Paracetamol may help protect against kidney damage in patients with malaria


Paracetamol is used in many illnesses for the relief of pain and fever, but a study just published in Clinical Infectious Diseases has shown that it may also help protect against kidney damage in patients with malaria.

The study led by former Menzies Ph.D. student Daniel Cooper with A/Professors Bridget Barber, Matthew Grigg, and Professor Nick Anstey at Menzies School of Health Research (Menzies), with partners in Malaysia, found that for patients with severe malaria caused by the malaria parasite Plasmodium knowlesi (the most common cause of malaria in Malaysia), taking paracetamol regularly for 3 days led to improvements in kidney function when tested one week later.

Dr. Daniel Cooper said the findings are important because they will help provide the best possible treatment to patients with severe malaria.

“Even minor kidney injury can have long-term effects, so anything we can do to minimize kidney injury from malaria will be beneficial for these patients’ long-term outcomes,” Dr. Cooper said.

In collaboration with international partners, the study involved 396 people with knowlesi malaria in Sabah, Malaysia.

A/Prof Bridget Barber said that in severe malaria, red blood cells can rupture, releasing hemoglobin which can have a toxic effect on kidneys, and it’s now believed that paracetamol can help to protect against these toxic effects.

“These results are consistent with other studies conducted in patients with other forms of malaria, including in adults in Bangladesh, and in children in Africa.

Importantly, these findings also suggest that paracetamol may help to protect the kidneys in other conditions that are also associated with rupture of red blood cells,” A/Prof Barber said.

People worldwide use paracetamol (acetaminophen) more than any other analgesic [1–3]; besides being readily available over-the-counter (OTC), its popularity rests on being generally well tolerated and considered safer than other analgesics when taken as directed, especially in high-risk users such as older people or adults with comorbidities [1-6]. Accordingly, international guidelines and medical experts consistently recommend paracetamol for first-line treatment of acute mild/moderate pain [6-8].

Paracetamol has antipyretic and analgesic effects (Fig. 1), with complex mechanisms that distinguish it from non-steroidal anti-inflammatory drugs (NSAIDs) and opioids [1, 2, 6, 9]. Its most common everyday uses in adults include headaches, and musculoskeletal, or menstrual pain [7]; musculoskeletal pain and sprains/injury account for 45% of pain episodes for which adults may use OTC or prescription analgesics (Fig. 2) [10]. The standard adult dose of paracetamol is 0.5–1.0 g, taken as needed at least 4–6 h apart, to a maximum of 4 g/d; it is recommended to use the lowest dose that relieves symptoms, taken for the shortest possible treatment duration1 [8, 11].

Paracetamol very rarely has adverse effects in healthy adults who take ≤4 g/d in episodic use2 [2, 12] and as directed by the label, but doses exceeding the recommended daily maximum may be harmful due to the accumulation of a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), that can cause liver failure (Fig. 1) [2, 4, 12].

Although some epidemiological studies have also implied that paracetamol use may contribute to kidney or cardiovascular disease (CVD), gastrointestinal (GI) disorders, and asthma, especially among chronic users, these findings remain inconclusive and of unproven relevance to episodic acute use [2, 4, 13, 14]. Nevertheless, such observations have raised questions about the suitability of paracetamol for people with underlying comorbidities or who are elderly, and whether dose reduction might be appropriate in certain circumstances [4, 14–16].

Such concerns compound widespread lack of awareness, especially among older people, which conduces to inappropriate use that may increase the likelihoods of both accidental overdose and inadequate pain management [3, 5, 17, 18]. Many overdoses are unintentional, because people do not know the recommended maximum dose or are unaware of the presence or amount of paracetamol as an ingredient of numerous OTC medications [2, 7, 17]. On the other hand, some adults take doses lower than are recommended [8] and inadequate pain relief may lead them to use stronger analgesics with well-documented side effects [5, 12].

