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Pain Among High-Risk Patients on Methadone Maintenance Treatment Voon, Pauline; Hayashi, Kanna; Milloy, M-J; Nguyen, Paul; Wood, Evan; Montaner, Julio; Kerr, Thomas Sep 30, 2015

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PAIN AMONG HIGH-RISK PATIENTS ON METHADONE MAINTENANCE TREATMENTPauline Voona,b, Kanna Hayashia, M-J Milloya,c, Paul Nguyena, Evan Wooda,c, Julio Montanera,c, and Thomas Kerra,caBritish Columbia Centre for Excellence in HIV/AIDS, St. Paul’s Hospital, 608-1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6bSchool of Population and Public Health, Faculty of Medicine, University of British Columbia, 2206 East Mall, Vancouver, BC, Canada, V6Z 1Z3cDepartment of Medicine, University of British Columbia, St. Paul’s Hospital, 608-1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6AbstractThe complexity of treating concurrent pain and opioid dependence among many methadone-maintained individuals presents a major challenge in many clinical settings. Furthermore, recent expert guidelines have called for increased research on the safety of methadone in the context of chronic pain. This study explores the prevalence and correlates of pain among a prospective cohort of people who use illicit drugs in Vancouver, Canada, who reported enrollment in methadone maintenance treatment (MMT) between 2011 and 2014. Among the 823 participants eligible for this analysis, 338 (40.9%) reported moderate pain and 91 (11.1%) reported extreme pain at the first study visit. In multivariable generalized linear mixed model analyses, higher pain severity was positively and independently associated with self-managing pain (adjusted odds ratio [AOR]=2.15, 95% confidence interval [CI]=1.77–2.60), patient perception of methadone dose being “too low” (AOR=1.82, 95% CI=1.41–2.34), older age (AOR=1.31, 95% CI=1.13–1.51), having a physical disability (AOR=4.59, 95% CI=3.73–5.64), having ever been diagnosed with a mental illness (AOR=1.44, 95% CI=1.13–1.84), Caucasian ethnicity (AOR=1.42, 95% CI=1.10–1.83), and marijuana use (AOR=1.25, 95% CI=1.02–1.52). These findings suggest several areas Send correspondence to: Thomas Kerr, PhD, Director, Urban Health Research Initiative, B.C. Centre for Excellence in HIV/AIDS, University of British Columbia, St. Paul’s Hospital, 608-1081 Burrard Street, Vancouver, B.C., V6Z 1Y6, Canada, Tel: +1 (604) 806-9116, Fax: +1 (604) 806-9044, uhri-tk@cfenet.ubc.ca. Conference presentation: Part of this data appeared as a poster presentation at the American Pain Society’s 34th Annual Scientific Meeting, Palm Springs, CA, May 13–16, 2015.Disclosures: This study was supported by the U.S. National Institutes of Health (R01DA011591 and R01DA021525). This research was undertaken, in part, thanks to funding from the Canada Research Chairs program through a Tier 1 Canada Research Chair in Inner City Medicine, which supports Dr. Evan Wood. Dr. Julio Montaner is supported with grants paid to his institution by the British Columbia Ministry of Health and by the US National Institutes of Health (R01DA036307). He has also received limited unrestricted funding, paid to his institution, from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. Pauline Voon and Kanna Hayashi are supported by the Canadian Institutes of Health Research. The authors have no other potential competing interests to declare.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.HHS Public AccessAuthor manuscriptJ Pain. Author manuscript; available in PMC 2016 September 01.Published in final edited form as:J Pain. 2015 September ; 16(9): 887–894. doi:10.1016/j.jpain.2015.06.003.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptfor clinical intervention, particularly related to patient education and alternative analgesic approaches for MMT patients experiencing pain.KeywordsPain; methadone; substance abuse; self-medication; opioid induced hyperalgesiaINTRODUCTIONMethadone is a long-acting opioid agonist that may be prescribed to treat opioid dependence or chronic pain. When treating opioid-dependent individuals, clinicians are often faced with the complex challenge of treating concurrent chronic pain, which is estimated to be prevalent among 55% to 61% of individuals on methadone maintenance treatment (MMT) compared to 31% of general adult population.14The physiological mechanisms that may explain the