Abstract
To the authors' knowledge, this is the first published report of an association between buprenorphine and elevated liver enzymes in a pediatric patient population.
Buprenorphine is a relatively new drug, and there are no reported cases of liver enzyme elevation or hepatoxicity in the pediatric population. Suboxone is available as a combination of buprenorphine and naloxone in a 4:1 ratio. Naloxone has been added to sublingual formulations of buprenorphine to reduce its abuse liability. Buprenorphine is a semisynthetic opioid derived from thebaine, a naturally occurring alkaloid of the opium poppy, Papaver somniferum. The pharmacology of buprenorphine is unique in that it is a partial agonist at the mu opiod receptor. Use of buprenorphine has been limited to children >16 years of age.
Buprenorphine undergoes extensive first-pass metabolism and, therefore, has very low oral bioavailability; however, its bioavailability sublingually is extensive enough to make this a feasible route of administration for treatment of opioid dependence. In adults, hepatitis due to buprenorphine has been reported in the past (Herve et al. 2004). Although sublingual buprenorphine is safely used as a substitution drug in heroin addicts, large overdoses or intravenous misuse may cause hepatitis. Buprenorphine impairs mitochondrial respiration and adenosine triphosphate formation. The hepatotoxicity of high doses of buprenorphine is related to its mitochondrial effects (Berson et al. 2001).
Buprenorphine is concentrated in mitochondria, collapses the membrane potential, inhibits beta-oxidation, and both uncouples and inhibits respiration in the liver mitochondria. Buprenorphine depletes cell adenosine triphosphate and causes necrotic cell death (Berson et al. 2001). Buprenorphine is mainly metabolized in the liver by cytochrome P450 (CYP) 3A4 system. Other factors such as genetic susceptibility, infection with hepatitis virus, or consumption of alcohol or drugs inhibiting the CYP3A4 system or mitochondrial function may also enhance the toxic effects of buprenorphine on the liver (Zuin et al. 2009). Buprenorphine hepatitis is uncommon and has a spontaneously good course (Berson et al. 2001). Better monitoring of hepatic profiles, especially in pediatric populations, is suggested because of the immaturity of liver functions in adolescents. Hepatitis C is the most prevalent chronic viral illness in the United States; hence, all opioid-dependent patients seeking treatment with buprenorphine should undergo a laboratory evaluation, including transaminases AST/ALT as well as for acute and chronic hepatitis.
In light of this dearth of information regarding buprenorphine and liver damage in the pediatric population, we report the case of a 17-year-old female who was admitted to an adolescent detox unit and was being detoxed from opioid by using Methadone initially, but was switched to sublingual buprenorphine because of poor response to Methadone. Hence, Methadone was discontinued on the second day of admission. The patient was started on buprenorphine on the third day of admission for opioid detox, with a plan to maintain her on buprenorphine after discharge for relapse prevention.
Appropriate consents were obtained and the risk and benefits of buprenorphine were explained to the patient and her family.
It was noted that her liver function test (LFT) results were within normal range on admission. Buprenorphine was started on the third day of admission at 16 mg/day; a maximum dose of 30 mg/day was given on the fifth day of admission. On the sixth day of admission, 16 mg/day was given, followed by 12 mg/day on seventh day, 8 mg/day on eighth day, and 4 mg/day on ninth day. The dose of buprenorphine was titrated according to the response in the symptoms of opioid withdrawal. On the ninth day of buprenorphine treatment, LFT was done to check liver function, as the patient complained of right upper quadrant pain. On examination, she had right upper quadrant tenderness. LFT revealed that ALT was 452 IU/L and AST was 215 IU/L, which were due to hepatotoxic effects from buprenorphine. AST and ALT then tapered slowly spontaneously after buprenorphine was discontinued after the ninth day. On the 13th day of admission, further downward trend of LFT results were noticed, as liver enzymes ALT and AST fell to 306 and 120 IU/L, respectively, after buprenorphine was discontinued. However, there was no jaundice noted. Chest X-ray was normal. Abdominal ultrasound was normal as well. Results of follow-up LFT after 3 months were within normal limits. Other tests done were HIV rapid screen (result was negative) and tests for hepatitis A antibody (nonreactive), hepatitis B core antibody (nonreactive), hepatitis B surface antigen (nonreactive), and hepatitis C antibody (nonreactive).
The patient had received quetiapine 50 mg by mouth on the first 2 days of admission for sleep only, and hence, quetiapine-induced hepatotoxicity was excluded. Assessing the link of causality between a specific medical treatment and the observed adverse reactions is a real challenge for any physician, particularly when other confounding factors are present, such as methadone, quetiapine, and tizanidine, which may be held responsible for the hepatitis observed. Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both these metabolites are pharmacologically inactive.
In vitro studies using human liver microsomes revealed that the CYP3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite. Hence, quetiapine is unlikely to interfere with the metabolism of drugs metabolized by CYP enzymes.
In vitro studies of CYP isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by CYP isoenzymes. Tizanidine is an inhibitor of CYP1A2.
As this is believed to be the only report of an association between buprenorphine and elevated liver enzymes in a pediatric patient population as of now, more research will be required in the future. It is our recommendation that, considering the relative immaturity of the adolescent liver, care of the adolescent on buprenorphine should be coordinated very closely with the pediatrician, encouraging a regular annual physical exam along with follow-up of liver enzymes periodically to prevent any ill effects.
Footnotes
Disclosures
The authors have no conflicts of interest or financial ties to disclose.