Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: A systematic review

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Asaolu, John E. Ehiri, Linda Jepkoeach Kimaru, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-16781/v3 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Jul, 2020 Read the published version in Systematic Reviews → Version 3 posted 7 You are reading this latest preprint version Show more versions Abstract Background: Medical cannabis (MC) is currently being used as an adjunct to opiates given its analgesic effects and potential to reduce opiate addiction. This review assessed if MC used in combination with opioids to treat non-cancer chronic pain would reduce opioid dosage. Methods: Four databases - Ovid (Medline), Psyc-INFO, PubMed, Web of Science, and grey literature – were searched to identify original research that assessed the effects of MC on non-cancer chronic pain in humans. Study eligibility included randomized controlled trials, controlled before-and-after studies, cohort studies, cross-sectional studies, and case reports. All databases were searched for articles published from inception to October 31, 2019. Cochrane’s ROBINS-I tool and the AXIS tool were used for risk of bias assessment. PRISMA guidelines was followed in reporting the systematic review. Results: Nine studies involving 7,222 participants were included. There was a 64%-75% reduction in opioid dosage when used in combination with MC. Use of MC for opioid substitution was reported by 32%-59.3% of patients with non-cancer chronic pain. One study reported a slight decrease in mean hospital admissions in the past calendar year (P=.53) and decreased mean emergency department visits in the past calendar year (P=.39) for patients who received MC as an adjunct to opioids in the treatment of non-cancer chronic pain compared to those who did not receive MC. All included studies had high risk of bias, which was mainly due to their methods. Conclusions: While this review indicated the likelihood of reducing opioid dosage when used in combination with MC, we cannot make a causal inference. Although medical cannabis’s recognized analgesic properties make it a viable option to achieve opioid dosage reduction, the evidence from this review cannot be relied upon to promote MC as an adjunct to opioids in treating non-cancer chronic pain. More so, the optimal MC dosage to achieve opioid dosage reduction remains unknown. Therefore, more research is needed to elucidate whether MC used in combination with opioids in the treatment of non-cancer chronic pain is associated with health consequences that are yet unknown. Systematic review registration : This systematic review was not registered. Clinical Pharmacology Opioid epidemic medical cannabis opioid substitution opioid crisis Figures Figure 1 Background Pain is an unpleasant experience that is subjective in nature;it differs in duration and etiology. Chronic pain, often describedas pain that persists for a minimum of three months, may stem froman initial injury (e.g. back sprain), illness, or an unexplainedcause. 1 Non-cancer chronic pain differs from cancer painbecause cancer pain arises from the invasion of a tumor and theinteraction among tumor cells, the nervous system, and anindividual’s immune system. 2,3 Cancer pain oftenadvances as the disease progresses. 2 Because ofdifferences in etiology and management of these forms of pain, thisreview focused on non-cancer chronic pain. The pain alleviating effect of MC is conferred by thetherapeutic effect of Tetrahydrocannabinol-alpha (THC) - thedominant component of the cannabis extract - and cannabidiol (CBD),a lesser (40%) component of the extract of MC 7 .Cannabisis considered an illicit drug by the U.S. Drug Enforcement Agency(DEA), and it is not approved by the Food and Drug Administration(FDA) 8 . Nevertheless, several U.S. states have policiespermitting cannabis use to treat certain medicalconditions 9 . A meta-analysis of MC for non-cancerchronic pain reported a significant effect on pain reduction,although its effect was marred with high number needed to treat,and a higher likelihood to harm 10 . More so, comparedwith placebo, while MC may increase the number of people achievingpain relief, it is associated with an increase in nervous systemadverse events 11 . These reports cast doubt on theeffectiveness of MC for non-cancer chronic pain. Pain, includingback pain, migraine, chronic pain, arthritis, and pain from cancerand surgery, is the most common condition for which MC isprescribed by health providers 6,8 . When MC is used bypatients taking opioids, it does not significantly change the areaunder the curve (AUC) of opioids or their metabolites, and there isa time delay to maximum serum concentration (Cmax) ofopioids. 12 In addition, MC has no significant effect onthe pharmacokinetics of opioids. 12 In one study, 35.8%of respondents substituted opioids for MC, with greatersubstitution among those with comorbidities like pain. 13 Consequently, MC is perceived as an effective remedy for non-cancerchronic pain as well as a potential substitute that may help curbthe on-going opioid epidemic. 13 This led to anincreasing interest in research on MC, though there is a limitedfocus on the use of MC for opioid dosage reduction or non-cancerchronic pain. For instance, a systematic review by Whiting et al.included patients with chronic cancer pain and studies thatcompared CBD to a placebo. 14 Another clinical review byHill discussed the indications for MC and patient eligibility forMC certification, without an appraisal of MC for non-cancer chronicpain. 15 In addition, a review by Campbell et. al.summarized literature on MC use for non-cancer chronicpain. 16 Therefore, in this review our objective of thisreview was to assess the effectiveness of MC in reducing opioiddosage or substituting opioids for the treatment of non-cancerchronic pain. Methods Inclusion criteria Type of Studies : Cohort, randomized controlled trials,controlled before-and-after studies, cross-sectional studies, andcase reports. Type of Participants : Human participants aged 18 yearsor older who received MC as an adjunct to opioids for the treatmentof non-cancer chronic pain. Studies involving cell lines, tissueculture, or animal models were excluded. Type of intervention : Use of MC as an adjunct toopioids in treating non-cancer chronic pain. Type of comparison : Participants who did not receive MCas an adjunct to opioids in treating non-cancer chronic pain. Type of Outcome Measures : The primary outcome ofinterest is the reduction of opioid dosage for non-cancer chronicpain treatment. Search strategy A Health Sciences Librarian (AN) developed the search strategy( Appendix 1 ) for the review and searched PubMed,Web of Science, PsycINFO, and Ovid (Medline). All databases weresearched for articles published from inception to October 31, 2019.Two reviewers searched the Grey literature using Google and GoogleScholar. Study selection Two reviewers (BO and IA) screened articles against theinclusion criteria, and disagreements regarding study eligibilitywere resolved by discussion with a third reviewer (JE). Dataextraction was done by a reviewer and cross checked by anotherreviewer. Overall, nine studies were included in the review asshown in the PRISMA diagram ( Figure 1 ). Studieswere eligible for inclusion if they were a cohort study, randomizedcontrolled trials, controlled before-and-after studies, cross-sectional studies, or case reports. The primary outcome of interestis reduction of opioid dosage for non-cancer chronic paintreatment. Study quality assessment Quality assessment of included studies was conductedindependently by two reviewers (LK and BO), using the ROBINS-I riskof bias tool for cohort studies and the AXIS tool forcross-sectional studies 17 . Disagreements were resolvedby discussion. Cohort studies were assessed for bias related to 1)confounding; 2) selection of participants; 3) classification ofinterventions; 4) deviations from intended interventions; 5)missing data; 6) measurement of outcomes; and 7) selection of thereported result. Each section of the bias assessment was judged tosee if there was a low, moderate, serious, or critical risk ofbias. An overall assessment of the risk of bias was made based onthe most severe form of risk of bias reported in any of thedomains. The cross-sectional studies were assessed for bias in eachsection of the publication as in Appendix 3: Introduction, Methods,Results, Discussion, and Others. Risk of bias criteria wereassessed as “Yes”, “NO” or “Do not know” (Appendix 3). Given theheterogeneity of included studies a meta-analysis was not possible.Thus, a qualitative summary of the evidence was conducted. Results The search yielded 4,316 articles and 24 reports from thedatabases and grey literature, respectively. 