Cannabis for Pain and Headaches: Primer

Purpose of Review

Marijuana has been used both medicinally and recreationally since ancient times and interest in its compounds for pain relief has increased in recent years. The identification of our own intrinsic, endocannabinoid system has laid the foundation for further research.

Recent Findings

Synthetic cannabinoids are being developed and synthesized from the marijuana plant such as dronabinol and nabilone. The US Food and Drug Administration approved the use of dronabinol and nabilone for chemotherapy-associated nausea and vomiting and HIV (Human Immunodeficiency Virus) wasting. Nabiximols is a cannabis extract that is approved for the treatment of spasticity and intractable pain in Canada and the UK. Further clinical trials are studying the effect of marijuana extracts for seizure disorders.

Summary

Phytocannabinoids have been identified as key compounds involved in analgesia and anti-inflammatory effects. Other compounds found in cannabis such as flavonoids and terpenes are also being investigated as to their individual or synergistic effects. This article will review relevant literature regarding medical use of marijuana and cannabinoid pharmaceuticals with an emphasis on pain and headaches.

     

Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents

Marijuana has been reported to be an effective antinauseant and antiemetic in patients receiving cancer chemotherapy. Whether this is due to psychological changes, central antiemetic properties and/or direct effects on gastrointestinal (GI) function is not known. The purpose of these investigations was to determine whether the major constituents of marijuana and the synthetic cannabinoid nabilone have any effects on GI function which can be detected in rodent models of GI transit and motility. Intravenous delta 9-tetrahydrocannabinol (delta 9-THC) slowed the rate of gastric emptying and small intestinal transit in mice and in rats. Delta 9,11-THC, cannabinol and nabilone given i.v. also inhibited small intestinal transit in mice, but were less effective in reducing gastric emptying. Cannabidiol given i.v. had no effect on gastric emptying or intestinal transit. Those cannabinoids which inhibited GI transit did so at doses equal to, or lower, than those reported to produce central nervous system activity. In rats, delta 9-THC produced greater inhibition of gastric emptying and small intestinal transit than large bowel transit, indicating a selectivity for the more proximal sections of the gut. In addition, i.v. delta 9-THC decreased the frequency of both gastric and intestinal contractions without altering intraluminal pressure. Such changes probably reflect a decrease in propulsive activity, without change in basal tone. These data indicate that delta 9-THC, delta 9,11-THC, cannabinol and nabilone (but not cannabidiol) exert an inhibitory effect on GI transit and motility in rats.     

Differential physiological and behavioral cues observed in individuals smoking botanical marijuana versus synthetic cannabinoid drugs

