Opioid use disorder (OUD) is defined by the Diagnostic and Statistical Manual of Mental Disorders (fifth edition)1 as the maladaptive use of opioids, prescribed or illicit, resulting in two or more criteria that reflect impaired health or function over a 12-month period. OUD is scaled according to severity (mild/moderate/severe) and does not require physiological tolerance or dependence in order to be considered a substance use disorder. Text Box 1 summarizes core criteria and provides a mnemonic to assist clinical diagnosis and teaching.
In the United States, rates of prescription opioid analgesic misuse rose exponentially in the preceding decade,2 as has the treatment received for both heroin use disorder and opioid analgesic use disorder.3 Among persons aged 12 years and older, self-reported lifetime misuse of heroin and opioid analgesics is estimated at nearly 2% and 14% of the population, respectively.3
Effective treatment of OUD has been identified as a national priority to reduce the rates and societal costs of individual disability associated with OUD, the infectious disease burden associated with intravenous opioid use (especially hepatitis C [HCV] and HIV transmission), and escalating rates of accidental opioid overdose deaths and pediatric opioid ingestions.2,4–8 Prior reviews of medication-assisted treatment (MAT) of OUD provide useful guidance to clinicians,9–12 yet algorithms for selecting medication treatment require continuous updating to remain current with the emerging evidence. The goal of this review is to succinctly provide this clinical update and to highlight unresolved challenges in treating OUD.
All randomized, controlled trials (RCTs) with English abstracts on medical management of OUD were searched using PubMed mesh terms [opioid dependence OR opioid addiction] AND medication, yielding 502 abstracts. These articles were screened for inclusion as contributing to the evidence on MAT for OUD. The resulting set of references was supplemented, based on an examination of abstracts, to include relevant case reports, reviews, meta-analyses, and clinical trials. Finally, the Provider’s Clinical Support System for Medication-Assisted Treatment website (www.pcssmat.org), which contains current practice training and educational support for opioid MAT, was reviewed to identify elements of expert consensus beyond the current evidence.
RESULTS: OVERVIEW OF MAT FOR OUD
Mu-Opioid Receptor Targeted Stabilization of OUD
The Food and Drug Administration (FDA) has approved three medications for preventing opioid relapse and for stabilization/maintenance treatment of OUD: buprenorphine, naltrexone, and methadone. All three are ligands that bind to central mu-opioid receptors as the molecular target for their therapeutic activity, yet they differ significantly in their respective intrinsic activities at the mu-opioid receptor, their pharmacokinetic and pharmacodynamic properties (with effects on efficacy and toxicity), and the mechanisms by which they confer relapse-prevention protection to treated individuals (Table 1).
In selecting MAT, the first consideration is whether an individual has OUD with physiological dependence. All three medications are FDA approved based on RCTs demonstrating efficacy and safety in OUD with historical symptoms of physiological dependence (Table 2). The addition of agonist maintenance to relapse-prevention treatment at least doubles the probability, compared to relapse-prevention treatment alone, that an individual will achieve opioid abstinence during active treatment,24–27 and the addition of antagonist maintenance nearly doubles opioid abstinence.23 Oral naltrexone, although FDA approved to treat OUD, is excluded from consideration here due to poor adherence rates and significant opioid-overdose mortality following medication discontinuation in clinical studies of OUD treatment outcomes.28–31 Attempts to pair oral naltrexone with psychosocial interventions aimed at improving compliance and retention in treatment have not yet demonstrated sustained positive results.29,32 Naltrexone implant and buprenorphine implant are not yet FDA approved for OUD, and trials to date provide insufficient evidence of safety and efficacy.33,34
The evidence for efficacy both in reducing opioid use and retaining patients in care is strongest for agonist treatment; methadone maintenance remains the gold standard of care for OUD.35 The evidence for antagonist treatment of OUD remains comparatively weak, given the mortality risk and poor adherence with oral naltrexone, plus the limited RCT evidence for extended-release naltrexone (naltrexone ER). The latter includes only a trial23 with open-label extension19 in a Russian population without access to agonist therapy and a small trial of employment contingency to improve naltrexone ER adherence in a US cohort.36 Also in Russia, a small RCT of employment contingency to improve adherence used a different, non-FDA-approved formulation of naltrexone ER. Efficacy in reducing opioid use (60%–70% opioid-free urines) was similar to the two above trials cited, and the employment-contingency condition improved adherence but did not affect opioid use.37 These studies do not adequately address either safety following medication discontinuation or efficacy compared to agonist therapy, and they pose problems for generalizability. A phase 4, multisite RCT comparing naltrexone ER to buprenorphine/naloxone maintenance is currently under way, with the expectation that results will resolve safety and efficacy questions regarding naltrexone ER as a treatment for OUD (NIDA Clinical Trials Network protocol 0051 [Principal Investigator: John Rotrosen/NewYork University School of Medicine]; ClinicalTrials.gov identifier NCT02032433).
Unknown Aspects of Mu-Opioid Receptor Functional Activity in MAT
Although it is commonly accepted that the functional effects of MAT differ according to their respective intrinsic activities at central mu-opioid receptors, this view is oversimplified. The many complexities of mu-opioid receptor ligand binding and biased agonism (e.g., “functional selectivity” according to mu-opioid receptor/effector coupling and intracellular environment, and agonist-induced receptor conformational changes with prolonged agonist exposure)38–40 are only now being discovered, and may account for the clinical effects of these medications that remain poorly understood and that appear to vary widely among individuals. For example, little is known about why only certain individuals develop OUD following recurrent opioid exposure, although population studies in patients receiving opioid analgesics identify co-occurring substance use and mental illness as risk factors for developing OUD,41 and a recent meta-analysis suggests that the rs1799971 polymorphism of the OPRM1 gene may confer vulnerability to OUD following exposure to either heroin or prescription opioids.42 Clinically, dosing needs in agonist maintenance therapies different significantly among individuals, and most patients do not develop tolerance to the relapse-prevention efficacy of buprenorphine or methadone maintenance. These observations suggest dynamic factors beyond ligand intrinsic activity at mu-opioid receptors. Whistler43 has presented a helpful summary of the converging evidence that opioid agonists having both high efficacy and high propensity to produce mu-opioid receptor desensitization and endocytosis (“molecular trafficking”) have lower liability for abuse and produce less tolerance than opioid agonists that induce comparatively little endocytosis. Examples of the former include endogenous opioid ligands and methadone, whereas the latter include morphine, codeine, buprenorphine,44 and most commonly misused prescription opioids. Thus, endocytosis may help to explain the lack of tolerance observed for relapse-prevention efficacy with methadone maintenance but would not explain the same observation with buprenorphine maintenance.
