Introduction
Pain in patients with chronic liver disease (CLD) is common, and its causes are usually similar to those in the general population. A higher prevalence of pain (40-79%) is observed in patients with liver cirrhosis, particularly nociceptive pain (from tissue damage, e.g., muscle cramping, abdominal distension, hepatocellular cancer, spontaneous bacterial peritonitis, osteoarthrosis) and neuropathic pain (from nervous system damage, e.g., toxic neuropathy, diabetic neuropathy). Pain often has a mixed character with a nociplastic component (from central sensitization, e.g., disorders of the brain-gut interaction). Chronic pain negatively impacts functional status and quality of life. Treatment should focus not only on improving pain control but also on patient safety [1].
The liver plays a key role in the metabolism of most analgesic drugs. In phase 1, reactions are mediated by cytochrome P450, which includes oxidation, reduction, and hydrolysis. Phase 2 involves conjugative reactions [2]. High variability in genes involved in drug absorption, distribution, metabolism, and elimination can affect the pharmacokinetic profile, the response to the drug, its action at the target site, and beyond. This is compounded by changes in genes that modulate pharmacodynamics [1].
Adverse drug reactions (ADRs) are a significant problem in hepatology practice [1]. Drugs can affect liver function directly or by changing liver blood flow [2]. The response to drugs and the risk of ADRs depend on many factors, such as sex, age, weight, hormones, genetic factors, chronic diseases, pregnancy, renal, and liver function. The situation is complicated by the widespread coadministration of drugs (including over-the-counter drugs), the use of supplements, and stimulants. This makes the potential effects of drugs unpredictable [1].
Drug-induced liver injury (DILI) is an important cause of morbidity and hospitalization. The magnitude of this phenomenon is difficult to determine due to varied clinical phenotypes, a lack of specific biomarkers, and the similarity of its course to other liver disorders. Many drugs, including analgesics, have hepatotoxic potential. Although the prognosis of DILI is generally good, some cases may develop into acute liver failure or chronic disease [3]. Significant factors for a worse prognosis include pre-existing liver disease (especially cirrhosis), the onset of jaundice, and hepatocellular damage with high aminotransferase activity. Among analgesics, DILI is most often caused by nonsteroidal anti-inflammatory drugs (NSAIDs), particularly ibuprofen and diclofenac [3-5].
Liver diseases affect the function of specific metabolizing enzymes differently. Unfortunately, no markers are available to predict the impact of the degree of liver dysfunction on drug metabolism and effects. Mild diseases usually do not affect drug metabolism. In cirrhosis, however, there is a significant decrease in the metabolic activity of all cytochrome P450 isoforms, although glucuronidation remains largely preserved due to extra-hepatic glucuronidation and upregulation of uridine diphosphate-glucuronyltransferase in remaining hepatocytes [6-8].
Drug metabolism depends on liver enzyme efficiency, liver blood flow, and binding by plasma proteins. Decreased hepatic blood flow and portosystemic shunting reduce first-pass metabolism and drug clearance, increasing bioavailability after oral administration, leading to prolonged half-life, accumulation of toxic metabolites, and increased risk of adverse effects [8, 9]. A decrease in serum binding proteins results in an increase in the amount of free drug that can accumulate in tissues, which translates into an increased volume of distribution and prolonged half-life. Renal failure accompanying cirrhosis further increases the risk of ADRs by increasing serum drug concentrations [2, 7]. Additionally, biliary excretion of drugs and metabolites is decreased in cholestatic liver diseases and biliary obstruction. Secondary hepatocellular damage that occurs may also reduce CYP450 isoenzyme activity [10].
Numerous factors affecting the efficacy and side effects of analgesics mean that the treatment of pain in patients with liver dysfunction or failure needs to be rationalized and individualized in terms of drug selection, dosing, and route of administration [2, 8]. This study reviews the safety of commonly used analgesics for the relief of mild and moderate nociceptive pain in patients with chronic liver diseases.