Acute pain is one of the most common reasons that people use primary care services [7, 10] and despite available consumer information, many still have questions about paracetamol, especially regarding its safety and dosing for people with specific health concerns [3]. In a survey of adults with liver disease, 60.5% said they would ask a physician before choosing an OTC analgesic containing paracetamol [17].

Physicians recommending any analgesic must be confident that its benefit will outweigh potential harms [2, 7, 14]. This necessitates thorough appraisal of each patient’s circumstances, based on which they can be advised which treatment options may be suitable, and on what dose to take. Healthcare professionals should be best placed to do this but may themselves be uncertain about the appropriate use of paracetamol, especially for patients with special health concerns, for whom there are limited clinical data or specific dosing instructions [3, 5, 16, 17]. Pertinently, patient information cautions people with liver or kidney disease, or who have aspirin-sensitive asthma, to consult their physician before using paracetamol, but does not specify whether or how dosing should be adjusted [11, 19].

To address knowledge gaps and augment existing guidance, we have reviewed published evidence and expert opinion pertaining to the acute use of paracetamol by adults with liver or kidney disease, CVD, GI disorders, asthma, or who are older. Briefly, independent researchers shortlisted articles retrieved from PubMed® searches that combined the terms ‘paracetamol’ or ‘acetaminophen’ with others chosen to retrieve articles relevant to each of the aforementioned areas of potential health concern, which the authors had prespecified.

The authors checked that selected articles were within the scope of their review and suggested others based on their specialist knowledge. Reference lists of reviewed articles were perused to identify additional sources. Although this review discusses the use of GlaxoSmithKline products in this context, the authors strove to remain impartial and produce an objective, evidence-based summary that reflects the current consensus of scientific expertise in these areas. We encourage physicians and other healthcare professionals to use this resource to help people make informed choices about pain management.

Liver disease and hepatotoxicity
Many patients and physicians do not know whether paracetamol is suitable for people with liver disease – potential hepatotoxicity is a particular concern [17, 20–22]. Paracetamol is almost entirely metabolized by the liver (Fig. 1): ∼80% is eliminated as inactive glucuronide (40–65%) and sulphate (25–35%) conjugates but 5–10% is oxidized by cytochrome P450 2E1 (CYP2E1) to generate NAPQI, a highly reactive intermediate that is normally rapidly neutralized by conjugation with glutathione, which is constantly replenished [4, 12, 22–24].

However, if NAPQI accumulates faster than it is detoxified (e.g., due to paracetamol overdose or, hypothetically, in glutathione-depleted states) it can cause acute necrotic liver failure [4, 6, 23, 24]. Theoretically, pathologies that affect this pathway could increase the risk of paracetamol-induced hepatotoxicity [25, 26]; for example, hyperglycemia and starvation induce CYP2E1 activity [27], and malnutrition may deplete hepatic glutathione, potentially abating NAPQI detoxification [23, 25].

Expert reviewers, however, maintain that paracetamol at therapeutic doses generates insufficient NAPQI to exhaust glutathione, and that there is no convincing clinical evidence that malnourished individuals who use paracetamol as directed are at increased risk of hepatotoxicity [23, 25]. Despite the lack of good-quality evidence, some precautionary guidance nevertheless suggests that people weighing <50 kg should take paracetamol at lower doses (contrary to the drug label) [25]. Studies on how diabetes influences paracetamol metabolism found limited effects on its conjugation and clearance pathways and there has been no suggestion that people with diabetes should use a lower dose [28, 29].

Perceived risk of hepatotoxicity may lead patients and physicians either to believe incorrectly that paracetamol is absolutely contraindicated in liver disease and opt for other drugs that may be less appropriate (e.g., NSAIDs), or use too low a dose to relieve pain satisfactorily [12, 17, 20–22]. The challenges of pain management in patients with liver disease are compounded by the dearth of prospective studies of analgesic pharmacology and safety in this population and lack of specific evidence-based dosing recommendations. As a result, prescribing and usage practices vary considerably and pain may be undertreated [12, 17, 19–22].