Within methadone-maintained patients, pharmacogenomic studies identify variability in treatment response and pharmacokinetics associated with the variants of several genes (OPRM1, ARRB2, KCNJ6, ABCB1) and hepatic CYP450 enzymes, suggesting layers of complexity in any given individual’s treatment response.45 For example, a recently published meta-analysis demonstrates that individuals homozygous for the CYP2B6*6 polymorphism are slow metabolizers of both the R- and S- enantiomers of methadone and therefore would be expected to have lower dosing requirements.46 The utility of pharmacogenomic screening may be especially important in future clinical practice with methadone maintenance.
Comparing MAT Tolerability and Convenience
RCTs examining methadone, buprenorphine, and extended-release naltrexone injection stabilization are all associated with acceptable adverse-effect profiles and with an acceptable level of patient tolerance.23–27 Agonist treatment is associated most frequently with opioid-class effects such as dose-dependent sedation, constipation, sweating, neurocognitive impairment, and sexual dysfunction. Dose-dependent respiratory depression is an adverse effect mainly of methadone, a full mu-opioid agonist, whereas the partial-agonist properties of buprenorphine prevent dose-dependent respiratory depression greater than 50% reduction of baseline even at IV doses of 2 mcg/kg in opioid-naive healthy volunteers.47 This “ceiling effect” on respiratory depression has obvious benefits for tolerability as well as for accidental or intentional overdose. Similarly, buprenorphine’s partial-agonist properties have a protective “ceiling effect” that does not induce euphoria in opioid-tolerant individuals, whereas methadone-induced euphoria may be present in the early treatment of OUD but decreases with steady-state dosing stabilization.48
Naltrexone ER is associated most commonly with insomnia, site reactions to injection, clinically insignificant elevation of transaminases, hypertension, nasopharyngitis, and influenza.19,23
Patient convenience for dosing is least burdensome with monthly injections of naltrexone ER or monthly maintenance visits with office-based buprenorphine/naloxone—both modeling typical outpatient treatment for severe chronic illness. Dosing is most burdensome with required observed daily dosing in opioid treatment programs prescribing methadone or buprenorphine maintenance in the early phases of recovery.
Retention in Treatment After the Initiation of MAT
All three medications show improved retention in treatment compared to placebo or no medication.24–27 Head-to-head comparisons are mainly available for buprenorphine versus methadone maintenance, with methadone demonstrating the highest rates of treatment retention in all studies,35,49 including the treatment of pregnant women50 and those with HIV.51 One RCT conducted in Iran compared all three medications in a cohort of men dependent on intravenous buprenorphine and found that retention in treatment over a 24-week period was best with methadone followed by buprenorphine and then oral naltrexone, although it was noted that the available daily dose of buprenorphine (5 mg) was not an agonist dose equivalent to the study’s daily dose of methadone (50 mg)—which likely contributed to poorer retention in the buprenorphine-treated group.52
Impact on HIV Risk Behaviors
In HIV-infected populations, methadone and buprenorphine maintenance significantly reduce the use of illicit opioids and the risk of HIV transmission through the use of injection drugs, though their impact is less robust on sexual risk behaviors.53–56 In a secondary analysis using a large national cohort from a safety RCT (comparing hepatic responses to 24 weeks methadone and buprenorphine maintenance for OUD),57 an interesting gender difference emerged: sexual risk behaviors increased among men maintained on buprenorphine but decreased in methadone-maintained men, whereas women decreased risk with either buprenorphine or methadone maintenance.51
Impact on Hepatitis C Risk Behaviors
Cumulative, lifetime HCV seroprevalence estimates among injection-drug users is up to 90%,58 with high seroconversion rates attributable to both sharing syringes/needles and sharing drug preparation equipment (e.g., drug cookers and spoons, filtration cottons, vehicle fluids).59,60 Two large, prospective cohort studies report the protective effect of methadone61,62 and buprenorphine62 maintenance, but not detoxification, in preventing HCV seroconversion among adult injection-drug users who are HCV negative at treatment entry.
Impact on Preventing Opioid Overdose
Several risk factors for unintended opioid overdose have been identified. They include misuse of heroin and opioid analgesics, misuse of diverted buprenorphine and methadone, increases in opioid prescribing, having four or more prescribers or pharmacies filling opioid prescriptions, being prescribed doses equivalent to more than 100 mg morphine, opioid ingestion coupled with alcohol or the use of other sedatives/hypnotics (with synergistic effects on respiratory depression), receipt of public subsidy income providing access to drug purchase and binge drug use, suboptimal methadone-induction practices in relation to both pain management and addiction, opioid-analgesic switching, previous overdose history, loss of opioid tolerance among OUD due either to extended abstinence during incarceration or to treatment-related abstinence, and older age, with smoking status and co-occurring medical conditions likely contributing to fatalities.2,63–71 Given that MAT reduces illicit opioid use, educates about OUD and accidental-overdose prevention, and may provide (where available) intranasal naloxone rescue kits to family and friends for use at the scene of an opioid overdose,68,72 it is expected that MAT would be an important factor in preventing accidental opioid-overdose deaths occurring in those with OUD while they remain in active treatment. While data to date suggest that that is indeed the case for buprenorphine, methadone, and naltrexone ER,19,63 more data are required to judge the safety of MAT following treatment dropout and planned medication discontinuation, particularly for antagonist therapies for which the preclinical20 and clinical28,31,73 evidence indicates increased risk for respiratory depression upon opioid agonist reexposure.
Safety Profile of MAT
Buprenorphine and methadone57 and naltrexone ER19,74 maintenance have favorable safety profiles, with HCV-infection being the most common predictor of mild-to-moderate increases in transaminases among adults, pregnant women,75 and youth.26,76 Methadone risk for QTc prolongation (associated with torsades de pointes, which has an estimated 10%–17% risk of sudden death due to cardiac arrhythmia77) is dose dependent, but screening baseline QTc intervals has not yet been shown to assist risk management during methadone maintenance.78 Neither buprenorphine nor naltrexone is associated with QTc prolongation.
