Adjusting pain medications in adult patients with cirrhosis

INTRODUCTION — 

Pain is a common symptom in patients with cirrhosis that may arise from cirrhosis-related conditions such as ascites (leading to abdominal and lower back pain) or gynecomastia (leading to mastalgia). Patients with cirrhosis may also develop pain from a condition unrelated to their liver disease.

The liver is responsible for the selective uptake, concentration, metabolism, and excretion of most drugs. Both prescription and over-the-counter medications can cause hepatotoxicity through a variety of mechanisms. Measures such as drug dose adjustment can help prevent adverse drug reactions in patients with cirrhosis.

This topic will discuss factors that inform adjusting pain medications in patients with cirrhosis. Drug-related factors include mechanism of action, route of administration, and adverse effects. Specific drug classes include nonopioid analgesics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]), opioids, and agents for neuropathic pain (eg, antiseizure medications).

Other aspects of care for patients with cirrhosis are discussed separately:

●General management – (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

●Overview of medication adjustments for other conditions – (See "Overview of medication adjustments for adult patients with cirrhosis".)

The clinical patterns of drug-induced hepatotoxicity are discussed separately. (See "Drug-induced liver injury".)

Management of chronic non-cancer pain including nonpharmacologic therapies is discussed separately. (See "Approach to the management of chronic non-cancer pain in adults" and "Overview of pharmacologic management of chronic pain in adults".)

GENERAL PRINCIPLES

Prevalence of pain — Pain is a common symptom among patients with cirrhosis who may often receive prescriptions for analgesic medications [1,2]. In a systematic review of five studies, the prevalence of pain in patients with end-stage liver disease ranged from 30 to 79 percent [1]. In a database study including over 100,000 patients with cirrhosis, the annual percentage of patients receiving an opioid prescription increased during a span of nine years from 36 percent to 47 percent [2].

Rationale for dose adjustment — The goal of adjusting pain medications in addition to monitoring patients with cirrhosis is to reduce the risk of adverse effects [3,4]. The exact cutoff at which drug doses should be altered is uncertain. Modifications of drug-prescribing should generally be considered in all patients with cirrhosis, particularly when accompanied by complications of portal hypertension (eg, gastroesophageal varices, ascites, hepatic encephalopathy) or by kidney impairment.

For specific details on dose adjustments, refer to the drug monographs included with UpToDate.

Factors that guide decision-making — Drug selection and dose adjustments are guided by the following [5,6]:

●Indication for drug therapy (ie, underlying diagnosis, need for long-term therapy).

●Pharmacokinetics of the medication (eg, hepatic metabolism, excretion). Drug metabolism is affected by liver function, hepatic blood flow, drug binding by plasma proteins, and biliary excretion [7,8].

●Potential side effects of medication.

●Coexisting conditions (eg, kidney impairment).

●Concurrent medications (ie, risk of drug-drug interaction). For specific drug interactions, refer to the drug interactions program included in UpToDate.

●Severity of liver disease, which may be categorized using a clinical definition (ie, compensated or decompensated cirrhosis) or a predictive model (ie, Model for End-stage Liver Disease [MELD] score or Child-Pugh classification). As an example, patients who have not developed a major complication are classified as having compensated cirrhosis, whereas patients who have a complication (eg, variceal bleeding, new onset ascites, spontaneous bacterial peritonitis, hepatic encephalopathy) are classified as having decompensated cirrhosis. These prognostic classifications may accurately predict survival, but they may be limited for guiding dose adjustments given the complexity of drug metabolism. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Prognosis'.)

●Options for nonpharmacologic therapies – Nonpharmacologic therapies may serve an important role in managing pain and may reduce the need for pain medications. Nonpharmacologic therapies may be grouped into exercise therapy, psychoeducational interventions (eg, cognitive-behavioral therapy), mind-body therapies (eg, mindfulness-based stress reduction), and physical interventions (eg, physical therapy [PT], acupuncture, massage) (table 1). (See "Approach to the management of chronic non-cancer pain in adults".)

