507429
research-article2013
AOPXXX10.1177/1060028013507429Annals of PharmacotherapyEiden et al
Case Report
Acute Hepatitis and Renal Failure Related to Intranasal Buprenorphine Misuse: Case Report and Analysis of Cases Reported to the French Network for Drug Monitoring
Annals of Pharmacotherapy 47(12) 1721–1726 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013507429 aop.sagepub.com
Céline Eiden, PharmD, PhD1, Marie-Pierre Ripault, MD2, Dominique Larrey, MD, PhD2, Jean-Luc Faillie, MD1, Véronique Pinzani, MD1, Georges-Philippe Pageaux, MD, PhD2, and Hélène Peyrière, PharmD, PhD1
Abstract Background: Rare cases of acute hepatitis have been reported following injection, overdose, and even during the use of buprenorphine (BPN) at therapeutic doses, especially in carriers of hepatitis C virus (HCV). Objectives: To report a case of acute hepatitis and renal failure related to intranasal BPN misuse in a HCV-negative patient and to analyze cases reported to the French postmarketing surveillance system (PMSS) of drugs and in the literature. Methods: All cases of hepatitis related to BPN reported to PMSS between January 1996 and December 2012 were analyzed. Results: A 42-year-old man with a history of intranasal BPN misuse (8 mg/d) for at least 10 years was admitted for flu-like symptoms and abdominal pain. At admission, the patient consumed alcohol, cannabis, and tobacco. Acute hepatitis and acute renal failure were diagnosed . Clinical signs and biological parameters resolved within 26 days. An objective causality assessment revealed that an adverse drug reaction (ADR) was possible. In the French PMSS database, 41 cases of suspected BPNinduced hepatitis are reported. In 36.6% of cases, BPN was misused by the intravenous route. In the literature, 16 cases of acute hepatitis related to BPN with or without renal failure are reported. In all cases, patients were HCV carriers. The primary mechanism of BPN-induced hepatitis is a mitochondrial dysfunction, exacerbated by cofactors (HCV, alcohol, and medications). Conclusion: Intranasal misuse of BPN is increasingly frequent. We report here the first documented case of acute hepatitis and renal failure related to intranasal BPN misuse in a patient negative for HCV infection. Keywords hepatitis, buprenorphine, misuse, intravenous route, intranasal route
Introduction In France, buprenorphine (BPN; sublingual 0.4-, 2-, and 8-mg tablets) was first introduced for opioid maintenance therapy (OMT) in February 1996. BPN is more widely prescribed than methadone because any physician in France is allowed to prescribe it. According to the French Observatory of Drugs and Addiction (OFDT), among the 120 000 patients treated by OMT in 2007, 80% received BPN.1 Cases of diversion and misuse (such as intravenous [IV] or intranasal administration after crushing BPN tablets) have been regularly reported with BPN. The French Observation of Illegal Drugs and Misused Psychotropic Medications (OPPIDUM) program is a survey performed each year in October, since 1998. This survey allows observation and evaluation of psychoactive substance dependence and abuse among drug users in addiction care centers.2 The OPPIDUM survey has recently shown that the intranasal route for licit or illicit substance
administration is increasing. In 2009, 46% of patients included in the OPPIDUM survey who obtained BPN without a medical prescription used BPN intranasally (vs 8% of patients having a medical order), and 16% of patients without a medical prescription used BPN intravenously (vs 7% of patients with a medical prescription).2 Misuse of BPN by injection is frequently associated with the occurrence of numerous infectious complications (eg, 1
Medical Pharmacology and Toxicology Department, University Hospital of Montpellier, France 2 Gastro-Enterology, Hepatology and Liver Transplantation Department, University Hospital of Montpellier, France Corresponding Author: Hélène Peyrière, Département de Pharmacologie Médicale et Toxicologie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. Email: [email protected]
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cutaneous abscess, endocarditis, osteoarticular infections, and sepsis).3 Acute hepatitis has also been reported.4 In addition, acute hepatitis can occur in other circumstances such as massive overdoses or at therapeutic doses, mainly in hepatitis C virus (HCV) carriers.5-8 The concomitant occurrence of acute hepatitis and renal abnormalities been reported in a few cases.5-7 We describe herein the first documented case of acute hepatitis and renal failure secondary to intranasal misuse of BPN in a patient without chronic viral hepatitis C. Cases of hepatitis related to BPN and reported to the postmarketing surveillance system (PMSS) of drugs in France and in the literature were also analyzed.