overlap between pain and opioid dependency remain a topic of on-going debate. One hypothesis that has garnered significant attention is the notion of opioid-induced hyperalgesia, which suggests that consistent exposure to opioids may lead to increased pain sensitivity and/or decreased pain thresholds. However, limited and conflicting evidence has precluded a consensus on this hypothesis.1, 15The complexity of concurrent pain and opioid dependence presents substantial challenges for both clinicians and patients. Often, it is difficult to achieve a balance between adequate pain relief and reduced opioid cravings, while at the same time minimizing the risks of deepened dependence, overdose, withdrawal, misuse, or diversion.23 Furthermore, practitioners’ treatment decisions may be influenced by stigma related to people who use illicit substances,34 interpretations of requests for opioids as ‘drug-seeking’,2 or views of MMT as a treatment for either pain or addiction separately.22 Altogether, these factors may contribute to inadequate pain management among individuals with high rates of disability and other causes of chronic pain.Importantly, in addition to the above issues, recent guidelines by the American Pain Society call for increased research on the safety of methadone among individuals with chronic pain.8, 45 Therefore, we undertook this study to investigate the prevalence and correlates of pain among opioid-dependent individuals on MMT in order to inform pain management and risk mitigation strategies among this particularly high-risk population.METHODSStudy Design and SettingData for these analyses were derived from two on-going prospective observational cohorts in Vancouver, Canada: the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS) of HIV-seropositive illicit drug users, and the Vancouver Injection Drug Users Study (VIDUS) of HIV-seronegative injection drug users. These cohorts have previously been described in detail and have received annual ethics approval from the University of British Columbia and Providence Health Care Research Ethics Board.39, 40 In brief, since Voon et al. Page 2J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscript1996, more than 2,000 subjects have been recruited into these cohorts through snowball sampling and street outreach methods in Vancouver’s Downtown Eastside (DTES). The DTES is a post-industrial neighbourhood with an established drug market and widespread illicit drug use, poverty, poor housing conditions, and infectious diseases such as HIV and hepatitis C.26 The present analyses were restricted to interviews that were conducted between December 1, 2011 and November 30, 2014. These dates coincided with the start of the Euroqol EQ-5D health utility instrument in the study questionnaire, and included all subsequent follow-up data available at the time of data analysis.ParticipantsParticipants are eligible for VIDUS if they are 18 years of age or older and have injected an illicit drug in the month prior to the baseline interview. Participants are eligible for ACCESS if they are HIV-seropositive, 18 years of age or older, and have used an illicit drug other than cannabinoids within the month prior to the baseline interview. At baseline and semi-annually, participants answer an interviewer-administered questionnaire and provide blood samples for serologic analysis (among HIV negative individuals) or disease monitoring (among HIV-positive individuals), and are referred as necessary to medical care and drug and alcohol treatment. All participants provide written informed consent and receive a $30 stipend at the end of each study visit. Participants were eligible for this analysis if they reported currently being on MMT at the time of their interview.Variables and MeasuresIn order to identify factors associated with pain among individuals enrolled in MMT, our outcome of interest was current pain severity, which was measured using ordinal multinomial categories of participants who reported no pain or discomfort, moderate pain or discomfort, or extreme pain or discomfort at the time of their interview. These data on pain severity were ascertained using the Euroqol EQ-5D health utility instrument, which has been shown to be a valid, responsive and reliable instrument for individuals with pain and opioid-dependence.18, 30, 43 Additionally, the Brief Pain Inventory (BPI) Short Form was used