 5HT-3 receptor antagonists are effective for acute onset nausea and vomiting, they are not so beneficial in delayed nausea and vomiting.
A recent systematic review concluded that nabilone is superior to placebo, domperidone and prochlorperazine in the management of CINV, but not superior to metoclopramide and chlorpromazine [ 88 ]. Oral dronabinol combined with prochlorperazine has been shown to be more effective than either agent alone in controlling CINV [ 89 ]. Smoked marijuana appears to have a beneficial role in reducing neuropathic pain in HIV, and the studies discussing this are detailed below.
In a subanalysis of data from a multicountry randomized clinical trial studying self-care symptom management in HIV patients, anxiety was found to be lower in marijuana users than nonusers.
Marijuana users reported better overall medication effectiveness than non-users, however it is unclear whether it is attributable to the euphoric effect of marijuana or a real synergism with the medications [ 93 ]. Thus, cannabinoids may have multiple therapeutic functions in both, the central nervous system and peripheral organ disease. Many randomized clinical trials with cannabinoid medications have been conducted in multiple sclerosis MS.
Patients with multiple sclerosis have diverse types of pain: Cannabinoids have a role in relieving pain, spasticity, tremor, nocturia and improving general well being in MS Table 5. The non-psychotropic cannabinnoid HU has been shown to decrease clinical signs and improve survival in rats with MS [ 90 ].
Cannabinoids, especially endocannabinoids and CB-2 agonists are postulated to protect against neuro-inflammation, and may thus be beneficial for management of MS [ 90 ]. It was found to decrease mean pain intensity and reduce sleep disturbance in MS [ 98 ]. Oral dronabinol achieved a modest reduction in pain intensity in MS and related conditions [ ].
Yet, a metanalysis of cannabis based medications in MS and other types of neuropathic pain concluded that cannabinoids were superior to placebo [ ]. All these studies found dizziness to be the most common adverse effect, and that the incidence was higher in the treatment groups.
Overall, cannabinoids appear to be effective in treating pain in MS, and would need to be further evaluated for their optimum use in MS. The trials focusing on MS and related etiologies have already been discussed above. The text below focuses on clinical studies using cannabinoids in other conditions associated with pain. Studies using smoked cannabis in HIV associated sensory neuropathy and other types of neuropathic pain have found that it offers clinically significant analgesia to a large number of subjects [ ], [ , ] but often with associated neurocognitive and psychoactive effects, especially at higher doses [ ].
Improvement was noted in pain, mood and daily functioning [ ], but not in evoked pain [ ]. It showed improvement in control of pain and an improved quality of sleep in all, while the psychoactive effects were noted to be manageable [ ]. However, a study comparing escalating daily doses of nabilone maximum 2 mg and dihydrocodeine maximum mg in patients with severe neuropathic pain found dihydrocodeine to offer clinically significant pain relief to more patients than nabilone; interestingly, no subject responded to both agents [ ].
In cancer patients, nabilone provided multi-symptom relief, including pain relief, as compared to patients who did not receive nabilone [ ].
As an adjuvant drug added to opioids, it also improved pain control and the quality of sleep in patients with chronic non-cancer pain [ ]. A systematic review in of all randomized controlled trials done with cannabinoids in various types of pain concluded that in cancer pain, cannabinoids were of the same efficacy of codeine, while being associated with dose limiting CNS depressant effects [ ].
The only condition where benefit was not noted was post-herpetic neuralgia [ 97 ]. Interestingly, studies in healthy human volunteers using oral cannabis extracts in acute pain models do not show any analgesic effect, but rather suggest a hyperalgesic action [ 85 ]. The effort needs to be targeted to identify disease and symptom-specific therapeutic potential of specific cannabis-derived drugs.
We did not find any studies evaluating cannabinoids as analgesic agents in sickle cell disease SCD. However, a questionnaire-based study evaluating the prevalence and reasons for marijuana use in SCD patients found that 31 of the 84 respondents reported cannabis use. Pain in SCD is a result of vascular occlusion, tissue infarction and inflammation [ ], and is widely prevalent and often undertreated [ ].
Currently used analgesics in SCD include acetaminophen, non-steroidal anti-inflammatory drugs NSAIDs , opioids, ketorolac, corticosteroids, tramadol and adjuvant agents. SCD patients with chronic pain are generally treated with a long acting opioid with addition of short acting opioids for breakthrough pain [ ] Patients being treated with opiods for acute pain often suffer from nausea and vomiting [ ].
Cannabinoids are commonly used to control nausea and vomiting in other settings, and could be potentially beneficial in this scenario as well. Cannabinoids, endocannabinoids and non-cannabinoid derivatives of the cannabis plant have also been found to have anti-inflammatory properties [ ], which may be helpful in SCD. Transgenic sickle mice have been found to be markedly sensitive to ischemia-reperfusion injury [ ].
