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Chronic pain and opioid misuse: a review of reviews Voon, Pauline; Karamouzian, Mohammad; Kerr, Thomas Aug 15, 2017

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REVIEWChronic pain and opioid mof reviewsarmmortality rates due to motor vehicle accidents and HIV- high risk of opioid dependence among individuals on POsrrent chronicconflicting re-Voon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 DOI 10.1186/s13011-017-0120-7number of systematic reviews have attempted to synthesizeBritish Columbia, 2206 East Mall, Vancouver, BC V6Z 1Z3, CanadaFull list of author information is available at the end of the articlesearch on the prevalence, risk factors, and clinical manage-ment approaches specific to this growing sub-population. AColumbia, St. Paul’s Hospital, 608-1081 Burrard Street, Vancouver, BC V6Z 1Y6,Canada2School of Population and Public Health, Faculty of Medicine, University ofamong chronic opioid users [5].The current body of literature on concupain and opioid misuse presents a range of* Correspondence: pvoon@cfenet.ubc.ca1British Columbia Centre for Excellence in HIV/AIDS, University of Britishrelated mortality [1, 2]. As such, increased attention is be-ing focused toward understanding the scale of the currentfor chronic pain [4] and, conversely, the potential for in-creased pain severity and decreased pain thresholdsescalating mortality rates that have surpassed nationalof comorbid chronic pain and PO or other substance misuse.Methods: A systematic database search was conducted to identify systematic reviews published between 2000 and2016. Eligible studies were systematic reviews related to chronic non-cancer pain and PO or other substance misuse.Evidence from the included reviews was synthesized according to epidemiology and clinical management themes.Results: Of 1908 identified articles, 18 systematic reviews were eligible for final inclusion. Two meta-analyses estimatedthe prevalence of chronic non-cancer pain in individuals using POs non-medically to be approximately 48% to 60%,which is substantially higher than the prevalence of chronic non-cancer pain in general population samples (11%to 19%). Five systematic reviews estimated the rates of PO or other opioid use in chronic pain populations withsubstantial variation in results (0.05% to 81%), likely due to widely varying definitions of dependence, substanceuse disorder, misuse, addiction, and abuse. Several clinical assessment and treatment approaches were identified,including: standardized assessment instruments; urine drug testing; medication counts; prescription drug monitoringprograms; blood level monitoring; treatment agreements; opioid selection; dosing and dispensing strategies; and opioidagonist treatment. However, the reviews commonly noted serious limitations, inconsistencies, and imprecision of studies,and a lack of evidence on effectiveness or clinical utility for the majority of these strategies.Conclusion: Overall, current systematic reviews have found a lack of high-quality evidence or consistent findings on theprevalence, risk factors, and optimal clinical assessment and treatment approaches related to concurrent chronic painand substance misuse. Given the role of systematic reviews in guiding evidence-based medicine and health policy,there is an urgent need for high-quality primary research to guide future systematic reviews to address the escalatingepidemic of harms related to chronic pain and substance misuse.Keywords: Chronic pain, Prescription opioid, Substance use, Addiction, Systematic review (3–10 keywords required)BackgroundAcross North America, the devastating crisis of prescrip-tion opioid (PO) related addiction and overdose has led toepidemic and implementing risk mitigation strategies. Inparticular, individuals demonstrating concurrent chronicpain and opioid misuse are considered to be at high riskfor opioid-related morbidity and mortality [3] given thehigh-risk populations. This review aims to synthesize systematic reviews on the epidemiology and clinical managementPauline Voon1,2* , Mohammad Karamouzian1,3 and ThomAbstractObjective: The crisis of prescription opioid (PO) related ha© The Author(s). 