Liver Dysfunction

Overview: 

Pain is common in patients with cirrhosis and other types of liver disease, but is often difficult to manage given concerns about impaired hepatic metabolism, hepatotoxicity and increased risk of adverse events. Cirrhosis patients suffer from musculoskeletal pain at rates that are similar to or higher than the general population, and may also have liver disease-specific causes of pain, including muscle cramps or abdominal pain secondary to ascites. Management of patients with chronic liver disease and pain is particularly challenging in inpatients who may have acute pain or acute-on-chronic pain due to their acute medical illness, and may also have acute hepatic decompensation resulting in increased impairment in hepatic metabolism, further limiting analgesic options. As a result, patients with liver disease are at high risk for undertreatment of their pain across clinical settings.

Challenges 

Managing pain in patients with liver disease is particularly challenging for several reasons:

1. There are potential harms associated with many of the common classes of analgesics (e.g. acetaminophen, NSAIDs, opioids) in this population as many of these agents are largely metabolized by the liver.

2. Liver disease is not a single disease entity, but rather ranges from acute liver injury, to chronic liver disease (e.g. nonalcoholic fatty liver disease, chronic hepatitis B) without significant fibrosis, to cirrhosis. Among patients with cirrhosis, there are different degrees of hepatic dysfunction, and there are no endogenous markers for hepatic clearance (unlike renal clearance) that can be used to guide drug dosing. Additionally, patients with cirrhosis may have particular complications (e.g. hepatic encephalopathy, volume overload), which may predispose them to different types of analgesic risk.

3. There is minimal real-world data on risks and harms of analgesics in this population

Treatment Recommendations 

  • Acetaminophen, up to 2g daily, is safe in most patients with chronic liver disease and should typically be used as a first-line agent in these patients (use cautiously if ongoing heavy alcohol use)
  • NSAIDs should be avoided in patients with decompensated cirrhosis; there is little data regarding their safety in patients with compensated cirrhosis, but most the conservative recommendation is to avoid them
  • Opioid doses should be minimized and frequency decreased, particularly in patients with hepatic encephalopathy; consider tramadol for short-term pain management – always give concurrent bowel regimen
  • Gabapentin and other adjuvant analgesics can be considered; consider side effect profile and tailor analgesic plan to specific liver disease complications (e.g. hepatic encephalopathy, fluctuating renal function, varices)
  • Consider nonpharmacologic therapy in this population given potential adverse effects of multiple analgesic agents 
  • Treat concurrent psychiatric comorbidities, such as anxiety, depresssion, and substance use disorders, which are present in many chronic liver disease patients

Special Considerations

Liver-disease specific considerations:

  • Patients with chronic liver disease without cirrhosis do not have liver dysfunction, and analgesic metabolism is therefore similar to the general population and pain should be treated similarly
  • For patients listed for liver transplant, there may be transplant center-specific rules regarding analgesic use and toxicology screens (particularly in patients with alcohol-related cirrhosis)
  • Many patients with cirrhosis have substance use disorders which increase their risk for prescription medication (e.g. opioid) misuse and abuse; this should be considered when making treatment decisions
  • Creatinine clearance may overestimate glomerular filtration rate (GFR) in patients with cirrhosis, so consider conservative dose-reduction in these patients

Analgesic-specific considerations:

  • Acetaminophen: two main mechanisms for heaptotoxicity are increased CYP activity and depleted glutathione stores; most chronic liver disease patients have lower than normal CYP activity and gluthathione stores that are not depleted to critical levels, so acetaminophen is safe within recommended doses. Those with ongoing alcohol use may have significant depletion in glutathione stores, so use acetaminophen cautiously.  
  • NSAIDs: in cirrhosis patients, there are two particular concerns: 
    • Inhibition of prostaglandins is thought to lead to decrease in renal perfusion, sodium retention and possible precipitation of hepatorenal syndrome (an often fatal complication of advanced liver disease)
    • Increased risk of mucosal bleeding in patients who already have coagulopathy, thrombocytopenia, and portal hypertensive-related complications (e.g. varices)
  • Opioids: known to be potential precipitant of hepatic encephalopathy, possibly through alteration of the gut flora. Additionally, cirrhosis patients may have decreased drug clearance, leading to drug accumulation, and longer drug half-life. Tramadol is thought to have less sedating effects, and is often used short-term, though there are no studies in this specific population and beware of hyponatremia and hypoglycemia. If patient is listed for transplant, check with transplant hepatology team regarding center-specific opioid use policies, as these vary significantly. 
  • Methadone/Buprenorphine: small study suggesting methadone disposition parameters in cirrhosis patients that are similar to general population; minimal data exists on buprenorphine
  • Gabapentin/pregabalin: not metabolized by the liver or bound by proteins, but consider renal dysfunction in cirrhosis patients, as well as other relevant side effects (e.g. sedation, dizziness); minimal data on safety of these agents. 
References: 

Arroyo V, Ginés P, Rimola A, Gaya J. Renal function abnormalities, prostaglandins, and effects of nonsteroidal anti-inflammatory drugs in cirrhosis with ascites. An overview with emphasis on pathogenesis. Am J Med. 1986;81(2B):104-122. doi:10.1016/0002-9343(86)90912-5

Chandok N, Watt KDS. Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc. 2010;85(5):451-458. doi:10.4065/mcp.2009.0534

Mehta SS, Fallon MB. Muscle Cramps in Liver Disease. Clinical Gastroenterology and Hepatology. 2013;11(11):1385-1391. doi:10.1016/j.cgh.2013.03.017

Rakoski M, Goyal P, Spencer-Safier M, Weissman J, Mohr G, Volk M. Pain management in patients with cirrhosis. Clinical Liver Disease. 2018;11(6):135-140. doi:10.1002/cld.711

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(5):1009-1016. doi:10.1016/j.cgh.2014.10.029

Author: 
Jessica Rubin