REVIEW

PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

Pain Management in the Cirrhotic Patient:

The Clinical Challenge

Natasha Chandok, MD, and Kymberly D. S. Watt, MD

Pain management in patients with cirrhosis is a difficult clinical drug metabolism may be altered, and thus concerns and
challenge for health care professionals, and few prospective stud-
ies have offered an evidence-based approach. In patients with end-
dose reductions, as discussed in this article, may be war-
stage liver disease, adverse events from analgesics are frequent, ranted.2-4 A patient with well-compensated cirrhosis and
potentially fatal, and often avoidable. Severe complications from near-normal synthetic function will have impaired drug
analgesia in these patients include hepatic encephalopathy, hepa-
torenal syndrome, and gastrointestinal bleeding, which can result
metabolism, but to a lesser extent than will patients with
in substantial morbidity and even death. In general, acetamino- abnormal synthetic function or decompensated cirrhosis.
phen at reduced dosing is a safe option. In patients with cirrhosis, Decompensated cirrhosis can be a result of progressive
nonsteroidal anti-inflammatory drugs should be avoided to avert
renal failure, and opiates should be avoided or used sparingly, with
liver dysfunction, worsened portal hypertension, or both.
low and infrequent dosing, to prevent encephalopathy. For this Such patients may have even greater restrictions on analge-
review, we searched the available literature using PubMed and sic choice. This article pertains to all patients with cirrhosis
MEDLINE with no limits.
(compensated or decompensated) and to patients with liver
Mayo Clin Proc. 2010;85(5):451-458 dysfunction (with elevated bilirubin levels and prothrom-
bin time), whether they do or do not have cirrhosis.
OTCA = over-the-counter analgesic; COX-2 = cyclooxygenase 2; CYP = The efficiency of drug removal by the liver relies on he-
cytochrome P450; FDA = Food and Drug Administration; GFR = glo- patic blood flow, hepatic enzyme capacity, and plasma pro-
merular filtration rate; HCV = hepatitis C virus; NAPQI = N-acetyl-p-ben-
zoquinone imine; NSAID = nonsteroidal anti-inflammatory drug; TCA = tein binding. Cirrhosis affects all these processes and may
tricyclic antidepressant also lead to formation of portosystemic shunts by which a
drug can circumnavigate hepatic elimination.2,4 Advanced
liver disease and cirrhosis alter the metabolism and effects
C irrhosis is a substantial public health problem, ac-
counting for approximately 770,000 deaths annually
and, according to autopsy studies, affecting 4.5% to 9.5%
of many drugs through a variety of mechanisms, including
changes in pharmacokinetic behavior, altered accumula-
of the global population.1 Pain management in patients tion of free drug in plasma, and end-organ response.
with cirrhosis generates considerable misconception and Major categories of pain medications, including over-
apprehension among health care professionals. In patients the-counter analgesics (OTCAs) such as acetaminophen
with end-stage liver disease, adverse events from analge- and nonsteroidal anti-inflammatory drugs (NSAIDs), as
sics are frequent and can be severe. The most important well as cyclooxygenase 2 (COX-2) inhibitors, anticonvul-
and concerning complications include hepatic encepha- sants, antidepressants, and opioids, are largely metabolized
lopathy, acute renal failure, and gastrointestinal bleeding, by the liver. Unfortunately, there are no endogenous mark-
which can lead to death in some patients. This article is a ers for hepatic clearance that can be used as a guide for drug
review (not a systematic review) of the available literature dosing, nor are there readily available tests to accurately es-
(using PubMed and MEDLINE with no search limits). timate the extent of residual liver function. Moreover, there
The greater the progression of liver dysfunction, the is a paucity of high-quality, prospective data that examine
greater the impairment in drug metabolism.2,3 Patients with the pharmacology and adverse effect profile of many anal-
asymptomatic chronic liver disease without cirrhosis do gesics in patients with advanced liver dysfunction.
not have liver dysfunction, and thus analgesic metabolism Drug metabolism in general occurs in the liver via 3
is similar to that in the general population. In patients with mechanisms: (1) oxidation, reduction, or hydrolysis reac-
severe liver disease but not cirrhosis (eg, severe hepatitis), tions of the hepatic cytochrome P450 (CYP) enzyme sys-
tem; (2) conjugation to glucuronic acid, sulfate, acetate,
From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, glycine, glutathione, or a methyl group; and (3) biliary
MN. Dr Chandok is now with the University of Western Ontario, London, excretion and elimination.3,5 The pharmacokinetics of an-
Ontario, Canada.
algesic medications rely heavily on liver and renal func-
An earlier version of this article appeared Online First.
tion. Drugs with high hepatic extraction (or first-pass
Individual reprints of this article are not available. Address correspondence to
Kymberly D. S. Watt, MD, Division of Gastroenterology and Hepatology, Mayo metabolism), such as morphine or fentanyl, have low bio-
Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). availability in healthy people but higher bioavailability in
© 2010 Mayo Foundation for Medical Education and Research cirrhotic patients. For drugs with a low hepatic extraction,

