Cannabinoids in the management of difficult to treat pain Efficacy, tolerability and safety of cannabis‐based medicines for chronic pain management – An overview of systematic reviews Long-term opioid use in non-cancer pain. Are oral cannabinoids safe and effective in refractory neuropathic 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. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study Open-Label, Add-on Study of Tetrahydrocannabinol for Chronic Nonmalignant Pain Cannabinoid–Opioid Interaction in Chronic Pain Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. Systemic local‐anaesthetic‐type drugs in chronic pain: A systematic review [Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosis--secondary publication]. Chronic pelvic pain in women A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Opioids for chronic non-cancer pain Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo‐controlled Study Reporting of Sex Effects by Systematic Reviews on Interventions for Depression, Diabetes, and Chronic Pain Cannabis in painful HIV-associated sensory neuropathy Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Bias in randomised controlled trials: comparison of crossover group and parallel group designs The Effectiveness of Psychosocial Interventions as Adjuncts to Orthopaedic Surgery: A Systematic Review Protocol
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 Medicinal cannabis has already entered mainstream medicine in some countries . This systematic review ( SR ) aim ed at evaluating the efficacy , acceptability and safety of cannabis-based medicines for chronic pain management . Qualitative systematic review of SRs of r and omized controlled trials with cannabis-based medicines for chronic pain management . The Cochrane data bases of SRs , Data base of Abstract s of Review s of Effects and PubMed were search ed for SR published in the period January 2009 to January 2017 . Assessment of the method ological quality of SR was performed by the AMSTAR checklist . Out of 748 papers identified , 10 SRs met the inclusion criteria . The method ological quality was high in four and moderate in six SRs . There were inconsistent findings of four SRs on the efficacy of cannabis-based medicines in neuropathic pain and of one SR for painful spasms in multiple sclerosis . There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain management in patients with rheumatic diseases ( three SRs ) and in cancer pain ( two SRs ) . Cannabis-based medicines undoubtedly enrich the possibilities of drug treatment of chronic pain conditions . It remains the responsibility of the health care community to continue to pursue rigorous study of cannabis-based medicines to provide evidence that meets the st and ard of 21st century clinical care . SIGNIFICANCE We provide an overview of systematic review s on the efficacy , tolerability and safety of cannabis-based medicines for chronic pain management . There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis . There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain BACKGROUND The long-term use of opioid analgesic drugs to treat chronic non-cancer pain ( CNCP ) is a major component of pain pharmacotherapy . The interpretation of the evidence concerning its efficacy and risks is currently debated . METHODS An interdisciplinary evidence - and consensus-based S3 guideline was up date d on the basis of a systematic literature search ( CENTRAL , Medline , and Scopus data bases , from October 2008 to October 2013 ) ; meta-analyses of r and omized controlled trials ( ≥ 4 weeks ) ; and a consensus procedure , as specified by the AWMF regulations , including 22 medical and psychological societies and 2 patient self-help organizations . RESULTS 119 publications were used to up date the guideline , and 6 systematic review s with meta-analyses were performed . A nominal group process was used to formulate recommendations concerning the indications and contraindications for the treatment of CNCP with opioid analgesics and the manner in which such treatments should be carried out . Opioid analgesics are an option for the short-term treatment ( 4 - 12 weeks ) of chronic pain due to osteoarthritis ( pain intensity , st and ardized mean difference [ SMD ] : -0.22 and -0.26 ) , diabetic polyneuropathy ( SMD -0.74 ) , post-herpetic neuralgia ( SMD -0.58 ) , and chronic low back pain ( SMD : -0.29 and -0.74 ) . Long-term opioid treatment ( ≥ 26 weeks ) for these diseases benefits only about 25 % of patients . For other conditions , either short- or long-term treatment with opioid analgesics should be considered an individual therapeutic trial . Opioid treatment for pain is contraindicated by primary headaches and by any functional or mental disorder of which pain is a leading manifestation . CONCLUSION To minimize the risks of opioid analgesic treatment , physicians must be aware of its contraindications and must regularly reassess its efficacy and side effects . Pharmacotherapy should be combined with other types of treatment 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 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 UNLABELLED Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge . Nabiximols ( Nabiximols is the U.S. Adopted Name [ USAN ] for Sativex [ GW Pharma Ltd , Wiltshire , U.K. ] , which does not yet have an INN ) , a novel cannabinoid formulation , is undergoing investigation as add-on therapy for this population . In a r and omized , double-blind , placebo-controlled , grade d-dose study , patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose ( 1 - 4 sprays/day ) , medium dose ( 6 - 10 sprays/day ) , or high dose ( 11 - 16 sprays/day ) . Average pain , worst pain and sleep disruption were measured daily during 5 weeks of treatment ; other question naires measured quality of life and mood .  