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 Adverse event assessment, analysis, and reporting in recent published analgesic clinical trials: ACTTION systematic review and recommendations Anesthetic therapy for acute pain relief after laparoscopic cholecystectomy: systematic review. Do sugar-sweetened beverages cause adverse health outcomes in children? A systematic review protocol Pain measurements and side effect profile of the novel cannabinoid ajulemic acid Analgesic and antihyperalgesic effects of nabilone on experimental heat pain. Medial branch neurotomy in management of chronic spinal pain: systematic review of the evidence. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Overview of Systematic Reviews: Yoga as a Therapeutic Intervention for Adults with Acute and Chronic Health Conditions Transcutaneous electrical nerve stimulation (TENS) for chronic pain - an overview of Cochrane Reviews. Pain and analgesic response after third molar extraction and other postsurgical pain The Subjective Psychoactive Effects of Oral Dronabinol Studied in a Randomized, Controlled Crossover Clinical Trial for Pain Evidence for and against the use of opioid analgesics for chronic nonmalignant low back pain: a review. Efficacy and Safety of Ledipasvir/Sofosbuvir With and Without Ribavirin in Patients With Chronic HCV Genotype 1 Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ION Trials. Opioids Compared With Placebo or Other Treatments for Chronic Low Back Pain: An Update of the Cochrane Review Evidence‐based management of pain after laparoscopic cholecystectomy: a PROSPECT review update Caries Removal by Chemomechanical (Carisolv™) vs. Rotary Drill: A Systematic Review Efficacy of Radiofrequency Procedures for the Treatment of Spinal Pain: A Systematic Review of Randomized Clinical Trials Effectiveness of workplace interventions in rehabilitating musculoskeletal disorders and preventing its consequences among workers with physical and sedentary employment: systematic review protocol Continuous infusion of ropivacaïne: an optimal postoperative analgesia regimen for iliac crest bone graft in children. Pregabalin in acute and chronic pain Chapter 46 Pain following spinal cord injury.
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 , & NA ; Adverse events in r and omized controlled trials of noninvasive , pharmacologic analgesics are frequently incompletely or inconsistently reported . A comprehensive reporting checklist is proposed to improve disclosure of adverse effects . & NA ; The development of valid and informative treatment risk – benefit profiles requires consistent and thorough information about adverse event ( AE ) assessment and participants ’ AEs during r and omized controlled trials ( RCTs ) . Despite a 2004 extension of the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement recommending the specific AE information that investigators should report , there is little evidence that analgesic RCTs adequately adhere to these recommendations . This systematic review builds on prior recommendations by describing a comprehensive checklist for AE reporting developed to capture clinical ly important AE information . Using this checklist , we coded AE assessment methods and reporting in all 80 double‐blind RCTs of noninvasive pharmacologic treatments published in the European Journal of Pain , Journal of Pain , and PAIN ® from 2006 to 2011 . Across all trials , reports of AEs were frequently incomplete , inconsistent across trials , and , in some cases , missing . For example , > 40 % of trials failed to report any information on serious adverse events . Trials of participants with acute or chronic pain conditions and industry‐sponsored trials typically provided more and better‐ quality AE data than trials involving pain‐free volunteers or trials that were not industry sponsored . The results of this review suggest that improved AE reporting is needed in analgesic RCTs . We developed an ACTTION ( Analgesic , Anesthetic , and Addiction Clinical Trial Translations , Innovations , Opportunities , and Networks ) AE reporting checklist that is intended to assist investigators in thoroughly and consistently capturing and reporting these critically important data in publications Inappropriate therapy of postoperative pain in laparoscopic cholecystectomy may lead to late mobilization , patient dissatisfaction , delayed hospital discharge , and chronic pain development . Our objective was to identify the best therapeutic strategy available to the anesthesiologist for the acute postoperative pain of patients su bmi tted to elective laparoscopic cholecystectomy . This is a systematic review that included 36 complete articles indexed in the Medline , Scopus , Web of Science and LILACS data bases , with a five-year time cut ( 2012 to 2016 ) , result ing from controlled and r and omized studies that were su bmi tted to qualitative analysis . In a proposal for multimodal analgesia , it is important to consider the contraindications , adverse effects , dose and optimal timing of interventions . Non-opioid drugs , such as non-steroidal anti-inflammatory drugs (NSAIDs)/cyclooxygenase-2 ( COX-2 ) inhibitors , gabapentin/pregabalin , N-methyl-D-aspartate ( NMDA ) receptor antagonists , and others . Opioids may be used at low doses associated with multimodal therapy or are restricted to cases where non-opioid multimodal analgesia is insufficient . We conclude that there is no consensus as to the best analgesic strategy to be