Monitoring — After initiating or adjusting pain medication, drug monitoring is individualized based on the risk of drug toxicity, the severity of cirrhosis, and the patient's coexisting conditions. In general, we monitor patients with cirrhosis for signs of decompensation (eg, ascites, hepatic encephalopathy) or extrahepatic adverse effects (eg, rash). We also ask patients to report any side effects (eg, anorexia, nausea, constipation) [9].  

Specialty referral — We typically refer patients with cirrhosis who require long-term analgesic therapy to a pain management program.

NONOPIOID ANALGESICS

Acetaminophen (paracetamol)

Contraindications and cautions — We do not use acetaminophen (paracetamol) in patients with any of the following conditions:

●Alcohol-associated hepatitis

●Acute liver injury

Before prescribing acetaminophen, we review the patient’s medication list and caution them to avoid nonprescription combination preparations containing acetaminophen. In addition, we counsel patients to read medication labels carefully and to discuss any new nonprescription medications with their health care provider. Patients may be at risk for liver injury when taking products that combine acetaminophen with opioids or other drugs including over-the-counter remedies. Clinicians need to use caution when prescribing combination formulations because of the potential for liver toxicity. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation".)

For specific drug interactions, refer to the drug interactions program included in UpToDate.

Patients who do not use alcohol — Acetaminophen is a widely available, effective, and safe analgesic for patients with cirrhosis who do not use alcohol.

For such patients, we typically limit the acetaminophen dose to 2 g per day [10]. For short-term or one-time use, a maximum dose of up to 4 g per day may be considered in patients with well compensated cirrhosis who do not consume alcohol. Based on the manufacturer drug label, the maximum recommended daily dose for acetaminophen is 3 g, while a maximum daily dose of 4 g may be prescribed at the discretion of the clinician [11].

Acetaminophen appears to be safe in patients with cirrhosis when used at or below the recommended dose [12,13]. In a study including 20 patients with cirrhosis who were given acetaminophen 4 g per day for 13 days, one patient developed abnormal liver enzymes [12]. After the laboratory values returned to normal, the same patient was subsequently challenged with 10- and 14-day courses of 4 g per day of acetaminophen without adverse effects.

It is well established that acetaminophen is hepatotoxic in larger doses. When ingested at doses greater than 10 g, acetaminophen causes severe hepatic necrosis and acute liver failure. The pharmacokinetics and toxicity of acetaminophen are discussed in more detail separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation".)

Patients who use alcohol — Patients with cirrhosis who use small amounts of alcohol (less than 10 to 20 g per day) may use acetaminophen cautiously by limiting the dose to 2 g per day and discontinuing the drug after a short course (ie, ≤7 days) (figure 1). (See "Clinical manifestations and diagnosis of alcohol-associated steatosis and cirrhosis".)

For patients who use alcohol, restricting the use of acetaminophen to low dose, short-term use is supported by clinical experience, limited published data, and the effect of alcohol on the drug's metabolism [6,14,15]. In a trial comparing acetaminophen 4 g per day for two days with placebo in 201 patients who were hospitalized for alcohol use disorder, there were no significant differences in liver enzymes or international normalized ratio (INR) between groups [15]. However, there are limitations when interpreting these data. Patients were hospitalized and were not actively drinking, and it was unclear whether patients had cirrhosis. In a study including 67 patients with active alcohol use who developed acetaminophen-induced liver injury, 60 percent of patients had ingested ≥4 g per day [14]. Most patients (90 percent) had aspartate aminotransferase levels ranging from 3000 to 48,000 units/L, indicating severe hepatic necrosis.

For individuals who do not use alcohol, only a fraction of acetaminophen is metabolized by the cytochrome P450 enzyme system to the hepatotoxic compound N-acetyl-p-benzoquinone imine (NAPQI). For patients who use alcohol chronically, the P450 system is induced and therefore more of the NAPQI is generated. The hepatotoxicity of NAPQI is diminished by glutathione conjugation. However, patients with chronic alcohol use may have reduced stores of glutathione secondary to impaired production and poor nutritional status. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment".)