A total of 360 patients were r and omized ; 263 completed . There were no baseline differences across groups . The 30 % responder rate primary analysis was not significant for nabiximols versus placebo ( overall P = .59 ) . A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall ( P = .035 ) , and specifically in the low-dose ( P = .008 ) and medium-dose ( P = .039 ) groups . In the low-dose group , results were similar for mean average pain ( P = .006 ) , mean worst pain ( P = .011 ) , and mean sleep disruption ( P = .003 ) . Other question naires showed no significant group differences . Adverse events were dose-related and only the high-dose group compared unfavorably with placebo . This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials . PERSPECTIVE Nabiximols , a novel cannabinoid formulation , may be a useful add-on analgesic for patients with opioid-refractory cancer pain . A r and omized , double-blind , placebo-controlled , grade d-dose study demonstrated efficacy and safety at low and medium doses Neuropathic pain ( NeP ) , generated by disorders of the peripheral and central nervous system , can be particularly severe and disabling . Prevalence estimates indicate that 2 % to 3 % of the population in the developed world suffer from NeP , which suggests that up to one million Canadians have this disabling condition . Evidence -based guidelines for the pharmacological management of NeP are therefore urgently needed . R and omized , controlled trials , systematic review s and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting . Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one method ologically sound , r and omized , controlled trial showing significant benefit relative to placebo or another relevant control group . Recommendations for treatment are based on degree of evidence of analgesic efficacy , safety , ease of use and cost-effectiveness .  Analgesic agents recommended for first-line treatments are certain antidepressants ( tricyclics ) and anticonvulsants ( gabapentin and pregabalin ) . Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine . Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain . Recommended fourth-line treatments include cannabinoids , methadone and anticonvulsants with lesser evidence of efficacy , such as lamotrigine , topiramate and valproic acid . Treatment must be individualized for each patient based on efficacy , side-effect profile and drug accessibility , including cost . Further studies are required to examine head-to-head comparisons among analgesics , combinations of analgesics , long-term outcomes , and treatment of pediatric and central Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain . Design R and omised , double blind , crossover trial of 14 weeks ’ duration comparing dihydrocodeine and nabilone . Setting Outpatient units of three hospitals in the United Kingdom . Participants 96 patients with chronic neuropathic pain , aged 23 - 84 years . Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain , as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period . Secondary outcomes were changes in mood , quality of life , sleep , and psychometric function . Side effects were measured by a question naire . Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks . Treatment periods were separated by a 2 week washout period . Results Mean baseline visual analogue score was 69.6 mm ( range 29.4 - 95.2 ) on a 0 - 100 mm scale . 73 patients were included in the available case analysis and 64 patients in the per protocol analysis . The mean score was 6.0 mm longer for nabilone than for dihydrocodeine ( 95 % confidence interval 1.4 to 10.5 ) in the available case analysis and 5.6 mm ( 10.3 to 0.8 ) in the per protocol analysis . Side effects were more frequent with nabilone . Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects , although no major adverse events occurred for either drug . Trial registration Current Controlled Trials IS RCT N15330757 Cannabinoids have been used for pain relief for centuries and recent studies have investigated their analgesic and anti-inflammatory mechanisms , as well as clinical efficacy , in treating chronic pain . We report an open-label study addressed to evaluate the effect and adverse events of orally administered Δ -9-tetrahydrocannabinol ( Δ -9-THC ) in 13 patients with chronic nonmalignant pain ( CNMP ) unresponsive to conventional pharmacotherapy . The effect of the treatment was assessed on an eight-item HRQoL question naire . Five out of 13 patients reported adequate response to the treatment while eight patients reported inadequate or no response . Seven patients did not experience any adverse events ( AEs ) , six patients reported AEs , two of which discontinued the treatment . We conclude that oral THC may be a valuable therapeutic option for selected patients with CNMP that are unresponsive to previous treatments , though further research is warranted to characterize those patients 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 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 Basic research indicates that systemic local‐anaesthetic‐type drugs that block sodium channels are effective in pain due to nerve damage . These drugs were first used as analgesics in the 1950s and they are still commonly used to try to relieve neuropathic pain and incident pain caused by cancer . As they are potentially toxic , these drugs should not be used without proven effectiveness . For these reasons , a systematic review of r and omized controlled trials of systemically administered local‐anaesthetic‐type drugs in chronic pain was performed . Main outcomes were pain relief or pain intensity difference and adverse effects .  