Drug-drug interactions are numerous with methadone, due to many cytochrome P450 isoenzymes involved in its hepatic metabolism (mainly CYP3A4, but also CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6).12,18 Metabolic inhibitors that increase methadone peak concentrations pose a risk for sedation and respiratory depression, bowel immotility, and QTc prolongation and cardiac arrhythmia; whereas metabolic potentiators that reduce methadone peak and trough concentrations pose a risk for opioid withdrawal and relapse to opioid use. Other substances and drugs having similar adverse effects (sedation, reduced bowel motility, QTc prolongation, and reductions in heart rate, blood pressure, and respiratory rate) may pose additive and synergistic effects, even if they do not alter methadone metabolism. Common examples include alcohol and benzodiazepines (sedation and reduced respiratory drive), antipsychotics, tricyclic antidepressants, and calcium channel blockers (QTc prolongation), and psychotropics with anticholinergic effects (constipation).
By comparison, buprenorphine and naltrexone have few drug-drug interactions and a benign side-effect profile. Owing to its partial-agonist properties, buprenorphine is not associated with a significant risk for respiratory depression;47 however, in combination with sedatives/hypnotics (especially diazepam),79–81 it poses a risk for sedation and reduced respiratory drive. Naltrexone has no risk for reduced respiratory drive, but attempts to “override” blockade with high-dose opioid use poses a risk for accidental-overdose death (see Vivitrol® package insert). Buprenorphine is metabolized primarily by CYP3A4 and has clinically significant drug-drug interactions with rifampin (reductions in buprenorphine concentrations pose a risk for opioid withdrawal, although this effect is not observed with rifabutin)82 and atazanavir (increased buprenorphine concentration and sedation/cognitive impairment).83 Buprenorphine has not had confirmed, clinically significant CYP3A4 or CYP2D6 interactions with other commonly prescribed psychotropics and medications, although infrequent case reports exist; definitive human studies are lacking.18,84 Naltrexone is not metabolized by cytochrome P450 isoenzymes; instead, it has hepatic metabolism via dihydrodiol dehydrogenase to β-naltrexol, which is then conjugated for urinary excretion.84 Its major drug interaction is blockade of opioid analgesic efficacy.
In pregnancy, naltrexone ER has no demonstrated safety, whereas both buprenorphine and methadone maintenance are safe and effective for maintaining maternal abstinence and retention in prenatal care,85 and are safely recommended during breastfeeding.86,87 Buprenorphine demonstrates less peak-dosing suppression of fetal heart rate, fetal heart rate reactivity, and biophysical profile scores, and generates a milder neonatal abstinence syndrome than methadone.88,89 Early neonatal development appears within normal limits for infants exposed to buprenorphine or methadone in utero.90 Longer-term neurodevelopmental safety is known for infants exposed in utero to methadone91 and is being investigated for buprenorphine-exposed infants.
Ease of Induction and Comparison of Available MAT Formulary
The MAT formulary available in the United States for treating OUD is summarized in Table 3. Naltrexone ER is available only under a brand name, whereas buprenorphine monotherapy, buprenorphine/naloxone, and methadone are all available both generically and under brand names. Oral methadone concentrates are dose-equivalent, but the differences in formulations for buprenorphine/naloxone are not reliably dose-equivalent (see, e.g., the dosing differences with buccal film). Converting between these forms of buprenorphine/naloxone requires careful attention to dosing practices (food and smoking should be avoided 30 minutes before and after dosing, and dissolved medication should be held with saliva for a full 10 minutes to optimize mucosal absorption) and to patient response. General dosing ranges for both induction and for stabilization/maintenance treatment are also listed in Table 3.
An advantage of methadone is that it can be started at any time during an overarching course of treatment. A disadvantage, however, is that it takes time to achieve a steady-state dose that is therapeutically effective in OUD, and this time period is one of high risk for treatment dropout and accidental overdose if titration is too rapid.17,92 Buprenorphine requires the individual to be in mild-moderate opioid withdrawal prior to dosing, in order to avoid precipitating severe opioid withdrawal (due to its partial-agonist activity), but relief is achieved within 24–72 hours of induction for both monotherapy and the naloxone-combined product. The partial-agonist “ceiling effect” protects against respiratory depression, thus rendering this medication safe for rapid induction. Buprenorphine monotherapy is recommended for observed induction and for stabilizing or maintaining pregnant women or those that may respond adversely to naloxone due to allergies or co-occurring medical conditions. The combination product is buprenorphine plus naloxone in a 4:1 ratio and was designed to prevent misuse and diversion of buprenorphine among injection drug users. Buprenorphine has good bioavailability via oral mucosal absorption, whereas naloxone does not. Taken sublingually, the naloxone component has poor bioavailability, but if crushed and injected, the naloxone component is readily available to exert opioid antagonist effects, thus reducing the risk of abuse in buprenorphine treatment. Buprenorphine/naloxone is consequently the formula of choice for inductions that are not fully observed and for routine maintenance, in order to reduce product diversion and misuse. Naltrexone ER has the most complicated induction profile because of the need to complete metabolism of opioid agonists prior to dosing (typically 7–14 days), thereby avoiding severe opioid withdrawal (due to its antagonist activity). Prolonged symptoms of opioid withdrawal during washout pose a high risk for treatment dropout and relapse. Attempts to abbreviate this period require more complex dosing algorithms as well as back-up options for environmental containment to prevent relapse to opioid use.93
Risk for Diversion and Negative Public Health Impact
Buprenorphine (all formulations) and methadone are known to be diverted by patients and to be commonly used illicitly,63,94,95 resulting in further opioid misuse and overdoses, in accidental pediatric exposures,96 and in accidental or intentional adolescent exposures.6 Since naltrexone ER has no known diversion value, it allows for the treatment of OUD without contributing to illicit opioid use.
Factors to Consider in Selecting Treatment with MAT
MAT is recommended for adults presenting for clinical treatment of OUD with physiological dependence: it significantly augments treatment retention, reduces illicit opioid use, reduces the burden of opioid craving, and, in the case of agonist therapies, provides effective relief of the opioid withdrawal syndrome. Thus, MAT is a stabilizing addition to relapse-prevention counseling and mutual help groups (such as Narcotics Anonymous) in that it increases the effectiveness of those interventions. Longer-term, abstinence-based residential treatment without MAT shows limited effectiveness, especially among recently detoxified heroin users,97,98 and loss of tolerance during this period of abstention poses an increased risk of fatal overdose if one relapses to opioid use upon discharge to home. Youth is a predictor of early dropout from psychosocial treatment of OUD,99 whereas medication adherence and early opioid abstinence predict greater retention and treatment success among youth treated with buprenorphine/naloxone.100 A 2005 Cochrane review noted that the available evidence was insufficient to support psychosocial treatment alone as effective for OUD.101 The evidence remains insufficient, even to predict which individuals, if any, are likely to do well without MAT.