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Pharmacology — The primary effect of NSAIDs is to inhibit cyclooxygenase (prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Two related isoforms of the cyclooxygenase (COX) enzyme have been described: COX-1 and COX-2. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

Contraindications and cautions — We avoid nonselective NSAIDs (including aspirin) in patients with cirrhosis complicated by portal hypertension (eg, ascites, gastroesophageal varices) and in patients with a history of gastrointestinal bleeding.

We may use a short course (ie, ≤7 days) of NSAIDs in patients with compensated cirrhosis who do not have other risk factors for NSAID-related adverse events (eg, history of gastrointestinal bleeding, kidney impairment). NSAIDS have been associated with increased risk of liver injury, gastrointestinal bleeding, and diuretic-resistant ascites [6].

Adverse effects — NSAID-related adverse effects are summarized here and presented in more detail separately:

●Gastrointestinal effects – The overall risk of NSAID-related gastrointestinal toxicity (eg, peptic ulcer disease) may be higher in patients with decompensated cirrhosis, although the association between variceal bleeding and NSAID use has been less clear [16,17]. In a large cohort study including adults with chronic viral hepatitis, the use of low dose aspirin was not associated with increased rates of gastrointestinal bleeding during 10 years of follow-up (7.8 versus 6.9 percent) [17]. However, there was a nonsignificant trend towards higher bleeding risk for patients with compensated or decompensated cirrhosis (HR 1.20, 95% CI 0.91-1.35, and HR 1.33, 95% CI 0.94-1.46, respectively).

NSAIDs inhibit the production of prostaglandins involved in protecting the gastrointestinal mucosa from noxious agents such as gastric acid. They also inhibit the production of thromboxane leading to decreased platelet aggregation and impaired hemostasis. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity" and "NSAIDs: Adverse effects on the distal small bowel and colon".)

●Kidney effects – Cirrhosis and diuretic use are risk factors for NSAID-induced acute kidney injury (table 2). Limited data suggested that NSAID use in patients with ascites resulted in reduced glomerular filtration rates [18].

In addition to hemodynamically-mediated acute kidney injury, NSAIDs can induce acute interstitial nephritis (which is often accompanied by nephrotic syndrome). Acute interstitial nephritis and perhaps nephrotic syndrome are directly related to reduced prostaglandin synthesis induced by the NSAID. The mechanisms of acute kidney injury including the impact of prostaglandin synthesis are discussed separately. (See "NSAIDs: Acute kidney injury" and "NSAIDs: Electrolyte complications".)

●Drug-induced liver injury – Acute liver injury is uncommon with NSAID use but has been reported [19-21]. Among the reports of drug-induced liver injury attributed to NSAIDs, sulindac and diclofenac were the most common agents. (See "Drug-induced liver injury".)

●Drug interaction with diuretics — Patients with cirrhosis and ascites are often treated with diuretics. Nonselective NSAIDs diminish the natriuretic effects of diuretics in patients with ascites, leading to impaired free water clearance and worsening of ascites and peripheral edema [18]. (See "Ascites in adults with cirrhosis: Diuretic-resistant ascites".)

●Other adverse effects – Other NSAID-related adverse effects include:

•Cardiovascular effects (See "NSAIDs: Adverse cardiovascular effects".)

•Anaphylaxis and allergy (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

•NSAID-exacerbated respiratory disease (See "Aspirin-exacerbated respiratory disease".)

COX-2 inhibitors — We do not routinely use selective cyclooxygenase (COX)-2 inhibitors in patients with cirrhosis because safety data are limited. We generally reserve the use of a short course (ie, ≤7 days) of a COX-2 inhibitor for patients with compensated cirrhosis who do not have complications of portal hypertension.  

COX-2 inhibitors (eg, celecoxib) are effective analgesics that have been associated with lower risk of gastrointestinal and kidney toxicity. However, COX-2 inhibitors have also been associated with increased incidence of adverse cardiovascular events. (See "NSAIDs: Adverse cardiovascular effects".)

