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Structural formula
Structural formula of buprenorphine
Non-proprietary name Buprenorphine
other names

(5 R , 6 R , 7 R , 9 R , 13 S , 14 S ) -17-Cyclopropylmethyl-7 - [( S ) -3,3-dimethyl-2-hydroxybutan-2-yl] -6-methoxy- 4,5-epoxy-6,14-ethanomorphinan-3-ol ( IUPAC )

Molecular formula C 29 H 41 NO 4
Brief description

White to almost white, crystalline powder

External identifiers / databases
CAS number
  • 52485-79-7
  • 53152-21-9 (hydrochloride)
EC number 257-950-6
ECHA InfoCard 100.052.664
PubChem 644073
ChemSpider 559124
DrugBank DB00921
Wikidata Q407721
Drug information
ATC code
Drug class
Molar mass 467.64 g · mol -1
Physical state


Melting point

209 ° C

pK s value

8.5; 10.0


very sparingly soluble in water , slightly soluble in acetone , soluble in methanol , sparingly soluble in cyclohexane

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning 08 - Dangerous to health


H and P phrases H: 302-361
P: 281
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Buprenorphine is a potent pain relievers ( analgesic ) from the group of opioids , the more pronounced especially for treating pain is used. Buprenorphine has a partial agonistic effect with a high affinity for µ-receptors.

Due to its good safety profile, it is considered to be the first choice for the treatment of severe chronic pain (such as pain syndromes ) in older people . In addition, buprenorphine has been used in high doses as a substitution agent in the therapy of opioid addiction since the mid-1990s ; in 2006 it was included in the list of indispensable drugs of the World Health Organization for this application .

Buprenorphine is semi-synthetically from the opium - alkaloid thebaine won and mediates its effects as a partial agonist via different opioid receptors . Its most important breakdown product is the pharmacologically active nor-buprenorphine .

Pharmacological properties

Pharmacodynamics (mode of action)

The so-called ceiling effect (saturation effect) of buprenorphine in respiratory depression is attributed, among other things, to a partial agonism . Even at maximum dosage, buprenorphine only leads to partial respiratory depression compared to a full agonist such as morphine.

The ligand binds with high affinity to µ-opioid receptors and acts there as a partial agonist . At the κ-opioid receptor, it acts as a partial agonist and very effective antagonist. Like other opioids , buprenorphine has a pain reliever and cough reliever , but also respiratory depression , nausea and constipation effect. Its analgesic potency is about 20 to 70 times that of morphine . In healthy volunteers, a so-called ceiling effect ( saturation effect ) for respiratory depression was demonstrated. Increasing the dose hardly increases the risk of respiratory depression. In people with previous opioid experience but no addiction, a measurable decrease in breathing activity to four breaths per minute is observed at a dose of 32 mg per day. Analgesically comparable doses of morphine (530 mg intramuscularly ) or methadone (1060 mg orally ) would be fatal due to the severe respiratory depression caused by these substances. This means that buprenorphine is safer than other opioids in the event of an overdose, especially after opioid withdrawal has been completed.


Buprenorphine is stored in the body due to its high lipophilicity and is only slowly excreted due to its sluggish receptor kinetics and the entero-hepatic circulation .

After oral administration, buprenorphine has a poor bioavailability of only about 6.5%, due to a pronounced first-pass effect (the immediate metabolism in the liver after absorption from the small intestine ). In the case of a single dose as sublingual tablet (s) (single dose: 0.2 to 0.6 mg for adults), the bioavailability is around twice as high by bypassing the first-pass effect, and around 4 to 8 times when administered sublingually as a liquid higher. However, if both medicinal preparations are taken for several days, the relative bioavailability of the sublingual tablet increases.

The most important metabolic product ( metabolite ) is nor-buprenorphine, for the formation of which the cytochrome P450 enzyme system is responsible. Nor-buprenorphine is also pharmacologically active, but its analgesic potency is reduced by a factor of 50 compared to its parent substance. 75% of the metabolism takes place via the isoenzymes CYP3A4 and CYP3A5 . Buprenorphine itself is an inhibitor of CYP3A4. Buprenorphine interactions are therefore possible with a variety of drugs. After an optional glucuronidation, buprenorphine and nor-buprenorphine are excreted mainly via the bile and thus via the faeces and only about 10 to 30% via the kidneys and thus via the urine .