The selection of MAT can be viewed from two different perspectives: individualized treatment versus population management. An individualized treatment approach will consider many factors, in addition to the evidence base, to guide medical decisions. These factors include the following: the availability of, and patient’s access to, MAT; the experience of the prescribing clinician; the clinical setting of treatment; patient and family preferences; occupational risks (see next paragraph); co-occurring medical and psychiatric illnesses; and the patient’s motivation for opioid abstinence, capacity to adhere to recommended treatment, and legal status. If the risk for treatment dropout is high, the evidence regarding MAT and retention in treatment significantly favors a recommendation for agonist therapy; methadone maintenance demonstrates the highest patient retention rates in all studies comparing methadone to buprenorphine. A recommendation of methadone or buprenorphine/naloxone maintenance must also be balanced by a discussion with the patient (including informed consent) regarding both the difficulty of terminating agonist therapies (due to reexperiencing opioid withdrawal and craving) and the high rates of opioid relapse following the discontinuation of either buprenorphine25,26 or methadone.102,103 Unfortunately, no long-term studies have compared taper outcomes with buprenorphine versus methadone. Clinicians are encouraged to monitor taper trials closely for any evidence of patient destabilization or relapse risk that would require returning to higher-dose agonist treatment. The benefits of extended methadone or buprenorphine/naloxone maintenance delivered within an opioid treatment program (requiring daily medication monitoring during early recovery, and providing structured psychosocial interventions and integrated care options) are especially pronounced for populations with significant drug-related legal charges and drug-using social networks, for patients with co-occurring medical illness related to injection drug use, and for socially disadvantaged patients, who may receive, through the integrated structure of the program, the intensive social and medical services needed to support sustained recovery.
In some situations, the selection of MAT may reflect risk-benefit assessments unrelated to the medical factors as such. For instance, the performance of pilots, physicians, professional athletes, or those carrying firearms could be compromised and even be dangerous because of opioid agonist treatment’s cognitive or sedative effects or its impact on reaction times.104,105 No studies specific to these professions have been conducted for agonist therapy of OUD, however, so this concern is empirical rather than evidence based at this time. In such cases, antagonist therapy may be preferred for a motivated, treatment-seeking individual who desires to continue such employment, despite the comparatively weak evidence supporting antagonist versus agonist therapies. Similarly, an individual with co-occurring OUD and alcohol use disorder might benefit most from antagonist therapy, given that the FDA has approved naltrexone ER as effective in preventing relapse to alcohol use.106,107 In all such situations, these matters should be covered in a collaborative informed consent process, and clinicians should carefully document the discussion.
A population-management approach would consider the public health impact of OUD, along with the cost-effectiveness of the available treatment options, over patient preferences and individualized selection of MAT. Primary consideration would be given to preventing opioid diversion into the community, opioid overdose deaths, and the transmission of infectious diseases (in particular, hepatitis C and HIV) through the use of injection opioids. To optimize such decisions, all three MAT options for OUD would need to be available, and prescribers would need to be trained in the appropriate use of each one. Lack of prescriber familiarity and comfort with MAT, as well as limits imposed on prescribers by managed care (e.g., dosing limits, prior authorization reviews, and limits on toxicology), continue to be barriers to dissemination of MAT for OUD in clinical practice.108 The availability of a regularly updated, evidence-based algorithm to assist in decision making would also contribute to the adoption of MAT in practice.109
An example of a simple, evidence-based algorithm for MAT selection—one designed to be flexible in relation to regional MAT availability—is outlined in Text Box 2. Failed treatment trials would result in the selection of an alternate MAT treatment or in the relocation of treatment itself—for example, from an office to a structured treatment setting with closer patient monitoring, such as an opioid treatment program, an integrated mental health care clinic, or a specialized integrated care clinic (following an integrated care model as is used for infectious diseases). In the United States, methadone maintenance must currently be delivered within a federally regulated opioid treatment program, but some evidence suggests, as a future option, that methadone maintenance can be effectively delivered within an office-based setting, especially for clinically stable patients who have achieved take-home doses.110–112 The use and implementation of a MAT algorithm would reduce discrepancies in treatment based on regional variations, prescriber expertise, or access to specialty clinics. The main weakness of this approach, however, is that it could reduce the role of patient preferences in selecting MAT. This consideration is a serious one in framing an effective population-management approach since patient engagement in substance use treatment is essential for optimal outcomes. Service-utilization research and feedback from programs using this approach are much needed.
MAT Selection in Adolescents
The buprenorphine/naloxone combination is FDA approved for adolescents aged 16 and older and has demonstrated safety and efficacy for youth with OUD.26 As such, it is currently the treatment of choice. Nevertheless, concern about adolescent nonadherence and the misuse and diversion of buprenorphine/naloxone has generated some support for empirical treatment with naltrexone ER. Caution is advised, however, because evidence is lacking as to the safety and efficacy of naltrexone ER in this population. In the United States, methadone maintenance is not available for the treatment of adolescents.
MAT Selection in Women of Childbearing Age
For women of childbearing age and those who are pregnant or planning pregnancy, careful discussion, along with informed consent, is required in selecting MAT. Although methadone maintenance is the current gold standard of clinical care during pregnancy, buprenorphine monotherapy (but not buprenorphine/naloxone, though early evidence suggests that the combination warrants further study)113 is a potential alternative based on studies comparing the safety and efficacy of these treatments during pregnancy.85 Postpartum breastfeeding mothers may be switched from buprenorphine monotherapy to combination buprenorphine/naloxone maintenance in order to prevent diversion, especially since naloxone is poorly absorbed sublingually and is unlikely to be absorbed by suckling infants.114
Lack of Clinical Studies for Using MAT in Nondependent OUD
No research has examined MAT in nondependent OUD, and even case reports are lacking on this topic. Such off-label use, which would require appropriate informed consent and risk-management consultation, should not be considered without careful deliberation and documentation of medical decision making. Theoretically, OUD without any history of physiological dependence would favor antagonist treatment in most cases, as maintenance on agonist therapy will induce physiological opioid dependence. In most cases, this risk would not be perceived to outweigh benefit except in the presence of an imminent risk of death by opioid overdose. Such situations include recurrent or recent near-fatal overdoses with opioids or a recent intentional opioid overdose in an impulsive individual returning to an outpatient setting. In these examples, the preserved or augmented opioid tolerance provided by agonist treatment might be considered protective against future toxic opioid use, in which case buprenorphine/naloxone would be favored over methadone because of its lower risk of opioid toxicity and fewer drug-drug interactions. Another example may be the patient with a co-occurring pain syndrome who requires intermittent opioid analgesia, satisfies criteria for OUD without physiological dependence, but misuses opioid analgesics. In this example, low-dose buprenorphine/naloxone maintenance in a divided-dosing regimen could potentially enable pain treatment and circumvent opioid misuse; indeed, studies of OUD with physiological dependence show buprenorphine/naloxone to provide a benefit in mild-to-moderate pain syndromes.25,115 Note, however, that the above comments reflect theoretical considerations only; evidence for efficacy and safety is lacking for all three medications in relation to nondependent OUD.