implemented in the acute postoperative pain of laparoscopic cholecystectomy , which requires its applicability in an individualized way , based on the scientific evidence found in the literature . As contribution to medical learning and practice , we point out the theoretical enrichment of the analgesic drug options available for the therapy of postoperative pain in patients su bmi tted to elective laparoscopic cholecystectomy , and alert the team to consider the adverse effects of the interventions implemented Background Cardiovascular disease and type 2 diabetes are examples of chronic diseases that impose significant morbidity and mortality in the general population worldwide . Most chronic diseases are associated with underlying preventable risk factors , such as elevated blood pressure , high blood glucose or glucose intolerance , high lipid levels , physical inactivity , excessive sedentary behaviours , and overweight/obesity . The occurrence of intermediate outcomes during childhood increases the risk of disease in adulthood . Sugar-sweetened beverages are known to be significant sources of additional caloric intake , and given recent attention to their contribution in the development of chronic diseases , a systematic review is warranted . We will assess whether the consumption of sugar-sweetened beverages in children is associated with adverse health outcomes and what the potential moderating factors are . Methods / Design Of interest are studies addressing sugar-sweetened beverage consumption , taking a broad perspective . Both direct consumption studies as well as those evaluating interventions that influence consumption ( e.g. school policy , educational ) will be relevant . Non-specific or multi-faceted behavioural , educational , or policy interventions may also be included subject to the level of evidence that exists for the other interventions /exposures . Comparisons of interest and endpoints of interest are pre-specified . We will include r and omized controlled trials , controlled clinical trials , interrupted time series studies , controlled before-after studies , prospect i ve and retrospective comparative cohort studies , case – control studies , and nested case – control design s. The MEDLINE ® , Embase , The Cochrane Library , CINAHL , ERIC , and PsycINFO ® data bases and grey literature sources will be search ed . The processes for selecting studies , abstract ing data , and resolving conflicts are described . We will assess risk of bias using design -specific tools . To determine sets of confounding variables that should be adjusted for , we have developed causal directed acyclic graphs and will use those to inform our risk of bias assessment s. Meta- analysis will be conducted where appropriate ; parameters for exploring statistical heterogeneity and effect modifiers are pre-specified . The Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) approach will be used to determine the quality of evidence for outcomes . Systematic review registration PROSPERO CRD42014009641 Pre clinical findings on ajulemic acid ( AJA ) showed analgesic and anti-allodynic effects without psychoactive properties making it an appealing substance for the treatment of pain . A recently published r and omized double-blind crossover clinical trial described the pain-reducing effects and side effect profile of AJA on 21 patients with chronic neuropathic pain . In this report from this same sample the effects of AJA on the mechanical hypersensitivity , on pain , and on psychological and physical performance were further characterized . During a 5-week study period , patients were divided into two 7-day treatment groups receiving either AJA or placebo capsules first , respectively . All patients received 40 and 80 mg of AJA or placebo daily in each treatment period . Pain measurements included the determination of mechanical hypersensitivity using the von Frey hair method as well as the visual analog scale ( VAS ) , for which the number needed to treat ( NNT ) was calculated . The side effect profile of the compound was evaluated using psychotropic and physical measurements as well as obtaining reports on possible subjective side effects . The results showed no significant reduction in mechanical hypersensitivity ( p=0.052 ) , although a tendency towards pain reduction could be seen . The VAS score showed significant pain reduction ( p=0.021 ) and NNT values for 30 % pain relief were 2.14 for the first treatment group and 5.29 for the second treatment group . No significant findings were observed regarding psychotropic or physical measurements . Reported subjective side effects were mainly dry mouth , tiredness and dizziness and did not increase with dose elevation . Overall , these study findings indicate that AJA shows pain-reducing effects on patients with chronic neuropathic pain without clinical ly relevant psychotropic or physical side effects OBJECTIVE In this study , we explored the analgesic and antihyperalgesic properties of a synthetic cannabinoid ( nabilone ) on experimental heat pain in men and women , as well as its effects on descending pain inhibitory systems . RESEARCH DESIGN AND METHODS A double-blind , placebo controlled , crossover study of nabilone single doses of 0.5 and 1 mg was conducted . Excitatory systems were elicited using a temporal summation test ( tonic heat pain evoked by a Peltier thermode ) administered before and after activation of descending inhibitory control ( triggered using a counter-irritation