Update on pharmacotherapy for treatment of opioid use disorder

Introduction: Opioid Use Disorder (OUD) is a significant public health concern, negatively impacting the medical, psychological, and social domains of an individual’s life as well as creating substantial burdens for society. Effective treatment interventions are necessary for reduction of OUD and its consequences. Pharmacotherapy represents a central component of management.

Areas covered: This review focuses on pharmacologic strategies for OUD treatment, discussing both primary as well as adjunctive therapy modalities. We will discuss both medications used during detoxification to treat withdrawal, as well as those used as maintenance therapy. Detox medications include alpha-2 adrenergic agonists, such as clonidine, as well as the μ-opioid agonist, methadone, and the μ-opioid partial agonist, buprenorphine. Opioid maintenance treatment (OMT) is also discussed, focusing on those medications meant to substitute abused opioids and includes the agonists, methadone and buprenorphine, as well as supervised intravenous heroin, and opioid antagonist, naltrexone.

Expert opinion: Medication therapy for treatment of OUD has demonstrated efficacy and is of great clinical benefit. While agonist treatment with methadone or buprenorphine remains the gold standard, there is an important place for use of long-acting antagonist therapy with naltrexone. Continued investigation into treatment paradigms and behavioral platforms which optimize medication therapy is most needed.     

Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine

Opioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants’ OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials.     

The problem of pain: Additive analgesic effect of tramadol and buprenorphine in a patient with opioid use disorder

Background: There is a paucity of published literature on the optimal treatment of pain in patients on buprenorphine treatment (BT) for opioid use disorder. Using this case report, we hope to demonstrate that tramadol may represent an effective treatment option for pain in patients on BT while encouraging future clinical trials. Case: The patient is a 56-year-old Caucasian male with a history of opiate use disorder on treatment with buprenorphine/naloxone 8/2?mg 2 times a day (BID) who was followed in an outpatient general psychiatry clinic that specializes in patients with co-occurring substance use disorders. Although maintaining sobriety from opioids, the patient continued to struggle with acute on chronic pain secondary to osteoarthritis that had left him walking with a cane. The patient was started on tramadol 50?mg 3 times a day (TID) for acute pain by his primary care physician (PCP) while he awaited surgical intervention. He reported analgesic effect with buprenorphine/naloxone but noted that it did not last the full period between his doses. He reported further improvement in his pain along with greater daily functioning with the additional use of tramadol, without side effects or withdrawal symptoms. Discussion: Current recommendations for pain management in patients on BT include discontinuation of BT therapy and/or addition of an adjunctive opioid analgesic (including additional buprenorphine/naloxone) while continuing agonist medication for treatment of opioid use disorder. However, determining which medication to use can be difficult, as there has been no literature examining this issue. In this case, the combination of buprenorphine and tramadol demonstrated an additive analgesic effect. Randomized control studies need to be performed to further understand the changes in pain measurement in patients on BT with tramadol compared with other adjunctive analgesic medications.     

Consideration of opioid agonist treatment in a pregnant adolescent: A case report and literature review

Abstract

Background: Opioid use greatly increases the risk of overdose death, as well as contracting human immunodeficiency virus (HIV) and hepatitis. Opioid agonist treatment is recommended for pregnant women who are dependent on opioids. However, there is a dearth of studies on the use of opioid agonist treatment in pregnant teenagers. Case: Ms. A, a 15?year-old G1PO in foster care, presented to our tertiary women’s hospital requesting opioid agonist treatment for use of pill opioids. She reported nasal inhalation of 5–6 opioid tablets daily, with recent attempts to self-taper using nonprescribed buprenorphine since learning of her pregnancy. Last reported opioid use was >24?hours prior to admission. Urine drug testing was positive only for opioids (negative for buprenorphine and methadone). She did not exhibit significant withdrawal symptoms while hospitalized. The psychiatric treatment team recommended deferring opioid agonist treatment and pursuing outpatient substance use treatment. Unfortunately, Ms. A did not attend outpatient treatment and was lost to follow up. Discussion: Based upon our experience and review of the studies regarding opioid use disorder (OUD) and perinatal and adolescent opioid use, we recommend that pregnant adolescents with OUD be referred to opioid agonist treatment with buprenorphine or methadone. Studies specifically addressing opioid agonist treatment in pregnant teenagers are needed.     

