Buprenorphine is a semi-synthetic opioid derived from thebaine which is typically used for treatment of opioid addiction. It is an analgesic, and has gained notoriety for its ability to successfully interrupt severe opiate addictions. Buprenorphine has a higher affinity for μ-opioid receptors compared to full opioid agonists. Because of this, buprenorphine can block the effects of other opioid agonists in a dose-dependent fashion. By its dual effects of reducing craving and attenuating the response to administered heroin, buprenorphine reduces the self-administration of heroin. Methadone, a full opioid agonistA substance that initiates a physiological response when combined with a receptor., also reduces the impact of additional heroin, but the effect of methadone is primarily due to the induction of cross-tolerance which is dose dependent. In contrast buprenorphine achieves its effect primarily by prolonged occupancy of a high proportion of opioid receptors, blocking the action of heroin and other opioid receptor agonists.
Addiction therapeutics arose within the historical context of efforts to develop a non-addicting analgesic that began in the United States in the early 1920s. Early 20th century efforts to respond to the “opium problem,” through regulation and control at the source of supply and to address public health concerns through innovation in the research laboratory set the stage for the gradual shift in researchers’ interests toward developing a treatment for addiction therapeutics.
The solution to the “opium problem” was first sought at the laboratory bench at a time when the United States was becoming a major player within the evolving international drug control framework. For such a narrowly tailored goal to be understood as meeting a broad social problem of unclear etimology, it had to be translated into a feasible research program. Reliable methods to test compounds in animals and human beings had to be developed and validated. In the CDA’s first decade, some 150 compounds were produced and evaluated; all but one - Metopon (5-methylhydromorphone) - demonstrated the elusiveness of the goal.
Methadone was introduced into the United States in 1947 by Eli Lilly and Company, however, researchers opposed using methadone for maintenance given the results of studies on former morphine and/or heroin addicts in the late 1940s indicating that the subjects expressed increased satisfaction as dosage increased. They concluded that “narcotic drug addicts would abuse methadone and would become habituated to it if it were freely available and not controlled”. They also noted that methadone “completely alleviated the morphine abstinence syndrome in man,” yet itself exhibited a mild abstinence syndrome.
In 1974, Congress became concerned with methadone diversion and amended the Controlled Substances Act (CSA), in 1970 to give DEA considerable powers despite the inception of the National Institute on Drug Abuse (NIDA) and sunset of SAODAP in 1973. Many clinicians came to view the methadone regulations as government interference with the practice of medicine. The restrictive climate had led SAODAP to prioritize development of narcotic antagonists.
Buprenorphine was discovered in 1966, at the research labs of a home products company, Reckitt & Colman (hereafter Reckitts), in Hull, England.
The story of the development of buprenorphine as an "addict treatment" began in 1975, when Lexington Addiction Research Center (ARC) scientist Jasinski countered growing opposition to using prisoners as clinical research subjects by arguing that many prisoners were addicts and the pharmacology of buprenorphine made it such an “attractive candidate" as a treatment for opiate dependence that its human abuse potential was in urgent need of study.
Jasinski singled out buprenorphine as having an “especially unique pharmacology in man” because it produced “very little physical dependence”, even with chronic administration. Citing his 1978 study, he speculated that buprenorphine “would not only have a therapeutic application as an analgesic of low abuse potential but also as a new type of drug treatment of narcotic addiction."
Jasinski heralded buprenorphine’s unique potential because it alone produced long-lasting “changes in feelings that are acceptable to addicts,” and was “less toxic than methadone,” declaring that the committee’s 50-year project to “potentially utilize narcotics therapeutically to both relieve pain and treat addiction without the production of physical dependence” had yielded buprenorphine, which “appears to have the advantage of both methadone and naltrexone but without the major disadvantage of each”.
