Buprenorphine (Subutex, Temgesic, or Suboxone [buprenorphine:naloxone 4:1 preparation] - sublingual tablets - Buprenex - for injection - and Norspan - transdermal patch) is a semi-synthetic opioid that is used to treat opioid addiction in higher dosages (>2 mg) and to control moderate pain in non-opioid tolerant individuals in lower dosages (~200 µg).
Buprenorphine is a Bentley-derivative opioid of the phenanthrene-morpholine class with extremely high binding affinity at the µ- and κ-opioid receptor. It has partial agonist activity at the µ-opioid receptor, partial or full agonist activity at the ORL1/nociceptin and δ-opioid receptor, and competitive antagonist activity at the κ-opioid receptor. Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, available generally as Temgesic 0.2 mg sublingual tablets, and as Buprenex in a 0.3 mg/ml injectable formulation. In October 2002, the Food and Drug Administration (FDA) of the United States of America additionally approved Suboxone and Subutex, buprenorphine's high-dose sublingual pill preparations indicated for detoxification and long-term replacement therapy in opioid dependency, and the drug is now used predominantly for this purpose. In the European Union, Suboxone and Subutex, buprenorphine's high-dose sublingual pill preparations, were approved for opioid addiction treatment in September 2006. In the Netherlands, Buprenorphine is a List II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation. In the USA, it has been a Schedule III drug under the United Nations' Convention on Psychotropic Substances since it was rescheduled from Schedule V just before FDA approval of Suboxone and Subutex. In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.
- 1 Commercial preparations
- 2 Pharmacology and pharmacokinetics
- 3 Clinical use
- 4 Recreational use
- 5 Commonly Used Slang Terminology
- 6 Use in animals
- 7 References
- 8 External links
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 formulationsTemplate:Dn from Reckitt Benckiser have been approved for opioid addiction treatment throughout most of the world, instead of Methadone. Subutex (white color, oval shape, bitter, no active additives) and Suboxone (orange color, hexagonal shaped tablet, orange flavored, one part naloxone for every four parts buprenorphine). Subutex and Suboxone are available in 2 mg and 8 mg sublingual dosages. On October 8, 2009 Roxane Laboratories of Columbus, Ohio, United States of America won FDA approval for a generic preparation of Subutex and as of October 23, 2009 announced that it is ready for distribution nation wide in 2 mg and 8 mg sublingual dosages. The demand for this generic is so high that Roxane did not produce enough to meet market demand, resulting in pharmacies running out and being unable to order more; this is being rectified by Roxane. Teva Pharmaceutical Laboratories of Tel Aviv, Israel has also received approval, as of 1 April 2010 for a generic formulation of Subutex sublingual tablets in 2 mg and 8 mg dosages which are currently available in limited distribution in America as of 20 June 2010.
In India: Tidigesic-0.2 mg (slow release)or 0.3 mg/mL injectable by Sun Pharmaceuticals;Bupregesic (0.3 mg/mL) by Neon Laboratories; Morgesic (0.3 mg/mL) by Samarth Pharma; Norphin (0.3 mg/mL) Unichem Laboratories.
Suboxone contains buprenorphine as well as the opioid antagonist naloxone to deter the abuse of tablets by intravenous injection. Controlled trials in human subjects suggest that buprenorphine and naloxone at a 4:1 ratio will produce unpleasant withdrawal symptoms if taken intravenously by patients who are addicted to opioids, but has no such effect when taken sublingually. However, the Suboxone formulation still has potential to produce an opioid agonist "high" if injected by non-dependent persons which may provide some explanation to street reports indicating that the naloxone is an insufficient deterrent to injection of suboxone.
Since 2001 buprenorphine is also available transdermally as 35, 52.5 and 70 microg per hour transdermal patches that deliver the dose over ninety-six hours. This application form is marketed as Transtec in most European countries by Grunenthal (Napp Pharmaceuticals in the UK, Norpharma in Denmark) for the treatment of moderate to severe cancer pain and severe non-cancer pain not responding to non-opioids. Moreover, a new 5, 10 and 20 mcg per hour patch is marketed as Butrans or Norspan, a once-weekly patch for moderate chronic pain not responding to non-opioids, marketed by Napp Pharmaceuticals Ltd., and Mundipharma and Grunenthal respectively.
A novel implantable formulation of buprenorphine (Probuphine), using a polymer matrix sustained-release technology, has been developed to offer treatment for opioid dependence while minimizing risks of patient noncompliance and illicit diversion.
In addition to the sublingual tablet, Suboxone is now marketed in the form of a sublingual film, available in both the 2mg/0.5mg and 8mg/2mg dosages. The makers of Suboxone, Reckitt Benckiser, claim that the film has some advantages over the traditional tablet in that it dissolves faster and, unlike the tablet, adheres to the oral mucosa under the tongue, preventing it from being swallowed or falling out; that patients favor its taste over the tablet, stating that "more than 71% of patients scored the taste as neutral or better"; that each film strip is individually wrapped in a compact unit-dose pouch that is child-resistant and easy to carry and that it is clinically interchangeable with the Suboxone tablet and can also be dosed once daily. Reckitt Benckiser also states that the film discourages misuse and abuse, as the paper-thin film is more difficult to crush and snort. Also, a 10-digit code is printed on each pouch which helps facilitate medication counts and therefore serves to deter diversion into the illegal drug market.
