Cannabinoids in the management of difficult to treat pain Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. [Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosis--secondary publication]. Are oral cannabinoids safe and effective in refractory neuropathic pain? A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. Cannabinoid–Opioid Interaction in Chronic Pain Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Initial experiences with medicinal extracts of cannabis for chronic pain: Results from 34 ‘N of 1’ studies Randomized Placebo-Controlled Double-Blind Clinical Trial of Cannabis-Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. Analgesic effect of delta-9-tetrahydrocannabinol. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain The Subjective Psychoactive Effects of Oral Dronabinol Studied in a Randomized, Controlled Crossover Clinical Trial for Pain An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.
This article review s recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms , as well as r and omized clinical trials employing cannabinoids in pain treatment .  Tetrahydrocannabinol ( THC , Marinol ® ) and nabilone ( Cesamet ® ) are currently approved in the United States and other countries , but not for pain indications . Other synthetic cannabinoids , such as ajulemic acid , are in development . Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation . Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC ( partial CB1 receptor agonist ) and cannabidiol ( CBD , a non-euphoriant , anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects ) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis , and in 2007 for intractable cancer pain . Numerous r and omized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain , rheumatoid arthritis and cancer pain . An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006 . Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles . Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise CONTEXT 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid ( CT-3 ) , a potent analog of THC-11-oic acid , produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids . Therefore , CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain . OBJECTIVE To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans . DESIGN AND SETTING R and omized , placebo-controlled , double-blind crossover trial conducted in Germany from May-September 2002 . PARTICIPANTS Twenty-one patients ( 8 women and 13 men ) aged 29 to 65 years ( mean , 51 years ) who had a clinical presentation and examination consistent with chronic neuropathic pain ( for at least 6 months ) with hyperalgesia ( n = 21 ) and allodynia ( n = 7 ) . INTERVENTIONS Patients were r and omized to two 7-day treatment orders in a crossover design . Two daily doses of CT-3 ( four 10-mg capsules per day ) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days . After a washout and baseline period of 1 week each , patients crossed over to the second 7-day treatment period . MAIN OUTCOME MEASURES Visual analog scale ( VAS ) and verbal rating scale scores for pain ; vital sign , hematologic and blood chemistry , and electrocardiogram measurements ; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale ; and adverse effects . RESULTS The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence ( mean [ SD ] , -11.54 [ 14.16 ] vs 9.86 [ 21.43 ] ; P = .02 ) . Eight hours after intake of the drug , the pain scale differences between groups were less marked . No dose response was observed . Adverse effects , mainly transient dry mouth and tiredness , were reported significantly more often during CT-3 treatment ( mean [ SD ] difference , -0.67 [ 0.50 ] for CT-3-placebo sequence vs 0.10 [ 0.74 ] for placebo-CT-3 sequence ; P = .02 ) . There were no significant differences with respect to vital signs , blood tests , electrocardiogram , Trail-Making Test , and Addiction Research Center Inventory-Marijuana scale . No carryover or period effects were observed except on the Trail-Making Test . CONCLUSIONS In this preliminary study , CT-3 was effective in reducing  chronic neuropathic pain  compared with placebo . No major adverse effects were observed Cannabinoids reduce allodynia/hyperalgesia in animal pain models , but few clinical studies evaluated the analgesic action in humans . We aim ed to evaluate the effect of delta-9-tetrahydrocannabinol ( dronabinol ) on central pain in MS patients . Twenty-four MS patients participated in a double-blind placebo-controlled crossover trial . Dronabinol reduced the spontaneous pain intensity significantly compared with placebo ( 4.0 ( 2.3 - 6.0 ) vs. 5.0 ( 4.0 - 6.4 ) , median ( 25th-75th percentiles ) , p = 0.02 ) . Though dronabinol 's analgesic effect is modest , its use should be evaluated considering the general difficulty in treating central pain Although cannabinoids have anti‐hyperalgesic effects in animal models of nerve injury , there are currently very few prospect i ve trials of the efficacy of cannabinoids in neuropathic pain in humans . This open label prospect i ve study investigated the safety , tolerability and analgesic benefit of oral Δ‐9‐tetrahydrocannabinol ( THC ) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain .  