Buprenorphine

Buprenorphine, also colloquially referred to as bupe, is an opioid drug with partial agonist and antagonist actions. Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, yet is now primarily used for the treatment of opioid addiction. It is a Schedule III drug under the Convention on Psychotropic Substances.

Commercial preparations
Britsh firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations, no active additives) and Buprenex (parenteral, no active additives). Two more recent formulations from Reckitt Benckiser have been approved for opioid addiction treatment in the U.S.: Subutex (lemon-lime flavored sublingual, no active additives; in 2mg and 8mg dosages) and Suboxone (orange-tang flavored sublingual, one part naloxone for every four parts buprenorphine; hexagon shaped tablet in 2mg and 8mg dosages). Suboxone contains the opioid antagonist naloxone to deter illicit intravenous preparation of the tablet, this is intended to attenuate the effects of buprenorphine on opioid-naive users should this formulation be injected - however no human studies have been done demonstrating the efficacy of this approach with buprenorphine and a growing number of street reports indicate that the naloxone is ineffective. It must also be noted that buprenorphine in and of itself will induce a precipitated withdrawal syndrome if ingested by an acutely opioid dependant individual via any route.

Buprenorphine is also delivered transdermally in 25, 50 and 75 mcg/hour. The trade name in the UK is Transtec, and manufactured by Napp. A new 5, 10 and 20 mcg/hour patch marketed as Bu'7rans (Bu-trans), where the 7 indicates its once weekly dosage for pain in osteoarthritis.

Pharmacology and pharmacokinetics
Buprenorphine is a thebaine derivative, and its analgesic effect is due to partial agonist activity at &mu;-opioid receptors. The partial agonist activity means that opioid receptor antagonists (e.g. naloxone) only partially reverse the effects of buprenorphine. Buprenorphine is also a &kappa;-opioid receptor partial agonist/antagonist, and partial/full agonist at the recombinant human ORL1 nociceptin receptor. (Huang et al., 2001)

Buprenorphine hydrochloride is administered by intramuscular injection, intravenous infusion, via a transdermal patch, or as a sublingual tablet. It is not administered orally, due to very high first-pass metabolism. Buprenorphine is metabolised by the liver, via the CYP3A4 isozyme of the cytochrome p450 enzyme system, into norbuprenorphine (by N-dealkylation) and other metabolites. The metabolites are further conjugated with glucuronic acid and eliminated mainly through excretion into the bile. The elimination half-life of buprenorphine is 20.4–72.9 hours (mean 34.6).

The main active metabolite, norbuprenorphine, is a &delta;-opioid receptor and ORL1 receptor agonist, &mu;- and &kappa;-opioid receptor partial agonist. (Huang et al., 2001)

Indications
Buprenorphine is indicated for the treatment of moderate to severe pain, peri-operative analgesia, and opioid dependence. It has a longer duration of action than morphine, and sublingual tablets offer an analgesic effect for 6 to 8 hours. (Joint Formulary Committee, 2004) Australian guidelines recommend against the use of buprenorphine as an analgesic because: its effect is not reversed by naloxone, it may precipitate withdrawal symptoms in people dependent on other opioids, and it may cause dependence itself and has potential for misuse. (Rossi, 2005) When used for opioid dependence, buprenorphine remains effective in the body for up to 48 hours, curbing withdrawal symptoms and counteracting other opioids that may be administered to the patient (licitly or illicitly).

Antidepressant
A clinical trial conducted at Harvard Medical School in the mid-1990s, demonstrated that a majority of unipolar non-psychotic patients with major depression refractory to conventional thymoleptic antidepressants could be successfully treated with buprenorphine (Bodkin JA, et al., 1995). See opioids for other (predominantly favorable) experiments with bupenorphine and other opioids for psychological relief. However, psychological distress is not an approved indication for the use of any opioid.

Adverse effects
Common adverse drug reactions associated with the use of buprenorphine are similar to those of other opioids and include: nausea and vomiting, drowsiness, dizziness, headache, itch, dry mouth, miosis, orthostatic hypotension, male ejaculatory difficulty, urinary retention, and constipation. (Rossi, 2005) Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, and hepatic function is commonly monitored during buprenorphine therapy.

The most severe and serious adverse reaction associated with opioid use in general is respiratory depression, the mechanism behind fatal overdose. This is particularly problematic with buprenorphine owing to the lack of an effective antagonist (antidote).

As with other opioids, buprenorphine can produce both physical and psychological dependence. However, unlike other opioids, users of buprenorphine rarely develop a tolerance to the drug. Maintenance dosages can remain at the same moderate level indefinitely, and in many cases even lowered, without discomfort. Due to buprenorphine's pharmacological actions, raising the dosage will not result in a stronger analgesic effect after a certain point (around 16–32 mg), beyond which the drug will actually have a reduced analgesic effect.