In addition a new formulation of Buprenorphine is being developed using Biodelivery Sciences FDA Approved BEMA (BioErodible MucoAdhesive)technology and will be developed both for acute pain conditions such as postoperative pain and chronic pain conditions such as low back, osteoarthritis, and neuropathic pain as well as opioid dependence.
Pharmacology and pharmacokinetics
Buprenorphine is a thebaine derivative with powerful analgesia approximately twenty-five to forty times as potent as morphine, 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 less likely to transduce a response in contrast to a 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. Overdose is unlikely in addicted patients or people with tolerance to opioids who use the drug sublingually as meant in the case of Subutex/Suboxone, especially if there is no alcohol involved. Concomitant use of alcohol with any opioid increases the risk of overdose. One French study showed a higher incidence of fatal overdose in patients who injected both buprenorphine and benzodiazepines, specifically, temazepam, together. Buprenorphine can be safely taken with prescribed benzodiazepines at normal dosage, as long as the patient is tolerant to either opioids or benzodiazepines, and the drugs are taken in the dosages prescribed and by the route of administration prescribed, and not injected. Use in persons physically dependent on full-agonist opioids while not already in withdrawal may trigger an extremely intense form of opioid withdrawal, - called "precipitated withdrawal" or "precipitated withdrawal syndrome" - that may be reversed by high doses of any other opioid, but will be increased in intensity if increased doses of buprenorphine are administered. This form of intense withdrawal may last anywhere from two to approximately thirty-six hours. This does not occur in all persons tolerant to full-agonist opioids, but rather depends on the severity of addiction and time elapsed from their last dose.
Buprenorphine has been shown to act as an epsilon-opioid antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor, Buprenorphine is also a κ-opioid receptor antagonist, and partial/full agonist at the recombinant human ORL1 nociceptin receptor. It should be noted that not much is known about the epsilon receptor.
Buprenorphine hydrochloride is administered by intramuscular injection, intravenous infusion, via a transdermal patch, as sublingual film or tablets or an ethanolic liquid oral solution. It is not administered orally, due to very high first-pass metabolism.
Buprenorphine is metabolised by the liver, via CYP3A4 (also CYP2C8 seems to be involved) isozymes of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation). The glucuronidation of buprenorphine is primarily carried out by UGT1A1 and UGT2B7, and that of norbuprenorphine by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into the bile. The elimination half-life of buprenorphine is 20–73 hours (mean 37). Due to the mainly hepatic elimination, there is no risk of accumulation in patients with renal impairment.
Buprenorphine's main active metabolite, norbuprenorphine, is a μ-opioid, δ-opioid, and nociceptin receptor full agonist, as well as a κ-opioid receptor partial agonist. Buprenorphine antagonizes its effects.
Plasma concentrations after application of transdermal buprenorphine increase steadily and the minimum effective therapeutic dose (100 pg/ml) is reached at eleven hours and twenty-one hours for a single 35 and 70 μg/h patch, respectively. Peak plasma concentration (Cmax) is reached in about sixty hours (305 and 624 pg/ml for the 35 and 70 μg/h strength patch, respectively), and is markedly longer than with 0.3 mg intravenous buprenorphine (0.41 hours). Transdermal buprenorphine has a half-life of approximately thirty hours, and a bioavailability of approximately 50%, which is comparable to sublingual buprenorphine.
Depending on the application form, buprenorphine is indicated for the treatment of moderate to severe chronic pain (pain that has outlived its use to prevent injury and after three months) or for peri-operative analgesia. For the treatment of chronic pain, the transdermal formulations (not currently available in the U.S.A and Canada as of October 2010, although the FDA recently approved the product Butrans, which is listed by its manufacturer as "available soon") are preferred, which can be used both for chronic cancer pain as well as chronic non-malignant pain, such as musculoskeletal and neuropathic pain. The intravenous formulation is mainly used in postoperative pain (for example, as patient controlled analgesia (PCA)) and the sublingual formulation is, for example, used as breakthrough medication for patients with basic transdermal treatment. Advantages of buprenorphine in the treatment of chronic pain are, from a clinical perspective, its relatively long half-life, the option of sublingual and transdermal application and the excellent safety profile (ceiling effect for respiratory depression, lack of immunosuppressive effect, low pharmacokinetic interaction potential, no accumulation in renal impairment). Although not enough western literature is available, use of inj. buprenorphine in 'spinal' anaesthesia is rising in countries like India. Up to 150 micrograms of the drug (0.5 ml) of the preservative free solution is added to the local anaesthetic bupivacaine, and a smoother analgesia is obtained with the benefit of the patient remaining pain-free until up to eight to ten hours of the spinal being given.
Buprenorphine (Subutex) itself binds more strongly to receptors in the brain than do other opioids, making it more difficult for opioids (or opiates) to react when buprenorphine is in the system.
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. See opioids for other (predominantly favorable) experiments with buprenorphine and other opioids for psychological relief. However, psychological distress, such as clinical depression, is currently not an approved indication for the use of any opioid, and legally it falls in to a "grey zone". Some doctors nevertheless are realising its potential as an antidepressant in cases where the patient cannot tolerate or is resistant to conventional thymoleptic antidepressants. Both mental and physical pain are regulated by the same chemical networks in the brain. Depression is commonly accompanied by co-morbid pain symptoms. Endogenous opiates, such as endorphins and enkephalins, mediate pain perception in the body. In the brain, they are significantly involved in regulating mood and behavior, and decreasing the perception of pain and depression. Even a partial agonist at the µ-opioid receptor (like buprenophine) releases serotonin and dopamine in the CNS, but to a lesser degree than full agonists do. This slight release of serotonin and dopamine may contribute to the anti-depressant properties of buprenorphine, especially those with a pre-existing mental disorder.