Reappraisal of reported paracetamol poisoning cases has suggested that acute hepatotoxicity is much rarer when used as its label recommends than was commonly supposed [4]; in retrospect, many purported cases can actually be attributed to unrecognized overdosing, which is mostly unintentional and often occurs in the context of alcoholism [4, 12, 20, 24, 30, 31]. Nonetheless, there has been conjecture as to whether hepatotoxicity at therapeutic doses of paracetamol might be more likely in people with liver disease [12, 20, 22, 32], especially chronic alcoholics, who may have depleted glutathione reserves and potentiated oxidation to NAPQI [4, 12, 20, 22, 23].

Relevant research over 40 years has consistently shown negligible risk of hepatotoxicity from short-term use of paracetamol at standard doses up to 4 g/d by patients with liver disease, including moderate to heavy drinkers (Table 1) [12, 21–23, 32–35]. Although patients with severe liver disease who took single doses of either 1 g or 1.5 g paracetamol had a longer plasma half-life versus controls, there was no evidence of impaired glutathione conjugation or clinical hepatotoxicity, nor of drug accumulation after taking 3 g/d for 5 days [33, 36].

Likewise, there were neither accumulation nor evidence of hepatotoxicity in patients with stable chronic liver disease who took 4 g/d paracetamol for 5 days consecutively, and no clinically significant changes after 13 days continuous use [32]. In patients with cirrhosis, including recent alcohol users, episodic doses of ≤3 g/d paracetamol during the previous month were not associated with acute hepatic decompensation (ascites, variceal bleeds, encephalopathy, jaundice) [37]. In other studies, there was no evident liver damage in newly abstinent chronic alcoholics who took 4 g/d paracetamol for 3 days [35], or in moderate drinkers who took 4 g/d for 10 days [34].

Collectively, these findings constitute persuasive evidence that short-term use (<1–2 weeks) of up to 4 g/d paracetamol is an appropriate treatment for mild to moderate pain in patients with cirrhotic liver disease, even moderate to heavy drinkers [12, 20, 22, 38]. No high-quality evidence supports reducing the maximum recommended dose of paracetamol (4 g/d) for short-term use by patients with compensated cirrhosis [19].

It is difficult to make dosing recommendations for people with decompensated alcoholic liver disease due to insufficient data on this group – 3–4 g/d short-term for acute pain may be reasonable [12]. Experts also concur that 2–3 g/d may be more prudent if used by alcoholics for more than 14 days, without significantly compromising analgesia [12, 19–22, 38].

The potential risks and benefits of paracetamol for patients with liver disease must be weighed against those of alternative treatment options, such as NSAIDs or opioids [4, 21, 23]. Given its established safety profile and lack of sedating or nephrotoxic effects, paracetamol is the analgesic of choice irrespective of liver disease etiology, whereas NSAIDs are best avoided due to increased risk of GI bleeding, renal failure, and antiplatelet effects [4, 12, 17, 21, 22, 38].

Cardiovascular disorders
People with CVD or cardiovascular (CV) risk factors account for a significant proportion of the primary care caseload [39, 40]. To relieve musculoskeletal pain in such patients, the American Heart Association has advocated stepwise escalation that starts by using analgesics with the least associated risk of adverse CV effects, usually paracetamol or aspirin at the lowest effective dose, and suggested paracetamol initially for people at risk of GI bleeding [41].

If first-line treatment is ineffective or poorly tolerated, a non-selective NSAID or cyclo-oxygenase 2 (COX-2) inhibitor may be considered but should be used cautiously, due to increased risks of serious CV or GI complications [39, 41–44]. Contrastingly, there is no conclusive evidence associating paracetamol with increased risk of CV events in patients with or at risk of CVD [39, 42, 45]. Many patients with CV comorbidities require polypharmacy, which substantially increases the likelihood of drug-drug interactions; using paracetamol instead of NSAIDs has been recommended to avoid potential interactions that may warrant avoiding a combination or modifying therapy [40]. Accordingly, CVD patients worldwide often use paracetamol for pain relief [43, 46].