Need for Development of Non-opioid Therapies to Ameliorate Acute and Protracted Opioid Withdrawal Syndromes
Opioid withdrawal is commonly misrepresented as a “flu-like” syndrome due to the constellation of physical symptoms characterizing acute hyperadrenergic rebound, along with malaise and gastrointestinal distress. This concept of opioid withdrawal is incomplete, however, in that it ignores the severe affective and cognitive distress (including treatment-resistant anxiety, dysphoria/depression, severe opioid craving, and loss of self-efficacy) that persists up to 30 days in untreated OUD abstinence116,117 and that contributes to opioid relapse and treatment dropout, even among young OUD patients with relatively brief histories of dependence.118
Potential non-opioid treatments to stabilize opioid withdrawal and opioid craving may be developed through an understanding of how neurobiological circuitry interacts with opioid pathways.119 Such treatments would be expected to relieve symptoms, improve retention in care, ease induction, and possibly increase the options for managing OUD during pregnancy. A small pilot RCT (n = 24) of buprenorphine detoxification with and without gabapentin, a GABAergic anticonvulsant, demonstrated better short-term opioid-use outcomes with gabapentin,120 but two RCTs assessing the use of memantine, a glutamatergic antagonist, as an adjunct to naltrexone ER induction and stabilization121 or to oral naltrexone122 had negative results. Further research on novel pharmacotherapies to ease opioid withdrawal are warranted.123,124
Clinicians are encouraged to educate patients about opioid withdrawal and its presenting a risk for opioid relapse and for dropping out of treatment. A collaborative plan should be developed, in advance, for managing opioid withdrawal. For example, informed consent with agonist therapies should include a discussion both of opioid withdrawal as presenting a risk for relapse and of the future inevitability of experiencing opioid withdrawal when discontinuing agonist treatment or if doses are missed. Collaborative treatment plans that include aggressive pharmacological management of symptom relief and options for safe containment in higher levels of care (such as partial or residential treatment programs) would be expected to improve retention in care and, more generally, the patient’s understanding of how to avoid relapse to opioid use.
Declaration of interest
The author reports no conflicts of interest. The author alone is responsible for the content and writing of this article.
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: APA, 2013.
2. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep 2011: 60: 1487–92.
3. Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: summary of national findings. Rockville, MD: SAMHSA, 2013. http://www.samhsa.gov/data/sites/default/files/NSDUHnationalfindingresults2012/NSDUHnationalfindingresults2012/NSDUHresults2012.pdf
4. Executive Office of the President of the United States. Epidemic: responding to America’s prescription drug abuse crisis. 2011. http://publications.iowa.gov/12965/1/NationalRxAbusePlan2011.pdf
5. Bailey JE, Campagna E, Dart RC; RADARS System Poison Center Investigators. The underrecognized toll of prescription opioid abuse on young children. Ann Emerg Med 2009; 53: 419–24.
6. Zosel A, Bartelson BB, Bailey E, Lowenstein S, Dart R. Characterization of adolescent prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-related Surveillance (RADARS(®)) System. J Am Acad Child Adolesc Psychiatry 2013; 52: 196–204.
7. Valdiserri R, Khalsa J, Dan C, et al. Confronting the emerging epidemic of HCV infection among young injection drug users. Am J Public Health 2014; 104: 816–21.
8. Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med 2014; 370: 2063–6.
9. Veilleux JC, Colvin PJ, Anderson J, York C, Heinz AJ. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev 2010; 30: 155–66.
10. Hill KP, Rice LS, Connery HS, Weiss RD. Diagnosing and treating opioid dependence. J Fam Pract 2012; 61: 588–97.
11. Bart G. Maintenance medication for opiate addiction: the foundation of recovery. J Addict Dis 2012; 31: 207–25.
12. World Health Organization. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva: WHO, 2009.
13. Correia CJ, Walsh SL, Bigelow GE, Strain EC. Effects associated with double-blind omission of buprenorphine
/naloxone over a 98-h period. Psychopharmacology 2006; 189: 297–306.
14. Amass L, Bickel WK, Higgins ST, Badger GJ. Alternate-day dosing during buprenorphine
treatment of opioid dependence. Life Sci 1994; 54: 1215–28.
15. Tompkins DA, Smith MT, Mintzer MZ, Campbell CM, Strain EC. A double blind, within subject comparison of spontaneous opioid withdrawal from buprenorphine
versus morphine. J Pharmacol Exp Ther 2014; 348: 217–26.
16. Sarton E, Teppema L, Dahan A. Naloxone reversal of opioid-induced respiratory depression with special emphasis on the partial agonist/antagonist buprenorphine
. Adv Exp Med Biol 2008; 605: 486–91.
17. Pilgrim JL, McDonough M, Drummer OH. A review of methadone
deaths between 2001 and 2005 in Victoria, Australia. Forensic Sci Int 2013; 226: 216–22.
18. McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone
, and other frequently prescribed medications: a review. Am J Addict 2010; 19: 4–16.
19. Krupitsky E, Nunes EV, Ling W, Gastfriend DR, Memisoglu A, Silverman BL. Injectable extended-release naltrexone
(XR-NTX) for opioid dependence: long-term safety and effectiveness. Addiction 2013; 108: 1628–37.
20. Diaz A, Pazos A, Florez J, Ayesta FJ, Santana V, Hurle MA. Regulation of mu-opioid receptors, G-protein-coupled receptor kinases and beta-arrestin 2 in the rat brain after chronic opioid receptor antagonism. Neuroscience 2002; 112: 345–53.