Spontaneous ongoing and paroxysmal pain , allodynia and paresthesias were assessed . The sensory and affective components of pain using the McGill pain question naire , quality of life , mood , anxiety and functionality were also evaluated . Seven patients suffered from  side effects  necessitating premature arrest of the drug in 5 of them . THC ( mean dosage : 16.6 ± 6.5 mg/day ) did not induce any significant effects on ongoing and paroxysmal pain , allodynia , quality of life , anxiety/depression scores and functional impact of pain . These results do not support an overall benefit  of  THC in pain and quality of life in patients with refractory neuropathic pain UNLABELLED The Food and Drug Administration ( FDA ) , Substance Abuse and Mental Health Services Administration ( SAMHSA ) , and the National Institute for Drug Abuse ( NIDA ) report that no sound scientific studies support the medicinal use of cannabis . Despite this lack of scientific validation , many patients routinely use " medical marijuana , " and in many cases this use is for pain related to nerve injury . We conducted a double-blinded , placebo-controlled , crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain . Thirty-eight patients with central and peripheral neuropathic pain underwent a st and ardized procedure for smoking either high-dose ( 7 % ) , low-dose ( 3.5 % ) , or placebo cannabis . In addition to the primary outcome of pain intensity , secondary outcome measures included evoked pain using heat-pain threshold , sensitivity to light touch , psychoactive side effects , and neuropsychological performance . A mixed linear model demonstrated an analgesic response to smoking cannabis . No effect on evoked pain was seen . Psychoactive effects were minimal and well-tolerated , with some acute cognitive effects , particularly with memory , at higher doses . PERSPECTIVE This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain , and may be an alternative for patients who do not respond to , or can not tolerate , other drugs . However , the use of marijuana as medicine may be limited by its method of administration ( smoking ) and modest acute cognitive effects , particularly at higher doses Cannabinoids and opioids share several pharmacologic properties and may act synergistically . The potential pharmacokinetics and the safety of the combination in humans are unknown . We therefore undertook a study to answer these questions . Twenty – one individuals with chronic pain , on a regimen of twice – daily doses of sustained – release morphine or oxycodone were enrolled in the study and admitted for a 5–day inpatient stay . Participants were asked to inhale vaporized cannabis in the evening of day 1 , three times a day on days 2–4 , and in the morning of day 5 . Blood sampling was performed at 12–h intervals on days 1 and 5 . The extent of chronic pain was also assessed daily . Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration – time curves for either morphine or oxycodone after exposure to cannabis . Pain was significantly decreased ( average 27 % , 95 % confidence interval ( CI ) 9 , 46 ) after the addition of vaporized cannabis . We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels . The combination may allow for opioid treatment at lower doses with fewer side effects UNLABELLED We assessed the efficacy of dronabinol ( Marinol capsules ; Solvay Pharmaceuticals , Brussels , Belgium ) , a synthetic Delta(9)-THC ( tetrahydrocannabinol ) , in 30 patients taking opioids for chronic pain to determine its potential analgesic effects as an adjuvant treatment . Phase I of this 2-phase study was a r and omized , single-dose , double-blinded , placebo-controlled , crossover trial in which subjects were r and omly administered either 10 mg or 20 mg of dronabinol or identical placebo capsules over the course of three , 8-hour visits . Baseline self-report measures , hourly ratings of pain intensity , pain relief , pain bothersomeness , treatment satisfaction , mood , side effects , and blood serum levels were obtained . Phase II was an extended open-label titrated trial of dronabinol as add-on medication to patients on stable doses of opioids . Results of the Phase I study showed that patients who received dronabinol experienced decreased pain intensity and increased satisfaction compared with placebo . No differences in benefit were found between the 20 mg and 10 mg doses . In the Phase II trial , titrated dronabinol contributed to significant relief of pain , reduced pain bothersomeness , and increased satisfaction