Buprenorphine

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Buprenorphine
Systematic (IUPAC) name
(2S)-2-[(-)-(5R,6R,7R,14S)-
9α-cyclopropylmethyl-4,5-epoxy-
6,14-ethanomorphinan-7-yl]-3-hydroxy-
6-methoxy-3,3-dimethylbutan-2-ol
Identifiers
CAS number 52485-79-7
ATC code N02AE01 N07BC01
PubChem 40400
DrugBank APRD00670
Chemical data
Formula C29H41NO4 
Mol. mass 467.64 g/mol
Pharmacokinetic data
Bioavailability 31% (sublingual, from ethanolic solution)
~10% (sublingual, high-dose tablet)
Protein binding 96%
Metabolism hepatic
Half life 37 hours
Excretion biliary and renal
Therapeutic considerations
Pregnancy cat.

C (USA)
Legal status

Schedule III (USA)
Schedule 8 (Aust)
Schedule III (UK)
Cat. A{Singapore}
Routes sublingual, IM, IV


Buprenorphine, also colloquially referred to as bupe or subbies, 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, available generally as Buprenex in a 0.3 mg/ml injectable formulation in the United States. In October 2002, the FDA additionally approved Suboxone and Subutex, buprenorphine's high-dose sublingual pill preparations for opioid addiction, and as such the drug is now also used for this purpose. It has been a Schedule III drug under the Convention on Psychotropic Substances[1] since it was rescheduled from Schedule V (the schedule with the lowest restrictions and penalties) just before FDA approval of Suboxone and Subutex.

Contents

[edit] Dangers of Taking Non-Medicinally

Like other opiates, buprenorphine can cause drowsiness, vomiting and respiratory depression. Taking buprenorphine in conjunction with central nervous system (CNS) depressants such as sedatives, tranquilizers, alcohol, and especially benzodiazepines can be particularly dangerous [2]. Falling asleep while abusing this drug, especially while combining such with other central nervous system depressants, can be extremely dangerous and thus greatly increases the chance of serious complications or death - even more so in non-tolerant users.

[edit] Commercial preparations

British 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 (flavorless sublingual, no active additives; in 2 mg and 8 mg dosages) and Suboxone (orange-tang flavored sublingual, one part naloxone for every four parts buprenorphine; hexagon shaped tablet in 2 mg and 8 mg 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.

Buprenorphine is also delivered transdermally in 35, 52.5 and 70 mcg/hour transdermal patch. The trade name in the U.K. for buprenorphine with this type of delivery in the UK is Transtec, and manufactured by Napp Pharmaceuticals.[3] 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.The transdermal preparation is also available in Australia and sold under the brand name of Norspan.

[edit] Pharmacology and pharmacokinetics

Buprenorphine is a thebaine derivative, and its analgesic effect is due to partial agonist activity at μ-opioid receptors, i.e., when the molecule binds to a receptor, it is only partially activated in contrast to an full agonist such as morphine. Buprenorphine also has very high binding affinity for the μ receptor such that opioid receptor antagonists (e.g. naloxone) only partially reverse its effects. These two properties must be carefully considered by the practitioner, as an overdose cannot be easily reversed (although overdose is unlikely in addicts or people with tolerance to opioids who use the drug sublingually as meant in the case of Subutex/Suboxone, especially if there are no benzodiazepines involved), and use in persons physically dependent on full-agonist opioids may trigger opioid withdrawal that also cannot be easily reversed and can last over 24 hours, as the drug's mean half-life is 37 hours. For this reason, patients switching to buprenorphine are required to abstain from the previous opioid for at least several half-lives of the given substance.

Buprenorphine is also a κ-opioid receptor antagonist, and partial/full agonist at the recombinant human ORL1 nociceptin receptor.[4]

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 20–73 hours (mean 37).