21. Volpe DA, McMahon Tobin GA, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol 2011; 59: 385–90.
22. Yuan Y, Zaidi SA, Elbegdorj O, et al. Design, synthesis, and biological evaluation of 14-heteroaromatic-substituted naltrexone
derivatives: pharmacological profile switch from mu opioid receptor selectivity to mu/kappa opioid receptor dual selectivity. J Med Chem 2013; 56: 9156–69.
23. Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended-release naltrexone
for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet 2011; 377: 1506–13.
24. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine
and naloxone. N Engl J Med 2003; 349: 949–58.
25. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine
-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry 2011; 68: 1238–46.
26. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine
-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA 2008; 300: 2003–11.
27. Mattick RP, Breen C, Kimber J, Davoli M. Methadone
maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009;(3): CD002209.
28. Gibson AE, Degenhardt LJ. Mortality related to pharmacotherapies for opioid dependence: a comparative analysis of coronial records. Drug Alcohol Rev 2007; 26: 405–10.
29. Nunes EV, Rothenberg JL, Sullivan MA, Carpenter KM, Kleber HD. Behavioral therapy to augment oral naltrexone
for opioid dependence: a ceiling on effectiveness? Am J Drug Alcohol Abuse 2006; 32: 503–17.
30. Kelty E, Hulse G. Examination of mortality rates in a retrospective cohort of patients treated with oral or implant naltrexone
for problematic opiate use. Addiction 2012; 107: 1817–24.
31. Degenhardt L, Larney S, Kimber J, Farrell M, Hall W. Excess mortality among opioid-using patients treated with oral naltrexone
in Australia. Drug Alcohol Rev 2014 Oct 10 [Epub ahead of print].
32. Dunn K, DeFulio A, Everly JJ, et al. Employment-based reinforcement of adherence to oral naltrexone
in unemployed injection drug users: 12-month outcomes. Psychol Addict Behav 2014 Aug 18 [Epub ahead of print].
33. Larney S, Gowing L, Mattick RP, Farrell M, Hall W, Degenhardt L. A systematic review and meta-analysis of naltrexone
implants for the treatment of opioid dependence. Drug Alcohol Rev 2014; 33: 115–28.
34. Ling W, Casadonte P, Bigelow G, et al. Buprenorphine
implants for treatment of opioid dependence: a randomized controlled trial. JAMA 2010; 304: 1576–83.
35. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine
maintenance versus placebo or methadone
maintenance for opioid dependence. Cochrane Database Syst Rev 2014; 2: CD002207.
36. DeFulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone
in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend 2012; 120: 48–54.
37. Everly JJ, DeFulio A, Koffarnus MN, et al. Employment-based reinforcement of adherence to depot naltrexone
in unemployed opioid-dependent adults: a randomized controlled trial. Addiction 2011; 106: 1309–18.
38. Thompson G, Kelly E, Christopoulos A, Canals M. Novel GPCR paradigms at the mu-opioid receptor. Br J Pharmacol 2015; 172: 287–96.
39. Williams JT, Ingram SL, Henderson G, et al. Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 2013; 65: 223–54.
40. Birdsong WT, Arttamangkul S, Clark MJ, et al. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure. J Neurosci 2013; 33: 4118–27.
41. Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain: a review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician 2012; 15 (3 suppl): ES67–92.
42. Haerian BS, Haerian MS. OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta-analysis. Pharmacogenomics 2013; 14: 813–24.
43. Whistler JL. Examining the role of mu opioid receptor endocytosis in the beneficial and side-effects of prolonged opioid use: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend 2012; 121: 189–204.
44. Grecksch G, Bartzsch K, Widera A, Becker A, Hollt V, Koch T. Development of tolerance and sensitization to different opioid agonists in rats. Psychopharmacology 2006; 186: 177–84.
45. Hajj A, Khabbaz L, Laplanche JL, Peoc’h K. Pharmacogenetics of opiates in clinical practice: the visible tip of the iceberg. Pharmacogenomics 2013; 14: 575–85.
46. Dennis BB, Bawor M, Thabane L, Sohani Z, Samaan Z. Impact of ABCB1 and CYP2B6 genetic polymorphisms on methadone
metabolism, dose and treatment response in patients with opioid addiction: a systematic review and meta-analysis. PLoS One 2014; 9: e86114.
47. Dahan A. Opioid-induced respiratory effects: new data on buprenorphine
. Palliat Med 2006; 20 suppl 1: s3–8.
48. Zweben JE, Payte JT. Methadone
maintenance in the treatment of opioid dependence. A current perspective. West J Med 1990; 152: 588–99.
49. Hser YI, Saxon AJ, Huang D, et al. Treatment retention among patients randomized to buprenorphine
/naloxone compared to methadone
in a multi-site trial. Addiction 2014; 109: 79–87.
50. Minozzi S, Amato L, Bellisario C, Ferri M, Davoli M. Maintenance agonist treatments for opiate-dependent pregnant women. Cochrane Database Syst Rev 2013; 12: CD006318.
51. Woody G, Bruce D, Korthuis PT, et al. HIV risk reduction with buprenorphine
-naloxone or methadone
: findings from a randomized trial. J Acquir Immune Defic Syndr 2014; 66: 288–93.
52. Ahmadi J, Ahmadi K, Ohaeri J. Controlled, randomized trial in maintenance treatment of intravenous buprenorphine
dependence with naltrexone
: a novel study. Eur J Clin Invest 2003; 33: 824–9.
53. Gowing L, Farrell MF, Bornemann R, Sullivan LE, Ali R. Oral substitution treatment of injecting opioid users for prevention of HIV infection. Cochrane Database Syst Rev 2011; (8): CD004145.
54. Edelman EJ, Chantarat T, Caffrey S, et al. The impact of buprenorphine
/naloxone treatment on HIV risk behaviors among HIV-infected, opioid-dependent patients. Drug Alcohol Depend 2014; 139: 79–85.
55. Otiashvili D, Piralishvili G, Sikharulidze Z, Kamkamidze G, Poole S, Woody GE. Methadone
-naloxone are effective in reducing illicit buprenorphine
and other opioid use, and reducing HIV risk behavior—outcomes of a randomized trial. Drug Alcohol Depend 2013; 133: 376–82.
56. Meade CS, Weiss RD, Fitzmaurice GM, et al. HIV risk behavior in treatment-seeking opioid-dependent youth: results from a NIDA clinical trials network multisite study. J Acquir Immune Defic Syndr 2010; 55: 65–72.
57. Saxon AJ, Ling W, Hillhouse M, et al. Buprenorphine
/naloxone and methadone
effects on laboratory indices of liver health: a randomized trial. Drug Alcohol Depend 2013; 128: 71–6.