2017 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zeOpen Accessisuse: a reviews Kerr1,4s has focused attention toward identifying and treatingle is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Given that systematic reviews are the foundation forFollowing the PRISMA guideline [7], we searched for sys-to identify eligible systematic reviews. Reviews were eligiblerameters: author name, publication year, journal name, re-Evidence synthesisFrom a total of 1908 unique hits, 1870 were removedat the title and abstract screening phase and 38 full-text papers were screened (Fig. 1). Eighteen systematicreview articles were eligible for final inclusion andsummarized below according to epidemiologic andclinical management themes. Of the eighteen reviews,seven were deemed to be of low quality, six of moder-ate quality, and five of high quality using AMSTARscoring (see Additional file 1). Notably, while thesearch was not restricted to North American studies,only four out of the eighteen reviews were conductedoutside of North America, in Europe [10–13].Epidemiology of chronic pain and PO useRates of pain in non-medical PO usersGeneral population samplesFischer et al. found a 48% pooled prevalence of pain(95% confidence interval [CI]: 37%–59%; range: 30%–Voon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 Page 2 of 9view period, databases used, theme of the review (e.g.,epidemiology, assessment, treatment), number of includedstudies, studied population, and summary of findings. Evi-dence synthesis was conducted using a narrative approachbased on thematic findings.Quality assessmentThe quality of the systematic reviews was assessed usingfor inclusion if they were: peer-reviewed; systematic re-views related to CNCP and PO or other illicit opioid mis-use; focused on adult populations; and published inEnglish. Studies were excluded if they were: non-systematicreviews; reviews of non-primary research (e.g., reviews ofclinical guidelines); specific to acute or specialized pain(e.g., cancer pain, terminal or palliate pain); specific tonon-adult or specialized settings (e.g., surgical or intensivecare units) or populations (e.g., pregnant women, adoles-cent, elderly, or palliative care populations); or focused onevaluating a specific analgesic brand.Data extraction and analysisData was extracted and summarized for the following pa-tematic reviews related to chronic non-cancer pain(CNCP) and PO or other opioid misuse that were pub-lished in the following databases from January 1, 2000 toOctober 1, 2016: Medline, Cochrane Library, PsycINFO,Web of Science, EMBASE, and Google Scholar. Searchterms were combined using appropriate Boolean operatorsand included subject heading terms or key words for threekey aspects: chronic pain (e.g., pain OR pain management)AND analgesics (e.g., opioid OR opiate OR painkiller ORanalgesic) AND abuse (e.g., misuse OR non-medical ORaberrant OR addiction).Inclusion and exclusion criteriaTwo reviewers independently screened the search resultsevidence-based clinical and policy decision-making [6],this ‘review of reviews’ seeks to summarize the findingsof published systematic reviews related to the epidemi-ology, assessment, and treatment of comorbid chronicpain and opioid misuse.MethodsSearch strategyvarious aspects of the epidemiology or clinical manage-ment of comorbid chronic pain and opioid misuse.the Assessment of Multiple Systematic Reviews (AMSTAR)validated scale [8, 9].68%) from four general U.S. population samples report-ing non-medical PO use (Table 1), although the distinc-tion between chronic versus acute pain was not specified[14]. The authors found significant heterogeneity be-tween studies, likely due to the variability in the popula-tions studied and the measures used to ascertain pain.For instance, the study samples included both youngerand older adult populations.Substance use treatment samplesLusted et al. found a 58% pooled prevalence of pain(95% CI: 53%–64%) from eight samples of adult patientsin substance use treatment (Table 1) [15]. AmongFig. 1 Summary of study identification and selectionnVoon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 Page 3 of 9studies in which POs were reported as the primary drugrequiring substance use treatment, or in which PO de-pendence was reported, the pooled prevalence of painwas slightly higher at 60% (95% CI: 52%–67%). Signifi-cant heterogeneity was found between studies, likely dueto varying definitions used to ascertain non-medical POuse and pain.Rates of dependence, substance use disorder, andproblematic use in chronic pain patientsDependenceMinozzi et al. [11] found a 0.5% incidence (range: 0%–24%)and 4.5% prevalence (range: 0%–31%) of opioid dependencesyndrome (defined by DSM-IV or ICD-10 criteria) across17 studies of patients receiving opioids for pain, while Chouet al. [16] found a prevalence of 3%–26% for opioid de-pendence among chronic pain patients prescribed long-term opioid therapy in primary care settings (Table 2). Thissubstantial heterogeneity in results may be due to severalfactors. First, low-quality study designs were primarily used,such as uncontrolled case series or cross-sectional designs.Second, there may be significant heterogeneity in the typesof populations being