The main active metabolite, norbuprenorphine, is a δ-opioid receptor and ORL1 receptor agonist, μ- and κ-opioid receptor partial agonist, but buprenorphine antagonizes its effects.[4]

Buprenorphine is also available in a Transdermal Patch marketed as "Norspan," The patch is a Schedule 8 Medicine in Australia and lasts for a period of days after application.

[edit] Clinical use

[edit] 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.[5] Australian guidelines recommend against the use of buprenorphine as an analgesic because: its effect is largely 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 although it is generally viewed to be less than other opioids.[6] When used (in the high-dose formula) for opioid dependence, buprenorphine remains effective in the body for up to 72 hours in some patients, 24-48 hours typically (the mean plasma half life of buprenorphine is 37 hours, with an active metabolite as well), curbing withdrawal symptoms and antagonizing (blocking) the effects of other opioids that may be administered to the patient (legally, for pain especially in an emergency, or illegally).

[edit] 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.[7] See opioids for other (predominantly favorable) experiments with buprenorphine and other opioids for psychological relief. However, psychological distress is currently not an approved indication for the use of any opioid, and legally it falls in a "grey zone" that is technically legal but a doctor could still face charges regardless (but not for off-label scripting in itself, simply being singled out by the DEA, who prosecute doctors often for using controlled substances for approved uses ("too much"). [1][2] The doctor still needs the proper DEA licensing under the Drug Addiction Treatment Act of 2000 to prescribe Subutex or Suboxone regardless of indication in this special case.

[edit] 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, decreased libido, urinary retention, and constipation.[6] Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets, 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). Additionally, concurrent use of buprenorphine and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression. Buprenorphine is a lipid soluble opioid and as such may have the same problems as fentanyl in causing sudden respiratory depression. Fentanyl was investigated in 2005 for causing respiratory deaths and has been known to do so since the 1980s when it first came out as a transdermal patch.

In people on medium- to long-term maintenance with Suboxone or Subutex do not have a major risk of overdose, as long as the drug is used properly (as prescribed), and benzodiazepines are not prescribed to individuals without a tolerance to opioids.

As with other Opioids, dependence and tolerance are rarely a problem when used safely. There is little evidence that buprenorphine is less likely to cause such problems. 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 activity of buprenorphine combined with its high affinity for μ-opioid receptor means that it may act clinically as an antagonist and thus precipitate opioid withdrawal symptoms when an opioid-dependent patient is commenced on the drug soon after the use of another opioid drug. Patients are advised to wait between 24 and 36 hours after their last use of short-acting opioids (such as heroin or oxycodone) before beginning treatment with buprenorphine. Those using long-acting opioids, such as methadone, should only commence treatment once withdrawal symptoms are present. Beginning any earlier may result in extreme cases of opioid withdrawal. Additionally, it is recommended that the patient be on no more than 30 mg of methadone per day when switching to buprenorphine.

[edit] Dependence treatment

Buprenorphine sublingual preparations are often used in the management of opioid dependence (that is, dependence on heroin, oxycodone, hydrocodone, morphine, oxymorphone, fentanyl or other opioids). The Suboxone and Subutex preparations were approved for this indication by the United States FDA in October 2002. This was only possible due to the Drug Addiction Treatment Act of 2000 that for the first time since 1914-1920 (conflicting Supreme Court rulings - rulings that would not stand to today's Supreme Court as they ruled that maintenance or detox treatment is not medical treatment, and likely was not what was indended by Congress) made it legal for doctors to prescribe opioids themselves to manage addiction ("maintenance") or for short-term detox (special doctors in registered clinics are excluded from these blanket restrictions). This law is limited to Schedules III through V only - thus excluding methadone and stronger opioids.