Factors associated with complicated buprenorphine inductions

Despite data supporting its efficacy, barriers to implementation of buprenorphine for office-based treatment are present. Complications can occur during buprenorphine inductions, yet few published studies have examined this phase of treatment. To examine factors associated with complications during buprenorphine induction, we conducted a retrospective chart review of the first 107 patients receiving buprenorphine treatment in an urban community health center. The primary outcome, defined as complicated induction (precipitated or protracted withdrawal), was observed in 18 (16.8%) patients. Complicated inductions were associated with poorer treatment retention (than routine inductions) and decreased over time. Factors independently associated with complicated inductions included recent use of prescribed methadone, recent benzodiazepine use, no prior experience with buprenorphine, and a low initial dose of buprenorphine/naloxone. Findings from this study and further investigation of patient characteristics and treatment characteristics associated with complicated inductions can help guide buprenorphine treatment strategies.     

Underutilization of the current clinical capacity to provide buprenorphine treatment for opioid use disorders within the Veterans Health Administration

Background: Opioid use disorder (OUD) is a critical concern among US veterans. The Veterans Health Administration (VHA) recommends buprenorphine as a first-line treatment for OUD; however, only 35% of veterans with an OUD currently receive medication treatment. Practical barriers, including the capacity of providers to prescribe, may affect delivery of buprenorphine. We examined the current state of buprenorphine treatment within the VHA. Methods: National VHA administrative databases were queried to identify all providers credentialed to prescribe buprenorphine as of January 2018. Data were extracted on providers’ prescribing capacity (30, 100, or 275 patients concurrently) and number of patients who received buprenorphine in the prior 180?days. Results: A total of 1458 VHA providers were credentialed to prescribe buprenorphine. Forty-three percent of providers had not prescribed buprenorphine to any VHA patients in the past 180?days. Of those that prescribed to at least 1 patient, providers still prescribed to fewer patients than their capacity, regardless of their patient panel size (30, 100, or 275), prescribing to 18.5 patients on average. Conclusions: VHA providers are prescribing buprenorphine below their capacity. A multipronged approach to increase the number of credentialed providers and address barriers to prescribing is needed to ensure that veterans get effective treatment for OUD.     

Managing opioid withdrawal precipitated by buprenorphine with buprenorphine

Buprenorphine is a partial opioid agonist commonly used to treat opioid dependence. The pharmacology of buprenorphine increases the risk of a precipitated opioid withdrawal when commencing patients on buprenorphine treatment, particularly when transferring from long acting opioids (e.g. methadone). There is little documented experience regarding the management of precipitated withdrawal. In our case, a patient developed a significant precipitated opioid withdrawal following buprenorphine administration, and was able to be successfully treated in hospital with further buprenorphine. This demonstrates that rapid increases in buprenorphine dose can be used as an effective treatment for buprenorphine-induced precipitated opioid withdrawal. The use of buprenorphine to manage withdrawal then allows the individual to continue on this highly effective treatment.     

Clinical outcomes of concomitant rifamycin and opioid therapy: A systematic review

Opioids are one of the most prescribed classes of analgesic medications. Their narrow therapeutic index and metabolism through cytochrome p450 (CYP) enzymes can result in a drug interaction when used concomitantly with rifamycins. In clinical scenarios where concurrent therapy with an opioid and a rifamycin occurs, there is no standardized guidance for managing the interaction. The objective of this review was to examine literature which evaluates the concomitant use of opioids and rifamycins with clinically relevant CYP-inducing properties. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria was performed. PubMed, Scopus, and OVID Embase were queried for studies from database inception to January 2020 related to rifamycin and opioid medications. Only full-text, peer-reviewed, English language articles addressing clinical outcomes from concomitant rifamycin and opioid therapy were included. The review isolated 12 articles for data extraction from an original 2260 citations identified. Rifampin (11; 92%) and rifabutin (2; 17%) were the rifamycins studied along with seven different opioids. Decreased effect of opioids with concomitant rifampin therapy manifested as withdrawal in numerous patients on methadone and a decreased analgesic effect from tramadol, morphine, and, most notably, oxycodone. Only the combinations of rifampin with buccal fentanyl and rifabutin with buprenorphine and methadone were found to have no clinically measurable interaction. Available literature suggests that a decrease in opioid clinical effects is appreciated with concomitant rifamycin therapy. Further research is needed to focus on specific mitigation strategies beyond opioid agent selection, such as dosing adjustment recommendations.     

The Pregnancy Recovery Center: A women-centered treatment program for pregnant and postpartum women with opioid use disorder