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PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

TABLE 1. Analgesic Medications and Their Routes of Excretion and albumin concentrations. If a drug is highly protein
Medication Route of excretion bound, a low albumin level can result in increased levels
of free drug and consequent increased adverse effects and
Acetaminophen Renal Renal: 85%
Aspirin Renal/other Renal: 5.6%-35.6%
toxicity.2 In patients with severe cholestasis, the clearance
Tears: salicylate detectable in tears of drugs with high biliary elimination, such as buprenor-
Codeine Renal/other Renal: 90% phine, may also be compromised because of dysfunction of
Fecal: 10%
Fentanyl Renal/other Renal: 75% metabolites
basolateral and/or apical transmembrane transport systems
Fecal: 9% primarily as metabolites in hepatocytes, requiring dose reduction or avoidance of
Hydrocodone Renal Renal: 26% use of the drug.4,6,7
Hydromorphone Renal Renal: 1.3%-13.2% unchanged,
22%-51% conjugated
Dosing of analgesic drugs with a predominant renal
Meperidine Renal/other Renal: 0.5%-5.2% unchanged, elimination may require adjustment in patients with liver
0.6%-21% active metabolite disease (Table 1). Cirrhotic patients often have impaired
Saliva: higher concentrations in
saliva than blood after IM injection
renal function despite a normal serum creatinine level be-
Methadone Biliary/renal/ Biliary: detectable in the bile cause of poor nutrition and reduced muscle mass resulting
other Renal: 21% unchanged in less creatinine production. Therefore, in cirrhotic pa-
Fecal: metabolites and conjugated
metabolites
tients, creatinine clearance should be measured or calcu-
Morphine Renal/other Renal: 90% lated using the Cockcroft and Gault equation to better esti-
Fecal: 7%-10% mate the dosing of analgesic drugs that have preponderant
Oxycodone Renal Renal: primarily
Propoxyphene Renal Renal: 20%-25%
renal elimination.2,8 Because the creatinine clearance tends
Tramadol Renal Renal: 60% as metabolite to overestimate the glomerular filtration rate (GFR) in cir-
NSAIDs rhotic patients, the dose of a given drug may still need to
Celecoxib Renal/other Renal: 27%
Fecal: 57%
be reduced. Unfortunately, criterion standard tests to esti-
Diclofenac Biliary/renal Biliary: 35% mate GFR, such as inulin or iothalamate clearance, are not
Renal: 65% as conjugated widely available, and their accuracy in this patient popula-
metabolites
Fenoprofen Renal/other Renal: 90%
tion is unknown.
Fecal: small percentage
Etodolac Renal/other Renal: 72%
Fecal: 16% OTCA MEDICATIONS
Ibuprofen Renal Renal: primary route, inactive
metabolites excreted Over-the-counter analgesics, principally acetaminophen
Indomethacin Biliary/renal/ Biliary: moderate due to entero- and NSAIDs, are commonly used medications worldwide.
other hepatic recirculation
Renal: 60%
Guidelines for the use of OTCAs in patients with chronic
Fecal: 33% liver disease are not readily available despite the possibility
Ketoprofen Biliary/renal Biliary: up to 40% due to entero- that such patients may be more susceptible to adverse reac-
hepatic recirculation (amount
increases with renal impairment)
tions. Patients are often counseled to modify use of these
Renal: 80% drugs. Health care professionals frequently recommend
Ketorolac Renal/other Renal: 92% avoidance of the use of acetaminophen in patients with
Fecal: 5.9%-6.3%
Meloxicam Billiary/renal/ Biliary: significant excretion
liver disease or cirrhosis, whereas NSAIDs are more com-
other Renal: 19% monly endorsed.9 Variability and misconception regarding
Fecal: 1.6% the safety of OTCAs for patients with hepatic dysfunction
Naproxen Renal Renal: 95%
Sulindac Renal/other Renal: 50%
are widespread among health care professionals.
Fecal: 25%
IM = intramuscular; NSAID = nonsteroidal anti-inflammatory drug.
ACETAMINOPHEN
Acetaminophen is the most common cause of fulminant he-
patic failure in the United States, creating the perception that
such as methadone, liver disease does not impact bioavail- it may be dangerous in patients with chronic liver disease.9-11
ability, but hepatic clearance may be altered substantially. Moreover, concern is increasing regarding the safety of acet-
The ability to clear drug metabolites decreases with liver aminophen at a maximal dosage of 4 g/d in the general popu-
dysfunction, resulting in altered parent drug or metabolite lation. Surveillance data from the United States from 1990 to
bioavailability and increased toxicity in cirrhotic patients. 1998 estimated 56,000 emergency department visits, 26,000
Thus, if such drugs are administered to cirrhotic patients, hospitalizations, and 458 deaths per annum because of acet-
the dose should be reduced and/or the drug used less fre- aminophen overdoses.12 When one considers that 28 billion
quently.2 Cirrhotic patients often have low serum protein doses of products containing acetaminophen were consumed

