Safe Analgesics In Liver Failure

Pain may coexist with renal or liver impairment from poisoning and non-poisoning causes such as advanced heart disease and end stage renal failure.

Advanced liver disease (deranged serum albumin, clotting factors and bilirubin) and cirrhosis alter the metabolism and effects of many drugs through a variety of mechanisms:

  • impaired hepatic drug metabolizing enzymes
  • altered production of drug binding proteins such as albumin and α1-acid glycoprotein (elevated levels of free drug)
  • impaired biliary excretion of drugs/metabolites
  • and portosystemic shunting (new blood vessels that divert blood from the gut to the heart, bypassing the liver which impairs first‐pass metabolism of drugs with high hepatic extraction & reduces oxygenation of hepatocytes leading to reduction of oxidative function of liver)

Such alteration of drug disposition increases the proportion of drug that is bioavailable which in turn may result in accumulation of toxic metabolites and consequent increased incidents of adverse effects.

In a setting of significant altered drug disposition, the dose should be reduced and/or the drug used less frequently or the drug is avoided altogether.

Cirrhotic patients often have impaired renal function despite a normal serum creatinine level (poor nutrition and reduced muscle mass cause less creatinine production). Therefore, dosing of analgesic drugs with a predominant renal elimination may require adjustment.

Fear of adverse effects, impaired drug elimination, and misconception regarding the safety of analgesics in hepatically impaired patients has led to sub-optimal pain management in this population.

NSAIDS

NSAIDs are largely metabolized by CYP enzymes and most are highly protein-bound to albumin. Thus, altered metabolism and bioavailability of NSAIDs can be anticipated in a setting of liver cirrhosis and severe liver failure/dysfunction.

Although NSAID-induced hepatotoxicity has been well described, the greater concern with NSAID use is renal impairment, in particular hepatorenal syndrome.

By inhibiting the synthesis of vasodilatory renal PGs and thromboxane A2 in the renal and gastrointestinal (GI) tract, NSAIDS causes a profound reduction in renal blood flow, glomerular filtration rate, salt and water retention, thereby worsening ascites and edema in advanced liver diseases like cirrhosis.

Furthermore, the reduced thromboxane A2 and resultant decreased platelet aggregation, increases the risk of mucosal bleeding (eg esophageal/gastric varices) as a result of thrombocytopenia and coagulopathy associated with advanced liver disease.

Complications such as bleeding due to antiplatelet activity, gastrointestinal irritation, and renal failure associated with NSAIDS in patients with severe hepatic impairment, means this analgesic class should be avoided in this population.

PARACETAMOL

Patients with advanced liver disease may metabolize acetaminophen more slowly than their healthy counterparts, though there is no evidence of toxic accumulation has been observed.

The theoretical mechanisms of paracetamol-induced hepatotoxicity include altered metabolism via CYP activity (CPP2E1) in combination with depleted glutathione stores that cause accumulation of a hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI).

However, studies in cirrhotic patients have shown that although the half-life of paracetamol may be prolonged (correlates with prothrombin time & albumin levels), CYP activity is not increased (potentially leading to a lesser degree of NAPQI formation) and glutathione stores are generally sufficient to avoid paracetamol hepatotoxicity. As a result, concerns about administration of therapeutic doses of paracetamol in the cirrhotic patients are often inaccurate

Glutathione is predictably depleted in the setting of long-term alcohol consumption (also induces CYP2E1, potentially causing elevated NAPQI levels) or malnutrition rendering alcoholic patients more susceptible to drug-induced liver injury.

Because of its proven safety profile (when given in recommended doses) and the lack of sedative effects and absence of nephrotoxicity, paracetamol has been recommended for long-term use (>14 days) in cirrhotic patients (not actively drinking alcohol) at 2-3 g/d. Nonetheless, short term use of <4g/day of paracetamol may be safely used.

Combination analgesics of opioids with paracetamol is discouraged because opiates induce its tolerance which necessitates dose escalation with an attendant risk of paracetamol overdose.

OPIOIDS

Liver is the major site of biotransformation for most opioids. With an exception of a few opiates, most opioids are metabolized by one or more of the CYP450 isozymes; thus, the elimination of these drugs may be affected in patients with hepatic disease.

However, there are a few opioids that are only minimally metabolized by CYP450 and, thus, may be safer options for patients with chronic liver disease. These include hydromorphone, oxymorphone, and tapentadol.

Opioids such as buprenorphine, tramadol, codeine, hydrocodone and oxycodone, that rely on hepatic biotransformation to active metabolites are ineffective analgesics in a setting of hepatic impairment. Coupled with a slow clearance, these drugs may accumulate and cause depression of respiratory system; thus, should be avoided or used with caution in this population.

Pethidine (meperidine) is metabolized largely to a normeperidine metabolite with serious CNS toxicity, particularly in the presence of renal dysfunction (comorbidity in cirrhosis); Pethidine should be avoided in patients with liver failure.

Methadone and fentanyl, though heavily protein bound and thus require reduced dosing in patients with cirrhosis, their metabolism does not yield toxic products. As a result, these compounds may be better tolerated than pethidine.

Furthermore, methadone pharmacokinetics in alcoholic cirrhosis patients was noted to be similar to those in healthy participants, suggesting that the usual methadone maintenance dosages are likely safe in patients with advanced liver disease.

Hydromorphone is metabolized solely by glucuronidation into an inactive metabolite; therefore, metabolism is less affected by cirrhosis. May be indicated for analgesia in patients with liver disease.

With morphine, although metabolized largely by glucuronidation, the resulting metabolite has central nervous system toxicity and is poorly excreted in the setting of renal insufficiency. Hence, dose reduction or avoidance of morphine in cirrhotic patients would be prudent.

Generally, all opioids can cause hepatic encephalopathy; they should be avoided in patients with cirrhosis. And if opioids are deemed necessary, it should be administrated at lower and less frequent dosing. Because of cross-addiction, opioids is avoided in patients with a history of addiction to any substance.

Careful follow-up is required to check for signs of sedation, constipation (a risk for precipitating encephalopathy), and early encephalopathy. Any sign of these complications necessitates immediate discontinuation of the opiate

Tricyclic antidepressants (TCAs) such as amitriptyline, nortriptyline, desipramine and imipramine have been the for treatment of neuropathic pain. TCAs rely on hepatic and renal elimination. Low doses are used in a setting of liver dysfunction to minimize the anticholinergic adverse effects of sedation and intestinal stasis which can precipitate hepatic encephalopathy.

In patients with advanced liver disease, nortriptyline and desipramine are generally recommended over amitriptyline and imipramine because they are less potent and appear to be less sedating than other TCAs.

Anticonvulsants such as carbamazepine or gabapentin have a role in neuropathic pain management.

Most anticonvulsants are metabolized by the liver (via CYPs) and excreted by the renal system, once again necessitating lower and less frequent dosing in cirrhotic patients.

Carbamazepine has been reported to cause hepatotoxicity in the general population and thus should be avoided.

However, gabapentin and pregabalin are not metabolized by the liver or bound to plasma proteins, and thus are preferred for neuropathic pain in patients with cirrhosis or severe liver disease. However, there are case reports of pregabalin‐induced hepatoxicity.

Serotonin‐Norepinephrine Reuptake Inhibitors (SNRIs) such as venlafaxine and duloxetine increasingly used for pain management, show significantly increased half‐life in a setting of liver dysfunction; duloxetine is associated with drug‐induced liver injury and should be avoided in liver failure.

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