Why paracetamol (acetaminophen) is a suitable first choice for treating mild to moderate acute pain in adults with liver, kidney or cardiovascular disease, gastrointestinal disorders, asthma, or who are older

Figures & data

Figure 1. Paracetamol (N-acetyl-p-aminophenol) pharmacotherapeutic mechanisms, metabolism, and toxicity. Abbreviations. TRPV, transient receptor potential cation channel subfamily V; CYP2E1, cytochrome P450 2E1; COX, cyclooxygenase.

Figure 2. Pain episodes from 6527 diary entries by adults aged 18–65 years. Data source: Hersch et al.¹⁰.

Table 1. Effects of short-term use of standard oral doses of paracetamol in adults who have liver disease, including alcoholic cirrhosis.

First author, year	Patient population	Study design (analytic cohort)	Paracetamol dosing	Main findings
Benson^32, 1983	Stable chronic liver disease	Open-pilot study in patients with advanced cirrhosis (n = 6)	1.0 g 4/day, 5 days consecutive	Clinical status and lab test results unchanged  – No progressive increase in plasma paracetamol level  – Paracetamol concentration never approached potentially toxic levels
		Double-blind randomized crossover to paracetamol or placebo (n = 20)	1.0 g 4/day, 13 days consecutive	No exacerbation of clinical features nor abnormal lab test results
Andreasen^33, 1979	Hepatic cirrhosis	Compared patients with cirrhosis (n = 11) vs without liver disease (n = 12)	Two 0.5 g tablets simultaneously then…	No clinical or biochemical signs of hepatotoxicity Cirrhotic patients had significantly higher plasma paracetamol levels, longer half-live (3.7 vs 2.1 h) and slower clearance (162 vs 337 mL/min)
		Cirrhosis (n = 4) vs controls (n = 9)	1.0 g 3/day, next 5 days	No paracetamol accumulation in blood
Heard^34, 2007	Moderate alcohol drinkers^a	Double-blind randomized to paracetamol (n = 100) vs placebo (n = 50)	Two 0.5 g capsules simultaneously 4/day, 10 days consecutive	No subjects met criteria for hepatotoxicity or liver failure or developed clinically evident liver injury  – Paracetamol group had increased mean ALT at day 11
Kuffner^35, 2007	Newly abstinent chronic alcoholics^b	Double-blind randomized to paracetamol (n = 258) vs placebo (n = 114)	Two 0.5 g capsules simultaneously 4/day, 3 days consecutive	No subjects had increased ALT, AST, or other markers of liver injury  – No statistical difference between paracetamol vs placebo in subgroup with alcoholic hepatitis
Forrest^36, 1979	Chronic liver disease	Compared groups with severe (n = 7) or mild (n = 8) liver disease, and normal controls (n = 8)	1.5 g single administration	No evidence for increased risk of hepatotoxicity in people with severe liver disease  – Mean plasma half-life significantly longer in severe liver disease group (4.3 h) vs mild liver disease (2.2 h) and normal groups (2.4 h)
Khalid^37, 2009	Hepatic cirrhosis^c	Cases with decompensated cirrhosis (n = 91) compared with compensated cirrhotic (n = 153) and non-cirrhotic (n = 89) controls	Highest doses in two cirrhotic controls: 3.0 g/day for 2 days ∼1.0 g/day for 25 days	Paracetamol at maximal doses of 3.0 g/day for ≤ 2 days/month or 1.0 g/day for ≤ 25 days/month is not associated with acute hepatic decompensation in cirrhotic patients, even those with recent alcohol ingestion

Abbreviations. ALT, alanine aminotransferase; AST, aspartate transaminase.

^aSubjects consuming an average of 1–3 alcoholic drinks/day.

^bIncluding 44 people fulfilling case definition for alcoholic liver disease.

^cIncluding 89 patients with alcoholic cirrhosis.

Table 2. Reported associations between frequency of paracetamol exposure and asthma incidence or prevalence.

