Alexander DeLuca, M.D.
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Does Naltrexone Cause Permanent Liver Disease? (No)
Can Naltrexone be Used in the Presence of Liver Disease (Yes)
[References with Abstract from Medline Search for 'naltrexone' and 'hepatotoxicity']

 
Compiled by Alexander DeLuca, M.D., MPH; Addiction Pain and Public Health website - doctordeluca.com; 2001-06-16; Updated: 2005-12-30
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 Related resources:
http://www.doctordeluca.com/Library/LibPages/PharmRx.htm
http://www.doctordeluca.com/ABS-MOD.htm
http://www.doctordeluca.com/Library/LibPages/AbsModAcademic-lib.htm
 
See also:
Dopey Docs and Naltrexone - Naltrexone FAQ and Links to Naltrexone References and Resources
 

 
IN REVERSE CHRONOLOGICAL ORDER (emphasis mine):

Brewer C; Wong VS
Naltrexone: report of lack of hepatotoxicity in acute viral hepatitis, with a review of the literature
Addict Biol; 9(1):81-87; 2004
Many clinicians appear to be concerned about the potential hepatotoxicity of the opiate antagonist naltrexone (NTX) and this may be one reason why it is not used more widely in treating both heroin and alcohol abusers. Some much-quoted early studies noted abnormalities in liver function tests (LFTs) in very obese patients taking high doses, although there was no evidence of clinically significant liver dysfunction. These concerns may be reinforced by advice in the UK product information sheet to perform LFTs before and during treatment, by high infection rates with hepatitis C virus (HCV) among injecting heroin addicts and by the frequency of abnormal LFTs in alcohol abusers. We describe a heroin abuser in whom clinical and laboratory manifestations of acute hepatitis B and C appeared a few days after the insertion of a subcutaneous naltrexone implant. A decision was made not to remove the implant but the hepatitis resolved completely and uneventfully well within the normal time-scale. A review of the literature indicates that even when given at much higher doses than are needed for treating heroin or alcohol abusers, there is no evidence that NTX causes clinically significant liver disease or exacerbates, even at high doses, serious pre-existing liver disease. During the past decade, NTX has been shown to be safe and effective in the treatment of pruritus associated with severe jaundice caused by severe and sometimes life-threatening cirrhosis and other liver diseases. Its safety, even in these extreme conditions, is particularly reassuring. We suggest that it may be more appropriate and economical to advise patients to report promptly any suspected side effects than to perform regular LFTs, which may be misleading

Lieber CS
Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy
Crit Rev Clin Lab Sci; 37(6); 551-584; 2000
Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in an improvement in treatment. Nutritional deficiencies should be corrected when present but, because of the alcohol-induced disease process, some of the nutritional requirements change. For instance, methionine, one of the essential amino acids for humans, must be activated to S-adenosylmethionine (SAMe), but, in severe liver disease, the activity of the corresponding enzyme is depressed. Therefore, the resulting deficiencies and associated pathology can be attenuated by the administration of SAMe, but not by methionine. Similarly, phosphatidylethanolamine methyltransferase (PEMT) activity, which is important for hepatic phosphatidylcholine (PC) synthesis, is also depressed in alcoholic liver disease, therefore calling for the administration of the products of the reaction. Inasmuch as free radical generation by the ethanol- induced CYP2E1 plays a key role in the oxidative stress, inhibitors of this enzyme have great promise and PPC, which is presently being evaluated clinically, is particularly interesting because of its innocuity. In view of the striking negative interaction between alcoholic liver injury and hepatitis C, an antiviral agent is eagerly awaited that, unlike Interferon, is not contraindicated in the alcoholic. Antiinflamatory agents may also be useful. In addition to steroids, down-regulators of cytokines and endotoxin are being considered. Finally, anticraving agents such as naltrexone or acamprosate should be incorporated into any contemplated therapeutic cocktail
 

Walsh K; Alexander G
Alcoholic liver disease
Postgrad Med J;76(895); 280-286; 2000
Alcohol is a major cause of liver cirrhosis in the Western world and accounts for the majority of cases of liver cirrhosis seen in district general hospitals in the UK. The three most widely recognized forms of alcoholic liver disease are alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic cirrhosis. The exact pathogenesis of alcoholic liver injury is still not clear but immune mediated and free radical hepatic injury are thought to be important. There is increasing interest in genetic factors predisposing to hepatic injury in susceptible individuals. Diagnosis is based on accurate history, raised serum markers such as gamma-glutamyltransferase, mean corpuscular volume, and IgA and liver histology when obtainable. Abstinence is the most important aspect of treatment. Newer drugs such as acamprosate and naltrexone are used to reduce alcohol craving. Vitamin supplements and nutrition are vital while corticosteroids have a role in acute alcoholic hepatitis where there is no evidence of gastrointestinal haemorrhage or sepsis. Liver transplantation has excellent results in abstinent patients with end stage liver disease but there are concerns about recidivism after transplant
 

