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Alcohol use in opioid agonist treatment Nolan, Seonaid; Klimas, Jan; Wood, Evan Dec 8, 2016

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Nolan et al. Addict Sci Clin Pract  (2016) 11:17 DOI 10.1186/s13722-016-0065-6REVIEWAlcohol use in opioid agonist treatmentSeonaid Nolan1,2*, Jan Klimas1,3 and Evan Wood1,2Abstract Alcohol misuse among individuals receiving agonist treatment for an opioid use disorder is common and is associ‑ated with significant morbidity and mortality. At present, though substantial research highlights effective strategies for the screening, diagnosis and management of an alcohol or opioid use disorder individually, less is known about how best to care for those with a dual diagnosis especially since common treatments for opioid addiction may be contraindicated in a setting of alcohol use. This review summarizes existing research and characterizes the prevalence, clinical implications and management of alcohol misuse among individuals with opioid addiction. Furthermore, it highlights clinically relevant management strategies in need of future research to advance care for this unique, but important, patient population.Keywords: Alcohol use, Alcohol misuse, Alcohol use disorder, Opioid agonist treatment, Methadone, Buprenorphine/naloxone© The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BackgroundApproximately one-third of individuals who receive opioid agonist treatment (OAT), such as methadone or buprenorphine/naloxone for the management of an opi-oid use disorder, also misuse alcohol [1]. Despite alcohol use being a risk factor for fatal overdose among individu-als prescribed opioids, as well as being an established risk factor for addiction treatment non-compliance among OAT participants [2–4], little guidance currently exists outlining effective management strategies for this patient population. Consequently, an individual’s alcohol misuse frequently goes undiagnosed and untreated [5–7]. The potential risk for relapse to opioid use, as a result of this missed opportunity, as well as the host of negative conse-quences that can occur from this or from untreated alco-hol misuse is significant among this patient population [8–15]. This review summarizes the existing research of alcohol misuse among OAT participants with a specific focus on prevalence, clinical implications and manage-ment. Clinically relevant management strategies in need of future research are additionally highlighted to advance care for this unique, but important, patient population.MethodsSearch strategyThis narrative review was based on a literature search using Pubmed and Ovid Medline databases. Keywords used described unhealthy patterns of alcohol use and included: alcohol, alcohol addiction, alcohol misuse, harmful alcohol use, hazardous alcohol use, heavy alco-hol use, alcohol abuse, alcohol dependence or alcohol use disorder. These terms were combined with terms refer-ring to OAT including: opioid addiction treatment, OAT, buprenorphine or methadone. Studies written in Eng-lish were included. Additionally, references for all stud-ies identified through the database search were examined to identify articles that may have been missed. Articles focused on prevalence, clinical implications, screening or management of alcohol misuse among OAT participants were reviewed in detail and are summarized.PrevalenceEstimating the prevalence of alcohol misuse among opi-oid dependent individuals receiving OAT is challeng-ing. Substantial variation exists within the literature among patient populations and treatment settings being Open AccessAddiction Science & Clinical Practice*Correspondence:  seonaidn@gmail.com 1 British Columbia Centre for Excellence in HIV/AIDS, St. Paul’s Hospital, 608‑1081 Burrard Street, Vancouver, BC V6Z 1Y6, CanadaFull list of author information is available at the end of the articlePage 2 of 7Nolan et al. Addict Sci Clin Pract  (2016) 11:17 studied. Furthermore a lack of standardization pertain-ing to alcohol misuse terminology and measurement of this is common. In this review, ‘alcohol misuse’ is defined as the consumption of alcohol in a quantity that exceeds low risk for developing an alcohol use disorder as defined by the National Institute on Alcohol Abuse and Alcohol-ism (i.e. no more than 3 drinks in a single day and no more than 7 drinks per week for women and no more than 4 drinks in a single day and no more than 14 drinks per week for men) and includes both people with ‘risky drinking,’ ‘alcohol abuse or dependence’ and those with an established ‘alcohol use disorder’ [16].A 2015 review by Soyka et  al., estimated one-third of methadone maintenance participants also have problem-atic alcohol use [1]. Other studies are in agreement with this estimate including a meta-analyses of U.S. clinical trials which demonstrated 38% of individuals seeking treatment for opioid use to have a concurrent alcohol use disorder, as defined by a diagnosis of either