Like full agonist opiates, buprenorphine can cause drowsiness, vomiting and respiratory depression. Taking buprenorphine in conjunction with central nervous system (CNS) depressants in people who are not tolerant to either agent can cause fatal respiratory depression. Sedatives, hypnotics, and tranquilizers can be dangerous if ingested with buprenorphine by a person who is tolerant to neither opioids nor benzodiazepines. Co-intoxication with ethanol carries the greatest risk for lethal overdose, with the lowest doses of a reported fatality in a 48 kg teenage girl with 5 mg of diazepam and the equivalent of 8 ounces of beer (1 unit of alcohol), plus around 2 mg of buprenorphine. However, this female was tolerant to none of the three drugs she ingested that were the cause of the MDI. 2 mg of buprenorphine is equal to roughly 80 milligrammes of morphine. 80 milligrammes of morphine itself is considered an extreme dose for an opioid-naive patient with doses starting around 5 to 10 milligrammes.
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, perspiration, itchiness, dry mouth, miosis, orthostatic hypotension, male ejaculatory difficulty, decreased libido, and urinary retention. Constipation and CNS effects are seen less frequently than with morphine. Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets.
The most severe and serious adverse reaction associated with opioid use in general is respiratory depression, the mechanism behind fatal overdose. Buprenorphine behaves differently than other opioids in this respect, as it shows a ceiling effect for respiratory depression. Moreover, former doubts on the antagonisation of the respiratory effects by naloxone have been disproved: Buprenorphine effects can be antagonised with a continuous infusion of naloxone. Concurrent use of buprenorphine and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression. Benzodiazepines, in prescribed doses, are not contraindicated in individuals who are tolerant to either opioids or benzodiazepines.
People on medium- to long-term maintenance with Suboxone or Subutex do not have a risk of overdose from buprenorphine alone, no matter what dosage is taken or route of administration it is taken by, due to the "ceiling effect" on respiratory depression. Overdoses occurring in maintenance patients are cases of multiple-drug intoxication, usually buprenorphine taken with excessive amounts of ethanol and/or benzodiazepine drugs. It is safe for a patient to take a prescribed dose of benzodiazepines with buprenorphine as long as the patient has a tolerance to either opioids or benzodiazepines. As a matter of course, all patients on buprenorphine maintenance are tolerant to opioids, and maintenance doses are always higher than the dose at which the "ceiling effect" on respiratory depression is reached (~3±1 milligrammes, depending on method of analysis).
People switching from other opiates should wait until mild to moderate withdrawal symptoms are encountered. Failure to do so can lead to the rapid onset of intense withdrawal symptoms, known as precipitated withdrawal. For short acting opioids such as codeine, hydrocodone, oxycodone, hydromorphone, pethidine, heroin, and morphine, 12–24 hours from the last dose is generally sufficient. For longer acting opioids such as methadone, 2–3 days from the last dose is needed to prevent precipitated withdrawal.
Conversely, switching from buprenorphine to other opioids is generally safe and can occur immediately. For users of Suboxone, it is advised to wait a few hours from the last dose before switching to other opioids to allow the naloxone in Suboxone to be eliminated from the body (it has a short half-life). Generally the new opioid will not be as strong or effective for several days until the remaining buprenorphine has been eliminated from the body. This is due to the blockade effect, where the buprenorphine is strongly bound to the opiate receptors in the brain and not allowing the new (full agonist) opioid to completely bind to and activate the receptors.
The "blockade effect" of buprenorphine further explains the phenomenon where Suboxone users trying to get high off of say oxycodone cannot until many (3 or more) days have passed since their last Suboxone dose. This discourages the patient using Suboxone properly for maintenance therapy from using other opioids recreationally to get high because either a) the "high" experienced by a typical recreational dosage of an opioid (say 30–75 mg of oxycodone) is subjectively poor i.e. not euphoric and/or b) the amount of money needed to get "high" off of other opioids becomes so large that the patient may feel that recreational usage of other opioids is simply not worth it and that the calming and soothing feeling of using Suboxone properly under the care of an approved physician is simply a better way to live life.
Detection in biological fluids
Buprenorphine and norbuprenorphine, its major active metabolite, may be quantitated in blood or urine to monitor use or abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. There is a significant overlap of drug concentrations in body fluids within the possible spectrum of physiological reactions ranging from asymptomatic to comatose, and therefore it is important to have knowledge of the route of administration of the drug and the individual's tolerance to opioids when interpreting analytical results.
Buprenorphine is also used recreationally, typically by opioid users, often by insufflation. Recreational users of Suboxone who crush the tablet and insufflate it report a euphoric rush similar to other opioids in addition to a slight "upper"-like effect. Those already using buprenorphine/Suboxone for opioid addiction therapy find that insufflation is only slightly, if any stronger than taking the pill sublingually, although it may have a quicker onset. Those taking it for addiction therapy also report that obtaining euphoria is virtually impossible after the first few doses. Many recreational users also report withdrawal symptoms. Due to the high potency of tablet forms of buprenorphine, only a small amount of the drug need be ingested to achieve the desired effects.
