Pain Management in the Cirrhotic Patient: The Clinical Challenge
2010; Elsevier BV; Volume: 85; Issue: 5 Linguagem: Inglês
10.4065/mcp.2009.0534
ISSN1942-5546
AutoresNatasha Chandok, Kymberly D. Watt,
Tópico(s)Epilepsy research and treatment
ResumoPain management in patients with cirrhosis is a difficult clinical challenge for health care professionals, and few prospective studies have offered an evidence-based approach. In patients with end-stage liver disease, adverse events from analgesics are frequent, potentially fatal, and often avoidable. Severe complications from analgesia in these patients include hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, which can result in substantial morbidity and even death. In general, acetaminophen at reduced dosing is a safe option. In patients with cirrhosis, nonsteroidal anti-inflammatory drugs should be avoided to avert renal failure, and opiates should be avoided or used sparingly, with low and infrequent dosing, to prevent encephalopathy. For this review, we searched the available literature using PubMed and MEDLINE with no limits. Pain management in patients with cirrhosis is a difficult clinical challenge for health care professionals, and few prospective studies have offered an evidence-based approach. In patients with end-stage liver disease, adverse events from analgesics are frequent, potentially fatal, and often avoidable. Severe complications from analgesia in these patients include hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, which can result in substantial morbidity and even death. In general, acetaminophen at reduced dosing is a safe option. In patients with cirrhosis, nonsteroidal anti-inflammatory drugs should be avoided to avert renal failure, and opiates should be avoided or used sparingly, with low and infrequent dosing, to prevent encephalopathy. For this review, we searched the available literature using PubMed and MEDLINE with no limits. Cirrhosis is a substantial public health problem, accounting for approximately 770,000 deaths annually and, according to autopsy studies, affecting 4.5% to 9.5% of the global population.1Lim YS Kim WR The global impact of hepatic fibrosis and end-stage liver disease.Clin Liver Dis. 2008; 12 (vii.): 733-746Abstract Full Text Full Text PDF Scopus (234) Google Scholar Pain management in patients with cirrhosis generates considerable misconception and apprehension among health care professionals. In patients with end-stage liver disease, adverse events from analgesics are frequent and can be severe. The most important and concerning complications include hepatic encephalopathy, acute renal failure, and gastrointestinal bleeding, which can lead to death in some patients. This article is a review (not a systematic review) of the available literature (using PubMed and MEDLINE with no search limits). The greater the progression of liver dysfunction, the greater the impairment in drug metabolism.2Verbeeck RK Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J Clin Pharmacol. 2008; 64: 1147-1161Crossref PubMed Scopus (463) Google Scholar, 3Elbekai R Korashy H El-Kadi A The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes.Curr Drug Metab. 2004; 5: 157-167Crossref Scopus (111) Google Scholar Patients with asymptomatic chronic liver disease without cirrhosis do not have liver dysfunction, and thus analgesic metabolism is similar to that in the general population. In patients with severe liver disease but not cirrhosis (eg, severe hepatitis), drug metabolism may be altered, and thus concerns and dose reductions, as discussed in this article, may be warranted.2Verbeeck RK Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J Clin Pharmacol. 2008; 64: 1147-1161Crossref PubMed Scopus (463) Google Scholar, 3Elbekai R Korashy H El-Kadi A The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes.Curr Drug Metab. 2004; 5: 157-167Crossref Scopus (111) Google Scholar, 4Tegeder I Lotsch J Geisslinger G Pharmacokinetics of opioids in liver disease.Clin Pharmacokinet. 