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 PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

Acetaminophen
Glucuronidation Cytochrome P450
and sulfation 90% 5% (CYP2E1, CYP1A3,
CYP3A4)
5%

Glucuronide and Reactive

sulfate metabolites metabolite

Glutathione No glutathione

Renal Mercapuric acid and Hepatotoxic

excretion cysteine conjugates NAPQI

FIGURE 1. Acetaminophen metabolism. At therapeutic doses, 90% of acetaminophen is metabolized

to glucuronide and sulfate compounds and ultimately excreted via the renal system. Of the remain-
ing acetaminophen, 50% is excreted unchanged in the urine, and the remainder is metabolized by
the cytochrome P450 system; a hepatotoxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), is
subsequently produced. Hepatic glutathione conjugates with NAPQI to produce nontoxic metabolites
that are renally excreted. With a toxic ingestion of acetaminophen, the glucuronidation and sulfation
pathways become overwhelmed, and glutathione stores diminish, resulting in hepatocyte necrosis
due to NAPQI.

in 2005 alone,13 the probability of an individual patient with- patients with cirrhosis. In such patients, the half-life of oral
out preexisting liver disease or concomitant alcohol con- acetaminophen is double that in healthy controls, but he-
sumption developing clinically important hepatotoxicity or patic injury and renal injury are rare when the dosage is
nephrotoxicity when acetaminophen dosing is limited to less limited to less than 4 g/d.5,22 This assumption is supported
than 4 g/d is exceedingly rare.13-16 However, liver failure can by a double-blind, 2-period crossover study of 20 patients
occur with a 1-time ingestion of high doses of acetaminophen with chronic stable liver disease (8 with cirrhosis), who
(>12 g in an adult or 250 mg/kg in a child).17,18 Case reports tolerated acetaminophen at a dosage of 4 g/d for 13 days
have demonstrated that long-term ingestion (often acciden- without adverse effects.23
tal) of supratherapeutic doses (>4 g/d) of acetaminophen in The prevailing mechanism of acetaminophen-induced
patients without known liver disease, and therapeutic doses hepatotoxicity includes altered metabolism via CYP activity
in alcoholic patients without cirrhosis, resulted in acute liver in combination with depleted glutathione stores that cause
failure.19-21 To address the fact that approximately half of all accumulation of a hepatotoxic intermediate, N-acetyl-Q-
cases of acetaminophen-induced acute liver failure are due benzoquinone imine (NAPQI) (Figure 1). Studies in patients
to unintentional overdosing,11 advisory committees to the with cirrhosis have shown that CYP activity is not increased
Food and Drug Administration (FDA) endorse relabeling of and glutathione stores are not depleted to critical levels in
acetaminophen-containing products to better inform the con- those taking recommended doses of acetaminophen. Gluta-
sumer of the potential for liver injury with supratherapeutic thione stores are variable in patients with and without under-
doses, and while concurrently consuming 3 or more alcoholic lying liver disease but generally have not been found to be
drinks per day. In addition, the advisory committees support depleted in cirrhotic patients.14 On the basis of these data, the
lowering the maximal dosage of acetaminophen to 2600 longer half-life, and very limited clinical studies, our recom-
mg/d and eliminating or reducing the availability of combina- mendation (expert opinion) for long-term acetaminophen use
tion analgesics, most commonly combinations of opioid with (>14 days) in cirrhotic patients (not actively drinking alco-
acetaminophen.13 Opiates can be addictive, and patients may hol) is for reduced dosing at 2 to 3 g/d.14 For short-term use
develop tolerance to these agents, necessitating dose escala- or 1-time dosing, 3 to 4 g appears safe; however, with the
tion and thereby increasing the risk of acetaminophen toxic- new FDA guidelines in mind, a maximum dosage of 2 to 3 g/d
ity. These recommendations have not yet been instituted. is recommended.
Unfortunately, no prospective, long-term studies have Glutathione is predictably depleted in the setting of
assessed the safety of long-term use of acetaminophen in long-term alcohol consumption or malnutrition.14,15,21 Alco-

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PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