Twenty‐one reports were found , and four publications were excluded . In the remaining 17 studies ( 450 patients ) , 10 used intravenous lignocaine , two used intranasal lignocaine , four used oral mexiletine and one used oral tocainide 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 # # # # Summary points Chronic pelvic pain in women is a debilitating condition that impairs quality of life . Studies using various definitions estimated that its prevalence ranges from 2.1 % to 24 % of the female population worldwide.1 It is a common presentation in UK primary care , with 38 per 1000 women affected annually — a rate comparable to those of asthma ( 37 per 1000 ) and back pain ( 41 per 1000).2 Because pelvic pain is associated with conditions such as endometriosis and interstitial cystitis , a diagnosis is often difficult to establish , leading to a delay in appropriate treatment . Social and psychological factors are strongly associated with chronic pelvic pain , so tailored , effective treatment can be challenging to provide . # # # # Sources and selection criteria We search ed EMBASE and Medline for articles with titles that included the keywords “ chronic pelvic pain ” with the limits “ meta- analysis , review and r and omised controlled trial ” . We restricted the search to articles published in English in the past five years . We identified all systematic review s and trial citations in the Cochrane Library under the MeSH terms pelvic pain and dysmenorrhoea . Articles of interest cited in these papers were identified . Finally we review ed published clinical guidelines from international pain associations and gynaecological societies and search ed the National Guidelines Clearing House . Chronic 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 A 36 year old carpenter has a six month history of lower back pain with no specific clinical or radiological findings . As his pain has not responded to paracetamol and non-steroidal anti-inflammatory drugs ( NSAIDs ) , he asks his doctor if he can have “ stronger painkillers ” such as morphine . Opioids are a group of compounds that act by binding to opioid receptors ( μ , κ , and δ ) , which are widely distributed in the brain , spinal cord , and peripheral tissues . They are the mainstay in the management of cancer pain , but published data show a continual increase in the volume of prescribed opioids to manage moderate to severe , chronic , non-cancer pain.1 2 Changes in attitude and aggressive marketing have driven a dramatic increase in use , with more adverse events , including deaths from overdose ( now the second leading cause of accidental death in the US).3 Proponents cl aim that opioids are underused for chronic pain,4 but lack of good scientific data has prevented the formulation of evidence based guidelines for their use , especially in primary care . Several meta-analyses of the effectiveness of opioids have been published . Most of the r and omised clinical trials summarised in these meta-analyses were funded by the pharmaceutical industry and report heterogeneous , short term outcomes in highly selected patients . Non-r and omised and uncontrolled observational studies make up the rest of the literature . Nevertheless , most studies have consistently shown some effectiveness in chronic non-cancer pain by reducing pain intensity . In particular , meta-analyses show the efficacy of opioids in neuropathic pain,5 6 7 although most guidelines regard opioids only as second or third line treatment for such pain because of their risk : benefit profile.8 9 The data are even less encouraging for chronic non-neuropathic pain , the focus of this paper . A 2009 Cochrane review of 10 r and omised or quasi-r and omised controlled trials compared BACKGROUND & AIMS Delta‐9‐tetrahydrocannabinol ( THC ) is the most abundant cannabinoid from the plant Cannabis sativa . There is only equivocal evidence that THC has analgesic effects . We performed a phase 2 controlled trial to evaluate the analgesic efficacy , pharmacokinetics , safety , and tolerability of an oral tablet containing purified THC in patients with chronic abdominal pain . METHODS Sixty‐five patients with chronic abdominal pain for 3 months or more ( numeric rating scale scores of 3 or more ) after surgery or because of chronic pancreatitis were r and omly assigned to groups given the THC tablet or identical matching placebos for 50–52 days . Subjects in the THC group were given the tablet first in a step‐up phase ( 3 mg 3 times daily for 5 days and then 5 mg 3 times daily for 5 days ) , followed by a stable dose phase ( 8 mg 3 times daily until days 50–52 ) . Preceding and during the entire study period , patients were asked to continue taking their medications ( including analgesics ) according to prescription . Patients reported any additional pain medications in a diary . Efficacy and safety assessment s were conducted preceding medication intake ( day 1 ) , after 15 days , and at 50–52 days . Plasma sample s were collected