| | Altered response and pharmacokinetics | Management suggestions |
| Non-opioid analgesics |
| Acetaminophen (paracetamol) | - Glutathione tissue stores needed to block formation of acetaminophen's toxic metabolite (NAPQI) are reduced in individuals with cirrhosis or malnutrition, thereby lowering the dose threshold of acetaminophen that can be safely administered each day.
- Active alcohol consumption further reduces available glutathione stores.
- Half-life of acetaminophen may be prolonged by up to 2-fold compared with healthy patients.
| - Acetaminophen is generally well tolerated in patients with CLD or cirrhosis who do not consume alcohol, provided the total daily dose is limited to no more than 2 g/day.
- For short-term or one-time use, a maximum total acetaminophen dose of up to 4 g/day may be considered in lower risk patients who do not consume alcohol and have CLD or early stage compensated cirrhosis.
- Warn patients concerning acetaminophen content in combination prescription analgesics (eg, oxycodone-acetaminophen) and non-prescription (OTC) preparations.
- Avoid use in patients with advanced CLD or cirrhosis who are actively consuming alcohol, malnourished, not eating, receiving multiple medications that undergo hepatic biotransformations, or any co-administered medication that is a potent inducer of hepatic enzymes.
- A list of medications that induce hepatic enzymes is provided in a separate table.
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| Nonselective nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin | - An increased risk of GI mucosal bleeding, variceal hemorrhage, impaired renal function, and development of diuretic-resistant ascites is seen with use of NSAIDs in patients with cirrhosis with portal hypertension.
- NSAIDs can decrease GFR and impair renal function in patients with advanced CLD or cirrhosis.
- Most NSAIDs are metabolized by CYP and highly bound to serum albumin, increasing drug bioavailability and potential for toxicity in patients with advanced CLD or cirrhosis.
- Individual NSAIDs (eg, diclofenac) have been associated with hepatotoxicity in general population.
| - NSAIDs and aspirin should be avoided in patients with advanced CLD or cirrhosis.
- Low-dose acetaminophen should be used instead of NSAIDs.
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| Selective COX-2 inhibitors | - Available data are inadequate to establish the safety of selective COX-2 inhibitors in patients with advanced CLD or cirrhosis. Refer to UpToDate content for detail.
- Excess cardiovascular events have been observed with this class of medications when used by patients without cirrhosis.
| - We advise against use of selective COX-2 inhibitors in patients with advanced CLD or cirrhosis, pending availability of additional safety data.
- If used, celecoxib product information suggests a 50% dose reduction for Child-Pugh class B cirrhosis.
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| Opioid analgesics (refer to important note)* |
| Fentanyl | - Metabolized by CYP3A4 to inactive (nontoxic) metabolites.
- Parent drug can accumulate after repeated dosing or when administered as a continuous infusion due to tissue and protein binding.
- Less histamine release than other opiates.
- Less hemodynamic disturbance than other opiates.
| - Generally a good choice for patients with CLD or cirrhosis when opiate treatment is indicated.
- Useful option in patients with renal failure in setting of cirrhosis.
- No dose adjustment needed for single dose.
- With repeated dosing, reduce dose and frequency by approximately 25 to 50%.
- Initiate transdermal patch at half usual dose.
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| Hydrocodone, oxycodone | - Metabolized to active metabolite by CYP2D6 and CYP3A4, which may result in a prolonged time to onset, variable analgesic efficacy, and risk of accumulation in patients with advanced CLD or cirrhosis.
| - Due to variability of onset and analgesic efficacy in hepatic insufficiency, fentanyl or hydromorphone may be better tolerated and more safely and predictably adjusted than hydrocodone and oxycodone in patients with advanced CLD or cirrhosis.
- If used, reduce dose and frequency.
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| Hydromorphone | - Hepatically metabolized by non-CYP transformations (glucuronidation) to apparently inactive metabolites.
- Oral bioavailability in advanced CLD or cirrhosis seems to be increased relative to healthy individuals due to diminished first-pass extraction, but specific data are lacking, and wide inter-individual variability is observed.
| - Generally a good choice for patients with advanced CLD or cirrhosis.
- Reduce dose and frequency by approximately 50%.
- Titrate dose gradually to avoid accumulation of active drug.
- Useful option in patients with renal failure in setting of cirrhosis.
- Small volume for IV preparation and non-CYP3A4 metabolism may be advantageous given clinical setting.
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| Meperidine (pethidine), codeine | - Altered oral bioavailability and elevated risk of accumulation of intermediates (codeine) or toxic metabolite (meperidine).
- Meperidine is highly bound to serum protein.