alcohol abuse or dependence using criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [9]. Beyond the U.S., data from the British National Treat-ment Outcome Research Study, a large prospective study of drug users, indicates that at the time of enrolment in a community methadone clinic just over one-third of cli-ents were drinking alcohol above the recommended lim-its with no statistically significant change observed after 1 year of follow-up [5]. Lastly, a cross-sectional study of current or former heroin users attending primary care for methadone maintenance treatment in Ireland revealed the prevalence of problem alcohol use [as defined by an Alcohol Use Disorder Identification Test (AUDIT) score of >7] to be 35% [17]. Collectively, these data suggest that approximately one-third of opioid addicted individuals in treatment may have concurrent alcohol misuse.InteractionsWhile interactions between alcohol and opioids have previously been described [1, 18], research focused spe-cifically on alcohol in the context of OAT is scarce [19]. Animal studies involving methadone predominate and repeatedly demonstrate an influence of ethanol on meth-adone metabolism and vice versa [19]. More specifically, among rat subjects, acute ethanol consumption increased peak methadone concentration [20, 21] while chronic ethanol use led to a reduction in peak methadone levels [21–23]. Similarly, acute methadone administration has been shown to decrease the rate of ethanol metabolism (and thus increase blood alcohol levels) [20] whereas chronic methadone use leads to a reduction in blood alcohol levels [24, 25]. Human research focused on this issue is scarce [19]. Clinical observations among individ-uals who receive methadone maintenance therapy report less of an effect of alcohol [23, 26], more sedation at the time of peak methadone levels as well as more rapid dis-sipation of methadone’s overall effect resulting in opioid withdrawal symptoms [23]. One study by Lenne et al. [27] did demonstrate a small but significant effect of increased blood alcohol concentration (BAC) among non-opioid study controls compared to those receiving regular OAT. A subsequent study by Clark et  al. [19] furthered these findings by demonstrating the interaction between alco-hol and opioids to be strongest at the time of peak plasma levels after opioid dosing (i.e. a dose–response relation-ship) as well as reporting an opioid-specific difference in the magnitude of this interaction (e.g. methadone versus buprenorphine). While these findings support the case for a true pharmacokinetic interaction among humans between alcohol and opioids, the specific site(s) of such interaction requires further study. Furthermore, it should be emphasized that the overall magnitude of the reduc-tion of BAC among individuals receiving OAT in these studies is small (and likely of limited clinical significance) and individuals who receive OAT and consume alcohol will still experience a greater opioid effect due to the combined sedative effect of both substances [19].Clinical implicationsKnowledge of the potential mechanisms of interaction between OAT and alcohol and their effect on blood levels is of importance, but equally so is determining the clini-cal significance of these mechanisms.Effect of OAT initiation on alcohol consumptionTo date, studies investigating the effect of OAT initiation on alcohol consumption among individuals with alcohol misuse and an opioid use disorder are mixed. For exam-ple, Caputo et  al. [28] demonstrated short term metha-done treatment to be associated with a reduction in alcohol levels while long term methadone maintenance therapy resulted in increased alcohol consumption. While an inverse relationship between heroin use and alcohol use has previously been described [29, 30], a recent study found methadone enrolment to have no effect on heavy drinking and may even appear to decrease the initiation of heavy drinking among heroin users [31]. Furthermore, a 12-month longitudinal study of individuals with both heroin addiction and alcohol dependence demonstrated both methadone and buprenorphine to be associated with a reduction in alcohol use, with buprenorphine being more efficacious [32]. Lastly, a recent meta-analy-ses involving 15 studies showed no clear pattern regard-ing the effects of OAT on alcohol consumption with 3 studies indicating an increase in alcohol consumption during treatment, 3 studies indicating a decrease in alco-hol consumption and 9 studies reporting no change [33].Page 3 of 7Nolan et al. Addict Sci Clin Pract  (2016) 11:17 Overdose and mortalityAlcohol use has previously been identified to be a risk factor for increased overdose and mortality among indi-viduals receiving OAT [34, 35]. The degree of increased risk conferred overall and according to alcohol consump-tion patterns however (i.e. hazardous or harmful use compared to an alcohol use disorder) is currently lack-ing. A cross-sectional study by Zador et  al. examined the number and