studied. For instance, Minozzi et al.found only one study that reported dependence within indi-viduals with a history of substance abuse [17]. Third, thedefinitions of dependence tend to vary widely acrossTable 1 Rates of pain in samples using prescription opioids (POs)Author PopulationFischer et al. (2012) General population samples of young adultsor adults reporting non-medical PO useLusted et al. (2013) Adult substance use treatment samplesreporting non-medical PO useAdult substance use treatment samples withPO analgesics reported as the primary drugrequiring substance use treatment, or POdependence reportedAdult substance use treatment sampleswith any PO abuse reportedstudies. For example, some studies used the DSM-IVdefinition of opioid dependence, which includes criteriafor loss of control over use and negative health or socialconsequences, while other studies used the ICD-10 def-inition for opioid dependence, which includes criteriafor tolerance, withdrawal, and craving [11]. It is alsoworth pointing out that ‘opioid dependence,’ which wasdistinct from ‘opioid abuse’ in the DSM-IV, has beenreplaced with a single classification of ‘opioid use dis-order’ in the revised DSM-5, which may lead to evenfurther variation in future estimates [18].Substance use disorderMorasco et al. was the only review that estimated ratesof substance use disorder. Across 21 studies of CNCPpatients, the authors found varying prevalence estimatesfor substance use disorder (not restricted to opioids),ranging from 3% to 48% for current substance use disor-ders, and 15% to 74% for lifetime history of substanceuse disorder (Table 2) [19]. The highest rates were ob-served in individuals seeking opioid prescriptions fromemergency departments (74%) [20], individuals withAIDS comorbidity (48%) [21], and individuals who werescreened for any substance use using urine toxicology(35%) [22]. However, the authors deemed the quality ofthe studies to be generally low, and there was substantialheterogeneity in the study settings (e.g., inpatient versusoutpatient) and definitions of chronic pain and sub-stance use disorder across studies.Problematic use (e.g., misuse, abuse, and addiction)The review by Vowles et al. sought to measure moreprecise estimates of problematic opioid use among adultCNCP patients by using more explicitly defined terms[23]. The three types of problematic use measured were:(1) misuse, defined as the use of opioids contrary to theprescriber’s directions; (2) abuse, defined as opioid usefor non-medical intentions (e.g., euphoria or alteredconsciousness); and (3) addiction, defined as continuedopioid use despite impaired control, compulsive use,craving, or demonstrated or potential harms. The overallon-medicallyNumber ofstudiesRate calculated Estimate4 Pooled prevalence of pain 48%(95% CI: 37%–59%)8 Pooled prevalence of pain 58%(95% CI: 53%–64%)7 Pooled prevalence of pain 60%(95% CI: 52%–67%)2 Pooled prevalence of pain 50%(95% CI: 40%–60%)rate of problematic use across 38 studies ranged from<1% to 81%, with rates of misuse, abuse, and addictionranging from 21%–29%, 8% (based on one study), and8%–12%, respectively. In comparison, other reviewsfound ranges from 8%–16% for opioid misuse [16],0.43%–8% for opioid abuse [16, 24], and 0.05%–14% foropioid addiction [16, 24] (Table 2). One additional re-view of randomized controlled trials comparing opioidsversus placebo for CNCP was unable to draw conclu-sions about rates of addiction due to small sample sizesand short follow-up periods across fifteen studies [10].Factors that may have influenced the variation in theseestimates include varying diagnostic criteria for deter-mining problematic use, recruitment methods and ex-clusion criteria (e.g., many of studies exclude individualsmumf st7711892Voon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 Page 4 of 9Table 2 Rates of dependence, substance use disorder, and probleAuthor Population NoMinozzi et al. (2012) Individuals receiving any opioidanalgesic for acute or chronicpain from any physical condition11Morasco et al. (2011) Chronic non-cancer pain patients,regardless of whether they wereprescribed opioids22Vowles et al. (2015) Adults with chronic non-cancer pain(≥3 months) using oral opioids3211Noble et al. (2008) Patients treated with opioids forchronic non-cancer pain for atleast six months72with a history of addiction or substance use from enroll-ment), lack of comparison groups, high rates of studywithdrawal, or lack of intention-to-treat analyses.Correlates of concurrent pain and opioid misuseDemographicsAnalyzing data from 14 studies, Morasco et al. did notfind any demographic factors that were consistently dif-ferent between CNCP patients with versus without co-morbid substance