1999; 37: 17-40Crossref Scopus (244) Google Scholar A patient with well-compensated cirrhosis and near-normal synthetic function will have impaired drug metabolism, but to a lesser extent than will patients with abnormal synthetic function or decompensated cirrhosis. Decompensated cirrhosis can be a result of progressive liver dysfunction, worsened portal hypertension, or both. Such patients may have even greater restrictions on analgesic choice. This article pertains to all patients with cirrhosis (compensated or decompensated) and to patients with liver dysfunction (with elevated bilirubin levels and prothrombin time), whether they do or do not have cirrhosis. The efficiency of drug removal by the liver relies on hepatic blood flow, hepatic enzyme capacity, and plasma protein binding. Cirrhosis affects all these processes and may also lead to formation of portosystemic shunts by which a drug can circumnavigate hepatic elimination.2Verbeeck RK Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J Clin Pharmacol. 2008; 64: 1147-1161Crossref PubMed Scopus (463) Google Scholar, 4Tegeder I Lotsch J Geisslinger G Pharmacokinetics of opioids in liver disease.Clin Pharmacokinet. 1999; 37: 17-40Crossref Scopus (244) Google Scholar Advanced liver disease and cirrhosis alter the metabolism and effects of many drugs through a variety of mechanisms, including changes in pharmacokinetic behavior, altered accumulation of free drug in plasma, and end-organ response. Major categories of pain medications, including over-the-counter analgesics (OTCAs) such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as cyclooxygenase 2 (COX-2) inhibitors, anticonvulsants, antidepressants, and opioids, are largely metabolized by the liver. Unfortunately, there are no endogenous markers for hepatic clearance that can be used as a guide for drug dosing, nor are there readily available tests to accurately estimate the extent of residual liver function. Moreover, there is a paucity of high-quality, prospective data that examine the pharmacology and adverse effect profile of many analgesics in patients with advanced liver dysfunction. Drug metabolism in general occurs in the liver via 3 mechanisms: (1) oxidation, reduction, or hydrolysis reactions of the hepatic cytochrome P450 (CYP) enzyme system; (2) conjugation to glucuronic acid, sulfate, acetate, glycine, glutathione, or a methyl group; and (3) biliary excretion and elimination.3Elbekai R Korashy H El-Kadi A The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes.Curr Drug Metab. 2004; 5: 157-167Crossref Scopus (111) Google Scholar, 5Villeneuve JP Raymond G Bruneau J Colpron L Pomier-Layrargues G Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic and cirrhotic subjects.Gastroenterol Clin Biol. 1983; 7: 898-902Google Scholar The pharmacokinetics of analgesic medications rely heavily on liver and renal function. Drugs with high hepatic extraction (or first-pass metabolism), such as morphine or fentanyl, have low bioavailability in healthy people but higher bioavailability in cirrhotic patients. For drugs with a low hepatic extraction, such as methadone, liver disease does not impact bioavailability, but hepatic clearance may be altered substantially. The ability to clear drug metabolites decreases with liver dysfunction, resulting in altered parent drug or metabolite bioavailability and increased toxicity in cirrhotic patients. Thus, if such drugs are administered to cirrhotic patients, the dose should be reduced and/or the drug used less frequently.2Verbeeck RK Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J Clin Pharmacol. 2008; 64: 1147-1161Crossref PubMed Scopus (463) Google Scholar Cirrhotic patients often have low serum protein and albumin concentrations. If a drug is highly protein bound, a low albumin level can result in increased levels of free drug and consequent increased adverse effects and toxicity.2Verbeeck RK Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J Clin Pharmacol. 2008; 64: 1147-1161Crossref PubMed Scopus (463) Google Scholar In patients with severe cholestasis, the clearance of drugs with high biliary elimination, such as buprenorphine, may also be compromised because of dysfunction of basolateral and/or apical transmembrane transport systems in hepatocytes, requiring dose reduction or avoidance of use of the drug.4Tegeder I Lotsch J Geisslinger G Pharmacokinetics of opioids in liver disease.Clin Pharmacokinet. 