causes of death among participants of a methadone maintenance treatment program in Australia and demonstrated drug-related death to account for the highest proportion of mortality (44%), with alcohol use being cited as the third most common substance of use after benzodiazepines and other opioids [34]. Similarly, a New-York based longitudinal follow-up study of active and discharged methadone patients reported excessive alcohol use (≥4 oz per day for a 3 month period) to be the leading cause of death among active methadone par-ticipants (35%) and the second most common cause of death, following complications with opiates, among dis-charged methadone patients (39%) [35].Mechanisms driving this process are likely diverse (e.g. suicide attempts, unintentional overdoses involving vari-ous substances including benzodiazepines, illicit opioids and OAT, etc.) and not well described, but likely relate to the interactions between alcohol and methadone out-lined previously. As such, individuals should routinely be advised of the compounded risk of acute and chronic alcohol consumption while in receipt of OAT and, in particular, of the risk of relapse to illicit opioid use. In addition, during methadone initiation, a period already known to be associated with an increased risk for over-dose and mortality [34, 36], concurrent acute ethanol consumption can further compound this risk by increas-ing CNS and/or respiratory depression [37, 38]. Similarly, though methadone maintenance treatment may lead to lower blood alcohol levels after consumption compared to non-methadone users, one’s overall risk for overdose and mortality is still increased given the combined seda-tive effect of both methadone and alcohol [26].Other clinical outcomesBeyond increasing one’s risk for overdose and mortality, alcohol misuse among individuals concurrently receiv-ing OAT has been associated with a host of other nega-tive clinical outcomes. Specific to addiction treatment, alcohol misuse has been shown to be risk factor for poor compliance with pharmacotherapy [9] and a predictor for negative treatment outcomes [2–4]. As such, individuals with ongoing alcohol misuse are at an increased risk for a relapse to opioids or other substances [9]. Furthermore, as hepatitis infection is a common comorbidity among opioid dependent individuals with prevalence estimates ranging from 64 to 100% in some cohorts [39–44], chronic alcohol misuse can result in hepatotoxicity and increase an individual’s risk for progression to cirrhosis [11, 13, 15]. Additionally, alcohol misuse can exacerbate psychiatric comorbidities such as anxiety, depression and suicidality, all of which are known to be more common among OAT recipients [8, 10, 12, 45, 46]. Lastly, a study by Sebanjo et al. demonstrated alcohol misuse to be asso-ciated with a significant reduction in quality of life and social functioning among methadone maintained indi-viduals [14].ScreeningAnnual screening and brief intervention for alcohol mis-use among OAT participants is recommended by clinical guidelines given both its prevalence and potential for a myriad of negative consequences. While the effective-ness of such practices among general populations has shown mixed results [47–49], a significant reduction in alcohol consumption has been observed among metha-done maintenance participants in several trials including part of a systematic review [50–54]. More specifically, these studies included participants of both community and designated methadone maintenance clinics in both a European [50, 53] and U.S. [51] setting with the inter-vention being delivered by either a clinician [50], nurse [51, 53] or trained therapist [51]. Despite this finding, implementation of these interventions among primary care providers of OAT has been slow [55] and remains variable with rates ranging between 2 and 93% [56, 57]. Furthermore, when screening does occur in these set-tings it is often completed without the use of a validated screening tool [7, 58]. Suggested reasons for these find-ings identify time restrictions, lack of resources and phy-sician attitudes about the effectiveness of screening and brief intervention for the detection and management of alcohol misuse [52].Creation of a guideline for alcohol misuse screening and treatment specific for OAT participants has previ-ously been described as a potential solution to mitigate these challenges [59]. Reasons for such a document include: (1) the high prevalence of alcohol misuse among OAT participants, suggesting the need for a more pro-active and systematic approach to screening and treat-ment; (2) consideration for the use of lower thresholds to not only define alcohol misuse but also guide timing for referral to treatment; and (3) the need for involvement of an addiction specialist for severe cases of recurrent or persistent alcohol misuse among this patient population.While no such dedicated guideline exists in the U.S., a recent clinical guideline was published in Europe and addressed