1,900 duplicates wereeliminated, leaving 2,440 unique studies. Two authors screened the2,440 studies and selected full texts of nine studies thatqualified for inclusion ( Figure 1 ). Characteristics of included studies The search of the four databases yielded 4316 titles, while thegrey literature search provided additional 24 research titles. Twothousand, four hundred and forty (2440) titles were remaining afterthe removal of duplicates; 2410 titles were ineligible and screenedout at the abstract stage. Thirty (30) full text articles werescreened, out of which 21 were excluded (Appendix 2). Nine observational studies involving 7,222 participants wereincluded in this review. Included studies (threecohort 18-20 , five cross sectional 21-25 andone case series 26 ) were published between 2003 and 2019in Australia, Canada, and the U.S. Although most of the studies didnot report the dosage of MC, two reported MC dosage range of 1.5mg-2000mg 23,24 . The participants ranged in age from 34 to70 years old. See Table 1, Characteristics of included studies, fordetailed indications for, and the setting of administration ofMC. Quality assessment of included studies One cohort study 18 had a serious risk of confoundingand did not provide enough information to make an overall risk ofbias assessment. The other cohort study 19 had a seriousrisk of bias related to missing data and inadequate measurement ofoutcomes The third cohort study 20 , had a serious risk ofbias for confounding and measurement of outcomes, and critical riskof bias related to missing data, with an overall critical risk ofbias assessment. See Appendix 3 for the risk of bias assessment ofincluded cohort studies. A complete assessment of the risk of bias for the five includedcross-sectional studies is presented in Appendix 4. Onestudy 21 had no clear study objectives andthree 21,23,24 , had poor outcome measurement. Also, itwas unclear what was used to determine statistical significance orprecision estimates for the studies 21,23,24 . In two ofthe studies 21,24 , the research methods wereinsufficiently described to facilitate possible replication. Twoothers 23,24 had funding sources or conflicts of interestthat might affect authors’ interpretation of the results. Thesestudies contributed 30% (2333/7222) of participants in thesystematic review. MC use and reduction of opioids dosage Among a cohort of 35 MC users in the cannabis program of NewHampshire or Vermont, U.S.., there was reduction in mean dailyopioid usage of 126.6mg, compared to 138.5mg in those not on theprogram 18 . In the same population, there was alsoreduction in mean emergency department visits and hospitaladmissions from chronic pain in the preceding calendaryear 18 . Furthermore, in 37 habitual opioid users forchronic pain enrolled in the medical cannabis program, patients onMC were more likely to reduce daily opioid dosage than those notusing MC (83.8% vs. 44.8%) over a 21-month period 19 . Acohort study, with a 4-year follow up period, reported anoccasional or regular reduction of opioid use with MC in 22% and30% of participants on the 3 rd and 4 th yearfollow-up waves, respectively 20 . In a cross-sectionalonline survey of 1513 members of dispensaries in New England,U.S.A., 76.7% of patients with non-cancer chronic pain usingopioids reduced opioid use after starting MC 25 .Similarly, a sample of 244 MC patients with non-cancer chronic painattending a Michigan MC dispensary reported a 64% reduction inopioid use after starting MC 21 , and 18.4% of 2032Canadian MC patients reported up to a 75% reduction in opioiddosage 23 . In a case series of three patients withnon-cancer chronic pain of 6-10 years duration, the use of MC ledto 60-100% reduction in the opioid dosage compared to when MC wasnot used 26 . Among 1514 respondents who used MC fornon-cancer chronic pain in Australia, there was an average of 70%pain relief, where 100% meant complete painrelief 22 . MC use and opioid substitution Three of the included studies reported an outright substitutionof opioids with MC in patients with non-cancer chronicpain 19,23,24 . There was opioid substitution with MC in40.5% of MC users compared to 3.4% in non-users 19 .Amongst MC users in a Canadian MC program, opioid medicationsaccounted for 35.3% (610/1730) of all prescription drugsubstitutions 23 , with 32% (80/251) 24 and59.3% (362/610) 23 of participants using MC fornon-cancer chronic pain reporting an outright stoppage ofopioids. Discussion The goal of this review was to assess the use of MC as anadjunct to opioids to reduce opioid dosage in the treatment ofnon-cancer chronic pain. After screening eligible studies, we foundnine studies that reported using MC to reduce opioid dosage for thetreatment of non-cancer chronic pain. This review found a muchhigher reduction in opioid dosage, reduced emergency room visits,and hospital admissions for chronic non-cancer pain by MC users,compared to people with no additional use of MC. There was 64%-75%reduction in opioid dosage for MC users, and complete stoppage ofopioid use for chronic non-cancer pain by 32%- 59.3% of MC users,when compared to patients without additional use of MC. The strength of the evidence is the adoption of a rigorousstandard approach to the review, based on the PRISMA checklist, theinclusion of publications from four databases and the independentscreening of study eligibility. Given the dearth of empiricalstudies about MC versus opioids for the treatment of non-cancerchronic pain, it is important that readers have information on thefull range of currently available evidence. Thus, this reviewrelaxed inclusion criteria allowing for the inclusion ofobservational studies, including case reports. Though findings fromthe nine included studies suggest that medical cannabis may be usedas an adjunct with opioids to reduce opioid dosage when treatingnon-cancer chronic pain, it is limited by the fact that it isderived from self-reports of reduction of opioid dosage as well asthe fact that most included studies did not report the MC dosagethat led to reduction of opioid dosage. More so, a study thatreported a 22-30% reduction of opioid medication use, when MC isused as an adjunct equally stated that 70-78% of participantsreported no influence of MC on the use of opioids. 20 Thewide range of MC dosage (1.5mg-2000mg) reported by two crosssectional studies suggests the difficulty in arriving at astandardized MC dosage for patients with non-cancer chronic pain.Furthermore, included cohort studies were assessed as havingserious or critical risk of bias overall. The lack of measurespreviously published to assess study outcomes, unclear precisionestimates and insufficiently described methods for these studiesunderscore the need for caution in interpretation of findings. The availability of, and access to, MC in states with MC lawsimplies that patients with non-cancer chronic pain who do notobtain relief with common medications might consider an MCprescription. Patient caregivers might suggest trialing MC torelieve pain or avoid the undesirable side effects of long-termopioid use, including dependence and addiction. Therefore, moreAmericans are likely to turn to MC especially with an estimated 50million living with non-cancer chronic pain. 3 While this review indicates the likelihood of reducing opioiddosage when used in combination with MC, there are shortcomings.One challenge is not knowing the optimal MC dosage to achieveopioid dosage reduction. Further studies are needed to graduallyincrease MC dosage titrated against a reduction in opioid dosageuntil an optimal pain relief effect is attained. A more notableconcern is the fact that none of the included studies discussedpotential adverse effects of using MC as an adjunct to opioids. Itis known that THC, the active ingredient of MC reducesgastrointestinal motility, drug absorption, andmetabolism 15,22 , resulting in reduced opioid absorptionand lowers the potential for addiction. MC used in combination withopioids in the treatment of non-cancer chronic pain may equallyhave yet unknown health consequences. Thus, there is an urgent needfor well-planned research studies to validate current evidence inthe scientific literature. Large scale and experimental studies areneeded to better understand MC’s use as an adjunct to opioids fortreating non-cancer chronic pain. Irrespective of the route ofadministration used, the different pharmacokinetic properties ofmedical cannabis dictate that standardized cannabis composition andpackages should be used to allow for comparison of researchfindings. In states where MC is legal, future research should assess theeffects of long-term MC use on opioid addiction and opioid-relateddeaths. Additionally, there is a need to assess the optimal/standardized MC dosage to achieve a reduction in opioid dosage andwhat routes of MC administration would most reduce opioid dosagethe fastest. Researchers must also assess the long-term health andwellness consequences of reduced gastrointestinal motility reportedto be beneficial to reduce opioid dependence and opioid-relatedmortality. Conclusion Given the current opioid epidemic in the U.S. and medicalcannabis’s recognized analgesic properties, MC could serve as aviable option to achieve opioid dosage reduction in managingnon-cancer chronic pain. Unfortunately, the evidence from thisreview cannot be relied upon to promote MC as an adjunct to opioidsin treating non-cancer chronic pain. The nine available studiesincluded in this review suggest that cannabis was effective as anadjunct to opioid in reducing the dosage of opioids in studyparticipants. However, the design of included studies provides alimited basis on which to make a rational, evidence-basedrecommendation. As the U.S. grapples with the opioid abuse epidemicand searches for less addictive alternatives, experimental studiesare urgently needed to assess the effects of cannabis on non-cancerchronic pain as well as its potential to reduce the need foropioids. If cannabis is found to be effective in reducingnon-cancer chronic pain, it could serve as a viable substitute forprescription opioids, thus mitigating the opioid epidemic. Declarations Ethical Approval and Consent to participate This is not applicable Consent for publication This is not applicable Availability of supporting data The systematic review included published studies that arereadily available to the public Competing interests Authors declare they have no competing interests. Funding This systematic review was funded through a grant entitled“Research and Evaluation Services” awarded by the c under contractnumber ADHS12-017291. The content of this publication is solelythat of its authors and does not necessarily represent the officialviews of ADHS. Authors' contributions JE and CR conceived the idea. IA, BO, JK and AO did studyeligibility screening. BO and JK performed quality assessment ofincluded studies. BO wrote the draft manuscript which had criticalinputs from all other authors. All authors agreed to the version ofthe manuscript submitted to systematic reviews. Acknowledgements Annabelle V. 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Can JAnaesth . 2016;63(3):307–310.doi:10.1007/s12630-015-0525-6 Table TABLE1: C haracteristics of includedstudies 1 Barlowe 2019 Methods RetrospectiveCohort Study Participants Patients atDartmouth-Hitchcock Medical Center enrolled in active opioidcontracts for painful chronic pancreatitis Intervention 35 out of 53patients were registered with a state therapeutic cannabis programin either New Hampshire or Vermont. Study did not report method ofuse of medical cannabis (MC). Outcomes Opioidprescription dose was converted into a morphine equivalentdose (MED). Patients registered on the cannabis program showed adecreased mean daily opioid use of 126.6 MED (±195.6 MED) comparedto those who were not enrolled183.5 MED (±284.5 MED) , =P= 0.39. Patients enrolled in state therapeutic cannabis programs haddecreased mean hospital admissions in the past calendar year as compared to the unenrolled group.; P= .53 and had reduced number of visits to the emergency department inthe past year as compared to those enrolled in the active opioidcontract,( P = 0.59) and a fall in mean emergency departmentvisits in the past calendar year as compared to patients notenrolled (P = .39). Average daily opioid use in patients atinitiation time is 190.34 MED (± 273.3MED). 