1999; 37: 17-40Crossref Scopus (244) Google Scholar, 6Bohan A Boyer JL Mechanisms of hepatic transport of drugs: implications for cholestatic drug reactions.Semin Liver Dis. 2002; 22: 123-136Crossref Scopus (105) Google Scholar, 7Delco F Tchambaz L Schlienger R Drewe J Krahenbuhl S Dose adjustment in patients with liver disease.Drug Saf. 2005; 28: 529-545Crossref Scopus (174) Google Scholar Dosing of analgesic drugs with a predominant renal elimination may require adjustment in patients with liver disease (Table 1). Cirrhotic patients often have impaired renal function despite a normal serum creatinine level because of poor nutrition and reduced muscle mass resulting in less creatinine production. Therefore, in cirrhotic patients, creatinine clearance should be measured or calculated using the Cockcroft and Gault equation to better estimate the dosing of analgesic drugs that have preponderant renal elimination.2Verbeeck RK Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J Clin Pharmacol. 2008; 64: 1147-1161Crossref PubMed Scopus (463) Google Scholar, 8Cockcroft DW Gault MH Prediction of creatinine clearance from serum creatinine.Nephron. 1976; 16: 31-41Crossref PubMed Scopus (13103) Google Scholar Because the creatinine clearance tends to overestimate the glomerular filtration rate (GFR) in cirrhotic patients, the dose of a given drug may still need to be reduced. Unfortunately, criterion standard tests to estimate GFR, such as inulin or iothalamate clearance, are not widely available, and their accuracy in this patient population is unknown.Table 1Analgesic Medications and Their Routes of excretionMedicationRoute of excretionAcetaminophenRenalRenal: 85%AspirinRenal/other Renal: 5.6%–35.6%Tears: salicylate detectable in tearsCodeineRenal/other Renal: 90%Fecal: 10%FentanylRenal/other Renal: 75% metabolitesFecal: 9% primarily as metabolitesHydrocodoneRenalRenal: 26%HydromorphoneRenalRenal: 1.3%–13.2% unchanged, 22%–51% conjugatedMeperidineRenal/other Renal: 0.5%–5.2% unchanged, 0.6%–21% active metaboliteSaliva: higher concentrations in saliva than blood after IM injectionMethadoneBiliary/renal/other Biliary: detectable in the bileRenal: 21% unchangedFecal: metabolites and conjugated metabolitesMorphineRenal/other Renal: 90%Fecal: 7%–10%OxycodoneRenalRenal: primarilyPropoxypheneRenalRenal: 20%–25%TramadolRenalRenal: 60% as metaboliteNSAIDs CelecoxibRenal/other Renal: 27%Fecal: 57% DiclofenacBiliary/renal Biliary: 35%Renal: 65% as conjugated metabolites FenoprofenRenal/other Renal: 90%Fecal: small percentage EtodolacRenal/other Renal: 72%Fecal: 16% IbuprofenRenalRenal: primary route, inactive metabolites excreted IndomethacinBiliary/renal/other Biliary: moderate due to entero-hepatic recirculationRenal: 60%Fecal: 33% KetoprofenBiliary/renal Biliary: up to 40% due to entero-hepatic recirculation (amount increases with renal impairment)Renal: 80% KetorolacRenal/other Renal: 92%Fecal: 5.9%–6.3% MeloxicamBilliary/renal/other Biliary: signifcant excretionRenal: 19%Fecal: 1.6% NaproxenRenalRenal: 95% SulindacRenal/other Renal: 50%Fecal: 25%IM = intramuscular; NSAID = nonsteroidal anti-infammatory drug. Open table in a new tab IM = intramuscular; NSAID = nonsteroidal anti-infammatory drug. Over-the-counter analgesics, principally acetaminophen and NSAIDs, are commonly used medications worldwide. Guidelines for the use of OTCAs in patients with chronic liver disease are not readily available despite the possibility that such patients may be more susceptible to adverse reactions. Patients are often counseled to modify use of these drugs. Health care professionals frequently recommend avoidance of the use of acetaminophen in patients with liver disease or cirrhosis, whereas NSAIDs are more commonly endorsed.9Rossi S Assis DN Awsare M et al.Use of over-the-counter analgesics in patients with chronic liver disease: physicians' recommendations.Drug Saf. 2008; 31: 261-270Crossref Scopus (48) Google Scholar Variability and misconception regarding the safety of OTCAs for patients with hepatic dysfunction are widespread among health care professionals. Acetaminophen is the most common cause of fulminant hepatic failure in the United States, creating the perception that it may be dangerous in patients with chronic liver disease.9Rossi S Assis DN Awsare M et al.Use of over-the-counter analgesics in patients with chronic liver disease: physicians' recommendations.Drug Saf. 2008; 31: 261-270Crossref Scopus (48) Google Scholar, 10Lee WM Etiologies of acute liver failure.Semin Liver Dis. 2008; 28: 142-152Crossref Scopus (160) Google Scholar, 11Larson A Polson J Fontana RJ Acute Liver Failure Study Group et al.Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.Hepatology. 2005; 42: 1364-1372Crossref PubMed Scopus (1464) Google Scholar Moreover, concern is increasing regarding the safety of acetaminophen at a maximal dosage of 4 g/d in the general population. Surveillance data from the United States from 1990 to 1998 estimated 56,000 emergency department visits, 26,000 hospitalizations, and 458 deaths per annum because of acetaminophen overdoses.12Nourjah P Ahmad SR Karwoski C Willy M Estimates of acetaminophen (Paracetamol)-associated overdoses in the United States.Pharmacoepidemiol Drug Saf. 2006; 15: 398-405Crossref PubMed Scopus (227) Google Scholar When one considers that 28 billion doses of products containing acetaminophen were consumedin 2005 alone,13US Department of Health and Human Services US Food and Drug Administration (FDA) Drugs: acetaminophen information.http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htmGoogle Scholar the probability of an individual patient without preexisting liver disease or concomitant alcohol consumption developing clinically important hepatotoxicity or nephrotoxicity when acetaminophen dosing is limited to less than 4 g/d is exceedingly rare.13US Department of Health and Human Services US Food and Drug Administration (FDA) Drugs: acetaminophen information.http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htmGoogle Scholar, 14Benson GD Koff RS Tolman KG The therapeutic use of acetaminophen in patients with liver disease.Am J Ther. 2005; 12: 133-141Crossref Scopus (114) Google Scholar, 15Dart R Bailey E Does therapeutic use of acetaminophen cause acute liver failure?.Pharmacotherapy. 2007; 27: 1219-1230Crossref Scopus (111) Google Scholar, 16Temple AR Lynch JM Vena J Auiler JF Gelotte CK Aminotransferase activities in healthy subjects receiving three-day dosing of 4, 6, or 8 grams per day of acetaminophen.Clin Toxicol (Phila). 2007; 45: 36-44Crossref Scopus (21) Google Scholar However, liver failure can occur with a 1-time ingestion of high doses of acetaminophen (>12 g in an adult or 250 mg/kg in a child).17Prescott LF Paracetamol overdosage: pharmacological considerations and clinical management.Drugs. 1983; 25: 290-314Crossref Scopus (343) Google Scholar, 18Makin AJ Wendon J Williams R A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993).Gastroenterology. 1995; 109: 1907-1916Abstract Full Text PDF Scopus (287) Google Scholar Case reports have demonstrated that long-term ingestion (often accidental) of supratherapeutic doses (>4 g/d) of acetaminophen in patients without known liver disease, and therapeutic doses in alcoholic patients without cirrhosis, resulted in acute liver failure.19Pezzano M Richard C Lampl E et al.Hepatic and renal toxicity of paracetamol in chronic alcoholic patient.Presse Med. 1988; 17: 21-24Google Scholar, 20Mofredj A Cadranel JF Darchy B et al.Hepatotoxicity caused by therapeutic doses of paracetamol in alcoholics: report of 2 cases of fatal hepatitis in cirrhosis.Ann Med Interne (Paris). 1999; 150: 507-511Google Scholar, 21Bolesta S Haber SL Hepatotoxicity associated with chronic acetaminophen administration in patients without risk factors.Ann Pharmacother. 2002; 36: 331-333Crossref Scopus (51) Google Scholar To address the fact that approximately half of all cases of acetaminophen-induced acute liver failure are due to unintentional overdosing,11Larson A Polson J Fontana RJ Acute Liver Failure Study Group et al.Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.Hepatology. 