Buprenorphine

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 Âµg/hour. It is available in a variety of formulations: Subutex, Suboxone (typically used for opioid addiction), Temgesic, 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. 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 US, 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.^[2] In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.

Pharmacology and pharmacokinetics

Buprenorphine is classed both as an orvinol and a thevinol; which means it can be derived from either oripavine or thebaine.[8] It is one of the Bentley compounds discovered by chemist K.W. Bentley from thebaine as the initial structure. Thebaine is one of the main alkaloids in the opium poppy Papaver somniferum.

Buprenorphine has an extremely high binding affinity at the µ- and k-opioid receptor. It has partial agonist activity at the µ-opioid receptor, partial or full agonist activity at the ORL1/nociceptin and d-opioid receptor, and competitive antagonist activity at the k-opioid receptor. Buprenorphine is a thebaine derivative with powerful analgesia approximately 20-40x more potent than morphine (at equivalent low doses).[9] Its analgesic effect are due to partial agonist activity at µ receptor. That is, 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 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. Concomitant use of alcohol with any opioid increases the risk of overdose. One French study showed a higher incidence of fatal overdose in patients having injected both buprenorphine and benzodiazepines, to be specific, temazepam, together.[10] 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.

Buprenorphine has been shown to act as an epsilon-opioid antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor,[11][12] Not much is known about the epsilon receptor. Buprenorphine is also a kappa-opioid receptor antagonist, and partial/full agonist at the recombinant human ORL1 nociceptin receptor.[13] 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.

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.^[14]

Buprenorphine's main active metabolite, norbuprenorphine, is a u-opioid, d-opioid, and nociceptin receptor full agonist, as well as a k-opioid receptor partial agonist.^[15][16] Buprenorphine antagonizes its effects.

Clinical use

Indications

Pain

Depending on the application form, buprenorphine is indicated for the treatment of moderate to severe chronic pain (pain that has outlasted its use to prevent injury and after three months) or for peri-operative analgesia. For the treatment of chronic pain, the transdermal formulations (Which was recently released in January 2011, It is available in 5mcg [micrograms per hour], 10mcg, 20mcg,Trans dermal patches^[17]) are preferred, which can be used both for chronic cancer pain as well as chronic non-malignant pain, such as musculoskeletal and neuropathic pain such as is found in diabetics with neuropathy. 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. understood whether or not an individual is recepted to a certain monotype class A buillian ocoxian. Therefor inhithoring a manufactual interlain receptor increase,:That within fact will subdo pain interlocking fire receptors. Inicated for the treatment of that certain individual.

Opioid dependence

History

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 Food and Drug Administration 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 stated that maintenance and detox treatments were not a form of medical treatment. Although the rulings had the power of legal precedent prior to 2000, it is likely that they were not the intended interpretation of the laws passed originally by Congress.

The Drug Addiction Treatment Act allowed medical professionals to prescribe and administer opioids to manage addiction ("maintenance") as well as for short-term (defined as <6 months) and long-term detoxification. Such use of opioids had been allowed only in specially registered drug treatment centers providing Opiate replacement therapy.

These restrictions were removed only for Schedule III through V drugs. As such they do not include methadone and stronger opioids, but do allow for the medical use of buprenorphine (formerly Schedule V, the least restrictive category; now Schedule III). Hypothetically, there is nothing in the Drug Addiction Treatment Act to prevent physicians from prescribing Schedule III opioids and other medications (including but not limited to: Codeine, hydrocodone, dihydrocodeinone), Schedule IV benzodiazepines (e.g., Valium, Xanax), and Schedule V (certain codeine-containing cough preparations) to treat addiction, to be specific the time-limited "opiate abstinence syndrome" -- also called "opiate withdrawal."