2 Boehnke 2016 Methods Crosssectional survey through online questionnaires to medical cannabispatient Participants 244 MedicalCannabis patients with CP who patronized a medical cannabisdispensary in Michigan between 2013-2015. Survey has 46questions detailing medical conditions for which MC was used andparticipants completed the 2011 Fibromyalgia Survey Criteria tostratify level of pain. Study did not report methods of use ofMC. Intervention Nointervention, however, survey was on participants who were alreadyon medical cannabis Outcomes Patients withlower pain centralization had the largest reductions in opioid useas compared to those who reported higher levels of paincentralization. Mean change in self-reported opioid use was-64% 3 Campbell 2018 Methods Cohort studywith a 4-year follow up.. Baseline interviews and self-completedsurveys were used to get participants'responses. Participants 1514participants 18 years or older using opioids, recruited acrosscommunity pharmacies across Australia. Although the questionnaireasked about the methods of use of MC, the study did not report onthis. Interventions None Outcomes At4 th -year follow up, 24% of participants had used MC forpain. At 3year- and 4 year- follow up waves, 78% and 70% ofparticipants with adjuvant MC usage, reported no effects of MC onopioid use, respectively. Also, at 3-year and 4-year follow upwaves, 22% and 30% of participants with adjuvant MC usage, reportedan occasional or regular reduction of opioids when usingMC. 4 Dengenhardt2015 Methods Communitysurvey of a sample of people previously prescribed opioids fornon-cancer chronic pain. Study included 1514 people in Australia tocollect data on cannabis use, ICD10- cannabis use disorder andcannabis use for pain. Participants 1514participants who had previous prescription of medical cannabis.Study did not report on method of use ofMC. Intervention Nointervention, however, survey was on participants who were alreadyon medical cannabis. Outcomes 16 % of thecohort used medical cannabis for pain relief on the survey month.Average pain relief was 70%. In contrast, the average reported painrelief they reported from opioid medication was 50%. Those who usedmedical cannabis were mostly younger, had greater pain severity,were on higher opioid doses and were more likely to be non-adherentto the prescribed opioid medication. Of those who had used cannabisfor pain relief, n = 34, felt that cannabis provided 100% painrelief; only four of these reported that their medications gavethem 100% pain relief (and among all those using cannabis for painrelief, n = 10 reported 100% pain relief from theirmedications). 5 Lucas2017 Methods CrossSectional Survey of registered customers of Tilray a registeredproducer of medical cannabis. Participants 301participants, 53% used medical cannabis for chronic pain. Methodsof MC use include: j oints(243; 90%), vaporizers (n=234; 86%), oral/edibles (baked goods,butter, tincture,etc.) (207; 76%) and cannabis-infused topicalointments (44;16%). Intervention Nointervention, however, survey was on participants who were alreadyon medical cannabis Outcomes 73% usemedical cannabis for CP; 335 of participants reported substitutingopioids with medical cannabis. 6 Lucas2019 Methods Crosssectional survey collected via email from Canadian medical cannabispatients collected information on patterns of use and impact ofmedical cannabis on use of prescription drugs, tobacco, illicitsubstances, alcohol and tobacco. Participants 2032participants, 91% Caucasian and 62% males. Primary method of use ofMC was vapourizer (31.1%), joint (30.4%) oral/edible(16.3%), pipe(11.3%) waterpipe/bong (10.4%), topical(0.3%, juicing(0.2%) Intervention Nointervention, however, survey was on participants who were alreadyon medical cannabis. Outcomes Prescriptiondrugs were the most cited substances that cannabis was used tosubstitute (69.1%). 35.3% of theses prescription medicines wasopiates and opioids. Patients cited the following reasons by rankfor substitution: a safer alternative, fewer adverse effects,better symptom management, fewer withdrawal symptoms, ability toobtain medical cannabis and greater social acceptance of cannabisthan prescription drugs. 7 Lynch2003 Methods Case Seriesof three patients who used small doses of smoked marijuana incombination with an opioid. Participants Patient A:47-year-old woman with a ten-year history of chronic progressivemultiple sclerosis with significant ambulatory function from jointpain and leg spasticity. Opioid regiment was long acting morphine75mg per day, tizanidine 24mg per day and Sertraline 150mg atbedtime. Patient B:35-year-old HIV Positive with painful peripheral neuropathy. Opioidregiment consisted of long-acting morphine 360 mg per day withmorphine sulfate 75mg 4 times daily and gabapentin 2,400 mg perday. Patient C: 44 year-old-man with a 6-year lower back and leg painfollowing a traumatic fall. Opioid regiment was long actingmorphine, 150mg per day and cyclobenzaprine 10mg three times perday. Methods ofuse of MC was smoked marijuana for the threepatients. Intervention Patient A:2-4 puffs of smoked marijuana at bedtime. Morphine regimentdecreased. Patient B:3-4 puffs 3-4 times per day. The morphine regiment decreased overtwo years. Patient C:Several puffs to one joint 4-5 time perday. Outcome Patient A:Reported improvement in pain. Patient B: Reported an improvement in pain except during an infectionwith Herpes Zoster and discontinued morphine after twoyears. Patient C:Reported improvement in pain and was able to reduce his dose ofmorphine. 8 Piper2017 Methods ConvenientSampling method for s cross sectionalsurvey Participants 1513participants from a convenient sampling of members ofdispensaries of New England U.S., primarily from Maine,Vermont and Rhode Island. Study did not report method of useof MC. Intervention 215 regularlyused opioids, 70% use MC for CP reported use of opioids withcannabis. Outcomes 76.7%reported a reduction in their opioid use, slightly or a lot sinceinitiating medical cannabis. 9 Vigil2017 Methods Quasi-experimental study of 37 habitual opioidusers for chronic pain enrolled in the Medical Cannabis Program(MCP) compared to 29 unenrolled patients over 21months. Intervention Nointervention, however, survey was on participants who were alreadyon medical cannabis. Study did not report on methods of use ofMC. Outcomes The medicalcannabis patients had 5.12 higher odds of reducing dailyprescriptions of opioids with improvements in pain reduction,quality of life, social life and activitylevels. Supplementary Files RevisedCleanAPPENDICES.docx Cite Share Download PDF Status: Published Journal Publication published 28 Jul, 2020 Read the published version in Systematic Reviews → Version 3 posted Editorial decision: Accept 10 Jul, 2020 Review # 1 received at journal 25 Jun, 2020 Reviewer # 1 agreed at journal 17 Jun, 2020 Reviewers invited by journal 16 Jun, 2020 Editor assigned by journal 01 Jun, 2020 Submission checks completed at journal 31 May, 2020 Editor invited by journal 31 May, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-16781","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":633588,"identity":"fbf81917-7761-4f3e-abd7-00077380bbee","order_by":0,"name":"Babasola Okusanya","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABH0lEQVRIiWNgGAWjYBACAwY2KIu9AcS1ABKMDVChBAJaeA6AuBKkaJEAK5BAlsSuxZy9LU3yR82dxP6Zj49u+FEgwcA/+3Dzh4877Bj42XMMsGmx7Dl2TJrn2LPEGbfT0m72AB0mcS6xwXDmmWQGyZ43WLUY3Ehvk2ZgO5zYcDvH7AYPyC9nGBuSeduYgVLYbQFpkfzx73Di/Jvnv938A9QiD9RymLetnsEep5a0YxK8bYcTN9zgYbsNssXgDGNjM1AEGHo4/ZJszdt32HjjmTSz2zIGEjyGZxibGWe2HeeROPOsAEeIGd788e2w7Lzjh5/dfPPHRk7uDPvjDx/bquX425M3YA1lKHBsgDJ4GNAZuIA9IQWjYBSMglEwggEAtwxlpyTO7TkAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-2381-873X","institution":"University of Arizona Mel and Enid Zuckerman College of Public Health","correspondingAuthor":true,"prefix":"","firstName":"Babasola","middleName":"","lastName":"Okusanya","suffix":""},{"id":633589,"identity":"514cd5c4-3664-4dd1-9821-2d4945ea4017","order_by":1,"name":"Ibitola O. Asaolu","email":"","orcid":"","institution":"University of Arizona Mel and Enid Zuckerman College of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Ibitola","middleName":"O.","lastName":"Asaolu","suffix":""},{"id":633590,"identity":"47b9401c-de1c-4f8a-8c37-99c2e962ef08","order_by":2,"name":"John E. Ehiri","email":"","orcid":"","institution":"University of Arizona Mel and Enid Zuckerman College of Public Health","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"E.","lastName":"Ehiri","suffix":""},{"id":633591,"identity":"be497b60-397f-48bf-bf6c-73072b3464f6","order_by":3,"name":"Linda Jepkoeach Kimaru","email":"","orcid":"","institution":"University of Arizona Mel and Enid Zuckerman College of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Linda","middleName":"Jepkoeach","lastName":"Kimaru","suffix":""},{"id":633592,"identity":"1870193a-4fd1-4ec4-b844-e1417acab10a","order_by":4,"name":"Abidemi Okechukwu","email":"","orcid":"","institution":"University of Arizona Mel and Enid Zuckerman College of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Abidemi","middleName":"","lastName":"Okechukwu","suffix":""},{"id":633593,"identity":"dc37bd81-af3b-40b4-a87f-f24c1fdc9281","order_by":5,"name":"Cecilia Rosales","email":"","orcid":"","institution":"University of Arizona Mel and Enid Zuckerman College of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Cecilia","middleName":"","lastName":"Rosales","suffix":""}],"badges":[],"createdAt":"2020-03-06 15:21:49","currentVersionCode":3,"declarations":"","doi":"10.21203/rs.3.rs-16781/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-16781/v3","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13643-020-01425-3","type":"published","date":"2020-07-28T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":1265719,"identity":"e0197962-83f7-4baa-8229-0ce7ab5a89f2","added_by":"auto","created_at":"2020-06-05 18:30:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35920,"visible":true,"origin":"","legend":"Detailed study selection process","description":"","filename":"fig1.PNG","url":"https://assets-eu.researchsquare.com/files/rs-16781/v3/fig1.PNG"},{"id":13536206,"identity":"4ad9da5c-6bc9-4a97-ae14-1ed31dc3ff4f","added_by":"auto","created_at":"2021-09-17 01:31:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":379382,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-16781/v3/243d26c8-b5cc-4889-95ac-058fff14f546.pdf"},{"id":1265721,"identity":"51f1f146-4eb8-4c5b-b23f-bf695cc76d78","added_by":"auto","created_at":"2020-06-05 18:30:39","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25736,"visible":true,"origin":"","legend":"","description":"","filename":"RevisedCleanAPPENDICES.docx","url":"https://assets-eu.researchsquare.com/files/rs-16781/v3/RevisedCleanAPPENDICES.