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Aust J Gen Pract 2020 06;49(6):339-343

BSc (Hons), MBChB, PhD, FRANZCP, FAChAM, Director, Turning Point, Eastern Health, Vic; Professor of Addiction Studies, Monash University, Vic.

Background: Opioids are frequently used to manage chronic non-cancer pain despite the lack of evidence of benefit and clear evidence of opioid-related harms. Patients undergoing high-dose opioid therapy are at risk of multiple complications, such as opioid toxicity, including fatal overdose and opioid dependence.

Objective: This article provides an overview of the pharmacology of buprenorphine and reviews current evidence for the use of high-dose sublingual buprenorphine-naloxone in the pharmacological management of patients at high risk of complications from chronic opioid use. Read More

J Pharm Biomed Anal 2020 Feb 16;180:113042. Epub 2019 Dec 16.

Inserm, U1144, Paris, France; Paris-Descartes University, UMR-S 1144, Paris, France; Paris-Diderot University, UMR-S 1144, Paris, France; Forensic Toxicology Unit, Forensic Sciences Institute of the French Gendarmerie, Pontoise, France.

Buprenorphine and buprenorphine/naloxone combination are maintenance treatments used worldwide. However, since their marketing, despite ceiling respiratory effects, poisonings and fatalities have been attributed to buprenorphine misuse and overdose. Therefore, to better understand the mechanisms of buprenorphine-related toxicity in vivo, experimental investigations have been conducted, mainly in the rat. Read More

Am J Emerg Med 2020 03 16;38(3):691.e3-691.e4. Epub 2019 Nov 16.

Cook County Health, Department of Emergency Medicine, Division of Medical Toxicology, Chicago, IL, United States.

Naloxone is a frequently utilized and effective treatment to reverse the life-threatening effects of illicit opioid intoxication. Excessive naloxone dosing in these circumstances, however, may lead to naloxone-precipitated opioid withdrawal in individuals with opioid dependence. Buprenorphine, a partial mu-opioid agonist, is increasingly utilized in the Emergency Department (ED) for the treatment of opioid withdrawal syndrome but little is known regarding its utility in cases of naloxone-precipitated opioid withdrawal. Read More

Sci Adv 2019 10 2;5(10):eaax9140. Epub 2019 Oct 2.

Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, NY, USA.

Opioid use disorders (OUDs) are diseases of the brain with behavioral, psychological, neurobiological, and medical manifestations. Vulnerability to OUDs can be affected by factors such as genetic background, environment, stress, and prolonged exposure to μ-opioid agonists for analgesia. Two standard-of-care maintenance medications, methadone and buprenorphine-naloxone, have a long-term positive influence on health of persons with opioid addiction. Read More

Can Fam Physician 2017 Mar;63(3):200-205

Staff physician in the Department of Family and Community Medicine at St Michael's Hospital in Toronto.

Objective: To advise physicians on which treatment options to recommend for specific patient populations: abstinence-based treatment, buprenorphine-naloxone maintenance, or methadone maintenance.

Sources Of Information: PubMed was searched and literature was reviewed on the effectiveness, safety, and side effect profiles of abstinence-based treatment, buprenorphine-naloxone treatment, and methadone treatment. Both observational and interventional studies were included. Read More

Subst Abus 2017 Jan-Mar;38(1):18-21. Epub 2016 Dec 7.

a Department of Addiction Psychiatry , University of California San Francisco , San Francisco , California , USA.

Background: Opioid overdose is a growing concern in the United States and internationally. Prehospital or pre-medical personnel (layperson) administration of naloxone, an opioid antagonist, to reverse overdose, is an expanding mode of harm reduction. Recently, community clinics, methadone clinics, needle exchanges, some pharmacies, and other health care facilities have made naloxone available to the community. Read More

Toxicol Sci 2017 02 1;155(2):389-399. Epub 2016 Nov 1.

Inserm, U1144, Paris, France;

Respiratory depression and fatalities have been attributed to ethanol/buprenorphine (BUP) combination in drug addicts maintained with BUP/naloxone or BUP alone. The exact mechanisms of the ethanol/BUP interaction and the contribution to the toxicity of norbuprenorphine (NBUP), the main BUP metabolite with respiratory depressant properties are unknown. We investigated the sedative and plethsymographic effects resulting from the co-administration of intragastric ethanol (3 g/kg) and intravenous BUP (30 mg/kg) in Sprague-Dawley rats. Read More

MMWR Morb Mortal Wkly Rep 2016 Oct 21;65(41):1148-1149. Epub 2016 Oct 21.