First author, year	Design (setting)	Analytic cohort(s) (age range)	Outcome of paracetamol use versus never-use	Association with prior exposure to paracetamol (OR/RR, 95% CI)^a
				← Lower		Higher →
Shaheen^101, 2000	Case/control (UK general practices)	644 asthmatics vs 910 non-asthmatics (16–49 years)	OR for prevalent asthma	Less than monthly: 1.06 (0.77–1.45)	Monthly: 1.22 (0.87–1.72)	Weekly: 1.79 (1.21–2.65)*	Daily: 2.38 (1.22–2.65)*
Barr^97, 2004	Prospective cohort (USA)	346 women with incident asthma (30–55 years)	RR for incident asthma	1–4 days/month: 1.27 (0.96–1.66)	5–14 days/month: 1.43 (0.99–2.07)	15–21 days/month 1.78 (1.04–3.04)*	>22 days/month: 1.53 (0.95–2.46)
				<14 days/month: NR		>14 days/month: 1.63 (1.11–2.39)*
Davey^100, 2005	Prospective cohort (Ethiopia)	78 people with self-reported asthma (5–≥70 years)^b	OR for self-reported asthma	1–3 doses/month: 1.36 (0.93–1.99)		>3 doses/month 1.28 (0.76–2.15)
McKeever^103, 2005	Cross-sectional (USA)	934 people with physician-diagnosed asthma (20–80 years)	OR for prevalent asthma	1–5 days/month: 1.15 (0.99–1.34)	6–29 days/month:1.40 (1.12–1.75)*		≥30 days/month: 1.75 (1.34–2.28)*
Kelkar^99, 2012	Retrospective case/control (USA)	28,892 people with incident asthma vs 86,676 non-asthmatics (≥18 years)	OR for incident asthma	Recent pre-index prescription		Chronic pre-index prescription
				>1/30 days: 0.97 (0.90–1.04)	≥1/7 days: 1.02 (0.93–1.11)	≤30/365 days: 1.07 (1.03–1.11)*	>30/365 days: 1.39 (1.27–1.53)*

Abbreviations. CI, confidence interval; NR, not reported; OR, odds ratio; RR, risk ratio.

^aAdjusted for confounding variables.

^bProbably includes some children, as there was no breakdown of people with asthma by age.

*Bold type indicates statistical significance.

Table 3. Potential drug interactions with paracetamol and their clinical relevance.^a

Drug action	Interacting drug(s)	Potential effect of interaction	Clinical evidence & implications
Antioxidant	N-acetylcysteine	Attenuates NAPQI-induced hepatotoxicity	Principal antidote for paracetamol overdose
Ion exchange substrate	Activated charcoal, cholestyramine	Reduced paracetamol absorption	Oral activated charcoal ≤ 1 h after paracetamol ingestion treats an overdose, cholestyramine reduces absorption if given within 1 h
Anticoagulant	Warfarin/coumarin	Potentiated anticoagulation, elevated warfarin INR, risk of bleeding may increase	Assiduous INR monitoring during and 1 week after concomitant paracetamol is prudent
Gastric emptying retardant	Propantheline, anti-cholinergic agents, opioid analgesics	Decrease paracetamol absorption rate	Effects have limited clinical importance and do not cause toxicity in therapeutic use
Accelerate gastric emptying	Metoclopramide	Increase paracetamol absorption rate	Lower peak paracetamol concentration but total clearance unaffected
	Cisapride		No clinically significant interaction
Anticonvulsants	Phenytoin	Increase paracetamol elimination rate	No good evidence for hepatotoxicity and possibly hepatoprotective.
	Carbamazepine^b	May increase NAPQI production but data are equivocal	No good evidence for hepatotoxicity, anecdotal association may reflect confounding factors
	Phenobarbitaone	Suppress glucuronidation	No good evidence for increased risk of hepatotoxicity
Antibiotics	Chloramphenicol	May increase chloramphenicol concentration or clearance	Conflicting evidence precludes firm conclusions
	Rifampicin^b	Increase paracetamol elimination rate	No good evidence of increased hepatotoxicity.
Tuberculosis drugs	Isoniazid^b	CYP2E1 induction, increased NAPQI production after discontinuing isoniazid	Effect too small to significantly potentiate hepatotoxicity
Antiviral (NTRI)	Zidovudine	Inhibited glucuronidation	Studies have not confirmed interactions at therapeutic doses; no good evidence for hepatotoxicity or hepatoprotection
Proton pump inhibitor	Omeprazole	Increased NAPQI production	No good evidence that omeprazole increases hepatotoxicity
H2 histamine receptor antagonists	Ranitidine	Inhibit glucuronidation	No noticeable change in efficacy
	Cimetidine	Decrease NAPQI clearance	No clinically significant interaction reported
Gout treatment	Probenecid	Inhibits glucuronic acid conjugation, reducing paracetamol clearance	Consider reducing paracetamol dose if taken concomitantly
Tyrosine kinase inhibitors	Sorafenib, dasatinib, imatinib	Reduced glucuronidation may increase NAPQI production	No good evidence that tyrosine kinase inhibitors increase paracetamol toxicity