on study days 1 , 15 , and 50–52 ; mean plasma concentration curves of THC and 11‐OH‐THC were plotted . The primary end point was pain relief , which was measured by a visual analogue scale ( VAS ) of the mean pain ( VAS mean scores ) on the basis of information from patient diaries . Secondary end points included pain and quality of life ( determined from patient question naires ) , pharmacokinetics , and safety . RESULTS At days 50–52 , VAS mean scores did not differ significantly between the THC and placebo groups ( F1,46 = 0.016 ; P = .901 ) . Between the start and end of the study , VAS mean scores decreased by 1.6 points ( 40 % ) in the THC group compared with 1.9 points ( 37 % ) in the placebo group . No differences were observed in secondary outcomes . Oral THC was generally well‐absorbed . Seven patients in the THC group stopped taking the tablets because of adverse events , compared with 2 patients in the placebo group . All ( possibly ) related adverse events were mild or moderate . CONCLUSIONS In a phase 2 study , we found no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain . THC , administered 3 times daily , was safe and well‐tolerated during a 50‐day to 52‐day treatment period . Clinical Trials.gov number : NCT01562483 and NCT01551511 Differences in disease prevalence , clinical manifestations , and health outcomes exist between men and women . Sources for this variation range from biological differentiation at the cellular level to behavioral differences influenced by societal gender norms . Typically , biologically based differences between men and women are called sex differences , whereas gender differences describe health differences related , at least in part , to societal constructs of gender ( 13 ) . For example , biological events unique to women , such as pregnancy and menopause , are probably associated with sex differences in occurrence of certain conditions or in response to some medical therapies ( 48 ) . Gender differences probably exist in health-related perceptions and behaviors for women and men with medical conditions that are prevalent for both sexes ( for example , heart disease and chronic pain ) ( 9 –16 ) . Although sex and gender differences are theoretically distinct , they remain difficult to disentangle when differences between men and women in health outcomes and treatment effectiveness are being examined . For this reason , and for brevity , we hereafter refer to sex and gender differences collectively as sex effects . In the past 2 decades , recognition of the importance of sex effects for health outcomes and treatment heterogeneity has been growing . Beginning in 1993 , the National Institutes of Health has issued policies requiring the inclusion of women and minorities in all clinical research and trial design s with valid analysis of sex effects or differences between racial and ethnic groups ( 17 , 18 ) . Since then , the inclusion of women in clinical trials has increased ( 19 , 20 ) , and sex effects have been identified for medications , such as nicotine replacement therapy , analgesics , and aspirin ( 13 , 14 , 21 ) . Recently , sex effects in adverse reactions led to sex-specific dosage recommendations for a widely used sedative ( 7 ) . Despite this progress , representation of women in clinical studies remains inadequate for many conditions ( 22 ) . Further , published clinical trials infrequently report sex effects or discuss the appropriateness of sex-specific analyses ( 19 , 20 , 23 ) . To advance the clinical evidence base and improve health outcomes for women , clinical research must include adequate numbers of women , appropriately conduct sex-specific analyses , and consistently report sex effects . Systematic review s ( SRs ) are a key source of information for clinicians , research ers , and guideline panels . By synthesizing the overall body of evidence for key clinical and research questions , SRs could potentially make a unique contribution to the evaluation of sex effects . To our knowledge , however , the reporting of sex effects by SRs has not been previously examined . Here , we use evidence mapping to systematic ally evaluate the reporting of sex effects by SRs examining a diverse set of interventions for chronic conditions common to women ( that is , depression , diabetes , and chronic pain ) . Evidence mapping is an emerging approach that describes key characteristics of studies for a broad area of medicine ( 2426 ) . Our evidence map addresses the volume and characteristics of eligible SRs , including the representation of women in primary studies , whether and how review s reported sex effects , and findings about sex effects . Methods This work was part of a larger report for the Veterans Health Administration ( VHA ) Evidence -based Synthesis Program ( ESP ) . The complete technical report is available online ( www.hsrd . research .va.gov/publications/esp ) and includes additional information on our methods . We focused on SRs to determine the reporting of sex effects , provide high-level information about the volume of current clinical evidence , and summarize information about actual sex effects . Prioritization of Conditions for Inclusion We used forced-ranking prioritization ( 27 ) with our VHA stakeholders to determine our conditions of interest . These stakeholders included representatives from the Health Services Research & Development Center for the Study of Healthcare Innovation , Implementation and Policy ; Health Services Research & Development Women 