Buprenorphine

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Buprenorphine
Systematic (IUPAC) name
(2S)-2-[(5R,6R,7R,14S)-9α-Cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol
Clinical data
Trade namesBuprenex, Subutex, Suboxone, Butrans
AHFS/Drugs.commonograph
MedlinePlusa605002
Pregnancy cat.C (USA)
Legal statusControlled (S8) (AU) Class C (UK) Schedule III (USA)
Routessublingual, IM, IV, transdermal, intranasal, rectally

on

Pharmacokinetic data
Bioavailability55%(sublingual)[1]/48.2% +/- 8.35%(intranasal)[2]
Protein binding96%
Metabolismhepatic
CYP3A4, CYP2C8
Half-life20–70, mean 37 hours
Excretionbiliary and renal
Identifiers
CAS number52485-79-7 YesY
ATC codeN02AE01 N07BC01
PubChemCID 644073
IUPHAR ligand1670
DrugBankDB00921
ChemSpider559124 YesY
UNII40D3SCR4GZ YesY
KEGGD07132 YesY
ChEBICHEBI:3216 YesY
ChEMBLCHEMBL1201894 N
Chemical data
FormulaC29H41NO4 
Mol. mass467.64 g/mol
 N (what is this?)  (verify)
 
  (Redirected from Subutex)
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Buprenorphine
Systematic (IUPAC) name
(2S)-2-[(5R,6R,7R,14S)-9α-Cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol
Clinical data
Trade namesBuprenex, Subutex, Suboxone, Butrans
AHFS/Drugs.commonograph
MedlinePlusa605002
Pregnancy cat.C (USA)
Legal statusControlled (S8) (AU) Class C (UK) Schedule III (USA)
Routessublingual, IM, IV, transdermal, intranasal, rectally

on

Pharmacokinetic data
Bioavailability55%(sublingual)[1]/48.2% +/- 8.35%(intranasal)[2]
Protein binding96%
Metabolismhepatic
CYP3A4, CYP2C8
Half-life20–70, mean 37 hours
Excretionbiliary and renal
Identifiers
CAS number52485-79-7 YesY
ATC codeN02AE01 N07BC01
PubChemCID 644073
IUPHAR ligand1670
DrugBankDB00921
ChemSpider559124 YesY
UNII40D3SCR4GZ YesY
KEGGD07132 YesY
ChEBICHEBI:3216 YesY
ChEMBLCHEMBL1201894 N
Chemical data
FormulaC29H41NO4 
Mol. mass467.64 g/mol
 N (what is this?)  (verify)
Suboxone 8 mg tablet

Buprenorphine is a semi-synthetic opioid that is used to treat opioid addiction in higher dosages (>2 mg), to control moderate acute pain in non-opioid-tolerant individuals in lower dosages (~200 µg), and to control moderate chronic pain in dosages ranging from 20–70 µg/hour. It is available in a variety of formulations: Subutex, Suboxone, Zubsolv (buprenorphine HCl and naloxone HCl; typically used for opioid addiction), Temgesic (sublingual tablets for moderate to severe pain), Buprenex (solutions for injection often used for acute pain in primary-care settings), Norspan and Butrans (transdermal preparations used for chronic pain).

Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, generally available 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 also approved Suboxone and Subutex, buprenorphine's high-dose sublingual tablet 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 tablet preparations, were approved for opioid addiction treatment in September 2006.[3] 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 United States, it was rescheduled to Schedule III drug from Schedule V just before FDA approval of Suboxone and Subutex.[4] In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.

Commercial preparations[edit]

British firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations) and Buprenex (parenteral). Subsequently, two more formulations were released: Subutex (white, oval-shaped, bitter, no active additives) and Suboxone (white color [orange in the U.S.], hexagonal tablet, lemon-lime-flavored, one part naloxone for every four parts buprenorphine). The orange film strips form of Suboxone are lemon flavor. More than 71% of patients gave Suboxone film a favorable taste rating.[5]