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eMedical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: A systematic review\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003ePain is an unpleasant experience that is subjective in nature;it differs in duration and etiology. Chronic pain, often describedas pain that persists for a minimum of three months, may stem froman initial injury (e.g. back sprain), illness, or an unexplainedcause.\u003csup\u003e1\u003c/sup\u003e Non-cancer chronic pain differs from cancer painbecause cancer pain arises from the invasion of a tumor and theinteraction among tumor cells, the nervous system, and anindividual’s immune system.\u003csup\u003e2,3\u003c/sup\u003e Cancer pain oftenadvances as the disease progresses.\u003csup\u003e2\u003c/sup\u003e Because ofdifferences in etiology and management of these forms of pain, thisreview focused on non-cancer chronic pain.\u003c/p\u003e\u003cp\u003eThe pain alleviating effect of MC is conferred by thetherapeutic effect of Tetrahydrocannabinol-alpha (THC) - thedominant component of the cannabis extract - and cannabidiol (CBD),a lesser (40%) component of the extract of MC\u003csup\u003e7\u003c/sup\u003e.Cannabisis considered an illicit drug by the U.S. Drug Enforcement Agency(DEA), and it is not approved by the Food and Drug Administration(FDA)\u003csup\u003e8\u003c/sup\u003e . Nevertheless, several U.S. states have policiespermitting cannabis use to treat certain medicalconditions\u003csup\u003e9\u003c/sup\u003e. A meta-analysis of MC for non-cancerchronic pain reported a significant effect on pain reduction,although its effect was marred with high number needed to treat,and a higher likelihood to harm\u003csup\u003e10\u003c/sup\u003e. More so, comparedwith placebo, while MC may increase the number of people achievingpain relief, it is associated with an increase in nervous systemadverse events\u003csup\u003e11\u003c/sup\u003e. These reports cast doubt on theeffectiveness of MC for non-cancer chronic pain. Pain, includingback pain, migraine, chronic pain, arthritis, and pain from cancerand surgery, is the most common condition for which MC isprescribed by health providers\u003csup\u003e6,8\u003c/sup\u003e. When MC is used bypatients taking opioids, it does not significantly change the areaunder the curve (AUC) of opioids or their metabolites, and there isa time delay to maximum serum concentration (Cmax) ofopioids.\u003csup\u003e12\u003c/sup\u003e In addition, MC has no significant effect onthe pharmacokinetics of opioids.\u003csup\u003e12\u003c/sup\u003e In one study, 35.8%of respondents substituted opioids for MC, with greatersubstitution among those with comorbidities like pain.\u003csup\u003e13\u003c/sup\u003eConsequently, MC is perceived as an effective remedy for non-cancerchronic pain as well as a potential substitute that may help curbthe on-going opioid epidemic.\u003csup\u003e13\u003c/sup\u003e This led to anincreasing interest in research on MC, though there is a limitedfocus on the use of MC for opioid dosage reduction or non-cancerchronic pain. For instance, a systematic review by Whiting et al.included patients with chronic cancer pain and studies thatcompared CBD to a placebo.\u003csup\u003e14\u003c/sup\u003e Another clinical review byHill discussed the indications for MC and patient eligibility forMC certification, without an appraisal of MC for non-cancer chronicpain.\u003csup\u003e15\u003c/sup\u003e In addition, a review by Campbell et. al.summarized literature on MC use for non-cancer chronicpain.\u003csup\u003e16\u003c/sup\u003e Therefore, in this review our objective of thisreview was to assess the effectiveness of MC in reducing opioiddosage or substituting opioids for the treatment of non-cancerchronic pain.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eType of Studies\u003c/em\u003e: Cohort, randomized controlled trials,controlled before-and-after studies, cross-sectional studies, andcase reports.\u003c/p\u003e\u003cp\u003e\u003cem\u003eType of Participants\u003c/em\u003e: Human participants aged 18 yearsor older who received MC as an adjunct to opioids for the treatmentof non-cancer chronic pain. Studies involving cell lines, tissueculture, or animal models were excluded.\u003c/p\u003e\u003cp\u003e\u003cem\u003eType of intervention\u003c/em\u003e: Use of MC as an adjunct toopioids in treating non-cancer chronic pain.\u003c/p\u003e\u003cp\u003e\u003cem\u003eType of comparison\u003c/em\u003e: Participants who did not receive MCas an adjunct to opioids in treating non-cancer chronic pain.\u003c/p\u003e\u003cp\u003e\u003cem\u003eType of Outcome Measures\u003c/em\u003e: The primary outcome ofinterest is the reduction of opioid dosage for non-cancer chronicpain treatment.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSearch strategy\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA Health Sciences Librarian (AN) developed the search strategy(\u003cstrong\u003eAppendix 1\u003c/strong\u003e) for the review and searched PubMed,Web of Science, PsycINFO, and Ovid (Medline). All databases weresearched for articles published from inception to October 31, 2019.Two reviewers searched the Grey literature using Google and GoogleScholar.\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy selection\u003c/em\u003e\u003c/p\u003e\u003cp\u003eTwo reviewers (BO and IA) screened articles against theinclusion criteria, and disagreements regarding study eligibilitywere resolved by discussion with a third reviewer (JE). Dataextraction was done by a reviewer and cross checked by anotherreviewer. Overall, nine studies were included in the review asshown in the PRISMA diagram (\u003cstrong\u003eFigure 1\u003c/strong\u003e). Studieswere eligible for inclusion if they were a cohort study, randomizedcontrolled trials, controlled before-and-after studies, cross-sectional studies, or case reports. The primary outcome of interestis reduction of opioid dosage for non-cancer chronic paintreatment.\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy quality assessment\u003c/em\u003e\u003c/p\u003e\u003cp\u003eQuality assessment of included studies was conductedindependently by two reviewers (LK and BO), using the ROBINS-I riskof bias tool for cohort studies and the AXIS tool forcross-sectional studies\u003csup\u003e17\u003c/sup\u003e. Disagreements were resolvedby discussion. Cohort studies were assessed for bias related to 1)confounding; 2) selection of participants; 3) classification ofinterventions; 4) deviations from intended interventions; 5)missing data; 6) measurement of outcomes; and 7) selection of thereported result. Each section of the bias assessment was judged tosee if there was a low, moderate, serious, or critical risk ofbias. An overall assessment of the risk of bias was made based onthe most severe form of risk of bias reported in any of thedomains. The cross-sectional studies were assessed for bias in eachsection of the publication as in Appendix 3: Introduction, Methods,Results, Discussion, and Others. Risk of bias criteria wereassessed as “Yes”, “NO” or “Do not know” (Appendix 3). Given theheterogeneity of included studies a meta-analysis was not possible.Thus, a qualitative summary of the evidence was conducted.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe search yielded 4,316 articles and 24 reports from thedatabases and grey literature, respectively. 1,900 duplicates wereeliminated, leaving 2,440 unique studies. Two authors screened the2,440 studies and selected full texts of nine studies thatqualified for inclusion (\u003cstrong\u003eFigure 1\u003c/strong\u003e).\u003c/p\u003e\u003cp\u003e\u003cem\u003eCharacteristics of included studies\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe search of the four databases yielded 4316 titles, while thegrey literature search provided additional 24 research titles. Twothousand, four hundred and forty (2440) titles were remaining afterthe removal of duplicates; 2410 titles were ineligible and screenedout at the abstract stage. Thirty (30) full text articles werescreened, out of which 21 were excluded (Appendix 2).\u003c/p\u003e\u003cp\u003eNine observational studies involving 7,222 participants wereincluded in this review. Included studies (threecohort\u003csup\u003e18-20\u003c/sup\u003e, five cross sectional\u003csup\u003e21-25\u003c/sup\u003e andone case series\u003csup\u003e26\u003c/sup\u003e) were published between 2003 and 2019in Australia, Canada, and the U.S. Although most of the studies didnot report the dosage of MC, two reported MC dosage range of 1.5mg-2000mg\u003csup\u003e23,24\u003c/sup\u003e. The participants ranged in age from 34 to70 years old. See Table 1, Characteristics of included studies, fordetailed indications for, and the setting of administration ofMC.\u003c/p\u003e\u003cp\u003e\u003cem\u003eQuality assessment of included studies\u003c/em\u003e\u003c/p\u003e\u003cp\u003eOne cohort study\u003csup\u003e18\u003c/sup\u003e had a serious risk of confoundingand did not provide enough information to make an overall risk ofbias assessment. The other cohort study\u003csup\u003e19\u003c/sup\u003e had a seriousrisk of bias related to missing data and inadequate measurement ofoutcomes The third cohort study\u003csup\u003e20\u003c/sup\u003e, had a serious risk ofbias for confounding and measurement of outcomes, and critical riskof bias related to missing data, with an overall critical risk ofbias assessment. See Appendix 3 for the risk of bias assessment ofincluded cohort studies.