CB-2 receptor activation by JWH has been found to protect from cardiac ischemia reperfusion injury [ ], [ ] and may help in SCD as well. CB-2 receptor activation and CB-1 receptor inhibition has beneficial effects in cerebral ischemia [ ], [ ]. Vasocclusion being the pathology behind the pain in SCD, these factors should be considered when evaluating the role of cannabinoids as analgesics in this condition.
Since SCD is a condition where the patient suffers severe acute episodes superimposed on a background of chronic lifelong pain, newer modalities need to be investigated to help achieve a better quality of life.
Cannabinoids could possibly be used as adjunct agents along with opioids to decrease opioid dose and achieve better pain control. They also possess the potential to favorably modify the disease process via various mechanisms of central and peripheral activity discussed above. Epidemiological studies have reached diverse conclusions regarding the association of cannabis with various cancers. A case-control study showed no increase in risk of head and neck cancer with cannabis use [ ].
Some studies show higher lung cancer rates in marijuana smokers [ ], [ ], while some do not find any such association [ ]. Maternal marijuana use, especially in the first trimester, is associated with an increased risk of neuroblastoma in the child [ ]. Marijuana smoke has been shown to be mutagenic [ , ], while THC by itself is not mutagenic [ , ]. These mice when treated with THC for 2 years showed an increased incidence of thyroid follicular cell adenoma [ , ].
In contrast, THC was found to increase apoptosis and improve survival in murine cancer models and in human lymphoma and leukemia [ ]. Moreover, the cannabinoid HU is anti-angiogenic in vivo and vitro, suggestive of an inhibitory effect on cancer progression [ ]. It appears that cannabinoids may have two opposite effects on cancer: WIN, and other cannabinoid agonists have been suggested as potential therapeutic options in prostate cancer [ ].
Cannabinoids obviously have a potential to be misused and carry the risk of addiction. Prior psychiatric evaluation before prescribing cannabinoids has been suggested as one way to decrease this risk. Cannabis use in adolescence and young adulthood may have lasting effects on the brain and behavior [ ].
Marijuana smoking has been postulated to contribute to the development of schizophreniform disorders [ ], besides the risk of brief psychotic features with acute use [ ], especially in the adolescent population.
Diminished cognitive function in adolescent cannabis users [ ] is also an area of concern. Chronic cannabis users are also at risk of developing the amotivational syndrome, characterized by apathy, lack of activity, incoherence, blunting of cognition and affect [ 90 ]. However, all this data is from marijuana users, and not from a controlled therapeutic use of cannabinoids.
It cannot be said for certain that long-term therapeutic use of cannabinoids will show the same risks. Some preclinical studies also show development of tolerance to various actions of cannabinoids [ ], including antinociception [ ]. Recreational cannabis use is associated with a withdrawal syndrome consisting of tiredness, yawning, depression, anxiety, psychomotor retardation, reported at a prevalence of Cannabinoids have been reported to cause motor impairment in the form of cerebellar incoordination [ ], and the pathway appears similar to that of ethanol induced incoordination [ ].
These concerns may need to be addressed while exploring the therapeutic use of cannabinoids. Management of severe chronic pain is best done by a multi-pronged approach, individualizing it not just according to the disease but also according to patient preferences and their side effect profiles. Currently there is intriguing evidence from animal studies showing efficacy of cannabinoids as antinociceptive agents, however data from human studies is still emerging.
Cannabinoids may form a useful adjunct to current analgesic drugs in many conditions, especially in low doses incapable of inducing hyperalgesia or other side effects. They can also be used as rescue drugs when opioid analgesia is ineffective or inadequate, or as opioid sparing agent. They also appear to antagonize several side effects of opioids, and the opioid-cannabinoid combination may become a very useful agent in the long-term management of severe pain.
Preclinical data also suggest a beneficial effect of cannabinoids on the disease process in HIV, cancer, and MS. While smoked marijuana tends to be a controversial territory, evidence points to significant multi-symptom relief from it especially in HIV patients. Cannabis derived medications deserve to be investigated in rigorously designed studies so that their role in managing severe and chronic pain in various conditions can be more clearly defined.
The legalization of medical marijuana would also enable more clinical trials in humans, and development of cannabis-derived drugs for multiple disease processes, in addition to treating severe pain.
Moreover, examination of cannabinoids and their receptors may potentially lead to a new understanding of disease processes as well. Thus, the medical, as well as the general community, need to move beyond preconceived notions about cannabis, and focus on its potential advantages in treating a host of conditions, including severe pain. National Center for Biotechnology Information , U.
Author manuscript; available in PMC Jul Author information Copyright and License information Disclaimer. This article has been corrected. See other articles in PMC that cite the published article. Abstract Historically and anecdotally cannabinoids have been used as analgesic agents.
Introduction Cannabinoids are derivatives of Cannabis sativa, the hemp plant, which evolved in the temperate regions of Central Asia. Classification of cannabinoids Based on their origin, cannabinoids are classified into 3 categories: Open in a separate window.