8mg Suboxone film strip

Subutex and Suboxone are available in 2 mg and 8 mg sublingual dosages. (Suboxone Film is also available in doses of 4 mg/1 mg & 12 mg/3 mg buprenorphine/naloxone respectively). On October 8, 2009, Roxane Laboratories of Columbus, Ohio, United States won FDA approval for a generic preparation of Subutex[6] and as of October 23, 2009, announced that it is ready for distribution nationwide in 2 mg and 8 mg sublingual dosages. The demand for this generic was so high that Roxane did not produce enough to meet market demand, resulting in pharmacies running out and being unable to order more.[7] Teva Pharmaceutical Laboratories of Tel Aviv, Israel also received approval (as of April 1, 2010) for a generic formulation of Subutex sublingual tablets in 2 mg and 8 mg dosages that are currently available in limited distribution in America as of June 20, 2010. In 2013, Reckitt Benckiser voluntarily discontinued the sale of Suboxone tablets in the United States based on data from Poison control centers that consistently found significantly higher rates (7.8–8.5 times greater) of accidental pediatric exposure with Suboxone tablets as compared with Suboxone Film.[8]

Since 2001, buprenorphine is also available transdermally as 35, 52.5, and 70 µg/h transdermal patches that deliver the dose over 96 hours. This dosage form is marketed as Transtec in most European countries by Grunenthal (Napp Pharmaceuticals in the UK,[9][10] Norpharma in Denmark) for the treatment of moderate to severe cancer pain and severe non-cancer pain not responding to non-opioids.

Other available buprenorphine formulations include a 5, 10, and 20 µg/h, 7-day patch, marketed as Butrans in the U.S. by Purdue Pharma (and by Napp Pharmaceuticals in the UK) indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time.[11] A similar transdermal system is marketed by a collaboration between Mundipharma and Grunenthal in Australia under the name Norspan, with indications for moderate chronic pain not responding to non-opioids, dosed in 5, 10, or 20 µg/h patches.[12]

In India: Addnok 0.4, 2 & 8 Mg Sublingual Tablets by Rusan Pharma Ltd.,[13] Tidigesic 0.2 mg (slow release) or 0.3 mg/mL injectable by Sun Pharmaceuticals;[14] Buprigesic (0.3 mg/mL) by Neon Laboratories;[15] Morgesic (0.3 mg/mL) by Samarth Pharma; Norphin (0.3 mg/mL) Unichem Laboratories.

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. FDA requested additional information about Probuphine on April 30, 2013, in a complete response letter to Titan Pharmaceuticals pending NDA.[16]

In addition to the sublingual tablet, Suboxone is now marketed in the form of a sublingual film, available in the 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and recently 12 mg/3 mg dosages; the film is not available in Canada or the United Kingdom (where it was discovered). 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.[17] 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 ten-digit code is printed on each pouch, which helps facilitate medication counts and, therefore, serves to deter diversion into the illegal drug market. Although Suboxone film may deter snorting the drug it makes injecting the drug much easier as the films are extremely easy to dissolve in water making for easy injection and the fact that the naloxone in suboxone is ineffective at blocking the effects of buprenorphine when injected by addicts not dependent on another opioid.

Physicochemical properties[edit]

Buprenorphine is a semi-synthetic derivative of thebaine, one of the most chemically reactive opium alkaloids. Buprenorphine has a molecular weight of 467 and its structure is typically opioid with the inclusion of a C-7 side-chain containing a t-butyl group. This group confers overall lipophilicity on the molecule which has an important influence on its pharmacology.

Opioids exert their pharmacological effects by binding to opioid receptors. The pharmacological effects are determined by the nature of opioid-receptor interaction. Some of these effects such as analgesia, mediated by an agonistic action at the μ-opioid receptor are desirable, whereas others such as nausea, sedation, or constipation can be considered as unwanted adverse effects. Buprenorphine is a μ-opioid receptor agonist with high affinity, but low intrinsic activity. Compared with morphine (a full μ-opioid agonist) buprenorphine is considered a partial μ-opioid agonist displaying high affinity for and slow dissociation from the μ-opioid receptor. A full dose-dependent effect on analgesia has been seen within the clinically relevant dose range (up to 10 mg), but no respiratory depression which levels off at higher doses (Dahan et al. 2005). Clinically, there is also a less marked effect of buprenorphine-binding to μ-opioid receptors on gastrointestinal transit times, and indeed constipation seen in the clinic is remarkably low (Griessinger et al. 2005). Buprenorphine also shows partial agonistic activity at the opioid receptor-like receptor 1 (ORL1)-receptors which are (at least at supraspinal receptors) postulated to induce a pronociceptive effect. A study by Lutfy et al. (2003) reported that co-activation of ORL1-receptors compromises the antinociception induced by activation of the μ-opioid receptor. ORL1-activation has also an effect on hyperalgesia. It might be that buprenorphine’s partial agonism reduces this effect compared with full ORL1-agonists such as morphine or fentanyl. Buprenorphine’s antagonistic action at the δ-receptors which have a marked anti-opioid action and seem to negatively modulate central analgesia seems further to contribute to its clinically seen analgesic effect. Its likewise antagonistic activity at the κ-opioid receptors might explain the fact that it induces much less sedation and psychotomimetic effects than morphine or fentanyl (Lewis 1985; Leander 1988). Animal studies have shown that buprenorphine has a 20–40 times higher potency than morphine (Martin et al. 1976).