Although some people do use buprenorphine for purely recreational reasons, the majority of its illicit users use it for addiction therapy. Many people report it being effective in preventing withdrawals in-between doses of their opiate of choice. Illicit users who do not want it on record may also obtain it on the street to use as a less-painful method of quitting than "cold-turkey". Some report needing as little as one 8 mg tab which is broken up into gradually smaller doses which they take in order to effectively wean themselves off the opiate/opioid they're addicted to. The illegal and potentially dangerous self-dosing of Buprenorphine is deemed by many street users as a less risky alternative to what an addict may do on the streets to obtain money for their addiction (an 8 mg tablet of either Suboxone or Subutex sells for as low as $5 in some areas, and as high as $20–25 a piece in Chicago, Illinois, with pharmacies charging generally around $14 for a single tablet and $6–8 per tablet in 30+ quantities under self-pay), and less dangerous than quitting cold turkey. Furthermore, most U.S. doctors authorized to prescribe Suboxone charge ~$300 for a first visit, plus several hundred more for follow-up visits, which makes going through official channels more expensive than simply maintaining the original opiate addiction, for some users.
Buprenorphine abuse is very common in Scandinavia, especially in Finland by Viimeinen Hidas and Sweden. In 2007, the authorities in Uppsala county in Sweden confiscated more buprenorphine than cocaine, ecstasy and GHB. In Finland recreational use of buprenorphine is on the rise; in 2005, Finland's incidence of Subutex abuse (most often injected intravenously) surpassed the incidence of recreational usage of amphetamines. Intravenous administration of dissolved Subutex pills and insufflation of pulverized pills are the most common modes of recreational buprenorphine use.
Commonly Used Slang Terminology
There are a number of slang terms used by recreational users to describe Buprenorphine. In the US, it is referred to as (Simply) 'Suboxone', 'Sobos', 'Bupe', 'Stops','Stop signs', 'Box', 'Oranges','Sub' and 'Subs'. 'White Bupe', 'Tecs' and 'Whites' for Subutex. In the United Kingdom, it is referred to as 'Bupey', 'Praedo', 'Wild Uno', 'Map Punch', 'Book Head' 'Subway' or just Subbies.
|This section needs additional citations for verification.|
Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (December 2010)
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 which overturned a series of 1914–1920 Supreme Court rulings that had found that maintenance and detox treatments were not a form of medical treatment. Although the rulings had the power of legal precedent prior to 2000, it is likely that they were not the intended interpretation of the laws passed originally by congress.
The Drug Addiction Treatment Act allowed medical professionals to prescribe and administer opioids to manage addiction ("maintenance") as well as for short-term (defined as <6 months) and long-term detoxification. Such use of opioids had been allowed only in specially registered drug treatment centers providing Opiate replacement therapy.
These restrictions were removed only for Schedule III through V drugs. As such they do not include methadone and stronger opioids, but do allow for the medical use of buprenorphine (formerly Schedule V, the least restrictive category; now Schedule III). Hypothetically, there is nothing in the Drug Addiction Treatment Act to prevent physicians from prescribing Schedule III opioids and other medications (including but not limited to: Codeine, hydrocodone, dihydrocodeinone), Schedule IV benzodiazepines (eg. Valium, Xanax), and Schedule V (certain codeine-containing cough preparations) to treat addiction, specifically the time-limited "opiate abstinence syndrome" -- also called "opiate withdrawal."
The first buprenorphine treatment program for opiate addiction in the United States was founded by Dr. David McDowell at Columbia University and reported an 88% success rate with its patients.
Nearly half a century after Doctors Dole and Nyswander pioneered methadone replacement treatment for opioid dependence, the medical treatment of narcotic addiction remains the most strictly regulated area of medicine. During this time Methadone has become one of the most scientifically researched drugs in situ. To call it controversial - since the discovery of stereo-specific opiate receptor sites in the brain, spinal cord, and G-I tract which modulate perception of pain, temperature, via endorphins ("endogenous morphine") & enkephalins has conclusively proven the metabolic nature of opioid addiction - is to ignore science.
The track record of Opiate replacement therapy, while not perfect, has permitted 100,000s of Americans (and millions more in all Western European countries and democratic nations world wide) to achieve a reduction in the number & severity of relapses to illicit opiate use & associated costs to society in terms of criminal activity (burglary, theft, robbery, muggings) necessary to obtain money for drugs which ultimately wind up financing the vast, globally connected drug cartels. Additionally, Opioid Replacement Therapy reduces the risk of contracting Hepatitis C and HIV among other communicable diseases. This, along with lowered rates of recidivism & incarceration for drug-Prohibition related crimes as formerly active addicts reorient their lives from the daily quest to stave off Heroin withdrawal and reintegrate into society as law-abiding citizens, has not changed the fact that the appearance of methadone clinics across the U.S.A. has changed little since their inception during the closing years of the Vietnam War, in the early 1970s. Opiate replacement therapy remains strictly regulated despite its proven success in harm reduction for both patients fortunate enough to live in a state where it is allowed by law and the larger populations of such states.
In the United States a special federal waiver (which can be granted after the completion of an eight-hour course) is required in order to treat outpatients for opioid addiction with Subutex and Suboxone, the two forms of buprenorphine tablets currently available. However the number of patients each approved doctor could initially treat was capped at 10. In no other area are physicians prevented from providing care to patients in need - except for addiction treatment. The history of The War on Drugs adverse effect on doctors began shortly after the passage of the Harrison Narcotics Tax Act in 1918. Since that time, doctors attempting to treat opiate addiction have faced disciplinary actions ranging from warnings & fines through suspension or permanent loss of their DEA License number (required by the Controlled Substances Act for a doctor to prescribe drugs "with abuse potential"); loss of their medical license to practice, and jail time. The stigma of opiate addiction has always tainted those physicians seeking to treat addiction, reflected in the low status of Addiction Medicine among medical students choosing a specialty.