Published data on the use of COX-2 inhibitors in patients with cirrhosis have been limited [18,22]. In a case-crossover study including 4876 adults with cirrhosis who were hospitalized with gastrointestinal bleeding, celecoxib use was not associated with increased risk of gastrointestinal bleeding, whereas nonselective NSAID use was associated with higher bleeding risk (adjusted odds ratio 1.87, 95% CI 1.66-2.11) [22]. In a small trial comparing a short course of naproxen (a nonselective NSAID) with celecoxib or placebo in 28 patients with cirrhosis, naproxen resulted in greater reductions in glomerular filtration rate (GFR), renal plasma flow, and urinary prostaglandin E2 excretion, in addition to suppressing the diuretic and natriuretic response to furosemide [18]. However, the study was limited by short-term duration of therapy and small number of patients.

OPIOIDS

Pharmacology — Opioids exert their analgesic effect through at least four groups of receptors and probably other subpopulations as well. The distribution of these receptors throughout the body, along with their tissue densities within numerous organ systems, account for the global and varied effects of these drugs. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Opioids'.)

Opioids are primarily metabolized by the liver through hepatic oxidation and glucuronidation. The clearance of opioids depends upon plasma protein binding, hepatic blood flow, and hepatic enzyme capacity. Oxidative enzyme pathways and opioid clearance are impaired in cirrhosis, which may lead to the accumulation of toxic metabolites [23,24]

Selecting an agent — We use selected opioids with caution in patients with cirrhosis, and these agents include fentanyl, hydromorphone, and morphine [10,24,25]. Drug dosing and metabolism is discussed below. (See 'Specific options' below.)

We avoid the following opioids in most patients with cirrhosis: oxycodone, codeine, meperidine, and tramadol.

We generally avoid oxycodone because of its variable onset and analgesic efficacy in patients with cirrhosis. Alternatives to oxycodone such as fentanyl or hydromorphone may be better tolerated.

We generally avoid codeine and meperidine because the effects are difficult to predict.

We avoid tramadol in patients with decompensated cirrhosis and in patients at risk for seizures.

General principles for dosing including cautions — Our general approach to dosing opioids in patients with cirrhosis includes initiating the opioid at a low dose and with longer intervals between doses. If the patient tolerates the drug with initial dosing, we slowly increase the dose to achieve symptomatic relief while minimizing the risk of adverse effects. We typically limit opioid use to treating acute pain for short courses (ie, ≤7 days), and we avoid long-term opioid therapy.

We counsel patients who are initiating opioids about the risk of constipation, which increases the risk of hepatic encephalopathy [26-28]. In a large database study including patients with cirrhosis, opioid use was associated with increased risk of hepatic encephalopathy after adjusting for confounders such as age, etiology of cirrhosis, and portal hypertension (adjusted hazard ratio 1.24, 95% CI 1.21-1.27) [26].

Opioid-induced constipation leads to increased absorption of toxic gut metabolites. Preventive strategies to avoid constipation include laxative therapy, and these issues are discussed separately. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel dysfunction'.)

Specific options — For patients with cirrhosis, dosing adjustments for specific opioids include [6,10,28]:

●Commonly used agents:

•Fentanyl – For patients with cirrhosis, we may use fentanyl as a transdermal patch and initiate therapy by reducing the usual dose by 50 percent. For patients receiving a single fentanyl dose by any route of administration, no dose adjustment is needed.

Fentanyl is also a reasonable option for patients with cirrhosis and kidney impairment. Fentanyl is a lipid-soluble synthetic opioid that is approximately 80 to 100 times as potent as morphine. It is converted by hydroxylation and dealkylation in the liver into inactive and nontoxic metabolites. In a study of patients with histologically confirmed cirrhosis, the pharmacokinetics of fentanyl were unchanged when compared with individuals without liver disease [29]. However, the patients with cirrhosis in this study had normal serum albumin, and the prothrombin times were only slightly abnormal. It is unknown if fentanyl metabolism is affected in patients with decompensated cirrhosis.