2005; 42: 1364-1372Crossref PubMed Scopus (1464) Google Scholar advisory committees to the Food and Drug Administration (FDA) endorse relabeling of acetaminophen-containing products to better inform the consumer of the potential for liver injury with supratherapeutic doses, and while concurrently consuming 3 or more alcoholic drinks per day. In addition, the advisory committees support lowering the maximal dosage of acetaminophen to 2600 mg/d and eliminating or reducing the availability of combination analgesics, most commonly combinations of opioid with acetaminophen.13US Department of Health and Human Services US Food and Drug Administration (FDA) Drugs: acetaminophen information.http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htmGoogle Scholar Opiates can be addictive, and patients may develop tolerance to these agents, necessitating dose escalation and thereby increasing the risk of acetaminophen toxicity. These recommendations have not yet been instituted. Unfortunately, no prospective, long-term studies have assessed the safety of long-term use of acetaminophen in patients with cirrhosis. In such patients, the half-life of oral acetaminophen is double that in healthy controls, but hepatic injury and renal injury are rare when the dosage is limited to less than 4 g/d.5Villeneuve JP Raymond G Bruneau J Colpron L Pomier-Layrargues G Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic and cirrhotic subjects.Gastroenterol Clin Biol. 1983; 7: 898-902Google Scholar, 22Hirschfield GM Kumagi T Heathcote EJ Preventative hepatology: minimising symptoms and optimising care.Liver Int. 2008; 28: 922-934Crossref PubMed Scopus (20) Google Scholar This assumption is supported by a double-blind, 2-period crossover study of 20 patients with chronic stable liver disease (8 with cirrhosis), who tolerated acetaminophen at a dosage of 4 g/d for 13 days without adverse effects.23Benson GD Acetaminophen in chronic liver disease.Clin Pharmacol Ther. 1983; 33: 95-101Crossref Scopus (109) Google Scholar The prevailing mechanism of acetaminophen-induced hepatotoxicity includes altered metabolism via CYP activity in combination with depleted glutathione stores that cause accumulation of a hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI) (Figure 1). Studies in patients with cirrhosis have shown that CYP activity is not increased and glutathione stores are not depleted to critical levels in those taking recommended doses of acetaminophen. Glutathione stores are variable in patients with and without underlying liver disease but generally have not been found to be depleted in cirrhotic patients.14Benson GD Koff RS Tolman KG The therapeutic use of acetaminophen in patients with liver disease.Am J Ther. 2005; 12: 133-141Crossref Scopus (114) Google Scholar On the basis of these data, the longer half-life, and very limited clinical studies, our recommendation (expert opinion) for long-term acetaminophen use (>14 days) in cirrhotic patients (not actively drinking alcohol) is for reduced dosing at 2 to 3 g/d.14Benson GD Koff RS Tolman KG The therapeutic use of acetaminophen in patients with liver disease.Am J Ther. 2005; 12: 133-141Crossref Scopus (114) Google Scholar For short-term use or 1-time dosing, 3 to 4 g appears safe; however, with the new FDA guidelines in mind, a maximum dosage of 2 to 3 g/d is recommended. Glutathione is predictably depleted in the setting of long-term alcohol consumption or malnutrition.14Benson GD Koff RS Tolman KG The therapeutic use of acetaminophen in patients with liver disease.Am J Ther. 2005; 12: 133-141Crossref Scopus (114) Google Scholar, 15Dart R Bailey E Does therapeutic use of acetaminophen cause acute liver failure?.Pharmacotherapy. 2007; 27: 1219-1230Crossref Scopus (111) Google Scholar, 21Bolesta S Haber SL Hepatotoxicity associated with chronic acetaminophen administration in patients without risk factors.Ann Pharmacother. 2002; 36: 331-333Crossref Scopus (51) Google Scholar Alcohol itself, its main metabolite acetaldehyde, and a malnourished state also deplete the antioxidant reserve, rendering alcoholic patients more susceptible to drug-induced liver injury. In addition, long-term alcohol ingestion induces CYP2E1, the major enzyme responsible for the metabolism of acetaminophen to its toxic metabolite NAPQI24Villeneuve JP Pichette V Cytochrome P450 and liver diseases.Curr Drug Metab. 