In October 2002, the Food and Drug Administration (FDA) approved 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 Schedule III, IV, or V medications to have received FDA approval for this indication. Note that aside from Subutex® and Suboxone®, other forms of buprenorphine (e.g., Buprenex®) are
not approved for treatment of opioid addiction.
The FDA approval of these buprenorphine
formulations does not affect the status of other medication-assisted opioid
addiction 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 treatments 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 codeine, that are not approved for
the treatment of addiction.
Suboxone®, a sublingual tablet, comes in two
dosage forms: 2 mg buprenorphine/0.5 mg naloxone and 8 mg buprenorphine/2 mg
naloxone. Subutex®, also a sublingual tablet, is available in 2 mg and 8 mg
strengths. The Subutex® and Suboxone® drug labels are available on the
FDA Web site at:
- Applied Pharmacology
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 dosethe ceiling effect. Thus, buprenorphine
carries a lower risk of abuse, addiction, 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 if administered to an opioid-addicted
individual while a full agonist is in the bloodstream.
has poor oral bioavailability and moderate sublingual bioavailability.
Formulations for opioid addiction treatment are in the form of sublingual
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
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
1632 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-addicted 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.
See Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction (pdf, 1.1 MB) for more information about the use of buprenorphine in pregnancy. Currently,
methadone remains the standard of care for the medication-assisted treatment of
opioid-addicted women in the United States.
- Side Effects
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:
- Drug Interactions, Cautions, and Contraindications
Refer to the Subutex® and Suboxone® package inserts
(http://www.fda.gov/cder/drug/infopage/subutex_suboxone/default.htm) for a
complete listing of drug interactions, contraindications, warnings, and
- Abuse Potential
Because of its opioid agonist
effects, buprenorphine is abusable, particularly by individuals who are not
physically addicted to 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-addicted user.
Naloxone via the parenteral route, however, has good bioavailability.
If the sublingual buprenorphine/naloxone tablets are crushed and injected by an
opioid-addicted individual, the naloxone effect predominates and can
precipitate the opioid withdrawal syndrome.
Under certain circumstances
buprenorphine by itself can also precipitate withdrawal in opioid-addicted
individuals. This is more likely to occur with higher levels of physical
addiction, 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.
- Non-pharmacological Therapies
Effective treatment of drug addiction requires comprehensive
attention to all of an individuals 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. This point is of such importance that physicians must attest to their
capacity to refer patients for counseling when they submit their Notification
of Intent to SAMHSA to begin prescribing Suboxone® and Subutex®.
Many different types of behavioral therapies (e.g., Motivational Enhancement Therapy, self-help
programs) have been used successfully for substance abuse disorders. The SAMHSA
Treatment Improvement Protocol (TIP) series (http://www.treatment.org/Externals/tips.html)
includes a number of documents that contain best practice guidelines for the
provision of interventions and therapies for individuals with substance abuse
- Opioid Addiction Therapy with Buprenorphine
This section provides a brief overview of the clinical use of buprenorphine
(Suboxone® and Subutex®) for opioid addiction therapy. For detailed
information on this topic see the Buprenorphine Clinical Practice Guidelines.
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-addicted
individual has abstained from using opioids for 1224 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.
typically initiated as observed therapy in the physicians office and may
be carried out using either Suboxone® or Subutex®, dependent upon the
physicians judgment. As noted above, Buprenex®, the parenteral
analgesic form of buprenorphine, is not FDA-approved for use in opioid
- The stabilization phase has begun when a
patient has discontinued or greatly reduced the use of his or her 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