ObjectiveTo evaluate the impact of women-centered substance abuse treatment programming on outcomes among pregnant women with opioid use disorder (OUD).MethodsWe compared two retrospective cohorts of pregnant women with OUD on buprenorphine maintenance therapy who delivered an infant at the University of Pittsburgh from 2014 to 2016. Cohort 1 was composed of pregnant women who received women-centered OUD treatment services through the Pregnancy Recovery Program (PRC) and Cohort 2 was composed of pregnant women who received buprenorphine at OUD programs without women-centered services (non-PRC). Women-centered outcomes were defined as a) pregnancy-specific buprenorphine dosing, b) prenatal and postpartum care attendance, c) breastfeeding and d) highly effective contraception utilization. Chi-square and t-tests were used to compare outcomes between PRC and non-PRC patients.ResultsAmong 248 pregnant women with OUD, 71 (28.6%) were PRC and 177 (71.4%) were non-PRC patients. PRC patients were significantly more likely to initiate buprenorphine during vs. prior to their pregnancy (81.4% vs. 44.2%; p < .01) and have a higher buprenorphine dose at the time of delivery (16.0 mg vs. 14.1 mg; p = .02) compared to non-PRC patients. Likewise, PRC patients were significantly more likely to attend their postpartum visit (67.9% vs. 52.6%; p = .05) and receive a long-acting reversible contraceptive (LARC) method (23.9% vs. 13.0%, p = .03) after delivery compared to non-PRC patients. Finally, PRC patients had a smaller percent decrease in the rate of breastfeeding during their delivery hospitalization (−14.7% vs. −37.1%).ConclusionsIncorporating women-centered services into OUD treatment programming may improve gender-specific outcomes among women with OUD.     

Treatment of chronic pain in older people: evidence-based choice of strong-acting opioids

In the treatment of chronic malignant and non-malignant pain, opioids are used as strong analgesics. Frail elderly patients often have multiple co-morbidities and use multiple medicines, leading to an increased risk of clinically relevant drug-drug and drug-disease interactions. Age-related changes and increased frailty may lead to a less predictable drug response, increased drug sensitivity, and potential harmful drug effects. As a result, physicians face a complex task in prescribing medication to elderly patients. In this review, the appropriateness of the strong-acting opioids buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone and tapentadol is determined for use in elderly patients. Evidence-based recommendations for prescribing strong opioids to the frail elderly are presented. A literature search was performed for all individual drugs, using a validated and published set of 23 criteria concerning effectiveness, safety, pharmacokinetics and pharmacodynamics, experience, and convenience in elderly patients. First, information on the criteria was obtained from pharmaceutical reference books and a MEDLINE search. The information obtained on the individual drugs in the class of opioids was compared with the reference drug morphine. Evidence-based recommendations were formulated on the basis of the pros and cons for the frail elderly. Using the set of 23 criteria, no differentiation can be made between the appropriateness of buprenorphine, fentanyl, hydromorphone, morphine and oxycodone for use in elderly patients. Methadone has strong negative considerations in the treatment of chronic pain in the frail elderly. Methadone has a high drug-drug interaction potential and is associated with prolongation of the QT interval and a potential risk of accumulation due to a long elimination half-life. In addition, methadone is difficult to titrate because of its large inter-individual variability in pharmacokinetics, particularly in the frail elderly. Because of a lack of empiric knowledge, the use of tapentadol is not recommended in frail elderly persons. Nevertheless, tapentadol may prove to be a useful analgesic for the treatment of chronic pain in frail elderly persons because of its possible better gastrointestinal tolerability. In the treatment of chronic pain in the frail elderly, the opioids of first choice are buprenorphine, fentanyl, hydromorphone, morphine and oxycodone. In order to improve the convenience for elderly patients, the controlled-release oral dosage forms and transdermal formulations are preferred.     

Unobserved versus observed office buprenorphine/naloxone induction: A pilot randomized clinical trial

Physician adoption of buprenorphine treatment of opioid dependence may be limited in part by concerns regarding the induction process. Although national guidelines recommend observed induction, some physicians utilize unobserved induction outside the office. The aim of this pilot randomized clinical trial was to assess preliminary safety and effectiveness of unobserved versus observed office buprenorphine/naloxone induction among patients entering a 12-week primary care maintenance study. Participants (N = 20) with DSM-IV opioid dependence were randomly assigned to unobserved or office induction, stratifying by past buprenorphine use. All patients received verbal and written instructions. A withdrawal scale was used during initiation and to monitor treatment response. Clinic visits occurred weekly for 4 weeks then decreased to monthly. The primary outcome, successful induction one week after the initial clinic visit, was defined as retention in buprenorphine/naloxone treatment and being withdrawal free. Secondary outcomes included prolonged withdrawal beyond 2 days after medication initiation and stabilization at week 4, defined as being in treatment without illicit opioid use for the preceding 2 weeks. Outcome results were similar in the two groups: 6/10 (60%) successfully inducted in each group, 3/10 (30%) experienced prolonged withdrawal, and 4/10 (40%) stabilized by week 4. These pilot study results suggest comparable safety and effectiveness of unobserved and office induction and point toward utilization of non-inferiority design during future definitive protocol development. By addressing an important barrier for physician adoption, further validation of the unobserved buprenorphine induction method will hopefully lead to increased availability of effective opioid dependence treatment.