hol itself, its main metabolite acetaldehyde, and a malnour- perfusion, reduction in GFR, and marked sodium retention.
ished state also deplete the antioxidant reserve, rendering Cirrhotic patients require prostaglandins to counteract the
alcoholic patients more susceptible to drug-induced liver renin-angiotensin-aldosterone and sympathetic systems
injury. In addition, long-term alcohol ingestion induces that reduce perfusion to the kidneys.30 Hepatorenal syn-
CYP2E1, the major enzyme responsible for the metabolism drome is a dreaded and frequently fatal complication of
of acetaminophen to its toxic metabolite NAPQI24 (Figure advanced liver disease.
1). Hence, the population at modestly higher risk of toxic- NSAIDs can cause mucosal bleeding in patients at in-
ity with long-term supratherapeutic dosing of acetamino- creased risk of bleeding as a result of thrombocytopenia
phen is the chronic alcoholic or malnourished patient, but and coagulopathy associated with advanced liver disease.
no prospective studies exist in these patient populations. This risk is even greater in patients with portal hyperten-
Toxicity has been seen in alcoholic patients taking greater sion–related complications, such as esophageal/gastric var-
than 4 g/d of acetaminophen.25,26 A randomized controlled ices and portal hypertensive gastropathy or gastric antral
trial of 4 g/d of acetaminophen for 10 days in patients con- vacular ectasias.31 NSAIDs may be tolerated in patients with
suming daily alcohol (defined as 1-3 drinks per day) sug- mild chronic liver disease, but they should be avoided in all
gested no significant toxicity after up to 10 days of use, but patients with cirrhosis because of the increased risk of hepa-
a small increase in liver enzymes (8 IU/mL) was observed, torenal syndrome and the dire consequences relating to this
the clinical importance of which is unclear.27 A study of al- complication.30 Preventive medicine, including avoidance of
cohol-dependent patients (defined as >6 drinks per day for NSAIDs, is exceedingly important in maintaining the clini-
>6 weeks) admitted to a chemical detoxification unit who cal stability of patients with well-compensated cirrhosis.
were receiving 4 g/d of acetaminophen for 3 days during No prospective studies have assessed the safety and ef-
the immediate withdrawal period showed no evidence of ficacy of COX-2 inhibitors in the management of chronic
toxicity.28 A systematic review of methodologically sound pain in patients with cirrhosis. Studies comparing NSAIDs
short-term studies suggested that the use of therapeutic with COX-2 inhibitors in patients without underlying liver
dosing of acetaminophen in patients with chronic alcohol- disease have demonstrated similar effectiveness in the treat-
ism has not been associated with liver injury, but no studies ment of musculoskeletal pain.32,33 Although some COX-2
of longer-term therapy have been performed.15 Thus, less inhibitors may protect against gastrointestinal hemorrhage