Context: Synthetic cannabinoid use has increased in many states, and medicinal and/or recreational marijuana use has been legalized in some states. These changes present challenges to law enforcement drug recognition experts (DREs) who determine whether drivers are impaired by synthetic cannabinoids or marijuana, as well as to clinical toxicologists who care for patients with complications from synthetic cannabinoids and marijuana. Our goal was to compare what effects synthetic cannabinoids and marijuana had on performance and behavior, including driving impairment, by reviewing records generated by law enforcement DREs who evaluated motorists arrested for impaired driving. Methods: Data were from a retrospective, convenience sample of de-identified arrest reports from impaired drivers suspected of using synthetic cannabinoids (n?=?100) or marijuana (n?=?33). Inclusion criteria were arrested drivers who admitted to using either synthetic cannabinoids or marijuana, or who possessed either synthetic cannabinoids or marijuana; who also had a DRE evaluation at the scene; and whose blood screens were negative for alcohol and other drugs. Exclusion criteria were impaired drivers arrested with other intoxicants found in their drug or alcohol blood screens. Blood samples were analyzed for 20 popular synthetic cannabinoids by using liquid chromatography-tandem mass spectrometry. Delta-9-tetrahydrocannabinol (THC) and THC-COOH were quantified by gas chromatography-mass spectrometry. Statistical significance was determined by using Fisher’s exact test or Student’s t-test, where appropriate, to compare the frequency of characteristics of those in the synthetic cannabinoid group versus those in the marijuana group. Results: 16 synthetic cannabinoid and 25 marijuana records met selection criteria; the drivers of these records were arrested for moving violations. Median age for the synthetic cannabinoid group (n?=?16, 15 males) was 20 years (IQR 19–23 years). Median age for the marijuana group (n?=?25, 21 males) was 20 years (IQR 19–24 years) (p?=?0.46). In the synthetic cannabinoid group, 94% (15/16) admitted to using synthetic cannabinoids. In the marijuana group, 96% (24/25) admitted to using marijuana. Blood was available for testing in 96% (24/25) of the marijuana group; 21 of these 24 had quantitative levels of THC (mean?+?SD?=?10.7?+?5 ng/mL) and THC-COOH (mean?+?SD?=?57.8?+?3 ng/mL). Blood was available for testing in 63% (10/16) of the synthetic cannabinoid group, with 80% (8/10) of these positive for synthetic cannabinoids. Those in the synthetic cannabinoid group were more frequently confused (7/16 [44%] vs. 0/25 [0%], p?≤?0.003) and disoriented (5/16 [31%] vs. 0/25 [0%], p?≤?0.003), and more frequently had incoherent, slurred speech (10/16 [63%] vs. 3/25 [12%], p?=?0.0014) and horizontal gaze nystagmus (8/16 [50%] vs. 3/25 [12%], p?=?0.01) than those in the marijuana group. Conclusion: Drivers under the influence of synthetic cannabinoids were more frequently impaired with confusion, disorientation, and incoherent, slurred speech than drivers under the influence of marijuana in this population evaluated by DREs.     

The emerging role of cannabinoid neuromodulators in symptom management

INTRODUCTION: The cannabinoids nabilone (Cesamet) and dronabinol (Marinol) are indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in cancer patients who have failed to respond adequately to conventional antiemetic therapy. DISCUSSION: The endocannabinoid (CB) system interacts with numerous other systems and pharmaceutical cannabinoids target ubiquitous CB1 and CB2 receptors in the central nervous system and periphery, relieving nausea and vomiting and pain. SUMMARY: The benefits of this novel class of medications in cancer may extend beyond CINV, as indicated by data from preclinical studies and animal models.     

Laboratory detection of cannabinoids

Cannabis, or marijuana, has been known and used as a drug for many thousands of years. Recent interest in drug abuse and detection has spurred the development of several methodologies for cannabinoid detection. These methods include immunoassays and chromatography. Laboratories routinely performing cannabinoid testing use two or more methodologies; the accepted method is to screen with one methodology and confirm by a second. These methodologies vary widely in sensitivity, specificity, and time required for analysis. Although therapeutic applications of cannabis constituents often produce undesirable side effects, two cannabinoids, delta 9-THC and nabilone, have been approved for use as antiemetics in chemotherapy. Further investigations of cannabinoid pharmacology and structure-activity relationships may result in the development of promising new therapeutic agents.     

Medical use of cannabis products

Introduction

The German government intends to reduce the barriers for the medical use of cannabis products. A discussion on the indications and contraindications of the medical use of cannabis and on the changes of the regulatory framework has already begun in Germany. It is useful to draw from the experiences of other countries with a more liberal medical use of cannabis.

Methods

The Israeli and Canadian experience is outlined by physicians who have been charged with expertise on the medical use of cannabis by their jurisdiction.