The pharmacology of paracetamol differs from NSAIDs and has only recently become better understood [2, 6, 9]. Given such widespread use, even slightly increased risk to potentially vulnerable patients would raise concern [13, 45, 47]; however, studies of CV-related outcomes in paracetamol users have produced inconsistent results [43, 48]. In particular, there are insufficient high-quality data to assess hypothetical CV risks associated with paracetamol in typical episodic use [49]. Further studies, especially randomized controlled trials (RCTs), may help to resolve remaining uncertainties [43, 45, 49].

Although some observational studies have associated paracetamol use with elevated blood pressure (BP) [14], there is inconclusive evidence of clinically significant hypertensive effects from episodic acute use [49, 50]. Reported epidemiological associations between chronic/frequent paracetamol use and incident hypertension [51–53], may be attributable in part to confounding factors [49]; for example, the more often people are prescribed analgesics by a physician, the likelier they are to have their BP measured and to have hypertension diagnosed [13].

Other investigators have found no association between paracetamol and hypertension [54, 55]. A retrospective cohort of adults with hypertension who were first prescribed NSAIDs had a 2 mmHg increase in systolic BP at 1-year follow-up relative to new paracetamol users, who were matched by propensity scores for baseline BP, age, and cardiometabolic comorbidities [56]. Besides clearly increasing BP and the risk of serious CV events in both normotensive and hypertensive individuals, NSAIDs directly interfere with the actions of many antihypertensive and diuretic agents, whereas paracetamol does not appear to [39, 42, 49, 52, 57]; reassuringly, there is no signal that hypertensive paracetamol users have increased risks of myocardial infarction or stroke [45], which have been associated with BP elevation by just a few mmHg during follow-up studies [39, 49]. In this context, it is noteworthy that the sodium salts in soluble paracetamol products can significantly raise BP [58, 59], which may partly explain apparent associations between paracetamol use and hypertension [60]; healthcare professionals should advise hypertensive patients to use sodium-free formulations [59].

Small prospective RCTs have also investigated whether paracetamol affects BP [14, 49]. The earliest found a 4 mmHg rise in systolic BP in 20 hypertensive patients who took 3 g paracetamol per day (two 500 mg tablets, 8-hourly for 4 weeks) [61]. However, subsequent RCTs found no significant BP changes in people with mild/moderate hypertension [57, 62, 63]. In another RCT, 33 patients with coronary heart disease who took 1 g paracetamol thrice-daily for 2 weeks had significantly increased ambulatory BP, which raised concern about using paracetamol in such patients [49, 64]; however, the validity and clinical relevance of this study have been challenged [47]. To augment this limited and conflicting evidence, a recent British RCT investigated the effect of giving 110 people with hypertension paracetamol 1 g four times per day for 14 consecutive days, typifying the dosing schedule used to treat chronic pain [65]. Uninterrupted use of 4 g/d paracetamol increased systolic BP by 4.7 mmHg versus placebo, suggesting that regular long-term use of paracetamol may be inadvisable for people with risk factors for CVD [65]; notably, however, the authors saw no grounds for such concern about short-term episodic use in this setting [66].

