, Volume 72, Issue 12, pp 1645–1669 | Cite as

Analgesics in Patients with Hepatic Impairment

Pharmacology and Clinical Implications
  • Marija Bosilkovska
  • Bernhard Walder
  • Marie Besson
  • Youssef Daali
  • Jules DesmeulesEmail author
Review Article


The physiological changes that accompany hepatic impairment alter drug disposition. Porto-systemic shunting might decrease the first-pass metabolism of a drug and lead to increased oral bioavailability of highly extracted drugs. Distribution can also be altered as a result of impaired production of drug-binding proteins or changes in body composition. Furthermore, the activity and capacity of hepatic drug metabolizing enzymes might be affected to various degrees in patients with chronic liver disease. These changes would result in increased concentrations and reduced plasma clearance of drugs, which is often difficult to predict.

The pharmacology of analgesics is also altered in liver disease. Pain management in hepatically impaired patients is challenging owing to a lack of evidence-based guidelines for the use of analgesics in this population. Complications such as bleeding due to antiplatelet activity, gastrointestinal irritation, and renal failure are more likely to occur with nonsteroidal anti-inflammatory drugs in patients with severe hepatic impairment. Thus, this analgesic class should be avoided in this population.

The pharmacokinetic parameters of paracetamol (acetaminophen) are altered in patients with severe liver disease, but the short-term use of this drug at reduced doses (2 grams daily) appears to be safe in patients with nonalcoholic liver disease.

The disposition of a large number of opioid drugs is affected in the presence of hepatic impairment. Certain opioids such as codeine or tramadol, for instance, rely on hepatic biotransformation to active metabolites. A possible reduction of their analgesic effect would be the expected pharmacodynamic consequence of hepatic impairment. Some opioids, such as pethidine (meperidine), have toxic metabolites. The slower elimination of these metabolites can result in an increased risk of toxicity in patients with liver disease, and these drugs should be avoided in this population.

The drug clearance of a number of opioids, such as morphine, oxycodone, tramadol and alfentanil, might be decreased in moderate or severe hepatic impairment. For the highly excreted morphine, hydromorphone and oxycodone, an important increase in bioavailability occurs after oral administration in patients with hepatic impairment. Lower doses and/or longer administration intervals should be used when these opioids are administered to patients with liver disease to avoid the risk of accumulation and the potential increase of adverse effects. Finally, the pharmacokinetics of phenylpiperidine opioids such as fentanyl, sufentanil and remifentanil appear to be unaffected in hepatic disease. All opioid drugs can precipitate or aggravate hepatic encephalopathy in patients with severe liver disease, thus requiring cautious use and careful monitoring.


Morphine Tramadol Cirrhotic Patient Remifentanil Buprenorphine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The preparation of this review was supported by a grant from the Swiss National Science Foundation (N°K-23K1-122264). The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet 1995 Nov; 29 (5): 370–91PubMedCrossRefGoogle Scholar
  2. 2.
    Larrey D, Pageaux G. Prescribing drugs in liver disease. In: Rodes J, Benhamou J, Blei A, editors. Textbook of hepatology: from basic science to clinical practice. Malden (MA): Blackwell Publishing, 2007: 1912-22Google Scholar
  3. 3.
    Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008 Dec; 64 (12): 1147–61PubMedCrossRefGoogle Scholar
  4. 4.
    US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for industry: pharmacokinetics in patients with impaired hepatic function. Study design, data analysis, and impact on dosing and labeling. 2003 May [online]. Available from URL: [Accessed 2011 Dec 19]
  5. 5.
    European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. London: 2005 Feb 17 [online]. Available from URL: [Accessed 2011 Dec 19]
  6. 6.
    Hebert MF. Guide to drug dosage in hepatic disease: Avery’s drug treatment. A guide to the properties, choice, therapeutic use and economic value of drugs in disease management. 4th ed. Auckland: Adis International, 1997: 1761-89Google Scholar
  7. 7.
    Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995 Oct 26; 333 (17): 1118–27PubMedCrossRefGoogle Scholar
  8. 8.
    Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005 Dec; 42 (6): 1364–72PubMedCrossRefGoogle Scholar
  9. 9.
    Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med 1998 Jul 27; 105 (1B): 13S-9SGoogle Scholar
  10. 10.
    Lee CH, Wang JD, Chen PC. Increased risk of hospitalization for acute hepatitis in patients with previous ex-posure to NSAIDs. Pharmacoepidemiol Drug Saf 2010 Jul; 19 (7): 708–14PubMedCrossRefGoogle Scholar
  11. 11.
    Traversa G, Bianchi C, Da Cas R, et al. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ 2003 Jul 5; 327 (7405): 18–22PubMedCrossRefGoogle Scholar
  12. 12.
    Laine L, White WB, Rostom A, et al. COX-2 selective in-hibitors in the treatment of osteoarthritis. Semin Arthritis Rheum 2008 Dec; 38 (3): 165–87PubMedCrossRefGoogle Scholar
  13. 13.
    Radner H, Ramiro S, Buchbinder R, et al. Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity. Cochrane Database Syst Rev 2012; 1: CD008951Google Scholar
  14. 14.
    Rossi 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 (3): 261–70PubMedCrossRefGoogle Scholar
  15. 15.
    Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 1999 Jul; 37 (1): 17–40PubMedCrossRefGoogle Scholar
  16. 16.
    Blaschke TF, Rubin PC. Hepatic first-pass metabolism in liver disease. Clin Pharmacokinet 1979 Nov–Dec; 4 (6): 423–32PubMedCrossRefGoogle Scholar
  17. 17.