to elicit information on pain duration and interference. The BPI has been shown to be a valid and reliable self-reported pain instrument that has been widely used in studies measuring pain among general and substance-using populations.6, 31, 35 Because the BPI was introduced later in the study period, data on these additional pain measures are only available for participants who completed the most recent follow-up period from June 1, 2014 to November 30, 2014.The self-reported demographic, behavioural, social and structural explanatory characteristics considered in the analyses were: age (per 10 years older), gender (male vs. female), ethnicity (Caucasian vs. other), homelessness (yes vs. no), residence in Vancouver’s DTES neighbourhood (yes vs. no), highest education status obtained (≥ high school diploma or equivalent vs. < high school diploma), HIV serostatus (positive vs. negative), hepatitis C status (positive vs. negative), lifetime history of mental illness diagnosis (yes vs. no), incarceration (yes vs. no), physical disability (yes vs. no), self-managed pain (yes vs. no), and having been denied pain medication by a health practitioner (yes vs. no). The variables related to methadone treatment or drug use included: non-fatal overdose (yes vs. no), current Voon et al. Page 3J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptmethadone dose (per 10 mg/day increase), methadone dose perceived to be “too low” (yes vs. no), any illicit methadone injection (yes vs. no), any crack cocaine use (yes vs. no), any crystal methamphetamine injection (yes vs. no), any heroin injection (yes vs. no), any cocaine injection (yes vs. no), any marijuana use (yes vs. no), any heavy alcohol use (yes vs. no), any prescription opioid misuse (yes vs. no), and any binge injection drug use (yes vs. no). As per the National Institute on Alcohol Abuse and Alcoholism (NIAAA), heavy alcohol use was defined as more than four drinks per day or more than fourteen drinks per week for males, or more than three drinks per day or more than seven drinks per week for females.28 Prescription opioid misuse was defined as the injection or non-injection use of prescription opiates not as prescribed or not prescribed to the individual.37 As per the definition of bingeing in previous studies, binge injection drug use was defined as any period of time within the previous six months from the time of interview during which any drugs were injected more frequently than usual.16,17 All variables referred to activities or events in the six months prior to the participant’s interview, unless otherwise indicated.Statistical MethodsA generalized linear mixed-effects model (GLMM) was chosen because of its abilities to longitudinally analyse individual trajectories of pain over time and capture within-subject correlation and heterogeneity of subjects, while attempting to identify individual-level factors.16, 24 The random intercept was used to account or the random variation between subjects. Using the GLMM approach, a cumulative ordered logit model was incorporated to investigate the bivariable and multivariable associations between the exposures of interest and the ordinal outcome (categorized as response variables of no pain or discomfort, moderate pain or discomfort, and extreme pain or discomfort). Specifically, the outcome was split into two ‘cut points’ in order to create three ordinal categories of pain: moderate or extreme pain or discomfort versus no pain or discomfort, and extreme pain or discomfort versus no or moderate pain or discomfort. Then, similar to standard logistic regression, we analysed the proportional odds of individuals belonging to the pain category above each cut point. Thus, the odds ratios reported herein represent the odds of an individual being in a higher pain category per unit change in the explanatory variable.5We then analysed the bivariable and multivariable associations between the explanatory variables of interest and increased pain severity. First, bivariable GLMM analyses were conducted to obtain unadjusted odds ratios and p-values for factors associated with higher pain severity. To adjust for potential confounding, all variables that had p<0.10 in the bivariable analyses were considered in the multivariable GLMM analysis. Standard backward model selection procedure was used to identify the model with the best overall fit as indicated by the