Opioid use disorder is a growing problem in the United States that can have devastating consequences on affected individuals. Buprenorphine is a partial mu-opioid agonist that can be used in the treatment of opioid dependence. In this article, the pharmacology of buprenorphine is discussed as is the dosing strategy. Formulations and product availability are mentioned and assessed. Several studies comparing the use of buprenorphine to methadone for opioid dependence are briefly reviewed.

Opioid use disorder is a growing problem in the United States. While the rate of abuse of heroin has remained unchanged, abuse of prescription opioids has increased over the past 15 years.1 In 2010, 1.9 million people in the U.S. were addicted to prescription opioids and 359,000 were addicted to heroin.2 Opioid use disorder is characterized by compulsive drug seeking/use despite negative consequences. It tends to cause structural and functional changes in the brain that can erode a person's ability to make decisions. While no single factor can predict whether or not an individual will become addicted to a drug, genetic, environmental and developmental factors can all play a role in opioid use disorder. Opioids work by binding to opioid receptors rapidly, causing a euphoric feeling. Consequences of opioid use disorder can be devastating in a psychosocial manner and can include physical ramifications such as unintentional overdoses and transmission of blood-borne diseases through the use of unsterile drug paraphernalia and other risky behaviors.3 

Treatments for opioid use disorder include psychosocial approaches, mutual help programs, abstinence based treatment programs, and pharmacological interventions. Naltrexone, an opioid antagonist, blocks the effects of opioids and can thus be used to prevent opioid use. It has been shown to reduce to use of opioids while individuals are in treatment and can reduce rates of recidivism of incarceration.4 However, retention in treatment with naltrexone is often poor, thus limiting its effectiveness.4 Naltrexone is available as an oral tablet taken daily and an intramuscular injection given once a month. The once monthly injection, which is given at a dose of 380mg, may be an option for individuals who do not want to take a pill every day or who may be non-compliant with oral therapy. Methadone is an opioid agonist that has long been used in the treatment of opioid use disorder. Methadone blocks the euphoria and sedation associated with opioids of abuse, relieves symptoms of opioid withdrawal and satisfies cravings for opioids. It generally does not cause euphoria or intoxication when dosed appropriately and given once a day.5 Methadone maintenance programs produce several positive outcomes including reduced mortality, reduced use of injection drugs, reduced risk of overdose, reduced transmission of blood-borne infections, reduced criminal activity and improved pregnancy outcomes.5 Methadone maintenance therapy has several limitations including public stigmatization, stringent requirements for access to treatment, and limited treatment availability. Many methadone clinics are for profit and privately owned, making it an expensive treatment option. Treatment participation requires patients to visit the clinic daily during a specified time window, which can add inconvenience.6 

Buprenorphine is an alternative to methadone maintenance therapy. Buprenorphine is a partial opioid agonist. It has high affinity for the mu-opioid receptor, but low intrinsic activity at those receptors. It is able to displace full opioid agonists, such as morphine and methadone, from the receptors thus blocking their effects. Buprenorphine has a higher affinity for the opioid receptors than full agonists, so the full agonists will not be able to displace buprenorphine from the receptors and thus will not exert their effects on receptors already occupied by buprenorphine.6 Buprenorphine dissociates slowly from opioid receptors thus suppressing opioid withdrawal and blocking exogenous opioids for a prolonged period of time. This allows buprenorphine to be given on a daily basis (or as infrequently as three times per week) to treat opioid use disorder. Buprenorphine's property of partial agonism allows for a ceiling effect on euphoria measures and respiratory depression.7 It dissociates slowly from the opioid receptors, resulting in a long duration of action and a potentially lower risk of dependence compared to other opioids.8,9 Similar to methadone, buprenorphine is able to satisfy cravings for opioids without causing the euphoria and sedation associated with opioids of abuse.

Buprenorphine/naloxone became available in the United States for office-based opioid maintenance therapy in 2003, bringing opioid use disorder treatment into the mainstream of medical practice and expanding access to care. Naloxone, an opioid antagonist, was co-formulated with buprenorphine in order to dissuade users from injecting it.10,11 Prior to the introduction of buprenorphine/naloxone, fewer than 25% of individuals with opioid use disorder received any form of treatment for it.6 Formulations include plain buprenorphine and buprenorphine/naloxone sublingual tablets and films with a 4:1 ratio of buprenorphine: naloxone. The original manufacturer, Reckitt Benckiser, discontinued distribution of their sublingual tablets in March 2013 to address several concerns with them including accidental pediatric exposure, taste, and long dissolving time.12 Generic versions of both plain buprenorphine and buprenorphine/naloxone are available from several manufacturers. Zubsolv™ (buprenorphine/naloxone) is a newly released product that was FDA approved in July 2013. According to the manufacturer, Zubsolv™ dissolves more quickly, possesses taste masking and requires a lower total dose compared to previous formulations.13 Due to a difference of the bioavailability in Zubsolv™ a 5.7/1.4mg tablet provides the same buprenorphine exposure as an 8/2mg tablet of Suboxone™ and 12% lower naloxone exposure.14  Table 1 below summarizes the different available buprenorphine products for opioid replacement therapy.