- Unpredictable analgesic efficacy and increased risk of toxicity in patients with advanced CLD or cirrhosis.
| - Meperidine and codeine should be avoided in patients with advanced CLD or cirrhosis.
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| Morphine | - Oral bioavailability in advanced CLD or cirrhosis increased up to 100% relative to healthy individuals due to diminished first-pass extraction. Wide inter-individual variability may be seen.
- Hepatically metabolized by non-CYP transformations (glucuronidation).
- Half-life can be increased by up to 2-fold.
- Accumulation of metabolites with complex effects (eg, respiratory depression, analgesic tolerance, neurotoxicity) can occur in patients with cirrhosis and renal failure.
| - Reduce dose and frequency by approximately 50% in advanced CLD or cirrhosis.
- Titrate dose gradually to avoid accumulation of active drug.
- Avoid in patients with cirrhosis and renal failure.
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| Naloxone-containing opioid combinations | - Orally administered naloxone, which is included in these combinations to deter abuse (ie, crushing, snorting) and counteract constipation by a local effect, is systemically absorbed in patients with moderate to severe hepatic impairment.
- Systemic absorption of naloxone will reverse analgesic efficacy and can precipitate opioid withdrawal.
| - Oxycodone-naloxone:
- Reduce starting dose by one-half to two-thirds in mild hepatic impairment.
- Use in advanced CLD or cirrhosis is contraindicated.
- Pentazocine-naloxone: Avoid use.
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| Remifentanil | - Cleared by nonspecific plasma esterases to inactive metabolites.
- Does not accumulate in hepatic or renal insufficiency.
- Prompt reversal of analgesia and sedation upon discontinuation.
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| Tramadol | - Hepatically metabolized to active metabolite by CYP3A4, CYP2D6, and glucuronidation.
- Unpredictable onset, variable analgesic efficacy, and risk of accumulation in patients with cirrhosis.
- Can interact with serotoninergic medications, including antidepressants.
| - Avoid use in patients with decompensated cirrhosis.
- Avoid use in patients at risk for seizures.
- Based on limited experience, a reduced dose of 25 mg every 8 hours may be considered for treatment of pain in patients with advanced CLD or well-compensated cirrhosis.
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| Adjunctive agents for neuropathic pain |
| Carbamazepine | - Carbamazepine is a potent inducer of hepatic enzymes and has been associated with hepatotoxicity and serious allergic reactions in genetically predisposed individuals.
- May precipitate rapid decompensation in patients with cirrhosis.
| - Carbamazepine should be avoided as there are safer options for treatment of neuropathic pain in patients with advanced CLD or cirrhosis.
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| Gabapentin | - Not hepatically metabolized or bound to plasma proteins.
- Highly dependent on renal function for clearance of unchanged drug.
- Sedation, ataxia, dizziness, and nausea may limit usefulness in patients with advanced CLD or cirrhosis.
| - Initiate treatment at 300 mg orally per day and gradually titrate dose if needed over weeks due to delayed onset of action and to improve tolerability.
- Maintenance dose is dependent on renal function. For specific adjustment, refer to Lexicomp monograph included with UpToDate.
- According to the product information, should not be abruptly stopped due to risk of discontinuation symptoms (eg, nausea, insomnia, anxiety) and/or rebound seizures in at-risk patients.
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| Lidocaine topical patch | - Low (3 to 5%) systemic absorption through intact skin.
| - A good choice for local relief of pain in limited areas of intact skin in patients with advanced CLD or cirrhosis.
- No adjustment needed in hepatic impairment.
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| Nortriptyline | - Subject to extensive first-pass metabolism and CYP2D6 transformations, which include active and inactive metabolites.
- Accumulation of metabolites in hepatic impairment is less likely with nortriptyline than amitriptyline.
- Dose-related anticholinergic and cardiovascular side effects may be poorly tolerated in medically ill patients with advanced CLD or cirrhosis.
| - Initiate treatment at 10 mg orally each night and gradually titrate dose if needed over weeks due to delayed onset of action and to improve tolerability.
- Use "low" maintenance dose for neuropathic pain (eg, 25 mg to no more than 50 mg daily) to decrease risk of accumulation.
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| Pregabalin | - Not hepatically metabolized or bound to plasma proteins.
- Highly dependent on renal function for clearance of unchanged drug.
- Sedation and dizziness may limit usefulness in patients with advanced CLD or cirrhosis.
| - Initiate treatment at 50 mg orally twice per day and gradually titrate dose if needed over weeks due to delayed onset of action.
- Maintenance dose is dependent on renal function. For specific adjustment, refer to Lexicomp monograph included with UpToDate.
- According to the product information, should not be abruptly stopped due to risk of discontinuation symptoms (eg, nausea, insomnia, anxiety) and/or rebound seizures in at-risk patients.
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