Buprenorphine, a derivative of thebaine, is an opiate that has been marketed in the United States as the Schedule V parenteral analgesic Buprenex®. In 2002, based on a re-evaluation of available evidence regarding the potential for abuse, diversion, dependence, and side effects, the DEA reclassified buprenorphine from a Schedule V to a Schedule III narcotic.
In October 2002, Reckitt Benckiser received FDA approval to market a buprenorphine monotherapy product, Subutex®, and a buprenorphine/naloxone combination product, Suboxone®, for use in opioid addiction treatment. The combination product is designed to decrease the potential for abuse by injection. Subutex® and Suboxone® are currently the only medications to have received FDA approval for this indication. In January 2003, Reckitt Benckiser began shipments of Suboxone® to pharmacies in the United States.
The approval of these formulations does not affect the treatment standards of previously approved medication-assisted treatments, such as methadone and LAAM (levo-alpha-acetyl-methadol). As indicated in Title 42 Code of Federal Regulations Part 8 (42 CFR Part 8), these therapies can only be dispensed, and only in the context of an Opioid Treatment Program. Also, neither the approval of Subutex® and Suboxone®, nor the provisions of DATA 2000, affect the use of other Schedule III, IV, or V medications, such as morphine, that are not approved for the treatment of addiction. Lastly, note that other forms of buprenorphine besides Subutex® and Suboxone®, e.g., Buprenex®, are not approved for treatment of opioid addiction.
Buprenorphine is an opioid partial agonist. This means that, although buprenorphine is an opioid, and thus can produce typical opioid agonist effects and side effects, such as euphoria and respiratory depression, its maximal effects are less than those of full agonists like heroin and methadone. At low doses, buprenorphine produces sufficient agonist effect to enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing withdrawal symptoms. The agonist effects of buprenorphine increase linearly with increasing doses of the drug until at moderate doses they reach a plateau and no longer continue to increase with further increases in dose—the so-called “ceiling effect.” Thus, buprenorphine carries a lower risk of abuse, dependence, and side effects compared to full opioid agonists. In fact, in high doses and under certain circumstances, buprenorphine can actually block the effects of full opioid agonists and can precipitate withdrawal symptoms in an acutely opioid-intoxicated individual.
Buprenorphine has poor oral bioavailability and moderate sublingual bioavailability. Thus, formulations for opioid dependence treatment are in the form of sublingual tablets.
Buprenorphine is highly bound to plasma proteins. It is metabolized by the liver via the cytochrome P4503A4 enzyme system into norbuprenorphine and other metabolites. The half-life of buprenorphine is 24–60 hours.
Because of its ceiling effect and poor bioavailability, buprenorphine is safer in overdose than opioid full agonists. The maximal effects of buprenorphine appear to occur in the 16–32 mg dose range for sublingual tablets. Higher doses are unlikely to produce greater effects.
Respiratory depression from buprenorphine (or buprenorphine/naloxone) overdose is less likely than from other opioids. There is no evidence of organ damage with chronic use of buprenorphine, although increases in liver enzymes are sometimes seen. Likewise, there is no evidence of significant disruption of cognitive or psychomotor performance with buprenorphine maintenance dosing.
Information about the use of buprenorphine in pregnant, opioid-dependent women is limited; the few available case reports have not demonstrated any significant problems due to buprenorphine use during pregnancy. Suboxone® and Subutex® are classified by the FDA as Pregnancy Category C medications.
Side effects of buprenorphine are similar to those of other opioids and include nausea, vomiting, and constipation. Buprenorphine and buprenorphine/naloxone can precipitate the opioid withdrawal syndrome. Additionally, the withdrawal syndrome can be precipitated in individuals maintained on buprenorphine. Signs and symptoms of opioid withdrawal include:
- Dysphoric mood
- Nausea or vomiting
- Muscle aches/cramps
- Pupillary dilation
- Mild fever
Because of its opioid agonist effects, buprenorphine is abusable, particularly by individuals who are not physically dependent on opioids. Naloxone is added to buprenorphine to decrease the likelihood of diversion and abuse of the combination product. Sublingual buprenorphine has moderate bioavailability, while sublingual naloxone has poor bioavailability. Thus, when the buprenorphine/naloxone tablet is taken in sublingual form, the buprenorphine opioid agonist effect predominates, and the naloxone does not precipitate opioid withdrawal in the opioid-dependent user.