58. Hagan H, Pouget ER, Des Jarlais DC, Lelutiu-Weinberger C. Meta-regression of hepatitis C virus infection in relation to time since onset of illicit drug injection: the influence of time and place. Am J Epidemiol 2008; 168: 1099–109.
59. Pouget ER, Hagan H, Des Jarlais DC. Meta-analysis of hepatitis C seroconversion in relation to shared syringes and drug preparation equipment. Addiction 2012; 107: 1057–65.
60. Palmateer N, Hutchinson S, McAllister G, et al. Risk of transmission associated with sharing drug injecting paraphernalia: analysis of recent hepatitis C virus (HCV) infection using cross-sectional survey data. J Viral Hepat 2014; 21: 25–32.
61. Nolan S, Dias Lima V, Fairbairn N, et al. The impact of methadone
maintenance therapy on hepatitis C incidence among illicit drug users. Addiction 2014; 109: 2053–9.
62. Tsui JI, Evans JL, Lum PJ, Hahn JA, Page K. Association of opioid agonist therapy with lower incidence of hepatitis C virus infection in young adult injection drug users. JAMA Intern Med 2014; 174: 1974–81.
63. Wikner BN, Ohman I, Selden T, Druid H, Brandt L, Kieler H. Opioid-related mortality and filled prescriptions for buprenorphine
. Drug Alcohol Rev 2014; 33: 491–8.
64. Baumblatt JA, Wiedeman C, Dunn JR, Schaffner W, Paulozzi LJ, Jones TF. High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA Intern Med 2014; 174: 796–801.
65. Chou R, Weimer MB, Dana T. Methadone
overdose and cardiac arrhythmia potential: 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: 338–65.
66. Zlotorzynska M, Milloy MJ, Richardson L, et al. Timing of income assistance payment and overdose patterns at a Canadian supervised injection facility. Int J Drug Policy 2014; 25: 736–9.
67. Darke S. Opioid overdose and the power of old myths: what we thought we knew, what we do know and why it matters. Drug Alcohol Rev 2014; 33: 109–14.
68. Walley AY, Doe-Simkins M, Quinn E, Pierce C, Xuan Z, Ozonoff A. Opioid overdose prevention with intranasal naloxone among people who take methadone
. J Subst Abuse Treat 2013; 44: 241–7.
69. White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction 1999; 94: 961–72.
70. Zedler B, Xie L, Wang L, et al. Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients. Pain Med 2014; 15: 1911–29.
71. Madadi P, Hildebrandt D, Lauwers AE, Koren G. Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in Ontario, Canada. PLoS One 2013; 8: e60600.
72. Centers for Disease Control and Prevention. Community-based opioid overdose prevention programs providing naloxone—United States, 2010. MMWR Morb Mortal Wkly Rep 2012; 61: 101–5.
73. Ritter AJ. Naltrexone
in the treatment of heroin dependence: relationship with depression and risk of overdose. Aust N Z J Psychiatry 2002; 36: 224–8.
74. Mitchell MC, Memisoglu A, Silverman BL. Hepatic safety of injectable extended-release naltrexone
in patients with chronic hepatitis C and HIV infection. J Stud Alcohol Drugs 2012; 73: 991–7.
75. McNicholas LF, Holbrook AM, O’Grady KE, et al. Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication. Addiction 2012; 1: 91–7.
76. Bogenschutz MP, Abbott PJ, Kushner R, Tonigan JS, Woody GE. Effects of buprenorphine
and hepatitis C on liver enzymes in adolescents and young adults. J Addict Med 2010; 4: 211–6.
77. Fung MC, Hsiao-hui Wu H, Kwong K, Hornbuckle K, Muniz E. Evaluation of the profile of patients with QTc prolongation in spontaneous adverse event reporting over the past three decades—1969–1998. Pharmacoepidemiol Drug Saf 2000; 9: S24.
78. Pani PP, Trogu E, Maremmani I, Pacini M. QTc interval screening for cardiac risk in methadone
treatment of opioid dependence. Cochrane Database Syst Rev 2013; 6:CD008939.
79. Lintzeris N, Mitchell TB, Bond AJ, Nestor L, Strang J. Pharmacodynamics of diazepam co-administered with methadone
under high dose conditions in opioid dependent patients. Drug Alcohol Depend 2007; 91: 187–94.
80. Cohier C, Chevillard L, Risede P, Roussel O, Megarbane B. Respiratory effects of buprenorphine
/naloxone alone and in combination with diazepam in naive and tolerant rats. Toxicol Lett 2014; 228: 75–84.
81. Lintzeris N, Mitchell TB, Bond A, Nestor L, Strang J. Interactions on mixing diazepam with methadone
in maintenance patients. J Clin Psychopharmacol 2006; 26: 274–83.
82. McCance-Katz EF, Moody DE, Prathikanti S, Friedland G, Rainey PM. Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine
-maintained patients. Drug Alcohol Depend 2011; 118: 326–34.
83. McCance-Katz EF, Moody DE, Morse GD, et al. Interaction between buprenorphine
and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend 2007; 91: 269–78.
84. Saber-Tehrani AS, Bruce RD, Altice FL. Pharmacokinetic drug interactions and adverse consequences between psychotropic medications and pharmacotherapy for the treatment of opioid dependence. Am J Drug Alcohol Abuse 2011; 37: 1–11.
85. Jones HE, Heil SH, Baewert A, et al. Buprenorphine
treatment of opioid-dependent pregnant women: a comprehensive review. Addiction 2012; 1: 5–27.
86. Gower S, Bartu A, Ilett KF, Doherty D, McLaurin R, Hamilton D. The wellbeing of infants exposed to buprenorphine
via breast milk at 4 weeks of age. J Hum Lact 2014; 30: 217–23.
87. Pritham UA. Breastfeeding promotion for management of neonatal abstinence syndrome. J Obstet Gynecol Neonatal Nurs 2013; 42: 517–26.
88. Gaalema DE, Scott TL, Heil SH, et al. Differences in the profile of neonatal abstinence syndrome signs in methadone
-exposed neonates. Addiction 2012; 1: 53–62.
89. Salisbury AL, Coyle MG, O’Grady KE, et al. Fetal assessment before and after dosing with buprenorphine
. Addiction 2012; 1: 36–44.
90. Coyle MG, Salisbury AL, Lester BM, et al. Neonatal neurobehavior effects following buprenorphine
exposure. Addiction 2012; 1: 63–73.