use disorder [19]. Specifically, amongCNCP patients, the authors found inconsistent resultsrelated to the relationship between substance use statusand gender, age, employment, race or ethnicity, maritalstatus, or education status. Conversely, both Chou et al.and Turk et al. found that younger age appeared to in-crease the risk of opioid misuse [16, 25]. Regarding sex,Turk et al. also found that while female sex did not ap-pear to be a predictor for opioid misuse, there weremixed findings for the effect of male sex [25]. Further-more, while Turk et al. found mixed results for the effectof race on opioid misuse [25], Cintron et al. found thatracial and ethnic minorities (e.g., African Americans,Hispanics) were less likely to misuse POs compared toKalso et al. (2004) Adult patients with chronicnon-cancer pain in randomizedcontrolled trials comparing opioidsversus placebo15Chou et al. (2015) Adults with chronic pain prescribedlong-term opioid therapy – inprimary care3Adults with chronic pain prescribedlong-term opioid therapy – in painclinics7atic use in samples of chronic non-cancer pain patientsberudiesRate calculated EstimateMedian incidence ofdependence0.5%(Range: 0%–24%)Median prevalence ofdependence4.5%(Range: 0%–31%)Overall prevalence of currentsubstance use disorder3–48%Lifetime prevalence of anysubstance use disorder16%–74%Rate of problematic use <1%–81%Rate of misuse 21%–29%(95% CI: 13%–38%)Rate of abuse 8%Rate of addiction 8%–12%(95% CI: 3%–17%)Rate of addiction 0.05%(1 out of 2042 patients)Rate of abuse 0.43%(3 out of 685 patients)Caucasian populations, and yet these same racial and eth-nic minorities were more likely to experience undertreatedpain and less likely to be prescribed opioid analgesics fromclinicians [26]. Turk et al. suggest that such mixed find-ings may be due to inconsistent reporting of demographicvariables and underrepresentation of women and racialand ethnic minorities in studies of chronic pain popula-tions [25].Psychiatric comorbidityMorasco et al. found mixed and inconclusive data on re-lationship between psychiatric comorbidity and sub-stance use disorder in CNCP patients [19]. Turk et al.found a greater risk of substance abuse in chronic painpatients with mood disorders, particularly unipolar de-pression, but noted that this was not a consistent pre-dictor across all studies reviewed [25]. Similarly, Chouet al. found that major depression, as well as use of psy-chotropic medications, were associated with increasedrisk for opioid misuse among chronic pain patients [16].In studies of individuals with opioid use disorder, Denniset al. found that pain was significantly associated withconcurrent psychiatric disorder (pooled odds ratio: 2.18;Rate of addiction Estimates could not becalculated due to smallsample sizes and shortfollow-up periodsPrevalence of abuse 0.6%–8%Prevalence of dependence 3%–26%Prevalence of misuse 8%–16%Prevalence of addiction 2%–14%tive samples within specialized outpatient pain clinic set-tings with limited representation of women, minoritypopulations, or opioid-naïve patients [25, 31]. Finally,there is a lack of evidence to evaluate the impact theseinstruments may have on patient outcomes or clinicianbehaviors [30, 31]. Without strong evidence to guidedecision-making based on the results of these instru-ments, these tools appear to lack significant utility in theclinical setting [30, 31].Urine drug testingAs urine drug testing (UDT) is the most objectivemethod of assessing opioid misuse in chronic pain pa-tients, it is often considered a “gold standard” monitor-ing approach [25, 29]. However, while UDT may beuseful for risk identification and documentation pur-poses, there remains a lack of strong evidence to supportits accuracy or effectiveness in predicting, preventing, orreducing problematic opioid use behaviors or related ad-verse clinical outcomes (e.g., overdose, mortality) inchronic pain patients [16, 25, 28, 31, 32]. The few studiesevaluating UDT for reducing opioid misuse have beenfound to be poor- to fair-quality observational studieswith high risk for bias. For instance, there is substantialVoon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 Page 5 of 995% CI: 1.6–2.9; I2 = 0.0%) as well as poorer physical,personal, and social functioning compared to individualswith opioid use disorder who did not have pain [27].Substance misuse factorsSeveral of the reviews found that CNCP patients witha past or present history of opioid or other substanceuse disorder appear to be at greater risk for PO mis-use [12, 16, 19, 25, 28, 29]. Further, the use of mul-tiple substances may be correlated with PO misuse[25, 28]. In individuals with opioid use disorder,Dennis et al. found two studies in which chronic painhad no