Buprenorphine - an overview | ScienceDirect Topics (2023)

Abuse of buprenorphine was associated with livedoid and necrotic skin lesions after intra-arterial administration of buprenorphine in two women with a history of drug abuse [201A].

From: Side Effects of Drugs Annual, 2012

Related terms:

  • Methadone
  • Anodyne
  • Opioid Dependence
  • Opiate
  • Naltrexone
  • Opiate Agonist
  • Diamorphine
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Chronic Pain during and after Pregnancy

David H. Chestnut MD, in Chestnut's Obstetric Anesthesia, 2020


Buprenorphine is used for treatment of both opioid use disorder and chronic pain; typically doses are lower when used to treat pain.149 It is a partial agonist at the µ-opioid receptor and an antagonist at the κ-opioid receptor (seeChapter 13). This profile allows for a ceiling effect for respiratory depression and an improved side-effect profile compared with full µ-opioid agonists. Partial µ-opioid agonism reduces the overdose risk, and daily observed dosing for the treatment of opioid use disorder is less commonly required than for methadone.150 However, the strong binding affinity to the µ-opioid receptor, combined with its action as a partial agonist, has raised the concern that it may not be possible to overcome the ceiling effect, and adequate treatment of post–cesarean delivery pain may be difficult to achieve. It is not known whether this problem is specific to buprenorphine treatment or a consequence of opioid use disorder and the use of high doses of opioids in general. One study found that post–cesarean delivery opioid requirements were high but equivalent in women treated with either methadone or buprenorphine.151

Buprenorphine is currently available in multiple formulations, including tablets, buccal films, transdermal patches, subcutaneous implants, and depo injections.152 Formulations that allow high doses (greater than 2 mg) may be combined with naloxone to prevent illicit injection. Some depo and implant forms of buprenorphine are very long lasting; strategies other than conversion to full-agonist opioid agonist therapy may need to be considered for peripartum pain management.

The Maternal Opioid Treatment: Human Experimental Research (MOTHER) trial compared the incidence of neonatal opioid withdrawal syndrome after maternal treatment with buprenorphine (n = 58) or methadone (n = 73) for maternal opioid use disorder.143 Treatment for withdrawal was required in 57% of neonates in the methadone group and 47% in the buprenorphine group, a nonsignificant difference (OR, 0.7; 95% CI, 0.2 to 1.8). However, the neonates in the buprenorphine group who did require treatment required significantly less morphine; duration of therapy and hospital stays were shorter than for neonates exposed to methadone. These results have led many clinicians to recommend buprenorphine over methadone for treatment of maternal opioid use disorder. It should be noted, however, that the maternal attrition rate was significantly greater in the buprenorphine group than in the methadone group.143

The peripartum management of pregnant patients receiving buprenorphine may be challenging, especially if treatment doses are high. Possible reasons include the high µ-opioid receptor affinity and partial agonist mechanism of buprenorphine, opioid tolerance, and/or opioid-induced hyperalgesia. Because buprenorphine can be administered in many forms and doses, the daily dose may not be immediately obvious (e.g., the extended-release subcutaneous formulation).152


William Dewey, in xPharm: The Comprehensive Pharmacology Reference, 2007


Buprenorphine hydrochloride is a partial agonist at mu opioid receptors, and a very weak partial agonist at kappa opioid receptors and an even weaker partial agonist at delta opioid receptors. On the other hand, buprenorphine has a similar high affinity for all three opioid receptor subtypes. The (-) stereoisomer is >2000 times as potent as the (+)isomer.

Buprenorphine relieves pain similar to morphine and other opiates. It is more potent and has a longer duration of action than morphine. It is well absorbed following most routes of administration including the sublingual route, and produces rapid analgesia. Buprenorphine hydrochloride also is an effective maintenance drug in the treatment of opioid dependence and is rapidly replacing methadone in this use.

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Substance Abuse in Pregnancy

Robert Resnik MD, in Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice, 2019

Choosing Between Buprenorphine and Methadone

When one is choosing to initiate a patient on buprenorphine versus methadone, many considerations should be taken: being mindful that the goals of both treatments are to stabilize the patient, prevent drug cravings, and prevent illicit drug use. Physicians need to be reminded that the initiating provider has an ethical and medical responsibility to ensure continued care if they begin opiate maintenance therapy. Simply initiating medication in the acute setting, without ensured follow-up with a prescribing physician to maintain them, is an inadequate attempt at treatment.