Results

In Israel, only the plant-based cannabinoid nabiximol (mixture of tetrahydrocannabinol/cannabidiol) can be prescribed for spasticity/chronic pain in multiple sclerosis and for cancer pain. The costs of nabiximole are reimbursed by some, but not by all health maintenance organizations. The medical use of marijuana is permitted; however, it is strictly regulated by the government. Selected companies are allowed to produce marijuana for medical use, and only certain physicians are licensed to prescribe marijuana as a therapeutic drug for specific indications such as chronic neuropathic, and cancer pain, inflammatory bowel diseases, or posttraumatic stress disorder if conventional treatments have failed. The costs of marijuana are not reimbursed by health insurance companies.In Canada, synthetic cannabinoids and the plant-based (nabiximol) are licensed for neuropathic and cancer pain, HIV-related anorexia and chemotherapy-associate nausea. The costs of these synthetic cannabinoids are covered by health insurance companies. The medical use of marijuana as a treatment option is allowed for individual patients suffering from any medical condition when authorized by a medical practitioner or nurse. Licensed producers are the only source for patients to newly access medical cannabis, although those with previous permission to grow may continue cultivation at the present time. The costs of marijuana are not reimbursed by health insurance companies.There are multiple contraindications for the medical use of cannabis products in both countries.

Conclusions

The use of standardized, synthetic, and plant-based cannabis products should be allowed in Germany for defined medical conditions when high-level evidence of efficacy and safety exists. The costs should be reimbursed by the health insurance companies. Contraindications for the medical use of cannabis should be defined. Growing marijuana by patients for their medical use should not be allowed.

     

Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain

OBJECTIVE: To review the literature concerning the physiology of the endocannabinoid system, current drug development of cannabinoid agonists, and current clinical research on the use of cannabinoid agonists for analgesia. DATA SOURCES: Articles were identified through a search of MEDLINE (1966-August 2005) using the key words cannabis, cannabinoid, cannabi*, cannabidiol, nabilone, THC, pain, and analgesia. No search limits were included. Additional references were located through review of the bibliographies of the articles identified. STUDY SELECTION AND DATA EXTRACTION: Studies of cannabinoid agonists for treatment of pain were selected and were not limited by pain type or etiology. Studies or reviews using animal models of pain were also included. Articles that related to the physiology and pharmacology of the endocannabinoid system were evaluated. DATA SYNTHESIS: The discovery of cannabinoid receptors and endogenous ligands for these receptors has led to increased drug development of cannabinoid agonists. New cannabimimetic agents have been associated with fewer systemic adverse effects than delta-9-tetrahydrocannabinol, including recent development of cannabis medicinal extracts for sublingual use (approved in Canada), and have had promising results for analgesia in initial human trials. Several synthetic cannabinoids have also been studied in humans, including 2 cannabinoid agonists available on the international market. CONCLUSIONS: Cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management, and cannabinoids are a potential addition to the arsenal of treatment options.     

Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors

Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the α3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified α3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the α3 GlyRs. Our findings suggest that the α3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction.     

A Case of Cannabinoid Hyperemesis Syndrome Caused by Synthetic Cannabinoids

Background

Cannabinoid hyperemesis syndrome (CHS) was initially described in 2004 and remains an under-recognized clinical entity that occurs in chronic heavy marijuana smokers.

Case Report

We describe the first report of CHS in an abuser of synthetic cannabinoids. CHS is thought to be caused by over-stimulation of the cannabinoid 1 receptor. The synthetic cannabinoids found in K2, Spice, and other commonly abused designer cannabinoids, including those used by our patient (JWH-018, JWH-073, JWH-122, AM-2201, and AM-694), are potent agonists of the cannabinoid 1 receptor.

Conclusion

Our report suggests that frequent habitual smoking of synthetic cannabinoids can cause cannabinoid hyperemesis syndrome.     

A spicy kind of high: a profile of synthetic cannabinoid users

Aims: Over the last 6 years, numerous products have been made available and marketed as “legal highs.” Many of these products contain compounds similar to those within cannabis and function to create a high comparable to that of smoking marijuana. Though governments have regulated these psychoactive compounds, variants are still sold. At this point, little is known about the characteristics of users of synthetic cannabinoids. Design and Participants: A self-report survey instrument was administered to 2349 university students at a large institute in the State of Georgia. Respondents reported on their lifetime, last-year, and last-month synthetic cannabinoid use and demographic characteristics. Results: Males, Whites and Hispanics, users of other substances, and those from more affluent families were significantly more likely to report having used a synthetic cannabinoid. In addition, those that self-identified as lesbian, gay, bisexual, or transgender (LGBT) were twice as likely to have used synthetic cannabinoids. Conclusions: This research is among the first to detail characteristics of synthetic cannabinoid users in a large random sample. It appears that use of synthetic cannabinoids (synthetic marijuana analogs) continued after initial bans and that use is concentrated in affluent White and Hispanic males and in the LGBT community.     