Abbreviations. INR, International Normalized Ratio; CYP2E1, cytochrome 450 2E1; NAPQI, N-acetyl-p-benzoquinoneimine; NTRI, nucleoside reverse transcriptase inhibitor.

^aData sources: Caparrotta et al.²⁵; Sharma and Mehta¹²³; Toes et al.¹²⁴.

^bDocumented hepatotoxicity.

Table 4. Studies comparing paracetamol absorption, concentration, and elimination in older versus younger adults.

First author, year	Participant population and stratification			Paracetamol dosing	Main findings (reported in older vs younger subjects, respectively)
	All subjects	Analysis groups^a	Age range (mean)
Gainsborough^128, 1993	Healthy  volunteers	Elderly (n = 19)	69–86 (75.0)	Oral tablets at ∼20.0 mg/kg	No significant difference in median T1/2abs (0.12 vs 0.11 h) or Tmax (0.57 vs 0.43 h) Gastric emptying does not become impaired with older age
		Young (n = 19)	20–33 (24.8)
Triggs^129, 1975	Apparently  healthy  individuals	Geriatric (n = 7)	73–91 (80.9)	0.8% solution at 14.3 mg/kg	Non-significant differences in absorption rate, Tmax (0.74 vs 0.67 h), volume distribution (1.05 vs 1.03 L/kg) or clearance (379 vs 477 mL/min/1.73 m^2) Older group had significantly longer T1/2 (130 vs 109 min) Plasma clearance correlated significantly (but not strongly) with creatinine clearance, not with age
		Young (n = 6)	22–30 (24.0)
Liukas^130, 2011	Orthopedic  surgery  patients	Older (n = 10)	60–70	1.0 g intravenous	Significant associations of age with total clearance (age 80–90 vs 20–40: 3.3 vs 4.6 mL/min/kg) and T1/2 (age 80–90 vs 20–40: 3.6 vs 2.7 h), but not with Tmax (age 80–90 vs 20–40: 0.26 vs 0.31 h) Drug exposure increased with age: 36–68% higher in 70–80 and 80–90-age groups vs ≤ 40-year-olds
		Older (n = 10)	70–80
		Oldest (n = 10)	80–90
		Young (n = 10)	20–40
Divoll^131, 1982	Considered  healthy^b	Older (n = 16)	61–78 (67.9)	0.65 g intravenous	Similar T1/2 in older vs young groups (mean 2.7 h) Older group had significantly lower weight-adjusted volume distribution Mean weight-adjusted clearance was lower in older vs young subjects of each sex, but differences had borderline significance
		Young (n = 16)	24–37 (29.0)
Bannwarth^132, 2001	Hospital inpatients	Very old (n = 12)	84–95 (89.0)	Two 0.5 g capsules simultaneously 3/day, 5 days consecutive	No drug accumulation despite mean plasma clearance ∼50–66% of that for healthy young adults given 1 g oral paracetamol (5–6 mL/min/kg) Longer mean T1/2 compared to value usual in young subjects (2.7 vs 2.0 h)
Miners^133, 1988	Healthy young or  older^c men	Elderly (n = 8)	72–92 (79.3)	Two 0.5 g tablets simultaneously	No significant difference in Tmax (0.76 vs. 0.87 h) or Cmax (14.5 vs 13.9 mg/L) No significant difference in apparent oral clearance, T1/2, or clearance to glucuronide or glutathione conjugates
		Young (n = 8)	18–26 (20.8)
Mitchell^117, 2011	Hospital  inpatients	Young (n = 11)	18–55 (35.6)	3–4 g/day, 5 days consecutive	All older vs younger participants had significantly higher mean day 5 paracetamol concentrations, with the highest in frail subjects who took 4 g/day ALT in frail paracetamol users remained within the normal range throughout
		Fit older (n = 12)	≥70 (81.7)
		Frail older (n = 13)	≥70 (85.4)