One of the first considerations to make when choosing between buprenorphine and methadone is any treatment history and response to treatment. Attention should be paid to the degree of the patient's drug use. Is the patient highly dependent on street drugs at high doses, or is her use of a milder variety? Keeping in mind that buprenorphine is a partial agonist with a ceiling effect, it would be prudent to initiate patients with significant use on the full agonist methadone, and vice versa.

Because the models of care are vastly different when prescribing methadone versus buprenorphine, social factors are sometimes pivotal in your decision as well. Methadone is largely distributed by federally funded treatment facilities, requiring daily arrival to the clinic for dosing. Buprenorphine can be prescribed in an office based setting by providers who have received specialized training and licensure, thus visits can be more flexible for patients who may have transportation issues, child care issues, or who happen to live far from treatment sites. There is no set algorithm for choice of medication, but these guiding principles, along with evaluating and respecting the patient's goals, should help identify the best choice for your patient.


In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016

Drug–drug interactions

See also Rifamycins


Buprenorphine is mainly metabolized by CYP3A4. Concomitant use of medications that induce CYP3A4 (for example rifampicin, phenytoin) or inhibit it (for example fluoxetine, cimetidine, saquinavir) may increase or inhibit buprenorphine metabolism and caution should be taken when buprenorphine is given with such drugs [61,81].

Antiretroviral drugs

The interaction of buprenorphine with antiretroviral drugs has been reviewed [82,83]. Adverse effects due to this interaction have been reported; the interaction of buprenorphine with atazanavir and ritonavir resulted in reduced mental functioning and central nervous system depression [84].

An interaction of buprenorphine+naloxone (Suboxone) with delavirdine or ritonavir, which inhibit CYP3A4, can prolong the QT interval. In 50 HIV-positive patients taking antiretroviral drugs, buprenorphine+naloxone caused QT interval prolongation which was statistically but not clinically significant; there was no prolongation in opioid-dependent subjects who were taking only buprenorphine+naloxone [85].


The concomitant use of buprenorphine with benzodiazepines is common among opiate addicts, both in and out of treatment. Benzodiazepines enhanced the response to buprenorphine (mean dose 11mg) in seven patients engaged in treatment, influencing attention, psychomotor skills, and sedation [86]. These changes peaked 1–2 hours after medication, suggesting an appropriate period for clinical monitoring.

Six deaths linked to misuse of buprenorphine plus benzodiazepine combinations have been described [48]. The authors emphasized that blood concentrations of buprenorphine were in the target range in three subjects, although higher in three others. Exhaustive screening detected no traces of opiates in postmortem blood, but all subjects had target range concentrations of both desmethyldiazepam and 7-aminoflunitrazepam. The risk of high-dose substitution therapy (2–8mg), if physicians do not comply with correct practices for the prescription, and use of buprenorphine were emphasized, particularly when there is a large population of patients being treated, as there was in France in 1997 (34000 patients).

An interaction of therapeutic doses of diazepam (10 and 20mg) with buprenorphine in 16 subjects resulted in increased subjective measures of sedation and some impairment of psychomotor performance (deterioration in cancellation time) [87]. This interaction of was compared with that of methadone and diazepam. The former caused less psychomotor impairment.


It has been postulated that the concomitant use of buprenorphine 5mg/day and cannabis 2–6 cigarettes/day contributed to the development of brain hemorrhage and cerebral vasospasm in a 34-year-old woman who had previously tolerated both substances for a long time [88]. The association was supported by the fact that angiographic abnormalities disappeared when the doses were reduced.

HIV-1 protease inhibitors

The metabolism of buprenorphine is inhibited by the HIV-1 protease inhibitors [89].

The interaction of atazanavir and atazanavir+ritonavir with buprenorphine has been explored in 40 opioid-dependent HI- negative volunteers taking buprenorphine+ naloxone [90]. Atazanavir and atazanavir+ritonavir in recommended doses were associated with increased concentrations of buprenorphine and its main metabolite. This was associated with sedation in 30%, suggesting that a reduction in dosage may be appropriate and that monitoring is clinically warranted. Concentrations of atazanavir and atazanavir+ritonavir were not affected.


An interaction has been reported between buprenorphine and the chemotherapeutic agent ifosfamide [91].