compared with baseline . The incidence of side effects was dose-related . Overall , the use of dronabinol was found to result in additional analgesia among patients taking opioids for chronic noncancer pain . PERSPECTIVE This study examines the effect of adding a cannabinoid to the regimen of patients with chronic pain who report significant pain despite taking stable doses of opioids . The results of our preliminary study suggest that dronabinol , a synthetic THC , may have an additive effect on pain relief Evidence for an analgesic interaction between delta-9-tetrahydrocannabinol ( Delta(9)-THC ) and morphine was sought using an experimental pain model applied to normal volunteers . The study incorporated a double blinded , four treatment , four period , four sequence , crossover design . Subjects received Delta(9)-THC 5 mg orally or placebo and 90 min later morphine 0.02 mg/kg intravenously or placebo . Fifteen minutes later subjects rated the pain associated with the application of thermal stimuli to skin using two visual analog scales , one for the sensory and one for the affective aspects of pain . Among sensory responses , neither morphine nor Delta(9)-THC had a significant effect at the doses used , and there was no significant interaction between the two . Among affective responses , although neither morphine nor Delta(9)-THC had a significant effect , there was a positive analgesic interaction between the two ( p = 0.012 ) , indicating that the combination had a synergistic affective analgesic effect . The surprisingly limited reported experimental experience in humans does not support a role for Delta(9)-THC as an analgesic or as an adjunct to cannabinoid analgesia , except for our finding of synergy limited to the affective component of pain . Comparison of our results with those of others suggests that extrapolation from experimental pain models to the clinic is not likely to be a straight-forward process . Future studies of Delta(9)-THC or other cannabinoids in combination with opiates should focus upon clinical rather than experimental pain Three Cannabis Based Medicinal Extracts ( CBMEs ) for sublingual use became available in 2000 . A total of 34 ‘ N of 1 ’ studies were undertaken using this novel therapy for patients with chronic , mainly neuropathic , pain and associated symptoms to explore efficacy , tolerability , safety and dosages . Three CBMEs ( Δ9 Tetrahydrocannabinol ( THC ) , Cannabidiol ( CBD ) and a 1 : 1 mixture of them both ) were given over a 12‐week period . After an initial open‐label period , the CBMEs were used in a r and omised , double‐blind , placebo controlled , crossover trial . Extracts which contained THC proved most effective in symptom control . Regimens for the use of the sublingual spray emerged and a wide range of dosing requirements was observed . Side‐effects were common , reflecting a learning curve for both patient and study team . These were generally acceptable and little different to those seen when other psycho‐active agents are used for chronic pain . These initial experiences with CBME open the way to more detailed and extensive studies OBJECTIVE To assess the efficacy of Sativex , a cannabis-based medicinal extract , as adjuvant treatment in painful diabetic peripheral neuropathy ( DPN ) . RESEARCH DESIGN AND METHODS In this r and omized controlled trial , 30 subjects with painful DPN received daily Sativex or placebo . The primary outcome measure was change in mean daily pain scores , and secondary outcome measures included quality -of-life assessment s. RESULTS There was significant improvement in pain scores in both groups , but mean change between groups was not significant . There were no significant differences in secondary outcome measures . Patients with depression had significantly greater baseline pain scores that improved regardless of intervention . CONCLUSIONS This first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN . Depression was a major confounder and may have important implication s for future trials on painful DPN This study compared the efficacy of a tetrahydrocannabinol : cannabidiol ( THC : CBD ) extract , a nonopioid analgesic endocannabinoid system modulator , and a THC extract , with placebo , in relieving pain in patients with advanced cancer . In total , 177 patients with cancer pain , who experienced inadequate analgesia despite chronic opioid dosing , entered a two-week , multicenter , double-blind , r and omized , placebo-controlled , parallel-group trial . Patients were r and omized to THC : CBD extract ( n = 60 ) , THC extract ( n = 58 ) , or placebo ( n = 59 ) . The primary analysis of change from baseline in mean pain Numerical Rating Scale ( NRS ) score was statistically significantly in favor of THC : CBD compared with placebo ( improvement of -1.37 vs. -0.69 ) , whereas the THC group showed a nonsignificant change ( -1.01 vs. -0.69 ) . Twice as many patients taking THC : CBD showed a reduction of more than 30 % from baseline pain NRS score when compared with placebo ( 23 [ 43 % ] vs. 12 [ 21 % ] ) . The associated odds ratio was statistically significant , whereas the number of THC group responders was similar to placebo ( 12 [ 23 % ] vs. 12 [ 21 % ] ) and did not reach statistical significance . There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups . No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment . However , the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Question naire showed a worsening in nausea and vomiting with THC : CBD compared with placebo ( P = 0.02 ) , whereas THC had no difference ( P = 1.0 ) . Most drug-related adverse events were mild/moderate in severity . This study shows that THC : CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids UNLABELLED A r and omized , double-blinded , placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis . In a crossover design , each participant was exposed to 4 single dosing sessions of placebo or to low ( 1 % tetrahydrocannabinol [ THC ] ) , medium ( 4 % THC ) , or high ( 7 % THC ) doses of cannabis . Baseline spontaneous pain , evoked pain , and cognitive testing were performed . Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective " highness " score was measured at 5 , 15 , 30 , 45 , and 60 minutes and then every 30 minutes for an additional 3 hours . Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours . The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models . There was a significant difference in spontaneous pain scores between doses ( P < .001 ) . Specific significant comparisons were placebo versus low , medium , and high doses ( P = .031 , .04 , and < .001 , respectively ) and high versus low and medium doses ( both P < .001 ) . There was a significant effect of the high dose on foam brush and von Frey evoked pain ( both P < .001 ) . There was a significant negative effect ( impaired performance ) of the high dose on 2 of the 3 neuropsychological tests ( Paced Auditory Serial Addition Test , Trail Making Test Part B. PERSPECTIVE This small , short-term , placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain . This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain A preliminary trial of oral delta-9-tetrahydrocannabinol ( THC ) demonstrated an analgesic effect of the drug in patients experiencing cancer pain .  Placebo and 5 , 10 , 15 , and 20 mg THC were administered double blind to ten patients .  Pain relief significantly superior to placebo was demonstrated at high dose levels ( 15 and 20 mg ) . At these levels , substantial sedation and mental clouding were reported CONTEXT Neuropathic pain caused by chemotherapy limits dosing and duration of potentially life-saving anti-cancer treatment and impairs quality of life . Chemotherapeutic neuropathy responds poorly to conventional treatments , and there is an urgent medical need for new treatments . Recent pre clinical studies demonstrate that cannabinoid agonists suppress established chemotherapy-evoked neuropathy . OBJECTIVES This was a pilot trial to begin to investigate a currently available cannabinoid agent , nabiximols ( oral mucosal spray containing cannabinoids ) , in the treatment of chemotherapy-induced neuropathic pain . METHODS A r and omized , placebo-controlled crossover pilot study was done in 16 patients with established chemotherapy-induced neuropathic pain . A 0 - 10 point numeric rating scale for pain intensity ( NRS-PI ) was used as the primary outcome measure . RESULTS When examining the whole group , there was no statistically significant difference between the treatment and the placebo groups on the NRS-PI . A responder analysis demonstrated that there were five participants who reported a two-point or greater reduction in pain that trended toward statistical significance and the number needed to treat was five . CONCLUSION Chemotherapy-induced neuropathic pain is particularly resistant to currently available treatments . This pilot trial found a number needed to treat of five and an average decrease of 2.6 on an 11-point NRS-PI in five " responders " ( as compared with a decrease of 0.6 with placebo ) and supports that it is worthwhile to study nabiximols in a full r and omized , placebo-controlled trial of chemotherapy-induced neuropathic pain ABSTRACT Background : Chronic pain is common in the United States and prescribed opioid analgesics use for noncancer pain has increased dramatically in the past two decades , possibly accounting for the current opioid addiction epidemic . Co-morbid drug use in those prescribed opioid analgesics is common , but there are few data on polysubstance use patterns . Objective : We explored patterns of use of cigarette , alcohol , and illicit drugs in HIV-infected people with chronic pain who were prescribed opioid analgesics .  