CV endpoints
The CV safety of widely used analgesics has become a major public health concern, especially given evidence accrued since 2011 that NSAIDs which are still often used by patients with CVD have no risk-neutral treatment window; even at low doses for <7 days, non-aspirin NSAIDs have been associated with increased risk of thrombotic CV events [44]. A Swedish national study found heart failure to be associated with NSAIDs but not paracetamol [67]. Among 70,971 United States (US) female nurses without known CVD, occasional paracetamol use (1–21 d/month) was not associated with increased CV risk; although women who took paracetamol frequently (≥22 d/month) were increasingly likely to have CV events compared with non-users, with greatest risk at ≥15 tablets/week [48], the analytic methodology has been criticized [13]. A 2016 meta-analysis also reported a dose-response relationship between paracetamol and adverse CV events [15] but its findings too have been disputed, particularly concerning inadequate treatment of potential biases [13, 68]. A 10-year follow-up study of 10,878 British hypertensive patients found no relationship between paracetamol use or exposure and the risk of any CV event or stroke [45]. In a recent cohort of frail nursing home residents with multimorbidity and polypharmacy, neither paracetamol use nor dosing affected CV mortality, although participants with diabetes had increased stroke risk [69].

Available evidence does not indicate that episodic use of paracetamol at recommended doses is associated with any additional risk of major CV events [43, 45]; it can therefore be considered the first-choice analgesic for mild to moderate acute pain in most people with CV risk factors, especially those liable to NSAID-related GI bleeding [6, 39, 41].

Gastrointestinal disorders
Paracetamol is generally accepted to have excellent GI tolerability and is consequently an analgesic of choice for patients at risk for adverse GI events [4, 6, 70]. Unlike aspirin and some other NSAIDs that reportedly increase the risk of GI bleeding at any dose [71], paracetamol appears to have negligible risk of causing or exacerbating GI ulcers or related complications [6, 70]. Prospective studies have shown that paracetamol does not damage the GI tract [4], and a meta-analysis found no significant effect of paracetamol at any dose on upper GI bleeding [72].

Epidemiological studies of health records have produced conflicting results; although some found no association between paracetamol use and GI bleeding [70], others have suggested that the incidence of adverse GI reactions may increase dose-dependently [73–75]. However, these positive associations must be interpreted cautiously, as they could reflect inherent biases and confounding factors that may invalidate inferences about causality. A likely explanation is that physicians recommend paracetamol preferentially over NSAIDs to patients at high risk for gastropathy because they consider paracetamol to be safer (confounding by indication), while widespread use of paracetamol means it is often the first-line treatment for GI pain due to a pre-existing condition (protopathic bias) [4, 70]. For example, observations that paracetamol users sometimes experience dyspepsia [75] probably reflect that paracetamol is the preferred analgesic for patients with GI risk factors [70]. A recent analysis of the Japanese Adverse Drug Event Report (JADER) pharmacovigilance database affirmed that paracetamol causes less GI injury than NSAIDs [1].

Based on evidence that paracetamol lacks major GI toxicity in short-term use and has GI safety superior to that of many NSAIDs [1, 4, 6, 70], paracetamol can be recommended as a first-line treatment for mild to moderate acute pain in patients at risk of GI ulceration or bleeding [6, 70].

Nevertheless, it is important for physicians to be aware of how GI disorders such as gastric dysmotility, which is a common complication of type 2 diabetes [76], GI ulcers, or other conditions, may affect the absorption and/or pharmacokinetics of paracetamol [77]. Absorption of orally administered paracetamol depends on its dissolution in the stomach and the gastric emptying rate [78]. A rapid-dissolving oral paracetamol formulation that enables faster absorption with less inter/intra user variability, may be more suitable than standard paracetamol tablets for people with delayed gastric emptying [79, 80].

Sixteen patients with gastric or duodenal ulcers had prolonged and increased absorption of 1 g paracetamol relative to healthy controls and slower clearance, particularly among those with duodenal ulceration, suggesting that reduced paracetamol dosing may be appropriate [81]; however, larger studies would be needed to corroborate this provisional evidence. Conversely, people with ulcerative colitis had no difference versus healthy controls in the clearance of 1 g peroral paracetamol or its metabolites [82], which would support these patients using a standard dose. The jejunum is the major site of paracetamol absorption, and people with short bowels are likely to have impaired uptake of oral doses [77]; a rectal paracetamol suppository may be administered in such cases but will have slower, less complete absorption and a less predictable effect compared with an oral dose [2, 6, 77].

