Hospital Opioid Usage and Adverse Events in Patients With End-Stage Liver Disease



      Patients with end-stage liver disease (ESLD) commonly experience pain and other symptoms that result in a poor quality of life. Few studies have examined opioid usage, adverse events (AEs), and other outcomes in ESLD patients receiving opioid analgesia.


      This study aimed to compare outcomes in ESLD patients who received opioids to those who did not and to determine risk factors for AEs.


      This was a retrospective case-cohort study of 270 hospitalized patients with ESLD that used administrative and clinical data from the electronic medical record.


      Two-thirds of patients with ESLD admitted during the study period received at least one opioid analgesic. Patients who received opioids presented with a greater number of liver related complications and higher rates of anxiety (32% vs. 17%, P= 0.007), had substantially worse initial and average pain scores (both P< 0.001), and received more palliative care consultations. The opioid group had somewhat more respiratory (22.2% vs. 11.1%, P= 0.02) and gastrointestinal (38.5% vs. 25.2%, P= 0.03) AEs, but no increase in CNS adverse events which included hepatic encephalopathy. Anxiety and disease severity (i.e., the number of liver related complications) but not opioid administration were risk factors for the number of AEs.


      Opioid administration was not an independent risk factor for the number of AEs in hospitalized patients with ESLD, whereas anxiety and more liver-related complications increased AE risk. Our findings suggest that opioids have an appropriate and reasonably safe role in alleviation of pain in patients with ESLD.

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        • Heron M.
        Deaths: leading causes for 2017.
        Natl Vital Stat Rep. 2019; 68: 1-77
        • Ge PS
        • Runyon BA.
        Treatment of patients with cirrhosis.
        N Engl J Med. 2016; 375: 767-777
      1. OPTN Metrics O. National OPTN data (All Donors) 2021. Available from: Accessed August 1, 2022.

      2. Centers for Disease Control and Prevention: Nation Center for Health Statistics. Chronic Liver Disease and Cirrhosis. 2018. Available from: Accessed. August 1, 2022.

