Buprenorphine is an orally available, semisynthetic opioid analgesic, which is used as an analgesic and for management of opioid dependence. Therapy with buprenorphine has not been associated with serum enzyme elevations, and clinically apparent liver injury has been reported largely with overdose and abuse (intravenous administration of the sublingual formulation).
Buprenorphine (bue" pre nor' feen) is a semisynthetic opioid that is 25 to 50 times more potent than morphine and has been used as an analgesic as well as therapy of opioid addiction. Buprenorphine is a partial µ-opioid receptor agonist and a κ-receptor antagonist accounting for its benefit for opioid deterrence. Buprenorphine competes with morphine and heroin for the µ receptor, but is only a partial agonist and has a “ceiling” effect. Buprenorphine was approved for treatment of opioid addiction in 2004 and is a schedule III controlled substance. Current indications include treatment of moderate to severe pain (in low doses ~200 µg) and opiate addiction (in higher doses 2 to 16 mg daily). Buprenorphine is available as 2 and 8 mg tablets for sublingual administration under the brand name Subutex, and in 1 mL ampules of 0.3 mg/mL for intravenous (iv) or intramuscular (im) injection under the brand name Buprenex. For opioid addiction, the usually recommended dose is 12 to 16 mg in a single daily dose. Buprenorphine is also available in fixed combination with naloxone for sublingual administration generically and under the brand name Suboxone. Naloxone is not absorbed orally, but provides full opioid antagonism if the combination is administer intravenously, as might occur with intentional abuse. Finally, parenteral forms of buprenorphine are used for moderate to severe pain and administered iv or im, the typical dose being 0.3 mg every 6 hours as needed. Common side effects of buprenorphine include headache, dizziness, fatigue, sedation, dry mouth, urinary retention, diaphoresis and withdrawal symptoms.
Buprenorphine therapy has not been associated with serum enzyme elevations during treatment, although the populations studied (opioid addiction) often have coexisting chronic liver diseases which complicate such assessments. Nevertheless, rates of ALT elevations during treatment with buprenorphine (with or without naloxone) have been no greater than with comparator arms (methadone).
In addition, there have been several reports and case series of acute, clinically apparent liver injury arising within 2 to 20 weeks of starting buprenorphine, usually following misuse and intravenous administration of sublingual tablets. However, some cases occurred in patients who denied intravenous use and were on conventional sublingual doses. In most cases, the pattern of serum enzyme elevations was hepatocellular and the presentation resembled acute toxic hepatic necrosis. Immunoallergic features (fever, rash and eosinophilia) were not present, nor were autoantibodies detected. Almost all patients with this injury had concurrent chronic hepatitis C, and several appeared to resolve the chronic infection with the acute liver injury (Case 1). Strikingly, most patients were able to continue buprenorphine without recurrence, some of whom admitted to continued intravenous abuse.
Mechanism of Injury
Buprenorphine undergoes extensive first pass hepatic extraction and is metabolized primarily by the cytochrome P450 system (CYP 3A4). The low doses used and rapid metabolism may account for its relative lack of hepatotoxicity when used in conventional doses. The appearance of an acute hepatic necrosis after intravenous injection of the sublingual tablets is likely due to direct toxicity of these high parenteral doses. The occurrence of this syndrome largely in patients with concurrent hepatitis C remains unexplained. Clearance of hepatitis C during this toxic injury raises the issue of whether the acute injury is actually due to an exacerbation of hepatitis C or whether the severe acute toxic injury can induce viral clearance.
Outcome and Management
The severity of liver injury attributed to buprenorphine has ranged from mild to severe hepatitis, and near fatal instances have been reported. Interestingly, most patients subsequently tolerated restarting buprenorphine at doses used prior to the toxic event, and some patients continued to misuse it by intravenous injection, but did not have recurrence of the liver injury.
Case 1. Acute liver injury attributed to buprenorphine use in a patient with chronic hepatitis C.
[Modified from Case 1 in: Peyriere H, Tatern L, Bories C, Pageua G-P, Blayac J-P, 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: 973-7]
A 33 year old male injection drug user with chronic hepatitis C (HCV genotype 1a) developed jaundice, abdominal pain and fever shortly after injecting 3 to 5 crushed and dissolved tablets of buprenorphine (8 mg, meant for sublingual administration) intravenously. He was known to have chronic hepatitis C, but had never been treated for the infection which was considered mild. He had no other history of liver disease but consumed alcohol regularly. He took no other medications. On admission, laboratory tests showed a serum bilirubin of 29.6 mg/dL with marked elevations in serum aminotransferase levels (ALT 4132 U/L, AST 3947 U/L) and mild increases in alkaline phosphatase (347 U/L) and GGT (127 U/L; normal <50) (Table). The prothrombin index was 43% of control (INR 1.7). A transjugular liver biopsy showed panlobular necrosis, diffuse lobular inflammation, and marked cholestasis indicative of acute hepatic injury. In addition, there was moderate portal fibrosis and portal inflammation suggestive of an underlying chronic hepatitis C. Tests for hepatitis A and B and HIV were negative. Anti-HCV was present, but serum HCV RNA was present at very low levels (15 IU/mL). Jaundice resolved within a week and serum enzymes fell rapidly. Sublingual buprenorphine was restarted without a change in the pattern of recovery. In follow up 3 months later, serum ALT levels were normal and HCV RNA was undetectable. When seen almost a year later, he admitted to continuing to self-inject buprenorphine, yet serum ALT levels were still normal and HCV RNA was undetectable.
|Medication:||Buprenorphine (24 mg intravenously)|
|Pattern:|| Hepatocellular (R=31)|
||4+ (jaundice and prolongation of INR)|
|Latency:||Short, specific time not provided|
|Recovery:||Rapid, within 1-2 months|
|Time After Stopping
||Alk P (U/L)
||Prothrombin time 18 sec
||HCV RNA negative
||HCV RNA negative
The clinical presentation of acute hepatic necrosis shortly after intravenous abuse of buprenorphine has been reported in several case reports and single center series of as many as 7 cases. Intriguingly, virtually all patients reported with this syndrome had a preexisting chronic hepatitis C, although many were HCV RNA negative at the time of the acute illness. The current case documents the loss of HCV RNA during the acute hepatic injury attributed to buprenorphine. Two explanations are possible. First, that the acute toxic hepatic injury caused an interruption in the replication of HCV or triggered host immune responses (the innate immune system and interferon production), resulting in clearance of hepatitis C. A second explanation is that the acute illness was due to an exacerbation of the chronic HCV infection, which led to an acute hepatitis C-like clearance of virus. The role of hepatitis C in this reaction is perhaps demonstrated best by the absence of recurrence of liver injury when buprenorphine was restarted and even when abused intravenously in high doses. The combination of buprenorphine with naloxone (a full µ opioid receptor antagonist) was developed to discourage such intravenous abuse.
REPRESENTATIVE TRADE NAMES
Buprenorphine – Buprenex®, Generic, Subutex® (SL Tablets)
Buprenorphine/Naloxone – Suboxone®
Substance Abuse Treatment Agents
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULA AND STRUCTURE
||CAS REGISTRY NUMBER
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