than 4 g/d of acetaminophen appears safe for short-term compared with NSAIDs, an increased risk of cardiovas-
dosing in patients with mild to moderate alcohol intake, cular adverse events has been observed. Cyclooxygenases
but most hepatologists (written communication, expert are highly regulated in response to changes in intravascular
opinion: see end of article for list of sources) advocate for volume, and COX-2 is implicated in the mediation of renin
lower dosing at 2 g or less per day, given the small margin release, sodium regulation, and the maintenance of renal
for error in a nonstudy population. Data do not exist for blood flow. COX-2 inhibitors may reduce portal pressure in
long-term acetaminophen use in patients with active alco- cirrhotic patients, but pilot data suggest a decreased GFR
hol use. Multiple hepatologists agree that 2 g or less per in patients with cirrhosis and ascites treated with celecox-
day of acetaminophen would be recommended for these ib.34 The safety of COX-2 inhibitors needs further study in
patients (written communication, expert opinion). Care- patients with cirrhosis.
ful follow-up of these patients is recommended. Patients
who have underlying alcohol-related liver disease but have OPIOID ANALGESICS
prolonged abstinence and are nutritionally replete can be Like anti-inflammatory medications, opioids can have del-
treated similarly to other cirrhotic patients. eterious effects in patients with cirrhosis. Although large
epidemiological studies are lacking, sedatives and opioids
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS are common precipitants of hepatic encephalopathy and
NSAIDs as a class are largely metabolized by CYPs, and hospitalization, and thus they should be avoided in patients
most are heavily protein bound. As such, altered metabo- with cirrhosis, especially in those with portal hypertension
lism and bioavailability that result in increased serum lev- and encephalopathy.22 The liver is the main site of metabo-
els can be anticipated in the cirrhotic patient.29 NSAID- lism for most opioids. The major metabolic pathways for
induced (and idiosyncratic) hepatotoxicity has also been most opioids are oxidation via the CYP system (CYP2D6
well described.9 However, in cirrhotic patients with por- and 3A4) or glucuronidation; both processes can be im-
tal hypertension, the greater concern with NSAID use is paired in the setting of end-stage liver disease, although
the associated renal impairment, in particular hepatorenal the CYP more so.2,3 Not only is the CYP system affected
syndrome. This is thought to be due to the inhibition of by liver dysfunction, but also it can be affected by malnu-
prostaglandins, which leads to a profound decrease in renal trition and suboptimal protein consumption, common is-

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 PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