Methods An initial descriptive analysis of patients with BPN-induced acute hepatitis reported to the PMSS of drugs in France was performed. This system is based on spontaneous declaration of adverse effects to the drug (pharmacovigilance).9,10 By law, every health professional is required to report “serious” or “unexpected” adverse drug reactions (ADRs) to the French Network of Pharmacovigilance centers and “misuse,” “diversion,” or “abuse” of drugs to the French Network of Addictovigilance centers. An ADR is considered “serious” if it is fatal or life threatening, causes hospitalization or prolongation of hospitalization or permanent or significant disability. All cases of ADRs reported to the French Pharmacovigilance system are entered into a national database.9 A causality assessment method designed to evaluate the causal relationship between an ADR and one or more drugs is applied to each case. Among the ADRs reported into the French Pharmacovigilance Database (FPD), we selected all cases of acute hepatitis in which BPN was considered as “suspect” (possibly involved) and entered between January 1, 1996, and December 31, 2012. For each case, the following data were collected: gender, age, BPN daily dosage, route of BPN administration, associated drugs, and description of the acute hepatitis (delay before onset, severity, outcome, and causality assessment score). The pattern of liver damage was classified according to the International Consensus Meeting criteria, which use alanine aminotransferase (ALT) and alkaline phosphatase (AP) activity, expressed as a multiple of the upper limit of normal (ULN), to determine the ratio (R) of ALT/AP. The pattern of liver damage is hepatocellular when R >5, cholestatic when R 2 but 5. Serologies were negative for hepatitis A, B, C, and E; herpes; syphilis; and toxoplasmosis. Serum ceruloplasmin was normal. Acetaminophen and alcohol plasma detection were negative. An abdominal computerized tomography scan showed normal liver and biliary tree. Liver injury was associated with renal failure: blood urea nitrogen = 52.9 mg/dL, plasma creatinine = 1.7 mg/dL, and estimated glomerular filtration rate determined by the Modification of Diet in Renal Disease (MDRD) method was 31 mL/min/1.73 m2. BPN was stopped at admission. BPN plasma concentrations were not measured. Clinical signs and most biological parameters spontaneously resolved within 26 days (Table 1). The role of intranasal BPN was evaluated as very likely according to the updated scale of the French Drug Reaction Assessment Method and the Drug-Induced Liver Injury Scale.12,13 The causal relationship between BPN and acute hepatitis was also evaluated using the Naranjo Probability Scale and scored possible.14
FPD Analysis In the FPD, 41 cases of BPN-induced acute hepatitis are reported (Table 2). The patients were mainly men (80%) with a median age of 31 years (IQR = 27-37). Among the 41 cases, 12 (31%) had a past or current history of alcoholism, 11 (29%) were infected by HIV, and 27 (70%) were HCV carriers. Other medical histories were cirrhosis (1 patient),
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Eiden et al Table 1. Patient-Specific Biological Markers at Days 0, 6, and 26.
AST (normal < 40 U/L) ALT (normal < 41 U/L) AP (normal < 130 U/L) GGT (normal < 60 U/L) Total bilirubin (mg/dL) Direct bilirubin (mg/dL) Indirect bilirubin (mg/dL) Serum prothrombin time (s) INR Factor V Serum lactate (mmol/L) Blood urea nitrogen (mg/dL) Serum creatinine (mg/dL) Creatinine clearance (MDRD mL/min/1.73m2) Serum uric acid (mg/dL) Serum sodium (mEq/L)
Day 0
Day 6
Day 26
2357 1856 51 75 2.0 1.35 0.65 31.4 2.56 16% 9.26 52.9 1.7 31 10.4 130.9
96 431 75 108 2.5 1.6 0.9 14.8 ND ND 0.91 8.4 0.7 >120 ND 140.9
25 38 93 136 1.2 0.8 0.4 10.7 ND ND ND 12.8 0.7 >120 ND 141.8
Abbreviations: AST, serum aspartate aminotransferase; ALT, serum alanine aminotransferase; AP, alkaline phosphatase; GGT, γ-glutamyl transferase; INR, international normalized ratio; ND, not determined.
diabetes (1 patient), and psychiatric disorders (4 patients). The median BPN daily dose was 8 mg (IQR = 4-12). In 10 cases (24%), BPN was consumed with drugs that can be associated with liver function impairment, such as aspirin, acetaminophen, antituberculosis therapy, or antiretroviral agents. The pattern of liver damage was classified with the ALT/AP ratio in 17 cases (AP not available in 24 cases): 11 hepatocellular, 2 cholestatic, and 4 mixed. Coagulation disorders were observed in 11 cases. Abdominal ultrasonography was performed in 10 cases and showed normal liver in all cases. A biopsy was performed in 9 cases and showed necrosis in 1 case, fibrosis in 2 cases, and chronic hepatitis in 5 cases; it was normal in 1 case. For 15 patients (36.6%), IV misuse of BPN was noted. The characteristics of hepatitis related to BPN in patients using BPN by the recommended route (sublingual administration) versus IV administration are summarized in Table 2. The profile of patients and hepatitis did not significantly differ, except for total bilirubin values, which were significantly higher in patients using BPN intravenously, and the rate of BPN discontinuation (sublingual administration: BPN stopped in 10/20, BPN not stopped in 10/20; IV administration: BPN stopped in 6/10, IV administration stopped in 3/10, BPN not stopped in 1/10; P = .009).
Discussion We report here the first documented case of acute liver and renal failure secondary to intranasal misuse of BPN in a patient without HCV chronic infection.