significant effect on illicit opioid use [27].Treatment-related factorsMorasco et al. found that CNCP patients with comorbidsubstance use disorder were more likely to be prescribedopioids—and at higher doses—than CNCP patients with-out substance use disorder [19]. The authors note thatthis counter-intuitive finding may reflect variation inhealthcare setting or comorbid conditions. Based on lim-ited and low-quality data, the authors did not find anysignificant differences related to treatment response out-comes for CNCP patients with versus without substanceuse disorder. However, it is important to note that suc-cessful treatment of comorbid CNCP and substance usedisorder may largely depend on access to opioid main-tenance treatment.Clinical assessment and management strategiesAssessment and monitoringStandardized instruments to assess for problematicsubstance useA number of standardized instruments have been devel-oped to predict or identify opioid misuse in chronic painpatients (Table 3). Four reviews concluded that there isinsufficient evidence to confidently support the accuracyor efficacy of any of these instruments [16, 25, 30, 31].Specifically, there is a limited number of studies evaluat-ing these instruments, and existing studies tend to be oflow to moderate quality with key methodological flaws,such as cross-sectional designs that are unable to deter-mine causality between observed clinical behaviors andsubsequent opioid misuse [16, 25, 30, 31]. The validityand reliability of these instruments have been found tobe either generally weak or not well evaluated, and po-tential biases related to patient selection and assessmenttiming may contribute to inflated estimates of diagnosticaccuracy [25, 30]. Furthermore, there is a lack of litera-ture evaluating the comparative utility of these instru-ments, and the definition of problematic or aberrantbehavior varies across each instrument [25, 31].Most importantly, the feasibility, acceptability, andclinical impact of these instruments remain uncertain.First, the instruments may be too lengthy to realisticallyadminister in most clinical settings [30, 31]. Second, thestudies of these instruments have limited generalizability,as they have mostly been tested in small, unrepresenta-Table 3 Instruments to predict or identify problematic opioiduse in individuals with chronic pain• Current Opioid Misuse Measure (COMM)ab• Opioid Risk Tool (ORT)a• Screener and Opioid Assessment for Patients with Pain (SOAPP) orScreener and Opioid Assessment for Patients with Pain—Revised(SOAPP-R)a• Prescription Drug Use Questionnaire (PDUQ) or Prescription Drug UseQuestionnaire—Patient Version (PDUQ-p)b• Pain Medication Questionnaire (PMQ) or Modified Pain MedicationQuestionnaire (mPMQ)b• Addiction Behaviors Checklist (ABC)a• Prescription Opioid Misuse Index (POMI)b• Pain Assessment and Documentation Tool (PADT)b• Prescribed Opioid Difficulties Scale (PODS)b• Physician Opioid Therapy Questionnaire (POTQ)a• Other instruments to assess substance use not specific to opioids (e.g.,DSM-IV, CAGE Questionnaire, Addiction Severity Index, Michigan AlcoholScreening Test, Minnesota Multiphasic Personality Inventory, ScreeningInstrument for Substance Abuse Potential)aDenotes instruments often used to predict risk of problematic opioid useprior to initiating opioid therapybDenotes instruments often used to identify current problematic opioid useduring ongoing management of opioid therapyheterogeneity across studies in terms of frequency ofurine testing, type of urine testing assays performedVoon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 Page 6 of 9(e.g., point-of-care immunoassay versus laboratory chro-matography), presence of a control group, patient popu-lation studied (e.g., certain studies recruited patientswho were referred for suspected substance abuse, whileother studies excluded individuals with known substanceabuse), and other interventions administered alongsideurine testing [32]. Additionally, there is high potentialfor false negative or false positive results that may com-promise diagnostic accuracy and the patient-provider re-lationship [32], and cost-effectiveness and accessibilityfactors may pose further barriers to clinicians. Giventhese barriers and the lack of evidence on the clinicalimpact of UDT on mitigating risk, perhaps it is not sur-prising that the review by Tournebize et al. estimatedthat UDT is used for pre-treatment screening and moni-toring during opioid treatment by only 15% and 26% ofphysicians, respectively [13]. Furthermore, even whenUDT is used, many prescribers do not accurately inter-pret the testing results [28, 33].Other assessment and monitoring strategiesThere are a variety of other assessment and