Abbreviations. T_max, time to maximum drug concentration; C_max, peak drug concentration; T_1/2abs, absorption half-life; T_1/2, elimination half-life; ALT, alanine aminotransferase.

^aAs designated in respective data sources.

^bThree older subjects were taking medications for cardiovascular disease, which was fully compensated and stable.

^cOlder group excluded men with evident renal hepatic or cardiovascular disease.

Table 5. First-line analgesia for acute mild to moderate pain in adults with special health concerns.

User group	Recommendations and expert advice for paracetamol use and dosing^a
All adults	Before taking paracetamol, users should carefully read the product information issued in their country/region regarding their specific formulation and pain indication The maximum recommended dose of paracetamol is 4 g/day, dosed as needed at ≥ 4–6-h intervals Use the lowest effective dose, for no longer than is necessary to relieve symptoms People whose symptoms persist or who experience adverse effects should seek medical advice
Liver disease	Use paracetamol in preference to NSAIDs Paracetamol ≤ 4 g/day is suitable for episodic acute^b use by patients with compensated cirrhosis, including moderate to heavy drinkers Paracetamol 3–4 g/day is suitable for patients with decompensated alcoholic liver disease; however, it is prudent to reduce the maximum recommended dose to 2–3 g/day for alcoholics who need to use paracetamol for > 14 days
Cardiovascular disease	Use paracetamol in preference to NSAIDs associated with increased risk of adverse CV events Episodic acute^b use of ≤ 4 g/day paracetamol poses very little, if any, increased risk of adverse CV events for most patients Hypertensive patients should use sodium-free paracetamol formulations
Gastrointestinal disorders	Use paracetamol in preference to NSAIDs in patients with risk factors for GI ulcers or bleeding Short-term use of paracetamol at recommended doses poses negligible risk of causing or exacerbating GI ulcers or related complications Dose reduction is generally unnecessary. Weak evidence that patients with gastric or duodenal ulcers may have increased paracetamol absorption and slower clearance is insufficient to support dose adjustment without corroborating studies.
Kidney disease	Use paracetamol in preference to NSAIDs, which have nephrotoxic class effects Dose modification is not necessary for patients on dialysis, who may take 1 g paracetamol orally as needed ≤ 3–4 times per day Paracetamol is suitable for patients with chronic kidney disease; however, patients with advanced kidney failure are recommended to use a reduced dose of ≤ 3 g/day
Asthma	Use paracetamol in preference to NSAIDs, which may exacerbate asthma symptoms in hypersensitive users Infrequent/short-term^c use of paracetamol at recommended therapeutic doses does not increase asthma severity People with analgesic-induced asthma that is known to be cross-sensitive to paracetamol, should use the lowest effective dose (e.g. ≤0.5 g) per dosing occasion
Older age (>60 years)	Paracetamol 0.5–1 g every 4–6 h (≤4 g/day) is suitable for healthy^c older people A reduced maximum dose of 0.5 g four times per day or 1 g three times per day is appropriate for older people with risk factors for hepatotoxicity (body weight < 50 kg; renal insufficiency; concomitant medications inducing liver enzymes; hepatitis or chronic alcohol use; glutathione depletion)

Abbreviations. NSAIDs, non-steroidal anti-inflammatory drugs; CV, cardiovascular; GI, gastrointestinal.

^aThis summary is intended only to supplement official product information and is not exhaustive.

^bShort-term use for treating intermittent acute pain episodes (e.g. headache, menstrual), as opposed to uninterrupted long-term use to treat chronic pain (e.g. osteoarthritis).

^cPeople without comorbidities or conditions to which product contraindications, warnings, or precautions apply.

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