Buprenorphine: Wikis

  
  

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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
Identifiers
CAS number 52485-79-7
ATC code N02AE01 N07BC01
PubChem 644073
DrugBank APRD00670
ChemSpider 559124
Chemical data
Formula C29H41NO4 
Mol. mass 467.64 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 31% (sublingual, from ethanolic solution)
~50-60% (sublingual, high-dose tablet)
~50% (transdermal)
Protein binding 96%
Metabolism hepatic
CYP3A4, CYP2C8
Half life 20-70, mean 37 hours
Excretion biliary and renal
Therapeutic considerations
Pregnancy cat. C (USA)
Legal status Schedule III (USA)
Schedule 8 (Aust)
Class C(UK)
Cat. ASingapore}
Schedule III Germany}
Routes sublingual, IM, IV,transdermal
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Buprenorphine is a semi-synthetic opiate with partial agonist actions at the mu opioid receptor and ORL1/nociceptin receptor and antagonist actions at the kappa 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 for opioid addiction, and as such the drug is now also used 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.[1] In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.

Contents

Commercial preparations

British firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations, no active additives) and Buprenex (parenteral, no active additives). Two more recent formulations from Reckitt Benckiser have been approved for opioid addiction treatment 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 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.

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,[2][3][4][5][6] 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.[7][8][citation needed]

A solution for injection (usually by the intramuscular route) is marketed for the British veterinary market by Alstoe Animal Health as Vetergesic, licensed for analgesia and sedation in dogs.

Since 2001 buprenorphine is also available transdermally as 35, 52.5 and 70 mcg 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[9] (Napp Pharmaceuticals in the UK[10], 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 severe 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 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.

Pharmacology and pharmacokinetics

Buprenorphine is a thebaine derivative with powerful analgesia approximately twenty-five to forty times as potent as morphine,[11] 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.[citation needed] 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 may trigger opioid withdrawal that also cannot be easily reversed and can last over twenty-four hours, as the drug's mean half-life is thirty-seven hours.

buprenorphine has been shown to act as an epsilon antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor,[12][13] Buprenorphine is also a κ-opioid receptor antagonist, and partial/full agonist at the recombinant human ORL1 nociceptin receptor.[14]

Buprenorphine hydrochloride is administered by intramuscular injection, intravenous infusion, via a transdermal patch, as a sublingual tablet 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.[15]

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.[16][17] Buprenorphine antagonizes it's 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.

Clinical use

Indications

Pain indications

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 January 2010) are preferred, which can be used both for chronic cancer pain as well as chronic non-malignant pain, such as musculosceletal 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.

=Blockade Effect

Buprenorphine (Suboxone)itself binds more strongly to receptors in the brain than do other opioids, making it more difficult for opioids to react when buprenorphine is in the system

Antidepressant potential

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.[18] 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".[19][20] 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.

Contraindication

Like full agonist opiates, buprenorphine can cause drowsiness, vomiting and respiratory depression. Taking buprenorphine in conjunction with central nervous system (CNS) depressants such as sedatives, hypnotics, tranquilizers, alcohol, and benzodiazepines can be particularly dangerous.[21] Falling asleep while abusing this drug, especially while combining it with other central nervous system depressants, can be extremely dangerous and thus greatly increases the chance of serious complications or death[citation needed].

Adverse effects

Common adverse drug reactions associated with the use of buprenorphine are similar to those of other opioids and include: nausea and vomiting, drowsiness, dizziness, headache, itch, dry mouth, miosis, orthostatic hypotension, male ejaculatory difficulty, decreased libido, and urinary retention. Constipation and CNS effects are seen less frequently than with morphine.[22] 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.[22] 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.[23] Concurrent use of buprenorphine and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression.

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

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 withdrawal symptoms, known as precipitated withdrawal.[24]

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.[25]

Recreational use

Buprenorphine is also used recreationally, typically by opioid users. Users sometimes report a feeling of general well being, perhaps even to the point that they may become more outgoing or talkative. 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. The buprenorphine preparation, Suboxone, comes in an orange lemon-lime flavored tablet for sublingual administration. The taste of Suboxone is described by some to be very unpleasant. Subutex is unflavored and very bitter. Possible explanations for this unpleasant taste could be the bitter taste of the buprenorphine itself, or the fact that it acts as a deterrent to abuse and was done intentionally by the pharmaceutical company, Reckitt Benckiser.

Buprenorphine abuse 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 GHB.[26] 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 ways of recreational buprenorphine use.[27]

Dependence treatment

Buprenorphine sublingual preparations are often used in the management of opioid dependence (that is, dependence on heroin, oxycodone, hydrocodone, morphine, oxymorphone, fentanyl or other opioids). The Suboxone and Subutex preparations were approved for this indication by the United States FDA in October 2002. This was only possible due to the Drug Addiction Treatment Act of 2000 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.[citation needed] 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.[citation needed]

The Drug Addiction Treatment Act allowed medical professionals to prescribe and administer opioids to manage addiction ("maintenance") as well to perform short-term detox. Such use of opioids was previously allowed only in specially registered drug treatment centers. These restrictions were removed only for Schedule III through V drugs. As such they do not include exclude methadone and stronger opioids, but do allow for the medical use of buprenorphine.