•Hydromorphone – We may use hydromorphone cautiously in patients with cirrhosis by reducing the dose and frequency of administration by approximately 50 percent. If a higher dose is needed, we may titrate the drug gradually to avoid accumulation of the active drug. Hydromorphone may be used in patients with cirrhosis and kidney failure.

Hydromorphone is a hydrogenated ketone of morphine that is metabolized by the liver to apparently inactive metabolites. Oral bioavailability in cirrhosis seems to be increased relative to healthy individuals due to diminished first-pass extraction, but specific data are lacking.  

•Morphine – We may use morphine cautiously in patients with cirrhosis by reducing the dose and frequency of administration by approximately 50 percent. If needed, we may titrate the dose gradually to avoid accumulation of the active drug.

We do not use morphine in patients with cirrhosis and kidney failure because accumulation of hydrophilic metabolites can lead to seizure activity, respiratory depression, and hepatic encephalopathy [30].

Morphine undergoes rapid glucuronidation in the liver with subsequent systemic metabolism. Although glucuronidation is usually preserved despite diminished liver function, multiple studies demonstrated that the clearance of morphine was delayed in patients with cirrhosis by 35 to 60 percent [23,31,32]. In addition, morphine has increased oral bioavailability in patients with cirrhosis secondary to reduced first-pass hepatic metabolism.

•Methadone – Methadone appears to be safe in patients with cirrhosis, at least for short-term administration. Methadone is a long-acting opioid that is often used for treating opioid use disorder. Limited data and clinical experience suggested that short-term methadone use was not associated with increased risk of toxicity in patients with cirrhosis who do not have acute liver failure [33]. In a small study comparing methadone therapy in patients who had alcohol use disorder and cirrhosis with patients who had alcohol use alone, the pharmacokinetic profiles of methadone were not significantly different between groups [33]. Although the drug half-life in patients with decompensated cirrhosis may be mildly prolonged, drug accumulation is not significantly altered.

●Agents to avoid or for restricted use:

•Buprenorphine/naloxone – Buprenorphine/naloxone is a combination opioid partial agonist that suppresses withdrawal symptoms in patients with opioid use disorder. While buprenorphine exposure is slightly increased with worsening liver function (eg, patients with Child-Pugh B or C cirrhosis), naloxone exposure is substantially increased. Thus, more data are needed before routinely using buprenorphine/naloxone in patients with cirrhosis. (See "Opioid use disorder: Pharmacologic management", section on 'Buprenorphine: Opioid partial agonist'.)

•Codeine – We avoid codeine in patients with cirrhosis. Codeine requires the oxidative enzyme capacity of the liver to convert the prodrug to its active metabolites, potentially decreasing its effectiveness in patients with cirrhosis.

•Meperidine – We avoid meperidine in patients with cirrhosis. Meperidine is metabolized extensively in the liver, and the oral bioavailability is altered with increased risk of accumulation of intermediates (codeine) and toxic metabolites [34,35]. In addition, meperidine is highly bound to serum protein and has unpredictable analgesic effects and an increased risk of toxicity in patients with cirrhosis [24].

•Hydrocodone/oxycodone – The risk of toxicity with hydrocodone or oxycodone may be increased in patients with cirrhosis. These drugs are metabolized in the liver to active compounds by CYP2D6 and CYP3A4, which may result in a prolonged time to onset, variable analgesic efficacy, and risk of accumulation in patients with cirrhosis [7,8]. If oxycodone is used, the dose and frequency of administration should be reduced by at least 50 percent.

•Tramadol – We generally avoid tramadol in patients with cirrhosis. However, we may use tramadol cautiously for patients with well-compensated cirrhosis by reducing the dose to 25 mg every eight hours for a short course. In patients with cirrhosis, the metabolism of tramadol may be decreased because it requires conversion to O-desmethyltramadol by hepatic oxidation. This may result in unpredictable analgesic effects because the active metabolites may be variable concentrations of opioid and serotonin–norepinephrine reuptake inhibitor [7,36]. Tramadol may interact with serotoninergic medications, including antidepressants. More studies are needed to establish the safety of tramadol in patients with cirrhosis.