Kidney disease
Many people with chronic kidney disease (CKD) need pain relief; some 40–60% of those receiving dialysis and 60–70% or more with advanced/end-stage renal disease are reported to suffer pain, predominantly musculoskeletal [83, 84]. However, high-quality evidence in this setting is limited, and diverse prescription practices suggest uncertainty as to the most expedient pharmacotherapeutic approach [85]. Consequently, pain management is suboptimal in many such patients, which diminishes their quality of life and imposes additional healthcare burdens [83, 86].

There has been speculation that paracetamol may be associated with renal impairment [87, 88]. Historically, realization that classic analgesic nephropathy was caused by phenacetin overuse raised concerns that paracetamol, its primary metabolite, might have similar injurious renal effects [88, 89]; however, this hypothesis has been dismissed [88–91]. Although acute nephrotoxicity has been documented in rodents given paracetamol doses of ≥500 mg/kg and following overdoses in a few clinical cases [87, 90, 91], there is no evidence that episodic use of paracetamol alone at recommended doses causes renal damage, nor that cumulative lifetime doses exacerbate advanced CKD [83, 87, 88, 90–92].

Epidemiologic inferences that paracetamol may increase users’ risk of developing CKD are contentious; contradictory findings of observational studies suggest that putative associations might be due to protopathic bias and/or confounding by indication rather than signifying underlying causation [4, 87, 88, 90, 93]. In particular, first-line use of paracetamol in preference to other analgesics by people with early renal impairment may lead to spurious associations with incident CKD in observational studies. [13, 87]. Conversely, besides increasing the risk of GI bleeding, NSAIDs have proven nephrotoxic class effects and should be avoided where possible in patients with symptoms of renal impairment, as should COX-2 inhibitors which induce similar adverse effects [83, 84, 86, 90, 94]. Unlike COX-2 inhibitors, there have been no reports that therapeutic doses of paracetamol are associated with acute renal failure [95]. Analysis of the large real-world JADER pharmacovigilance database supports the acute renal safety of paracetamol versus NSAIDs [1].

Prevailing guidance from the US Kidney Foundation and other nephrology experts, advocates stepwise escalation of analgesia, starting with non-opioids for mild pain, and recommends paracetamol as the preferred first-line analgesic for episodic treatment of mild pain in patients with renal dysfunction, CKD, and/or requiring dialysis [83, 84, 86, 90, 92, 95]. Concordantly, a recent meta-analysis found paracetamol to be the mainstay of treatment for mild to moderate pain in CKD patients [85]. Dose modification is not necessary for patients on dialysis, who may take 1 g orally 3–4 times per day [86]. Among CKD patients on hemodialysis, 500 mg peroral paracetamol has been used to treat headaches, shivering, or fever [96]. However, dose minimization may sometimes be warranted [84]; for example, a maximum of 3 g/d has been recommended for patients with advanced kidney failure [83].

Several studies over the years have investigated the hypothesis that adulthood asthma might be related to paracetamol use [97–105]; however, almost all were non-interventional association studies (Table 2) [106], and only one analyzed whether occasional use of paracetamol affects symptom severity in adults with established asthma [101]. Consequently, there is a paucity of high-quality clinical evidence on which to base guidance [107].

Epidemiological studies have consistently shown that paracetamol is associated with asthma incidence/prevalence, especially with more frequent exposure [97, 99, 101–104]. These positive associations do not prove causality and may be partly attributable to confounding factors or biases, particularly people with asthma avoiding NSAIDs and preferentially using paracetamol. Nevertheless, accruing evidence supports a weak association between having asthma and frequent paracetamol use [14, 99, 101–104, 106, 108, 109]. Asthma etiology hypothetically involves depletion of glutathione, an antioxidant that abates airway inflammation, [101, 102, 108, 109], though some doubt that this is significant at standard therapeutic doses of paracetamol [23]. Glutathione depletion also suppresses T-helper 1 production, thus favoring allergenic T-helper 2 responses [102, 108]. Other biologically plausible mechanisms are antigenic effects of paracetamol that stimulate immunoglobulin E responses, and COX inhibition that increases leukotriene levels and reduces prostaglandin E2 production [14, 99, 104, 108].