At recommended sublingual doses, BPN seems to be well tolerated. Over the 17 years of BPN marketing, only 41 cases of acute hepatitis have been reported to the French PMSS (estimated event: 41/17 years, or 2.4/year, corresponding to 2.4/120 000 treated patients = 0.002%). However, because the French PMSS is based on a spontaneous reporting of ADRs, this value is probably underestimated. A community prospective study performed in France over a 3-year period found an annual incidence of hepatic reactions to drugs that were 16 times higher than the number reported to the French Pharmacovigilance System.15 Among the 41 cases notified to the French Pharmacovigilance system, 14 were also published in the literature as case reports and were all related to the misuse of BPN by injection.4,5,8 Two additional cases are reported in the literature only.6,7 Acute renal failure was seen in 3 cases.5-7 One of these cases involved severe hepatitis associated with renal failure and anuria secondary to the ingestion of 112 mg of BPN.6 In the second case, the patient presented with a severe liver impairment associated with signs of renal failure (serum creatinine = 4.6 mg/dL) after 3 weeks of BPN treatment at therapeutic dosage (20 mg/d) and via the recommended route (sublingual).7 In both these cases, favorable outcomes for liver and renal functions were observed after BPN discontinuation and hemodialysis. In these 2 cases, serum BPN concentrations were very high (224 and 115 ng/mL, respectively).6,7 The last case is a part of the series of Berson et al5 (case 5). This patient, with HIV and HCV coinfection, presented with a severe liver impairment associated with signs of renal failure (blood urea nitrogen = 89.9 mg/dL and serum creatinine = 7.94 mg/dL) after several months of
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Annals of Pharmacotherapy 47(12)
Table 2. Characteristics of BPN-Related Hepatitis Analyzed From the French Pharmacovigilance Database. Route of Administration All Patients, n = 41
Sociodemographic characteristics Median age, years (IQR25%-75%) Men History HIV infected (n = 38) Hepatitis C virus carriers (n = 39) Alcoholism (n = 39) Hepatitis AST (IQR25%-75%), n = 36 ALT (IQR25%-75%), n = 27 Total bilirubin (IQR25%-75%), n = 12 Classification (17 cases) Hepatocellular Cholestatic Mixed Associated symptoms Increased prothrombin time Decreased factor V Outcome Median time to normalize (days), n = 19 Severity,a n = 40 Not severe Severe I Severe III Outcome, n = 38 No sequelae Sequelae Not recoveredb Other concomitant drugs
31 (27-37) 33 (80%) 11/38 (29%) 27/39 (70%) 12/39 (31%) 17 (9-40) 16 (5-41) 27 (8-115)
Recommended: Sublingual, n = 26 (%)
Misuse: Injection, n = 15 (%)
31.5 (27-37) 21 (81%) 10/26 (38%) 17/26 (65%) 8/24 (33%) 17 (6-40) 15 (4-29) 9 (6-20)
31.0 (25-36) 12 (80%) 1/12 (8.3%) 10/13 (77%) 4/15 (26%) 26 (13-43) 33 (13-50) 122 (109-200)
11 2 4
6 2 3
5
8 3
5 1
3 2
1
12 (7-19)
11 (7-15)
7 (7-11)
9/40 (22%) 30/40 (75%) 1/40 (2%)
7/26 (27%) 18/26 (69%) 1/26 (4%)
2/14 (14%) 12/14 (86%)
26/38 (68%) 1/38 (2%) 11/38 (29%) 10
14/25 (56%) 1/25 (4%) 10/25 (40%) 10
12/13 (92%) 1/13 (8%) .
P .676 1.000 .120 .714 .660 .225 .141 .025
Abbreviations: BPN, buprenorphine; IQR, interquartile range; AST: serum aspartate aminotransferase; ALT: serum alanine aminotransferase. a Severity: I, hospitalization or prolongation of hospitalization; II, permanent or temporary disability or incapacity; III, life threatening; IV, death. b At the time of the report.
BPN treatment at therapeutic dosage (16 mg/d) and via the recommended route (sublingual). He also took small doses of acetaminophen and aspirin during the 3 preceding days.5 All medications were withheld, and the patient quickly improved. Some authors suggested that the acute nephrotoxic effect of BPN could be linked to high serum BPN concentrations. This hypothesis is supported by the 10% renal BPN excretion rate.7 However, the mechanism of such damage has not been elucidated. In the literature, all patients with hepatitis related to BPN were HCV carriers. In our analysis, 70% of patients were HCV carriers. The median increase in ALT from the ULN in patients misusing BPN was not significantly different from that in patients without misuse (33-fold vs 15.5-fold; P = .141).