TABLE 1:

BUPRENORPHINE PRODUCTS AVAILABLE

BUPRENORPHINE PRODUCTS AVAILABLE
BUPRENORPHINE PRODUCTS AVAILABLE

In order to prescribe buprenorphine/naloxone, providers must complete at least eight hours of approved training in the treatment of opioid use disorder or have other qualifications such as clinical research experience with the medication or a certification in addiction medicine. They must also attest that they can provide or refer patients to concurrent psychosocial services. For individuals physically dependent on full opioid agonists, buprenorphine can act as an opioid antagonist in higher doses by displacing the full agonist from the opioid receptors and may precipitate acute opioid withdrawal.6 Therefore, establishing a solid patient-provider relationship is key, and obtaining a thorough and complete history from the patient is vital to ensuring a safe and comfortable transition from opioid misuse to buprenorphine treatment. Providers should also monitor patients for diversion of their medications. Buprenorphine is a schedule III narcotic medication and was initially thought to have a lower abuse potential compared to full opioid agonists. However, a recent crowdsourcing survey revealed that diverted buprenorphine had a street value $2.13 per milligram of morphine equivalent, which was higher than clinically equi-analgesic dose prices for oxymorphone, oxycodone, methadone, hydrocodone, morphine and tramadol.15 Street value can be an indicator of drug availability, demand and abuse potential.15 

There are three phases of buprenorphine maintenance treatment- induction, stabilization and maintenance.6 Induction involves switching the patient from opioids of abuse to buprenorphine and finding the minimum dose of buprenorphine at which the patient has no withdrawal symptoms, few or no side effects, and no uncontrollable cravings for drugs of abuse.6 Induction should occur when patients are experiencing mild symptoms of withdrawal, and the exact timing will depend on what type of opioid the patient abused (short vs long acting). Initial induction doses should be administered in a physician's office, and the patients should be observed for at least two hours after the dose.6 Initial doses on the first day should be in 2 or 4mg increments and should not exceed 8mg. On day 2, the dose may be titrated to a maximum of 16mg of buprenorphine if the patient is still experiencing withdrawal symptoms. The dose may be increased on subsequent days up to a maximum of 32mg of buprenorphine.6 Induction is complete when the patient has no withdrawal symptoms or cravings for abused opioid and is not experiencing side effects to the buprenorphine formulation. Stabilization usually takes 1–2 months during which weekly assessments may be indicated in order to make further dosage adjustments.6 Subjective reporting of cravings and illicit opioid use should be collected as well as urine toxicology.6 Once the patient has an established dose of buprenorphine and has demonstrated stability (no/few cravings, no other opioid use), the maintenance phase begins during which follow-up may be less frequent.6 The maintenance phase may be short term (<12 months) or indefinite, depending on the patient's personal goals and usually involved few if any dose changes.6 

Treatment with buprenorphine/naloxone has been shown to be superior to placebo in terms of retention in treatment and opioid negative urine samples and non-inferior to methadone when dosed appropriately.16 A recent open-label, randomized, multi-site analysis of 1,267 opioid dependent individuals found that methadone had significantly better retention in treatment and treatment completion rate compared to buprenorphine overall.17 However, as the dose of buprenorphine increased, the retention in treatment increased as well, suggesting that under-dosing of buprenorphine may have negative treatment outcomes.17 Additionally, for those that remained in treatment, opioid positive urine results were significantly lower in those taking buprenorphine compared to methadone during the first 9 weeks of treatment suggesting that induction with buprenorphine takes less time than induction with methadone17. Finally, all participants in this study received daily doses of their medication in clinic, deflecting the advantage of flexible, office based dosing that buprenorphine has over methadone.17 A recent economic evaluation found that total costs for treatment programs using buprenorphine or methadone were not significantly different.18 

Buprenorphine continues to be a viable treatment option for opioid use disorder. It has potential to be safer, more convenient and more conducive to daily living compared to methadone, although this may come at a price of lower efficacy if not administered at sufficient doses. Future research should continue to explore factors that contribute to treatment success and other ways to maximize the benefit of this medication in the treatment of opioid use disorder.

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