Cannabinoids in Pain Treatment: An Overview

The current landscape contains conflicting reports regarding the use of medical marijuana, creating fields of misinformation and lack of understanding by health care providers about cannabinoids. In this article we provide a dispassionate look at medical marijuana, while providing a clinical overview focusing on pain management. We examine the mechanisms of the endocannabinoid system, along with the pharmacology of cannabinoids. Current research on the use of marijuana for the treatment of pain is reviewed. Finally, recommendations for pain management nurses on integrating research, clinical practice, and U.S. drug policy are made.     

Cannabinoide und Immunsystem

The medical use of cannabis or cannabinoid compounds is controversial. Cannabinoids like the Delta(9)-THC (tetrahydrocannabinol) or the synthetic derivative Nabilone are available against cancer- and HIV-associated cachexia, nausea and vomiting. Over the last 20 years, the cannabinoid receptors CB(1) and CB(2) and their endogenous ligands have been found. The involvement of this endogenous cannabinoid signalling system in feeding, appetite, pain perception and immunomodulation could be demonstrated using animal and in vitro studies. Thus, the concern about immunosuppressive effects in humans using medical cannabinoid preparations grew. However, up to now most human studies have failed to demonstrate a well-defined and reproducible immunosuppressive cannabinoid-effect. Only the smoking of marijuana showed a significant local immunosuppression of the bactericidal activity of human alveolar macrophages.In animal studies, cannabinoids were identified as potent modulators of cytokine production, causing a shift from Th1 to Th2 cytokines. In consequence, a compromised cellular immunity was observed in these animals, resulting in enhanced tumor growth and reduced immunity to viral infections. In vitro, immunosuppressive effects were shown in all immune cells, but only at high micromolar cannabinoid concentrations not reached under normal clinical conditions. In conclusion, there is no evidence that cannabinoids induce a serious, relevant immunosuppression in humans, with the exception of marijuana-smoking which may affect local broncho-alveolar immunity.     

Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation

Synthetic cannabinoids have been popular recreational drugs of abuse for their psychoactive properties. Five of the many synthetic cannabinoids have been recently banned in the United States because of their unknown and potentially harmful adverse effects. Little is known about these substances. They are thought to have natural cannabinoid-like effects but have different chemical structures. Adverse effects related to synthetic cannabinoids are not well known. We provide clinical effects and patient outcome following K9 use. In addition, we briefly review synthetic cannabinoids. We present a 17-year-old adolescent boy with chest pain, tachycardia, and then bradycardia associated with smoking K9. Two synthetic cannabinoids, JWH-018 and JWH-073, were confirmed on laboratory analysis. In addition to the limited current data, we demonstrate harmful adverse effects related to toxicity of 2 synthetic cannabinoids. Further studies are needed.     

Using cannabinoids in pain and palliative care

Interest in the use of cannabinoids in a clinical setting is gradually increasing, particularly in patients where more conventional treatments have failed. They have been reported as offering perceived benefits in a wide range of conditions, but the major interest at present is centred on their place in pain management and in the palliation of symptoms secondary to terminal cancer and neurological disease. The potential benefits include symptomatic relief for patients suffering from intractable neuropathic pain, anorexia, anxiety and muscle spasm. There is clear consensus that cannibinoids should not be used as a first-line monotherapy, but should be considered as valuable adjuvants to more commonly indicated therapeutic options in the management of palliative care patients. Scientific evidence documenting the benefits of the canibinoids nabilone and sativex is accumulating, but needs to be evaluated carefully in the light of the paucity of available data. Both drugs are usually used under the guidance of specialist units. Nabilone and Sativex are now controlled drugs, and are frequently used outside of their licensed indication (control of chemotherapy-induced nausea and vomiting) and hence particular care needs to be taken in evaluating the rational for their use. Sativex has been recently licenced for use in the management of patients with multiple sclerosis.     