procedure ) . These tests were given before and after drug treatment . Primary outcome measures included average heat pain , temporal summation of heat pain , and drug-induced changes in the strength of descending analgesia . Possible adverse reactions were monitored throughout treatment . Seven men ( mean age = 22.5 years , SD = + /- 1.5 ) and 10 women ( mean age = 23.2 years , SD = + /- 2.8 ) completed this study . RESULTS Nabilone ( 1 mg and 0.5 mg ) did not reduce the global pain intensity experienced during tonic heat pain ( all values of p > 0.18 ) . It also failed to potentiate the strength of descending inhibitory responses ( all values of p > 43 ) . Nevertheless , at the highest dose ( 1 mg ) , and only for women , nabilone significantly ( p = 0.003 ) dampened the temporal summation experienced during the last portion of the tonic heat pulse test ( i.e. , the period of time during which temporal summation is greatest ) . This antihyperalgesic effect was not observed for men ( at either 0.5 mg or 1 mg dose ) , suggesting that the antihyperalgesic properties of cannabinoids are greater for women than for men . Adverse reactions encountered were generally mild and did not provoke the cessation of testing . CONCLUSIONS Nabilone failed to produce analgesic effects and it did not interact with descending pain inhibitory systems . However , we found that a single 1 mg dose of nabilone reduced temporal summation for women but not men . Although a titration regime and a larger sample of subjects might have provided more robust effects , these preliminary results suggest that nabilone appears effective at relieving hyperalgesic responses in women . Possible neurobiological mechanisms and clinical implication s are further discussed Zygapophysial or facet joints have been implicated as cause of low back , mid back , upper back and neck pain with referred pain . Cervical , thoracic and lumbar facet joints are innervated by the medial branches of the dorsal rami . Zygapophysial ( facet ) joints have been implicated as the source of chronic pain in 15 % to 45 % of the patients with chronic low back pain , 54 % to 60 % of the patients with chronic neck pain and 48 % of the patients with thoracic pain . A systematic review of the evidence of effectiveness of radiofrequency denervation in the management of chronic spinal pain was undertaken . This review included r and omized clinical trials , as well as non-r and omized or observational studies in the analysis . Literature search included MEDLINE , EMBASE , systematic review s , narrative review s , cross-references to the review s and various published trials ; and peer review ed abstract s from scientific meetings during the past two years . An algorithmic approach was followed in study evaluation with a description of inclusion and exclusion criteria . A set of high-performing scales or checklists pertaining to r and omized clinical trials and observational trials derived from the Agency for Healthcare Research and Quality ( AHRQ ) was utilized ; Systems to Rate the Strength of Scientific Evidence . Qualitative analysis was conducted , using five levels of evidence for effectiveness of medial branch neurotomy . Our search strategy identified over 1,000 citations as the result of electronic and manual screening . A total of 7 r and omized trials of radiofrequency neurotomy for spinal pain were identified . However , only 4 related to medial branch neurotomy . Two of the four met the inclusion criteria . Among the multiple observational studies considered for inclusion , 4 prospect i ve evaluations were included in the systematic review . In addition , 3 retrospective evaluations were also included . Two r and omized trials comprised of 27 patients receiving active treatment . The first study consisted of cervical facet joint pain and the second consisted of lumbar facet joint pain . Both studies showed positive results . Similar to r and omized trials , prospect i ve , as well as retrospective evaluations showed positive evidence , both in short-term and long-term . The results of this systematic review of 2 well- design ed r and omized trials , 4 prospect i ve well- design ed trials without r and omization and 3 retrospective evaluations provided strong evidence that radiofrequency denervation offers short-term relief and moderate evidence of long-term pain relief of facet joint origin BACKGROUND Multiple sclerosis is associated with muscle stiffness , spasms , pain , and tremor . Much anecdotal evidence suggests that cannabinoids could help these symptoms . Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis . METHODS We did a r and omised , placebo-controlled trial , to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity . 630 participants were treated at 33 UK centres with oral cannabis extract ( n=211 ) , Delta9-tetrahydrocannabinol ( Delta9-THC ; n=206 ) , or placebo ( n=213 ) . Trial duration was 15 weeks . Our primary outcome measure was change in overall spasticity scores , using the Ashworth scale . Analysis was by intention to treat . FINDINGS 611 of 630 patients were followed up for the primary endpoint . We noted no treatment effect of cannabinoids on the primary outcome ( p=0.40 ) . The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 ( 95 % CI -1.04 to 1.67 ) , and for those taking Delta9-THC versus placebo it was 0.94 ( -0.44 to 2.31 ) . There was evidence of a treatment effect on patient-reported spasticity and pain ( p=0.003 ) , with improvement in spasticity reported in 61 % ( n=121 , 95 % CI 54.6 - 68.2 ) , 60 % ( n=108 , 52.5 - 66.8 ) , and 46 % ( n=91 , 39.0 - 52.9 ) of participants on cannabis extract , Delta9-THC , and placebo , respectively . INTERPRETATION Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale . However , though there was a degree of unmasking among the patients in the active treatment groups , objective improvement in mobility and patients ' opinion of an improvement in pain suggest cannabinoids might be clinical ly useful Objectives . Overview the quality , direction , and characteristics of yoga interventions for treatment of acute and chronic health conditions in adult population s. Methods . We search ed for systematic review s in 10 online data bases , bibliographic references , and h and - search es in  yoga-related  journals . Included review s satisfy Oxman criteria and specify yoga as a primary intervention in one or more r and omized controlled trials for treatment in adults . The AMSTAR tool and GRADE approach evaluated the method ological quality of review s and quality of evidence . Results . We identified 2202 titles , of which 41 full-text articles were assessed for eligibility and 26 systematic review s satisfied inclusion criteria . Thirteen systematic review s include quantitative data and six papers include meta- analysis . The quality of evidence is generally low . Sixteen different types of health conditions are included . Eleven review s show tendency towards positive effects of yoga intervention , 15 review s report unclear results , and no , review s report adverse effects of yoga . Yoga appears most effective for reducing symptoms in anxiety , depression , and pain . Conclusion . Although the quality of systematic review s is high , the quality of supporting evidence is low . Significant heterogeneity and variability in reporting interventions by type of yoga , setting s , and population characteristics limit the generalizability of results BACKGROUND Chronic pain , considered to be pain lasting more than three months , is a common and often difficult to treat condition that can significantly impact upon function and quality of life . Treatment typically includes pharmacological and non-pharmacological approaches . Transcutaneous electrical nerve stimulation ( TENS ) is an adjunct non-pharmacological treatment commonly recommended by clinicians and often used by people with pain . OBJECTIVES To provide an overview of evidence from Cochrane Review s of the effectiveness of TENS to reduce pain in adults with chronic pain ( excluding headache or migraine).To provide an overview of evidence from Cochrane Review s of the safety of TENS when used to reduce pain in adults with chronic pain ( excluding headache or migraine).To identify possible sources of inconsistency in the approaches taken to evaluating the evidence related to TENS for chronic pain ( excluding headache or migraine ) in the Cochrane Library with a view to recommending strategies to improve consistency in methodology and reporting . To highlight areas of remaining uncertainty regarding the effectiveness of TENS for chronic pain ( excluding headache or migraine ) with a view to recommending strategies to reduce any uncertainty . METHODS Search methods We search ed the Cochrane Data base of Systematic Review s ( CDSR ) , in the Cochrane Library , across all years up to Issue 11 of 12 , 2018 . Selection of review sTwo authors independently screened the results of the electronic search by title and abstract against inclusion /exclusion criteria . We included all Cochrane Review s of r and omised controlled trials ( RCTs ) assessing the effectiveness of TENS in people with chronic pain . We included review s if they investigated the following : TENS versus sham ; TENS versus usual care or no treatment/waiting list control ; TENS plus active intervention versus active intervention alone ; comparisons between different types of TENS ; or TENS delivered using different stimulation parameters . Data extraction and analysis Two authors independently extracted relevant data , assessed review quality using the AMSTAR checklist and applied GRADE judgements where required to individual review s. Our primary outcomes included pain intensity and nature/incidence of adverse effects ; our secondary outcomes included disability , health-related quality of life , analgesic medication use and participant global impression of change . MAIN RESULTS We included nine review s investigating TENS use in people with defined chronic pain or in people with chronic conditions associated with ongoing pain . One review investigating TENS for phantom or stump-associated pain in people following amputation did not have any included studies . We therefore extracted data from eight review s which represented 51 TENS-related RCTs representing 2895 TENS-comparison participants entered into the studies .The included review s followed consistent methods and achieved overall high scores on the AMSTAR checklist . The evidence reported within each review was consistently rated as very low quality . Using review authors ' assessment of risk of bias , there were significant method ological limitations in included studies ; and for all review s , sample sizes were consistently small ( the majority of studies included fewer than 50 participants per group).Six of the eight review s presented a narrative synthesis of included studies . Two review s reported a pooled analysis . Primary and secondary outcomes One