Paracetamol
Paracetamol (acetaminophen) is one of the most commonly used analgesic and antipyretic drugs. It is available over the counter (OTC) in most countries. Its central inhibition of prostaglandin synthesis affects body temperature, while its analgesic effect may also result from the activation of descending serotonergic pathways [11, 12].
Using paracetamol at the standard therapeutic dose (4 g/day) is safe and effective. Despite its widespread use, it has a narrower margin of safety compared to other OTC analgesics. Overdose, even from a dose of 10 g per day, can lead to severe liver damage and death [12, 13]. Paracetamol is responsible for approximately 7.3% of DILI cases, with the highest percentage in the United States (around 30%). Of the DILI cases associated with paracetamol, 2-5% involve liver failure, with 0.2-0.5% resulting in fatalities [12]. Nearly half of paracetamol overdose cases are unintentional and occur when using a single-tablet regimen in combination with opioids for pain relief [14].
The bioavailability of paracetamol is excellent – almost the entire dose is absorbed from the gastrointestinal tract, and binding to plasma proteins is low. Approximately 70% of paracetamol is metabolized in the liver through glucuronidation and 30% through sulfation, with the metabolites being eliminated by the kidneys. Under normal conditions, only a negligible amount of the drug is metabolized by cytochrome P450 (primarily CYP2E1), resulting in the formation of a potentially toxic compound, N-acetyl-p-benzoquinone imine (NAPQI), which is quickly neutralized by glutathione and excreted without harm to the body [12, 13]. In certain conditions, such as acute and chronic liver diseases, alcoholism, severe malnutrition, and the use of drugs that induce cytochrome P450 (e.g., rifampicin, isoniazid, phenobarbital, carbamazepine, corticosteroids, omeprazole, phenytoin, and St. John’s wort), hepatocyte damage may occur through excessive activation of cytochrome P450 and glutathione deficiency [12, 13, 15].
Acetaminophen overdose leads to a rapid increase in NAPQI concentration, forming protein adducts that are crucial in causing hepatocyte damage. Hepatocellular necrosis induced by paracetamol overdose primarily affects cells surrounding the central vein in the hepatic lobules [16]. This process results from various forms of programmed cell death, including necrosis (dominant), apoptosis, ferroptosis, and pyroptosis [17]. Residual hepatic macrophages (Kupffer cells) and peripheral neutrophils are involved in removing dead hepatocytes through a sterile inflammatory response. Although generally beneficial, this process can exacerbate liver damage and increase liver failure in cases of significant overdose [12, 17].
The clinical picture of acute paracetamol overdose depends on the dose taken. Severe cases may present with nausea, vomiting, and abdominal pain. Laboratory tests show hyperbilirubinemia and a significant increase in aminotransferase activity within 8 hours of drug intake [12, 15]. Paracetamol poisoning may also cause acute kidney injury, with nephrotoxicity resulting from renal tubular necrosis caused by NAPQI or the development of hepatorenal syndrome [12]. It is important to note that renal failure from hepatorenal syndrome affects the metabolism and elimination of drugs excreted by the kidneys, including paracetamol [6].
The safety of paracetamol use in doses < 2 g/day in chronic liver diseases, including liver cirrhosis, has been established [18, 19]. Based on its metabolic profile, paracetamol is the preferred analgesic for patients with liver cirrhosis [6]. This is supported by recommendations from the American Association for the Study of Liver Diseases (AASLD) [20]. The United States Food and Drug Administration’s (FDA) Drug-Induced Liver Injury Rank (DILIrank) classifies paracetamol among the drugs with a confirmed significant association with DILI (most-DILI-concern) [21]. Of note, while paracetamol is effective for treating nociceptive pain, it is not active against neuropathic pain. In treating nociplastic symptoms, it may help relieve peripheral pain symptoms that contribute to central sensitization [1].