monitoringstrategies intended to mitigate the harms of opioid misusein chronic pain populations. Additional strategies includemedication counts, which involve visual verification to en-sure that a patient’s remaining medication supply matchesthe expected amount remaining on their prescription; pre-scription drug monitoring programs, which utilize central-ized databases to track the opioid prescription history ofpatients and prescribers; or blood level monitoring toidentify opioid misuse, similar to urine drug testing. How-ever, none of the systematic reviews found sufficient reli-able data to evaluate the effectiveness of these strategies[16, 28, 31]. Despite this, a growing number of settings arebeginning to mandate that clinicians use prescription drugmonitoring programs prior to prescribing opioids [34].Treatment and intervention approachesTreatment agreementsTreatment agreements—also referred to as treatmentcontracts or controlled substance agreements—are writ-ten documents with stipulations to which the patientformally agrees to prior to initiating opioid treatment.The specific set of terms in a treatment agreement ishighly variable, with no strong evidence to support theinclusion or exclusion of particular clauses [32]. Often,the patient must agree to: receive opioid prescriptionsfrom only one physician and pharmacy; not divert theirmedications; comply with monitoring protocols such asUDT; comply with a prescription refill schedule thatdoes not allow for early refills; and acknowledge thattheir treatment may be discontinued at the provider’sdiscretion [28, 32]. While treatment agreements mayhelp promote transparent patient-provider dialogue, andthere is some evidence that treatment agreements maypromote beneficial clinical outcomes in other patientpopulations (e.g., addiction, hypertension, obesity) [35],there remains weak and insufficient evidence to supportthe efficacy of treatment agreements in reducing harmfulopioid use behaviors or related adverse clinical outcomesin patients with chronic pain [28, 32]. This lack of evi-dence to support clinical applicability may be drivinglow rates of implementation, with an estimated 47% ofphysicians actually implementing treatment agreementsin clinical practice [13].Opioid selectionThe review by Argoff et al. highlighted the need for carefulattention when prescribing opioids for pain managementin individuals with past or present substance misuse [28].The authors concluded that if opioid treatment is consid-ered in this population (e.g., if non-opioid analgesics havebeen ineffective for diagnosed pain), weaker opioids (e.g.,codeine, tramadol) are preferable to stronger opioids (e.g.,oxycodone, hydromorphone), as some evidence has foundlower risk for abuse with weaker opioids [28].Regarding immediate-release formulations, Argoff et al.suggests these may be preferable to extended-release for-mulations, as there are greater amounts of opioid con-tained in extended-release formulations that may beassociated with higher abuse potential, and there is a pau-city of evidence to suggest that long-acting formulationsprovide superior benefit compared to short-acting formu-lations [28]. However, Chou et al. noted that the results ofresearch comparing long-acting versus short-acting opioidformulations are inconsistent and difficult to interpret dueto variable dosing protocols [16].Tamper-deterrent formulations are another strategy de-signed to deter abuse by way of their physical design (e.g.,crush-resistant tablets) or ingredients (e.g., nasal irritantsto deter snorting, naltrexone to block euphoria from injec-tion, or emulsifying agents to deter injecting). Argoff et al.found some evidence to suggested such formulations canbe effective in reducing abuse and tampering, yet otherevidence suggests that these formulations are ineffectivein that individuals may simply seek other opioids that donot have abuse-deterring properties [28].Opioid dosing and dispensingOne review found weak evidence to suggest that titratingopioids using slow and small dose increases may preventexcessively high doses and promote clinical monitoring ofpatient responses or potential aberrant behaviors [28].However, there is a lack of evidence to evaluate the effectof slow and small dose increases on preventing misuse[28]. Given the strong evidence demonstrating the in-creased risk of overdose and mortality associated with highopioid doses, Argoff et al. found that close monitoring isVoon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 Page 7 of 9recommended for patients with high opioid doses, al-though the definition of what constitutes a ‘high dose’tends to vary substantially in the literature [28]. Maximumdose restrictions may reduce opioid-related