\u003c/p\u003e\u003cp\u003eA complete assessment of the risk of bias for the five includedcross-sectional studies is presented in Appendix 4. Onestudy\u003csup\u003e21\u003c/sup\u003e had no clear study objectives andthree\u003csup\u003e21,23,24\u003c/sup\u003e, had poor outcome measurement. Also, itwas unclear what was used to determine statistical significance orprecision estimates for the studies\u003csup\u003e21,23,24\u003c/sup\u003e. In two ofthe studies\u003csup\u003e21,24\u003c/sup\u003e, the research methods wereinsufficiently described to facilitate possible replication. Twoothers\u003csup\u003e23,24\u003c/sup\u003e had funding sources or conflicts of interestthat might affect authors’ interpretation of the results. Thesestudies contributed 30% (2333/7222) of participants in thesystematic review.\u003c/p\u003e\u003cp\u003e\u003cem\u003eMC use and reduction of opioids dosage\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAmong a cohort of 35 MC users in the cannabis program of NewHampshire or Vermont, U.S.., there was reduction in mean dailyopioid usage of 126.6mg, compared to 138.5mg in those not on theprogram\u003csup\u003e18\u003c/sup\u003e. In the same population, there was alsoreduction in mean emergency department visits and hospitaladmissions from chronic pain in the preceding calendaryear\u003csup\u003e18\u003c/sup\u003e. Furthermore, in 37 habitual opioid users forchronic pain enrolled in the medical cannabis program, patients onMC were more likely to reduce daily opioid dosage than those notusing MC (83.8% vs. 44.8%) over a 21-month period\u003csup\u003e19\u003c/sup\u003e. Acohort study, with a 4-year follow up period, reported anoccasional or regular reduction of opioid use with MC in 22% and30% of participants on the 3\u003csup\u003erd\u003c/sup\u003e and 4\u003csup\u003eth\u003c/sup\u003e yearfollow-up waves, respectively\u003csup\u003e20\u003c/sup\u003e. In a cross-sectionalonline survey of 1513 members of dispensaries in New England,U.S.A., 76.7% of patients with non-cancer chronic pain usingopioids reduced opioid use after starting MC\u003csup\u003e25\u003c/sup\u003e.Similarly, a sample of 244 MC patients with non-cancer chronic painattending a Michigan MC dispensary reported a 64% reduction inopioid use after starting MC\u003csup\u003e21\u003c/sup\u003e, and 18.4% of 2032Canadian MC patients reported up to a 75% reduction in opioiddosage\u003csup\u003e23\u003c/sup\u003e. In a case series of three patients withnon-cancer chronic pain of 6-10 years duration, the use of MC ledto 60-100% reduction in the opioid dosage compared to when MC wasnot used\u003csup\u003e26\u003c/sup\u003e. Among 1514 respondents who used MC fornon-cancer chronic pain in Australia, there was an average of 70%pain relief, where 100% meant complete painrelief\u003csup\u003e22\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eMC use and opioid substitution\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThree of the included studies reported an outright substitutionof opioids with MC in patients with non-cancer chronicpain\u003csup\u003e19,23,24\u003c/sup\u003e. There was opioid substitution with MC in40.5% of MC users compared to 3.4% in non-users\u003csup\u003e19\u003c/sup\u003e.Amongst MC users in a Canadian MC program, opioid medicationsaccounted for 35.3% (610/1730) of all prescription drugsubstitutions\u003csup\u003e23\u003c/sup\u003e, with 32% (80/251)\u003csup\u003e24\u003c/sup\u003e and59.3% (362/610)\u003csup\u003e23\u003c/sup\u003e of participants using MC fornon-cancer chronic pain reporting an outright stoppage ofopioids.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe goal of this review was to assess the use of MC as anadjunct to opioids to reduce opioid dosage in the treatment ofnon-cancer chronic pain. After screening eligible studies, we foundnine studies that reported using MC to reduce opioid dosage for thetreatment of non-cancer chronic pain. This review found a muchhigher reduction in opioid dosage, reduced emergency room visits,and hospital admissions for chronic non-cancer pain by MC users,compared to people with no additional use of MC. There was 64%-75%reduction in opioid dosage for MC users, and complete stoppage ofopioid use for chronic non-cancer pain by 32%- 59.3% of MC users,when compared to patients without additional use of MC.\u003c/p\u003e\u003cp\u003eThe strength of the evidence is the adoption of a rigorousstandard approach to the review, based on the PRISMA checklist, theinclusion of publications from four databases and the independentscreening of study eligibility. Given the dearth of empiricalstudies about MC versus opioids for the treatment of non-cancerchronic pain, it is important that readers have information on thefull range of currently available evidence. Thus, this reviewrelaxed inclusion criteria allowing for the inclusion ofobservational studies, including case reports. Though findings fromthe nine included studies suggest that medical cannabis may be usedas an adjunct with opioids to reduce opioid dosage when treatingnon-cancer chronic pain, it is limited by the fact that it isderived from self-reports of reduction of opioid dosage as well asthe fact that most included studies did not report the MC dosagethat led to reduction of opioid dosage. More so, a study thatreported a 22-30% reduction of opioid medication use, when MC isused as an adjunct equally stated that 70-78% of participantsreported no influence of MC on the use of opioids.\u003csup\u003e20\u003c/sup\u003e Thewide range of MC dosage (1.5mg-2000mg) reported by two crosssectional studies suggests the difficulty in arriving at astandardized MC dosage for patients with non-cancer chronic pain.Furthermore, included cohort studies were assessed as havingserious or critical risk of bias overall. The lack of measurespreviously published to assess study outcomes, unclear precisionestimates and insufficiently described methods for these studiesunderscore the need for caution in interpretation of findings.\u003c/p\u003e\u003cp\u003eThe availability of, and access to, MC in states with MC lawsimplies that patients with non-cancer chronic pain who do notobtain relief with common medications might consider an MCprescription. Patient caregivers might suggest trialing MC torelieve pain or avoid the undesirable side effects of long-termopioid use, including dependence and addiction. Therefore, moreAmericans are likely to turn to MC especially with an estimated 50million living with non-cancer chronic pain.\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eWhile this review indicates the likelihood of reducing opioiddosage when used in combination with MC, there are shortcomings.One challenge is not knowing the optimal MC dosage to achieveopioid dosage reduction. Further studies are needed to graduallyincrease MC dosage titrated against a reduction in opioid dosageuntil an optimal pain relief effect is attained. A more notableconcern is the fact that none of the included studies discussedpotential adverse effects of using MC as an adjunct to opioids. Itis known that THC, the active ingredient of MC reducesgastrointestinal motility, drug absorption, andmetabolism\u003csup\u003e15,22\u003c/sup\u003e, resulting in reduced opioid absorptionand lowers the potential for addiction. MC used in combination withopioids in the treatment of non-cancer chronic pain may equallyhave yet unknown health consequences. Thus, there is an urgent needfor well-planned research studies to validate current evidence inthe scientific literature. Large scale and experimental studies areneeded to better understand MC’s use as an adjunct to opioids fortreating non-cancer chronic pain. Irrespective of the route ofadministration used, the different pharmacokinetic properties ofmedical cannabis dictate that standardized cannabis composition andpackages should be used to allow for comparison of researchfindings.\u003c/p\u003e\u003cp\u003eIn states where MC is legal, future research should assess theeffects of long-term MC use on opioid addiction and opioid-relateddeaths. Additionally, there is a need to assess the optimal/standardized MC dosage to achieve a reduction in opioid dosage andwhat routes of MC administration would most reduce opioid dosagethe fastest. Researchers must also assess the long-term health andwellness consequences of reduced gastrointestinal motility reportedto be beneficial to reduce opioid dependence and opioid-relatedmortality.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eGiven the current opioid epidemic in the U.S. and medicalcannabis’s recognized analgesic properties, MC could serve as aviable option to achieve opioid dosage reduction in managingnon-cancer chronic pain. Unfortunately, the evidence from thisreview cannot be relied upon to promote MC as an adjunct to opioidsin treating non-cancer chronic pain. The nine available studiesincluded in this review suggest that cannabis was effective as anadjunct to opioid in reducing the dosage of opioids in studyparticipants. However, the design of included studies provides alimited basis on which to make a rational, evidence-basedrecommendation. As the U.S. grapples with the opioid abuse epidemicand searches for less addictive alternatives, experimental studiesare urgently needed to assess the effects of cannabis on non-cancerchronic pain as well as its potential to reduce the need foropioids. If cannabis is found to be effective in reducingnon-cancer chronic pain, it could serve as a viable substitute forprescription opioids, thus mitigating the opioid epidemic.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis is not applicable\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis is not applicable\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe systematic review included published studies that arereadily available to the public\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAuthors declare they have no competing interests.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis systematic review was funded through a grant entitled“Research and Evaluation Services” awarded by the c under contractnumber ADHS12-017291. The content of this publication is solelythat of its authors and does not necessarily represent the officialviews of ADHS.