review reported a beneficial effect of TENS versus sham therapy at reducing pain intensity on a 0 to 10 scale ( MD -1.58 , 95 % CI -2.08 to -1.09 , P < 0.001 , I² = 29 % , P = 0.22 , 5 studies , 207 participants ) . However the quality of the evidence was very low due to significant method ological limitations and imprecision . A second review investigating pain intensity performed a pooled analysis by combining studies that compared TENS to sham with studies that compared TENS to no intervention ( SMD -0.85 , 95 % CI -1.36 to -0.34 , P = 0.001 , I² = 83 % , P < 0.001 ) . This pooled analysis was judged as offering very low quality evidence due to significant method ological limitations , large between-trial heterogeneity and imprecision . We considered the approach of combining sham and no intervention data to be problematic since we would predict these different comparisons may be estimating different true effects . All remaining review s also reported pain intensity as an outcome measure ; however the data were presented in narrative review form only . Due to method ological limitation and lack of useable data , we were unable to offer any meaningful report on the remaining primary outcome regarding nature/incidence of adverse effects , nor for the remaining secondary outcomes : disability , health-related quality of life , analgesic medication use and participant global impression of change for any comparisons . We found the included review s had a number of inconsistencies when evaluating the evidence from TENS studies . Approaches to assessing risk of bias around the participant , personnel and outcome -assessor blinding were perhaps the most obvious area of difference across included review s. We also found wide variability in terms of primary and secondary outcome measures , and inclusion /exclusion criteria for studies varied with respect to including studies which assessed immediate effects of single interventions . AUTHORS ' CONCLUSIONS We found the method ological quality of the review s was good , but quality of the evidence within them was very low . We were therefore unable to conclude with any confidence that , in people with chronic pain , TENS is harmful , or beneficial for pain control , disability , health-related quality of life , use of pain relieving medicines , or global impression of change . We make recommendations with respect to future TENS study design s which may meaningfully reduce the uncertainty relating to the effectiveness of this treatment in people with chronic pain & NA ; There is uncertainty over whether the patient group in which acute pain studies are conducted ( pain model ) has any influence on the estimate of analgesic efficacy . Data from four recently up date d systematic review s of aspirin 600/650 mg , paracetamol 600/650 mg , paracetamol 1000 mg and ibuprofen 400 mg were used to investigate the influence of pain model . Area under the pain relief versus time curve equivalent to at least 50 % maximum pain relief over 6 h was used as the outcome measure . Event rates with treatment and placebo , and relative benefit ( RB ) and number needed to treat ( NNT ) were used as outputs from the meta‐analyses . The event rate with  placebo was systematic ally statistically lower for dental than postsurgical pain for all four treatments . Event rates with analgesics , RB and NNT were infrequently different between the pain models . Systematic difference in the estimate of analgesic efficacy between dental and postsurgical pain models remains unproven , and , on balance , no major difference is likely 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 INTRODUCTION Opioid analgesics are very effective for treating pain , but their chronic use in nonmalignant conditions is controversial . Low back pain is a common condition , and chronic low back pain ( CLBP ) is the most frequent regional pain syndrome in the United States . This article review s the evidence for and against the use of chronic opioid analgesic therapy ( COAT ) for patients with CLBP unrelated to cancer . METHODS A literature review was conducted looking for reports of oral or transdermal opioid analgesic therapy for CLBP . RESULTS There are very few r and omized controlled trials of COAT for CLBP . The scant evidence that is available suggests that over the short-term , COAT is helpful with patients with CLBP . In the published reports , most of which are brief in duration , COAT is associated with moderate side effects but a low risk of abuse or drug addiction .  COAT was not associated with adverse long-term sequelae . Longer-acting opioid analgesics may be preferable to shorter-acting agents . Patient selection and close follow-up are critical to good outcomes . CONCLUSIONS There is a place for the use of chronic oral or transdermal opioid analgesics in the treatment of some patients with CLBP BACKGROUND Interferon-based hepatitis C virus ( HCV ) therapy is safe and effective among people receiving opioid substitution therapy ( OST ) , but treatment uptake remains low . Our aim was to evaluate the impact of OST and drug use during therapy on completion , adherence , sustained virologic response ( SVR12 ) , and safety of ledipasvir/sofosbuvir ± ribavirin . METHODS The phase 3 ION studies evaluated a fixed-dose combination of ledipasvir/sofosbuvir ± ribavirin administered for 8 , 12 , or 24 weeks in patients with chronic HCV genotype 1 . People with clinical ly significant drug use ( prior 12 months ) or noncannabinoids