Expanding access to office-based medication-assisted treatment with buprenorphine/naloxone for opioid dependence is a key part of the national strategy to address the opioid abuse epidemic (1). However, as buprenorphine/naloxone prescribing increased, emergency department (ED) visits and hospitalizations for unsupervised ingestions by young children began to increase, with buprenorphine/naloxone ingestions becoming the most common cause of hospitalization for medication ingestions by young children during 2010-2011 (2). Buprenorphine ingestions might be asymptomatic or can cause drowsiness, vomiting, or respiratory depression, which if untreated can result in death (3). Read More

Clin Toxicol (Phila) 2017 Jan 19;55(1):12-17. Epub 2016 Oct 19.

a Harvard Medical Toxicology Program , Boston Children's Hospital , Boston , MA , USA.

Context: Exploratory buprenorphine ingestions in young children have been associated with clinically significant toxicity. However, detailed data on the clinical presentation and management of these patients are lacking. In an attempt to obtain more comprehensive data, we sought to examine a single center cohort of patients with report of buprenorphine exposure and provide descriptive analysis of rates of respiratory depression, time to respiratory depression, interventions, disposition, and outcomes. Read More

Am J Addict 2015 Aug 3;24(5):388-90. Epub 2015 Jun 3.

Atlanta VA Medical Center, Decatur, Georgia.

Background: This is a case report describing a reversal of fentanyl overdose with naloxone nasal spray. The patient was not aware that he overdosed on fentanyl being sold as heroin.

Methods: The Veterans Health Administration (VHA) has implemented an initiative to provide education for veterans, their families, friends and significant others about opioid overdose and use of naloxone reversal kits. Read More

Hosp Pediatr 2015 Mar;5(3):164-6

Palmetto Health Children's Hospital, Division of Pediatric Critical Care, Columbia, South Carolina

Toxicol Lett 2015 Feb 12;232(3):590-4. Epub 2014 Dec 12.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

The method of choice for reversal of opioid-toxicity is administration of naloxone. This treatment can be accompanied by complications including acute lung-injury, myocardial infarction, or withdrawal-syndrome (in dependent-patients). We aimed to evaluate the efficacy of buprenorphine in reversal of opioid-overdose syndrome in dependent-rats. Read More

Am J Addict 2014 Nov-Dec;23(6):563-9. Epub 2014 Sep 22.

Department of Psychiatry, Ludwig Maximilian University, Munich, Germany; Private Hospital Meiringen, Meiringen, Switzerland.

Background: Some case series mention possible liver toxicity in opioid-dependent patients under buprenorphine treatment.

Methods: This 12-month prospective observational follow-up study in opioid-dependent patients under buprenorphine-naloxone treatment assessed outcome and safety issues. At baseline, 337 eligible datasets were available; 181 patients completed the 12-month study. Read More

Drug Alcohol Depend 2014 Sep 19;142:139-45. Epub 2014 Jun 19.

National Institute of Allergy and Infectious Diseases, Division of AIDS, Prevention Sciences Branch, 6700 B Rockledge Drive, Room 5121, Bethesda, MD 20892, United States.

Background: Buprenorphine/naloxone (BUP/NX), an effective treatment for opioid dependence, has been implicated in hepatic toxicity. However, as persons taking BUP/NX have multiple hepatic risk factors, comparative data are needed to quantify the risk of hepatoxicity with BUP/NX.

Methods: We compared rates of alanine aminotransferase (ALT) elevation≥grade 3 (ALT≥5. Read More

Toxicol Lett 2014 Jul 21;228(2):75-84. Epub 2014 Apr 21.

Inserm, U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France; Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, 2 rue Ambroise Paré, 75010 Paris, France. Electronic address:

Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. Read More

Drug Alcohol Depend 2014 May 23;138:118-23. Epub 2014 Feb 23.

Department of Psychiatry, University of Maryland School of Medicine, 22 S. Greene Street Box 349 P-1-H-10, Baltimore, MD 21201, USA.

Background: Polysubstance use is prevalent in individuals using buprenorphine or methadone nonmedically, with benzodiazepines being a common co-ingestant. The objective of this study was to compare the severity of buprenorphine and methadone toxicity with concomitant use of benzodiazepines.

Methods: A retrospective analysis of buprenorphine and methadone cases from November 1, 2002 to December 31, 2010 reported to the American Association of Poison Control Centers' National Poison Data System (NPDS) was conducted. Read More

Am J Addict 2014 Jan-Feb;23(1):34-40. Epub 2013 Jun 10.

Department of Psychiatry, University of California, San Francisco, California.

Background And Objectives: The purpose of this study was to examine the effect of hepatitis C virus (HCV) infection on buprenorphine pharmacokinetics in opioid-dependent, buprenorphine/naloxone-maintained adults.

Methods: A retrospective analysis of buprenorphine pharmacokinetics in HCV seropositive and seronegative buprenorphine/naloxone-maintained individuals (N = 49) was undertaken.

Results: Relative to HCV seronegative subjects, HCV seropositive subjects had higher buprenorphine exposure, as demonstrated by elevated buprenorphine AUC and Cmax values (p = . Read More

J Emerg Med 2013 Aug 11;45(2):199-205. Epub 2013 May 11.