The first buprenorphine treatment program for opiate addiction in the United States was founded by Dr. David McDowell at Columbia University^[18] and reported an 88% success rate with its patients.^[19]

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 100,000s of Americans (and millions more in all Western European countries and democratic nations world wide) to achieve a reduction in the number and severity of relapses to illicit opiate use & associated costs to society in terms of criminal activity (burglary, theft, robbery, muggings) necessary to obtain money for drugs which ultimately wind up financing the vast, globally connected drug cartels. Additionally, Opioid Replacement Therapy reduces the risk of contracting Hepatitis C and HIV among other communicable diseases. This, along with lowered rates of recidivism and incarceration for drug-Prohibition related crimes as formerly active addicts reorient their lives from the daily quest to stave off Heroin withdrawal and reintegrate into society as law-abiding citizens, has not changed the fact that the appearance of methadone clinics across the U.S.A. has changed little since their inception during the closing years of the Vietnam War, in the early 1970s. Opiate replacement therapy remains strictly regulated despite its proven success in harm reduction for both patients fortunate enough to live in a state where it is allowed by law and the larger populations of such states.

In the United States, a special federal waiver (which can be granted after the completion of an eight-hour course) is required in order to treat outpatients for opioid addiction with Subutex and Suboxone, the two forms of buprenorphine tablets currently available. However, the number of patients each approved doctor could initially treat was capped at 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.^[20]

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. It allows physicians with at least one year of clinical experience with buprenorphine to request an additional exemption within DATA 2000, which increases the limit to a hundred outpatients, effective as of 12/29/2006 (public law 109-469).

Similar restrictions are placed on prescribers in many other jurisdictions/nations. For example, buprenorphine liquid is regulated in the same way as methadone in Australia, and while the number of patients per doctor isn't capped, the patient is required to visit a pharmacy daily in order to receive a supervised dose of their medication. Buprenorphine transdermal patches are regulated as a controlled substance, with GPs requiring approval for all prescriptions and a limited number of repeats available.

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),^[21] to up to 100 mg (high dose)^[22] 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.^{[21][22][23][24]} 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.^[25] 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. 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 needing to visit a methadone dispensing facility daily. The facilities, which are regulated at the state and federal level in the US, 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 the US state of 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. 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. Like methadone treatment, buprenorphine treatment can last anywhere from several days (for detoxification purposes) to an indefinite period of time (life-long maintenance) if patient and doctor both feel that is the best course of action. Additionally, the opinion of those in the medication-assisted treatment field is generally shifting to longer-term treatment periods, which may last indefinitely, due to the anti-depressant effects opioids seem to have on some patients as well as the high relapse potential among those patients discontinuing maintenance therapy. The choice of buprenorphine versus methadone in the mentioned situation (by the patient) is usually due to the benefits of the less-restrictive outpatient treatment; prescriptions for take-home doses for up to a month early versus the possibility of heavy restrictions in some states and frequent visits to the clinic and the possibility of the "stigma" of going to a methadone clinic as compared to making trips to a doctor's office. Buprenorphine is also significantly more expensive than methadone and this seems to add to its better reputation. Also, in some states, there is a long waiting list for admission to a methadone maintenance program versus those with the money to afford seeing an addiction specialist each month in addition to the cost of medication. In studies done, methadone is considered more addicting physically and mentally.^{[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 (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.^[26] 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. 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. 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.^[27] 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 circumvent the substance abuse treatment system and detoxify themselves with the methadone or simply by people wishing 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.In North America (Canada) it is reversed,buprenorphine nis found to be readily available on the black market,as methadone is usually not seen,buprenorphine is as easy to obtain as heroin.. 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 90s in Austria, slow release oral morphine has been used alongside methadone and buprenorphine for OST and more recently it has been approved in Slovenia and Bulgaria, and it has gained approval in other EU nations including the United Kingdom, although its use currently is not as widespread. 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 percent 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 morphines use in OST may allow for better functioning and engagement in society.

Inpatient rehabilitation and detoxification

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 12-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 12-step fellowships (such as Methadone Anonymous) or depart entirely from the 12-step model of recovery (using a program such as SMART Recovery).^[28][29]

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.^[21][22]

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 forty-eight to seventy-two hours, but medical professionals in many treatment facilities prescribe one or more doses every twenty-four hours to ensure that a consistent, active level of the medication remains in the patient's central nervous system, a key element of maintenance; also the level of dosage is usually around the previously described plateau, after which there is no noticeable increase in the effects of the drug. Typically, the first day dosage is no more than 8 mg or it may precipitate withdrawals after which initial daily dose totals around 8–16 mg of either Suboxone or Subutex. The dosage is slowly tapered each day and the medication is usually stopped thirty-six to forty-eight hours prior to the end of the detox program, with the patient's vitals monitored up until discharge from the detox program.