mortality, assuggested by one study of a 120 mg per day morphine-equivalent maximum dose restriction in Washington statethat reduced opioid-related mortality by 50% [36], butmore research is needed. There is insufficient evidence toevaluate the efficacy of maximum dispensation restrictionson reducing problematic use [31].Opioid agonist treatmentFor individuals with CNCP who have or are at risk ofopioid addiction, Eilender et al. and other recent studieshave found evidence to support the effectiveness of opi-oid agonist treatment via buprenorphine/naloxone ormethadone [29, 37]. Buprenorphine/naloxone may befavourable over methadone due to the lower risk for re-spiratory depression, potentially lower risk for hyperalge-sia or tolerance, and lower dispensing burden, but adownside compared to methadone is that opioids maynot be co-prescribed for additional pain control due tothe blocking effect of naloxone [29]. A small number ofstudies have found that individuals may effectively transi-tion from opioid analgesics to buprenorphine/naloxoneand achieve reduced pain severity [29, 37], but more re-search is needed to determine the optimal morphineequivalent dose range prior to buprenorphine/naloxonetransition, as higher opioid doses may pose a risk for lossto follow-up due to precipitated withdrawal or other ad-verse events [29]. Divided doses of buprenorphine/nalox-one or methadone may also promote pain control, butthere is a limited body of evidence to evaluate this [29].Other treatment approachesEilender et al. found a small body of evidence suggestingthat psychotherapeutic interventions for concurrent painand substance misuse using mindfulness or cognitive be-havioral therapy approaches may reduce pain severityand opioid misuse [29]. Notably, abstinence-based de-toxification treatment is not recommended for CNCPpatients with substance use disorders, as it poses highrisk for relapse and fatal overdose [38].ConclusionsThis review has synthesized the findings from 18 sys-tematic reviews related to the epidemiology and clinicalmanagement of concurrent CNCP and opioid misuse.Two meta-analyses estimated the prevalence of CNCPin individuals using POs non-medically to be approxi-mately 48% to 60%, which is substantially higher thanthe prevalence of chronic pain in general populationsamples in the United States (11%) and Canada (19%)[39, 40]. Six reviews estimated the rates of dependence,substance use disorder, and problematic opioid use (e.g.,misuse, addiction, abuse) in chronic pain patients withhighly variable results, which highlights the need formore explicit and consistent definitions of these out-comes in future studies, as well as clear descriptions ofthe types of populations being studied. In this regard,further research would be useful to determine whetherrecent changes to the DSM-5 definition of ‘opioid usedisorder’, which replaces the previously distinct classifi-cations of ‘opioid dependence’ and ‘opioid abuse’ in theDSM-IV, leads to increased or decreased variation inprevalence estimates.There are mixed and inconsistent findings regardingdemographic factors that may predict opioid misuse inchronic pain populations, perhaps due to inconsistentreporting and underrepresentation of minority demo-graphics [19, 25, 26]. There appears to be a high preva-lence of opioid misuse among CNCP patients withpsychiatric comorbidity, with potentially greater risk inthose with mood disorders, but this evidence is also in-consistent [16, 19, 25, 27]. The most consistent findingacross reviews is that a past or present history of opioid orother substance use disorder appears to increase the riskof PO misuse in CNCP patients [12, 16, 19, 25, 28, 29].More research is also needed on the effect of chronicpain on illicit opioid use in individuals with substanceuse disorders, the effect of substance use disorders ontreatment response outcomes for CNCP patients, andthe biological pathways that may exist between thesecomorbidities.A number of assessment and monitoring strategiesexist to assess for problematic opioid use in CNCPpopulations, including standardized assessment instru-ments, urine drug testing, medication counts, prescrip-tion drug monitoring programs, and blood levelmonitoring [25, 28, 30–32]. However, there is a generalconsensus across reviews that the effectiveness andclinical utility of these strategies for predicting or miti-gating problematic opioid use and adverse clinical out-comes have not been well-established, which may inpart explain low rates of implementation in clinical set-tings [13, 16, 25, 28, 30–32]. Similarly, there is a lack ofimplementation or strong evidence to support the ef-fectiveness of treatment agreements [13, 28, 32].In terms of other treatment and intervention