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs are a diverse category of medications commonly used in therapy for their analgesic, antipyretic, anti-inflammatory, and antiplatelet effects [22]. The main mechanism of action for all NSAIDs is inhibition of the enzyme cyclooxygenase (COX), which catalyzes the production of local inflammatory mediators, including prostaglandins, leukotrienes, and thromboxanes from arachidonic acid. There are at least two isoforms of COX: COX-1 and COX-2. COX-1 is a constitutive enzyme, meaning it is consistently produced and holds physiological significance. Prostaglandins synthesized by COX-1 contribute to functions such as gastric mucus production, renal perfusion regulation, and thrombocyte aggregation control. Conversely, COX-2 is mainly induced during inflammation by cytokines such as interleukin and tumor necrosis factor alpha. Prostaglandins play a crucial role in the inflammatory response by dilating blood vessels, increasing their permeability, and altering the excitability of nociceptors [22, 23]. Because these drugs share the same primary mechanism of action, using them together in treatment is contraindicated due to the increased risk of side effects without additional clinical benefits. Since many NSAIDs are available as OTC drugs, the risk of self-overuse is high [23].
NSAIDs are classified based on their chemical structure into six main groups: salicylates (e.g., acetylsalicylic acid – ASA), derivatives of acetic acid (e.g., diclofenac), derivatives of propionic acid (e.g., ibuprofen, naproxen), oxicams (e.g., meloxicam), coxibs (e.g., celecoxib), and sulfonanilides (e.g., nimesulide). Other classification criteria include drug activity against the COX-2 isoform (non-selective, preferential, selective) and duration of action. Most NSAIDs are non-selective, while preferential inhibitors include nimesulide and oxicams. Coxibs are selective COX-2 inhibitors. Drugs with a short duration of action (up to 6 hours) include ASA, ibuprofen, ketoprofen, and diclofenac, whereas long-acting drugs include naproxen, celecoxib, and meloxicam [24].
NSAIDs come in multiple forms, including oral, intravenous, intramuscular, rectal, and topical [20]. They are rapidly and efficiently absorbed from the gastrointestinal tract, exhibit a high binding affinity to serum proteins, are predominantly metabolized by cytochrome P450 (mainly CYP2C9), glucuronidated, and mainly excreted via the renal pathway [6, 25].
NSAIDs may have hepatotoxic effects, observed in about 1 to 10 out of 100,000 patients. Liver function in healthy individuals is rarely impaired. The most frequent sign of DILI is asymptomatic elevation of aminotransferase and/or cholestatic enzyme activities. Nevertheless, in patients with pre-existing liver conditions, the risk of organ failure is higher [22, 24]. Although NSAIDs have a relatively low potential for liver toxicity, their extensive usage accounts for approximately 10% of DILI cases [24, 26]. The onset of injury can occur at any phase of treatment, typically emerging within the first 6-12 weeks. Most instances of liver toxicity are idiosyncratic and not related to dosage. The mechanisms behind NSAID-induced liver injury are complex, involving higher drug concentrations in the liver due to impaired elimination, generation of reactive toxic metabolites leading to oxidative stress, covalent binding to proteins impairing their functions, and mitochondrial damage. Seven drugs contribute to 99% of NSAID-related DILI: diclofenac, ibuprofen, sulindac, ASA, naproxen, piroxicam, and nimesulide [24, 26, 27]. Currently available coxibs (celecoxib and etoricoxib) tend to cause fewer cases of DILI compared to other NSAIDs, although data on accurate incidence are limited. However, they are linked to a higher risk of cardiovascular side effects. With celecoxib, there have been published isolated reports of cholestatic hepatitis, while etoricoxib is mostly linked to asymptomatic hypertransaminasemia [28]. Drugs that affect CYP2C9 activity, such as amiodarone, fluconazole, and isoniazid, along with other medications metabolized by this enzyme (e.g., sartans, warfarin, torasemide, clopidogrel), might exacerbate hepatic cell damage by increasing the concentration of NSAIDs or their metabolites [25, 26].
In the setting of liver cirrhosis, notable alterations in drug pharmacokinetics can occur. These include compromised first-pass metabolism, an increased fraction of drugs unbound to proteins, restricted metabolism leading to the accumulation of metabolites, and decreased excretion when NSAIDs are used. These factors significantly elevate drug bioavailability and enhance toxicity [22]. Therefore, NSAIDs are contraindicated in the setting of liver cirrhosis. Although the safety of their topical formulations has not been extensively studied in this patient group, they appear to be safe [20, 25].