detected at screening by urine drug tests ( not explained by prescriptions ) were ineligible . Stored sample s were available from ION-1 for retrospective testing for illicit drugs by enzyme-linked immunosorbent assay . RESULTS Among 1952 patients enrolled in the ION studies , 4 % ( n = 70 ) were receiving OST . Among those receiving ( n = 70 ) and not receiving OST ( n = 1882 ) , there was no difference in treatment completion ( 97 % vs 98 % ; P = .40 ) , ≥80 % adherence ( 93 % vs 92 % ; P = 1.00 ) , SVR12 ( 94 % vs 97 % ; P = .28 ) , and serious adverse events ( 4 % vs 3 % ; P = .43 ) , respectively . Among participants in the ION-1 trial , 23 % ( n = 196 ) used illicit drugs during therapy ( 15 % cannabinoids alone ; 8 % other illicit drugs ± cannabinoids ) . There was no difference in treatment completion , ≥80 % adherence , SVR12 , or serious AEs in those with no drug use during treatment compared with those who used cannabinoids and /or other illicit drugs . No cases of HCV reinfection were observed in the 24 weeks following treatment . CONCLUSIONS OST and drug use during HCV therapy did not impact treatment completion , adherence , SVR12 , or safety . CLINICAL TRIALS REGISTRATION ION-1 ( NCT01701401 ) ; ION-2 ( NCT01768286 ) ; and ION-3 ( NCT01851330 ) Study Design . Systematic review and meta- analysis . Objective . To assess the efficacy of opioids in adults with chronic low back pain ( CLBP ) . Summary of Background Data . Opioids for CLBP has increased dramatically . However , the benefits and risks remain unclear . Methods . We up date d a 2007 Cochrane Review through October 2012 of r and omized controlled trials from multiple data bases . Use of noninjectable opioids in CLBP for at least 4 weeks was compared with placebo or other treatments ; comparisons with different opioids were excluded . Outcomes included pain and function using st and ardized mean difference ( SMD ) or risk ratios with 95 % confidence intervals ( CIs ) , and absolute risk difference with 95 % CI for adverse effects . Study quality was evaluated using Grading of Recommendations Assessment , Development , and Evaluation criteria . Results . Fifteen trials ( 5540 participants ) , including twelve new , met the criteria . Tramadol was better than placebo for pain ( SMD , −0.55 ; 95 % CI , −0.66 to −0.44 ) and function ( SMD , −0.18 ; 95 % CI , −0.29 to −0.07 ) . Compared with placebo , transdermal buprenorphine  decreased pain ( SMD , −2.47 ; 95 % CI , −2.69 to −2.25 ) , but not function ( SMD , −0.14 ; 95 % CI , −0.53 to 0.25 ) . Strong opioids ( morphine , hydromorphone , oxycodone , oxymorphone , and tapentadol ) , were better than placebo for pain ( SMD , −0.43 ; 95 % CI , −0.52 to −0.33 ) and function ( SMD , −0.26 ; 95 % CI , −0.37 to −0.15 ) . One trial demonstrated little difference with tramadol compared with  celecoxib for pain relief .  Two trials ( 272 participants ) found no difference between opioids and antidepressants for pain or function . Review ed trials had low to moderate quality , high drop-out rates , short duration , and limited interpretability of functional improvement . No serious adverse effects , risks ( addiction or overdose ) , or complications ( sleep apnea , opioid-induced hyperalgesia , hypogonadism ) were reported . Conclusion . There is evidence of short-term efficacy ( moderate for pain and small for function ) of opioids to treat CLBP compared with placebo . The effectiveness and safety of long-term opioid therapy for treatment of CLBP remains unproven . Level of Evidence : Background : Significant pain can be experienced after laparoscopic cholecystectomy . This systematic review aims to formulate PROSPECT ( PROcedure SPECific Postoperative Pain ManagemenT ) recommendations to reduce postoperative pain after laparoscopic cholecystectomy . Methods : R and omised controlled trials published in the English language from January 2006 ( date of last PROSPECT review ) to December 2017 , assessing analgesic , anaesthetic , or operative interventions for laparoscopic cholecystectomy in adults , and reporting pain scores , were retrieved from MEDLINE and Cochrane data bases using PRISMA ( Preferred Reporting Items for Systematic Review s and Meta‐Analyses ) search protocol s. PROSPECT methodology was used , and recommendations were formulated after review and discussion by the PROSPECT group ( an international group of leading pain specialists and surgeons ) . Results : Of 1988 r and omised controlled trials identified , 258 met the inclusion criteria and were included in this review . The studies were of mixed method ological quality , and quantitative analysis was not performed because of heterogeneous study design and how outcomes were reported . Conclusions : We recommend basic analgesic techniques : paracetamol + NSAID or cyclooxygenase‐2 specific inhibitor + surgical site local anaesthetic infiltration . Paracetamol and NSAID should be started before or during operation with dexamethasone ( GRADE A ) . Opioid should be reserved for rescue analgesia only ( GRADE B ) . Gabapentanoids , intraperitoneal local anaesthetic  , and  transversus abdominis plane blocks  are not recommended ( GRADE D ) unless basic analgesia is not possible . Surgically , we recommend low‐pressure pneumoperitoneum , postprocedure saline lavage , and aspiration of pneumoperitoneum ( GRADE A ) . Single‐port incision techniques are not recommended to reduce pain ( GRADE A ) Background :  Chemomechanical caries removal  is an effective