A 34-year-old man was given transdermal buprenorphine for pain, initially 35 micrograms/hour, later increased to 52.5 micrograms/hour. He developed respiratory depression, which resolved on withdrawal of the patch.

The authors suggested that respiratory depression had been triggered by the dual action of buprenorphine and ifosfamide on CYP3A4.


Naloxone is of limited use in reversing the effects of buprenorphine, because of its relative inability to displace it from opioid receptors. Naloxone 1mg had little effect on the respiratory depression caused by buprenorphine 300 micrograms/70kg, although both 5 and 10 micrograms produced consistent reversal, which was more complete with the larger dose [92]. Insignificant effects on circulation and respiration have been reported at lower doses of buprenorphine (4.5–10 micrograms/kg) [93].

The addition of ultra-low doses of naloxone to buprenorphine in healthy subjects enhanced the analgesic effect without increasing the incidence of adverse effects; in fact respiratory depression was less pronounced with the addition of naloxone in a 10:1 ratio [94].

Opioid receptor agonists

Under some conditions the antagonist action of buprenorphine can jeopardize the effect of subsequently administered pure opioid agonists, by blocking MOR(OP3, μ) opioid receptors so effectively that normal doses of the opioid agonist are ineffective, necessitating the administration of a higher dose, with the attendant risk of respiratory depression, from which deaths have been reported [95]. Fortunately such instances appear to be rare.

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J.K. Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM, in Meyler's Side Effects of Drugs, 2016

Drug abuse

Abuse of buprenorphine has been reported in many countries and it is now widely dealt with under psychotropic drug legislation.

Although sublingual buprenorphine has been used in the management of heroin addiction [38], widespread abuse of buprenorphine by addicts is known [39], including the snorting of crushed sublingual tablets [40].

Buprenorphine is taken in the form of a sublingual tablet, which takes 3–5 minutes to dissolve and be absorbed. In order to reduce the likelihood of intravenous abuse of buprenorphine, it has been combined with naloxone. This combined product is poorly absorbed by mouth and if injected can precipitate unpleasant opioid withdrawal reactions. Further large-scale studies are needed to study the efficacy and safety profile of buprenorphine, with or without naloxone, in different opioid-dependent populations, in order to determine the cumulative effect of repeated administration [41], and to explore alternative delivery systems, such as intravenous [42], intramuscular [43], and depot formulations [44].

Buprenorphine is increasingly being used as a substitute for other opioids in the treatment of opioid abuse and is generally considered to be safe because of the ceiling effect. One report from Vienna described 50 opioid-dependent subjects who received gradual (10-day) detoxification with buprenorphine, contacting the outpatient clinic daily, so that buprenorphine could be administered according to their clinical need in a free dosage scheme [45]. The mean daily dosage was 2.3mg on day 1 and the highest mean daily dose was administered on day 2, followed by daily reduction over the study period. There was 70% compliance with the regimen and withdrawal symptoms during the study period were described as moderate.

Less satisfactory outcomes have been reported from France [46–48], where acute poisoning during buprenorphine substitution has been described in three series of patients. The first included 29 opiate addicts taking high-dosage sublingual buprenorphine with non-fatal poisoning and the second included 20 addicts who died [47]. Blood concentrations of buprenorphine in the first group were low (1.0–2.3ng/ml, mean 1.4ng/ml), but there was concomitant intake of psychotropic medication, especially benzodiazepines, in 18 cases. Blood concentrations of buprenorphine in the fatal cases were 1.1–29 (mean 8.4) ng/ml, while concentrations of its primary metabolite, norbuprenorphine, were 0.2–13 (mean 2.6) ng/ml, within or slightly over the target range. Extensive tissue distribution buprenorphine was reported (myocardium, kidney, brain, and liver) but the highest concentrations of buprenorphine and norbuprenorphine were found in the bile, and the authors suggested that this may be the sample of choice for postmortem screening. Buprenorphine was also identified in eight of 11 hair samples assayed. Intravenous injection of crushed tablets and the concomitant use of benzodiazepines were identified as the major risk factors in the fatal cases [47].

