naloxone and Liver-Diseases

Opioids such as oxycodone are recommended in the management of moderate-to-severe, chronic cancer pain. All opioids can potentially cause constipation, which may be a significant barrier to their use. Multiple randomised clinical trials have shown that the use of naloxone as a peripherally acting mu-opioid receptor antagonist, in combination with oxycodone can prevent or reduce opioid-induced constipation while having equivalent analgesic efficacy to oxycodone alone. However, clinical experience has shown that unexpected events may occur in some patients when unrecognized liver impairment is present. We describe the underlying biological reasons and propose simple, but effective steps to avoid this unusual but potentially serious occurrence. In healthy individuals, naloxone undergoes extensive hepatic first pass metabolism resulting in low systemic bioavailability. However, in patients with hepatic impairment, porto-systemic shunting can increase systemic bioavailability of naloxone, potentially compromising the analgesic efficacy of oral naloxone-oxycodone combinations. This reduced first pass effect can occur in a range of settings that may not always be apparent to the treating clinician, including silent cirrhosis, non-cirrhotic portal hypertension and disruption of liver internal vasculature by metastases. Hepatic function test results correlate poorly with presence and extent of liver disease, and are not indicative of porto-systemic shunting. Presence of hepatic impairment should thus be considered when medication-related outcomes with oxycodone-naloxone combination are not as expected, even if liver function test results are normal.

Topics: Analgesics, Opioid; Cancer Pain; Constipation; Delayed-Action Preparations; Humans; Liver Diseases; Naloxone; Neoplasms; Oxycodone; Tablets

Opioid substitution therapy (OST) for opioid dependence is common, and injection drug users have significant medical and psychiatric comorbidity. Many physicians will encounter OST patients in their usual practice. This article provides guidance on management of common clinical problems in this population, including OST management in hepatic failure, respiratory disease, pain management and potential drug interactions.

Topics: Analgesics; Australia; Buprenorphine; Comorbidity; Drug Interactions; Female; Humans; Liver Diseases; Mental Disorders; Methadone; Naloxone; Opiate Substitution Treatment; Pain; Pain Management; Palliative Care; Polypharmacy; Pregnancy; Pregnancy Complications; Respiratory Insufficiency; Substance-Related Disorders; Virus Diseases

Topics: Analgesics, Opioid; Delayed-Action Preparations; Humans; Liver; Liver Diseases; Naloxone; Oxycodone

Topics: Aged; Analgesics, Opioid; Cancer Pain; Carcinoma, Ductal; Delayed-Action Preparations; Drug Combinations; Drug Substitution; Female; Humans; Liver Diseases; Naloxone; Oxycodone

Opioid preconditioning against ischemia reperfusion injury has been well studied in myocardial and neuronal tissues. The objective of this study was to determine whether remifentanil could attenuate hepatic injury and to investigate the mechanisms.. A rat model of hepatic ischemia reperfusion injury and a hepatocyte hypoxia reoxygenation (HR) injury model were used, respectively, in two series of experiments. Remifentanil was administered before ischemia or hypoxia and the experiments were repeated with previous administration of naloxone, L-arginine and N-ω-nitro-L-arginine methyl ester, a nonselective opioid receptor antagonist, a nitric oxide donor, and nitric oxide synthase (NOS) inhibitor, respectively. Serum aminotransferase, cytokines, and hepatic lipid peroxidation were measured. Histopathology examination and apoptotic cell detection were assessed. For the in vitro study, cell viability, intracellular nitric oxide, apoptosis, and NOS expression were evaluated.. Remifentanil and L-arginine pretreatment reduced concentrations of serum aminotransferases and cytokines, decreased the concentrations of hepatic malondialdehyde and myeloperoxidase activity, and increased superoxide dismutase, nitric oxide, and inducible NOS expression in vivo. Decreased histologic damage and apoptosis were also seen in these two groups. These changes were prevented by previous administration of N-ω-nitro-L-arginine methyl ester but not naloxone. There was an increase in inducible NOS protein expression but not endogenous NOS in remifentanil and L-arginine pretreated groups compared with control, naloxone, and N-ω-nitro-L-arginine methyl ester groups.. Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response.

Topics: Analgesics, Opioid; Animals; Arginine; Blotting, Western; Cell Survival; Cytokines; Disease Models, Animal; Ischemic Preconditioning; Lipid Peroxidation; Liver; Liver Diseases; Male; Naloxone; Narcotic Antagonists; Nitric Oxide Synthase; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Reperfusion Injury; Transaminases

Plasma methionine-enkephalin (Met-Enk) immunoreactivity has been determined in 24 patients with varying degrees of renal impairment and 14 patients with hepatic failure. Plasma Met-Enk immunoreactivity correlated inversely with creatinine clearance (r = -0.71, P less than 0.001) but was not affected by even severe hepatic failure in the absence of renal impairment. In two patients, with renal failure and elevated plasma prolactin, administration of naloxone (16 mg) had no effect on circulating prolactin concentrations. These studies indicate that the kidney has a major role in Met-Enk metabolism while the liver does not, and further suggest that elevated circulating endogenous opiates are not responsible for the increased production of prolactin found in renal failure.

Topics: Enkephalin, Methionine; Female; Humans; Hyperprolactinemia; Kidney; Kidney Diseases; Kidney Failure, Chronic; Liver; Liver Diseases; Male; Naloxone

Acute toxic interactions of intravenously administered benzyl alcohol and Escherichia coli O55:B5 (Boivin preparation) endotoxin were examined in rodents. Lethality studies in male CD-1 mice demonstrated that these agents were more toxic when administered in combination than when either was administered alone. Prophylactic treatment with diazepam (5 mg/kg intraperitoneally) protected against lethality induced by either the combination or the endotoxin yet offered little, if any, protection against the lethal effects of benzyl alcohol. Similar treatments with naloxone (5 mg/kg intraperitoneally) failed to protect against either endotoxin-induced or benzyl alcohol-induced lethality, but they significantly protected against the lethal effects of the combination. Although hexobarbital-induced sleeping time was prolonged in endotoxin-treated mice (but was normal in benzyl alcohol-treated mice), a more protracted effect on sleeping time was observed in mice treated with both benzyl alcohol and endotoxin. Moreover, male Wistar rats treated with benzyl alcohol (40 mg) showed no evidence of hepatic lesions, but rats treated in combination with sublethal doses of the alcohol (40 mg) and the endotoxin (0.4 mg) developed hepatic lesions which were severe than those observed in rats treated with endotoxin (0.4 mg) alone. A correlation between altered blood chemistry values and severity of hepatic lesions was demonstrated. These data show in vivo toxic interactions between benzyl alcohol and bacterial endotoxin. In addition, our results indicate that the toxic effects induced by the benzyl alcohol-endotoxin combination are due to an enhancement of the lethal properties of bacterial endotoxin.

Topics: Animals; Benzyl Alcohol; Benzyl Alcohols; Benzyl Compounds; Blood Chemical Analysis; Chemical and Drug Induced Liver Injury; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; Endotoxins; Escherichia coli; Hexobarbital; Liver Diseases; Male; Mice; Naloxone; Rats; Rats, Inbred Strains; Sleep

Topics: Acute Kidney Injury; Adult; Codeine; Humans; Infusions, Parenteral; Liver Diseases; Male; Naloxone

Topics: Adult; Female; Humans; Liver Diseases; Naloxone; Necrosis; Shock