alternative to the traditional rotary drilling method . The advantages of chemomechanical techniques in terms of the need for anesthesia , pain perception and patient preference are systematic ally review ed and a meta- analysis of the time required for caries removal is reported . Method : R and omized controlled studies of comparison of chemomechanical techniques with conventional rotary drill were selected from a systematic search of st and ard biomedical data bases , including the PubMed and Cochrane clinical trials . Non-repeated search results were screened for relevance and risk of bias assessment , followed by methodology assessment . Statistical models were applied to the outcome parameters - time required , pain perception , need of anesthesia and patient preference - extracted from the studies . Results : Out of the 111 non-repeated search results , 26 studies receiving a low bias score were selected for the review , and 16 r and omized clinical trials of rotary and Carisolv techniques were considered for meta- analysis . Meta- analysis by fixed effect as well as r and om effect models indicate that Carisolv takes more time ( 3.65 ± 0.05 and 4.09 ± 0.29 min ) than rotary drill ( 8.65 ± 0.09 and 8.97 ± 0.66 min ) method . Advantages of reduced pain ( 14.67 for Carisolv vs. 6.76 for rotary drill ) , need for anesthesia ( 1.59 % vs. 10.52 % ) outweigh the longer time requirement and make it the preferred ( 18.68 % vs. 4.69 % ) method . Conclusion : Chemomechanical techniques st and out as a minimally invasive and preferred method based on the meta-analyses . Evaluation of pain experienced using robust methods is needed to strengthen the evidence for their use Background and Objectives The use of radiofrequency ( RF ) procedures in the peripheral nervous system to treat  chronic spinal pain  has been the subject of controversy . Publications concerned only uncontrolled studies , and irreversible nervous tissue damage was believed to be responsible for the effect , if any . In recent years , r and omized , controlled studies have appeared , which have attested to an increasing use of these techniques . This is a systematic review of r and omized controlled trials on RF procedures for spinal pain . Methods We performed a st and ardized literature search for r and omized , controlled trials . Three adjudicators independently registered trial methodology and outcome using vali date d and subject-related instruments . Interadjudicator disagreement was resolved by discussion . It was found necessary to devise additional parameters of study assessment . Results Six trials met the inclusion criteria . This small number , along with clinical and technical heterogeneity precluded statistical analysis . All studies , whether high or low quality , reported positive outcomes . Conclusions We conclude that there is moderate evidence that RF lumbar facet denervation is more effective for chronic low back pain  than placebo . Limited evidence exists for efficacy of RF neurotomy in chronic cervical zygapophyseal joint pain after flexion-extension injury . There is limited evidence that RF heating of the dorsal root ganglion is more effective than placebo in chronic cervicobrachialgia .  We recommend the systematic application of our additional parameter assessment s for future evaluations of RF studies . These additional parameters should also be used in the preparation of future trial protocol s of RF procedures for the treatment of chronic pain Background Musculoskeletal disorders ( MSDs ) are the leading cause of work disability and sickness absence worldwide . The prevalence of MSDs increases with age , consequently challenging sustainable employability among the growing ageing workforce . Knowledge of feasible and efficient workplace-based interventions to rehabilitate MSD or prevent its consequences is therefore warranted . This systematic review will evaluate the effectiveness of workplace-based interventions on MSDs and its consequences among adult workers with physical and sedentary work tasks , respectively . Methods We will search the following bibliographic data bases : PubMed ( including the data base ‘ MEDLINE ’ ) and Web of Science Core Collection ( including the data bases ‘ Science Citation Index Exp and ed ’ , ‘ Social Sciences Citation Index ’ and ‘ Arts & Humanities Citation Index ’ ) . Manual search es will also be performed . We will include r and omised controlled trials ( RCTs ) and non- RCTs reported in English in which ( 1 ) participants are adult workers with MSD , ( 2 ) interventions are aim ing at rehabilitating pain symptoms of MSD or preventing the consequences of MSD and ( 3 ) interventions are initiated and /or carried out at the workplace . The review will adhere to the ‘ Preferred Reporting Items for Systematic review s and Meta-Analyses ’ ( PRISMA ) guidelines for reporting systematic review s and the Institute for Work and Health ( IWH ) guidelines for workplace-based interventions . For the primary evaluation of the review , the quality assessment and evidence synthesis will conform to the IWH guidelines . Secondary evaluation will include a meta- analysis ( unless the included studies do not allow this due to heterogeneity ) and employ the risk of bias domains recommended by Cochrane along with the Grading of Recommendations , Assessment , Development and Evaluations ( GRADE ) approach on the studies with pain intensity as an outcome . Discussion This systematic review will provide knowledge on effective