The strong binding of buprenorphine to the μ-opioid receptor has several consequences. Initial binding is relatively slow compared with other opioids such as fentanyl (Boas and Villiger 1985). However, the onset of analgesia is not dissimilar, since buprenorphine achieves effective analgesia at relatively low receptor occupancy (5%–10%) (Tyers 1980) and thus relatively low plasma concentrations of buprenorphine are sufficient to provide effective pain relief. The slow dissociation of buprenorphine from the receptor results in a long duration of effect and also confers another advantage in that when the drug is withdrawn an abstinence syndrome is rarely seen because of the long time taken for the drug to come off the receptor (Bickel et al. 1988).[18]

Metabolism[edit]

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.[19]

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.[20][21] Due to these actions it is likely that buprenorphine would antagonise its effects.

Clinical use[edit]

Indications[edit]

Pain[edit]

Depending on the application form, buprenorphine is indicated for the palliation of moderate to severe acute or chronic pain with no neuralgic component (or when the neuralgia is otherwise treated, such as with pregabalin), or for peri-operative analgesia. For the treatment of chronic pain, the transdermal formulations (which were released in the United States in January 2011, but were available in Australia and many European countries years beforehand) are preferred. The intravenous formulation is mainly used in postoperative pain (for example, as patient controlled analgesia [PCA]).

Sublingual buprenorphine (also sometimes taken buccally) for pain is available in the United Kingdom, as well as the Republic of India, in dosages of 200 and 400 µg. It is not available in the United States or in Canada, although Subutex or Suboxone (sublingual buprenorphine for addiction) is sometimes used off-label for this purpose, up to a dosage of 2 mg (the lowest-strength Subutex/Suboxone tablet). Sublingual formulations, such as Addnok, Temgesic, Subutex, and Suboxone, are used either as breakthrough medication for patients on transdermal treatment, or as monotherapy in cases where other treatments are not suitable. Niche pain indications for which sublingual/buccal buprenorphine may be a medication of choice include obstruction of the small bowel; continuous nasogastric suction; oesophageal fistula; malignancy in the head or neck; and other cases where the patient is unable to swallow or this is difficult. Additionally, this form of buprenorphine may be an interesting alternative to sustained-release opioids such as morphine (MS Contin) and oxycodone (Targin).[22]

Advantages of buprenorphine in general 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).[23] 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.

Furthermore, buprenorphine is somewhat sleep-inducing, and may be of particular help when pain leads to sleeplessness. Other prototypical opioid side-effects may prove beneficial in the management of chronic pain, such as its characteristic euphoria (to alleviate depression due to pain, or in cases where the patient cannot tolerate or is resistant to conventional thymoleptic antidepressants), as well as its anxiolytic effects. Buprenorphine is best used in opioid-naïve patients; its efficacy decreases dramatically with tolerance, and the high doses required in this situation, if combined with other opioids, may lead to opioid discontinuation syndrome.

Opioid dependence[edit]

History[edit]

Starting in 1958 a British company, Reckitt & Colman (now Reckitt Benckiser), known predominantly for their home cleaning products began a partnership with McFarlin Smith, a pharmaceutical company with the intent of producing over-the-counter analgesics. With the assistance of Kenneth Bentley, father of the Bentley compounds, seeking to form an opioid compound "with structures substantially more complex than morphine [that] could retain the desirable actions whilst shedding the undesirable side effects (addiction)" Reckitt chemists began to formulate different opioid compounds to make Bentley's idea possible.[24] In 1969 as Bentley retired, John Lewis had been promoted to lead chemist at Reckitt. After years of synthesizing different opioid compounds (such as etorphine) the team finally had a candidate that had showed success in reducing dependence in test animals, RX6029. RX6029 began trials on humans in 1971, with John Lewis and other researchers at Reckitt as the first subjects.[25] By 1978 buprenorphine was first launched in the UK as an injection to treat severe pain, with a sublingual formulation released in 1982.