Cannabinoid receptors and signaling pathways Cannabinoids mainly act via 2 different receptors: Routes of cannabinoid use Smoking and oral ingestion are the common routes of cannabinoid use. Cannabinoids for analgesia — animal studies a Neuropathic pain Cannabinoids have been studied in various types of neuropathic pain including nerve injury, chemotherapy-induced, diabetic neuropathy, etc.
Synergism with opioids a Experimental studies Opioids and cannabinoids both provide antinociception through G-protein coupled mechanisms, and many studies have explored synergistic interactions between them. Table 4 A comparision of opioids and cannabinoids in pain management. Shown to be not useful in acute nociceptive pain in humans [ 84 ], [ 85 ], [ 86 ]. Cannabinoids In Multiple sclerosis Many randomized clinical trials with cannabinoid medications have been conducted in multiple sclerosis MS.
Agent; route; daily dose Clinical Condition Study design Number. Numerical rating scale for pain [ ]. Expanded Disability Status Scale [ ]. Clinical studies with cannabinoids in pain The trials focusing on MS and related etiologies have already been discussed above. The Edmonton Symptom Assessment System [ ]. A THC predominant cannabis extract [ ]. Can Cannabinoids be useful in Sickle cell disease? Side effects of cannabinoids Epidemiological studies have reached diverse conclusions regarding the association of cannabis with various cancers.
Conclusion Management of severe chronic pain is best done by a multi-pronged approach, individualizing it not just according to the disease but also according to patient preferences and their side effect profiles. Molleman A, Demuth DG. Thomas Dunne Books; History of cannabis as a medicine: Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain.
Practical guide to opioids and their complications in managing cancer pain. What oncologists need to know. Oncology Williston Park ; 21 Opioid tolerance and hyperalgesia. Med Clin North Am. Efficacy of opioids for chronic pain: Cannabinoid receptors 1 and 2 CB1 and CB2 , their distribution, ligands and functional involvement in nervous system structures—a short review.
Endocannabinoid-mediated control of synaptic transmission. Demuth DG, Molleman A. Cannabinoid physiology and pharmacology: GPR55 is extensively expressed in human brain.
Brain Res Mol Brain Res. Biochemistry and pharmacology of endovanilloids. Biochem Biophys Res Commun. JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. The cannabinoid CB1 receptor antagonist rimonabant SR inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism.
Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line. A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain. Acute and chronic administration of the cannabinoid receptor agonist CP 55, attenuates tumor-evoked hyperalgesia. Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat.
Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Selective activation of cannabinoid CB 2 receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Cannabinoid CB 1 receptor upregulation in a rat model of chronic neuropathic pain. Upregulation of spinal cannabinoidreceptors following nerve injury enhances the effects of Win 55, on neuropathic pain behaviors in rats.
Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain. Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain. Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain.
Cannabinoids blocks tactile allodynia in diabetic mice without attenuation of its antinociceptive effect. A cannabinoid agonist, WIN 55,, reduces neuropathic nociception induced by paclitaxel in rats. Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. WIN 55, prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat. Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats.
J Pharmacol Exp Ther. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Antinociceptive effect of the cannabinoid agonist, WIN 55,, in the orofacial and temporomandibular formalin tests.
A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain. Peripheral cannabinoids attenuate carcinoma-induced nociception in mice. The cannabinoid receptor agonist, WIN 55, , attenuates tumor-evoked hyperalgesia through peripheral mechanisms.
Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent morphine antinociception. Sodium-dependent calcium efflux from adrenal chromaffin cells following exocytosis. Possible role of secretory vesicle membranes. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat.
Antinociceptive synergy between delta 9 -tetrahydrocannabinol and opioids after oral administration. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Topical cannabinoid enhances topical morphine antinociception. Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol.
Paquette J, Olmstead MC. Ultra-low dose naltrexone enhances cannabinoid-induced antinociception. Decreased basal endogenous opioid levels in diabetic rodents: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. The analgesic effect of oral deltatetrahydrocannabinol THC , morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions.
Delta 9 -tetrahydrocannabinol and the opioid receptor agonist piritramide do not act synergistically in postoperative pain. Mechanisms of morphine enhancement of spontaneous seizure activity.
The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy.
Cannabinoids in the management of difficult to treat pain
In contrast, the CB2 receptors are most populated in those cells that are responsible for immune mediation . Full-text available Thus, development of drugs capable of binding to the cannabinoid receptors without psychoactive effects. The discovery of cannabinoid receptors and endogenous ligands for these receptors has led to humans, including 2 cannabinoid agonists available on the international market. . est in the development of drugs that can specifically inter-. The mechanisms of the analgesic effect of cannabinoids include inhibition of the All of these provide an opportunity for the development of new multiple target .. like all presently available drugs for the treatment of chronic pain in humans.