The partial agonist/antagonist activity of buprenorphine means that it may precipitate opioid withdrawal symptoms when an opioid-dependent patient is commenced on the drug soon after the use of another opioid drug.

Dependence treatment
Buprenorphine sublingual preparations are often used in the management of opioid dependence (that is, dependence on heroin, oxycodone, hydrocodone, morphine, or other opioids). The Suboxone and Subutex preparations were approved for this indication by the United States FDA in October 2002.

The use of opioid-replacement therapy in the management of opioid dependence is highly regulated, owing to the sometimes controversial nature of this aspect of harm reduction policy. In the United States, a special federal waiver is required to prescribe Subutex and Suboxone for opioid addiction treatment on an outpatient basis. Each approved prescriber is allowed to manage only 30 patients on buprenorphine for opioid addiction as outpatients. Similar restrictions are placed on prescribers in many other jurisdictions.

Buprenorphine vs methadone
Buprenorphine and methadone are both used for short-term and long-term opioid maintenance therapy. Each agent has its relative advantages, and several are cited for buprenorphine.

Buprenorphine sublingual tablets (Suboxone and Subutex) have a long duration of action which may allow dosing every two days, compared with the daily dosing required with methadone. In the United States, following initial management, a patient may be prescribed one month supply for self-administration on the condition that the patient receive other dependence therapy.

Buprenorphine may have a lower dependence-liability than methadone. Buprenorphine treatment typically lasts several months (though sometimes for only a few weeks or up to two or three years), as opposed to an indefinite, often life-long methadone regimen. However, there have been as yet no studies indicating that patients withdrawn from buprenorphine relapse any less frequently than those withdrawn from other opioids. Buprenorphine itself appears to have less-severe withdrawal effects than methadone, and thus it is easier to discontinue use, but no evidence exists that sustaining abstinence post-buprenorphine maintenance is any more likely than post-methadone maintenance, or post-heroin withdrawal. Buprenorphine, as a partial &mu;-opioid receptor agonist, has been claimed to have a less euphoric effect compared to the full agonist methadone, and was therefore predicted to be less likely to be diverted to the black market. The Suboxone preparation contains the &mu;-opioid receptor antagonist naloxone which is intended ONLY to prevent abuse of the buprenorphine, NOT, as is commonly misunderstood, to block the effects of other opiates. Buprenorphine itself binds more strongly to receptors in the brain than do other opiates, so it is almost almost impossible to get high on other opiates if enough buprenorhine is in the system, regardless of the presence of the naloxone.

Inpatient rehabilitation
The practice of using buprenorphine (Subutex or Suboxone) in an inpatient rehabilitation setting is increasing rapidly. These rehabilitation programs consist of "detox" and "treatment" phases. The detoxification ("detox") phase consists of medically-supervised withdrawal from the drug of dependency, sometimes aided by the use of medications such as buprenorphine and oxazepam. The treatment phase begins once the patient receives medical clearance and has completed the initial acute detoxification process. This portion of treatment is comprised of multiple therapy sessions, which include both group and individual counseling with various chemical dependency counselors, psychologists, psychiatrists, social workers, and other professionals. Additionally, many of these treatment centers strongly base their treatment models on 12-step fellowship traditions and principles, such as those practised by Alcoholics Anonymous and Narcotics Anonymous despite the fact that research has never demonstrated any efficacy for such groups.

Patients who enter rehabilitation voluntarily, as opposed to those who are court-ordered, can often choose a facility with the option of only staying for detox, or they can enter treatment facilities that provide the option to complete both detox and rehab. Completing both portions of the treatment increases the probability of success. Rehabilitation programs typically average about 28 days for primary care, but some may extend anywhere from 90 days to 6 months in an extended care unit.

Buprenorphine is sometimes used only during the detox protocol with the purpose of reducing the patient's use of mood-altering substances. It considerably reduces opioid withdrawal symptoms that are normally experienced by opioid-dependent patients on cessation of those opioids, including diarrhea, vomiting, fever, chills, cold sweats, muscle and bone aches, muscle cramps and spasms, restless legs, agitation, gooseflesh, insomnia, nausea, watery eyes, runny nose and post-nasal drip, nightmares, etc. The buprenorphine detox protocol usually lasts about 7-10 days, provided that the patient does not need to be detoxed from any additional substances such as barbiturates, benzodiazepines, or alcohol.

During this time, Suboxone or Subutex will be administered by a nurse or doctor. Generally, the patient receives a single dose each day (despite the fact that a single dose lasts for up to 48 hours, medical professionals in many treatment facilities administer a dose every 24 hours to ensure a consistent active level of the medication remains in the patient's central nervous system). Typically, the initial daily dose totals around 8-16mg (of either Suboxone or Subutex). The dosage is slowly tapered each day and the medication is usually stopped 36-48 hours prior to the end of the detox program, with the patient's vitals monitored up until discharge from the detox program.