Due to the response of patients seeking a treatment alternative to methadone clinics, the law was modified to allow properly trained and licensed doctors to treat up to a hundred patients with buprenorphine for opioid addiction in an outpatient setting, alleviating the bottleneck that was created with the 10 patient limit.(see next paragraph) Other obstacles to treatment still remain however.
On December 12, 2006 the U.S. Congress passed additional legislation which relaxed the patient restriction for doctors who specialize in treating addiction through group therapy. It allows physicians with at least one year of clinical experience with Buprenorphine to request an additional exemption within DATA 2000, which increases the limit to a hundred outpatients, effective as of 12/29/2006 (public law 109-469).
Similar restrictions are placed on prescribers in many other jurisdictions/nations. For example, Buprenorphine liquid is regulated in the same way as methadone in Australia, and while the number of patients per doctor isn't capped, the patient is required to visit a pharmacy daily in order to receive a supervised dose of their medication. Buprenorphine transdermal patches are regulated as a controlled substance, with GPs requiring approval for all prescriptions, and a limited number of repeats available.
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'. The withdrawal from buprenorphine after short-term use is generally far milder than other potent opioids, but can have a longer duration than short-acting opioids of abuse.
Buprenorphine versus methadone
|This section needs additional citations for verification.|
Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (March 2009)
Buprenorphine and methadone are medications used for detoxification, short- and long-term maintenance treatment. Each agent has its relative advantages and disadvantages.
In terms of efficacy (i.e. treatment retention, mostly 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 per day (low dose) and equatable anywhere between 50–70 mg (moderate dose), to up to 100 mg (high dose) of methadone a day. 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. It is also worth noting that while methadone's effectiveness is generally thought to increase with dose, buprenorphine has a ceiling effect at 32 mg That is, while a methadone dose of 80 mg will likely be more effective than a methadone dose of 60 mg, (see Methadone dosage) a buprenorphine dose of 40 mg will not be more effective than a buprenorphine dose of 32 mg.
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 (some patients receive twice daily dosing) required to prevent withdrawals with methadone. Once one has been taking a maintenance dose of methadone for some time, withdrawal effects do not begin in earnest until 48–72 hours and in some cases 96 hours or more after the last dose taking. 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, such as psychotherapy or support groups.
Buprenorphine may be more convenient for some users because patients can be given a thirty day take home dose relatively soon after starting treatment, hence making treatment more convenient relative to those who need to visit a methadone dispensing facility daily. The facilities, which are regulated at the state and federal level in the US, initially are only permitted to allow patients to receive take home doses (to be self-administered at the appropriate time) on a day when the clinic is regularly closed or on a pre-scheduled holiday. It is only after a minimum of several months of compliance (i.e., proven sobriety, demonstration of being able to safely store the medication) that patients of methadone clinics in most countries are permitted regularly scheduled take home doses aside from the possible exceptions for weekends and holidays. Ultimately, American patients on methadone maintenance therapy are permitted a maximum of a one month supply of take home medication, and this is only permitted after a minimum of two years compliance. In the US state of Florida, patients cannot receive a month supply until five years of compliance. Most buprenorphine patients are not prescribed more than one month's worth of buprenorphine at a time. However, buprenorphine patients, as a rule, are able to get their one month supply much earlier in their use of the drug than methadone patients.
Buprenorphine as a maintenance treatment thereby offers an advantage of convenience over methadone. Buprenorphine patients are also generally not required to make daily office visits and are often very quickly permitted to obtain a one month prescription for the medication. Methadone patients in the United States who are not subject to additional strictures beyond the federal law regarding a patient's take-home supply also benefit in convenience. States with excessive regulation on methadone dispensation see professionals advocating for office-based methadone treatment, similar to the standard of office-based buprenorphine treatment. Such treatment with full opiate agonists is already available on a limited basis in the UK, and has been ever since heroin was made illegal, with an interruption of a few decades which occurred, likely under pressure from the United States, during the worldwide escalation of the War on Drugs which occurred during the 1960s and 1970s. In fact, in the UK a doctor may prescribe any opiate to a person, regardless of their complaint (excluding diamorphine and dipipanone for addiction, where they require a special licence from the Home Office). In practice, methadone is most often used, although morphine and heroin are also less frequently prescribed on a maintenance basis. The UK has a smaller number of opiate users, per capita, than the United States, which many attribute to the availability of full opiate agonist prescriptions to users, which reduces the amount of opiates sold illicitly and, in turn, the number of users of other drugs who encounter and begin using the opiates. Therefore, it could be argued that buprenorphine may not be as attractive a treatment option in the UK due to full opiate agonists such as heroin maintenance being an option for a small amount of addicts seeking treatment. (see Heroin prescription)
Buprenorphine may and is generally viewed to have a lower dependence-liability than methadone. In other words, withdrawal from buprenorphine is less difficult. Like methadone treatment, buprenorphine treatment can last anywhere from several days (for detoxification purposes) to an indefinite period of time (life-long maintenance) if patient and doctor both feel that is the best course of action. Additionally, the opinion of those in the medication assisted treatment field is generally shifting to longer-term treatment periods, which may last indefinitely, due to the anti-depressant effects opioids seem to have on some patients, as well as the high relapse potential among those patients discontinuing maintenance therapy. The choice of buprenorphine versus 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 early versus the possibility of heavy restrictions in some states and frequent visits to the clinic and the possibility of the "stigma" of going to a methadone clinic as compared to making trips to a doctor's office. Buprenorphine is also significantly more expensive than methadone and this seems to add to its better reputation. Also, in some states, there is a long waiting list for admission to a methadone maintenance program versus those with the money to afford seeing an addiction specialist each month in addition to the cost of medication. In studies done methadone is considered more addicting physically and mentally. The sometimes less-severe withdrawal effects may make it easier for some patients to discontinue use as compared with methadone, which is generally thought to be associated with a more severe and prolonged withdrawal. However, no evidence thus far exists that sustaining abstinence post-buprenorphine maintenance is any more likely than post-methadone maintenance.
