The Medical Letter on Drugs and Therapeutics
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Buprenorphine Implants (Probuphine) for Opioid Dependence
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 Select a term to see related articles  Bunavail   Buprenorphine   Methadone   Naloxone   Naltrexone   Opioid dependence   Opioids   Probuphine   Suboxone   Zubsolv 

The FDA has approved subdermal implants of the partial opioid agonist buprenorphine (Probuphine – Titan) for maintenance treatment of opioid dependence in patients stabilized on low to moderate doses of transmucosal buprenorphine. Probuphine was designed to provide continuous low levels of buprenorphine for 6 months and to safeguard against illicit use of the drug.

DRUGS FOR OPIOID DEPENDENCE — Methadone was the first successful treatment for opioid addiction; it can diminish the craving for opioids without causing euphoria or sedation, but it is itself a Schedule II controlled substance and can be dangerous in overdosage. Naltrexone is a long-acting opioid antagonist; it is effective in diminishing the euphoric effects of opioids, but it is much less effective than methadone in treating addiction because it does not abolish the craving for opioids.

Buprenorphine, which is both a weak opioid agonist and a strong antagonist, is available alone and in combination with the opioid antagonist naloxone as an alternative to methadone (and alone for management of chronic pain).1-3 Taken orally, naloxone is poorly absorbed and generally has no clinical effects; its presence in sublingual or buccal formulations with buprenorphine is intended to discourage intravenous or intranasal abuse of buprenorphine. Buprenorphine is a Schedule III controlled substance and has fewer prescribing restrictions than Schedule II drugs such as methadone.

PHARMACOKINETICS — Buprenorphine levels after insertion of 4 Probuphine implants (0.5-1 ng/mL) are comparable to those achieved with 8 mg/day of sublingual buprenorphine. In one unpublished pharmacokinetic study, summarized in the package insert, subjects were given sublingual buprenorphine 16 mg daily for a minimum of 5 consecutive days, followed by insertion of 4 buprenorphine implants. Peak plasma concentrations of buprenorphine were much lower after insertion of the implants than with daily sublingual tablets.

CLINICAL STUDIES — One unpublished trial found that buprenorphine implants were noninferior to sublingual buprenorphine/naloxone in maintaining clinical stability in opioid-dependent patients. A total of 177 patients treated with ≤8 mg/day of sublingual buprenorphine who met criteria for clinical stability (e.g., no reports of illicit opioid use, significant withdrawal symptoms, or hospitalization) were randomized to receive buprenorphine implants and placebo tablets or sublingual buprenorphine/naloxone tablets and placebo implants. During the 6-month study period, 63% of patients in the buprenorphine implant group and 54% of those in the buprenorphine/naloxone group had no evidence of illicit opioid use.4

ADVERSE EFFECTS — Probuphine is only available through a restricted-access (REMS) program. The most common implant-site adverse effects have been pain, pruritus, and erythema, but insertion and removal of the implants are associated with serious risks such as implant migration, extrusion, and nerve injury. Healthcare providers must complete a live training session and become certified before they can prescribe, insert, or remove buprenorphine implants.

DRUG INTERACTIONS — Buprenorphine in any form may interfere with the analgesic efficacy of full opioid agonists. It is metabolized primarily by CYP3A4; plasma levels of buprenorphine should be monitored in patients who are taking a CYP3A4 inducer or inhibitor5 when switching to Probuphine or who begin taking one while on Probuphine treatment. As with any opioid, concomitant use of buprenorphine with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, or other serotonergic drugs can result in serotonin syndrome.

DOSAGE AND ADMINISTRATION — Patients who are eligible for treatment with buprenorphine implants should be clinically stable and maintained on a stable transmucosal buprenorphine dose, such as ≤8 mg/day of sublingual buprenorphine or Suboxone, for ≥3 months. Each buprenorphine implant, measuring 26 mm in length and 2.5 mm in diameter, contains 74.2 mg of buprenorphine. A total of 4 buprenorphine implants are inserted subdermally in the inner upper arm. They should be removed after 6 months. Four new implants could then be placed in the opposite arm.

CONCLUSION — Buprenorphine implants (Probuphine) may provide more consistent dosing for opioid-dependent patients stabilized on low to moderate doses of transmucosal buprenorphine. The implants also provide an additional safeguard against illicit use of buprenorphine, but they are much more expensive than oral transmucosal buprenorphine, which is similarly effective.

  1. RP Mattick et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2014; 2:CD002207.
  2. Bunavail: another buprenorphine/naloxone formulation for opioid dependence. Med Lett Drugs Ther 2015; 57:19.
  3. Buprenorphine buccal film (Belbuca) for chronic pain. Med Lett Drugs Ther 2016; 58:47.
  4. R Rosenthal et al. Sensitivity analysis of a comparative trial of 6 month buprenorphine implants (Probuphine) and sublingual buprenorphine in stable opioid-dependent patients (abstract). Presented at College on Problems of Drug Dependence 78th annual meeting, Palm Springs, California, June 11-16, 2016.
  5. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2016; 58:e46.
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