NSAIDs have a number of side effects in addition to hepatotoxicity, including nephrotoxicity. The mechanism of NSAIDs through COX inhibition can result in acute kidney injury (AKI) as well as disturbances in sodium and potassium metabolism. This pathway is more relevant in the setting of liver cirrhosis, in which prostaglandins in the kidneys are synthesized in excess to counteract renin-angiotensin-aldosterone and sympathetic system changes. Indomethacin is known to have the highest nephrotoxic potential [6, 29].
As the inhibition of COX-1 suppresses the production of prostaglandins in the stomach, the secretion of protective mucus is reduced. This mucus deficiency allows NSAIDs easier access to the epithelial cells, where they dissociate due to a higher intracellular pH, making their elimination from epithelium more challenging and potentially increasing toxicity. Although most adverse reactions occur in the upper gastrointestinal tract, NSAIDs can also affect the lower gastrointestinal tract through mechanisms such as enterohepatic circulation and bile excretion. Complications associated with NSAID use include dyspeptic symptoms, erosions, ulcers, gastrointestinal bleeding, perforation, lumen narrowing (typically in the small intestine), ileus, enteritis resembling inflammatory bowel disease, and diverticulitis [25, 27]. Side effects from the upper gastrointestinal tract significantly increase with the coexistence of portal hypertension. Ketoprofen has the highest relative risk for upper gastrointestinal bleeding, while ibuprofen has the lowest [29]. Risk factors for gastrointestinal adverse reactions include pre-existing bleeding or ulcers, age over 60 years, high doses or chronic usage of NSAIDs, concurrent use of steroids, antiplatelet and anticoagulant therapies, active Helicobacter pylori infection, and the use of selective serotonin reuptake inhibitors. Coxibs present the least gastrointestinal toxicity; however, their “protective” effect significantly diminishes when combined with ASA therapy [25, 27].
The hepatotoxicity of selected NSAIDs is described in Table 1. The laboratory findings exhibit a hepatocellular pattern with some exceptions. The timeframes for onset and recovery can differ.
Table 1
Metamizole
Metamizole (dipyrone) is a multifunctional drug with analgesic, antipyretic, and spasmolytic effects. According to the European Medicines Agency (EMA), it is indicated for severe, acute, or chronic pain and fever that do not respond to other treatments [30]. While it is a prescription drug in most countries, it is available OTC in Poland, China, Israel, and Russia. Due to its adverse effects, primarily life-threatening agranulocytosis, it has been withdrawn from use in the United States, Canada, Australia, the United Kingdom, and Scandinavian countries [31, 32]. The exact mechanism of action is not fully understood, but it is believed to involve the inhibition of prostaglandin synthesis (similar to COX) and effects on the central (thermoregulatory center) and peripheral nervous systems. The maximum daily dose for oral administration is 4 g divided into 3-4 doses, while for the parenteral route, it is 5 g (the maximum single dose is 2.5 g) [33].
After oral administration, metamizole is almost completely hydrolyzed within the gastrointestinal tract wall to form the first active metabolite, 4-methylaminoantipyrine (4-MAA). The bioavailability of oral preparations is close to 100% [34]. 4-MAA is further metabolized by CYP3A4 in the liver, producing two more metabolites: the active 4-aminoantipyrine (4-AA) and the inactive 4-formylaminoantipyrine (4-FAA) [32, 35]. Plasma protein binding is 58% for 4-MAA and 43% for 4-AA, ensuring both rapid and prolonged action of the drug [33, 35]. Approximately 96% of the dose is excreted in urine [33].
A life-threatening, though rare, side effect of metamizole is agranulocytosis, triggered by drug-dependent autoantibodies directed against neutrophils [36]. This effect is independent of the drug dose, route of administration, or duration of use – most cases of agranulocytosis occur within a week, but it can also manifest after several months [32]. Other common adverse effects include respiratory symptoms (bronchospasm), low blood pressure, cardiac arrhythmias, maculopapular rash, and allergic urticaria [32].