Kim SW
Opioid antagonists in the treatment of impulse-control disorders
J Clin Psychiatry; 59(4); 159-164; 1998
BACKGROUND: Symptoms of impulse-control disorders are generally refractory to psychotherapeutic or pharmacologic treatments. Recent study results suggest that opioid antagonists may reduce human urges, one of the core symptoms of impulse-control disorders. The author discusses the rationale for and the potential utility of the opioid antagonists in the treatment of impulse-control disorders.
METHOD: Work by preclinical and clinical investigators on the subject of motivation and its contextually relevant behavior is reviewed. The review includes the pharmacologic modulation of the motivation or drive and subsequent changes in behavior in animals and humans. On the basis of these reviews, the author prescribed naltrexone for up to 9 months to 15 patients who had impulse-control disorder, and 3 select cases are reported.
RESULTS: Naltrexone was generally well tolerated, and there were no hepatic side effects. Naltrexone appears to reduce urge-related symptoms and decreases the problematic behaviors such as pathological gambling. The effect appears to be sustained. In general, 50 mg/day of naltrexone was not effective. Most patients required higher doses. Results were similar in the 12 other cases not reported here.
CONCLUSION: Naltrexone may be of use in select impulse-control disorder patients. Other opioid antagonists such as nalmefene also need to be tested. Until controlled study data become available, the present report should be viewed as preliminary

Bertolotti M, Ferrari A, Vitale G, et. al.
Effect of liver cirrhosis on the systemic availability of naltrexone in humans
J Hepatol; 27(3); 505-511; 1997
BACKGROUND/AIMS: Naltrexone is a competitive opiate antagonist with high hepatic extraction. It is used for detoxification treatment for heroin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver function, underscoring the need to understand the pharmacokinetic behavior of naltrexone in liver disease. These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone.
METHODS: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). A bolus of 100 mg of naltrexone was administered orally in the morning, after an overnight fast. Blood samples were taken in basal conditions and at fixed intervals, up to 24 h after administration. Serum levels of naltrexone and of its major active metabolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysis.
RESULTS: In control subjects, circulating concentrations of naltrexone were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200 +/- 97 ng/ml x 24 h; 6 beta- naltrexol, 2467 +/- 730 ng/ml x 24 h, p < 0.01). In severe cirrhosis serum levels of 6 beta-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta- naltrexol/naltrexone ratio at 2 h: controls, 10.91 +/- 4.80; cirrhosis, 0.39 +/- 0.18, p < 0.01). The area under the curve for naltrexone (1610 +/- 629 ng/ml x 24 h) was significantly greater than in controls, whereas that for 6 beta-naltrexol (2021 +/- 955 ng/ml x 24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups.
CONCLUSIONS: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency

Sax DS, Kornetsky C, Kim A
Lack of hepatotoxicity with naltrexone treatment
J Clin Pharmacol;34(9); 898-901; 1994
Naltrexone, a specific opiate receptor antagonist, is used clinically in the treatment of heroin addiction and more recently, for the treatment of dyskinesia associated with Huntington's disease (HD). Naltrexone may act as a potential hepatotoxin, as reflected in the elevation of transaminase levels. However, one study concluded that, for a brief treatment period of 12 weeks, there is no contraindication to naltrexone treatment based solely on increased hepatic enzyme values. This study monitored liver transaminase levels, in ten HD patients receiving daily doses, between 50 mg/day and 300 mg/day, of naltrexone for periods of 10 to 36 months. Serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were obtained before treatment and at intervals of 1 to 4 months during treatment. Only one of the ten patients treated with naltrexone had increased levels of both SGOT and SGPT, whereas one other patient showed elevated levels of SGPT. These elevations, which initially appeared dose related decreased to normal limits with continued treatment. Because many of the patients were receiving other medications, a combination of drugs with naltrexone may contribute to the increased transaminase levels seen in two of the patients. In summary, chronic administration of naltrexone in doses up to 300 mg/day for periods up to 36 months does not significantly change hepatic function, as measured by SGOT and SGPT levels