On the other hand, epidemiological studies found no significant associations with asthma among the least frequent paracetamol users (Table 2) [97, 99, 101, 103]. In one study, increasing asthma severity was associated with weekly or daily paracetamol use, whereas monthly users were no more likely to have asthma compared with never users [101]. However, in the only RCT to date in adults, 1 g paracetamol taken twice daily for 12 weeks had no statistically significant effect on the severity or control of stable mild to moderate asthma, probably ruling out overt morbid effects with short-term, low-dose use [105].

Analgesic-induced asthma
Aspirin and other NSAIDs provoke bronchospasm and exacerbate asthma in up to ∼20% of asthmatics who are hypersensitive to COX inhibitors; these acute reactions may be severe, even life-threatening [1, 107–111]. Although most people with asthma tolerate paracetamol well, its weak COX inhibitory action has dose-dependent bronchospastic effects in 20–30% of individuals with aspirin-induced asthma (AIA) who are cross-sensitive to paracetamol [107, 109].

In one study, 17 of 50 patients with AIA had bronchospastic reactions to paracetamol challenges of 1 g/d or 1.5 g/d [112]. However, less than 2% of asthmatics overall are hypersensitive to paracetamol, and such reactions are generally mild, occur at high doses, and are not known to have caused fatalities [107, 109, 111, 112]. Most people with asthma, even those with AIA, have little risk of bronchospasm at paracetamol doses of <650 mg [112]. The JADER database showed little sign of asthma induction with real-world use of paracetamol compared with NSAIDs [1].

Given the risks of hypersensitivity and GI bleeding associated with NSAIDs, paracetamol may be preferable for short-term treatment of mild to moderate pain in people with asthma [6, 14, 99, 101, 107, 110, 111]. Although there are no RCTs on the respiratory effects of short-term standard doses of paracetamol in adults with established asthma, available evidence suggests that episodic paracetamol use does not exacerbate respiratory symptoms [1, 14, 99, 105, 109]. However, people with AIA that is known to be cross-sensitive to paracetamol should use the lowest effective single dose, for example, ≤500 mg per dosing occasion [14, 109, 110, 113].

Older age
Pain is considerably more common among people older than 60 versus younger adults and affects up to half or more of older community-dwellers, with even higher prevalence in elderly care home residents [114, 115]. But despite older adults being among the highest users of analgesics, their pain is often inadequately treated and significantly impairs their quality of life [5, 114–120]. Managing pain in older people is often complicated by comorbidities, potential drug-drug interactions from polypharmacy, and age-related physiological and pharmacokinetic/dynamic changes [5, 119–122]; however, a ‘start low and go slow’ approach may make physicians over-cautious about up-titrating analgesic dosing as necessary, leading to undertreatment [118]. In such circumstances, paracetamol may be the first choice for treating mild to moderate acute pain [6, 16, 69, 122], especially musculoskeletal [115], and is often prescribed to avoid using NSAIDs associated with increased risks of GI bleeding and renal dysfunction in older people [5, 16, 118, 121].

Drug interactions
Paracetamol may alter the International Normalized Ratio of oral anticoagulants, notably warfarin, potentially increasing the risk of bleeding [25, 122–124]. There is no convincing evidence that other potential drug interactions with paracetamol are clinically significant (Table 3) [25, 124].