    Moreno AH, Burchell AR, Rousselot LM, et al. Portal blood flow in cirrhosis of the liver. J Clin Invest 1967 Mar; 46 (3): 436–45PubMedCrossRefGoogle Scholar
  18. 18.
    McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991 Jul; 21 (1): 42–69PubMedCrossRefGoogle Scholar
  19. 19.
    Davis M. Cholestasis and endogenous opioids: liver disease and exogenous opioid pharmacokinetics. Clin Pharmacokinet 2007; 46 (10): 825–50PubMedCrossRefGoogle Scholar
  20. 20.
    Hoyumpa AM, Schenker S. Is glucuronidation truly pre-served in patients with liver disease?. Hepatology 1991 Apr; 13 (4): 786–95PubMedCrossRefGoogle Scholar
  21. 21.
    Angus PW, Morgan DJ, Smallwood RA. Review article: hypoxia and hepatic drug metabolism. Clinical implications. Aliment Pharmacol Ther 1990 Jun; 4 (3): 213–25CrossRefGoogle Scholar
  22. 22.
    Morgan DJ, McLean AJ. Therapeutic implications of im-paired hepatic oxygen diffusion in chronic liver disease. Hepatology 1991 Dec; 14 (6): 1280–2PubMedCrossRefGoogle Scholar
  23. 23.
    Frye RF, Zgheib NK, Matzke GR, et al. Liver disease se-lectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther 2006 Sep; 80 (3): 235–45PubMedCrossRefGoogle Scholar
  24. 24.
    Debinski HS, Lee CS, Danks JA, et al. Localization of uridine 5’-diphosphate-glucuronosyltransferase in human liver injury. Gastroenterology 1995 May; 108 (5): 1464–9PubMedCrossRefGoogle Scholar
  25. 25.
    Mazoit JX, Sandouk P, Scherrmann JM, et al. Extrahepatic metabolism of morphine occurs in humans. Clin Pharmacol Ther 1990 Dec; 48 (6): 613–8PubMedCrossRefGoogle Scholar
  26. 26.
    Gines P, Guevara M, Arroyo V, et al. Hepatorenal syn-drome. Lancet 2003 Nov 29; 362 (9398): 1819–27PubMedCrossRefGoogle Scholar
  27. 27.
    Papadakis MA, Arieff AI. Unpredictability of clinical evaluation of renal function in cirrhosis: prospective study. Am J Med 1987 May; 82 (5): 945–52PubMedCrossRefGoogle Scholar
  28. 28.
    Cocchetto DM, Tschanz C, Bjornsson TD. Decreased rate of creatinine production in patients with hepatic disease: implications for estimation of creatinine clearance. Ther Drug Monit 1983 Jun; 5 (2): 161–8PubMedCrossRefGoogle Scholar
  29. 29.
    Cockcroft DW, Gault MH. Prediction of creatinine clear-ance from serum creatinine. Nephron 1976; 16 (1): 31–41PubMedCrossRefGoogle Scholar
  30. 30.
    Caregaro L, Menon F, Angeli P, et al. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 1994 Jan 24; 154 (2): 201–5PubMedCrossRefGoogle Scholar
  31. 31.
    Andreasen PB, Hutters L. Paracetamol (acetaminophen) clearance in patients with cirrhosis of the liver. Acta Med Scand Suppl 1979; 624: 99–105PubMedGoogle Scholar
  32. 32.
    Arnman R, Olsson R. Elimination of paracetamol in chronic liver disease. Acta Hepatogastroenterol (Stuttg) 1978 Aug; 25 (4): 283–6Google Scholar
  33. 33.
    Forrest JA, Adriaenssens P, Finlayson ND, et al. Parace-tamol metabolism in chronic liver disease. Eur J Clin Pharmacol 1979 Jul; 15 (6): 427–31PubMedCrossRefGoogle Scholar
  34. 34.
    Forrest JA, Finlayson ND, Adjepon-Yamoah KK, et al. Antipyrine, paracetamol, and lignocaine elimination in chronic liver disease. Br Med J 1977 May 28; 1 (6073): 1384–7PubMedCrossRefGoogle Scholar
  35. 35.
    Roberts MS, Rumble RH, Wanwimolruk S, et al. Pharmacokinetics of aspirin and salicylate in elderly subjects and in patients with alcoholic liver disease. Eur J Clin Phar-macol 1983; 25 (2): 253–61CrossRefGoogle Scholar
  36. 36.
    Williams RL, Upton RA, Cello JP, et al. Naproxen dis-position in patients with alcoholic cirrhosis. Eur J Clin Pharmacol 1984; 27 (3): 291–6PubMedCrossRefGoogle Scholar
  37. 37.
    Juhl RP, Van Thiel DH, Dittert LW, et al. Ibuprofen and sulindac kinetics in alcoholic liver disease. Clin Pharmacol Ther 1983 Jul; 34 (1): 104–9PubMedCrossRefGoogle Scholar
  38. 38.
    Brater DC. Lasseter Profile of etodolac: pharmacokinetic evaluation in special populations. Clin Rheumatol 1989 Mar; 8 Suppl. 1: 25–35PubMedCrossRefGoogle Scholar
  39. 39.
    Davies NM, McLachlan AJ, Day RO, et al. Clinical pharmacokinetics and pharmacodynamics of celecoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet 2000 Mar; 38 (3): 225–42PubMedCrossRefGoogle Scholar
  40. 40.
    Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993 Aug; 46 (2): 313–40PubMedCrossRefGoogle Scholar
  41. 41.