The rate of elimination of buprenorphine follows a complex bi- or tri-exponential scheme. The cause is considered to be complex distribution processes of buprenorphine in the organism, which include its reabsorption from the gastrointestinal tract ( enterohepatic circulation ) and slow diffusion from the fatty tissue. In addition, the type of administration has an impact on the distribution behavior of buprenorphine and thus also on its pharmacokinetic properties. For these reasons and depending on the determination method used, different plasma half- lives are determined for buprenorphine. These are between 3 and 44 hours. Because of the long-lasting receptor binding, the duration of action does not correlate directly with blood concentrations or the plasma half-life of buprenorphine. The duration of action of 24 to 69 hours is at least as long as that of methadone .

Clinical information

Application areas (indications)

Buprenorphine is approved for the treatment of severe pain, excluding toothache, headache, and other pain that can be treated with peripheral analgesics or antispasmodics . The areas of application of buprenorphine include, in particular, pain after operations and injuries, after a heart attack or chronic pain associated with tumor diseases . For these areas of application, buprenorphine is available as an injection solution , sublingual tablet or transdermal patch (release of 35, 52.6 or 70 micrograms of buprenorphine per hour), for another area of ​​application - substitution therapy for opioid addiction in combination with other medical, social work and psychotherapeutic measures - only as a sublingual tablet.

Pain therapy

Buprenorphine has proven itself in the therapy of chronic pain conditions. The transdermal form of administration using pain patches is indicated in the case of swallowing disorders that exist at the same time or if regular intake is not guaranteed and enables the active ingredient to be released evenly over a period of up to seven days. For the treatment of acute severe pain as well as for the treatment of breakthrough pain , fast-acting drug forms such as injection solutions and sublingual tablets are also available. Intravenous administration is mainly indicated for postoperative pain, in palliative medicine for unstable pain and high opioid consumption in the form of patient-controlled pain treatment .


In the substitution therapy of opioid-dependent (mostly heroin-dependent ) patients with buprenorphine, it should be noted that when switching to buprenorphine - especially if there are still significant amounts of other opioids in the body and buprenorphine is given in too low a dose - due to its partially antagonistic character, there is an increased risk Withdrawal symptoms can be triggered. Nevertheless, a methadone> buprenorphine conversion method has been practiced for some time, which consciously takes this aspect into account, the so-called Ravensburger model. With the correct dosage and a time difference of at least twice the half-life of the last opiate consumed to the first dose of buprenorphine, however, no (additional) withdrawal symptoms occur, as these are already maximally pronounced due to the vacancy. The physical symptoms are now eliminated immediately by the ligand , while the psychological withdrawal can take a long time. The often-cited, characteristic "like-in-cotton-wool" of heroin or methadone is missing. The ingestion itself can theoretically take place every other day (double the amount) or even only every third day (three times the amount), although in most countries the dosage is daily.

Its proven effectiveness as a substitute drug has led the World Health Organization (WHO) to add buprenorphine to its Essential Medicines List in 2006, along with methadone . In 1995, both methadone and buprenorphine were approved for substitution therapy in France, and a year later all licensed doctors could prescribe buprenorphine without having to show any further training. As a result, in 1999 ten times more patients were treated with buprenorphine than with methadone, twelve percent of patients received buprenorphine from more than two prescribers and 43 percent had an additional use of benzodiazepines (mostly flunitrazepam ).

Buprenorphine is well suited as a substitute for those opiate addicts who can do without a sedating effect or who cannot keep their plans for the day (work, sport, etc.) with the strongly sedating effect of methadone or morphine (substitute): At the kappa receptor buprenorphine has an antagonistic effect , d. that is, it blocks the action on that receptor. Since this special receptor is held responsible for the sedative and dysphoric effects of full agonists such as morphine, this effect is absent with buprenorphine or is much less pronounced. Patients tend to stay clearer and more active throughout the day. However, the lack of sedation can also be a disadvantage for some patients, as unresolved psychological problems come to the surface undamped. The difference to the fasting condition is only marginal compared to the condition with methadone or morphine. Buprenorphine is therefore primarily used in younger patients with less pronounced symptoms.

Often, buprenorphine is abusively consumed nasally, on the one hand to counteract addictive pressure and on the other hand to increase bioavailability through better use of the mucous membranes . Buprenorphine has spread rapidly on the European black market in recent years. In contrast to methadone, it is also being used more and more frequently by young people without a history of heroin and must therefore be regarded as the main drug rather than a substitute in this context. A combination preparation made from buprenorphine and naloxone has been on the German market since 2007 . It is used for substitution and has the advantage that the opioid antagonist naloxone triggers withdrawal symptoms in the event of improper nasal or intravenous use.