lowest Akaike information criterion (AIC) value. All p-values were two sided, and significant associations were defined as p<0.05. All statistical analyses were performed using the SAS software version 9.3 (SAS, Cary, NC).RESULTSParticipants in this sample contributed to a total of 3,018 observations during the study period. Table 1 presents the baseline characteristics of the sample at the time of their first Voon et al. Page 4J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptvisit during this study period. Of the 823 participants eligible for the present analysis, 326 (39.6%) were female, and 512 (62.2%) self-reported Caucasian ethnicity. The median age at the first study visit was 46 years (interquartile range [IQR]: 39 to 52 years). At the first study visit, 395 (48.0%) participants reported no pain, 337 (40.9%) reported moderate pain, and 91 (11.1%) reported extreme pain. The median methadone doses at the first study visit for individuals reporting no pain, moderate pain, and extreme pain were 80 mg/day (IQR: 45–130 mg/day), 85 mg/day (IQR: 38–120 mg/day), and 90 mg/day (IQR: 60–140 mg/day), respectively.Of the 256 participants who provided data on pain duration during the final follow-up period included in this analysis, 213 (83.2%) reported chronic pain lasting more than six months in duration. The median pain interference score was 5.0 out of 10 (IQR: 3.0 to 6.5) for the total sample that provided data on pain interference during the final follow-up period included in this analysis (n=211), with median interference scores of 3.8 (IQR: 1.7 to 5.5), 5.2 (IQR: 3.5 to 6.5) and 5.7 (IQR: 4.0 to 7.3) for the no pain, moderate pain and extreme pain groups, respectively.Table 2 presents the results of the bivariable and multivariable GLMM analyses. Factors that were significantly associated with higher pain severity in the bivariable analyses only, but were no longer significant in the multivariable analysis, included: prescription opioid use (p<0.001, unadjusted odds ratio [OR]=1.65, 95% confidence interval [CI]=1.28–2.13), having been denied prescription analgesia (p<0.001, OR=1.58, 95% CI=1.24–2.01), higher education status (p=0.006, OR=1.53, 95% CI=1.13–2.06), and recent non-fatal overdose (p=0.010, OR=1.79, 95% CI=1.15–2.80). In multivariable GLMM analysis, factors that remained significantly and independently associated with higher pain severity included: having a physical disability (p<0.001, adjusted odds ratio [AOR]=4.59, 95% CI=3.73–5.64), self-managing pain (p<0.001, AOR=2.15, 95% CI=1.77–2.60), patient perception of methadone dose being “too low” (p<0.001, AOR=1.82, 95% CI=1.41–2.34), older age (p<0.001, AOR=1.31, 95% CI=1.13–1.51), having ever been diagnosed with a mental illness (p=0.004, AOR=1.44, 95% CI=1.13–1.84), Caucasian ethnicity (p=0.007, AOR=1.42, 95% CI=1.10–1.83), and marijuana use (p=0.033, AOR=1.25, 95% CI=1.02–1.52).DISCUSSIONIn this study, a high proportion of participants on MMT reported moderate or extreme pain. Factors that were positively and independently associated with higher pain severity included physical disability, self-managing pain, patient perception of methadone dose being “too low”, older age, lifetime history of mental health diagnosis, Caucasian ethnicity, and marijuana use.The high prevalence of moderate to severe pain at the first study visit in our study (52.0%) is consistent with previous literature that has found high rates of pain among individuals on MMT. Specifically, other studies have found that 55% to 61% of patients on MMT report having a current chronic pain condition, with rates of moderate to severe pain among MMT patients to ranging from 24% to 39%.3, 20, 32, 33, 35, 41 Considering that the prevalence of chronic pain among the general adult population is estimated to be 31% in the United States Voon et al. Page 5J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptand between 15% to 29% in Canada, the comparatively higher prevalence of pain among individuals on MMT is not surprising given the known higher rates of injury and disability among this population and warrants increased attention to pain management strategies for this population.4, 21, 27, 42Our finding that MMT patients with higher pain severity in this study were more likely to self-manage their pain is concerning given our previous research on self-managed pain,44 which found that participants who