    Nucynta® (tapentadol) immediate-release oral tablets. US prescribing information. Raritan (NJ): Ortho-McNeil-Janssen Pharmaceuticals, Inc., 2009 [online]. Available from URL: [Accessed 2012 May 22]
  42. 42.
    Crotty B, Watson KJ, Desmond PV, et al. Hepatic extraction of morphine is impaired in cirrhosis. Eur J Clin Pharmacol 1989; 36 (5): 501–6PubMedCrossRefGoogle Scholar
  43. 43.
    Hasselström J, Eriksson S, Persson A, et al. The metabo-lism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990 Mar; 29 (3): 289–97PubMedCrossRefGoogle Scholar
  44. 44.
    Mazoit JX, Sandouk P, Zetlaoui P, et al. Pharmacokinetics of unchanged morphine in normal and cirrhotic subjects. Anesth Analg 1987 Apr; 66 (4): 293–8PubMedCrossRefGoogle Scholar
  45. 45.
    Kotb HI, el-Kabsh MY, Emara SE, et al. Pharmacokinetics of controlled release morphine (MST) in patients with liver cirrhosis. Br J Anaesth 1997 Dec; 79 (6): 804–6PubMedCrossRefGoogle Scholar
  46. 46.
    Kaiko RF. Pharmacokinetics and pharmacodynamics of controlled-release opioids. Acta Anaesthesiol Scand 1997 Jan; 41 (1 Pt 2): 166–74PubMedCrossRefGoogle Scholar
  47. 47.
    Tallgren M, Olkkola KT, Seppala T, et al. Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation. Clin Pharmacol Ther 1997 Jun; 61 (6): 655–61PubMedCrossRefGoogle Scholar
  48. 48.
    Durnin C, Hind ID, Ghani SP, et al. Pharmacokinetics of oral immediate-release hydromorphone (Dilaudid IR) in subjects with moderate hepatic impairment. Proc West Pharmacol Soc 2001; 44: 83–4PubMedGoogle Scholar
  49. 49.
    Neal EA, Meffin PJ, Gregory PB, et al. Enhanced bio-availability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 1979 Jul; 77 (1): 96–102PubMedGoogle Scholar
  50. 50.
    Pond SM, Tong T, Benowitz NL, et al. Presystemic me-tabolism of meperidine to normeperidine in normal and cirrhotic subjects. Clin Pharmacol Ther 1981 Aug; 30 (2): 183–8PubMedCrossRefGoogle Scholar
  51. 51.
    Klotz U, McHorse TS, Wilkinson GR, et al. The effect of cirrhosis on the disposition and elimination of meperidine in man. Clin Pharmacol Ther 1974 Oct; 16 (4): 667–75PubMedGoogle Scholar
  52. 52.
    Danziger LH, Martin SJ, Blum RA. Central nervous system toxicity associated with meperidine use in hepatic disease. Pharmacotherapy 1994 Mar-Apr; 14 (2): 235–8PubMedGoogle Scholar
  53. 53.
    Novick DM, Kreek MJ, Fanizza AM, et al. Methadone disposition in patients with chronic liver disease. Clin Pharmacol Ther 1981 Sep; 30 (3): 353–62PubMedCrossRefGoogle Scholar
  54. 54.
    Novick DM, Kreek MJ, Arns PA, et al. Effect of severe alcoholic liver disease on the disposition of methadone in maintenance patients. Alcohol Clin Exp Res 1985 Jul–Aug; 9 (4): 349–54PubMedCrossRefGoogle Scholar
  55. 55.
    Haberer JP, Schoeffler P, Couderc E, et al. Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis. Br J Anaesth 1982 Dec; 54 (12): 1267–70PubMedCrossRefGoogle Scholar
  56. 56.
    Chauvin M, Ferrier C, Haberer JP, et al. Sufentanil pharmacokinetics in patients with cirrhosis. Anesth Analg 1989 Jan; 68 (1): 1–4PubMedCrossRefGoogle Scholar
  57. 57.
    Ferrier Marty J, Bouffard Y, et al. Alfentanil pharm-acokinetics in patients with cirrhosis. Anesthesiology 1985 Apr; 62 (4): 480–4CrossRefGoogle Scholar
  58. 58.
    Bower S, Sear JW, Roy RC, et al. Effects of different he-patic pathologies on disposition of alfentanil in anaesthetized patients. Br J Anaesth 1992 May; 68 (5): 462–5PubMedCrossRefGoogle Scholar
  59. 59.
    Baririan N, Van Obbergh L, Desager JP, et al. Alfentanil-induced miosis as a surrogate measure of alfentanil pharmacokinetics in patients with mild and moderate liver cirrhosis. Clin Pharmacokinet 2007; 46 (3): 261–70PubMedCrossRefGoogle Scholar
  60. 60.
    Dershwitz M, Hoke JF, Rosow CE, et al. Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesthesiology 1996 Apr; 84 (4): 812–20PubMedCrossRefGoogle Scholar
  61. 61.
    Navapurkar VU, Archer S, Gupta SK, et al. Metabolism of remifentanil during liver transplantation. Br J Anaesth 1998 Dec; 81 (6): 881–6PubMedCrossRefGoogle Scholar
  62. 62.
    Graham GG, Scott KF, Day RO. Tolerability of parace-tamol. Drug Saf 2005; 28 (3): 227–40PubMedCrossRefGoogle Scholar
  63. 63.
    Altomare E, Vendemiale G, Albano Hepatic glutathione content in patients with alcoholic and non alcoholic liver diseases. Life Sci 1988; 43 (12): 991–8Google Scholar
  64. 64.