However, the mere examination of ALT levels is not a specific way to assess the potential for a drug to cause clinically important liver injury.16 The earliest biological biomarker of potentially serious liver injury is the concomitant increase in serum ALT >3ULN and serum total bilirubin >2ULN, signaling dysfunction of the liver. In our study, total bilirubin level was significantly different between the 2 groups (P = .025), suggesting a higher risk of severe liver injury when BPN is injected. In our case, it was found that serum GGT increased during follow-up, and for this reason, we cannot rule out resumption of alcohol use by the patient. In our case, presented in detail, the severity of hepatic injury could be estimated as level 4 (on a 5-level severity scale) with acute liver failure (increase in serum enzyme activities), increase in serum total bilirubin (1.4 times normal), and serum prothrombin time (31.4 s) with secondary
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Eiden et al loss of other organ function, that is, the kidney.16 Our patient had no history of renal impairment and no sign suggesting a prerenal cause for kidney impairment. Renal function improved within a few days after the discontinuation of BPN therapy and getting normal care, including fluids. The primary mechanism of BPN-induced hepatitis is a mitochondrial dysfunction, toxicity that can be exacerbated by cofactors such as HCV, alcohol, and concomitant medications. However, 2 potential molecular mechanisms could be considered.17 First, BPN is a lipophilic tertiary amine that is taken up by mitochondria and impairs fatty β-oxidation and/or mitochondrial energy production, causing depletion of adenosine triphosphate and liver cell necrosis.5,17 Second, BPN or norbuprenorphine can form reactive metabolites that covalently bind to microsomal proteins and deplete cellular glutathione.17 However, it seems that the first mechanism plays a predominant role in the hepatotoxicity of BPN. Literature case reports and animal model experimentation argue for a concentration-dependent mechanism.4,5,17 After sublingual administration of BPN (8-16 mg daily), peak plasma concentrations (time period 1 hour) reach a maximum of 5.8 to 14 µg/L. Even if there are no validated references concerning toxic concentrations of BPN reported in the literature, the therapeutic range of BPN is usually 1 to 10 µg/L.18 After IV administration of BPN, the maximum plasma concentration is attained almost immediately, and the increase is larger (ie, 0.3 mg IV of BPN leads to a mean maximum plasma concentration of 15 µg/L).19 When administered as a sublingual tablet, the bioavailability of BPN ranged between 15% and 30%, whereas the bioavailability of intranasal BPN from crushed tablets ranged between 38% and 44% in a study of 10 individuals using recreational prescription opioids.20 BPN concentrations following intranasal administration in this study were approximately 2- to 3-fold higher than in studies with sublingual dosing (for BPN 2 and 8 mg, maximum plasma concentration range was 4.94-16.31 and 2.02-3.82 µg/L, respectively). Intranasal BPN misuse is increasing and was reported to be prevalent in 8% to 46% of BPN-treated patients in 2009 according to the French OPPIDUM program survey.2 The highly lipophilic nature of the molecule and the extensive vasculature of the nasal mucosa lead to a higher bioavailability of the crushed tablets and an increase in ingested BPN, when compared with the sublingual route.20 Our case demonstrates that BPN misuse by the nasal route can also lead to severe hepatitis, even in a patient without chronic HCV. However, our patient has a history of alcohol consumption, which can induce dysfunction in mitochondrial DNA and can cause mitochondrial DNA deletions as a result of oxidative stress. Our study has some limitations. We retrospectively analyzed cases of hepatitis entered in the FPD. Some data are
therefore lacking. Among the patients using sublingual BPN, 47% had a history of illicit substance injection; we cannot rule out that those patients could also have concomitantly misused BPN (IV and/or intranasal route of administration), which could have led to hepatitis. In the case report, BPN plasma concentrations were not available at the time of hepatitis and acute renal failure.
Conclusion Misuse of BPN remains a public health problem, with potentially serious clinical consequences such as infections or severe acute hepatitis. The case report presented in this publication shows that abuse of BPN intranasally, like alcohol abuse, should be considered as a risk factor for acute hepatitis, even in patients without chronic HCV. In patients misusing BPN, a change in the OMT has to be envisaged, with the use of methadone or a recently marketed combination of BPN and naloxone (Suboxone) in the same tablet to limit misuse through injection. Acknowledgments The authors thank the network of the French Addictovigilance centers (CEIP), the network of the French Pharmacovigilance centers (CRPV), and the French Medicine Agency (ANSM for “Agence Nationale de Sécurité des Médicaments et des produits de santé”).
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Canarelli T, Coquelin A. Données récentes relatives aux traitements de substitution aux opiacés. Premiers résultats d’une analyse de données de remboursement concernant plus de 4500 patients en 2006 et 2007. http://www.ofdt.fr/BDD/publications/docs/eftxtcp5.pdf. Accessed September 20, 2013. 2. AFSSAPS. Results of the OPPIDUM survey 2009 [in French]. http://www.ansm.sante.fr/var/ansm_site/storage/original/appl ication/83d45de068482ab831466a00a97e4962.pdf. Accessed September 20, 2013. 3. Grau D, Vidal N, Faucherre V, et al. Complications infectieuses induites par le mésusage de la buprénorphine haut dosage (Subutex®): analyse rétrospective de 42 observations. Rev Med Int. 2010;31:188-193. 4. Peyrière H, Tatem L, Bories C, Pageaux GP, Blayac JP, Larrey D. Hepatitis after intravenous injection of sublingual buprenorphine in acute hepatitis C carriers: report of two cases of disappearance of viral replication after acute hepatitis. Ann Pharmacother. 2009;43:973-977.