During the detox period, because of risk of naloxone related side-effects, Subutex is urged over Suboxone by the manufacturer.

Suboxone and Naloxone

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.^{[30][31][32][33][34]} These studies show the strength of buprenorphine/naloxone in displacing opiates, but do not show the effectiveness of naloxone displacing buprenorphine and causing withdrawal symptoms. 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.^[35][36] 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.^[37] 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 100-1000 times greater.^[38] 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.

Contraindication

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]} 2 mg of buprenorphine is equal to roughly 80 milligrammes of oral morphine. 80 milligrammes of morphine itself is considered an extreme dose for an opioid-naive patient with doses starting around 5 to 10 milligrammes.^[45]

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, 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.^[46] 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.^[46] 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.^[47] 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).

People switching from other opiates should wait until mild to moderate withdrawal symptoms are encountered. Failure to do so can lead to the rapid onset of intense withdrawal symptoms, known as precipitated withdrawal.^[48] 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 then even Naloxone, resulting in a fairly limited effect of the antagonist in any scenario.

References

1. "Lawriter - ORC - 3719.41 Controlled substance schedules". Codes.ohio.gov. 2000-05-17. http://codes.ohio.gov/orc/3719.41. Retrieved 2010-08-30. 
2. List of psychotropic Substances under international control
3. Transtec Summary of Product Characteristics
4. Napp Pharmaceuticals
5. electronic Medicines Compendium (eMC) of UK medicines, Transtec product characteristics
6. "Butrans", accessed January 23, 2011.
7. -----
8. Primary Industry Centre for Science Education (PICSE) - Morphine and Derivatives - Java Applet "Buprenorphine"
9. Reckitt Benckiser Buprenorphine Bibliography
10. "Buprenorphine replacement therapy: a confirmed benefit.". Prescrire Int. 15 (82): 64–70. April 2006. PMID 16604748. http://www.ncbi.nlm.nih.gov/pubmed/16604748. 
11. Fujii H, Narita M, Mizoguchi H, Murachi M, Tanaka T, Kawai K, Tseng LF, Nagase H (August 2004). "Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid receptor". Bioorg. Med. Chem. 12 (15): 4133-45. doi:10.1016/j.bmc.2004.05.024. PMID 15246090. 
12. Fujii H, Nagase H (2006). "Rational drug design of selective epsilon opioid receptor agonist TAN-821 and antagonist TAN-1014". Curr. Med. Chem. 13 (10): 1109-18. doi:10.2174/092986706776360851. PMID 16719773. 
13. Huang P., Kehner GB, Cowan A, Liu-Chen LY (2001). "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist". J. Pharmacol. Exp. Ther. 297 (2): 688–95. PMID 11303059. 
14. http://dmd.aspetjournals.org/content/early/2009/09/22/dmd.109.028605.full.pdf
15. Yassen A, Kan J, Olofsen E, Suidgeest E, Dahan A, Danhof M (May 2007). "Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of norbuprenorphine in rats". The Journal of Pharmacology and Experimental Therapeutics 321 (2): 598–607. doi:10.1124/jpet.106.115972. PMID 17283225. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17283225. 
16. Huang P, Kehner GB, Cowan A, Liu-Chen LY (May 2001). "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist". The Journal of Pharmacology and Experimental Therapeutics 297 (2): 688–95. PMID 11303059. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11303059. 
17. http://www.butrans.com/hcphome.aspx
18. Buprenorphine: New Medication to Treat Substance Abuse, Matthew Dougherty.
19. New Ways to Loosen Addiction's Grip, Anahahd O'Connor, The New York Times, August 3, 2004
20. naabt.org
21. R. S. Schottenfeld et al. (1997) Department of Psychiatry, Yale University School of Medicine