Another issue of concern for patients considering beginning any maintenance therapy or switching from one maintenance therapy to another is the transition associated with this switch. Due to buprenorphine's high-affinity to opioid receptors in the brain, care needs to be taken when a patient is transitioning from one drug (e.g., heroin) or medication (e.g., methadone) to buprenorphine. Essentially, if an opioid-dependent patient is not in sufficient withdrawal, introduction of buprenorphine may precipitate withdrawal. In layman's terms, in a sufficient dose, buprenorphine "pushes" any other opioids off of the receptors, but is itself not always "strong enough" to counteract the withdrawal symptoms this causes. Thus, opioid-dependent patients, particularly those on methadone or another long-acting medication or drug should be thoroughly honest with their prescribing doctor about their drug use, particularly in the days immediately preceding their induction onto buprenorphine, whether for detoxification or maintenance. In contrast, the transition from buprenorphine or other opioids to methadone is generally easier, and any discomfort or side effects are more likely to be easily remedied with dose adjustments.
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 Schedule III status versus methadone's more restrictive Schedule II status in the USA), as well as that buprenorphine is generally accepted as having less potential for abuse than methadone. It is also worth noting that neither methadone nor buprenorphine are to cause euphoria when taken long-term at the appropriate dose. However, in at least one study in which opiate users who were currently not using were given buprenorphine, several other opioids, and placebo intramuscularly, subjects identified the drug they were injected with as heroin when it was actually buprenorphine. This evidence tends to support the contentions of those who reject the notion that buprenorphine, when injected, is only marginally euphoric, or significantly less euphoric than other opiates.
It should be noted that, in an effort to prevent injection of the drug, the Suboxone formulation includes naloxone in addition to the buprenorphine. When naloxone is injected, it is supposed to precipitate opiate withdrawal and blocks the effects of any opiate. The naloxone does not precipitate withdrawal or block the effect of the buprenorphine when taken sublingually. The Subutex formulation does not include naloxone, and therefore has a higher potential for injection abuse. However, Subutex is prescribed significantly less than Suboxone for just this reason. Methadone, on the other hand, is typically given to patients at clinics in a liquid solution, to which water is generally added. This makes injection difficult without evaporating the liquid and taking other measures. Therefore, injection of buprenorphine as found in the preparations provided to opiate users is simpler than injection of methadone, although data on the relative incidence is not currently available. Although methadone is generally not a drug of choice for opioid addicts due to its long-acting nature and relatively little euphoria associated with its use, especially when compared to other drugs of abuse such as heroin and Oxycodone, it is used by addicts to relieve withdrawal symptoms when their opiate of choice cannot be obtained. Most methadone bought from the black market is thought to be bought by already opioid-dependent persons attempting to circumvent the substance abuse treatment system and detoxify themselves with the methadone or simply by people who wish to use the drug recreationally, just as other opiates are used. In the US, buprenorphine is found far less often on the black market as compared to methadone. The vast majority of the methadone diverted to the black market is not diverted from methadone clinics for opioid dependent persons, but rather it is diverted by a minority of the people who receive prescription methadone for pain.
|This section needs additional citations for verification.|
Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (March 2009)
The Suboxone preparation contains the μ-opioid receptor antagonist naloxone. Buprenorphine itself is a mixed agonist/antagonist, and, as such, buprenorphine blocks the activity of other opiates and induces withdrawal in opiate dependent individuals who are currently physically dependent on another opiate. This is why users must wait until they are in withdrawal before beginning treatment with buprenorphine.
Buprenorphine itself binds more strongly to receptors in the brain than do other opioids, making it more difficult, regardless of the presence of the naloxone, to become intoxicated via other opioids when buprenorphine is in the system. If enough buprenorphine is in the system, however, it has the same type of effect as naloxone, i.e. it completely or nearly completely blocks or reverses opiate effects from other opioids. 0.3 mg of buprenorphine parenterally is equivalent in antagonistic effect to between 0.4 and 2.0 mg of naloxone parenterally, but with a much longer half-life. Methadone also blocks the effects of other opioids at higher doses, however under ~40 mg, the block in effects is barely present. At commonly used methadone maintenance doses, the degree of blockade is similar to that produced by equivalent buprenorphine doses. Unlike buprenorphine, however, this is not due to opiate antagonist-like action. Instead, daily use of methadone, like daily use of any of the opiate agonists, results in tolerance to all opiates, called "cross-tolerance". However, it is still possible to use other opioids on either treatment regime, although many people find "getting high" to be difficult or unattainable.