In 1979, following the ban on use of federal prisoners as research subjects, NIDA had moved the ARC’s Clinical Research Program, now under the direction of Jasinski, to the medical campus of The Johns Hopkins University (JHU) in Baltimore, Maryland; the preclinical program followed in 1981. The JHU site was chosen partly because Baltimore provided a suitable source of research subjects: inner-city heroin addicts. Addiction researchers considered it unethical and unwise to carry out research involving addictive substances on people who were not or had not been addicted.
By 1985, injectable buprenorphine had been marketed for analgesic applications in 29 countries and the sublingual tablet in 16 countries. In the United Kingdom, Reckitts had launched injectable buprenorphine for severe pain in 1978,with the sublingual analgesic following in 1982. It licensed Norwich–Eaton to distribute buprenorphine hydrochloride (Buprenex) in the United States, where the analgesic was launched in 1985, after FDA approval.
The difficulties of coordinating public and private interests, local and global effects, changes in domestic regulatory mechanisms, and perceptions of addiction and its treatment charted buprenorphine’s tortuous, 30-year path to FDA approval and market. Buprenorphine arose as a maintenance therapy at a time when addicts - like other citizens - were expected to take personal responsibility for health and healthcare, and where such decisions were seen as individual matters of choice and political entitlement.
Buprenorphine is usually sold in the form of sublingual tablets (Suboxone), or transdermal patches (Butrans). Patches can be attached to skin for long release as treatment for opioid withdrawal, or cut and chewed for recreational use. Usual (30 minutes) sub-lingual use of patches is not 100% effective, so patches can be re-used. Buprenorphine is water-soluble, and can be extracted with a Cold Water Extraction (takes more time, usually 24 hours, or around 4 hours with few drops of strong alcohol). Since buprenorphine is a long acting opioid antagonistA substance that interferes with or inhibits the physiological action of another., other opioids won't work for at least 36 hours after dosing buprenorphine (though some negative effects will be garnered).
Buprenorphine will cause withdrawal if you have an opioid tolerance and don't wait long enough (typically 48~ hours) before taking it.
Respiratory depression from buprenorphine (or buprenorphine/naloxone) overdose is less likely than from other opioids. There is no evidence of organ damage with chronic use of buprenorphine, although increases in liver enzymes are sometimes seen. Likewise, there is no evidence of significant disruption of cognitive or psychomotor performance with buprenorphine maintenance dosing.
Dosage is usually 2-3mg (assuming 100% effectiveness), and most users don't feel the need to take more. Ceiling effect is 16-32mg, and redosing is not effective.
600µg is considered equivalent to 10 mg morphine for pain relief.
|Total (low dose)||8-12 hours|
|Total (high dose)||24-72 hours|
Because of its ceiling effect and poor bio-availability, buprenorphine is safer in high doses compared to full opioid agonists. The maximal effects of buprenorphine appear to occur in the 16–32 mg dose range for sublingual tablets. Higher doses are unlikely to produce greater effects.
Unlike methadone, the effect of buprenorphine on respiratory depression reaches a ceiling, therefore higher doses do not increase risk of respiratory depression to a significant degree.
However, if buprenorphine is used in combination with other central nervous system depressants, such as benzodiazepines and other CNSCentral Nervous System Depressants, the combined effect on respiration can be life threatening.
Combination of buprenorphine and SSRIs can cause SerotoninA monoamine neurotransmitter, biochemically derived from tryptophan, that is primarily found in the gastrointestinal (GI) tract, platelets, and central nervous system (CNS) of humans and animals. It is a well-known contributor to feelings of well-being. Syndrome.
Buprenorphine is a derivative of the opioid alkaloid thebaine that is a more potent (25 – 40 times) and longer lasting analgesic than morphine. It appears to act as a partial agonistA substance that initiates a physiological response when combined with a receptor. at the μ- and κ-opioid receptors and as an antagonistA substance that interferes with or inhibits the physiological action of another. at δ-opioid-receptors. The lack of δ-opioid agonism has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use.
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).