's Health Research Network ; Women 's Health Research in the Office of Research & Development ; Women 's Health Services ; and Mental Health Services . We initially selected 34 conditions ( Appendix Table 1 ) based on disease prevalence in women , disease burden in women , availability and breadth of effective treatments for men or women , and women veterans ' priorities for gender-specific care . Stakeholders ranked this initial set of conditions , discussed the rankings , and reranked conditions that initially received intermediate priority rankings . After 2 rounds of iterative prioritization , the following conditions were selected : depressive disorders , type 2 diabetes mellitus , and chronic pain ( that is , chronic low back pain , fibromyalgia , and chronic knee pain due to osteoarthritis ) . Appendix Table 1 . Conditions Presented to Stakeholders for Prioritization * Data Sources and Search es In collaboration with an expert reference librarian , we search ed PubMed and Cochrane Data base of Systematic Review s to identify eligible SRs published after 1 October 2009 through 31 October 2014 for depression , 13 February 2015 for diabetes , and 27 February 2015 for chronic pain . Search strategies used Medical Subject Headings and free-text terms for the conditions of interest , eligible interventions , and SRs ( Appendix Table 2 ) . We restricted the search to the past 6 years because SRs are typically out date d within 5 years of publication ( 28 ) , and our goal was to describe the current state of the clinical literature . In addition to electronic search ing , we screened published review s of review s for eligible articles . Appendix Table 2 . Search Strategies Study Selection and Quality Assessment Eligible SRs evaluated interventions in several broad categories ( that is , medications , behavioral interventions , supervised exercise , and quality improvement or organizational interventions ) . We also included condition-specific interventions , such as bariatric surgery for diabetes . Review s that evaluated mixed conditions or multiple interventions must have reported results separately for at least 1 eligible condition or intervention . We included review s of interventions in any setting , with any type of active or inactive comparator , and with any duration of follow-up . Detailed inclusion and exclusion criteria are provided in Appendix Table 3 . Appendix Table 3 . Detailed Inclusion and Exclusion Criteria for Review Eligibility Two investigators screened citations for eligibility , and citations that were considered to be relevant by either person were retained for full-text review . Full-text articles were review ed by 2 investigators , and disagreements were resolved through discussion or adjudicated by a third person . Formal assessment of review quality was beyond the scope of this project . However , we noted whether review s originated from organizations known for high- quality review s ( that is , Cochrane Collaboration , Agency for Healthcare Research and Quality Evidence -based Practice Centers , and VHA ESP ) . For review s reporting sex effects , we also assessed industry funding and whether statistical power was considered . Data Abstract ion Data were abstract ed by 1 investigator and review ed by a second person . Disagreements were resolved by discussion or by a third review er . Abstract ed data included the analysis method ( that is , qualitative synthesis , meta- analysis , network meta- analysis , or individual-patient data [ IPD ] meta- analysis ) ; clinical conditions ; interventions ; main outcomes ; number and design of primary studies ( for example , r and omized , controlled trials [ RCTs ] or observational cohorts ) ; proportion of women in the included primary studies ; and if sex effects were part of the study aims , analysis plan , or results . For review s reporting sex effects , we also recorded the number of primary studies used for sex-specific analyses , effect estimates , and the method used ( for example , metaregression , subgroup analysis , or IPD meta- analysis ) . All eligible review s on depressive disorders and chronic pain conditions were fully abstract ed . All diabetes review s of nonpharmacologic interventions were also fully abstract ed . For eligible diabetes medication review s ( n= 120 ) , we applied an additional prioritization procedure before full abstract ion . We prioritized review s that examined multiple classes of medications or evaluated a single class of medications when 6 or fewer eligible review s were identified . For SRs evaluating a single class ( > 6 eligible review s were identified ) , we used additional prioritization criteria ( for example , the most recent review published in a high-impact journal or work done by an organization known for high- quality review s ) . The remaining unselected but eligible review s ( n= 58 ) had a keyword text search for sex effects and were fully abstract ed only when this search yielded positive results ( n= 13 ) . Data Synthesis and Analysis of SRs We grouped eligible review s by intervention category and described the overall volume of clinical literature for interventions addressing each condition of interest . We also determined the number of review s reporting sex effects and summarized these results . Time trends for the proportion of these review s were examined for depression and diabetes . Examination of Primary RCTs for Selected Interventions We anticipated that some interventions for each condition would have few