Withdrawal symptoms up to a normal state of mind and body are (dose-dependent) between those of morphine (about one month) and those of methadone (about nine months), depending on the constitution, between two and five months, but they are usually less pronounced is attributed, among other things, to the significantly longer half-life and the only partial occupation of the opioid receptors .

New dosage forms:

In November 2018, the first buprenorphine depot (trade name Buvidal) was approved by the European Medicines Agency (EMA) for the treatment of opioid addiction. Healthcare professionals can inject the pre-filled syringe, available in seven different doses, under the patient's skin. As with a vaccination, no anesthesia is necessary. Thanks to the special properties of the natural lipids contained (FluidCrystal technology), a gel-like liquid crystal forms in the body when it comes into contact with tissue water, which continuously releases therapeutically effective amounts of buprenorphine in the body. The effects last for a week (4 doses) or a month (3 doses). The liquid crystal is completely broken down in the body. The FluidCrystal technology and the depot preparation were developed by Camurus AB (Lund, Sweden), which currently sells the product in 6 European countries (as of the end of 2019) and Australia.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended a buprenorphine implant for substitution treatment for approval (trade name: Sixmo ) at its meeting in April 2019 . Specially trained doctors should / can apply four small sticks to the patient's upper arm under local anesthesia. The implant continuously releases small amounts of buprenorphine in the body. The implant has been approved under the name Probuphin for three years in the USA . It was developed by Titan Pharmaceuticals . The trading partner in the EU, who also submitted the application for approval to the EMA, is the Italian company Molteni Farmaceutici . As a rule, the European Commission follows such a recommendation and grants approval.

Experimental stage depression

According to various studies, an antidepressant effect has been demonstrated in non-psychotic unipolar depression . An antidepressant effect was also achieved in those test subjects who had previously neither responded to conventional antidepressants nor to electroconvulsive therapy (ECT). Due to the inevitable development of opioid addiction, buprenorphine is not indicated in the EU for depression.

In the USA, however, a drug based on buprenorphine and samidorphan, a μ-receptor antagonist, has been developed under the name ALKS-5461 for non-psychotic unipolar and therapy-resistant depression. The drug was approved for the US market by the Food and Drug Administration (FDA) on January 31, 2018.

Contraindications (contraindications)

In addition to known hypersensitivity, severe respiratory insufficiency and severe hepatic insufficiency are absolute contraindications. Therefore, buprenorphine must not be used in these diseases and when using MAOIs at the same time . Other absolute or relative contraindications are alcoholism , delirium tremens , severe head injuries and increased intracranial pressure. Use in mild forms of respiratory and hepatic insufficiency as well as renal insufficiency is possible provided that the dose is adjusted and other precautionary measures are taken.


The simultaneous use of buprenorphine with other opioids, alcohol, anesthetics , hypnotics , sedatives , antidepressants , neuroleptics and other drugs with a depressant effect on the central nervous system can intensify central nervous effects. The sedative side effects of buprenorphine are particularly increased when alcohol is taken at the same time. Benzodiazepines especially increase the respiratory depressive side effects of buprenorphine. When buprenorphine is used together with CYP3A4 inhibitors such as ketoconazole , gestodene , triacetyloleandomycin , ritonavir , indinavir and saquinavir , the effects of buprenorphine may be increased. A marked increase in the buprenorphine level has also been described with simultaneous consumption of grapefruit juice , which is also CYP3A4-inhibiting . A possible interaction with CYP3A4 inducers such as phenobarbital , carbamazepine , phenytoin and rifampicin has not been adequately investigated, but is considered possible due to the pharmacokinetic properties of buprenorphine and can lead to a reduction in the effect of buprenorphine. In addition, there have been isolated reports of an increase in the side effects of phenprocoumon caused by buprenorphine.

Side effects

In the indication of analgesic therapy, buprenorphine has a more favorable side effect profile among opioids - compared to e.g. B. Morphine, symptoms such as constipation and itching occur much less frequently. Initially occurring nausea or vomiting are quickly subject to a tolerance effect and can be minimized by prophylactic administration of an antiemetic and a slow increase in dose. Since most of the excretion takes place via the bile (biliary), there is no need to adjust the dose in the case of impaired renal function and therefore no risk of substance accumulation and intoxication in patients with renal impairment (even in older patients).

The side effects of buprenorphine in substitution therapy are less severe compared to the side effects that a methadone substitution brings with it (e.g. profuse sweating, water retention in the body, listlessness, sleep disorders, poor concentration, decreased sexual sensation, depression, constipation) pronounced.