Current knowledge about the hepatotoxicity of metamizole is based on retrospective analyses of individual cases or series; there are no cross-sectional prospective data in this field. Its status has not been determined in the DILIrank database, likely due to the lack of access to the drug in the United States [21]. Various potential mechanisms of hepatotoxicity have been suggested, including allergic-immunological processes and secondary effects due to multi-organ failure [32]. Despite this, metamizole appears to be well tolerated, with a relatively low risk of liver complications compared to other analgesics. A study conducted by Sabate et al. in a group of 126 patients in Barcelona found that metamizole had the lowest risk (relative risk – RR) of acute liver damage (RR = 3.1) compared to paracetamol (RR = 7.0), diclofenac (RR = 7.6), and aspirin (RR = 5.4) [37]. However, an analysis of 154 patients with DILI hospitalized in a single center in Germany showed that metamizole was the second most common cause of this complication in the analyzed group (23 cases, 14.9%) [31]. These discrepancies highlight the need for further research into metamizole as a potential cause of DILI.
In patients with chronic liver diseases, liver metabolism, including that related to metamizole, is reduced. After administration of the drug, lower concentrations of its metabolites are observed in the serum of patients with liver diseases compared to those without, potentially translating to lower drug efficacy [38]. The only study to date evaluating the use of metamizole in patients with decompensated liver cirrhosis showed an elevated, dose-dependent risk of acute kidney injury [39]. It was determined that 10 g of metamizole per week was the threshold for increasing the risk of this complication.
Metamizole is used to relieve pain of various origins, especially spastic symptoms from the gastrointestinal tract, as well as to treat fever that does not respond to other treatments. The drug has a very weak anti-inflammatory mechanism. When combined with paracetamol, morphine, or ketoprofen, a stronger antinociceptive effect is achieved [40].
Tramadol
Tramadol is a weak, centrally acting synthetic opioid that primarily functions as a μ-receptor agonist. It also inhibits serotonin and norepinephrine reuptake. When administered orally, it is rapidly absorbed, reaching a maximum concentration within 2 hours. The bioavailability of the drug is 65-75%, and the protein binding rate is 20%. It is excreted via the kidneys. Tramadol undergoes hepatic metabolism involving the CYP2D6, CYP2B6, and CYP3A4 isoforms of cytochrome P450 [6, 8]. Although the genetic polymorphism of CYP2D6 plays a key role in the pharmacokinetics, efficacy, and toxicity of tramadol, many other genetic factors modify the response to tramadol and are related to metabolism, transport, the body’s response to the drug, and the perception and modulation of the pain response [41-43].
The genetic variability of CYP2D6 translates into four phenotypes: poor metabolizers, intermediate metabolizers, normal metabolizers, and ultra-rapid metabolizers. Poor metabolizers, who have two non-functional alleles, are unable to metabolize or bioactivate drugs in the CYP2D6 pathway (< 10% of the European population), resulting in reduced efficacy. In contrast, ultra-rapid metabolizers are carriers of at least one allele of increased function and have two or more copies of the functional allele on one chromosome, in addition to the normal function allele. Tramadol should be avoided or administered in reduced doses in this group [41-43].
As tramadol and its main metabolite are eliminated metabolically and via the kidneys, the half-life (standard 5-6 hours) may be prolonged in cases of hepatic and/or renal impairment. The prolongation of the elimination half-life is relatively minor as long as one of these organs is functioning properly. In patients with advanced cirrhosis, the elimination half-life of tramadol is prolonged to an average of approximately 13 hours (up to 22 hours), and the renal clearance of unchanged tramadol is additionally increased [44]. It is important to remember that CYP2D6 is the main pathway for the elimination or bioactivation of many centrally acting drugs, including selective serotonin reuptake inhibitors, tricyclic antidepressants, opioids, antiemetics, antiarrhythmics, and antihistamines. In addition to the CYP2D6 isoform, CYP3A4 plays an important role in tramadol metabolism, widening the range of potential drug interactions [7, 45].