workplace-based interventions among physical and sedentary workers with MSD . RCTs are considered the most powerful experimental design in clinical trials , but solely including these may be too restrictive to underst and effective workplace-based interventions where r and omised and carefully controlled trials ( RCTs ) are not always possible . In order to maximize practical relevance , the selection process will , therefore , include both RCTs and non- RCTs and the quality assessment and evidence synthesis will conform to IWH guidelines focusing on developing practical guidelines for stakeholders . The result of this work will form the basis for industry-specific evidence -based recommendations on effective workplace-based interventions for rehabilitation of MSDs and its consequences that will later be operationalised into concrete and user-friendly practical tools for workplaces . Systematic review registration International Prospect i ve Register of Systematic Review s ( PROSPERO ) number CRD42018116752 BACKGROUND Postoperative analgesia of iliac crest ( IC ) donor site can be performed by on site infiltrations of local anesthetics ( LA ) or morphine . Single injections or continuous infusions of LA proved their efficacy in adults , but was not reported in children . We prospect ively evaluated the interest of a continuous infusion of 0.2 % ropivacaïne at the IC donor site in terms of postoperative pain relief and rescue analgesics consumption . METHODS Sixteen consecutive patients , aged from 4 to 16 years scheduled for maxillar alveolar graft with IC bone , were included . After IC bone graft surgery under general anesthesia , they received a 0.2 - 0.4 ml x kg(-1 ) bolus of 0.2 % ropivacaïne through the IC catheter ; then a continuous infusion of 0.2 % ropivacaïne at 0.125 ml x kg(-1 ) x h(-1 ) was administrated for 48 h with disposable elastomeric pumps . Children systematic ally received paracetamol ( 15 mg x kg(-1 ) four times a day ) and niflumic acid ( 40 mg x kg(-1 ) twice a day ) . Postoperative pain was evaluated using a Visual Analog Scale ( > 7 years old ) or Children and Infants  Postoperative Pain Score ( between 4 and 7 years old ) every 4 h until H48 . Doses of rescue analgesics and adverse events ( LA toxicity , catheter 's removal , nausea-vomiting ) were also noted . Three months after surgery a blinded clinical research assistant review ed all children and assessed functional recovery , neuropathic chronic pain symptoms or local complications . RESULTS The median value of IC graft pain scores was 0 during whole studied period . Of the patients , 31.2 % did not require any rescue analgesics and 43.8 % needed only once . No adverse events related to LA and no removal of catheter were noted . One child had nausea in the 48-h postoperative period , and one child had neuropathic pain symptoms at 3 months at the donor site . CONCLUSION Continuous infusion of 0.2 % ropivacaïne through an IC catheter is an optimal and safe technique of regional postoperative analgesia after bone graft harvest in children Pregabalin is a gamma-amino-butyric acid analog shown to be effective in several models of neuropathic pain , incisional injury , and inflammatory injury . In this review , the role of pregabalin in acute postoperative pain and in chronic pain syndromes has been discussed . Multimodal perioperative analgesia with the use of gabapentinoids has become common . Based on available evidence from r and omized controlled trials and meta- analysis , the perioperative administration of pregabalin reduces opioid consumption and opioid-related adverse effects in the first 24 h following surgery . Postoperative pain intensity is however not consistently reduced by pregabalin . Adverse effects like visual disturbance , sedation , dizziness , and headache are associated with higher doses . The advantage of the perioperative use of pregabalin is so far limited to laparoscopic , gynecological , and daycare surgeries which are not very painful . The role of the perioperative administration of pregabalin in preventing chronic pain following surgery , its efficacy in more painful surgeries and surgeries done under regional anesthesia , and the optimal dosage and duration of perioperative pregabalin need to be studied . The efficacy  of pregabalin in  chronic pain conditions like  painful diabetic neuropathy , postherpetic neuralgia , central neuropathic pain  , and fibromyalgia has been demonstrated Publisher Summary This chapter explores that spinal cord injury ( SCI ) has a number of severe and disabling consequences . Although loss of function is often considered the primary issue , pain is also a major problem . In central pain conditions , small r and omized trials have shown the effectiveness of amitriptyline and lamotrigine in central post-stroke pain and of dronabinol , a cannabinoid , in pain in multiple sclerosis . It is not known whether the efficacy of drugs in other central or peripheral neuropathic pain conditions can be anticipated to have similar effects in SCI neuropathic pain . Central neuropathic pain is often considered more refractory than peripheral neuropathic pain . It has been suggested that central post-stroke pain responds better to antidepressants than SCI pain . The chapter also review s that because of the lack of sufficient data in neuropathic SCI pain , efficacy in other neuropathic pain conditions has to be considered in choosing treatment
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 .