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. However, if the doctor meets none of the other clarifications, an 8-hour course is all that is required). Each approved prescriber is allowed to manage only 30 patients on buprenorphine for opioid addiction as outpatients;[8] the U.S. Senate has passed a bill relaxing this restriction for group practices only as of May 25, 2006[citation needed]. Legislation was passed by Congress in the last few hours prior to Holiday recess in December, 2006 allowing physicians with one year of clinical experience to request an additional exemption within DATA 2000 allowing the 30 patient limit to be raised to 100 patients. Similar restrictions are placed on prescribers in many other jurisdictions. Buprenorphine is heavily regulated in Australia relatively, and while the number of patients isn't limited generally daily visits for supervised dosing at a pharmacy is required, such as methadone, and methadone where used is used in lower relative doses.[citation needed] On September 21, 2006, actor and comedian Artie Lange revealed on the Howard Stern Show that he had overcome heroin addiction the previous year. He said buprenorphine was essential to countering the effects of opioid withdrawal and described it as a 'miracle pill'. However, others have found that once they begin the treatment, they become addicted to the Buprenorphine, this is because Buprenorphine is still an opiate. The withdrawals from Buprenorphine is quite similar to that of other opiates, but like methadone, it has a long half life, causing a longer, but milder withdrawal.

[edit] 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 disadvantages.

In terms of efficacy (i.e. treatment retention, negative urine samples), high-dose buprenorphine (such as that commonly found with Subutex/Suboxone treatment; 8-16 mg typically) has been found to be superior to 20-40 mg of methadone/day (low dose) and equatable anywhere between 50 mg-70 mg (moderate dose)[9] to up to 100 mg (high dose)[10] methadone/day. (Methadone, however, can continue to increase in effectiveness over 100 mg, although it is a debatable topic, but this would consistute "very high dose" in this measurement commonly used by studies, including those quoted). In all cases, high-dose buprenorphine has been found to be far superior to placebo and an effective treatment for opioid addiction, with retention rates of 50% as a minimum.[9][10][11][12]

Buprenorphine sublingual tablets (Suboxone and Subutex for opioid addiction) have a long duration of action which may allow for dosing every two or three days, as tolerated by the patient, compared with the daily dosing required to prevent withdrawals with methadone. In the United States, following initial management, a patient is typically prescribed up to a one month supply for self-administration. It is often misunderstood that the patient has to receive other therapy in this situation, but the law simply states that the prescribing physician needs to be capable of referring the patient to other addiction treatment (i.e. psychotherapy or support groups,) and many (but not all) physicians are aware of this and simply recommend therapy, or as they deem fit have therapy required.

Buprenorphine may and is generally viewed to have a lower dependence-liability than methadone. Buprenorphine treatment can last anywhere from several days (for detoxification purposes) to several months (sometimes for only a few weeks or up to two or three years) or in more rare cases longer. While not the general goal, and often not intentional with buprenorphine, it can sometimes but rarely be used in an indefinite, often life-long regimen just as methadone can be. The choice of buprenorphine vs. methadone in the mentioned situation (by the patient) is usually due to the benefits of the less-restrictive outpatient treatment; prescriptions for take-home doses for up to a month vs. the heavy restrictions for take-home methadone doses and frequent visits to the clinic, as well as the stigma of going to a methadone clinic.

The usually less-severe withdrawal effects make it usually much easier to discontinue use as opposed to methadone, but no evidence thus far exists that sustaining abstinence post-buprenorphine maintenance is any more likely than post-methadone maintenance, or post-heroin withdrawal. On the other side, going from heroin/other potent opioids to buprenorphine is generally harder than going from the same to methadone. In the eyes of addicts this is an important consideration. Buprenorphine, as a partial μ-opioid receptor agonist, has been claimed and is generally viewed to have a less euphoric effect compared to the full agonist methadone, and was therefore predicted less likely to be diverted to the black market (as reflected by its CIII status vs. methadone's more restrictive CII status), as well as that buprenorphine is generally accepted as unable to be abused (for euphoria) by those with a heroin or other potent opioid habit (however neither drug is supposed to have a euphoric effect when used long-term). Thus far in the United States it is far less often found on the black market vs. methadone, but most street heroin addicts don't even know it exists, and its (legitimate) usage is far less than methadone (and according to many newspapers "underused"). In France where it is used more often than methadone there is more black market availability, although this and the apparent attraction is possibly due to a heroin dry-spell, possible evidence indicated by how it is often combined with benzodiazepines for more of an effect.