91. Kaltenbach K, Finnegan LP. Developmental outcome of children born to methadone
maintained women: a review of longitudinal studies. Neurobehav Toxicol Teratol 1984; 6: 271–5.
92. Bell J, Trinh L, Butler B, Randall D, Rubin G. Comparing retention in treatment and mortality in people after initial entry to methadone
treatment. Addiction 2009; 104: 1193–200.
93. Sigmon SC, Bisaga A, Nunes EV, O’Connor PG, Kosten T, Woody G. Opioid detoxification and naltrexone
induction strategies: recommendations for clinical practice. Am J Drug Alcohol Abuse 2012; 38: 187–99.
94. Larance B, Lintzeris N, Ali R, et al. The diversion and injection of a buprenorphine
-naloxone soluble film formulation. Drug Alcohol Depend 2014; 136: 21–7.
95. Schuman-Olivier Z, Connery H, Griffin ML, et al. Clinician beliefs and attitudes about buprenorphine
/naloxone diversion. Am J Addict 2013; 22: 574–80.
96. Pedapati EV, Bateman ST. Toddlers requiring pediatric intensive care unit admission following at-home exposure to buprenorphine
/naloxone. Pediatr Crit Care Med 2011; 12: e102–7.
97. Keen J, Oliver P, Rowse G, Mathers N. Residential rehabilitation for drug users: a review of 13 months’ intake to a therapeutic community. Fam Pract 2001; 18: 545–8.
98. Kosten TR, Gorelick DA. The Lexington narcotic farm. Am J Psychiatry 2002; 159: 22.
99. McHugh RK, Murray HW, Hearon BA, et al. Predictors of dropout from psychosocial treatment in opioid-dependent outpatients. Am J Addict 2013; 22: 18–22.
100. Warden D, Subramaniam GA, Carmody T, et al. Predictors of attrition with buprenorphine
/naloxone treatment in opioid dependent youth. Addict Behav 2012; 37: 1046–53.
101. Mayet S, Farrell M, Ferri M, Amato L, Davoli M. Psychosocial treatment for opiate abuse and dependence. Cochrane Database Syst Rev 2005;(1): CD004330.
102. Masson CL, Barnett PG, Sees KL, et al. Cost and cost-effectiveness of standard methadone
maintenance treatment compared to enriched 180-day methadone
detoxification. Addiction 2004; 99: 718–26.
103. Magura S, Rosenblum A. Leaving methadone
treatment: lessons learned, lessons forgotten, lessons ignored. Mt Sinai J Med 2001; 68: 62–74.
104. Soyka M. Opioids and traffic safety—focus on buprenorphine
. Pharmacopsychiatry 2014; 47: 7–17.
105. Rapeli P, Fabritius C, Kalska H, Alho H. Cognitive functioning in opioid-dependent patients treated with buprenorphine
, and other psychoactive medications: stability and correlates. BMC Clin Pharmacol 2011; 11: 13.
106. Garbutt JC, Kranzler HR, O’Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone
for alcohol dependence: a randomized controlled trial. JAMA 2005; 293: 1617–25.
107. O’Malley SS, Garbutt JC, Gastfriend DR, Dong Q, Kranzler HR. Efficacy of extended-release naltrexone
in alcohol-dependent patients who are abstinent before treatment. J Clin Psychopharmacol 2007; 27: 507–12.
108. Heinrich CJ, Cummings GR. Adoption and diffusion of evidence-based addiction medications in substance abuse treatment. Health Serv Res 2014; 49: 127–52.
109. Lang K, Neil J, Wright J, Dell CA, Berenbaum S, El-Aneed A. Qualitative investigation of barriers to accessing care by people who inject drugs in Saskatoon, Canada: perspectives of service providers. Subst Abuse Treat Prev Policy 2013; 8: 8–35.
110. Fiellin DA, O’Connor PG, Chawarski M, Pakes JP, Pantalon MV, Schottenfeld RS. Methadone
maintenance in primary care: a randomized controlled trial. JAMA 2001; 286: 1724–31.
111. Roux P, Michel L, Cohen J, et al. Methadone
induction in primary care (ANRS-Methaville): a phase III randomized intervention trial. BMC Public Health 2012; 12: 488.
112. Kahan M, Wilson L, Midmer D, Ordean A, Lim H. Short-term outcomes in patients attending a primary care-based addiction shared care program. Can Fam Physician 2009; 55: 1108–9.
113. Debelak K, Morrone WR, O’Grady KE, Jones HE. Buprenorphine
+ naloxone in the treatment of opioid dependence during pregnancy—initial patient care and outcome data. Am J Addict 2013; 22: 252–4.
115. Neumann AM, Blondell RD, Jaanimagi U, et al. A preliminary study comparing methadone
in patients with chronic pain and coexistent opioid addiction. J Addict Dis 2013; 32: 68–78.
116. Shi J, Li SX, Zhang XL, et al. Time-dependent neuroendocrine alterations and drug craving during the first month of abstinence in heroin addicts. Am J Drug Alcohol Abuse 2009; 35: 267–72.
117. Li SX, Shi J, Epstein DH, et al. Circadian alteration in neurobiology during 30 days of abstinence in heroin users. Biol Psychiatry 2009; 65: 905–12.
118. Marsch LA, Bickel WK, Badger GJ, et al. Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Arch Gen Psychiatry 2005; 62: 1157–64.
119. Chartoff EH, Connery HS. It’s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system. Front Pharmacol 2014; 5: 116.
120. Sanders NC, Mancino MJ, Gentry WB, et al. Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, buprenorphine
-assisted detoxification procedure. Exp Clin Psychopharmacol 2013; 21: 294–302.
121. Bisaga A, Sullivan MA, Glass A, et al. A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone
for opioid dependence. J Subst Abuse Treat 2014; 46: 546–52.
122. Bisaga A, Sullivan MA, Cheng WY, et al. A placebo controlled trial of memantine as an adjunct to oral naltrexone
for opioid dependence. Drug Alcohol Depend 2011; 119: e23–9.
123. Tabatabai SM, Dashti S, Doosti F, Hosseinzadeh H. Phytotherapy of opioid dependence and withdrawal syndrome: a review. Phytother Res 2014; 28: 811–30.
124. Gao JL, Tu SA, Liu J, et al. An-jun-ning, a traditional herbal formula, attenuates spontaneous withdrawal symptoms via modulation of the dopamine system in morphine-dependent rats. BMC Complement Altern Med 2014; 14: 308.