Methods : We conducted a secondary data analysis of screening interviews conducted as part of a parent r and omized trial of financial incentives to improve HIV outcomes among drug users . In a convenience sample of people with HIV and chronic pain , we collected self-report data on demographic characteristics ; pain ; patterns of opioid analgesic use  ( both prescribed and illicit ) ; cigarette , alcohol , and illicit drug use ( including cannabis , heroin , and cocaine ) within the past 30 days ; and current treatment for drug use and HIV . Results : Almost half of the sample of people with HIV and chronic pain reported current prescribed opioid analgesic use ( N = 372 , 47.1 % ) . Illicit drug use was common ( N = 505 , 63.9 % ) , and cannabis was the most commonly used illicit substance ( N = 311 , 39.4 % ) . In multivariate analyses , only cannabis use was significantly associated with lower odds of prescribed opioid analgesic use ( adjusted odds ratio = 0.57 ; 95 % confidence interval : 0.38–0.87 ) . Conclusions / Importance : Our data suggest that new medical cannabis legislation might reduce the need for opioid analgesics for pain management , which could help to address adverse events associated with opioid analgesic use Background : Many cannabinoid medications are approved in North America or in phase III trials , such as dronabinol , nabilone , or nabiximols . Little is known about their subjective psychoactive effects when used for pain management . We hypothesized that when used for pain , dronabinol has psychoactive effects in a dose-response relationship , whose peak effects are comparable with smoking marijuana . Methods : This was a r and omized controlled trial of single dose placebo , 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana . Participants completed the Addiction Research Center Inventory ( ARCI ) hourly for 8 hours during 3 monitored sessions . Comparison sample was the ARCI ratings in participants with no pain ( N=20 ) , monitored every 30 minutes after smoking a 1.99 % THC ( low ) and a 3.51 % ( high strength ) marijuana cigarette . Results : The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo ( P<0.05 ) . Average daily morphine use , total pain relief ( TOTPAR ) , age , sex , and baseline pain level were not significant covariates . ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes ( P=0.80 , 10 mg = low strength , 20 mg = high strength ) . Conclusions : In pain patients , oral dronabinol has similar psychoactive effects to smoking marijuana . This risk must be considered in any decision to prescribe cannabinoid medications for pain CONTEXT Chronic pain in patients with advanced cancer poses a serious clinical challenge . The Δ9-tetrahydrocannabinol (THC)/cannabidiol ( CBD ) oromucosal spray ( U.S. Adopted Name , nabiximols ; Sativex ( ® ) ) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group . OBJECTIVES This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer . METHODS In total , 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing , who had participated in a previous three-arm ( THC/CBD spray , THC spray , or placebo ) , two-week parent r and omized controlled trial , entered this open-label , multicenter , follow-up study . Patients self-titrated THC/CBD spray ( n=39 ) or THC spray ( n=4 ) to symptom relief or maximum dose and were regularly review ed for safety , tolerability , and evidence of clinical benefit . RESULTS The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for " pain severity " and " worst pain " domains showed a decrease ( i.e. , improvement ) at each visit in the THC/CBD spray patients . Similarly , the European Organization for Research and Treatment of Cancer Quality of Life Question naire-C30 scores showed a decrease ( i.e. , improvement ) from baseline in the domains of insomnia , pain , and fatigue . No new safety concerns associated with the extended use of THC/CBD spray arose from this study . CONCLUSION This study showed that the long-term use of THC/CBD spray was generally well tolerated , with no evidence of a loss of effect for the relief of cancer-related pain with long-term use . Furthermore , patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time , suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit
Conclusions and Relevance Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced ; instead , cannabinoids may make experimental pain feel less unpleasant and more tolerable , suggesting an influence on affective processes .
Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain
Importance Cannabinoid drugs are widely used as analgesics , but experimental pain studies have produced mixed findings .
The analgesic properties of cannabinoids remain unclear .
Objective To conduct a systematic review and meta- analysis of the association between cannabinoid drug administration and experimental pain outcomes in studies of healthy adults .