[edit] Blockade Effect

The Suboxone preparation contains the μ-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 opioids, making it more difficult to become intoxicated due to other opioids when buprenorphine is in the system, regardless of the presence of the naloxone. (Measurable amounts of naloxone can be absorbed and detected via the sublingual route, and while this is insignificant and has no subjective effect, there are anecdotal reports of hypersensitivity to naloxone in (if proven) rare cases.) If enough buprenorphine is in the system, however, it has the same effect as naloxone in completely or nearly completely blocking or reversing opiate effects from another opioid. 0.3 mg of buprenorphine parenterally is equivalent in antagonistic effect to between 0.4 and 2.0 mg of naloxone parenterally with a much longer half-life. Methadone too blocks the effects of other opioids, and generally just as well, but it is more due to the fact that so much is often used and the tolerance to opiates that comes with it. However, it is still possible to abuse other opioids on either treatment regime.

In the case of preganancy, buprenorphine causes less neo-natal withdrawals than methadone.[13] (and is one of the few cases where Subutex is likely to be used over Suboxone in the United States.) Thus, buprenorphine is preferable during pregnancy.

Switching to buprenorphine from methadone is very difficult and withdrawals lasting several days or more are often encountered mostly when the dose is any higher than 30 mg/day (the suggested and usual dose for switching to buprenorphine), a very low (sub-therapeutic) methadone dose that many methadone maintenance patients have difficulting reaching. Switching to buprenorphine at a higher dose may cause a long-term withdrawal syndrome. Unfortunately due to this, buprenorphine being used during pregnancy over methadone might be a moot point unless the difference is taken into account beforehand by women whom possibly will become pregnant. On the other side, switching from buprenorphine to methadone is relatively easy.

[edit] Inpatient rehabilitation

The practice of using buprenorphine (Subutex or Suboxone) in an inpatient rehabilitation setting is increasing rapidly[citation needed], whereas methadone-based detox is the standard. It is also being used in social model treatment settings. These rehabilitation programs consist of "detox" and "treatment" phases. The detoxification ("detox") phase consists of medically-supervised withdrawal from the drug of dependency on to buprenorphine, sometimes aided by the use of medications such as benzodiazepines like oxazepam or diazepam (modern milder tranquilizers that assist with anxiety, sleep, and muscle relaxation), clonidine (a blood-pressure medication that may reduce some opioid withdrawal symptoms), and anti-inflammatory/pain relief drugs such as ibuprofen. Switching to buprenorphine from a short-acting drug including Heroin, morphine, fentanyl, hydromorphone and hydrocodone (Vicodin), or oxycodone (Oxycontin and Percocet) is not too difficult for most people, and as long as the patient waited until they were in full withdrawals or longer before starting the buprenorphine medication, little further acute symptoms are an issue; The patient needs to be stabilized on a proper dose and monitored regardless. Switching from methadone is much more difficult, and with all cases if the patient takes buprenorphine prematurely (before full withdrawal symptoms) it can precipitate worse withdrawals than would have been had if the person had waited properly, and they can be long-lasting. The treatment phase begins once the patient is stabilized and receives medical clearance. 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 principles, such as those practiced by Alcoholics Anonymous and Narcotics Anonymous. Narcotics Anonymous and many other 12-step programs do not accept maintenance (medium to long-term use of buprenorphine or methadone as just described) however, it's viewed as non-abstinent drug use, but there are systems similar to or modelled after 12-step programs that accept its use and even acknowledge its power as a tool.