Buprenorphine sublingual preparations are often used in the management of opioid dependence. The Suboxone and Subutex preparations were approved for this indication by the United States Food and Drug Administration in October 2002.[26] The same year, the Drug Enforcement Agency scheduled buprenorphine and buprenorphine-containing products under Schedule III of the Controlled Substances Act.[27]

The Drug Addiction Treatment Act of 2000 (DATA 2000) granted authority to the Secretary of Health and Human Services to grant a waiver to physicians with certain training to prescribe and administer Schedule III, IV, or V narcotic drugs for the treatment of addiction or detoxification. Prior to the passage of this law, such treatment was only available in traditional Opioid Treatment Program.[28]

The first buprenorphine treatment program for opiate addiction in the United States was founded by David McDowell at Columbia University[29] and reported an 88% success rate with its patients.[30]

Nearly half a century after 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.

The track record of opiate replacement therapy, while not perfect, has permitted hundreds of thousands of Americans (and millions more world wide) to achieve a reduction in the number and severity of relapses to illicit opiate use and 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 and incarceration for drug-Prohibition related crimes as formerly active addicts reorient their lives from the daily quest to stave off opiate withdrawal and reintegrate into society as law-abiding citizens, has not changed the fact that the appearance of methadone clinics across the United States has changed little since their inception in the early 1970s. Opiate replacement therapy remains strictly regulated despite its success in harm reduction for both patients and society.

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 ten. 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 and 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 ten-patient limit (see next paragraph). Other obstacles to treatment still remain however.[31]

On December 12, 2006, the U.S. Congress passed additional legislation that relaxed the patient restriction for doctors who specialize in treating addiction through group therapy.[citation needed] 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).[citation needed]

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.[citation needed]

The withdrawal from buprenorphine after short-term use generally is far milder than other potent opioids but can have a longer duration than short-acting opioids of abuse. Opioids with shorter half-lives tend to have shorter initial withdrawal periods, while those with longer half-lives add length to the total withdrawal period.[citation needed]

Buprenorphine versus methadone[edit]

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),[32] to up to 100 mg (high dose)[33] 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.[32][33][34][35] 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.[36] 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 has been proven to be effective in treating opioid addiction in primary care settings.[37][38][39] Currently, providers must complete a training program on opioid dependence and buprenorphine in order to be able to prescribe the drug.[40]

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. 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.[citation needed]

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 needing to visit a methadone dispensing facility daily.[citation needed] The facilities, which are regulated at the state and federal level in the United States, initially are permitted to allow patients to receive take-home doses (to be self-administered at the appropriate time) only 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 permitted only after a minimum of two years compliance. In Florida, patients cannot receive a one-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. In general, buprenorphine patients are also not required to make daily office visits and are often very quickly permitted to obtain a one-month prescription for the medication.[citation needed] 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[citation needed] 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 patient, 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[citation needed], 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 number of addicts seeking treatment. (See Heroin prescription.)

Buprenorphine may have, and is generally viewed to have, a lower dependence-liability than methadone. In other words, withdrawal from buprenorphine is less difficult[dubious ].[citation needed] Like methadone treatment, buprenorphine treatment can last anywhere from several days (for detoxification purposes) to an indefinite period of time (lifelong 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.[citation needed] 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.[neutrality is disputed] Buprenorphine is also significantly more expensive than methadone and this seems to add to its better reputation.[weasel words] 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.[citation needed] 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.[dubious ] However, no evidence thus far exists that sustaining abstinence post-buprenorphine maintenance is any more likely than post-methadone maintenance.[citation needed]

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. In essence, if an opioid-dependent patient is not in sufficient withdrawal, introduction of buprenorphine may precipitate withdrawal. In lay 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.[41] Thus, opioid-dependent patients, in particular those on methadone or another long-acting medication or drug, should be thoroughly honest with their prescribing doctor about their drug use, in particular in the days immediately preceding their induction onto buprenorphine, whether for detoxification or maintenance so not to risk immediate withdrawal. In contrast, in general the transition from buprenorphine or other opioids to methadone is 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.[citation needed] It is also worth noting that neither methadone nor buprenorphine causes euphoria when taken long-term at the appropriate dose. However, in at least one study in which opiate users who were currently not using an opioid were given buprenorphine, several other opioids, and placebo intramuscularly, subjects identified the drug they were injected with as heroin when it was actually buprenorphine.[42] 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.