    Shigesawa T, Sato C, Marumo F. Significance of plasma glutathione determination in patients with alcoholic and non-alcoholic liver disease. J Gastroenterol Hepatol 1992 Jan–Feb; 7 (1): 7–11PubMedCrossRefGoogle Scholar
  65. 65.
    Lauterburg BH. Analgesics and glutathione. Am J Ther 2002 May–Jun; 9 (3): 225–33PubMedCrossRefGoogle Scholar
  66. 66.
    Myers RP, Shaheen AA. Hepatitis C, alcohol abuse, and unintentional overdoses are risk factors for acetaminophen-related hepatotoxicity. Hepatology 2009 Apr; 49 (4): 1399–400PubMedCrossRefGoogle Scholar
  67. 67.
    Nguyen GC, Sam J, Thuluvath PJ. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis. Hepatology 2008 Oct; 48 (4): 1336–41PubMedCrossRefGoogle Scholar
  68. 68.
    Lee WM. Acetaminophen and the US Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology 2004 Jul; 40 (1): 6–9PubMedCrossRefGoogle Scholar
  69. 69.
    Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther 1983 Jan; 33 (1): 95–101PubMedCrossRefGoogle Scholar
  70. 70.
    Khalid SK, Lane J, Navarro V, et al. Use of over-the-counter analgesics is not associated with acute decom-pensation in patients with cirrhosis. Clin Gastroenterol Hepatol 2009 Sep; 7 (9): 994–9; quiz 13-4PubMedCrossRefGoogle Scholar
  71. 71.
    Dargere S, Collet T, Crampon D, et al. Lack of toxicity of acetaminophen in patients with chronic hepatitis randomized controlled trial [abstract]. Gastroenterology 2000; 118 (4 Part 1): A947Google Scholar
  72. 72.
    Lauterburg BH, Velez ME. Glutathione deficiency in al-coholics: risk factor for paracetamol hepatotoxicity. Gut 1988 Sep; 29 (9): 1153–7PubMedCrossRefGoogle Scholar
  73. 73.
    Benson GD, Koff RS, Tolman KG. The therapeutic use of acetaminophen in patients with liver disease. Am J Ther 2005 Mar–Apr; 12 (2): 133–41PubMedCrossRefGoogle Scholar
  74. 74.
    Girre Lucas D, Hispard E, et al. Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics. Biochem Pharmacol 1994 Apr 29; 47 (9): 1503–8CrossRefGoogle Scholar
  75. 75.
    Villeneuve JP, Raymond G, Bruneau J, et al. Pharmaco-kinetics and metabolism of acetaminophen in normal, alcoholic and cirrhotic subjects [in French]. Gastroenterol Clin Biol 1983 Nov; 7 (11): 898–902PubMedGoogle Scholar
  76. 76.
    Zimmerman HJ, Maddrey WC. Acetaminophen (parace-tamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995 Sep; 22 (3): 767–73PubMedCrossRefGoogle Scholar
  77. 77.
    Lesser PB, Vietti MM, Clark WD. Lethal enhancement of therapeutic doses of acetaminophen by alcohol. Dig Dis Sci 1986 Jan; 31 (1): 103–5PubMedCrossRefGoogle Scholar
  78. 78.
    Wootton FT, Lee WM. Acetaminophen hepatotoxicity in the alcoholic. South Med J 1990 Sep; 83 (9): 1047–9PubMedCrossRefGoogle Scholar
  79. 79.
    Prescott LF. Paracetamol, alcohol and the liver. Br J Clin Pharmacol 2000 Apr; 49 (4): 291–301PubMedCrossRefGoogle Scholar
  80. 80.
    Kuffner EK, Dart RC, Bogdan GM, et al. Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial. Arch Intern Med 2001 Oct 8; 161 (18): 2247–52PubMedCrossRefGoogle Scholar
  81. 81.
    Heard K, Green JL, Bailey JE, et al. 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 Jul 15; 26 (2): 283–90PubMedCrossRefGoogle Scholar
  82. 82.
    Zapater P, Lasso de la Vega MC, Horga JF, et al. Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status. Aliment Pharmacol Ther 2004 Jul 1; 20 (1): 29–36PubMedCrossRefGoogle Scholar
  83. 83.
    Barshop NJ, Capparelli EV, Sirlin CB, et al. Acetamino-phen pharmacokinetics in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2011 Feb; 52 (2): 198–202PubMedCrossRefGoogle Scholar
  84. 84.
    Jorup-Ronstrom C, Beermann Wahlin-Boll E, et al. Re-duction of paracetamol and aspirin metabolism during viral hepatitis. Clin Pharmacokinet 1986 May–Jun; 11 (3): 250–6PubMedCrossRefGoogle Scholar
  85. 85.
    Laffi G, La Villa G, Pinzani M, et al. Arachidonic acid derivatives and renal function in liver cirrhosis. Semin Nephrol 1997 Nov; 17 (6): 530–48PubMedGoogle Scholar
  86. 86.
    Arroyo V, Gines P, Rimola A, et al. Renal function ab-normalities, prostaglandins, and effects of nonsteroidal anti-inflammatory drugs in cirrhosis with ascites: an overview with emphasis on pathogenesis. Am J Med 1986 Aug 25; 81 (2B): 104–22PubMedCrossRefGoogle Scholar
  87. 87.
    Perez-Ayuso RM, Arroyo V, Camps J, et al. Evidence that renal prostaglandins are involved in renal water metabolism in cirrhosis. Kidney Int 1984 Jul; 26 (1): 72–80PubMedCrossRefGoogle Scholar
  88. 88.