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5. Berson A, Gervais A, Cazals D, et al. Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol. 2001;34:346-350. 6. Houdret N, Asnar V, Szostak-Talbodec N, et al. Hepatonephritis and massive ingestion of buprenorphine. Acta Clin Belg (Suppl). 1999;1:29-31. 7. Zuin M, Giorgini A, Selmi C, et al. Acute liver and renal failure during treatment with buprenorphine at therapeutic dose. Dig Liver Dis. 2009;41:e8-e10. 8. Hervé S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol. 2004;16:1033-1037. 9. Begaud B, Evreux JC, Jouglard J, Lagier G. Imputation of the unexpected or toxic effects of drugs: actualization of the method used in France. Thérapie. 1985;40:115-118. 10. Baumevielle M, Miremont G, Haramburu F, Maurain C, Bégaud B. Le système français d’évaluation de la pharmacodépendance et de l’abus: consécration juridique. Thérapie. 2001;56:15-22. 11. Benichou C. Criteria of drug-induced liver disorders: report of an international consensus meeting. J Hepatol. 1990;11:272-276. 12. Arimone Y, Bidault I, Dutertre JP, et al. Update of the French drug reaction assessment method. Thérapie. 2011;66:517-525. 13. Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89:806-815.
14. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245. 15. Sgro C, Clinard F, Ouazir K, et al. Incidence of drug induced hepatic injuries: a French population-based study. Hepatology. 2002;36:451-455. 16. Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to learn more about acute druginduced liver injury. Hepatology. 2008;48:1680-1689. 17. Berson A, Fau D, Fornacciari R, et al. Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation. J Hepatol. 2001;34:261-269. 18. Kintz P. Médicaments de substitution aux opiacés. In: Traité de Toxicologie médico-judiciaire. 2nd ed. Paris, France: Elsevier Masson; 2012:411-453. 19. Vidal-Trecan G, Varescon I, Nabet N, Boissonnas A. Intravenous use of prescribed sublingual buprenorphine tablets by drug users receiving maintenance therapy in France. Drug Alcohol Depend. 2003;69:175-181. 20. Middleton LS, Nuzzo PA, Lofwall MR, Moody DE, Walsh SL. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers. Addiction. 2011;106:1460-1473.
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research-article2013
AOPXXX10.1177/1060028013507429Annals of PharmacotherapyEiden et al
Case Report
Acute Hepatitis and Renal Failure Related to Intranasal Buprenorphine Misuse: Case Report and Analysis of Cases Reported to the French Network for Drug Monitoring
Annals of Pharmacotherapy 47(12) 1721–1726 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013507429 aop.sagepub.com
Céline Eiden, PharmD, PhD1, Marie-Pierre Ripault, MD2, Dominique Larrey, MD, PhD2, Jean-Luc Faillie, MD1, Véronique Pinzani, MD1, Georges-Philippe Pageaux, MD, PhD2, and Hélène Peyrière, PharmD, PhD1
Abstract Background: Rare cases of acute hepatitis have been reported following injection, overdose, and even during the use of buprenorphine (BPN) at therapeutic doses, especially in carriers of hepatitis C virus (HCV). Objectives: To report a case of acute hepatitis and renal failure related to intranasal BPN misuse in a HCV-negative patient and to analyze cases reported to the French postmarketing surveillance system (PMSS) of drugs and in the literature. Methods: All cases of hepatitis related to BPN reported to PMSS between January 1996 and December 2012 were analyzed. Results: A 42-year-old man with a history of intranasal BPN misuse (8 mg/d) for at least 10 years was admitted for flu-like symptoms and abdominal pain. At admission, the patient consumed alcohol, cannabis, and tobacco. Acute hepatitis and acute renal failure were diagnosed . Clinical signs and biological parameters resolved within 26 days. An objective causality assessment revealed that an adverse drug reaction (ADR) was possible. In the French PMSS database, 41 cases of suspected BPNinduced hepatitis are reported. In 36.6% of cases, BPN was misused by the intravenous route. In the literature, 16 cases of acute hepatitis related to BPN with or without renal failure are reported. In all cases, patients were HCV carriers. The primary mechanism of BPN-induced hepatitis is a mitochondrial dysfunction, exacerbated by cofactors (HCV, alcohol, and medications). Conclusion: Intranasal misuse of BPN is increasingly frequent. We report here the first documented case of acute hepatitis and renal failure related to intranasal BPN misuse in a patient negative for HCV infection. Keywords hepatitis, buprenorphine, misuse, intravenous route, intranasal route
Introduction In France, buprenorphine (BPN; sublingual 0.4-, 2-, and 8-mg tablets) was first introduced for opioid maintenance therapy (OMT) in February 1996. BPN is more widely prescribed than methadone because any physician in France is allowed to prescribe it. According to the French Observatory of Drugs and Addiction (OFDT), among the 120 000 patients treated by OMT in 2007, 80% received BPN.1 Cases of diversion and misuse (such as intravenous [IV] or intranasal administration after crushing BPN tablets) have been regularly reported with BPN. The French Observation of Illegal Drugs and Misused Psychotropic Medications (OPPIDUM) program is a survey performed each year in October, since 1998. This survey allows observation and evaluation of psychoactive substance dependence and abuse among drug users in addiction care centers.2 The OPPIDUM survey has recently shown that the intranasal route for licit or illicit substance
administration is increasing. In 2009, 46% of patients included in the OPPIDUM survey who obtained BPN without a medical prescription used BPN intranasally (vs 8% of patients having a medical order), and 16% of patients without a medical prescription used BPN intravenously (vs 7% of patients with a medical prescription).2 Misuse of BPN by injection is frequently associated with the occurrence of numerous infectious complications (eg, 1
Medical Pharmacology and Toxicology Department, University Hospital of Montpellier, France 2 Gastro-Enterology, Hepatology and Liver Transplantation Department, University Hospital of Montpellier, France Corresponding Author: Hélène Peyrière, Département de Pharmacologie Médicale et Toxicologie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. Email: [email protected]
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cutaneous abscess, endocarditis, osteoarticular infections, and sepsis).3 Acute hepatitis has also been reported.4 In addition, acute hepatitis can occur in other circumstances such as massive overdoses or at therapeutic doses, mainly in hepatitis C virus (HCV) carriers.5-8 The concomitant occurrence of acute hepatitis and renal abnormalities been reported in a few cases.5-7 We describe herein the first documented case of acute hepatitis and renal failure secondary to intranasal misuse of BPN in a patient without chronic viral hepatitis C. Cases of hepatitis related to BPN and reported to the postmarketing surveillance system (PMSS) of drugs in France and in the literature were also analyzed.