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Authors' contributions\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eJE and CR conceived the idea. IA, BO, JK and AO did studyeligibility screening. BO and JK performed quality assessment ofincluded studies. BO wrote the draft manuscript which had criticalinputs from all other authors. All authors agreed to the version ofthe manuscript submitted to systematic reviews.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAnnabelle V. Nuñez, of the Arizona Health Sciences Library,University of Arizona, Tucson, AZ, USA who developed the searchstrategies and performed the initial search of the databases.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAuthors' information\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis is as in the list of authors\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003col\u003e\u003cli\u003eArea under the curve: AUC\u003c/li\u003e\u003cli\u003eCannabidiol: CBD\u003c/li\u003e\u003cli\u003eMaximum serum concentration: Cmax\u003c/li\u003e\u003cli\u003eS. Drug Enforcement Agency: DEA\u003c/li\u003e\u003cli\u003eFood and Drug Administration: FDA\u003c/li\u003e\u003cli\u003eMedical Cannabis: MC\u003c/li\u003e\u003cli\u003eTetrahydrocannabinol alpha: THC\u003c/li\u003e\u003c/ol\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003ePlu NM. Chronic Pain: Symptoms, Diagnosis, \u0026 Treatment.\u003c/li\u003e\u003cli\u003eDahlhamer J, Lucas J, Zelaya C, et al. 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Effect of cannabis usein people with chronic non-cancer pain prescribed opioids: findingsfrom a 4-year prospective cohort study. \u003cem\u003eThe Lancet Publichealth.\u003c/em\u003e 2018;3(7):e341-e350.\u003c/li\u003e\u003cli\u003eBoehnke KF, Litinas E, Clauw DJ. Medical Cannabis Use IsAssociated With Decreased Opiate Medication Use in a RetrospectiveCross-Sectional Survey of Patients With Chronic Pain. \u003cem\u003eThejournal of pain : official journal of the American PainSociety.\u003c/em\u003e 2016;17(6):739-744.\u003c/li\u003e\u003cli\u003eDegenhardt L, Lintzeris N, Campbell G, et al. Experience ofadjunctive cannabis use for chronic non-cancer pain: findings fromthe Pain and Opioids IN Treatment (POINT) study. \u003cem\u003eDrug andalcohol dependence.\u003c/em\u003e 2015;147:144-150.\u003c/li\u003e\u003cli\u003eLucas P, Baron EP, Jikomes N. 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Legalization of medical marijuana andincidence of opioid mortality. JAMA internal medicine. 2014 Oct1;174(10):1673-4.\u003c/li\u003e\u003cli\u003eKaskie B, Ayyagari P, Milavetz G, Shane D, Arora K. Theincreasing use of cannabis among older Americans: A public healthcrisis or viable policy alternative? The Gerontologist. 2017 Nov10;57(6):1166-72.\u003c/li\u003e\u003cli\u003eCichewicz DL. Synergistic interactions between cannabinoid andopioid analgesics. Life sciences. 2004 Jan 30;74(11):1317-24.\u003c/li\u003e\u003cli\u003eMcCarty D. Does Medical Cannabis Reduce Use of PrescriptionOpioids?\u003c/li\u003e\u003cli\u003eCarter GT, Flanagan AM, Earleywine M, Abrams DI, Aggarwal SK,Grinspoon L. Cannabis in palliative medicine: improving care andreducing opioid-related morbidity. American Journal of Hospice andPalliative Medicine®. 2011 Aug;28(5):297-303.\u003c/li\u003e\u003cli\u003eCarter GT, Javaher SP, Nguyen MH, Garret S, Carlini BH.Re-branding cannabis: the next generation of chronic pain medicine?Pain management. 2015 Jan;5(1):13-21.\u003c/li\u003e\u003cli\u003eWilson M, Gogulski HY, Cuttler C, Bigand TL, Oluwoye O,Barbosa-Leiker C, Roberts MA. Cannabis use moderates therelationship between pain and negative affect in adults with opioiduse disorder. Addictive behaviors. 2018 Feb 1;77:225-31.\u003c/li\u003e\u003cli\u003eCollen M. Prescribing cannabis for harm reduction. Harmreduction journal. 2012 Dec 1;9(1):1.\u003c/li\u003e\u003cli\u003eHurd YL. Cannabidiol: swinging the marijuana pendulum from‘weed’to medication to treat the opioid epidemic. Trends inNeurosciences. 2017 Mar 1;40(3):124-7.\u003c/li\u003e\u003cli\u003eBagcchi S. Laws on medical cannabis lower opioid overdosemortality. The Lancet Oncology. 2014 Oct 1;15(11):e477.\u003c/li\u003e\u003cli\u003e\u003cem\u003ePeloquin M., Peters L. R., Mclarnon M. E., Barrett S.P.\u003c/em\u003e \u003cstrong\u003eDoes cannabis have therapeutic benefits forwithdrawing opioid addicts?\u003c/strong\u003e Heroin addiction and relatedclinical problems. 2011, Vol. 13 (1).\u003c/li\u003e\u003cli\u003eMeng H, Hanlon JG, Katznelson R, Ghanekar A, McGilvray I,Clarke H. The prescription of medical cannabis by a transitionalpain service to wean a patient with complex pain from opioid usefollowing liver transplantation: a case report.\u0026nbsp;\u003cem\u003eCan JAnaesth\u003c/em\u003e. 2016;63(3):307–310.doi:10.1007/s12630-015-0525-6\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table","content":"\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);\"\u003eTABLE1: C\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style='font-family: \"Helvetica Neue\";'\u003eharacteristics of includedstudies\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003ctable style=\"border: none;width:505.7pt;border-collapse:collapse;\"\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border: 1pt solid black;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e1\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: 1pt solid black;border-right: 1pt solid black;border-bottom: 1pt solid black;border-image: initial;border-left: none;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eBarlowe 2019\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eRetrospectiveCohort Study\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatients atDartmouth-Hitchcock Medical Center enrolled in active opioidcontracts for painful chronic pancreatitis\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e35 out of 53patients were registered with a state therapeutic cannabis programin either New Hampshire or Vermont. Study did not report method ofuse of medical cannabis (MC).\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOpioidprescription dose was converted \u0026nbsp;into a morphine equivalentdose (MED). Patients registered on the cannabis program showed adecreased mean daily opioid use of 126.6 MED (±195.6 MED) comparedto those \u003cspan style=\"background-image: initial; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;\"\u003ewho were not enrolled183.5 MED (±284.5 MED)\u003c/span\u003e, \u0026nbsp;=P= 0.39.\u0026nbsp;Patients enrolled in state therapeutic cannabis programs haddecreased mean hospital admissions in the past calendar year\u0026nbsp;as compared to the unenrolled group.; P= .53 and had reduced\u0026nbsp; number of visits to the \u0026nbsp;emergency department \u0026nbsp;inthe past year as compared to those enrolled in the active opioidcontract,( P = 0.59) \u0026nbsp;and a fall in mean emergency departmentvisits in the past calendar year as compared to \u0026nbsp;patients notenrolled (P = .39). Average daily opioid use \u0026nbsp;in patients atinitiation time is 190.34 MED (± 273.3MED).\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e2\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eBoehnke 2016\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eCrosssectional survey through online questionnaires to medical cannabispatient\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.25pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.25pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e244 MedicalCannabis patients with CP who patronized a medical cannabisdispensary in Michigan\u0026nbsp;between 2013-2015. Survey has 46questions detailing medical conditions for which MC was used andparticipants completed the 2011 Fibromyalgia Survey Criteria tostratify level of pain. Study did not report methods of use ofMC.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eNointervention, however, survey was on participants who were alreadyon medical cannabis\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid windowtext;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatients withlower pain centralization had the largest reductions in opioid useas compared to those who reported higher levels of paincentralization. Mean change in self-reported opioid use was-64%\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-top: none;border-left: 1pt solid black;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;padding: 0in;height: 10.6pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e3\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;padding: 3pt;height: 10.6pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eCampbell 2018\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-top: none;border-left: 1pt solid black;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;padding: 0in;height: 33pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(208, 206, 206);padding: 3pt;height: 33pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 0in;height: 33pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eCohort studywith a 4-year follow up.. Baseline interviews and self-completedsurveys were used to get participants'responses.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 3pt;height: 23.75pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;padding: 0in;height: 23.75pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e1514participants 18 years or older using opioids, recruited acrosscommunity pharmacies across Australia. Although the questionnaireasked about the methods of use of MC, the study did not report onthis.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(208, 206, 206);padding: 3pt;height: 15pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eInterventions\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 0in;height: 15pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eNone\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 3pt;height: 57pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;padding: 0in;height: 57pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eAt4\u003csup\u003eth\u003c/sup\u003e-year follow up, 24% of participants had used MC forpain. At 3year- and 4 year- follow up waves, 78% and 70% ofparticipants with adjuvant MC usage, reported no effects of MC onopioid use, respectively. Also, at 3-year and 4-year follow upwaves, 22% and 30% of participants with adjuvant MC usage, reportedan occasional or regular reduction of opioids when usingMC.