22. Rolley Johnson et al., NEJM, 343(18):1290–1297, 2000
23. Strain et al. (1998)
24. Ling et al. (1998).
25. Buprenorphine
26. Suboxone.com - Frequently Asked Questions
27. Buprenorphine and reward
28. Glickman L, Galanter M, Dermatis H, Dingle S (December 2006). "Recovery and spiritual transformation among peer leaders of a modified methadone anonymous group". J Psychoactive Drugs 38 (4): 531-3. PMID 17373569. 
    Gilman SM, Galanter M, Dermatis H (December 2001). "Methadone Anonymous: A 12-Step Program for Methadone Maintained Heroin Addicts". Subst Abus 22 (4): 247-256. doi:10.1080/08897070109511466. PMID 12466684. 
    McGonagle D (October 1994). "Methadone anonymous: a 12-step program. Reducing the stigma of methadone use". J Psychosoc Nurs Ment Health Serv 32 (10): 5-12. PMID 7844771. 
29. Horvath A. Thomas (2000). Journal of Rational-Emotive and Cognitive-Behavior Therapy 18 (3): 181–191. doi:10.1023/A:1007831005098. ISSN 08949085. 
30. Mendelson J, Jones RT, Fernandez I, Welm S, Melby AK, Baggott MJ. Buprenorphine and naloxone interactions in opiate-dependent volunteers. Clin Pharmacol Ther. 1996 Jul;60(1):105-14.
31. Fudala PJ, Yu E, Macfadden W, Boardman C, Chiang CN. Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts. Drug Alcohol Depend. 1998 Mar 1;50(1):1-8.
32. Stoller KB, Bigelow GE, Walsh SL, Strain EC. Abstract Effects of buprenorphine/naloxone in opioid-dependent humans. Psychopharmacology (Berl). 2001 Mar;154(3):230-42.
33. Strain EC, Preston KL, Liebson IA, Bigelow GE. Abstract Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers. J Pharmacol Exp Ther. 1992 Jun;261(3):985-93.
34. Harris DS, Jones RT, Welm S, Upton RA, Lin E, Mendelson J. Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine. Drug Alcohol Depend. 2000 Dec 22;61(1):85-94.
35. Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl). 2000 Mar;148(4):374-83.
36. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) 40. Laura McNicholas. US Department of Health and Human Services.
37. Donna A. Volpe, Grainne A McMahon Tobin, R. Daniel Mellon, Aspandiar G. Katki, Robert J. Parker, Thomas Colatsky, Timothy J. Kropp, S. Leigh Verbois. Uniform assessment and ranking of opiod Mu receptor binding constants for selected opiod drugs. Regulatory Toxicology and Pharmacology. 2011. 59. 385-390.
38. John W. Villiger, Kenneth M. Taylor. Buprenorphine: characteristics of binding sites in the rat central nervous system. Life Sciences. 1981. 29(26). 2699-2708.
39. Bodkin JA., Zornberg GL, Lukas SE, Cole JO (1995). "Buprenorphine treatment of refractory depression". Journal of Clinical Psychopharmacology 15 (1): 49–57. doi:10.1097/00004714-199502000-00008. PMID 7714228. 
40. Drug War Ensnares Doctors, Not Dealers - Oct 2, 2003
41. The War on Drugs Is a War on Doctors by Rep. Ron Paul
42. Kraft WK, Gibson E, Dysart K, Damle VS, Larusso JL, Greenspan JS, Moody DE, Kaltenbach K et al (September 2008). "Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial.". Pediatrics 122 (3): e601-7. doi:10.1542/peds.2008-0571. PMC 2574639. PMID 18694901. http://pediatrics.aappublications.org/cgi/content/full/122/3/e601. 
43. Clinicaltrials.gov NCT00521248
44. http://www.pswi.org/communications/journal/
45. Suboxone FAQ
46. Budd K, Raffa RB. (edts.) Buprenorphine - The unique opioid analgesic. Thieme 2005
47. Van Dorp E. et al. (2006) Naloxone reversal of buprenorphine- induced respiratory depression. Anesthesiology 105 (1): 51-57
48. "naabt web sell sheets" (PDF). http://www.naabt.org/documents/naabt_precipwd.pdf. Retrieved 2010-08-30. 
49. AJ Giannini. Drugs of Abuse--Second Edition. Los Angeles, Practice Management Information Corporation, 1997.
50. R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 190-192.
51. "Subutex Abuse on the Rise (Swedish)", Upsala Nya Tidning, 2007-05-06. Retrieved on 2008-08-27.
52. Hermansson, Gunnar "Subutex Instead of Heroin (Swedish)". Retrieved on 2008-08-27.
53. http://www.petplace.com/drug-library/buprenorphine-buprenex/page1.aspx