2004; 5: 273-282Crossref Scopus (157) Google Scholar (Figure 1). Hence, the population at modestly higher risk of toxicity with long-term supratherapeutic dosing of acetaminophen is the chronic alcoholic or malnourished patient, but no prospective studies exist in these patient populations. Toxicity has been seen in alcoholic patients taking greater than 4 g/d of acetaminophen.25Whitcomb DC Block GD Association of acetaminophen hepatotoxicity with fasting and ethanol use.JAMA. 1994; 272: 1845-1850Crossref Scopus (406) Google Scholar, 26Prescott LF Paracetamol, alcohol and the liver.Br J Clin Pharmacol. 2000; 49: 291-301Crossref Scopus (184) Google Scholar A randomized controlled trial of 4 g/d of acetaminophen for 10 days in patients consuming daily alcohol (defined as 1-3 drinks per day) suggested no significant toxicity after up to 10 days of use, but a small increase in liver enzymes (8 IU/mL) was observed, the clinical importance of which is unclear.27Kuffner EK Green JL Bogdan GM et al.The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients: a multicenter randomized study.BMC Med. 2007; 5: 13Crossref PubMed Scopus (63) Google Scholar A study of alcohol-dependent patients (defined as >6 drinks per day for >6 weeks) admitted to a chemical detoxification unit who were receiving 4 g/d of acetaminophen for 3 days during the immediate withdrawal period showed no evidence of toxicity.28Heard K Green JL Bailey JE Bogdan GM Dart RC A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol.Aliment Pharmacol Ther. 2007; 26: 283-290Crossref Scopus (67) Google Scholar A systematic review of methodologically sound short-term studies suggested that the use of therapeutic dosing of acetaminophen in patients with chronic alcoholism has not been associated with liver injury, but no studies of longer-term therapy have been performed.15Dart R Bailey E Does therapeutic use of acetaminophen cause acute liver failure?.Pharmacotherapy. 2007; 27: 1219-1230Crossref Scopus (111) Google Scholar Thus, less than 4 g/d of acetaminophen appears safe for short-term dosing in patients with mild to moderate alcohol intake, but most hepatologists (written communication, expert opinion: see end of article for list of sources) advocate for lower dosing at 2 g or less per day, given the small margin for error in a nonstudy population. Data do not exist for long-term acetaminophen use in patients with active alcohol use. Multiple hepatologists agree that 2 g or less per day of acetaminophen would be recommended for these patients (written communication, expert opinion). Careful follow-up of these patients is recommended. Patients who have underlying alcohol-related liver disease but have prolonged abstinence and are nutritionally replete can be treated similarly to other cirrhotic patients. NSAIDs as a class are largely metabolized by CYPs, and most are heavily protein bound. As such, altered metabolism and bioavailability that result in increased serum levels can be anticipated in the cirrhotic patient.29Williams RL Upton RA Cello JP et al.Naproxen disposition in patients with alcoholic cirrhosis.Eur J Clin Pharmacol. 1984; 27: 291-296Crossref Scopus (48) Google Scholar NSAID-induced (and idiosyncratic) hepatotoxicity has also been well described.9Rossi S Assis DN Awsare M et al.Use of over-the-counter analgesics in patients with chronic liver disease: physicians' recommendations.Drug Saf. 2008; 31: 261-270Crossref Scopus (48) Google Scholar However, in cirrhotic patients with portal hypertension, the greater concern with NSAID use is the associated renal impairment, in particular hepatorenal syndrome. This is thought to be due to the inhibition of prostaglandins, which leads to a profound decrease in renal perfusion, reduction in GFR, and marked sodium retention. Cirrhotic patients require prostaglandins to counteract the renin-angiotensin-aldosterone and sympathetic systems that reduce perfusion to the kidneys.30Laffi G La Villa G Pinzani M Marra F Gentilini P Arachidonic acid derivatives and renal function in liver cirrhosis.Semin Nephrol. 