Methods An initial descriptive analysis of patients with BPN-induced acute hepatitis reported to the PMSS of drugs in France was performed. This system is based on spontaneous declaration of adverse effects to the drug (pharmacovigilance).9,10 By law, every health professional is required to report “serious” or “unexpected” adverse drug reactions (ADRs) to the French Network of Pharmacovigilance centers and “misuse,” “diversion,” or “abuse” of drugs to the French Network of Addictovigilance centers. An ADR is considered “serious” if it is fatal or life threatening, causes hospitalization or prolongation of hospitalization or permanent or significant disability. All cases of ADRs reported to the French Pharmacovigilance system are entered into a national database.9 A causality assessment method designed to evaluate the causal relationship between an ADR and one or more drugs is applied to each case. Among the ADRs reported into the French Pharmacovigilance Database (FPD), we selected all cases of acute hepatitis in which BPN was considered as “suspect” (possibly involved) and entered between January 1, 1996, and December 31, 2012. For each case, the following data were collected: gender, age, BPN daily dosage, route of BPN administration, associated drugs, and description of the acute hepatitis (delay before onset, severity, outcome, and causality assessment score). The pattern of liver damage was classified according to the International Consensus Meeting criteria, which use alanine aminotransferase (ALT) and alkaline phosphatase (AP) activity, expressed as a multiple of the upper limit of normal (ULN), to determine the ratio (R) of ALT/AP. The pattern of liver damage is hepatocellular when R >5, cholestatic when R 2 but 5. Serologies were negative for hepatitis A, B, C, and E; herpes; syphilis; and toxoplasmosis. Serum ceruloplasmin was normal. Acetaminophen and alcohol plasma detection were negative. An abdominal computerized tomography scan showed normal liver and biliary tree. Liver injury was associated with renal failure: blood urea nitrogen = 52.9 mg/dL, plasma creatinine = 1.7 mg/dL, and estimated glomerular filtration rate determined by the Modification of Diet in Renal Disease (MDRD) method was 31 mL/min/1.73 m2. BPN was stopped at admission. BPN plasma concentrations were not measured. Clinical signs and most biological parameters spontaneously resolved within 26 days (Table 1). The role of intranasal BPN was evaluated as very likely according to the updated scale of the French Drug Reaction Assessment Method and the Drug-Induced Liver Injury Scale.12,13 The causal relationship between BPN and acute hepatitis was also evaluated using the Naranjo Probability Scale and scored possible.14
FPD Analysis In the FPD, 41 cases of BPN-induced acute hepatitis are reported (Table 2). The patients were mainly men (80%) with a median age of 31 years (IQR = 27-37). Among the 41 cases, 12 (31%) had a past or current history of alcoholism, 11 (29%) were infected by HIV, and 27 (70%) were HCV carriers. Other medical histories were cirrhosis (1 patient),
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Eiden et al Table 1. Patient-Specific Biological Markers at Days 0, 6, and 26.
AST (normal < 40 U/L) ALT (normal < 41 U/L) AP (normal < 130 U/L) GGT (normal < 60 U/L) Total bilirubin (mg/dL) Direct bilirubin (mg/dL) Indirect bilirubin (mg/dL) Serum prothrombin time (s) INR Factor V Serum lactate (mmol/L) Blood urea nitrogen (mg/dL) Serum creatinine (mg/dL) Creatinine clearance (MDRD mL/min/1.73m2) Serum uric acid (mg/dL) Serum sodium (mEq/L)
Day 0
Day 6
Day 26
2357 1856 51 75 2.0 1.35 0.65 31.4 2.56 16% 9.26 52.9 1.7 31 10.4 130.9
96 431 75 108 2.5 1.6 0.9 14.8 ND ND 0.91 8.4 0.7 >120 ND 140.9
25 38 93 136 1.2 0.8 0.4 10.7 ND ND ND 12.8 0.7 >120 ND 141.8
Abbreviations: AST, serum aspartate aminotransferase; ALT, serum alanine aminotransferase; AP, alkaline phosphatase; GGT, γ-glutamyl transferase; INR, international normalized ratio; ND, not determined.