    Zipser RD. Role of renal prostaglandins and the effects of nonsteroidal anti-inflammatory drugs in patients with liver disease. Am J Med 1986 Aug 25; 81 (2B): 95–103PubMedCrossRefGoogle Scholar
  89. 89.
    Ackerman Z, Cominelli F. Reynolds Effect of mis-oprostol on ibuprofen-induced renal dysfunction in patients with decompensated cirrhosis: results of a double-blind placebo-controlled parallel group study. Am J Gastroenterol 2002 Aug; 97 (8): 2033–9PubMedCrossRefGoogle Scholar
  90. 90.
    Laffi G, Daskalopoulos G, Kronborg I, et al. Effects of sulindac and ibuprofen in patients with cirrhosis and ascites: an explanation for the renal-sparing effect of sulindac. Gastroenterology 1986 Jan; 90 (1): 182–7PubMedGoogle Scholar
  91. 91.
    Zipser RD, Hoefs JC, Speckart PF, et al. Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab 1979 Jun; 48 (6): 895–900PubMedCrossRefGoogle Scholar
  92. 92.
    Arroyo V, Planas R, Gaya J, et al. Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin E2 in cirrhosis: relationship to functional renal failure and sodium and water excretion. Eur J Clin Invest 1983 Jun; 13 (3): 271–8PubMedCrossRefGoogle Scholar
  93. 93.
    Claria J, Kent JD, Lopez-Parra M, et al. Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites. Hepatology 2005 Mar; 41 (3): 579–87PubMedCrossRefGoogle Scholar
  94. 94.
    Brater DC, Anderson SA, Brown-Cartwright D. Reversible acute decrease in renal function by NSAIDs in cirrhosis. Am J Med Sci 1987 Sep; 294 (3): 168–74PubMedCrossRefGoogle Scholar
  95. 95.
    Mirouze D, Zipser RD. Reynolds Effect of inhibitors of prostaglandin synthesis on induced diuresis in cirrhosis. Hepatology 1983 Jan–Feb; 3 (1): 50–5PubMedCrossRefGoogle Scholar
  96. 96.
    Guevara M, Abecasis R, Terg R. Effect of celecoxib on renal function in cirrhotic patients with ascites: a pilot study. Scand J Gastroenterol 2004 Apr; 39 (4): 385–6PubMedCrossRefGoogle Scholar
  97. 97.
    Harris RC. COX-2 and the kidney. J Cardiovasc Pharmacol 2006; 47 Suppl. 1: S37–42PubMedCrossRefGoogle Scholar
  98. 98.
    Peck-Radosavljevic M. Review article: coagulation dis-orders in chronic liver disease. Aliment Pharmacol Ther 2007 Nov; 26 Suppl. 1: 21–8PubMedCrossRefGoogle Scholar
  99. 99.
    Laffi G, La Villa G, Pinzani M, et al. Altered renal and platelet arachidonic acid metabolism in cirrhosis. Gastroenterology 1986 Feb; 90 (2): 274–82PubMedGoogle Scholar
  100. 100.
    De Ledinghen V, Heresbach D, Fourdan O, et al. Anti-inflammatory drugs and variceal bleeding: a case-control study. Gut 1999 Feb; 44 (2): 270–3PubMedCrossRefGoogle Scholar
  101. 101.
    Bessone F. Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage?. World J Gastroenterol 2010 Dec 7; 16 (45): 5651–61PubMedCrossRefGoogle Scholar
  102. 102.
    Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepide-miol Drug Saf 2006 Apr; 15 (4): 213–20CrossRefGoogle Scholar
  103. 103.
    Bjorkman D. Nonsteroidal anti-inflammatory drug-associated toxicity of the liver, lower gastrointestinal tract, and esophagus. Am J Med 1998 Nov 2; 105 (5A): 17S–21SPubMedCrossRefGoogle Scholar
  104. 104.
    Li G, Treiber G, Maier et al. Disposition of ibuprofen in patients with liver cirrhosis: stereochemical considerations. Clin Pharmacokinet 1993 Aug; 25 (2): 154–63PubMedCrossRefGoogle Scholar
  105. 105.
    Zimmerer J, Tittor W, Degen P. Anti-rheumatic therapy in patients with liver diseases. Plasma levels of diclofenac and elimination of diclofenac and metabolites in urine of patients with liver disease [in German]. Fortschr Med 1982 Sep 23; 100 (36): 1683–8Google Scholar
  106. 106.
    Lill JS, O’Sullivan T, Bauer LA, et al. Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis. J Clin Pharmacol 2000 Mar; 40 (3): 250–7PubMedCrossRefGoogle Scholar
  107. 107.
    Celebrex® (celecoxib): Compendium Suisse des Médicaments. Zurich: Pfizer AG, 2009 [online]. Available from URL: [Accessed 2012 Jul 17]
  108. 108.
    Laidlaw J, Read AE, Sherlock S. Morphine tolerance in hepatic cirrhosis. Gastroenterology 1961 Mar; 40: 389–96PubMedGoogle Scholar
  109. 109.
    Fraser CL, Arieff AI. Hepatic encephalopathy. N Engl J Med 1985 Oct 3; 313 (14): 865–73PubMedCrossRefGoogle Scholar
  110. 110.
    Bergasa NV, Rothman RB, Mukerjee E, et al. Up-regulation of central mu-opioid receptors in a model of hepatic encephalopathy: a potential mechanism for increased sensitivity to morphine in liver failure. Life Sci 2002 Feb 22; 70 (14): 1701–8PubMedCrossRefGoogle Scholar
  111. 111.