Naloxone via the parenteral route, however, has good bioavailability. If the sublingual buprenorphine/naloxone tablets are crushed and injected by an opioid-dependent individual, the naloxone effect predominates and can acutely precipitate the opioid withdrawal syndrome.
Under certain circumstances buprenorphine by itself can also precipitate withdrawal in opioid-dependent individuals. This is more likely to occur with higher levels of physical dependence, with short time intervals (e.g., less than 2 hours) between a dose of opioid agonist (e.g., methadone) and a dose of buprenorphine, and with higher doses of buprenorphine.
Evidence of Effectiveness
Studies have shown that buprenorphine is more effective than placebo and is equally as effective as moderate doses of methadone and LAAM in opioid maintenance therapy. Buprenorphine is unlikely to be as effective as more optimal-dose methadone, and therefore may not be the treatment of choice for patients with higher levels of physical dependence.
Few studies have been reported on the efficacy of buprenorphine for completely withdrawing patients from opioids. In general, the results of studies of medically assisted withdrawal using opioids (e.g., methadone) have shown poor outcomes. Buprenorphine, however, is known to cause a milder withdrawal syndrome compared to methadone and for this reason may be the better choice if opioid withdrawal therapy is elected.
Effective treatment of drug addiction requires comprehensive attention to all of an individual’s medical and psychosocial co-morbidities. Pharmacological therapy alone rarely achieves long-term success. Thus Suboxone® and Subutex® treatment should be combined with concurrent behavioral therapies and with the provision of needed social services.
The choice of treatment setting in which to provide non-pharmacological therapies should be determined based on the intensity of intervention required for a patient. The continuum of treatment setting intensities ranges from episodic office-based therapy to intensive inpatient therapy.
Ideal candidates for opioid addiction treatment with buprenorphine are individuals who have been objectively diagnosed with opioid addiction, are willing to follow safety precautions for treatment, can be expected to comply with the treatment, have no contraindications to buprenorphine therapy, and who agree to buprenorphine treatment after a review of treatment options. There are three phases of buprenorphine maintenance therapy: induction, stabilization, and maintenance.
The induction phase is the medically monitored startup of buprenorphine therapy. Buprenorphine for induction therapy is administered when an opioid-dependent individual has abstained from using opioids for 12–24 hours and is in the early stages of opioid withdrawal. If the patient is not in the early stages of withdrawal, i.e., if he or she has other opioids in the bloodstream, then the buprenorphine dose could precipitate acute withdrawal.
Induction is typically initiated as observed therapy in the physician’s office and may be carried out using either Suboxone® or Subutex®, dependent upon the physician’s judgment. As noted above, Buprenex®, the parenteral analgesic form of buprenorphine, is not FDA-approved for use in opioid addiction treatment.
The stabilization phase has begun when the patients have discontinued or greatly reduced the use of their drug of abuse, no longer has cravings, and is experiencing few or no side effects. The buprenorphine dose may need to be adjusted during the stabilization phase. Because of the long half-life of buprenorphine it is sometimes possible to switch patients to alternate-day dosing once stabilization has been achieved.
The maintenance phase is reached when the patient is doing well on a steady dose of buprenorphine (or buprenorphine/naloxone). The length of time of the maintenance phase is individualized for each patient and may be indefinite. The alternative to going into (or continuing) a maintenance phase, once stabilization has been achieved, is medically supervised withdrawal. This takes the place of what was formerly called “detoxification.”