diabetes (1 patient), and psychiatric disorders (4 patients). The median BPN daily dose was 8 mg (IQR = 4-12). In 10 cases (24%), BPN was consumed with drugs that can be associated with liver function impairment, such as aspirin, acetaminophen, antituberculosis therapy, or antiretroviral agents. The pattern of liver damage was classified with the ALT/AP ratio in 17 cases (AP not available in 24 cases): 11 hepatocellular, 2 cholestatic, and 4 mixed. Coagulation disorders were observed in 11 cases. Abdominal ultrasonography was performed in 10 cases and showed normal liver in all cases. A biopsy was performed in 9 cases and showed necrosis in 1 case, fibrosis in 2 cases, and chronic hepatitis in 5 cases; it was normal in 1 case. For 15 patients (36.6%), IV misuse of BPN was noted. The characteristics of hepatitis related to BPN in patients using BPN by the recommended route (sublingual administration) versus IV administration are summarized in Table 2. The profile of patients and hepatitis did not significantly differ, except for total bilirubin values, which were significantly higher in patients using BPN intravenously, and the rate of BPN discontinuation (sublingual administration: BPN stopped in 10/20, BPN not stopped in 10/20; IV administration: BPN stopped in 6/10, IV administration stopped in 3/10, BPN not stopped in 1/10; P = .009).
Discussion We report here the first documented case of acute liver and renal failure secondary to intranasal misuse of BPN in a patient without HCV chronic infection.
At recommended sublingual doses, BPN seems to be well tolerated. Over the 17 years of BPN marketing, only 41 cases of acute hepatitis have been reported to the French PMSS (estimated event: 41/17 years, or 2.4/year, corresponding to 2.4/120 000 treated patients = 0.002%). However, because the French PMSS is based on a spontaneous reporting of ADRs, this value is probably underestimated. A community prospective study performed in France over a 3-year period found an annual incidence of hepatic reactions to drugs that were 16 times higher than the number reported to the French Pharmacovigilance System.15 Among the 41 cases notified to the French Pharmacovigilance system, 14 were also published in the literature as case reports and were all related to the misuse of BPN by injection.4,5,8 Two additional cases are reported in the literature only.6,7 Acute renal failure was seen in 3 cases.5-7 One of these cases involved severe hepatitis associated with renal failure and anuria secondary to the ingestion of 112 mg of BPN.6 In the second case, the patient presented with a severe liver impairment associated with signs of renal failure (serum creatinine = 4.6 mg/dL) after 3 weeks of BPN treatment at therapeutic dosage (20 mg/d) and via the recommended route (sublingual).7 In both these cases, favorable outcomes for liver and renal functions were observed after BPN discontinuation and hemodialysis. In these 2 cases, serum BPN concentrations were very high (224 and 115 ng/mL, respectively).6,7 The last case is a part of the series of Berson et al5 (case 5). This patient, with HIV and HCV coinfection, presented with a severe liver impairment associated with signs of renal failure (blood urea nitrogen = 89.9 mg/dL and serum creatinine = 7.94 mg/dL) after several months of
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Table 2. Characteristics of BPN-Related Hepatitis Analyzed From the French Pharmacovigilance Database. Route of Administration All Patients, n = 41
Sociodemographic characteristics Median age, years (IQR25%-75%) Men History HIV infected (n = 38) Hepatitis C virus carriers (n = 39) Alcoholism (n = 39) Hepatitis AST (IQR25%-75%), n = 36 ALT (IQR25%-75%), n = 27 Total bilirubin (IQR25%-75%), n = 12 Classification (17 cases) Hepatocellular Cholestatic Mixed Associated symptoms Increased prothrombin time Decreased factor V Outcome Median time to normalize (days), n = 19 Severity,a n = 40 Not severe Severe I Severe III Outcome, n = 38 No sequelae Sequelae Not recoveredb Other concomitant drugs
31 (27-37) 33 (80%) 11/38 (29%) 27/39 (70%) 12/39 (31%) 17 (9-40) 16 (5-41) 27 (8-115)
Recommended: Sublingual, n = 26 (%)
Misuse: Injection, n = 15 (%)
31.5 (27-37) 21 (81%) 10/26 (38%) 17/26 (65%) 8/24 (33%) 17 (6-40) 15 (4-29) 9 (6-20)
31.0 (25-36) 12 (80%) 1/12 (8.3%) 10/13 (77%) 4/15 (26%) 26 (13-43) 33 (13-50) 122 (109-200)
11 2 4
6 2 3
5
8 3
5 1
3 2
1
12 (7-19)
11 (7-15)
7 (7-11)
9/40 (22%) 30/40 (75%) 1/40 (2%)
7/26 (27%) 18/26 (69%) 1/26 (4%)
2/14 (14%) 12/14 (86%)
26/38 (68%) 1/38 (2%) 11/38 (29%) 10
14/25 (56%) 1/25 (4%) 10/25 (40%) 10
12/13 (92%) 1/13 (8%) .
P .676 1.000 .120 .714 .660 .225 .141 .025
Abbreviations: BPN, buprenorphine; IQR, interquartile range; AST: serum aspartate aminotransferase; ALT: serum alanine aminotransferase. a Severity: I, hospitalization or prolongation of hospitalization; II, permanent or temporary disability or incapacity; III, life threatening; IV, death. b At the time of the report.