TABLE 2. Opioid Analgesic Metabolism

Protein
Half-life binding Hepatic
Drug (h) (%) metabolism Special note
Codeine 4-6 7 CYP2D6 Metabolized to morphine in liver; ceiling effect; serum levels unpredictable
Morphine 3-12 35 Glucuronidation Metabolite increases toxicity in patients with renal failure; adjust dose in these
patients
Meperidine 2-4 70 CYP2B6, 3A4 Avoid in patients with renal failure; increased bioavailability of CNS active
metabolite (t½ = 15-30 h) in patients with renal/liver disease; avoid in
patients with liver impairment
Hydromorphone 1-3 15 Glucuronidation Consider dose reduction in patients with liver impairment; safe to use in those
with renal failure
Hydrocodone 3-4 7 CYP2D6 Active metabolite is hydromorphone
Fentanyl IV, 1-3 80 CYP3A4 Lipid soluble: stores in fat and muscle; continuous infusion = prolonged
patch 17 sedation; less histamine release, less hemodynamic disturbance
Oxycodone 2-12 45 CYP3A4, 2D6 Multiple metabolite levels unpredictable; reduce dose and frequency in patients
with liver impairment
Tramadol 7 20 CYP3A4, 2D6, and Reduce dose and frequency in patients with renal and liver impairment
glucuronidation
Methadone 8-24 80 CYP3A4, 2D6, Consider dose reduction; equivalence ratios to methadone are dose-dependent
several others (may range from 1:1 to 20:1)—cautious dose titration
CNS = central nervous system; CYP = cytochrome P450; IV = intravenous.

sues in cirrhotic patients. Although there are phenotypic dosing in patients with cirrhosis, the metabolism of these
variations of CYP2D6 in the general population, data are agents does not yield toxic metabolites, and hence they,
inconclusive on how CYP isoenzymes are affected by cir- along with hydromorphone, may be better tolerated37,38
rhosis.4 As a result, patients with cirrhosis have decreased (Table 2).
drug clearance and/or increased oral bioavailability, lead- Patients with cirrhosis have a high prevalence of and
ing to drug accumulation in the body, especially with re- increased likelihood for renal dysfunction. This is relevant
peated administration. to the risk of adverse drug events in these patients because
Glucuronidation is thought to be less affected by cirrho- renal function has a significant impact on the toxicity of
sis,2 but studies have consistently shown that the half-life several opioids. Most opioids require adjustment of dose
of morphine, for instance, is prolonged in patients with cir- based on GFR. With morphine, although metabolized
rhosis. Compared with healthy controls, in cirrhotic patients largely by glucuronidation, the resulting metabolite has
the half-life of morphine is approximately double (3 to 4 vs central nervous system toxicity and is poorly excreted in
1.5 to 2 hours), which is attributable to a reduction in total the setting of renal insufficiency. Hence, dose reduction or
body clearance4,35 (Table 2). Similarly, other opioids have avoidance of morphine in cirrhotic patients would be pru-
also been shown to have increased bioavailability and pro- dent. Hydromorphone and fentanyl appear to be the least
longed half-life.36 Codeine is another frequently prescribed affected by renal dysfunction, and fentanyl has less hemo-
opioid in patients with cirrhosis. The analgesic effect from dynamic disturbance (due to lack of histamine release as-
codeine is presumed to be secondary to its conversion to sociated with other opioids).39
morphine via CYP2D6; thus, in patients with cirrhosis, Tramadol is another opiate occasionally used in low
serum levels can be even more variable. Similarly, hydro- doses in patients with cirrhosis who are experiencing in-
codone and oxycodone are metabolized to hydromorphone tractable pain because of its impact on peripheral pain
and oxymorphone via CYP2D6 and CYP3A4, which may pathways, partial inhibition of serotonin reuptake, and low
also result in variability in serum levels. Ineffective drug affinity for opioid receptors, thought to result in less se-
metabolism in this patient population can also lead to de- dation, respiratory depression, and potential for tolerance;
creased analgesic action of these medications.2,4 Meperi- however, constipation can still be problematic because of
dine is metabolized largely by CYP2B6 and CYP3A4 to anticholinergic adverse effects.40 Caution should be exer-
normeperidine, a metabolite with serious central nervous cised in administering tramadol to epileptic patients be-
system toxicity, particularly in the setting of concomitant cause this drug is known to lower the seizure threshold. In
renal dysfunction.36 Meperidine should be avoided in pa- addition, tramadol should not be combined with drugs such
tients with liver dysfunction because of the increased bio- as morphine, selective serotonin reuptake inhibitors, tricy-
availability (heavily protein bound) and prolonged half-life clic antidepressants (TCAs), or anticonvulsants because it
of its toxic metabolite.36 Although methadone and fentanyl can precipitate serotonin syndrome.41 Doses may need to
are also heavily protein bound and as such require reduced be reduced in patients with renal failure.