University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Background: There exists a significant amount of misinformation regarding methadone and buprenorphine, and a belief that toxicity associated with nonmedical use of methadone and nonmedical use of buprenorphine is similar in severity and outcomes.

Objective: The objective of this study is to compare outcomes associated with nonmedical use of methadone vs. nonmedical use of buprenorphine in patients presenting to the Emergency Department (ED) and reported to poison centers. Read More

Curr Drug Abuse Rev 2013 Mar;6(1):63-70

Department of Psychiatry, University of Munich, Germany.

Opioid maintenance therapy with methadone or buprenorphine is an established and first-line treatment for opioid dependence. Risk of diversion and toxicity of opioid prescription drugs, including buprenorphine, causes significant concerns. This is particularly the case in the United States, where the number of related emergency visits is increasing, especially in children. Read More

Eur Respir J 2013 Aug 25;42(2):394-403. Epub 2012 Oct 25.

LDS Hospital, Salt Lake City, UT 84143, USA.

Patients using chronic opioids are at risk for exceptionally complex and potentially lethal disorders of breathing during sleep, including central and obstructive apnoeas, hypopnoeas, ataxic breathing and nonapnoeic hypoxaemia. Buprenorphine, a partial μ-opioid agonist with limited respiratory toxicity, is widely used for the treatment of opioid dependency and chronic nonmalignant pain. However, its potential for causing sleep disordered breathing has not been studied. Read More

Mol Neurobiol 2011 Dec 24;44(3):250-68. Epub 2011 Sep 24.

Department of Psychiatry and McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA.

Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. Read More

J Acquir Immune Defic Syndr 2011 Mar;56 Suppl 1:S62-7

The CORE Center, Chicago, IL, USA.

Background: The safety of buprenorphine/naloxone (bup/nx) in HIV-infected patients has not been established. Prior reports raise concern about hepatotoxicity and interactions with atazanavir.

Methods: We conducted a prospective cohort study of 303 opioid-dependent HIV-infected patients initiating bup/nx treatment. Read More

Pediatr Crit Care Med 2011 Mar;12(2):e102-7

Department of Pediatrics and Pediatric Critical Care, University of Massachusetts Medical School, Worcester, MA, USA. ernest.pedapaticchmc.org

Background: Sublingual buprenorphine is an alternative to methadone for office-based treatment of opioid dependence. Recent reports have examined a growing number of unintentional buprenorphine exposures in children resulting in significant toxicity, even after a single lick or taste of a sublingual tablet. Here, we report a series of unintentional buprenorphine exposures in toddlers over a 2. Read More

Clin Drug Investig 2010 ;30 Suppl 1:21-6

U.O.C. Ser.T Cosenza Provincial Health Agency, Cosenza, Italy.

Opioid dependence is a growing problem. Methadone is an established agent for the treatment of opioid dependence, but there is a risk of this agent being abused, a potential for interaction with antiretroviral agents and a risk of cardiac toxicity. Another option is the partial mu-opioid receptor opioid agonist buprenorphine, which has been used successfully to manage opioid dependence. Read More

Eur J Anaesthesiol 2010 Feb;27(2):174-80

Clinics of Vascular Surgery, University Clinics of Duesseldorf, Duesseldorf, Germany.

Background And Objective: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure.

Methods: To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Read More

Pediatrics 2008 Apr;121(4):e782-6

PharmD, Maryland Poison Center, University of Maryland School of Pharmacy, 220 Arch St, Office Level 1, Baltimore, MD 21201, USA.

Objective: There are few reports in children of overdoses of buprenorphine, a partial opioid agonist used in the treatment of opioid dependence and pain. The purpose of this study was to analyze buprenorphine overdoses in young children reported by US poison centers to the Researched Abuse, Diversion, and Addiction-Related Surveillance System.

Methods: A retrospective review of buprenorphine overdoses in children < 6 years of age reported to the Researched Abuse, Diversion, and Addiction-Related Surveillance System from November 2002 through December 2005 was performed. Read More

Regul Toxicol Pharmacol 2008 Apr 17;50(3):285-93. Epub 2007 Nov 17.

The Procter & Gamble Co, Miami Valley Innovation Center, P.O. Box 538707, Cincinnati, OH 45253, USA.

Dextromethorphan (DMP) is an effective and widely used antitussive drug. While DMP has over a 50 year safe-marketing history, the only available genotoxicity data was an unpublished, negative Ames assay (Roche). Lack of a complete genotoxicity profile on DMP, specifically covering the chromosomal damage endpoint, prompted a regulatory request for an in vitro chromosome aberration assay. Read More

Pediatr Emerg Care 2007 Sep;23(9):651-2

California Poison Control System, San Diego Division, University of California, San Diego Medical Center, San Diego, CA 92103, USA.