reported self-managing pain often did so using high-risk methods, which most commonly included injecting heroin or obtaining diverted prescription analgesia (most commonly opioid-based) off the street or from another person. In this study, we found that a 61.1% of participants with moderate pain reported self-managing pain, compared to a slightly higher proportion of participants with extreme pain who reported self-managing pain (68.1%) at their first study visit. The strong association between self-managed pain and higher pain severity in this study further suggests that pain may be poorly managed among this sample of individuals on MMT. In this regard, clinicians have a key role to play in addressing patients’ pain concerns and self-management behaviors, in order to prevent high-risk self-medication in ways that pose high risk for morbidity and mortality.In this study, individuals on MMT with higher pain severity were more likely to perceive that their methadone dose was “too low”. Although we did not find current methadone dose to be significantly associated with higher pain severity in our statistical analysis, we found that the median methadone doses in our sample appeared to trend upward with increasing pain severity (80 mg/day, 85 mg/day, and 90 mg/day for no pain, moderate pain, and extreme pain, respectively), as consistent with other literature that have found higher doses of methadone among patients with higher pain severity.20, 32 While the responses to this question in our survey did not specify whether participants believed their doses were insufficient in regards to reducing pain, opioid cravings, or both, this finding presents several potential implications in the context of pain management. First, if we assume that our participants believed their doses were insufficient in regards to reducing pain, this finding is consistent with other literature suggesting that pain may be undertreated among MMT patients.20, 35, 38 Conversely, in the context of the theory of opioid-induced hyperalgesia, consistent exposure to opioids may paradoxically exacerbate rather than relieve pain-related symptoms, which may lead patients to believe that they require a higher opioid dose in order to relieve their heightened pain.14 Ultimately, this finding illustrates the need for patient and practitioner education related to methadone dosing for individuals with concurrent pain; the need for conclusive evidence related to opioid-induced hyperalgesia and how best to counteract its potential effects; and the need for effective and evidence-based treatment regimens for MMT patients with pain, whether via alternative methadone dosing or timing strategies, alternative opioid therapies with less potential for hyperalgesia or other adverse effects such as buprenorphine, or non-opioid analgesic alternatives.23Our finding that MMT patients with physical disabilities were more likely to report higher pain severity is consistent with other studies investigating pain among MMT patients.33, 35 Previous literature suggests that individuals with physical disabilities are more likely to experience chronic problematic pain that impacts their lifestyle choices, and that these individuals may be hesitant to discuss pain management with health care providers.10, 13 Voon et al. Page 6J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptTherefore, clinicians may consider proactively discussing pain management approaches and behaviors among MMT patients with physical disabilities. Furthermore, greater pain catastrophizing has been found to be associated with increased pain-related disability and greater pain intensity among MMT patients.17 Additional research on pain-related disability among MMT patients is necessary given the limited amount of literature on this topic at present.The observed significant associations between higher pain severity and older age and lifetime diagnosis with mental illness are consistent with other studies investigating pain among MMT patients.14, 35 As noted by Eyler et al. (2013), an increasing demand for effective pain management is likely to coincide with the aging population of MMT patients, which necessitates increased attention to pain research and care for these individuals.14 Furthermore, MMT patients with pain would benefit greatly from improved integration of pain, addiction, and psychiatric care, rather than clinicians from