1997; 17: 530-548PubMed Google Scholar Hepatorenal syndrome is a dreaded and frequently fatal complication of advanced liver disease. NSAIDs can cause mucosal bleeding in patients at increased risk of bleeding as a result of thrombocytopenia and coagulopathy associated with advanced liver disease. This risk is even greater in patients with portal hypertension–related complications, such as esophageal/gastric varices and portal hypertensive gastropathy or gastric antral vacular ectasias.31Castro-Fernandez M Sanchez-Munoz D Galan-Jurado MV et al.Influence of nonsteroidal antiinflammatory drugs in gastrointestinal bleeding due to gastroduodenal ulcers or erosions in patients with liver cirrhosis.Gastroenterol Hepatol. 2006; 29: 11-14Crossref Scopus (15) Google Scholar NSAIDs may be tolerated in patients with mild chronic liver disease, but they should be avoided in all patients with cirrhosis because of the increased risk of hepatorenal syndrome and the dire consequences relating to this complication.30Laffi G La Villa G Pinzani M Marra F Gentilini P Arachidonic acid derivatives and renal function in liver cirrhosis.Semin Nephrol. 1997; 17: 530-548PubMed Google Scholar Preventive medicine, including avoidance of NSAIDs, is exceedingly important in maintaining the clinical stability of patients with well-compensated cirrhosis. No prospective studies have assessed the safety and efficacy of COX-2 inhibitors in the management of chronic pain in patients with cirrhosis. Studies comparing NSAIDs with COX-2 inhibitors in patients without underlying liver disease have demonstrated similar effectiveness in the treatment of musculoskeletal pain.32Hur C Chan AT Tramontano AC Gazelle GS Coxibs versus combination NSAID and PPI therapy for chronic pain: an exploration of the risks, benefits, and costs.Ann Pharmacother. 2006; 40: 1052-1063Crossref Scopus (31) Google Scholar, 33Chen YF Jobanputra P Barton P et al.Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.Health Technol Assess. 2008; 12 (iii.): 1-278Google Scholar Although some COX-2 inhibitors may protect against gastrointestinal hemorrhage compared with NSAIDs, an increased risk of cardiovascular adverse events has been observed. Cyclooxygenases are highly regulated in response to changes in intravascular volume, and COX-2 is implicated in the mediation of renin release, sodium regulation, and the maintenance of renal blood flow. COX-2 inhibitors may reduce portal pressure in cirrhotic patients, but pilot data suggest a decreased GFR in patients with cirrhosis and ascites treated with celecoxib.34Guevara M Abecasis R Jimenez W et al.Effect of celecoxib on renal function in cirrhotic patients with ascites: a pilot study [abstract].J Hepatol. 2002; 36: 203Abstract Full Text PDF Google Scholar The safety of COX-2 inhibitors needs further study in patients with cirrhosis. Like anti-inflammatory medications, opioids can have deleterious effects in patients with cirrhosis. Although large epidemiological studies are lacking, sedatives and opioids are common precipitants of hepatic encephalopathy and hospitalization, and thus they should be avoided in patients with cirrhosis, especially in those with portal hypertension and encephalopathy.22Hirschfield GM Kumagi T Heathcote EJ Preventative hepatology: minimising symptoms and optimising care.Liver Int. 2008; 28: 922-934Crossref PubMed Scopus (20) Google Scholar The liver is the main site of metabolism for most opioids. The major metabolic pathways for most opioids are oxidation via the CYP system (CYP2D6 and 3A4) or glucuronidation; both processes can be impaired in the setting of end-stage liver disease, although the CYP more so.2Verbeeck RK Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J Clin Pharmacol. 2008; 64: 1147-1161Crossref PubMed Scopus (463) Google Scholar, 3Elbekai R Korashy H El-Kadi A The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes.Curr Drug Metab. 2004; 5: 157-167Crossref Scopus (111) Google Scholar not only is the CYP system affected by liver dysfunc
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