The first buprenorphine treatment program for opiate addiction in the United States was founded by Dr. David McDowell at Columbia University[28] and reported an 88% success rate with its patients.[29]

The use by medical professionals of medication-assisted treatment in the management of opioid dependence is still regulated, owing in part to the controversy of this form of harm reduction treatment. 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. In addition, each approved prescriber is only allowed to treat thirty patients with buprenorphine for opioid addiction in an outpatient setting.[30]

On of December 12, 2006 the U.S. Congress passed additional legislation which relaxed the latter 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 hundred outpatients, effective as of 12/29/2006 (public law 109-469).[citation needed]

Similar restrictions are placed on prescribers in many other jurisdictions. For example, Buprenorphine 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.[citation needed]

On September 21, 2006, actor and comedian Artie Lange revealed on The Howard Stern Show that he had overcome heroin addiction the previous year. He said buprenorphine was essential to countering the effects of opioid withdrawal and described it as a 'miracle pill'. The withdrawal from buprenorphine is generally far milder than other potent opioids. However, this is true only if the patient's use of buprenorphine is limited to a few days or weeks for rapid withdrawal therapy, not for maintenance. Those maintained on buprenorphine for longer periods have reported serious withdrawal symptoms, comparable to withdrawal from long-term use of other opiates such as methadone.

Buprenorphine versus methadone

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)[31], to up to 100 mg (high dose)[32] 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.[31][32][33][34] 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[35] 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, much more than most buprenorphine patients get, 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,[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 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,[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 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 eighteen months 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.[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. 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 (i.e., heroin) or medication (i.e., 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.[36] 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 C–III status versus methadone's more restrictive C–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.[37] 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 for methadone for pain.

Blockade effect

The Suboxone preparation contains the μ-opioid receptor antagonist naloxone. Buprenorphine itself is 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 to become intoxicated via other opioids when buprenorphine is in the system, regardless of the presence of the naloxone. 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 any opiate antagonist-like action of methadone. 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.[38] 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.

Inpatient rehabilitation

The practice of using buprenorphine (Subutex or Suboxone) in an inpatient rehabilitation setting is increasing rapidly,[citation needed] whereas methadone-based detox is the standard. It is also being used in social model treatment settings. These rehabilitation programs consist of "detox" and "treatment" phases. The detoxification ("detox") phase consists of medically-supervised withdrawal from the drug of dependency on to buprenorphine, sometimes aided by the use of medications such as benzodiazepines like oxazepam or diazepam (modern milder tranquilizers that assist with anxiety, sleep, and muscle relaxation), clonidine (a blood-pressure medication that may reduce some opioid withdrawal symptoms), and anti-inflammatory/pain relief drugs such as ibuprofen. Switching to buprenorphine from a short-acting drug including heroin, morphine, fentanyl, hydromorphone (Dilaudid) and hydrocodone (Vicodin), or oxycodone (Oxycontin, Percocet) is not too difficult for most people, and as long as the patient waited until they were in full withdrawals or longer before starting the buprenorphine medication, little further acute symptoms are an issue; The patient needs to be stabilized on a proper dose and monitored regardless. Switching from methadone is much more difficult, and with all cases if the patient takes buprenorphine prematurely (before full withdrawal symptoms) it can precipitate worse withdrawals than would have been had if the person had waited properly, and they can be long-lasting.

The treatment phase begins once the patient is stabilized and receives medical clearance. This portion of treatment 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[39]) or depart entirely from the 12-step model of recovery (using a program such as SMART Recovery.[40])

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.[citation needed] Abstinence alone has a very low efficacy in rehabilitating patients. In contrast, buprenorphine maintenance has a high efficacy.[31][32] Most rehabilitation programs do not have or do not allow scientific studies to be conducted to contrast to abstinence alone and buprenorphine or methadone maintenance, including Narcotics Anonymous. NA's twelve traditions and overriding principle of anonymity would make such research potentially contentious and internally problematic.[citation needed] While the maintenance / abstinence debate is a hot topic and strong arguments in support of both Narcotics Anonymous and buprenorphine maintenance have been made, individuals tend to gravitate 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 that the patient does not need to be detoxed from any additional addictive substances, as previously mentioned.

During this time, Suboxone or Subutex will be administered or the patient will be monitored taking the medication. Generally, the patient takes a single dose each day (a single dose may keep the patient comfortable for up to forty-eight to seventy-two hours, but medical professionals in many treatment facilities prescribe one or more than one dose 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 of any situation, 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.[41] Use currently is limited to infants enrolled in a clinical trial conducted under an FDA approved investigational new drug (IND) application.[42]

References

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