ap-proaches, there is evidence to support opioid agonisttreatment for individuals with chronic pain at risk forproblematic drug use, particularly buprenorphine/nalox-one [29]. However, more research is needed to determineoptimal dosing for patients transitioning from opioid sadfor analgesia. Should opioids be prescribed in chronic painpatients at risk for problematic drug use, weaker potencyand immediate-release formulations may be preferred[28]. More evidence is needed to determine whethertamper-deterring formulations effectively reduce misuseThis review has a number of limitations, includingses and highlight areas for future systematic review.Voon et al. Substance Abuse Treatment, Prevention, and Policy  (2017) 12:36 Page 8 of 9Nonetheless, to our knowledge, this is the first ‘review ofreviews’ to summarize the range of synthesized evidenceon various epidemiologic and clinical aspects of concur-rent chronic pain and opioid misuse.In summary, the purpose of this review is to provide asynthesis of systematic reviews related to concurrentchronic pain and opioid misuse, given that this is a sub-population at very high risk for morbidity and mortality,and given that systematic reviews are the basis forevidence-based clinical and policy decision-making. Over-all, there is a lack of high-quality evidence or consistentfindings on the risk factors for concurrent chronic painand opioid misuse, as well as clinical approaches to effect-ively reduce drug-related harms in this population. Whileupdated clinical guidelines have recently been released inan attempt to mitigate the ongoing opioid crisis [3], un-fortunately many of the recommendations are based onevidence with serious limitations, inconsistencies, and im-precision as highlighted in this review. Thus, high-qualityprimary research and comprehensive meta-analyses areurgently needed to guide evidence-based clinical practiceto address the escalating public health epidemic of opioid-related harms.Additional fileAdditional file 1: Methodological quality assessment of the includedsystematic reviews using AMSTAR scoring. (DOCX 26 kb)AbbreviationsAIDS: Acquired immune deficiency syndrome; AMSTAR: Assessment ofMultiple Systematic Reviews; CNCP: Chronic non-cancer pain; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; ICD-10: International Statistical Classification of Diseases and Related HealthProblems, 10th Revision; PO: Prescription opioid; PRISMA: Preferred ReportingItems for Systematic reviews and Meta-Analyses; UDT: Urine drug testingpublication bias and varying criteria for inclusion, exclu-sion and outcome measures across reviews. Additionally,this review excludes findings from primary studies thatmay have been published after these reviews; however,the intent of this review is to summarize existing synthe-risk, or if individuals alternate to other drugs that maycontinue to pose risk. Additionally, greater evidence isneeded to evaluate whether slow and small dose increases,maximum dose restrictions, or maximum dispensation re-strictions effectively mitigate risky drug behaviors and ad-verse clinical outcomes.AcknowledgmentsThe authors thank Tricia Collingham and Deborah Graham for theiradministrative assistance.FundingPV is supported through a Vanier Canada Graduate Scholarship from theCanadian Institutes of Health Research and a Trudeau Doctoral Scholarshipfrom The Pierre Elliott Trudeau Foundation.Availability of data and materialsNot applicable.Authors’ contributionsPV developed the research question. PV and MK conducted the systematicsearch. All authors contributed to the analysis and critical revision of themanuscript. All authors read and approved the final manuscript.Ethics approval and consent to participateNot applicable.Consent for publicationAll authors have consented the current manuscript for publication.Competing interestsThe authors have no competing interests to declare.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in publishedmaps and institutional affiliations.Author details1British Columbia Centre for Excellence in HIV/AIDS, University of BritishColumbia, St. Paul’s Hospital, 608-1081 Burrard Street, Vancouver, BC V6Z 1Y6,Canada. 2School of Population and Public Health, Faculty of Medicine,University of British Columbia, 2206 East Mall, Vancouver, BC V6Z 1Z3,Canada. 3HIV/STI Surveillance Research Center, and WHO CollaboratingCenter for HIV Surveillance, Institute for Futures Studies in Health, KermanUniversity of Medical Sciences, Kerman, Iran. 4Department of Medicine,University of British Columbia, St. Paul’s Hospital, 608-1081 Burrard Street,Vancouver, BC V6Z 1Y6, Canada.Received: 13 December 2016 Accepted: 6 August 2017References1. 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