or no eligible SRs that addressed sex effects . Thus , for a subset of interventions for each condition , we evaluated primary RCTs to determine the feasibility of conducting a future review to evaluate sex effects . Specifically , we examined  quality improvement interventions and psychotherapy for depression ; diet , physical activity , and culturally tailored psychoeducation for diabetes ; behavioral interventions for chronic low back pain ; and exercise interventions Objective : To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model . Methods : Prospect i ve r and omized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy . Patients were r and omly assigned to smoke either cannabis ( 3.56 % tetrahydrocannabinol ) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days . Primary outcome measures included ratings of chronic pain and the percentage achieving > 30 % reduction in pain intensity . Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model . Results : Fifty patients completed the entire trial . Smoked cannabis reduced daily pain by 34 % ( median reduction ; IQR = −71 , −16 ) vs 17 % ( IQR = −29 , 8) with placebo ( p = 0.03 ) . Greater than 30 % reduction in pain was reported by 52 % in the cannabis group and by 24 % in the placebo group ( p = 0.04 ) . The first cannabis cigarette reduced chronic pain by a median of 72 % vs 15 % with placebo ( p < 0.001 ) . Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli ( p ≤ 0.05 ) but appeared to have little effect on the painfulness of noxious heat stimulation . No serious adverse events were reported . Conclusion : Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy . The findings are comparable to oral drugs used for chronic neuropathic pain 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 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 The efficacy and side effects of the synthetic cannabinoid nabilone were compared with those of the weak opioid dihydrocodeine in the treatment of chronic neuropathic pain . A r and omised , double blind , crossover trial study design was used . Participants received a maximum daily dose of 2 mg nabilone or 240 mg dihydrocodeine . The trial lasted for 14 weeks and comprised two treatment periods , each of six weeks ’ duration , separated by a two week washout period . Participants were patients with chronic neuropathic pain aged 23 - 84 years , who were recruited using convenience sampling from outpatient units at three hospitals in the United Kingdom . The sample comprised 96 patients , who were r and omised to nabilone ( n=48 ) and dihydrocodeine ( n=48 ) in the first treatment period.1 The main outcome was pain as measured on a visual analogue scale over the final two weeks of each treatment period . Side effects were measured by a question naire . The research ers reported that dihydrocodeine provided better pain relief than nabilone and had slightly fewer side effects , although no major adverse events occurred for either drug . Which of the following statements , if any , are true ? Statements a , b , c , d , and e are all true . The aim of the trial was to compare the efficacy and side effects of nabilone with dihydrocodeine in the treatment of chronic neuropathic pain . A r and omised double blind crossover trial was conducted . Participants received both treatments in succession , AIMS Pain and anxiety are commonly reported among those undergoing orthopaedic surgery . Improvement in anxiety and pain control might be achieved by supplementing st and ard care with psychological interventions . However , the effectiveness of adjunctive psychosocial interventions in anxiety and pain control have not been addressed sufficiently by previous systematic review s in orthopaedic surgeries . The present study aim ed to assess the effectiveness of adjunctive psychosocial techniques to improve perioperative clinical care in orthopaedic surgery , to identify the most effective intervention types and to evaluate potential moderators . METHODS We will perform a systematic review and meta- analysis to address the study aims . PubMed , PsycINFO , CINAHL and ProQuest Dissertations & Theses will be search ed between 1980 and 2015 . Prospect i ve controlled clinical trials completed in adults , contrasting st and ard care and st and ard care supplemented with psychosocial methods  , will be eligible for inclusion . Effectiveness will be assessed through the outcomes of postoperative pain intensity , analgesic requirement , perioperative anxiety , quality of life and postoperative recovery . The results of a r and om-effect meta- analysis will be reported . To aid implementation of best practice , moderating effects of the type and timing of psychosocial intervention , type of surgical intervention and type of anaesthesia will be evaluated through meta-regression . Sensitivity analyses and subgroup contrasts will follow as necessary . DISCUSSION Recommendations will be made to improve medical care in orthopaedic procedures . The quality of evidence will be rated using GRADE criteria . Copyright © 2016 John Wiley & Sons ,
Pain intensity of chronic non-cancer patients was reduced by cannabinoids consumption , but effect sizes were small .
Efficacy for neuropathic and non-neuropathic pain was similar
There is growing interest in using cannabinoids for chronic pain .
We performed a systematic review and meta- analysis of r and omized controlled trials to evaluate the analgesic efficacy and adverse effects of cannabinoids for chronic non-cancer pain .