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PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

If opiates are required for pain control, lower doses and/ minish chronic pain by blocking presynaptic serotonin and/
or longer intervals between doses are needed to minimize or noradrenalin reuptake in neurons involved in pain trans-
risks.4,40 Hydromorphone and fentanyl may be the better mission or dampened endogenous opioid systems.46 Tricy-
choices. Careful follow-up is required to check for signs clic antidepressants rely on hepatic biotransformation with
of sedation, constipation (a risk for precipitating encepha- first-pass effects (via CYP2D6 largely) and renal elimina-
lopathy), and early encephalopathy. Any sign of these com- tion. Health care professionals should start a TCA at a low
plications necessitates immediate discontinuation of the dose because these agents are sedating, and patients may
opiate. be more susceptible to the anticholinergic adverse effects,
Health care practitioners should be prudent in not using including dry mouth, blurry vision, drowsiness, tachycar-
potentially addictive substances like opioids in cirrhotic pa- dia, and orthostatic hypotension due to altered metabolism
tients with a history of alcoholism because of increased risk in the setting of liver dysfunction. The clinician and patient
of cross-addiction.42 For many transplant programs, ongo- must be particularly watchful for intestinal stasis as an ad-
ing opioid use in such patients may be a contraindication verse effect of a TCA because this can precipitate hepatic
to liver transplant because opioid dependency is widely be- encephalopathy. If TCAs are deemed necessary, nortrip-
lieved to predict alcohol recidivism, and discussion with tyline and desipramine are less potent and appear to be less
the transplant program is advised before initiating these sedating than other TCAs. Additionally, nortriptyline and
drugs.42 desipramine may have less tachycardia and hypotension
Polysubstance abuse treated with methadone mainte- associated with their use than older and more potent TCAs,
nance is particularly common among patients with chronic particularly amitriptyline and doxepin.45
liver disease from hepatitis C virus (HCV). The prevalence Anticonvulsants such as carbamazepine or gabapentin
of anti-HCV antibodies is as high as 67% to 96% among also have an established role in neuropathic pain manage-
patients in methadone programs.43 Methadone is well-ab- ment. The rationale for their use is that neuropathic pain
sorbed from the gastrointestinal tract and has high oral bio- presumably involves an imbalance of excitatory and inhibi-
availability, corresponding with low hepatic extraction. It tory neurotransmitters, and anticonvulsants may modulate
undergoes considerable biotransformation in the liver. Al- peripheral and central components of neurotransmission
though no prospective studies have assessed the safety of to correct this imbalance and thus diminish pain.46 Most
methadone in patients with hepatic dysfunction, 11 patients anticonvulsants are metabolized by the liver (via CYPs)
with alcoholic cirrhosis were noted to have disposition pa- and excreted by the renal system, once again necessitat-
rameters similar to those in healthy participants, suggesting ing lower and less frequent dosing in cirrhotic patients.
that usual methadone maintenance dosages are likely safe Carbamazepine has been reported to cause hepatotoxicity
in patients with advanced liver disease.4,38 Nevertheless, in the general population; it may precipitate a rapid dete-
avoidance of methadone in patients actively consuming rioration in cirrhotic patients and thus should be avoided.46
alcohol is advisable because alcohol inhibits the metabo- Gabapentin is unique among many anticonvulsants be-
lism of methadone, leading to elevated plasma methadone cause it is not metabolized by the liver or bound to plasma
concentrations.38 Patients who take methadone for heroin proteins, making it a preferred anticonvulsant in patients
addiction have a similar rate of treatment response to anti- with cirrhosis. However, the general use of gabapentin in
HCV therapy and, more importantly, a decreased likeli- patients with cirrhosis may be limited by other potential
hood of heroin use. For patients with chronic liver disease adverse effects, including sedation, nausea, and dizziness.
in the absence of active alcoholism, no absolute contraindi- Doses should be adjusted for renal failure because gaba-
cations exist, and the benefits of methadone maintenance to pentin is renally excreted.
achieve abstinence from heroin would likely outweigh the Pregabalin is another anticonvulsant shown to be effec-
potential risks.43,44 tive for neuropathic pain; its mechanism of action is as a
potent ligand for the α-2-δ subunit of voltage-gated cal-
OTHER ANALGESICS cium channels in the central nervous system.46 Like gaba-
Not infrequently, patients with cirrhosis experience neuro- pentin, it is not subject to hepatic metabolism and hence
pathic pain due to neuropathies from a variety of causes, may be an appealing agent of choice in cirrhotic patients
including diabetes, alcoholism, nutrient deficiencies, and with neuropathic pain. A recent case report from Sweden
cryoglobulinemia. Tricyclic antidepressants such as ami- determined that pregabalin was a probable cause of acute
triptyline and imipramine have been the mainstay treatment liver failure in a 61-year-old healthy man with no previ-
of neuropathic pain for decades, although their use in this ous liver disease.47 Although this may have been an idio-
capacity is off-label.45,46 The exact mechanism of antineu- syncratic event because no further case reports have been
ralgic action of these agents is unknown, but they may di- published in the literature, clinicians must be mindful of