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 27.75pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e4\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 27.75pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eDengenhardt2015\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eCommunitysurvey of a sample of people previously prescribed opioids fornon-cancer chronic pain. Study included 1514 people in Australia tocollect data on cannabis use, ICD10- cannabis use disorder andcannabis use for pain.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e1514participants who had previous prescription of medical cannabis.Study did not report on method of use ofMC.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eNointervention, however, survey was on participants who were alreadyon medical cannabis.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e16 % of thecohort used medical cannabis for pain relief on the survey month.Average pain relief was 70%. In contrast, the average reported painrelief they reported from opioid medication was 50%. Those who usedmedical cannabis were mostly younger, had greater pain severity,were on higher opioid doses and were more likely to be non-adherentto the prescribed opioid medication. Of those who had used cannabisfor pain relief, n = 34, felt that cannabis provided 100% painrelief; only four of these reported that their medications gavethem 100% pain relief (and among all those using cannabis for painrelief, n = 10 reported 100% pain relief from theirmedications).\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e5\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eLucas2017\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eCrossSectional Survey of registered customers of Tilray a registeredproducer of medical cannabis.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e301participants, 53% used medical cannabis for chronic pain. Methodsof MC use include: j\u003cspan style=\"background-image: initial; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;\"\u003eoints(243; 90%), vaporizers (n=234; 86%), oral/edibles (baked goods,butter, tincture,etc.) (207; 76%) and cannabis-infused topicalointments (44;16%).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eNointervention, however, survey was on participants who were alreadyon medical cannabis\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e73% usemedical cannabis for CP; 335 of participants reported substitutingopioids with medical cannabis.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e6\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eLucas2019\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(237, 237, 237);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(237, 237, 237);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eCrosssectional survey collected via email from Canadian medical cannabispatients collected information on patterns of use and impact ofmedical cannabis on use of prescription drugs, tobacco, illicitsubstances, alcohol and tobacco.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e2032participants, 91% Caucasian and 62% males. Primary method of use ofMC was vapourizer (31.1%), joint (30.4%) oral/edible(16.3%), pipe(11.3%) waterpipe/bong (10.4%), topical(0.3%, juicing(0.2%)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(237, 237, 237);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(237, 237, 237);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eNointervention, however, survey was on participants who were alreadyon medical cannabis.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePrescriptiondrugs were the most cited substances that cannabis was used tosubstitute (69.1%). 35.3% of theses prescription medicines wasopiates and opioids. Patients cited the following reasons by rankfor substitution: a safer alternative, fewer adverse effects,better symptom management, fewer withdrawal symptoms, ability toobtain medical cannabis and greater social acceptance of cannabisthan prescription drugs.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e7\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eLynch2003\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eCase Seriesof three patients who used small doses of smoked marijuana incombination with an opioid.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient A:47-year-old woman with a ten-year history of chronic progressivemultiple sclerosis with significant ambulatory function from jointpain and leg spasticity. Opioid regiment was long acting morphine75mg per day, tizanidine 24mg per day and Sertraline 150mg atbedtime.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient B:35-year-old HIV Positive with painful peripheral neuropathy. Opioidregiment consisted of long-acting morphine 360 mg per day withmorphine sulfate 75mg 4 times daily and gabapentin 2,400 mg perday.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient C:\u0026nbsp;44 year-old-man with a 6-year lower back and leg painfollowing a traumatic fall. Opioid regiment was long actingmorphine, 150mg per day and cyclobenzaprine 10mg three times perday.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods ofuse of MC was smoked marijuana for the threepatients.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient A:2-4 puffs of smoked marijuana at bedtime. Morphine regimentdecreased.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient B:3-4 puffs 3-4 times per day. The morphine regiment decreased overtwo years.\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient C:Several puffs to one joint 4-5 time perday.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcome\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient A:Reported improvement in pain.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient B:\u0026nbsp;Reported an improvement in pain except during an infectionwith Herpes Zoster and discontinued morphine after twoyears.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003ePatient C:Reported improvement in pain and was able to reduce his dose ofmorphine.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e8\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003ePiper2017\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd rowspan=\"4\" style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;background: white;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eConvenientSampling method for s cross sectionalsurvey\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eParticipants\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e1513participants \u0026nbsp; from a convenient sampling of members ofdispensaries of New England \u0026nbsp;U.S., primarily from Maine,Vermont and Rhode Island.\u0026nbsp;Study did not report method of useof MC.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e215 regularlyused opioids, 70% use MC for CP reported use of opioids withcannabis.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e76.7%reported a reduction in their opioid use, slightly or a lot sinceinitiating medical cannabis.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003e9\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd colspan=\"2\" style=\"width: 462.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px;\"\u003eVigil2017\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eMethods\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eQuasi-experimental study of 37 habitual opioidusers for chronic pain enrolled in the Medical Cannabis Program(MCP) compared to 29 unenrolled patients over 21months.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eIntervention\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 3pt;height: 9.7pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eNointervention, however, survey was on participants who were alreadyon medical cannabis. Study did not report on methods of use ofMC.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd style=\"width: 43.4pt;border-top: none;border-left: 1pt solid black;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;padding: 0in;height: 21.75pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 66pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 21.75pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eOutcomes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd style=\"width: 396.3pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid black;background: rgb(208, 206, 206);padding: 3pt;height: 21.75pt;vertical-align: top;\"\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003eThe medicalcannabis patients had 5.12 higher odds of reducing dailyprescriptions of opioids with improvements in pain reduction,quality of life, social life and activitylevels.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"background-color: rgb(255, 255, 255);\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp style='margin:0in;margin-bottom:.0001pt;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Opioid epidemic, medical cannabis, opioid substitution, opioid crisis","lastPublishedDoi":"10.21203/rs.3.rs-16781/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-16781/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eMedical cannabis (MC) is currently being used as an adjunct to opiates given its analgesic effects and potential to reduce opiate addiction. This review assessed if MC used in combination with opioids to treat non-cancer chronic pain would reduce opioid dosage.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e\u0026nbsp;Four databases - Ovid (Medline), Psyc-INFO, PubMed, Web of Science, and grey literature – were searched to identify original research that assessed the effects of MC on non-cancer chronic pain in humans. Study eligibility included randomized controlled trials, controlled before-and-after studies, cohort studies, cross-sectional studies, and case reports. All databases were searched for articles published from inception to October 31, 2019. Cochrane’s ROBINS-I tool and the AXIS tool were used for risk of bias assessment. PRISMA guidelines was followed in reporting the systematic review.