BPN treatment at therapeutic dosage (16 mg/d) and via the recommended route (sublingual). He also took small doses of acetaminophen and aspirin during the 3 preceding days.5 All medications were withheld, and the patient quickly improved. Some authors suggested that the acute nephrotoxic effect of BPN could be linked to high serum BPN concentrations. This hypothesis is supported by the 10% renal BPN excretion rate.7 However, the mechanism of such damage has not been elucidated. In the literature, all patients with hepatitis related to BPN were HCV carriers. In our analysis, 70% of patients were HCV carriers. The median increase in ALT from the ULN in patients misusing BPN was not significantly different from that in patients without misuse (33-fold vs 15.5-fold; P = .141).
However, the mere examination of ALT levels is not a specific way to assess the potential for a drug to cause clinically important liver injury.16 The earliest biological biomarker of potentially serious liver injury is the concomitant increase in serum ALT >3ULN and serum total bilirubin >2ULN, signaling dysfunction of the liver. In our study, total bilirubin level was significantly different between the 2 groups (P = .025), suggesting a higher risk of severe liver injury when BPN is injected. In our case, it was found that serum GGT increased during follow-up, and for this reason, we cannot rule out resumption of alcohol use by the patient. In our case, presented in detail, the severity of hepatic injury could be estimated as level 4 (on a 5-level severity scale) with acute liver failure (increase in serum enzyme activities), increase in serum total bilirubin (1.4 times normal), and serum prothrombin time (31.4 s) with secondary
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Eiden et al loss of other organ function, that is, the kidney.16 Our patient had no history of renal impairment and no sign suggesting a prerenal cause for kidney impairment. Renal function improved within a few days after the discontinuation of BPN therapy and getting normal care, including fluids. The primary mechanism of BPN-induced hepatitis is a mitochondrial dysfunction, toxicity that can be exacerbated by cofactors such as HCV, alcohol, and concomitant medications. However, 2 potential molecular mechanisms could be considered.17 First, BPN is a lipophilic tertiary amine that is taken up by mitochondria and impairs fatty β-oxidation and/or mitochondrial energy production, causing depletion of adenosine triphosphate and liver cell necrosis.5,17 Second, BPN or norbuprenorphine can form reactive metabolites that covalently bind to microsomal proteins and deplete cellular glutathione.17 However, it seems that the first mechanism plays a predominant role in the hepatotoxicity of BPN. Literature case reports and animal model experimentation argue for a concentration-dependent mechanism.4,5,17 After sublingual administration of BPN (8-16 mg daily), peak plasma concentrations (time period 1 hour) reach a maximum of 5.8 to 14 µg/L. Even if there are no validated references concerning toxic concentrations of BPN reported in the literature, the therapeutic range of BPN is usually 1 to 10 µg/L.18 After IV administration of BPN, the maximum plasma concentration is attained almost immediately, and the increase is larger (ie, 0.3 mg IV of BPN leads to a mean maximum plasma concentration of 15 µg/L).19 When administered as a sublingual tablet, the bioavailability of BPN ranged between 15% and 30%, whereas the bioavailability of intranasal BPN from crushed tablets ranged between 38% and 44% in a study of 10 individuals using recreational prescription opioids.20 BPN concentrations following intranasal administration in this study were approximately 2- to 3-fold higher than in studies with sublingual dosing (for BPN 2 and 8 mg, maximum plasma concentration range was 4.94-16.31 and 2.02-3.82 µg/L, respectively). Intranasal BPN misuse is increasing and was reported to be prevalent in 8% to 46% of BPN-treated patients in 2009 according to the French OPPIDUM program survey.2 The highly lipophilic nature of the molecule and the extensive vasculature of the nasal mucosa lead to a higher bioavailability of the crushed tablets and an increase in ingested BPN, when compared with the sublingual route.20 Our case demonstrates that BPN misuse by the nasal route can also lead to severe hepatitis, even in a patient without chronic HCV. However, our patient has a history of alcohol consumption, which can induce dysfunction in mitochondrial DNA and can cause mitochondrial DNA deletions as a result of oxidative stress. Our study has some limitations. We retrospectively analyzed cases of hepatitis entered in the FPD. Some data are
therefore lacking. Among the patients using sublingual BPN, 47% had a history of illicit substance injection; we cannot rule out that those patients could also have concomitantly misused BPN (IV and/or intranasal route of administration), which could have led to hepatitis. In the case report, BPN plasma concentrations were not available at the time of hepatitis and acute renal failure.
Conclusion Misuse of BPN remains a public health problem, with potentially serious clinical consequences such as infections or severe acute hepatitis. The case report presented in this publication shows that abuse of BPN intranasally, like alcohol abuse, should be considered as a risk factor for acute hepatitis, even in patients without chronic HCV. In patients misusing BPN, a change in the OMT has to be envisaged, with the use of methadone or a recently marketed combination of BPN and naloxone (Suboxone) in the same tablet to limit misuse through injection. Acknowledgments The authors thank the network of the French Addictovigilance centers (CEIP), the network of the French Pharmacovigilance centers (CRPV), and the French Medicine Agency (ANSM for “Agence Nationale de Sécurité des Médicaments et des produits de santé”).
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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