Switching to buprenorphine from methadone is often difficult and withdrawals lasting several days or more are often encountered mostly when the methadone dose is any higher than 30 mg/day (the suggested and usual dose for switching to buprenorphine). A 30 mg dose of methadone is relatively low, and some patients have difficulty reaching that dose, for a variety of reasons, usually the emergence of withdrawal symptoms. Healthy users of methadone who commit to a slow taper, however, frequently find success in tapering to 30 mg in order to switch to buprenorphine, as well as in tapering off of methadone completely without the use of buprenorphine. Switching to buprenorphine at higher doses of methadone may be uncomfortable for the user. One reason is that users must be in withdrawal before switching to buprenorphine, and users of opiates with long half-lives, like methadone, may need to wait several days after their last dose of methadone before they are fully in withdrawal and ready to begin buprenorphine. Users of heroin, hydrocodone, oxycodone, and morphine, as well as most other common opiates, only need to wait a maximum of twenty-four hours before they are fully in withdrawal and ready to begin buprenorphine. For this reason, some doctors switch methadone users to a shorter acting opiate, such as morphine, for a few days before allowing withdrawal to occur and beginning buprenorphine. Unfortunately, due to the unique qualities of both methadone and buprenorphine, switching to and using buprenorphine during pregnancy instead of methadone is unlikely to be helpful, since the strain of withdrawal on the body is far more dangerous for a fetus than the use of an opiate such as methadone—about which the data suggests that after the first few weeks of life, no developmental differences are found between children born to mothers who were stable on an opiate during pregnancy versus those who were not taking any opiates during pregnancy. This stands in stark contrast to the results of using the otherwise socially acceptable drug alcohol during pregnancy. Also, data regarding buprenorphine's safety during pregnancy is less available than data on methadone during pregnancy—data which has established the safety of methadone during pregnancy and the lack of lasting effects on children of mothers on methadone during pregnancy. On the other hand, switching from buprenorphine to methadone is relatively easy as methadone is a full opiate agonist which does not have a ceiling, and can stop the withdrawal symptoms of users at any dosage of other opiates, including buprenorphine.
|This section needs additional citations for verification.|
Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (March 2009)
The practice of using buprenorphine (Subutex or Suboxone) in an inpatient rehabilitation setting is increasing rapidly, though 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 (Dilaudid) and hydrocodone (Vicodin), or oxycodone (Oxycontin, Percocet) is not too difficult for most people and, as long as the patient waits until they are 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 – and sometimes longer lasting – withdrawals than had they waited until full withdrawal symptoms were present.
The treatment phase begins once the patient is stabilized and receives medical clearance. This portion of treatment comprises multiple therapy sessions, which include both group and individual counseling with various chemical dependency counselors, psychologists, psychiatrists, social workers, and other professionals. Additionally, many treatment centers utilize 12-step facilitation techniques, embracing the 12-step programs practiced by such organizations as Alcoholics Anonymous and Narcotics Anonymous. Some on maintenance therapies have veered away from such organizations as Narcotics Anonymous, instead opting to create their own 12-step fellowships (such as Methadone Anonymous) or depart entirely from the 12-step model of recovery (using a program such as SMART Recovery).
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. Alternatively they can enter treatment facilities that provide the option to complete both detox and longer-term treatment. Completing both increases the probability of success. Abstinence alone has a very low efficacy in rehabilitating patients. In contrast, buprenorphine maintenance has a high efficacy. Most rehabilitation programs, including Narcotics Anonymous, do not have or allow scientific studies to be conducted to compare abstinence alone with buprenorphine or methadone maintenance. NA's twelve traditions and overriding principle of anonymity would make such research potentially contentious and internally problematic. While the maintenance / abstinence debate is a hot topic, and strong arguments have been made in support of both Narcotics Anonymous and buprenorphine maintenance, individuals tend to gravitate to the alternative that works best for them. Furthermore, the two approaches need not necessarily be mutually exclusive.
Rehabilitation programs typically average about thirty days for primary care, but some may extend anywhere from ninety days to six 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 addiction survivors and engage in mutual-help groups, aftercare and other related activities after treatment in order to improve their chances of achieving long-term abstinence from opioids. Statistically, long-term abstinence is not widely prevalent.
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 seven to ten days, provided 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 forty-eight to seventy-two hours, but medical professionals in many treatment facilities prescribe one or more doses every twenty-four 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 thirty-six to forty-eight 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, because of risk of naloxone related side-effects, Subutex is urged over Suboxone by the manufacturer.
Indications under investigation
Buprenorphine has been used in the treatment of the neonatal abstinence syndrome, a condition in which newborns exposed to opioids during pregnancy demonstrate signs of withdrawal. Use currently is limited to infants enrolled in a clinical trial conducted under an FDA approved investigational new drug (IND) application.
Use in animals
In the United States, use of buprenorphine for pain management in animals has become increasingly common. Although only registered for human use by the Food and Drug Administration, it is legal for veterinarians to prescribe it for off label use in animals they treat.
In the United Kingdom, buprenorphine is licensed for analgesia and sedation in dogs. A solution for injection is made available for the British veterinary market by Alstoe Animal Health under the trade name Vetergesic.
- List of psychotropic Substances under international control
- Mendelson J, Jones RT, Fernandez I, Welm S, Melby AK, Baggott MJ. Buprenorphine and naloxone interactions in opiate-dependent volunteers. Clin Pharmacol Ther. 1996 Jul;60(1):105-14.
- Fudala PJ, Yu E, Macfadden W, Boardman C, Chiang CN. Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts. Drug Alcohol Depend. 1998 Mar 1;50(1):1-8.