Cannabinoids and multiple sclerosis

There is a growing amount of evidence to suggest that cannabis and individual cannabinoids may be effective in suppressing certain symptoms of multiple sclerosis and spinal cord injury, including spasticity and pain. Anecdotal evidence is to be found in newspaper reports and also in responses to questionnaires. Clinical evidence comes from trials, albeit with rather small numbers of patients. These trials have shown that cannabis, Delta(9)-tetrahydrocannabinol, and nabilone can produce objective and/or subjective relief from spasticity, pain, tremor, and nocturia in patients with multiple sclerosis (8 trials) or spinal cord injury (1 trial). The clinical evidence is supported by results from experiments with animal models of multiple sclerosis. Some of these experiments, performed with mice with chronic relapsing experimental allergic encephalomyelitis (CREAE), have provided strong evidence that cannabinoid-induced reductions in tremor and spasticity are mediated by cannabinoid receptors, both CB(1) and CB(2). Endocannabinoid concentrations are elevated in the brains and spinal cords of CREAE mice with spasticity, and in line with this observation, spasticity exhibited by CREAE mice can be ameliorated by inhibitors of endocannabinoid membrane transport or enzymic hydrolysis. Research is now needed to establish whether increased endocannabinoid production occurs in multiple sclerosis. Future research should also be directed at obtaining more conclusive evidence about the efficacy of cannabis or individual cannabinoids against the signs and symptoms of these disorders, at devising better modes of administration for cannabinoids and at exploring strategies that maximize separation between the sought-after therapeutic effects and the unwanted effects of these drugs.     

Cannabinoids modulate pain by multiple mechanisms of action

Historically, the evidence for cannabinoids acting as analgesics has been mostly anecdotal. Recently, studies utilizing animal models have indicated that cannabinoids produce antinociception and antihyperalgesia by acting at peripheral, spinal, and supraspinal sites to inhibit mast cell degranulation, primary afferent activity, and responses of nociceptive neurons. Additionally, a number of studies indicate that the cannabinoid system tonically regulates nociceptive thresholds, raising the possibility that hypoactivity of the cannabinoid system produces or prolongs hyperalgesia and chronic pain. Other studies have indicated that inactive doses of cannabinoids potentiate the antinociceptive effects of opioids. Collectively, these studies suggest that administration of peripherally selective cannabinoids, enhancement of endogenous cannabinoid activity, and coadministration of inactive doses of cannabinoids with other analgesics, such as morphine, may prove therapeutically beneficial and may also provide ways to separate the analgesic effects of cannabinoids from their side effects.     

Wirksamkeit,Verträglichkeit und Sicherheit von Cannabinoiden bei neuropathischen Schmerzsyndromen

Background

Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain.

Material and methods

A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30?% or 50?% reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool.

Results

We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2? with nabilone and 1? with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95?% confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD ??0.10 (95?% CI ??0.20– ??0.00, p?=?0.05, 13 studies with 1565 participants), in the frequency of at least a 30?% reduction in pain with an RD of 0.10 [95?% CI 0.03–0.16, p?=?0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95?% CI 8–45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95?% CI 0.01–0.17, p?=?0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50?% reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95?% CI 0.01–0.07, p?=?0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95?% CI 13–37], reported central nervous system side effects more frequently with an RD of 0.38 (95?% CI 0.18–0.58, p?=?0.0003, 9 studies with 1304 participants, NNTH 3, 95?% CI 2–4) and psychiatric side effects with an RD of 0.11 (95?% CI 0.06–0.16, p?<?0.0001, 9 studies with 1304 participants, NNTH 8, 95?% CI 7–12).