    Larsen FS, Wendon J. Brain edema in liver failure: basic physiologic principles and management. Liver Transpl 2002 Nov; 8 (11): 983–9PubMedCrossRefGoogle Scholar
  112. 112.
    Hirschfield GM, Kumagi T, Heathcote EJ. Preventative hepatology: minimising symptoms and optimising care. Liver Int 2008 Aug; 28 (7): 922–34PubMedCrossRefGoogle Scholar
  113. 113.
    Larson AM, Curtis JR. Integrating palliative care for liver transplant candidates: “too well for transplant, too sick for life”. JAMA 2006 May 10; 295 (18): 2168–76PubMedCrossRefGoogle Scholar
  114. 114.
    Findlay JW, Jones EC, Butz RF, et al. Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics. Clin Pharmacol Ther 1978 Jul; 24 (1): 60–8PubMedGoogle Scholar
  115. 115.
    Mignat C, Wille U, Ziegler A. Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes. Life Sci 1995; 56 (10): 793–9PubMedCrossRefGoogle Scholar
  116. 116.
    Desmeules J, Gascon MP, Dayer P, et al. Impact of en-vironmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991; 41 (1): 23–6PubMedCrossRefGoogle Scholar
  117. 117.
    Sindrup SH, Arendt-Nielsen L, Brosen K, et al. The effect of quinidine on the analgesic effect of codeine. Eur J Clin Pharmacol 1992; 42 (6): 587–91PubMedCrossRefGoogle Scholar
  118. 118.
    Sindrup SH, Brosen K, Bjerring P, et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 1990 Dec; 48 (6): 686–93PubMedCrossRefGoogle Scholar
  119. 119.
    Girardin F, Daali Y, Gex-Fabry M, et al. Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection. J Viral Hepat 2012 Aug; 19 (8): 568–73PubMedCrossRefGoogle Scholar
  120. 120.
    Desmeules JA. The tramadol option. Eur J Pain 2000; 4 Suppl. A: 15–21PubMedGoogle Scholar
  121. 121.
    Gillen C, Haurand M, Kobelt DJ, et al. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000 Aug; 362 (2): 116–21PubMedCrossRefGoogle Scholar
  122. 122.
    Dayer P, Collart L, Desmeules J. The pharmacology of tramadol. Drugs 1994; 47 Suppl. 1: 3–7PubMedCrossRefGoogle Scholar
  123. 123.
    Rollason V, Samer C, Piguet V, et al. Pharmacogenetics of analgesics: toward the individualization of prescription. Pharmacogenomics 2008 Jul; 9 (7): 905–33PubMedCrossRefGoogle Scholar
  124. 124.
    Stamer UM, Lehnen Hothker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003 Sep; 105 (1–2): 231–8PubMedCrossRefGoogle Scholar
  125. 125.
    Enggaard TP, Poulsen L, Arendt-Nielsen L, et al. The an-algesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 2006 Jan; 102 (1): 146–50PubMedCrossRefGoogle Scholar
  126. 126.
    Kotb HI, Fouad IA, Fares KM, et al. Pharmacokinetics of oral tramadol in patients with liver cancer. J Opioid Manag 2008 Mar–Apr; 4 (2): 99–104PubMedGoogle Scholar
  127. 127.
    Tzschentke TM, Christoph T, Kogel et al. (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 2007 Oct; 323 (1): 265–76PubMedCrossRefGoogle Scholar
  128. 128.
    Xu XS, Smit JW, Lin R, et al. Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain. Clin Pharmacokinet 2010 Oct; 49 (10): 671–82PubMedCrossRefGoogle Scholar
  129. 129.
    Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother 2004; 18 (4): 17–30PubMedCrossRefGoogle Scholar
  130. 130.
    Samer CF, Daali Y, Wagner M, et al. Genetic poly-morphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010 Jun; 160 (4): 919–30PubMedCrossRefGoogle Scholar
  131. 131.
    Samer CF, Daali Y, Wagner M, et al. The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone. Br J Pharmacol 2010 Jun; 160 (4): 907–18PubMedCrossRefGoogle Scholar
  132. 132.
    Lugo RA, Kern SE. Clinical pharmacokinetics of mor-phine. J Pain Palliat Care Pharmacother 2002; 16 (4): 5–18PubMedCrossRefGoogle Scholar
  133. 133.
    Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of in-travenous and intramuscular morphine. Clin Pharmacol Ther 1978 Jul; 24 (1): 52–9PubMedGoogle Scholar
  134. 134.
    Olsen GD, Bennett WM, Porter GA. Morphine and phenytoin binding to plasma proteins in renal and hepatic failure. Clin Pharmacol Ther 1975 Jun; 17 (6): 677–84PubMedGoogle Scholar
  135. 135.
    Patwardhan RV, Johnson RF, Hoyumpa Jr A, et al. Normal metabolism of morphine in cirrhosis. Gastroenterology 1981 Dec; 81 (6): 1006–11PubMedGoogle Scholar
  136. 136.
    Kotb HI, El-Kady SA, Emara SE, et al. Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma. Br J Anaesth 2005 Jan; 94 (1): 95–9PubMedCrossRefGoogle Scholar
  137. 137.
    Vallner JJ, Stewart JT, Kotzan JA, et al. Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects. J Clin Pharmacol 1981 Apr; 21 (4): 152–6PubMedCrossRefGoogle Scholar
  138. 138.