these specialties providing fragmented care for this complex population.23Our finding that higher pain severity was significantly associated with Caucasian ethnicity differs from existing literature on ethnicity and pain, much of which has focused on general populations in the Unites States and has found that Caucasians tend to have lower pain severity compared to Hispanics or African-Americans.9, 12 There have been few comparisons of pain among ethnic populations outside the United States and among individuals with a history of substance use and/or opioid dependence in particular. Therefore, this is an area that would benefit from further research.Finally, this study found a significant association between marijuana use and higher pain severity among individuals on MMT, which is consistent with other studies that have found marijuana to be commonly used among MMT patients with significant and/or chronic pain, particularly compared to the less frequent use of marijuana among MMT patients without significant or chronic pain.19, 25, 35 Taking into consideration that patients in these studies reported using marijuana specifically for treating pain,35 and that MMT was found to be effective in reducing illicit opioid use at comparable rates between patients with and without pain independent of marijuana use,19 these findings warrant further investigation into the effectiveness of medicinal marijuana as a potential adjunct treatment for MMT patients with significant or chronic pain.This study has several limitations. First, our study relied on self-reported data that is susceptible to socially desirable reporting and recall bias. Second, our analysis did not adjust for potential false positives; however, as previously described, the prevalence of pain in our study is comparable to other literature among similar populations. Additionally, the Euroqol EQ-5D has been previously demonstrated to be a valid, responsive and reliable survey instrument among individuals with pain and substance users.18, 30, 43 Furthermore, we would expect that potential misclassification of pain severity in our study would be non-differential, which would likely mean that our observed estimates are more conservative (i.e., biased toward the null) than they would be if there were no false positives in our study.36 Third, the Euroqol EQ-5D captures participants’ self-reports of “pain or discomfort,” and while discomfort is certainly related to pain, caution should be taken when Voon et al. Page 7J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptinterpreting the results pertaining to pain severity in this study, as it is possible that factors other than physical pain (e.g., discomfort related to opioid withdrawal) may have contributed to participants’ responses. Fourth, our analysis used assessments of pain at the time of participants’ interviews, compared to other variables that were assessed with a reference period of six months prior to participants’ interviews. This approach has been widely adopted in the literature and found to be valid.7, 11, 29, 35 Fifth, because the study sample was not randomly selected, these results may not be generalizable to other populations. Finally, as in all observational studies of this kind, we are unable to disentangle the temporal ordering of the observed associations, particularly when ascertaining whether certain factors preceded or followed one another within each given 6-month follow-up period.In summary, a high proportion of individuals on MMT reported higher pain severity in our study. We found that patients on MMT with higher pain severity were more likely to have a physical disability, believe their methadone dose was insufficient, self-manage pain, have a lifetime history of mental illness, and have a higher education status. Collectively, these findings suggest several areas for future research, clinical intervention, and patient education, particularly regarding the risks of self-managing pain, the potential for opioid-induced hyperalgesia, and the potential for alternative analgesic approaches for MMT patients experiencing pain.AcknowledgmentsThe authors thank the VIDUS and ACCESS study participants for their contribution to the research, as well as current and past researchers and staff. We would specifically like to thank Sabina Dobrer, Tricia Collingham, Carmen Rock, Deborah Graham, Peter Vann, Jennifer Matthews, Steve Kain and Lianping Ti for their assistance with this research.References1. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006; 104:570–587. [PubMed: 16508405] 2. Baldacchino A, Gilchrist G, Fleming R, Bannister J. 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Van Den Kerkhof EG, Hopman WM, Towheed TE, Anastassiades TP, Goldstein DH. The impact of sampling and measurement on the prevalence of self-reported pain in Canada. Pain Res Manag. 2003; 8:157–163. [PubMed: 14657983] 43. van der Zanden BP, Dijkgraaf MG, Blanken P, de Borgie CA, van Ree JM, van den Brink W. Validity of the EQ-5D as a generic health outcome instrument in a heroin-dependent population. Drug and alcohol dependence. 2006; 82:111–118. [PubMed: 16168573] 44. Voon P, Callon C, Nguyen P, Dobrer S, Montaner J, Wood E, Kerr T. Self-management of pain among people who inject drugs in Vancouver. Pain Manag. 2014; 4:27–35. [PubMed: 24641341] 45. Weimer MB, Chou R. Research gaps on methadone harms and comparative harms: findings from a review of the evidence for an American Pain Society and College on Problems of Drug Dependence clinical practice guideline. J Pain. 2014; 15:366–376. [PubMed: 24685460] Voon et al. Page 10J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptPERSPECTIVETo better understand the complexity of concurrent pain and opioid dependency among individuals on methadone maintenance treatment, this article describes the prevalence and correlates of higher pain severity among methadone-maintained people who use illicit drugs. Methadone patients with comorbid pain may benefit from education and alternative analgesic approaches.Voon et al. Page 11J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptHIGHLIGHTS• A high proportion of patients on methadone maintenance had moderate to extreme pain.• Those with higher pain severity were more likely to self-manage their pain.• Those with higher pain severity were more likely to perceive their methadone dose was “too low”.• Methadone patients may be prone to undertreated pain or opioid-induced hyperalgesia.• Patient education and assessment may prevent high-risk self-management behaviors.Voon et al. Page 12J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptVoon et al. Page 13Table 1Baseline characteristics of methadone-maintained people who use illicit drugs in Vancouver, Canada, stratified by pain severity (n=823)VariableValueTotal 823 (100%) n (%)No pain 395 (48.0%) n (%)Moderate pain 337 (40.9%) n (%)Extreme pain 91 (11.1%) n (%)AgeTotal823 (100.0)395 (100.0)337 (100.0)91 (100.0)Median years (IQR)46 (39–52)44 (38–50)47 (42–53)48 (43–53)GenderMale497 (60.4)238 (60.3)201 (59.6)58 (63.7)Female326 (39.6)157 (39.7)136 (40.4)33 (36.3)EthnicityCaucasian512 (62.2)228 (57.7)216 (64.1)68 (74.7)Other311 (37.8)167 (42.3)121 (35.9)23 (25.3)Homelessness*†Yes106 (12.9)54 (13.7)42 (12.5)10 (11.0)No715 (86.9)340 (86.1)294 (87.2)81 (89.0)Downtown Eastside residence*Yes510 (62.0)244 (61.8)207 (61.4)59 (64.8)No313 (38.0)151 (38.2)130 (38.6)32 (35.2)Highest education level obtained†≥ High school diploma396 (48.1)173 (43.8)180 (53.4)43 (47.3)< High school diploma407 (49.5)214 (54.2)149 (44.2)44 (48.4)HIV serostatus*Positive348 (42.3)168 (42.5)143 (42.4)37 (40.7)Negative475 (57.7)227 (57.5)194 (57.6)54 (59.3)Hepatitis C status*Positive758 (92.1)362 (91.6)316 (93.8)80 (87.9)Negative65 (7.9)33 (8.4)21 (6.2)11 (12.1)Mental illness diagnosisΔYes505 (61.4)220 (55.7)222 (65.9)63 (69.2)No318 (38.6)175 (44.3)115 (34.1)28 (30.8)Incarceration*†Yes55 (6.7)26 (6.6)24 (7.1)5 (5.5)No765 (93.0)368 (93.2)311 (92.3)86 (94.5)Physical disability*Yes376 (45.7)102 (25.8)204 (60.5)70 (76.9)No447 (54.3)293 (74.2)133 (39.5)21 (23.1)Self-managed pain*†Yes446 (54.2)178 (45.1)206 (61.1)62 (68.1)No370 (45.0)215 (54.4)128 (38.0)27 (29.7)Denied pain medication*†Yes104 (12.6)32 (8.1)50 (14.8)22 (24.2)No714 (86.8)361 (91.4)284 (84.3)69 (75.8)Non-fatal overdose*†Yes35 (4.3)12 (3.0)18 (5.3)5 (5.5)No786 (95.5)382 (96.7)319 (94.7)85 (93.4)J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptVoon et al. Page 14VariableValueTotal 823 (100%) n (%)No pain 395 (48.0%) n (%)Moderate pain 337 (40.9%) n (%)Extreme pain 91 (11.1%) n (%)Current methadone dose†Total808 (98.2)391 (99.0)327 (97.0)90 (98.9)Median mg/day (IQR)85 (50–130)80 (45–130)85 (38–120)90 (60–140)Methadone dose perceived to be “too low”*†Yes133 (16.2)53 (13.4)58 (17.2)22 (24.2)No679 (82.5)335 (84.8)275 (81.6)69 (75.8)Illicit methadone injection*Yes4 (0.5)2 (0.5)2 (0.6)0 (0.0)No819 (99.5)393 (99.5)335 (99.4)91 (100.0)Crack cocaine use*Yes483 (58.7)230 (58.2)201 (59.6)52 (57.1)No340 (41.3)165 (41.8)136 (40.4)39 (42.9)Crystal meth injection*Yes139 (16.9)68 (17.2)62 (18.4)9 (9.9)No684 (83.1)327 (82.8)275 (81.6)82 (90.1)Heroin injection*†Yes355 (43.1)175 (44.3)147 (43.6)33 (36.3)No467 (56.7)220 (55.7)189 (56.1)58 (63.7)Cocaine injection*†Yes217 (26.4)95 (24.1)98 (29.1)24 (26.4)No605 (73.5)299 (75.7)239 (70.9)67 (73.6)Marijuana use*†Yes331 (40.2)153 (38.7)140 (41.5)38 (41.8)No490 (59.5)241 (61.0)196 (58.2)53 (58.2)Heavy alcohol use*†Yes99 (12.0)47 (11.9)42 (12.5)10 (11.0)No722 (87.7)348 (88.1)293 (86.9)81 (89.0)Prescription opioid use*†Yes124 (15.1)47 (11.9)55 (16.3)22 (24.2)No697 (84.7)347 (87.9)281 (83.4)69 (75.8)Binge injection drug use*†Yes195 (23.7)84 (21.3)91 (27.0)20 (22.0)No625 (75.9)309 (78.2)245 (72.7)71 (78.0)*Denotes activities/events in the previous six monthsΔ Denotes activities/events within the participant’s lifetime† Indicates missing responses as follows: homelessness (2 missing responses), highest education level obtained (20 missing responses), incarceration (3 missing responses), self-managed pain (7 missing responses), denied pain medication (5 missing responses), non-fatal overdose (2 missing responses), current methadone dose (15 missing responses), methadone dose perceived to be “too low” (11 missing responses), heroin injection (1 missing response), cocaine injection (1 missing response), marijuana use (2 missing responses), heavy alcohol use (2 missing responses), prescription opioid use (2 missing responses), binge injection drug use (3 missing responses).J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptVoon et al. Page 15Table 2Bivariable and multivariable generalized linear mixed-effects model analyses of factors associated with higher pain severity among methadone-maintained people who use illicit drugs in Vancouver, Canada (n=823 contributing to a total of 3,018 observations)Unadjusted AdjustedVariable Odds Ratio (95% CI) p - value Odds Ratio (95% CI) p - valueAge (per 10 years older) 1.64 (1.38 – 1.95) <0.001 1.31 (1.13 – 1.51) <0.001Gender (male vs. female) 1.01 (0.74 – 1.36) 0.970Ethnicity (Caucasian vs. other) 1.88 (1.38 – 2.56) <0.001 1.42 (1.10 – 1.83) 0.007Homelessness* (yes vs. no) 0.99 (0.72 – 1.36) 0.941Downtown Eastside residence* (yes vs. no) 1.21 (0.94 – 1.55) 0.134Highest education level obtained (≥ high school diploma vs. < high school diploma) 1.53 (1.13 – 2.06) 0.006 1.21 (0.95 – 1.53) 0.120HIV serostatus* (positive vs. negative) 0.94 (0.70 – 1.28) 0.702Hepatitis C status* (positive vs. negative) 0.89 (0.50 – 1.58) 0.695Mental illness diagnosisΔ (yes vs. no) 1.78 (1.31 – 2.41) <0.001 1.44 (1.13 – 1.84) 0.004Incarceration* (yes vs. no) 1.25 (0.80 – 1.94) 0.323Physical disability* (yes vs. no) 5.28 (4.32 – 6.45) <0.001 4.59 (3.73 – 5.64) <0.001Self-managed pain* (yes vs. no) 2.80 (2.31 – 3.39) <0.001 2.15 (1.77 – 2.60) <0.001Denied pain medication* (yes vs. no) 1.58 (1.24 – 2.01) <0.001 1.20 (0.94 – 1.52) 0.146Non-fatal overdose* (yes vs. no) 1.79 (1.15 – 2.80) 0.010 1.40 (0.90 – 2.18) 0.137Current methadone dose (per 10 mL/day increase) 1.01 (0.99 – 1.03) 0.451Methadone dose perceived to be “too low” (yes vs. no) 1.85 (1.43 – 2.41) <0.001 1.82 (1.41 – 2.34) <0.001Illicit methadone injection* (yes vs. no) 0.59 (0.11 – 3.09) 0.528J Pain. Author manuscript; available in PMC 2016 September 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptVoon et al. Page 16Unadjusted AdjustedVariable Odds Ratio (95% CI) p - value Odds Ratio (95% CI) p - valueCrack cocaine use* (yes vs. no) 1.08 (0.86 – 1.36) 0.523Crystal meth injection* (yes vs. no) 1.05 (0.79 – 1.41) 0.735Heroin injection* (yes vs. no) 1.17 (0.94 – 1.45) 0.163Cocaine injection* (yes vs. no) 1.19 (0.94 – 1.51) 0.158Marijuana use* (yes vs. no) 1.32 (1.07 – 1.63) 0.009 1.25 (1.02 – 1.52) 0.033Heavy alcohol use* (yes vs. no) 1.31 (0.94 – 1.81) 0.106Prescription opioid use* (yes vs. no) 1.65 (1.28 – 2.13) <0.001 1.23 (0.95 – 1.58) 0.112Binge injection drug use* (yes vs. no) 1.06 (0.84 – 1.34) 0.604*Denotes activities/events in the previous six monthsΔDenotes activities/events within the participant’s lifetimeJ Pain. Author manuscript; available in PMC 2016 September 01.

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