problem alcohol use among substance users who attended primary care (the vast majority for OAT) Page 4 of 7Nolan et al. Addict Sci Clin Pract  (2016) 11:17 in Ireland [59]. Screening recommendations from this guideline suggest random, but at least annual, screening for alcohol misuse using AUDIT C (a 3-item version of the Alcohol Use Disorder Identification Test) as an ini-tial screening instrument, with a positive result requiring administration of the full AUDIT. While other diagnostic screening tools (e.g. blood or urine tests, breathalyzer) can be incorporated into the screening process, their utility is limited and should be reserved to either pro-vide pertinent information to a treating physician or help motivate a patient to address their alcohol misuse. A pos-itive screening test for alcohol misuse should be followed up with screening for other substance use and medical comorbidities including hepatitis and other chronic dis-eases (e.g. cardiac, liver).ManagementDespite one-third of OAT participants misusing alco-hol, treatment for this has widely been ignored [1]. One New York study demonstrated 21% of methadone main-tenance patients to misuse alcohol with only 5% being enrolled in outpatient alcohol detox and 7% engaging in psychosocial intervention [6]. A more recent 12-month follow up study among people who use drugs demon-strated little improvement in patterns of drinking among the majority of participants [5]. These findings may be explained by the limited access to alcohol treatment pro-grams that exists for this patient population given many such programs require termination of a patient’s OAT use as a condition of acceptance [6, 60]. To date, though a theoretical risk for over sedation or overdose may exist among OAT participants being treated for alcohol with-drawal, no research to date has clearly quantified the magnitude of this risk or demonstrated any clear inter-action between sedative medications used during alcohol detoxification or treatment (e.g. benzodiazepines, bar-biturates) and OAT regarding these specific outcomes (though a precipitated opioid withdrawal syndrome has previously been reported with concurrent methadone and phenobarbital administration) [61]. This may relate to the use of these medications within a therapeutic dose range and their administration, which often occurs in a supervised setting. As such, at the present time, no jus-tifiable clinical reason exists to deny entry for treatment of alcohol misuse to an individual that is well established on an OAT program or the need for any modification in dose. Doing so may only increase one’s risk for opioid relapse and the host of negative medical and psychosocial consequences as described above.Based on the above, all OAT participants identified as having alcohol misuse should be offered treatment. In the acute period, management of alcohol withdrawal in an effective and safe manner is the most important consideration. Unfortunately strategies on how best to accomplish this are lacking in the literature and warrant further study. Validation of risk scoring tools like the Pre-diction of Alcohol Withdrawal Severity Scale (PAWSS) among this patient population may be of benefit to iden-tify individuals who are at low risk of developing severe, complicated alcohol withdrawal and thus do not require inpatient admission or benzodiazepine therapy for symp-tom management [62].Psychosocial interventions for alcohol misuse among OAT participants have previously been described [50, 51, 53]. More specifically, clinician delivered brief interven-tion was shown to reduce alcohol consumption among OAT participants without alcohol use disorders (AUDIT score <20). Such a treatment approach is recommended for all alcohol misusers identified through screening by the European clinical guidelines previously described [59]. Furthermore a pilot study and randomized con-trolled trial have identified motivational interviewing to be an effective strategy to reduce alcohol consumption among alcohol misusing methadone maintained partici-pants [51, 53]. Though not specific to OAT participants, psychosocial interventions for alcohol misuse among concurrent substance users have been described in a sys-tematic review [52]. Four studies involving 594 partici-pants evaluated 6 psychosocial interventions through 4 comparison groups: cognitive-behavioral coping skills training versus 12-step facilitation (n  =  41) [63], brief intervention versus treatment as usual (n  =  110) [64], hepatitis health promotion versus motivational inter-viewing (n =  256) [51] and brief motivational interven-tion versus assessment only group (n = 187) [65]. Higher rates of decreased alcohol use were found at 3 and 9 months among the treatment as usual group when com-pared to brief intervention [64] and more people reduced their alcohol use at 6 months (by 7 or more days in the preceding 30 days) in the brief motivational intervention group compared to control [65]. No other comparisons were found