Buprenorphine
About Buprenorphine Therapy
Buprenorphine, a derivative of thebaine, is an opiate that has been
marketed in the United States as the Schedule V parenteral analgesic
Buprenex®. In 2004, 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 2004, 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.
Formulations
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:
http://www.fda.gov/cder/drug/infopage/subutex_suboxone/default.htm
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 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.
Safety
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.
See the Buprenorphine Clinical Practice Guidelines (available soon
on this Web site) for more information about the use of buprenorphine
in pregnancy. Currently, methadone remains the standard of care
for the medication-assisted treatment of opioid-dependent 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:
- Dysphoric mood
- Nausea or vomiting
- Muscle aches/cramps
- Lacrimation
- Rhinorrhea
- Pupillary dilation
- Sweating
- Piloerection
- Diarrhea
- Yawning
- Mild fever
- Insomnia
- Craving
- Distress/irritability
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 precautions.
Abuse Potential
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.
Non-pharmacological Therapies
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. 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 begin prescribing Suboxone® and Subutex® to SAMHSA.
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. For more information on this topic refer to the American
Society of Addiction Medicine’s Patient Placement Criteria (ASAM
PPC-2R, (www.asam.org), the most
widely used and comprehensive national guidelines for placement,
continued stay, and discharge of patients with alcohol and other
drug problems.
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.samhsa.gov/publications/publications.html) includes
a number of documents that contain best practice guidelines for
the provision of interventions and therapies for individuals with
substance abuse disorders.
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 (available soon).
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 withdrawal phase is reached when the patient is doing well on a steady dose of buprenorphine (buprenex). Once the patient shows no sign of opiate withdrawal, the patient is the titrated (stepped-down) from the buprenorphine therapy, until they are drug-free. This phase replaces what was once named "detoxification".
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