The most common disorders of the nervous system, particularly tiredness, sleep disorders and drowsiness, occur with a frequency of over 10%. Dizziness and headaches as well as occasional (0.1 to 1%) exhaustion, dry mouth, slurred speech, coma , tremors , cramps and lack of muscle coordination can also occur frequently (1 to 10%) . Occasional psychiatric disorders such as confusion, disorientation, nervousness, depression, psychosis , hallucinations, depersonalization, euphoria, dysphoria and restlessness can also occur. The characteristic opioid side effect of miosis can be observed in about 1 to 10% of patients, while other disorders of the eye, such as double vision, visual disturbances and conjunctivitis , or of the ear, such as tinnitus , occur only occasionally. The most common side effect on the cardiovascular system is an orthostatic drop in blood pressure (1 to 10%). Occasionally, tachycardia , bradycardia , cyanosis , AV block, and hypotension also occur. Respiratory depression can often be observed, but it only occasionally escalates into shortness of breath or respiratory arrest. A bronchospasm occurs only very rarely (<0.01%). Nausea and vomiting can often be observed as characteristic opioid side effects, while constipation, dyspepsia , loss of appetite and diarrhea occur only occasionally. Occasionally, micturition problems and urinary retention can also be observed. Disorders that affect the skin often manifest themselves in sweating and occasionally in paresthesia , itching, rash, pallor and urticaria . The angioedema rarely occurs very. General hypersensitivity reactions can occasionally occur, severe anaphylactic reactions are very rare.

Since a prolongation of the QT interval has often been observed during high-dose sublingual therapy with buprenorphine , precautions should be taken in patients with known or suspected changes in the ECG, electrolyte imbalance, slowing of the heart rate ( bradycardia ) or when concomitantly treated with Medicines for cardiac arrhythmias necessary. An ECG should therefore be performed before and 2 weeks after the start of treatment or when the dose is increased. Various studies describe a safe therapy with buprenorphine with no effects on the QT interval.


In any case, symptoms similar to those to be expected with other centrally acting analgesics occur after an overdose of buprenorphine. They include respiratory depression, sedation , somnolence , nausea, vomiting, circulatory collapse, and severe miosis . It should be noted that because of the above-mentioned high receptor affinity, buprenorphine only dissociates very slowly from the receptor, so it works for a comparatively long time, which must be taken into account when treating an overdose. A continuous infusion with naloxone should take place, as naloxone has a much shorter half-life (approx. 70 minutes) and thus a shorter duration of action. Furthermore, naloxone must be dosed much higher than when antagonizing morphine, for example . Respiratory depression cannot be safely reversed with naloxone, so that artificial ventilation may be necessary. An analeptic such as doxapram can be used to stimulate breathing .



Buprenorphine was patented as a potent analgesic in 1968 by Reckitt & Colman .


The starting substance for the partially synthetic production of buprenorphine is the opium minor alkaloid thebaine. The cycloaddition product 7-acetyl-6,14-endoethenotetrahydrothebaine is formed in a first reaction step by reaction with methyl vinyl ketone . After reduction under palladium - charcoal - catalysis , the reaction product is tert -Butylmagnesiumchlorid in the sense of a Grignard reaction to 6,14-endo-ethano-7- (2-hydroxy-3,3-dimethyl-2-butyl) -tetrahydrothebain implemented. The tertiary amino group of this intermediate product is demethylated with cyanogen bromide and alkylated with the aid of cyclopropylcarboxylic acid chloride under reductive conditions in the presence of lithium aluminum hydride . After hydrolytic cleavage of the phenolic methoxy group , buprenorphine can be isolated.


The European Pharmacopoeia uses IR spectroscopy to check the identity of buprenorphine. The determination of the content of both the base and the hydrochloride is carried out as an acidimetric titration with perchloric acid in glacial acetic acid and a potentiometric endpoint display .

A rapid test based on an immunoassay is available for the detection of buprenorphine in urine . In addition, a confirmatory analysis for buprenorphine using chromatographic methods such as high-performance liquid chromatography with photodiode line detection , gas chromatography with mass spectrometry coupling or liquid chromatography with mass spectrometry coupling can be carried out from biological samples.


Buprenorphine has seven neighboring centers of asymmetry , four of which are introduced by synthetic steps.

Trade names

  • Norspan (D, A), Subutex (D, A, CH, FR, BE), Buvidal (D, UK, DK, NO, SW, SF), Bupensan (A), Temgesic (D, A, CH, FR, BE), Transtec (D, A, CH, FR, BE), Triquisic (A) and generics
  • Buprenovet (veterinary medicine, D)
Combination preparations
  • Fixed combination with naloxone : Suboxone (EU)

Web links

Individual evidence

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