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eNine studies involving 7,222 participants were included. There was a 64%-75% reduction in opioid dosage when used in combination with MC. Use of MC for opioid substitution was reported by 32%-59.3% of patients with non-cancer chronic pain. One study reported a slight decrease in mean hospital admissions in the past calendar year (P=.53) and decreased mean emergency department visits in the past calendar year (P=.39) for patients who received MC as an adjunct to opioids in the treatment of non-cancer chronic pain compared to those who did not receive MC. All included studies had high risk of bias, which was mainly due to their methods. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Conclusions: \u003c/strong\u003eWhile this review indicated the likelihood of reducing opioid dosage when used in combination with MC, we cannot make a causal inference. Although medical cannabis’s recognized analgesic properties make it a viable option to achieve opioid dosage reduction, the evidence from this review cannot be relied upon to promote MC as an adjunct to opioids in treating non-cancer chronic pain. More so, the optimal MC dosage to achieve opioid dosage reduction remains unknown. Therefore, more research is needed to elucidate whether MC used in combination with opioids in the treatment of non-cancer chronic pain is associated with health consequences that are yet unknown.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSystematic review registration\u003c/strong\u003e: This systematic review was not registered.\u003c/p\u003e","manuscriptTitle":"Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: A systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2020-06-05 18:30:37","doi":"10.21203/rs.3.rs-16781/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-07-10T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-06-25T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept\nForm responses:\n---\n\nComments to Author:\n---\nI think the authors have adequately addressed the issues I raised and I am content to accept this version as is.* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n"},{"type":"reviewerAgreed","content":"","date":"2020-06-17T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-06-16T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-06-01T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-05-31T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-05-31T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2020-03-30 15:26:18","doi":"10.21203/rs.3.rs-16781/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-05-25T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-05-10T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major Revision\nForm responses:\n---\n\nComments to Author:\n---\nThe authors of the article reviewed studies on the impact of supplementary medical cannabis on reductions in opioid use. The authors make a good case why this is an important question. However, the reporting of the articles needs improvement. I encourage the authors to go through their article using the PRISMA reporting guidelines for systematic reviews and the PRISMA-A extension for abstracts of systematic reviews. Furthermore, given the weak underlying evidence, results should be interpreted very carefully. There are also some discrepancies in the manuscript that need to be addressed.\n\nAbstract:\n1) In accordance with PRISMA-A please add the following information to the abstract: study designs searched for and included; search date; information on risk of bias assessment.\n2) The results section of the abstract (arguably being the most important part of any article) suggests very impressive effects of medical cannabis. However, as the authors write in the conclusion of the main text: \"Unfortunately, the evidence from this review, though somewhat promising, cannot be relied upon to promote MC as an adjunct to opioids in treating non-cancer chronic pain.\" To make this transparent, the results section in the abstract should start with a clear statement on the designs of the included studies and their limitations/risk of bias. It should be clarified that the included studies do not allow for causal inference.\n3) The p-values reported in the abstract do not correspond to the stated findings as they seem to be statistically nonsignificant (or their notation is unusual).\n4) The conclusion in the abstract also seems to be at odds with the much more cautious (and appropriate) conclusion in the article. This should be corrected.\n\nBackground:\n5) Please summarize the evidence for the effectiveness of medical cannabis and opioids in chronic non-cancer pain as this seems quite relevant to the review. Several systematic reviews have recently been conducted (e.g. Busse et al. JAMA. 2018 Dec 18;320(23):2448-2460, Stockings et al. Pain. 2018 Oct;159(10):1932-1954 and Mücke et al. Cochrane Database Syst Rev. 2018 Mar 7;3(3):CD012182.).\n\nMethods:\n6) The inclusion criteria described in the beginning and throughout the section are inconsistent regarding study design.\n7) Please provide in addition to the risk of bias assessment for the cross-sectional studies in Appendix 3 a table of the ROBINS-I assessments for the cohort studies.\n\nResults:\n8) Please add more information to the descriptive summary of the included studies in the introduction of the results section (including e.g. the medical conditions studies and the settings). Where this information was not available from the included study reports, please state this.\n\nCharacteristics of included studies:\n9) The reporting of the statistics in the characteristics of included studies table need to be improved (e.g. it is unclear what \"126.6 195.6 MED\" means). According to the original study the second number refers to the standards deviation, which suggests a skewed distribution (which as far as I can see, also makes use of a parametric test in the primary study questionable, although I am not a statistician).\n\nMinor comments:\n10) Please review the manuscript for formatting errors (e.g. reference 8 in line 57, page 3).\n11) Please avoid using the term \"promising\" in the conclusion as it can lead to spin.\n12) In the sentence \"data extraction was also done independently by a reviewer and cross checked by another\" in the methods section please avoid the term \"independently\", as this should only be used for independent duplicate extraction.\n* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2020-04-23T12:00:00+00:00","index":1,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nI believe the authors of the systematic review did a thorough job examining the evidence for the use of medical cannabis for the management of non-cancer chronic pain. I believe that some minor revisions are required, as listed below:\n1) Page 3, line 57: there is an issue with reference number 8\n2) Page 5, line 8: 4 databases (not including the grey literature) were searched. Of these, 2 were Pubmed and Ovid Medline. Both Pubmed and Ovid search Medline, but Pubmed also includes other content, so basically the authors duplicated their search. Can the authors explain why this was done?\n3) Page 5, lines 11-15 \u0026 line 26: the authors list the number of records identified at each stage. Technically, the number of retrieved records qualify as results and should not be listed in the Methods. I suggest moving any numbers from here to the results section and deleting the rest.\n4) Page 5, lines 28-32: Study designs, specifically, case reports and cross-sectional studies are included. This contradicts the inclusion criteria listed on page 4, line 44, which lists only cohort studies, randomized controlled trials and controlled before-and-after studies.\n5) Results: It would be useful to know the route of administration of medical cannabis for each of the included studies (perhaps in Table 1?) Can any conclusions be drawn on varying routes of administration?\n6) I believe there is an issue with the flowchart. There were 4316 (main search strategy) + 24 (grey literature) = 4340 records identified. 1901 duplicates were removed, which means there should be 4340-1901=2439 records screened at title \u0026 abstract screening stage, not 2440.\n7) The quality assessment for cross-sectional studies (AXIS)is provided in appendix 3, but not ROBIN-I for cohort studies. Can the authors provide this as well?* Level of interest: **An article of importance in its field that should be highlighted to relevant networks**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"reviewerAgreed","content":"","date":"2020-04-19T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-04-17T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-04-14T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-03-25T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-03-24T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-03-24T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-03-11 15:19:44","doi":"10.21203/rs.3.rs-16781/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revise before peer review","date":"2020-03-11T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-03-10T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-03-09T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-03-06T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-03-05T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"54dc7876-6162-4d07-ba70-c9536062fdf0","owner":[],"postedDate":"June 5th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":76374,"name":"Clinical Pharmacology"}],"tags":[],"updatedAt":"2020-08-04T21:17:46+00:00","versionOfRecord":{"articleIdentity":"rs-16781","link":"https://doi.org/10.1186/s13643-020-01425-3","journal":{"identity":"systematic-reviews","isVorOnly":false,"title":"Systematic Reviews"},"publishedOn":"2020-07-28 12:00:00","publishedOnDateReadable":"July 28th, 2020"},"versionCreatedAt":"2020-06-05 18:30:37","video":"","vorDoi":"10.1186/s13643-020-01425-3","vorDoiUrl":"https://doi.org/10.1186/s13643-020-01425-3","workflowStages":[]},"version":"v3","identity":"rs-16781","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-16781","identity":"rs-16781","version":["v3"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}