Very little is known about the hepatotoxicity of tramadol. According to the DILIrank Dataset, the association between tramadol use and the occurrence of DILI is inconclusive [21]. Available data suggest that a small number of patients may develop self-limiting, mild increases in liver enzyme activity, even without discontinuing the drug, particularly with high doses. Only case reports of chronic inflammation and drug-induced acute liver failure are found in the literature, usually after overdose and in combination with other drugs/toxic substances [46-49]. Potential mechanisms include shock, ischemia, and hypoxia secondary to respiratory failure. Liver damage from tramadol overdose may be accompanied by hyperammonemia, lactic acidosis, and hepatic steatosis, suggesting direct mitochondrial damage. Idiosyncratic cases of liver damage are not observed as long as the correct dosage is adhered to [46].
According to AASLD recommendations, tramadol should be avoided in patients with cirrhosis because of the first-pass effect in the liver; in this group, the drug has variable pharmacokinetics, dose adjustment is difficult, and it causes unpredictable side effects [20]. Reduced and highly individual CYP2D6 efficiency, prolonged half-life, delayed elimination, risk of drug accumulation, serious drug interactions, and doubts about actual pain relief in this patient group dictate the search for alternative drugs, particularly in patients with decompensated cirrhosis, concomitant renal failure, and inadequate response to the drug [8, 44]. However, if no alternative treatment is available, the lowest effective doses should be used, extending the time between doses and avoiding drugs with prolonged therapeutic effects [10]. Additionally, tramadol can cause constipation due to its anticholinergic side effects, which may be associated with a higher risk of bacterial translocation [1, 6].
Codeine
Codeine has opiate-like analgesic effects and is converted to morphine in the liver by the enzyme CYP2D6 [26, 50]. About 10% is demethylated to morphine, and only this part is responsible for the analgesic properties. The drug is 25% protein-bound and is mostly excreted by the kidney. Similar to tramadol, ultra-rapid metabolizers should not receive codeine. It has been approved for use in the United States as an oral analgesic for mild-to-moderate pain. There are multiple products combining codeine with acetaminophen [26].
In animal studies, codeine has been shown to induce hepatic injury via oxido-inflammatory damage and caspase-3-mediated apoptosis [51]. In rats, increased bilirubin concentration and dose-dependent liver enzyme activity were observed [50]. In humans, codeine has not been linked to aminotransferase enzyme elevation during therapy, and there have been no convincing cases of clinically apparent liver injury [26]. According to DILIrank, there is no evidence of codeine hepatotoxicity [21]. If necessary, codeine can be used in patients with CLD without cirrhosis. According to AASLD recommendations, codeine should generally be avoided in patients with cirrhosis. Caution should be taken in dosing due to slow clearance, which may cause drug accumulation, prolonged half-life, and increased risk of respiratory depression. In this group, the analgesic effect is variable due to unstable metabolite production. Renal insufficiency due to hepatorenal syndrome also affects drug metabolism [20]. An adverse effect of the drug is constipation, which requires treatment.
A summary of the hepatotoxicity and safety of analgesics used in the treatment of mild and moderate pain in patients with chronic liver disease is presented in Table 2.
Table 2
Summary of hepatotoxicity and safety of analgesics in chronic liver disease
Conclusions
The treatment of pain in patients with CLD should consider the type and severity of pain, the progression of the disease and its complications, concomitant conditions, medications being taken, and individual sensitivity and needs. All analgesics, except codeine, have hepatotoxic potential, with the highest risk associated with NSAIDs (especially diclofenac). Therefore, these drugs should be used in recommended or reduced doses as indicated. For mild to moderate nociceptive pain, paracetamol is considered the safest drug in patients with CLD, provided the correct dosage is followed, with metamizole being the second option. Tramadol should be avoided in liver cirrhosis due to its metabolic pathway and unpredictable effect. If necessary, the lowest effective dose should be used, with extended intervals between doses. The treatment of pain in patients with cirrhosis poses additional challenges, as most analgesics are metabolized in the liver. Liver failure affects enzymatic efficiency, half-life, risk of drug accumulation, reduced potency, and the risk of side effects.