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 in general water is 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, in general, methadone is 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 hold them over so they do not get sick or simply by people wishing to use the drug recreationally, just as other opiates are used. In the United States, buprenorphine is found far less often on the black market as compared to methadone.[citation needed] In North America (Canada) it is reversed, buprenorphine is found to be readily available on the black market, as methadone is usually not seen, buprenorphine is as easy to obtain as heroin.[citation needed] 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[citation needed]

Since the late 1990s in Austria, slow release oral morphine has been used alongside methadone and buprenorphine for opiate substitution therapy (OST) and more recently it has been approved in Slovenia and Bulgaria, and it has gained approval in other EU nations including the UK, although its use currently is not as widespread[citation needed]. The more attractive side-effect profile of morphine compared to buprenorphine or methadone has led to the adoption of morphine as an OST treatment option, and currently in Vienna over 60% of substitution therapy utilizes slow release oral morphine. Illicit diversion has been a problem, but, to the many proponents of the utilization of morphine for OST, the benefits far outweigh the costs, taking into account the much higher percentage of addicts who are "held" or, from another perspective, satisfied by this treatment option, as opposed to methadone and buprenorphine treated addicts, who are more likely to forgo their treatment and revert to using heroin etc., in many cases by selling their methadone or buprenorphine prescriptions to afford their opiate of choice. Driving impairment tests done in the Netherlands that have shown morphine to have the least negative effects on cognitive ability on a number of mental tasks also suggest morphine's use in OST may allow for better functioning and engagement in society.[citation needed]

Inpatient rehabilitation and detoxification[edit]

The practice of using buprenorphine (Subutex or Suboxone) in an inpatient rehabilitation setting is increasing rapidly,[citation needed] 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.

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. In addition, many treatment centers utilize twelve-step facilitation techniques, embracing the 12-step programs practiced by such organizations as Alcoholics Anonymous and Narcotics Anonymous. Some people on maintenance therapies have veered away from such organizations as Narcotics Anonymous, instead opting to create their own twelve-step fellowships (such as Methadone Anonymous) or depart entirely from the twelve-step model of recovery (using a program such as SMART Recovery).[43][44]

Patients entering rehabilitation voluntarily (as opposed to those court-ordered) can often choose a facility with the option of only staying for detox. As an alternative, 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, buprenorphine maintenance has a high efficacy.[32][33]

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. In terms of statistics, 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. 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 a detoxification, Suboxone or Subutex will be administered or the patient will be monitored taking the medication. In general, the patient takes a single dose each day (a single dose may keep the patient comfortable for up to 48 to 72 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 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 to 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, because of risk of naloxone related side effects, Subutex is urged over Suboxone by the manufacturer.

Suboxone and Naloxone[edit]

Suboxone contains buprenorphine as well as the opioid antagonist naloxone to deter the abuse of tablets by intravenous injection. Even though 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, these studies administered buprenorphine/naloxone to patients already addicted to less powerful opiates such as morphine.[45][46][47][48][49] These studies show the strength of buprenorphine/naloxone in displacing opiates, but do not show the effectiveness of naloxone displacing buprenorphine and causing withdrawal. 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.[50][51] The addition of naloxone and the reasons for it are conflicting. Published data clearly shows the Ki or binding affinity of buprenorphine is 0.2157 nM, while that for naloxone is 1.1518 nM.[52] Furthermore, the IC50 or the half maximal inhibitory concentration for buprenorphine to displace naloxone is 0.52 nM, while the IC50s of other opiates in displacing buprenorphine, is 100 to 1,000 times greater.[53] These studies help explain the ineffectiveness of naloxone in preventing suboxone abuse, as well as the potential dangers of overdosing on buprenorphine, as naloxone is not strong enough to reverse its effects.

Indications under investigation[edit]

Antidepressant potential[edit]

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 antidepressants and electroconvulsive therapy could be successfully treated with buprenorphine.[54][55][56][57][58][59][60] Clinical depression is currently not an approved indication for the use of any opioid, but some doctors are realizing its potential as an antidepressant in cases where the patient cannot tolerate or is resistant to conventional antidepressants.