Opioid Analgesics

Dhanalakshmi Koyyalagunta, in Pain Management, 2007

Therapeutic Uses and Preparations

Buprenorphine is used to treat moderate to severe pain conditions. Parenteral buprenorphine can be given in a dose of 0.3 mg every 6 to 8 hours. It may not be a good choice for intravenous patient-controlled analgesia because of slow onset of action. Few studies have described effective analgesia with minimal respiratory depression associated with buprenorphine via intravenous patient-controlled analgesia. Sublingual buprenorphine 0.4 mg every 8 hours provides analgesia equivalent to 10 mg of morphine intramuscularly every 4 hours. Literature is available describing the use of epidural buprenorphine for cesarean section and postoperative pain.

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Improving Medication Use in AddictionsTreatment

Amanda J. Abraham, in Interventions for Addiction, 2013

Buprenorphine (Suboxone®, Subutex®)

Buprenorphine was FDA approved for the treatment of opiates in 2002. Before buprenorphine was FDA approved for opiate treatment it was used for pain management. FDA approval of buprenorphine for treatment of opiate dependence was intended to increase access for opiate addiction by allowing physicians in office-based settings to prescribe the medication.

Buprenorphine is a partial opioid agonist compared to methadone and heroin which are full opioid agonists. Buprenorphine has a lower risk of abuse, addiction, and side effects compared to full agonists. Buprenorphine can be used for detoxification, maintenance, and pain management.

There are currently two buprenorphine products FDA approved for the treatment of opioid addiction: Subutex and Suboxone. Subutex is comprised of only buprenorphine and is a partial mu-opioid agonist. Suboxone combines buprenorphine with naloxone and is both a partial mu-opioid agonist and a mu antagonist. The buprenorphine/naloxone combination appears to reduce abuse potential as compared to buprenorphine alone. Naloxone is added to buprenorphine to decrease the likelihood of diversion and abuse. Both Suboxone and Subutex are sublingual tablets that are available in two dosages.

In contrast to methadone, which can be administered only by OTPs, buprenorphine can be administered by waivered office-based physicians. In fact, one of the reasons for the FDA approval of buprenorphine was to facilitate greater access to treatment for opiate dependence, especially in areas of the county that do not have OTPs.

Buprenorphine is a controlled substance (Schedule III drug) that is monitored and regulated by the federal government (i.e. DEA and CSAT). Buprenorphine may be prescribed only by a waivered physician. To qualify for a waiver, physicians must complete 8h of training; waivers are granted by CSAT. During the first year, physicians can treat only 30 patients at a time. After the first year, physicians may apply to CSAT to treat up to 100 patients.

Prior to 2003, OTPs were not allowed to dispense buprenorphine. However, in 2003, SAMHSA began allowing OTPs to also get certified to prescribe Subutex and Suboxone for maintenance or detox (not pain management). OTPs providing buprenorphine must conform to 42 CRF 8.12 which requires that OTPs provide medical, counseling, drug abuse testing, and other services to patients admitted to treatment. OTPs must also modify their registration with the DEA to add Schedule III narcotics to their registration certificates.

Clinical trials indicate that buprenorphine is more effective than placebo and equally effective to moderate doses of methadone and LAAM in opiate maintenance therapy. Results also show that buprenorphine is unlikely to be as effective as more optimal-dose methadone and, therefore, may not be the treatment of choice for patients with higher levels of physical dependence. Buprenorphine has been shown to be effective in short-term detox as well and may be used with pregnant women and adolescents.

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Prescription Opioids: An Overview

Amitava Dasgupta, in Fighting the Opioid Epidemic, 2020


Buprenorphine is a semisynthetic opiate that is synthesized from natural alkaloid thebaine found in opium. Buprenorphine was introduced in the early 1980s as an opioid analgesic in Europe and subsequently for the treatment of opioid addiction in France in 1996. Buprenorphine was approved by the US FDA in October 2002 as a Schedule III narcotic for use in treating opioid-dependent men and opioid-dependent women who are not pregnant. Buprenorphine has a significantly different mechanism of interaction with opioid receptors compared with other opioids such as morphine. Buprenorphine is a potent but partial agonist of μ-opioid receptor, showing a high affinity but low intrinsic activity. High potency and slow off rate (half-life of association/dissociation is 2–5h) help buprenorphine displace other μ-opioid agonists such as morphine from receptors and overcome opioid dependence issues. Buprenorphine is approximately 25–100 times more potent than morphine and has a prolonged therapeutic effect that is very useful to opioid dependance, as well as pain. Interestingly, buprenorphine is a potent κ-receptor antagonist, as well as an antagonist for δ-opioid receptors. Buprenorphine is a preferred opioid for treatment of pain in patients with renal or liver dysfunction [68]. Chemical structure of buprenorphine is given in Fig.2.3.