- Stoller KB, Bigelow GE, Walsh SL, Strain EC. Abstract Effects of buprenorphine/naloxone in opioid-dependent humans. Psychopharmacology (Berl). 2001 Mar;154(3):230-42.
- Strain EC, Preston KL, Liebson IA, Bigelow GE. Abstract Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers. J Pharmacol Exp Ther. 1992 Jun;261(3):985-93.
- Harris DS, Jones RT, Welm S, Upton RA, Lin E, Mendelson J. Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine. Drug Alcohol Depend. 2000 Dec 22;61(1):85-94.
- Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl). 2000 Mar;148(4):374-83.
- Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) 40. Laura McNicholas. US Department of Health and Human Services.
- Transtec Summary of Product Characteristics
- Napp Pharmaceuticals
- Reckitt Benckiser Buprenorphine Bibliography
- Fujii H, Narita M, Mizoguchi H, Murachi M, Tanaka T, Kawai K, Tseng LF, Nagase H (August 2004). "Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid receptor". Bioorg. Med. Chem. 12 (15): 4133–45. doi:10.1016/j.bmc.2004.05.024. PMID 15246090.
- Fujii H, Nagase H (2006). "Rational drug design of selective epsilon opioid receptor agonist TAN-821 and antagonist TAN-1014". Curr. Med. Chem. 13 (10): 1109–18. doi:10.2174/092986706776360851. PMID 16719773.
- Huang P. et al., Kehner GB, Cowan A, Liu-Chen LY (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.
- Yassen A, Kan J, Olofsen E, Suidgeest E, Dahan A, Danhof M (May 2007). "Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of norbuprenorphine in rats". The Journal of Pharmacology and Experimental Therapeutics 321 (2): 598–607. doi:10.1124/jpet.106.115972. PMID 17283225. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17283225.
- Huang P, Kehner GB, Cowan A, Liu-Chen LY (May 2001). "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist". The Journal of Pharmacology and Experimental Therapeutics 297 (2): 688–95. PMID 11303059. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11303059.
- Bodkin JA. et al., Zornberg GL, Lukas SE, Cole JO (1995). "Buprenorphine treatment of refractory depression". Journal of Clinical Psychopharmacology 15 (1): 49–57. doi:10.1097/00004714-199502000-00008. PMID 7714228.
- Drug War Ensnares Doctors, Not Dealers - Oct 2, 2003
- The War on Drugs Is a War on Doctors by Rep. Ron Paul
- Suboxone FAQ
- Budd K, Raffa RB. (edts.) Buprenorphine - The unique opioid analgesic. Thieme 2005 (ISBN 3-13-134211-0)
- Van Dorp E. et al. (2006) Naloxone reversal of buprenorphine- induced respiratory depression. Anesthesiology 105 (1): 51-57
- "naabt web sell sheets" (PDF). http://www.naabt.org/documents/naabt_precipwd.pdf. Retrieved 2010-08-30.
- R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 190-192.
- "Subutex Abuse on the Rise (Swedish)", Upsala Nya Tidning, 2007-05-06. Retrieved on 2008-08-27.
- Hermansson, Gunnar "Subutex Instead of Heroin (Swedish)". Retrieved on 2008-08-27.
- Buprenorphine: New Medication to Treat Substance Abuse, Matthew Dougherty.
- New Ways to Loosen Addiction's Grip, Anahahd O'Connor, The New York Times, August 3, 2004
- R. S. Schottenfeld et al. (1997) Department of Psychiatry, Yale University School of Medicine
- Rolley Johnson et al., NEJM, 343(18):1290–1297, 2000
- Strain et al. (1998)
- Ling et al. (1998).
- Suboxone.com - Frequently Asked Questions
- Buprenorphine and reward
- AJ Giannini. Drugs of Abuse--Second Edition. Los Angeles, Practice Management Information Corporation, 1997.
- Glickman L, Galanter M, Dermatis H, Dingle S (December 2006). "Recovery and spiritual transformation among peer leaders of a modified methadone anonymous group". J Psychoactive Drugs 38 (4): 531–3. PMID 17373569.
Gilman SM, Galanter M, Dermatis H (December 2001). "Methadone Anonymous: A 12-Step Program for Methadone Maintained Heroin Addicts". Subst Abus 22 (4): 247–256. doi:10.1080/08897070109511466. PMID 12466684.
McGonagle D (October 1994). "Methadone anonymous: a 12-step program. Reducing the stigma of methadone use". J Psychosoc Nurs Ment Health Serv 32 (10): 5–12. PMID 7844771.
- Horvath A. Thomas (2000). Journal of Rational-Emotive and Cognitive-Behavior Therapy 18 (3): 181–191. doi:10.1023/A:1007831005098. ISSN 08949085.
- Kraft WK, Gibson E, Dysart K, Damle VS, Larusso JL, Greenspan JS, Moody DE, Kaltenbach K et al. (September 2008). "Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial.". Pediatrics 122 (3): e601–7. doi:10.1542/peds.2008-0571. PMC 2574639. PMID 18694901. http://pediatrics.aappublications.org/cgi/content/full/122/3/e601.
- Clinicaltrials.gov NCT00521248
cs:Buprenorfin da:Buprenorfin de:Buprenorphin es:Buprenorfina fr:Buprénorphine it:Buprenorfina hu:Buprenorfin nl:Buprenorfine ja:ブプレノルフィン no:Buprenorfin pl:Buprenorfina pt:Buprenorfina ro:Buprenorfină ru:Бупренорфин fi:Buprenorfiini sv:Buprenorfin th:บิวพรีนอร์ฟีน