    Babul N, Darke AC, Hagen N. Hydromorphone metabolite accumulation in renal failure. J Pain Symptom Manage 1995 Apr; 10 (3): 184–6PubMedCrossRefGoogle Scholar
  139. 139.
    Paramanandam G, Prommer E, Schwenke DC. Adverse ef-fects in hospice patients with chronic kidney disease receiving hydromorphone. J Palliat Med 2011 Sep; 14 (9): 1029–33PubMedCrossRefGoogle Scholar
  140. 140.
    Michaelis M. Scholkens Rudolphi An anthology from Naunyn-Schmiedeberg’s archives of pharmacology. Naunyn Schmiedebergs Arch Pharmacol 2007 Apr; 375 (2): 81–4PubMedCrossRefGoogle Scholar
  141. 141.
    Marinella MA. Meperidine-induced generalized seizures with normal renal function. South Med J 1997 May; 90 (5): 556–8PubMedCrossRefGoogle Scholar
  142. 142.
    Szeto HH, Inturrisi CE, Houde R, et al. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Intern Med 1977 Jun; 86 (6): 738–41PubMedCrossRefGoogle Scholar
  143. 143.
    Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 2002; 41 (14): 1153–93PubMedCrossRefGoogle Scholar
  144. 144.
    Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 2005; 19 (4): 13–24PubMedCrossRefGoogle Scholar
  145. 145.
    Jiao M, Greanya ED, Haque M, et al. Methadone main-tenance therapy in liver transplantation. Prog Transplant 2010 Sep; 20 (3): 209–14; quiz 15PubMedGoogle Scholar
  146. 146.
    Novick DM, Kreek MJ. Critical issues in the treatment of hepatitis C virus infection in methadone maintenance patients. Addiction 2008 Jun; 103 (6): 905–18PubMedCrossRefGoogle Scholar
  147. 147.
    Maxwell S, Shinderman MS, Miner A, et al. Correlation between hepatitis C serostatus and methadone dose requirement in 1,163 methadone-maintained patients. Heroin Add & Rel Clin Probl 2002; 4 (2): 5–10Google Scholar
  148. 148.
    Kreek MJ, Schecter AJ, Gutjahr CL, et al. Methadone use in patients with chronic renal disease. Drug Alcohol Depend 1980 Mar; 5 (3): 197–205PubMedCrossRefGoogle Scholar
  149. 149.
    Bullingham RE, McQuay HJ, Porter EJ, et al. Sublingual buprenorphine used postoperatively: ten hour plasma drug concentration analysis. Br J Clin Pharmacol 1982 May; 13 (5): 665–73PubMedCrossRefGoogle Scholar
  150. 150.
    Kuhlman Jr JJ, Lalani S, Magluilo Jr J, et al. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol 1996 Oct; 20 (6): 369–78PubMedCrossRefGoogle Scholar
  151. 151.
    Elkader A, Sproule B. Buprenorphine: clinical pharmaco-kinetics in the treatment of opioid dependence. Clin Pharmacokinet 2005; 44 (7): 661–80PubMedCrossRefGoogle Scholar
  152. 152.
    Pergolizzi J, Boger RH, Budd K, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract 2008 Jul–Aug; 8 (4): 287–313PubMedCrossRefGoogle Scholar
  153. 153.
    Escher M, Daali Y, Chabert J, et al. Pharmacokinetic and pharmacodynamic properties of buprenorphine after a single intravenous administration in healthy volunteers: a randomized, double-blind, placebo-controlled, crossover study. Clin Ther 2007 Aug; 29 (8): 1620–31PubMedCrossRefGoogle Scholar
  154. 154.
    Cone EJ, Gorodetzky CW, Yousefnejad D, et al. The me-tabolism and excretion of buprenorphine in humans. Drug Metab Dispos 1984 Sep–Oct; 12 (5): 577–81PubMedGoogle Scholar
  155. 155.
    Walter DS, Inturrisi CE. Absorption, distribution, metab-olism and excretion of buprenorphine in animals and humans. In: Cowan A, Lewis JW, editors. Buprenorphine: combatting drug abuse with a unique opioid. New York: Wiley-Liss, 1995: 113-37Google Scholar
  156. 156.
    Herve S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol 2004 Oct; 16 (10): 1033–7PubMedCrossRefGoogle Scholar
  157. 157.
    Verrando R, Robaeys G, Mathei C, et al. Methadone and buprenorphine maintenance therapies for patients with hepatitis C virus infected after intravenous drug use. Acta Gastroenterol Belg 2005 Jan-Mar; 68 (1): 81–5PubMedGoogle Scholar
  158. 158.
    Zuin M, Giorgini A, Selmi C, et al. Acute liver and renal failure during treatment with buprenorphine at therapeutic dose. Dig Liver Dis 2009 Jul; 41 (7): e8–10PubMedCrossRefGoogle Scholar
  159. 159.
    Petry NM, Bickel WK, Piasecki D, et al. Elevated liver enzyme levels in opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict 2000 Summer; 9 (3): 265–9PubMedCrossRefGoogle Scholar
  160. 160.
    Bogenschutz MP, Abbott PJ, Kushner R, et al. Effects of buprenorphine and hepatitis C on liver enzymes in adolescents and young adults. J Addict Med 2010 Dec; 4 (4): 211–6PubMedCrossRefGoogle Scholar
  161. 161.
    Bruce RD, Altice FL. Case series on the safe use of buprenorphine/naloxone in individuals with acute hepatitis infection and abnormal hepatic liver transaminases. Am J Drug Alcohol Abuse 2007; 33 (6): 869–74PubMedCrossRefGoogle Scholar
  162. 162.