Buprenorphine is a lipophilic chiral molecule and has low solubility in water. Compared to 100% bioavailability of buprenorphine after intravenous administration, bioavailability is 49% after administration of sublingual solution and 29% with sublingual tablets. Sublingual and transdermal formulations tend to show long half-life (20–73h). With a sublingual formulation, buprenorphine shows onset of effects at 30–60min after dosing, and the peak clinical effects are observed at 1–4h. The duration of effect may last for 6–12h at low dose (<4mg) and 24–72h at higher dose (>16mg). The longer effect at higher buprenorphine sublingual dose may be linked to sustained, effective drug levels for extended duration because of its slower elimination and enterohepatic recirculation. Buprenorphine has a large volume of distribution, and the drug is strongly protein bound (approximately 96%) mostly to α- and β-globulins. Serum buprenorphine concentration is usually low. Buprenorphine is extensively metabolized in the liver, and the major metabolite, norbuprenorphine, is formed by CYP3A4-mediated N-dealkylation of buprenorphine. In addition, buprenorphine is conjugated with glucuronic acid during Phase II metabolism by the action of UGT2B7 enzyme, while norbuprenorphine is also conjugated with glucuronic acid by the enzyme UDP-glucuronosyltransferase 1A1 in the liver. Buprenorphine is eliminated primarily via a stool (as free forms of buprenorphine and norbuprenorphine), while 10%–30% of the dose is excreted in urine as conjugated forms of buprenorphine and norbuprenorphine. The plasma levels of conjugate metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide can exceed the parent drug levels [68].

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Pharmacologic Therapy for Neonatal Abstinence Syndrome

Prabhakar Kocherlakota MD, in Infectious Disease and Pharmacology, 2019


Buprenorphine, a semisynthetic partial µ-receptor agonist, is a new addition in NAS treatment. A long half-life (approximately 20 hours, based on limited data from premature infants102) is a major advantage for buprenorphine. There is also no cardiovascular toxicity associated with buprenorphine. Phenobarbital has minimal effect on buprenorphine clearance.103 Kraft et al., in a prospective, randomized, open-label phase I study with buprenorphine in a dose of 4.4 µg/kg/dose every 8 hours, were unable to decrease either LOS or LOT in 12 infants compared with 13 infants treated with oral neonatal opium solution.104 However, with a higher initial dose of buprenorphine (5.3 µg/kg/dose every 8 hours) and more aggressive dose advancement for high NAS scores, Kraft et al. were able to decrease LOT and LOS in a buprenorphine group (n = 12) compared with the oral neonatal opium solution group (n = 12) in another prospective phase I study.85 Hall et al., in a retrospective study, had shown decreased LOT and LOS in 38 infants treated with a buprenorphine protocol compared with 163 infants treated with a methadone protocol.105 Because buprenorphine must be given sublingually, further PK studies are needed to determine the absorption, bioavailability, and efficacy of buprenorphine in infants.103 A large prospective study might further define the role of buprenorphine in the management of NAS.

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Issues of Interference in Drugs of Abuse Testing and Toxicology

Amitava Dasgupta PhD, in Biotin and Other Interferences in Immunoassays, 2019

Interferences in Immunoassays for Other Opioids

Buprenorphine CEDIA is subjected to cross-reactivity from tramadol, a synthetic opioid, at a cutoff of 5ng/mL. However, when cutoff was increased to 20ng/mL, this interference was eliminated.65 Opiate, if present in high concentrations, may also cause false-positive buprenorphine immunoassay test results. In one study the authors reviewed data on falsely positive buprenorphine immunoassay screen results (cutoff≥5ng/mL) but negative for buprenorphine GC/MS in urine specimens, which also tested positive by opiate immunoassay at 300ng/mL cutoff. The authors found that cross-reactivity in the CEDIA buprenorphine immunoassay by opiates at concentrations <2000ng/mL will not cause a false-positive buprenorphine result.66 In addition, morphine, codeine, and dihydrocodeine, as well as amisulpride or sulpiride, if present in high concentrations in urine are known to interfere with the CEDIA buprenorphine assay.67

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