Other opioids such as propoxyphene are metabolized by oxidative systems and have decreased clearance which increases bioavailability in patients with cirrhosis [30]. Thus, use of such drugs can lead to accumulation of the drugs and their toxic metabolites.

AGENTS FOR NEUROPATHIC PAIN — 

We may use selected neuropathic agents (ie, antiseizure therapies, tricyclic antidepressants) for treating pain in patients with cirrhosis. We initiate the drug at a low dose and gradually titrate the dose while monitoring for symptom relief and adverse effects.

●Antiseizure therapies – Initial doses for antiseizure medications are:

•Gabapentin 300 mg orally per day

•Pregabalin 50 mg orally twice per day

The dose can be gradually titrated over several weeks because the drugs have delayed onset of action. Both drugs require dose adjustments in patients with kidney impairment. According to product information, such drugs should not be stopped abruptly due to the risk of discontinuation symptoms (eg, nausea, insomnia, anxiety) and/or rebound seizures. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Antiseizure medications'.)

Gabapentin and pregabalin are antiseizure therapies that are not metabolized by the liver and are not bound to plasma proteins. These drugs depend on kidney function for clearance [10,24]. Adverse effects include sedation, ataxia, dizziness, and nausea.

We avoid the use of carbamazepine in patients with cirrhosis because it is a potent inducer of liver enzymes, has been associated with hepatotoxicity, and may precipitate rapid liver decompensation [10,24].

●Tricyclic antidepressants – Initial doses of tricyclic antidepressants are:

•Amitriptyline 10 mg orally each night

•Nortriptyline 10 mg orally each night

We may gradually titrate the dose over several weeks because the drug has a delayed onset of action. We generally use low maintenance doses (eg, 25 to 50 mg) to reduce the risk of drug and metabolite accumulation. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Pharmacologic therapy for neuropathic or nociplastic pain'.)

Tricyclic antidepressants have extensive first-pass hepatic metabolism and dose-related anticholinergic and cardiovascular side effects [10,24]. Accumulation of metabolites in liver impairment is less likely with nortriptyline than amitriptyline.

OTHER AGENTS

Topical lidocaine — We may use topical lidocaine for local relief of pain in limited areas of intact skin in patients with cirrhosis. No dose adjustment is needed because rates of systemic absorption through intact skin are low (3 percent) [37].

Cannabis — We do not endorse cannabis for medical use in patients with cirrhosis and pain because its safety has not been established [38]. In addition, transplant center policies on cannabis use are variable, and positive urine toxicology for delta-9-tetrahydrocannabinol (THC) may negatively impact candidacy for liver transplantation.

The long-term effects of cannabis on liver disease are uncertain. Cross-sectional studies in patients with hepatitis C virus infection suggested that daily cannabis use was associated with liver steatosis and fibrosis [39-41]. However, longitudinal studies in patients with HIV-hepatitis C virus coinfection have not found an association between cannabis use and progression of liver fibrosis [42,43]. Cannabis intoxication may worsen or mimic hepatic encephalopathy.

The active component of cannabis is THC, and there are two known cannabinoid receptors (CB1 and CB2). THC is metabolized by CYP2C9 and CYP3A4 in the liver. In cell culture, CB1 receptor activation is associated with hepatic stellate cell activation, inflammation, and fibrosis. Conversely, CB2 receptor activation inhibits liver fibrosis [44].

The medical use of cannabis for pain control and other beneficial effects (nausea control, anxiolysis, appetite stimulation) are discussed separately [45]. (See "Medical use of cannabis and cannabinoids in adults".)

SPECIAL POPULATIONS

Patients with end-stage liver disease — Pain management is one aspect of palliative care for patients with end-stage liver disease. The term "end-stage liver disease" is synonymous with advanced liver disease, liver failure, and decompensated cirrhosis, given the general irreversibility of these conditions. Other important aspects of care for patients with end-stage liver disease include managing other symptoms (eg, pruritus, muscle cramps), discussing goals of care, and helping to plan end-of-life care. These issues are discussed separately. (See "Palliative care for patients with end-stage liver disease".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cirrhosis".)