        • Boyd K
        • Kimbell B
        • Murray S
        • Iredale J.
        Living and dying well with end-stage liver disease: time for palliative care?.
        Hepatology. 2012; 55: 1650-1651
        • Moon AM
        • Singal AG
        • Tapper EB.
        Contemporary epidemiology of chronic liver disease and cirrhosis.
        Clin Gastroenterol Hepatol. 2020; 18: 2650-2666
        • Kaplan A
        • Fortune B
        • Ufere N
        • Brown Jr., RS
        • Rosenblatt R
        National trends in location of death in patients with end-stage liver disease.
        Liver Transpl. 2021; 27: 165-176
        • Mazzarelli C
        • Prentice WM
        • Heneghan MA
        • Belli LS
        • Agarwal K
        • Cannon MD.
        Palliative care in end-stage liver disease: time to do better?.
        Liver Transpl. 2018; 24: 961-968
        • Waterman BL
        • Ramsey SU
        • Whitsett MP
        • et al.
        Top ten tips palliative care clinicians should know about end-stage liver disease.
        J Palliat Med. 2021; 24: 924-931
        • Madan A
        • Barth KS
        • Balliet WE
        • et al.
        Chronic pain among liver transplant candidates.
        Prog Transplant. 2012; 22: 379-384
        • Rogal SS
        • Winger D
        • Bielefeldt K
        • Rollman BL
        • Szigethy E.
        Health care utilization in chronic liver disease: the importance of pain and prescription opioid use.
        Liver Int. 2013; 33: 1497-1503
        • Klinge M
        • Coppler T
        • Liebschutz JM
        • et al.
        The assessment and management of pain in cirrhosis.
        Curr Hepatol Rep. 2018; 17: 42-51
        • Dwyer JP
        • Jayasekera C
        • Nicoll A.
        Analgesia for the cirrhotic patient: a literature review and recommendations.
        J Gastroenterol Hepatol. 2014; 29: 1356-1360
        • Moon AM
        • Jiang Y
        • Rogal SS
        • Tapper EB
        • Lieber SR
        • Barritt ASt
        Opioid prescriptions are associated with hepatic encephalopathy in a national cohort of patients with compensated cirrhosis.
        Aliment Pharmacol Ther. 2020; 51: 652-660
        • Rogal SS
        • Bielefeldt K
        • Wasan AD
        • et al.
        Inflammation, psychiatric symptoms, and opioid use are associated with pain and disability in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2015; 13: 1009-1016
        • Konerman MA
        • Rogers M
        • Kenney B
        • et al.
        Opioid and benzodiazepine prescription among patients with cirrhosis compared to other forms of chronic disease.
        BMJ Open Gastroenterol. 2019; 6e000271
        • Rhee C
        • Broadbent AM.
        Palliation and liver failure: palliative medications dosage guidelines.
        J Palliat Med. 2007; 10: 677-685
        • Desai AP
        • Knapp SM
        • Orman ES
        • et al.
        Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis - a US population-based study.
        J Hepatol. 2020; 73: 1092-1099
        • Sacleux SC
        • Samuel D.
        A critical review of MELD as a reliable tool for transplant prioritization.
        Semin Liver Dis. 2019; 39: 403-413
        • Coppel S
        • Mathur K
        • Ekser B
        • et al.
        Extra-hepatic comorbidity burden significantly increases 90-day mortality in patients with cirrhosis and high model for endstage liver disease.
        BMC Gastroenterol. 2020; 20: 302
        • Oderda GM
        • Gan TJ
        • Johnson BH
        • Robinson SB.
        Effect of opioid-related adverse events on outcomes in selected surgical patients.
        J Pain Palliat Care Pharmacother. 2013; 27: 62-70
        • Oderda GM
        • Senagore AJ
        • Morland K
        • et al.
        Opioid-related respiratory and gastrointestinal adverse events in patients with acute postoperative pain: prevalence, predictors, and burden.
        J Pain Palliat Care Pharmacother. 2019; 33: 82-97
        • Shafi S
        • Collinsworth AW
        • Copeland LA
        • et al.
        Association of opioid-related adverse drug events with clinical and cost outcomes among surgical patients in a large integrated health care delivery system.
        JAMA Surg. 2018; 153: 757-763
        • Moon AM
        • Jiang Y
        • Rogal SS
        • Becker J
        • Barritt ASt
        In inpatients with cirrhosis opioid use is common and associated with length of stay and persistent use post-discharge.
        PLoS One. 2020; 15e0229497
        • Rubin JB
        • Lai JC
        • Shui AM
        • Hohmann SF
        • Auerbach A.
        Patterns of inpatient opioid use and related adverse events among patients with cirrhosis: a propensity-matched analysis.
        Hepatol Commun. 2021; 5: 1081-1094
        • Dworkin RH
        • Turk DC
        • Wyrwich KW
        • et al.
        Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.
        J Pain. 2008; 9: 105-121
        • McDonagh MS
        • Selph SS
        • Buckley DI
        • et al.
        • AHRQ Comparative Effectiveness Reviews
        Nonopioid pharmacologic treatments for chronic pain.
        Agency for Healthcare Research and Quality (US), Rockville (MD)2020
        • Rakoski M
        • Goyal P
        • Spencer-Safier M
        • Weissman J
        • Mohr G
        • Volk M.
        Pain management in patients with cirrhosis.
        Clin Liver Dis (Hoboken). 2018; 11: 135-140
        • Bair MJ
        • Wu J
        • Damush TM
        • Sutherland JM
        • Kroenke K.
        Association of depression and anxiety alone and in combination with chronic musculoskeletal pain in primary care patients.
        Psychosom Med. 2008; 70: 890-897
        • Hernaez R
        • Kramer JR
        • Khan A
        • et al.
        Depression and anxiety are common among patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2022; 20: 194-203
        • Katon W
        • Lin E
        • Kroenke K.
        The association of depression and anxiety with medical symptom burden in patients with chronic medical illness.
        Gen Hosp Psychiatry. 2007; 29: 147-155
        • Löwe B
        • Spitzer RL
        • Williams JBW
        • Mussell M
        • Schellberg D
        • Kroenke K.
        Depression, anxiety, and somatization in primary care: syndrome overlap and functional impairment.
        Gen Hosp Psychiatry. 2008; 30: 191-199
        • Kroenke K
        • Spitzer RL
        • Williams JBW
        • et al.
        Physical symptoms in primary care: predictors of psychiatric disorders and functional impairment.
        Arch Fam Med. 1994; 3: 774-779
        • Chandok N
        • Watt KD.
        Pain management in the cirrhotic patient: the clinical challenge.
        Mayo Clin Proc. 2010; 85: 451-458
        • Haberer JP
        • Schoeffler P
        • Couderc E
        • Duvaldestin P.
        Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis.
        Br J Anaesth. 1982; 54: 1267-1270
      3. C Brown, N Aksan and AJ. Muir, MELD-Na accurately predicts 6-Month mortality in patients with decompensated cirrhosis: potential trigger for hospice referral, J Clin Gastroenterol, 56, 2021, 902-907.

        • Langberg KM
        • Taddei TH.
        Balancing quality with quantity: the role of palliative care in managing decompensated cirrhosis.
        Hepatology. 2016; 64: 1014-1016
        • Walling AM
        • Wenger NS.
        Palliative care and end-stage liver disease.
        Clin Gastroenterol Hepatol. 2014; 12: 699-700