Background: Suboxone, a combination of buprenorphine and naloxone in sublingual tablet form, was recently approved in the United States for management of opioid dependence. Little information exists regarding the potential for opioid toxicity after Suboxone exposure in the pediatric population. We report a case of opioid toxicity after exposure to Suboxone in a pediatric patient and a review of other cases of pediatric Suboxone ingestion in the literature. Read More

Ann Emerg Med 2007 Feb 12;49(2):172-7. Epub 2006 Jul 12.

University of California, San Francisco, Department of Medicine, Section of Emergency Medicine, and the Treatment Research Center, USA.

The mortality and morbidity from heroin overdose have increased in the United States and internationally in the last decade. The lipid solubility allows the rapid deposition of heroin and its metabolites into the central nervous system and accounts for the "rush" experienced by users and for the toxicity. Risk factors for fatal and nonfatal heroin overdoses such as recent abstinence, decreased opiate tolerance, and polydrug use have been identified. Read More

J Pharmacol Exp Ther 2001 Aug;298(2):797-804

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, USA.

The developmental effects of exposure to various doses of buprenorphine, methadone, or water during the perinatal period were studied in the rat. Rats were exposed to buprenorphine (0.3, 1. Read More

Eur J Pharmacol 1998 Apr;347(1):105-12

Department of Biological Pharmaceutical Sciences, College of Pharmacy, Nihon University, Chiba, Japan.

A morphine alkaloid derivative, buprenorphine hydrochloride, induces apoptosis in NG108-15 cells. Apoptosis was detected mainly by apoptosis-specific DNA fragmentation and morphological changes. This apoptosis was dose-dependent and the time-course experiment indicated that DNA fragmentation occurred within 4 h after administration of buprenorphine hydrochloride. Read More

Inflamm Res 1996 Jun;45(6):299-302

Ciba-Geigy Ltd., Research Department, Basel, Switzerland.

We have examined the effect of the micro-opioid analgesic buprenorphine on osteoclastic bone resorption in vitro and in the rat adjuvant arthritis model. In the bone slice assay buprenorphine inhibited osteoclastic bone resorption with an IC50 of 1 microM. This effect was not mimicked by the micro-opioid agonist ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin and was not prevented by the micro-opioid antagonist naloxone. Read More

Arch Int Pharmacodyn Ther 1994 Jul-Aug;328(1):99-105

Department of Pharmacology, Goa Medical College, India.

Morphine has a significant protective effect on ethanol-induced gastric lesions. This effect is antagonized by naloxone, suggesting that it is mediated by opioid receptors. In the rat, mu-receptors have been shown to be involved in other gastrointestinal actions of opioids. Read More

Eur J Pharmacol 1993 May;236(2):193-9

Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140.

Naloxone is known to decrease, increase or have no effect on nociceptive thresholds. Here, using two commonly accepted pain-related behaviors (licking and flinching) associated with injection of noxious formalin into a hind paw in rats, naloxone (0.1-1 mg/kg s. Read More

Life Sci 1991 ;49(25):1887-93

Department of Anesthesiology, New York University Medical Center, NY 10016.

The effect of buprenorphine pretreatment on the acute cocaine toxicity was assessed in male Swiss Webster mice. Buprenorphine pretreatment (0.15 or 0. Read More

Biopharm Drug Dispos 1990 May-Jun;11(4):311-50

The Beehive, College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville 32610-0494.

Specific and sensitive reverse-phase HPLC assays of buprenorphine and its metabolite in biological fluids were developed with sensitivities of 2-6 ng ml-1 using fluorimetric detection. Pharmacokinetics were monitored on acute bolus administration of buprenorphine in 6 dogs within the 0.7-2. Read More

Neuropeptides 1984 Dec;5(1-3):19-22

The capacity of morphine to suppress natural and precipitated withdrawal was compared in morphine-dependent rhesus monkeys. A similar severity of withdrawal was induced by 14-hr deprivation or precipitated by naloxone, naltrexone, cyclazocine, Win 44,441 or MR 2266. Regardless of the procedure used to induce withdrawal, behavioral signs were completely suppressed by a cumulative dose of 17. Read More

Drugs 1979 Feb;17(2):81-110

Buprenorphine, a derivative of the morphine alkaloid thebaine, is a strong analgesic with marked narcotic antagonist activity. In studies in relatively small groups of postoperative patients with moderate to severe pain, one or a few doses of buprenorphine parenterally (by intramuscular or slow intravenous injection) or sublingually were at least as effective as standard doses of other strong analgesics such as morphine, pethidine or pentazocine, and buprenorphine was longer acting than these agents. Only a small number of patients with chronic pain have received repeated doses, but in such patients there was no need for increased doses during several weeks to months of treatment. Read More