Both mental and physical pain are regulated by the same chemical networks in the brain. Depression is commonly accompanied by comorbid 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 buprenorphine) releases serotonin and dopamine in the CNS, but to a lesser degree than full agonists do. This slight release of serotonin and dopamine may also contribute to the anti-depressant properties of buprenorphine, especially those with a pre-existing mental disorder.

Neonatal abstinence[edit]

Buprenorphine has been used in the treatment of the neonatal abstinence syndrome,[61] a condition in which newborns exposed to opioids during pregnancy demonstrate signs of withdrawal.[62] Use currently is limited to infants enrolled in a clinical trial conducted under an FDA approved investigational new drug (IND) application.[63] An ethanolic formulation used in neonates is stable at room temperature for at least 30 days.[64]

Off-label use[edit]

As an opioid, buprenorphine lends itself to some uses for which it has not been approved by the drug regulatory agency of the country in which it is used (such as the U.S. Food and Drug Administration). One such off-label use (perhaps the most common) is the use of Subutex or Suboxone, a formulation intended solely for the treatment of opioid abuse, in palliation of severe pain with no neuralgic component or when the neuralgia is otherwise treated, such as with pregabalin. Niche pain indications for which Subutex or Suboxone may be a medication of choice include obstruction of the small bowel; continuous nasogastric suction; oesophageal fistula; malignancy in the head or neck; and other cases where the patient is unable to swallow or this is difficult. Additionally, Subutex or Suboxone may be an interesting alternative to sustained-release opioids such as morphine (MS Contin) and oxycodone (Targin).[22]

Furthermore, buprenorphine is somewhat sleep-inducing, and may be of particular help when pain leads to sleeplessness. Other prototypical opioid side-effects may prove beneficial in the management of chronic pain, such as its characteristic euphoria (to alleviate depression due to pain, or in cases where the patient cannot tolerate or is resistant to conventional thymoleptic antidepressants), as well as its anxiolytic effects. These effects manifest themselves chiefly when buprenorphine is used in patients not tolerant to opioids; use of a partial agonist such as buprenorphine in those tolerant or dependent will simply lead to precipitated withdrawal (if a different opioid is used concomitantly) or relief of withdrawal (if used as monotherapy).

Precipitated withdrawal and blockade effect[edit]

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". This does not occur in all persons tolerant to full-agonist opioids, but rather depends on the severity of dependence and time elapsed from their last dose.

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. The blockade effect also has the result of blocking endogenous endorphins from binding to receptors, which can lead to psychological alterations in mood and mental capacity. This can cause cognitive and memory deficiencies via blockade of the reward system, which is pertinent to memory formation and normal mental function.[citation needed]

Contraindication[edit]

For opiate potency comparison see: Opioid comparison

Like full agonist opiates, buprenorphine can cause drowsiness, vomiting and respiratory depression. Taking buprenorphine in conjunction with central nervous system (CNS) depressants in people not tolerant to either agent can cause fatal respiratory depression. Sedatives, hypnotics, and tranquilizers can be dangerous if ingested with buprenorphine by a person 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 multiple drug intoxication fatality.[citation needed]

Adverse effects[edit]

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, memory loss, cognitive and neural inhibition, 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.[65] Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets.[citation needed]

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.[65] 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.[66] 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 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. 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).[citation needed]

People switching from other opiates should wait until mild to moderate withdrawal symptoms are encountered. Failure to do so can, in some cases, lead to the rapid onset of intense withdrawal symptoms, known as precipitated withdrawal. [67] 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.

Switching from buprenorphine to other opioids is generally safe but requires careful dosing in the first few days. Initially, high doses of the alternate opioid are required to overcome buprenorphine's high receptor affinity. Over the next few days, these doses are reduced as buprenorphine's receptor blockade wears off. This issue is of particular relevance when the drug is used for analgesia: adequate levels of analgesia may be difficult or impossible to obtain without high (and potentially dangerous) levels of the alternate opioid.

Precipitated withdrawal can occur when an antagonist (or partial antagonist, such as buprenorphine) is administered to a patient dependent on full agonist opioids. Due to Buprenorphine's high affinity but low intrinsic activity at the mu receptor, it displaces agonist opioids from the mu receptors, without activating the receptor to an equivalent degree, resulting in a net decrease in agonist effect, thus precipitating a withdrawal syndrome.