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 PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

Pain

Visceral or
Neuropathic
musculoskeletal

Acetaminophen, ≤2-3 g/d Nortriptyline, 10 mg orally at night

or
Desipramine, 10 mg orally at night
or/and
Gapapentin, 300 mg orally daily
or
Tramadol, 25 mg every 8 h
Pregabalin, 150 mg orally twice daily
and
Acetaminophen, ≤2-3 g/d

For intractable pain, consider:

Hydromorphone, 1 mg orally every 4 h
or
Fentanyl, 12.5
g topically every 72 h

Do not combine these agents with tramadol

FIGURE 2. A pharmacological approach to analgesia in patients with cirrhosis who have no renal failure,
active alcoholism, or active substance abuse. Starting doses are used unless otherwise indicated. Doses
should be carefully titrated as tolerated. Minimize total acetaminophen to less than or equal to 2 to 3 g/d.
Avoid polypharmacy and monitor for adverse drug events.

the increased risk of drug-induced liver injury in patients gesic options may vary depending on a number of factors,
with underlying liver disease. such as nutritional status, adherence, renal function, and
liver transplant candidacy.
SUMMARY
CONCLUSION
No evidence-based guidelines exist on the use of analge-
sics in patients with liver disease and cirrhosis. This review In general, our recommendation (expert opinion) for long-
underscores the paucity of prospective studies that have term acetaminophen use in cirrhotic patients (not actively
assessed the safety of various analgesics in patients with drinking alcohol) is for reduced dosing at 2 to 3 g/d.14
advanced hepatic dysfunction. It has been an unspoken For short-term use or 1-time dosing, 3 to 4 g/d appears to
standard of practice by hepatologists alike to err on the be safe; however, with the new FDA recommendations, a
side of caution, recommending 2 to 3 g/d of acetamino- maximum dosage of 2 to 3 g/d is recommended. NSAIDs
phen. Because the FDA may recommend limiting acet- and opioids may be used at reduced doses in patients with
aminophen to a maximum daily dosage of 2.6 g, we have chronic liver disease without cirrhosis. Patients with cir-
provided a uniform recommendation and a practical guide rhosis have fewer analgesic options. NSAIDs should be
to approaching analgesia in the cirrhotic patient (Figure avoided in those with both compensated and decompen-
2), which has been reviewed and agreed on by hepatolo- sated cirrhosis, primarily because of the risk of acute re-
gists within our group practices (unpublished survey of nal failure due to prostaglandin inhibition. Opiates should
10 hepatologists). An important caveat is that the care of be avoided or used sparingly at low and infrequent doses
patients with cirrhosis must be individualized, and anal- because of the risk of precipitating hepatic encephalopa-

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PAIN MANAGEMENT IN THE CIRRHOTIC PATIENT

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