Bryant HU, Kuta CC. Story JA, Yim GK
Stress- and morphine-induced elevations of plasma and tissue cholesterol in mice: reversal by naltrexone
Biochem Pharmacol; 37(19); 3777-3780; 1988
Our earlier studies indicated that stress-induced facilitation of gallstone formation could be prevented by the opiate antagonist naltrexone. In view of the possible link between gallstone formation and atherosclerosis, the present study examined the possibility that endogenous opioids might also mediate stress-induced hypercholesterolemia. A 28-day immobilization stress schedule was used to induce increases in plasma, aortic and liver cholesterol of mice maintained on a high cholesterol diet. These stress-induced increases in plasma, hepatic and aortic cholesterol were reversed by pretreatment with the opiate antagonist, naltrexone (1 mg/kg). Exposure of mice to morphine (0.1% in the drinking water for 28 days) resulted in elevations of plasma, liver, and aortic cholesterol levels, similar to those observed following immobilization. In contrast, chronic exposure to the peripherally restricted opiate agonist, loperamide (0.1% in the drinking water for 28 days), was ineffective. The antagonism by naltrexone and duplication by morphine but not loperamide suggest that stress-induced hypercholesterolemia may require the activation of central endogenous opioid systems

Brahen LS, Capone TJ, Capone DM
Naltrexone: lack of effect on hepatic enzymes
J Clin Pharmacol;28(1); 64-70; 1988
A number of studies have established the clinical efficacy of naltrexone in the treatment of opiate addiction. However, questions have been raised regarding its hepatotoxic potential and warnings have been given prominence in the package insert regarding its use for those with even less severe liver disease. The current study monitored 53 male patients receiving naltrexone 350 mg weekly for 12 weeks. The lactic acid dehydrogenase (LDH) and serum glutamic oxalacetic transaminase (SGOT) levels were determined at pretreatment and at monthly intervals thereafter for three months. LDH and SGOT were found to drop significantly from baseline over this three-month period. This decrease appeared most notable for those with pretreatment hepatic enzyme levels exceeding the normal range. Moreover, changes in hepatic enzyme levels were not consistently correlated with the patients use of illicit drugs such as opioids, benzodiazepines, cocaine, barbiturates, and amphetamines. Based on these data, we have concluded that contrary to cautions implied in the naltrexone package insert, the benefit of admitting patients with the sole problem of elevated hepatic enzymes generally exceeds the risk

Mitchell JE; Morley JE; Levine AS; Hatsukami D; Gannon M; Pfohl D
High-dose naltrexone therapy and dietary counseling for obesity
Biol Psychiatry;22(1); 35-42; 1987
There is considerable evidence that antagonism of the endogenous opioids will suppress food intake in a variety of animal species. The authors report a double-blind, placebo-controlled trial of the long-acting, orally active narcotic antagonist naltrexone in the promotion of weight loss in obese male subjects who were also undergoing dietary counseling for weight reduction. Subjects received medication (naltrexone, 300 mg/day or placebo) for 8 weeks following an initial 2-week single-blind placebo phase. The results failed to demonstrate an advantage for the active drug. However, the naltrexone was associated with [reversible] hepatotoxicity when used at this dosage in this population

James RC; Goodman DR; Harbison RD
Hepatic glutathione and hepatotoxicity: changes induced by selected narcotics
J Pharmacol Exp Ther; 221(3;:708-714; 1982
Propoxyphene and morphine lowered hepatic glutathione and increased serum glutamic-pyruvic transaminase (SGPT) activity when administered to male mice. Maximal changes were seen at 3 to 6 hr after administration, but the effects lasted for as long as 18 hr. Morphine-induced hepatic changes potentiated both acetaminophen and cocaine-induced hepatotoxicity. Naltrexone, a narcotic antagonist, abolished the glutathione depletion produced by both propoxyphene and morphine, but did not alter the propoxyphene-induced elevations of SGPT. Naltrexone also was tested against other narcotic agonists we have previously demonstrated to be hepatotoxic. Naltrexone pretreatment of antagonized L-alpha-acetylmethadol (LAAM)-induced depletion of glutathione and elevations of SGPT. Similarly, naltrexone antagonized norLAAM-induced depletion of glutathione and elevations of SGPT, but only lessened the magnitude of the changes induced by SKF525-A. The narcotic agonists morphine, LAAM, norLAAM and propoxyphene lower hepatic glutathione and induce hepatocellular damage, but these two effects appear to be unrelated

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