SUMMARY AND RECOMMENDATIONS

●Background – Pain is a common symptom in patients with cirrhosis that may arise from cirrhosis-related conditions such as ascites (leading to abdominal and lower back pain) or gynecomastia (leading to breast pain). Patients with cirrhosis may also develop pain from a condition unrelated to their liver disease. (See 'Introduction' above.)

●Rationale for dose adjustment – Empiric dose reduction of pain medications combined with clinical monitoring is a commonly used strategy to reduce the risk of adverse reactions. Modifications of drug prescribing should generally be considered in all patients with cirrhosis, particularly when accompanied by complications of portal hypertension (eg, gastroesophageal varices, ascites, hepatic encephalopathy) or by kidney impairment. (See 'Rationale for dose adjustment' above.)

For specific details on dose adjustments, refer to drug monographs included with UpToDate.

●Factors guiding drug selection and dose adjustment – Drug selection and dose adjustments are guided by the following (see 'Factors that guide decision-making' above):

•Indication for drug therapy (ie, underlying diagnosis, need for long-term therapy)

•Pharmacokinetics of the medication (eg, hepatic metabolism, excretion)

•Potential drug side effects

•Coexisting conditions (eg, kidney impairment, alcohol use)

•Concurrent medications (ie, risk of drug-drug interaction)

•Severity of liver disease

•Options for nonpharmacologic therapies

●Acetaminophen – Acetaminophen is an effective and safe analgesic when used cautiously in patients with cirrhosis (See 'Acetaminophen (paracetamol)' above.):

•Contraindications and cautions – We do not use acetaminophen (paracetamol) in patients with alcohol-associated hepatitis or acute liver injury.

The pretreatment evaluation includes reviewing the patient's medication list and cautioning them to avoid nonprescription combination preparations containing acetaminophen. We counsel patients with cirrhosis to read medication labels carefully and to discuss any new nonprescription medications with their health care provider.

•Dosing – For patients with cirrhosis who do not use alcohol, we typically limit acetaminophen use to 2 g per day. For short-term or one-time use, a maximum dose of up to 3 to 4 g per day may be considered in patients with well compensated cirrhosis who do not consume alcohol.

Patients who consume alcohol may use acetaminophen cautiously by limiting the dose to 2 g per day and discontinuing the drug after a short course (ie, ≤7 days).

●Nonsteroidal anti-inflammatory drugs (NSAIDs):

•Nonselective NSAIDs – We generally avoid nonselective NSAIDs (including aspirin) in patients with cirrhosis complicated by portal hypertension (eg, ascites, gastroesophageal varices) and in patients with a history of gastrointestinal bleeding. (See 'Nonsteroidal anti-inflammatory drugs (NSAIDs)' above.)

We may use a short course of NSAIDs in patients with compensated cirrhosis who do not have other risk factors for NSAID-related adverse events (eg, history of gastrointestinal bleeding, kidney impairment).

•Cyclooxygenase (COX)-2 inhibitors – We do not routinely use selective COX-2 inhibitors in patients with cirrhosis because safety data are limited. We generally reserve the use of a short course (ie, ≤7 days) of COX-2 inhibitors for patients with compensated cirrhosis who do not have complications of portal hypertension. (See 'COX-2 inhibitors' above.)

●Opioids – We may use selected opioids (eg, fentanyl, hydromorphone, morphine) with caution in patients with cirrhosis. Our general approach includes initiating the opioid at a low dose and with longer intervals between doses. We typically limit opioid use to short courses (ie, ≤7 days), and we avoid long-term opioid therapy. (See 'Opioids' above.)

●Neuropathic agents – We may use selected neuropathic agents (ie, gabapentin, pregabalin, nortriptyline, amitriptyline) for treating pain in patients with cirrhosis. We initiate the drug with a low initial dose and gradually titrate the dose while monitoring for symptom relief and adverse effects. (See 'Agents for neuropathic pain' above.)