It is a common misconception that the Naloxone in Suboxone initiates precipitated withdrawal. This is false. The Naloxone can only initiate precipitated withdrawal if injected into a person tolerant to opioids other than buprenorphine. Taken sublingually the Naloxone has virtually no effect. Even in injection scenarios Buprenorphine has a higher binding affinity for opioid receptors than even Naloxone, resulting in a fairly limited effect of the antagonist in any scenario.

Blockade effect and opioid withdrawal[edit]

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. It is suggested that a person should wait until withdrawal symptoms begin before starting Suboxone.

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. This effect is present even at low dosages. A daily dose of 2 mg is enough to produce a blocking effect. If >32 mg buprenorphine is in the system, however, it becomes a full agonist; i.e., it not only completely or nearly completely blocks or reverses opiate effects from other opioids, but also itself, causing full withdrawal symptoms. 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 blocking effect is less pronounced. At commonly used methadone maintenance doses, the degree of blockade is similar to that produced by equivalent buprenorphine doses. The blockade effect also has the result of blocking endogenous endorphins from binding to receptors, which can lead to psychological alterations in mood and mental capacity. This can cause cognitive and memory deficiencies via blockade of the reward system, which is pertinent to memory formation and normal mental function. 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.[68] 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, need to wait a maximum of only 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.[citation needed] On the other hand, switching from buprenorphine to methadone is relatively easy as methadone is a full opiate agonist that does not have a ceiling, and can stop the withdrawal symptoms of users at any dosage of other opiates, including buprenorphine.[citation needed]

There is a common misconception that naloxone, a potent opioid antagonist included in the Suboxone formulation, is active and responsible for this blockade effect. This is not true. Instead, Buprenorphine alone is responsible for the blockade effect due to its high binding affinity at the brains opioid receptors, a higher affinity than that of naloxone. The naloxone is in effect not active regardless of the route of administration.

Use in pregnancy[edit]

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 to the fetus than using a traditional opiate such as methadone. Data suggest that, after the first few weeks of life, no developmental differences are found between children born to mothers that were stable on an opiate during pregnancy versus those that were not taking opiates during pregnancy. Babies born to mothers addicted to opiates show signs of withdrawal if not addressed soon after birth[citation needed] This stands in stark contrast to the pathology seen after using the (otherwise socially acceptable) drug alcohol during pregnancy. It is notable that data regarding buprenorphine's safety during pregnancy is less available than is data on methadone use during pregnancy. There is a considerable body of evidence that proper methadone use during pregnancy is safe, and that there are few (if any) significant lasting effects on the children of mothers who use medically supervised methadone regimens during the gestation period. However, recent research has indicated methadone during pregnancy does indeed[citation needed] have a negative effect on the fetus, and needs to be followed up with further research to determine the full amount of damage done to the developing fetus by the methadone.

Detection in biological fluids[edit]

Buprenorphine and norbuprenorphine (the major active metabolite of buprenorphine) may be quantitated in blood or urine to monitor use or abuse, confirm a diagnosis of poisoning, or assist in a medicolegal investigation. There is a significant overlap of drug concentrations in body fluids within the possible spectrum of physiological reactions ranging from asymptomatic to comatose. Therefore it is critical to have knowledge of both the route of administration of the drug and the level of tolerance to opioids of the individual when results are interpreted.[69]

Recreational use[edit]

Buprenorphine is also used recreationally, typically by opioid users, often by insufflation. Recreational users of buprenorphine who crush the tablet and snort 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, even when doubling or tripling their dosage. 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.[citation needed]

Recreational use of buprenorphine is very common in Scandinavia, especially in Finland and Sweden. In 2007, the authorities in Uppsala County in Sweden confiscated more buprenorphine than cocaine, ecstasy, and heroin.[70] In Finland recreational use of buprenorphine is on the rise; in 2005, Finland's incidence of buprenorphine misuse (most often injected intravenously) surpassed the incidence of recreational usage of amphetamine.[citation needed]

Intravenous administration of dissolved buprenorphine pills and insufflation of pulverized pills are the most common modes of recreational buprenorphine use.[71] This method of recreational use of Subutex is also seen in the Finnish documentary Reindeerspotting. The importer of legal Subutex to Sweden has in November 2012 stopped the sales of Subutex in Sweden due to problems with recreational use and drug induced deaths linked to Subutex.[72]

Use in animals[edit]

In the United States and Canada, use of buprenorphine for pain management in animals has become increasingly common, and is a favored analgesic in feline patients for moderate to severe pain. Although registered only 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.[73]

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.

See also[edit]

References[edit]

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