Paracetamol pharmacokinetics and pharmacodynamics in older people
Although some guidance advocates reduced dosing of paracetamol for older people, there is limited supporting evidence, because this population is under-represented in clinical trials and the pharmacodynamics of paracetamol in older people have not been studied systematically [5, 118, 120]. Consequently, questions about whether or how therapeutic doses should be adapted for both frail and robust older people remain unresolved [120, 125]. Understanding the pharmacology of paracetamol in older people can help to improve pain management [118].

Conjecture that gastric emptying slows with advancing age is based largely on indirect findings or small cohorts of aged people with related comorbidities (e.g., Parkinson’s disease, diabetes) and/or medication use [126, 127]. Healthy older people, however, generally have gastric emptying rates within the normal range, and modestly slower emptying than in younger people is unlikely to be clinically significant [126–128]. Paracetamol absorption was not impaired in healthy older study subjects and time to maximum plasma concentration also appeared unaffected by age (Table 4) [120, 128–132]; however, exposure to a 1 g intravenous dose increased with age because paracetamol had a longer elimination half-life [130] and somewhat slower clearance in older people compared with young adults [130–133], with creatinine clearance rather than age determining the clearance rate [129].

Paracetamol users aged 84–95 years who took three 1 g doses per day for 5 days consecutively had no drug accumulation [133], and although frail inpatients older than 70 who took 3–4 g/day for 5 days did have higher plasma concentrations than younger patients, none had abnormally elevated serum alanine aminotransferase, which suggests that slower clearance of therapeutic paracetamol doses in geriatric patients may not necessarily increase the risk of hepatotoxicity [117].

A study of 36 inpatients ≥80 years old who received 3 g/day paracetamol (concomitant with other analgesics), found wide inter-individual variations in all pharmacokinetic metrics; however, only seven had an average plasma concentration above the predefined analgesic target of 10 mg/L [125]. Pharmacokinetic analyses in 30 fit, older people given 1 g intravenous paracetamol after knee surgery also found large (unexplained) variability; in population simulations, 1 g/6 h achieved a steady state of 10 mg/L on average, whereas a longer dosing interval of 1 g/8 h resulted in underdosing for most patients [134].

Despite decreasing volume of distribution and clearance of paracetamol with advancing age [16, 118], most older people tolerate 1 g/6 h per day well, with no need for dose reduction provided physicians have carefully considered patient-specific risk factors such as liver disease, heavy alcohol intake, or renal insufficiency [16, 119, 121]. Although liver damage from standard therapeutic doses (0.5–1 g/4–6 h, max ≤4 g/d) rarely occurs in healthy older people [16], it may nevertheless be prudent to consider lower or less frequent doses in those with risk factors for hepatotoxicity, which include weighing <50 kg, renal insufficiency, concomitant medications inducing liver enzymes, hepatitis or chronic alcohol use, or glutathione-depleted states [16]; 0.5 g four times per day or 1 g thrice daily may be suitable for such patients [16].

Speculation that paracetamol could increase the risk of hypothermia in vulnerable older adults remains unsubstantiated [135–137]. Rare case reports have linked pediatric hypothermia to therapeutic doses of paracetamol [135] and limited experimental data suggest that paracetamol (20 mg/kg lean body mass) may impair thermogenesis in adult subjects during cold stress, but not in thermoneutral conditions [136, 137]. However, the mechanisms are not well understood and there is currently no evidence that paracetamol at a standard dose is a factor in adult cold-related hypothermia deaths [135–137].

In summary, there is insufficient evidence to conclude that reduced paracetamol clearance with age is clinically significant, or to support routine dose reduction for older patients [119, 120, 132]. Although some guidelines provide general dosing advice, specific recommendations for managing acute pain in older people are lacking [16, 120]. Based on pharmacokinetic data, adjusting the dose of paracetamol is generally unnecessary [131, 132]. A dose of 0.5–1 g every 4–6 h (maximum of 4 g/d) is probably appropriate for healthy older people, while it may be advisable for very elderly or frail people or those otherwise at increased risk for hepatotoxicity to take the lowest effective dose, not exceeding 3 g/d [16, 133].

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