to be statistically significant and because of methodological study differences, no meta-analysis could be performed. Overall the authors were unable to recom-mend for or against the use of psychosocial interventions for alcohol misuse among concurrent substance users, which is similar to previous findings [66, 67].While the effectiveness of medications for alcohol relapse prevention including naltrexone and acamprosate has been described among the general population [68, 69], opioid antagonist use among those on OAT is not possible given the effects of naltrexone on OAT and the emergence of precipitated withdrawal. In terms of acam-prosate, no studies to date have been conducted among Page 5 of 7Nolan et al. Addict Sci Clin Pract  (2016) 11:17 OAT participants who misuse alcohol. The use of disul-firam for reducing heavy alcohol consumption among patients receiving methadone maintenance therapy was evaluated in one randomized double-blind controlled trial [70] with the results showing no significant differ-ence compared to placebo (though the trial was stopped early when sample size targets were not achieved). While two subsequent meta-analyses [71, 72] did demonstrate efficacy with the use of disulfiram when administered in a supervised setting among individuals with alcohol abuse or dependence regarding short term abstinence, days until relapse and number of drinking days, it should be noted that receipt of methadone was an exclusion criteria in one of these studies [71] with the other [72] including only 2 small randomized controlled trials of methadone maintenance patients. Given these findings, there is an urgent need to evaluate the use of such medications, or others used off label for the treatment of alcohol addic-tion (e.g. gabapentin) [73–75] specifically among OAT participants, as their administration in this setting is a feasible strategy.Another promising option for this treatment popu-lation is extended release naltrexone. Here, while oral naltrexone has not been shown to be superior to pla-cebo in the context of opioid dependence, studies of extended release naltrexone (XR-NTX) have shown promise for the treatment of both alcohol misuse and opioid dependence [76–78]. Prior to initiation with this opioid antagonist, patients are required to have completed opioid detoxification and not be receiving any ongoing opioids (including either methadone or buprenorphine). In settings where XR-NTX is availa-ble, this would be an option and its rigorous evaluation in the context of alcohol and opioid poly-substance addiction is warranted.ConclusionsAlcohol misuse is common among OAT participants and is associated with a number of adverse outcomes including overdose and mortality. Despite this, the lit-erature suggests that screening and treatment for alco-hol misuse among this patient population consistently goes overlooked. To overcome these challenges, future research should focus on the development of strategies to increase rates and frequency of alcohol screening and brief intervention among OAT providers. Guidance for effective alcohol detoxification strategies and an evalu-ation of acamprosate’s and XR-NTX’s effectiveness for relapse prevention among this patient population is also of importance. Lastly, eliminating barriers for accessing alcohol addiction treatment programs for individuals on OAT is essential as is the integration of alcohol misuse treatment into OAT primary care settings.Authors’ contributionsSN and EW designed and prepared the first draft of the manuscript. All co‑authors contributed to drafting the final manuscript. All authors read and approved the final manuscript.Author details1 British Columbia Centre for Excellence in HIV/AIDS, St. Paul’s Hospital, 608‑1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada. 2 Department of Medicine, University of British Columbia,  St. Paul’s Hospital, 608‑1081 Bur‑rard Street, Vancouver, BC V6Z 1Y6, Canada. 3 School of Medicine and Medical Science, University College Dublin, Coombe Healthcare Centre, Dolphins Barn, Dublin, Ireland. AcknowledgementsNot applicable.Competing interestsThe authors declare that they have no competing interests.FundingJK is supported by The ELEVATE Grant: Irish Research Council International Career Development Fellowship—co‑funded by Marie Cure Actions (ELEVATEPD/2014/6); and the European Commission Grant (701698). EW is supported by funding from the Canada Research Chairs program through a Tier 1 Canada Research Chair in Inner City Medicine.Received: 11 July 2016   Accepted: 29 November 2016References 1. Soyka M. Alcohol use disorders in opioid maintenance therapy: preva‑lence, clinical correlates and treatment. Eur Addict Res. 2015;21(2):78–87. 2. Degenhardt L, Hall W. Patterns of co‑morbidity between alcohol use and other substance use in the Australian population. Drug Alcohol Rev. 2003;22(1):7–13. 3. Potter JS, Marino EN, Hillhouse MP, Nielsen S, Wiest K, Canamar CP, et al. 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