Conclusion

Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

     

Cannabinoids

Controversy is associated with the issue of cannabis and cannabinoids in clinical care in the United States. Recent research has demonstrated the underlying mechanisms of cannabinoid analgesia via endocannabinoids, an endogenous system of retrograde neuromodulatory messengers that work in tandem with endogenous opioids. Additional receptor and non-receptor mechanisms of cannabinoid drugs have pertinent activity, including anti-carcinogenesis and neuroprotection, that may be of key importance in aging and terminal patient populations. The results of clinical trials with synthetic and plant-based cannabinoids suggest that the role of formulation and delivery system is critical in optimizing the risk-benefit profile of cannabinoid products. Synergy between opioids and cannabinoids may produce opioidsparing effects, as well as extend the duration of analgesia and reduce opioid tolerance and dependence. This article reviews the mechanism of action of cannabinoids, examines marketed agents and those in clinical trials, and addresses their role in treatment of chronic pain, cancer, neurodegenerative diseases, and HIV/ AIDS. The ability of cannabinoid medicines to treat pain, associated sleep disorders, appetite loss, muscle spasm and a wide variety of other symptoms suggests that such agents may in the future play an important role in palliative care.     

Nabilone for the treatment of pain in fibromyalgia.

A randomized, double-blind, placebo-controlled trial was conducted to determine the benefit of nabilone in pain management and quality of life improvement in 40 patients with fibromyalgia. After a baseline assessment, subjects were titrated up on nabilone, from 0.5 mg PO at bedtime to 1 mg BID over 4 weeks or received a corresponding placebo. At the 2- and 4-week visits, the primary outcome measure, visual analog scale (VAS) for pain, and the secondary outcome measures, number of tender points, the average tender point pain threshold, and the Fibromyalgia Impact Questionnaire (FIQ), were evaluated. After a 4-week washout period, subjects returned for reassessment of the outcome measures. There were no significant differences in population demographics between groups at baseline. There were significant decreases in the VAS (-2.04, P < .02), FIQ (-12.07, P < .02), and anxiety (-1.67, P < .02) in the nabilone treated group at 4 weeks. There were no significant improvements in the placebo group. The treatment group experienced more side effects per person at 2 and 4 weeks (1.58, P < .02 and 1.54, P < .05), respectively. Nabilone appears to be a beneficial, well-tolerated treatment option for fibromyalgia patients, with significant benefits in pain relief and functional improvement. PERSPECTIVE: To our knowledge, this is the first randomized, controlled trial to assess the benefit of nabilone, a synthetic cannabinoid, on pain reduction and quality of life improvement in patients with fibromyalgia. As nabilone improved symptoms and was well-tolerated, it may be a useful adjunct for pain management in fibromyalgia.     

Cannabinoids:their role in pain and palliation

Controversy is associated with the issue of cannabis and cannabinoids in clinical care in the United States. Recent research has demonstrated the underlying mechanisms of cannabinoid analgesia via endocannabinoids, an endogenous system of retrograde neuromodulatory messengers that work in tandem with endogenous opioids. Additional receptor and non-receptor mechanisms of cannabinoid drugs have pertinent activity, including anti-carcinogenesis and neuroprotection, that may be of key importance in aging and terminal patient populations. The results of clinical trials with synthetic and plant-based cannabinoids suggest that the role of formulation and delivery system is critical in optimizing the risk-benefit profile of cannabinoid products. Synergy between opioids and cannabinoids may produce opioid-sparing effects, as well as extend the duration of analgesia and reduce opioid tolerance and dependence. This article reviews the mechanism of action of cannabinoids, examines marketed agents and those in clinical trials, and addresses their role in treatment of chronic pain, cancer, neurodegenerative diseases, and HIV/ AIDS. The ability of cannabinoid medicines to treat pain, associated sleep disorders, appetite loss, muscle spasm and a wide variety of other symptoms suggests that such agents may in the future play an important role in palliative care.