    Hand CW, Sear JW, Uppington J, et al. Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites. Br J Anaesth 1990 Mar; 64 (3): 276–82PubMedCrossRefGoogle Scholar
  163. 163.
    Boger RH. Renal impairment: a challenge for opioid treatment? The role of buprenorphine. Palliat Med 2006; 20 Suppl. 1: s17–23PubMedGoogle Scholar
  164. 164.
    Scholz J, Steinfath M, Schulz M. Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil: an update. Clin Pharmacokinet 1996 Oct; 31 (4): 275–92PubMedCrossRefGoogle Scholar
  165. 165.
    Jin SJ, Jung JY, Noh MH, et al. The population pharmaco-kinetics of fentanyl in patients undergoing living-donor liver transplantation. Clin Pharmacol Ther 2011 Sep; 90 (3): 423–31PubMedCrossRefGoogle Scholar
  166. 166.
    Durogesic® Matrix (fentanyl): Compendium Suisse des Medicaments, Janssen-Cilag AG, Baar ZG, 2010; Available from URL: [Accessed 2012 Jul 17]
  167. 167.
    Murtagh FE, Chai MO, Donohoe P, et al. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother 2007; 21 (2): 5–16PubMedGoogle Scholar
  168. 168.
    Niscola P, Scaramucci L, Vischini G, et al. The use of major analgesics in patients with renal dysfunction. Curr Drug Targets 2010 Jun; 11 (6): 752–8PubMedCrossRefGoogle Scholar
  169. 169.
    King S, Forbes K, Hanks GW, et al. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med 2011 Jul; 25 (5): 525–52PubMedCrossRefGoogle Scholar
  170. 170.
    Koehntop DE, Rodman JH. Fentanyl pharmacokinetics in patients undergoing renal transplantation. Pharmacotherapy 1997 Jul–Aug; 17 (4): 746–52PubMedGoogle Scholar
  171. 171.
    Sufenta®/-forte (sufentanil): Compendium Suisse des Medicaments, Janssen-Cilag AG, Baar ZG. 2010 [online]. Available from URL: [Accessed 2012 Jul 17]
  172. 172.
    Klees TM, Sheffels P, Dale et al. Metabolism of alfentanil by cytochrome p4503a enzymes. Drug Metab Dispos 2005 Mar; 33 (3): 303–11PubMedCrossRefGoogle Scholar
  173. 173.
    Davis PJ, Stiller RL, Cook DR, et al. Effects of cholestatic hepatic disease and chronic renal failure on alfentanil pharmacokinetics in children. Anesth Analg 1989 May; 68 (5): 579–83PubMedCrossRefGoogle Scholar
  174. 174.
    Hoke JF, Cunningham F, James MK, et al. Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs. J Pharmacol Exp Ther 1997 Apr; 281 (1): 226–32PubMedGoogle Scholar
  175. 175.
    Westmoreland CL, Hoke JF, Sebel PS, et al. Pharmaco-kinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993 Nov; 79 (5): 893–903PubMedCrossRefGoogle Scholar
  176. 176.
    Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care 2005 Jun; 33 (3): 311–22PubMedGoogle Scholar
  177. 177.
    Besson M, Piguet V, Dayer P, et al. New approaches to the pharmacotherapy of neuropathic pain. Expert Rev Clin Pharmacol 2008; 1 (5): 683–93CrossRefGoogle Scholar
  178. 178.
    Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010 Sep; 17 (9): 1113–e88PubMedCrossRefGoogle Scholar
  179. 179.
    Dworkin RH, O’Connor AB, Backonja M, et al. Pharma-cologic management of neuropathic pain: evidence-based recommendations. Pain 2007 Dec 5; 132 (3): 237–51PubMedCrossRefGoogle Scholar
  180. 180.
    Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatry 2010 Dec; 81 (12): 1372–3PubMedCrossRefGoogle Scholar
  181. 181.
    Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995 Feb; 49 (2): 280–94PubMedCrossRefGoogle Scholar
  182. 182.
    Suri A, Reddy S, Gonzales et al. Duloxetine pharm-acokinetics in cirrhotics compared with healthy subjects. Int J Clin Pharmacol Ther 2005 Feb; 43 (2): 78–84PubMedGoogle Scholar
  183. 183.
    Vuppalanchi R, Hayashi PH, Chalasani N, et al. Dulox-etine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther 2010 Nov; 32 (9): 1174–83PubMedCrossRefGoogle Scholar
  184. 184.
    Andrade C, Sandarsh S, Chethan KB, et al. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry 2010 Dec; 71 (12): 1565–75PubMedCrossRefGoogle Scholar
  185. 185.
    Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 2010 Oct; 49 (10): 661–9PubMedCrossRefGoogle Scholar
  186. 186.
    Sendra JM, Junyent TT, Pellicer MJ. Pregabalin-induced hepatotoxicity. Ann Pharmacother 2011 Jun; 45 (6): e32PubMedCrossRefGoogle Scholar
  187. 187.
    Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010 Mar; 85 (3 Suppl.): S3–14PubMedCrossRefGoogle Scholar
  188. 188.
    Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 2005 Jun 22; 293 (24): 3043–52PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Marija Bosilkovska
    • 1
  • Bernhard Walder
    • 2
  • Marie Besson
    • 1
  • Youssef Daali
    • 1
  • Jules Desmeules
    • 1
    Email author
  1. 1.Division of Clinical Pharmacology and ToxicologyUniversity Hospitals of GenevaGenevaSwitzerland
  2. 2.Division of AnesthesiologyGeneva University HospitalsGenevaSwitzerland

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