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 longer-term treatment. Completing both increases the probability of success.[citation needed]. Abstinence alone has a very low efficacy in rehabilitating patients, in contrast to buprenorphine maintenance which has a high efficacy,[14][9] Unfortunately most rehabilitation programs don't have or don't allow scientific studies to be conducted to contrast to abstinence alone and buprenorphine or methadone maintenance, including Narcotics Anonymous[citation needed], although this is a hot topic and strong arguments in support of Narcotics Anonymous have been made and arguments against buprenorphine maintenance (in general for all) have been made, and methods (asbstinence and maintenance) have worked for different people, and sometimes they don't have to be mutually exclusive. Rehabilitation programs typically average about 30 days for primary care, but some may extend anywhere from 90 days to 6 months in an extended care unit. It is considered essential by the programs that administer them that patients in abstinence-based treatment form networks with other recovering addicts and engage in self-help groups, aftercare and other related activities after treatment in order to be more likely to achieve long-term abstinence from opioids, a statistically difficult achievement.

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 acute 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 addictive substances, as previously mentioned.

During this time, Suboxone or Subutex will be administered or the patient will be monitored taking the medication. Generally, the patient takes a single dose each day (a single dose may keep the patient comfortable for up to 48-72 hours, but medical professionals in many treatment facilities prescribe one or more than one dose every 24 hours to ensure that a consistent, active level of the medication remains in the patient's central nervous system, a key element of maintenance; also the level of dosage is usually around the previously described plateau, after which there is no noticeable increase in the effects of the drug. Typically, the first day dosage is no more than 8 mg or it may precipitate withdrawals as antagonistic effects overwhelm agonistic effects, after which initial daily dose totals around 8-16 mg (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.

During the detox period of any situation, despite the evidence that suggests that the naloxone in Suboxone has no clinically significant effect (except for anecdotal reports of hypersensitivity in (if proven) rare cases), Subutex is urged over Suboxone by the manufacturer and you are likely to receive it during the first few days.

[edit] References

  1. ^ List of psychotropic Substances under international control
  2. ^ Suboxone FAQ
  3. ^ Napp Pharmaceuticals
  4. ^ a b Huang P. et al. (2001): "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist", J. Pharmacol. Exp. Ther. 297(2):688-95. PMID 11303059
  5. ^ Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004. ISBN 0-85369-584-9
  6. ^ a b Rossi S, editor. Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook; 2005. ISBN 0-9578521-9-3
  7. ^ Bodkin JA. et al. (1995): "Buprenorphine treatment of refractory depression", Journal of Clinical Psychopharmacology 15:49-57. PMID 7714228
  8. ^ naabt.org
  9. ^ a b c R. S. Schottenfeld et. al (1997) Department of Psychiatry, Yale University School of Medicine
  10. ^ a b Rolley Johnson et al., NEJM, 343(18):1290-1297, 2000
  11. ^ Strain et al. (1998)
  12. ^ Ling et al. (1998)
  13. ^ G Fischer, P Etzersdorfer, H Eder, R Jagsch, M Langer, M Weninger (1998). Buprenorphine Maintenance in Pregnant Opioid Addicts. European Addiction Research;4 (suppl 1):32-36
  14. ^

[edit] External links

v • d • e
Analgesics (N02A, N02B)
Opioids Bezitramide, Buprenorphine, Butorphanol, Dextromoramide, Dextropropoxyphene, Diamorphine, Dihydrocodeine, Fentanyl, Hydromorphone, Ketobemidone, Methadone, Morphine, Nalbufine, Nicomorphine, Opium, Oxycodone, Papaveretum, Pethidine, Piritramide, Tramadol (see also longer list)
Salicylic acid and derivatives Aspirin (Acetylsalicylic Acid), Diflunisal, Ethenzamide -- See also: NSAIDs
Pyrazolones Aminophenazone, Metamizole, Phenazone
Anilides Paracetamol (acetaminophen), Phenacetin
Others Ziconotide, Tetrahydrocannabinol, Ibuprofen, Ketoprofen, Mefenamic Acid, Naproxen, Diclofenac, Flurbiprofen, Diflunisal, Fenoprofen, Indomethacin, Ketorolac, Meclofenamate, Meloxicam, Piroxicam, Tolmetin
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