What are the side effects of paracetamol (acetaminophen)?

Paracetamol Side Effects

Paracetamol at recommended therapeutic doses (≤4 g/day) is generally well-tolerated with minimal side effects, but carries significant risks of severe hepatotoxicity with overdose and emerging evidence suggests dose-dependent cardiovascular, gastrointestinal, and renal adverse effects with chronic use. 1, 2

Acute Toxicity and Hepatotoxicity

The most serious concern with paracetamol is severe liver damage, which occurs with overdose or repeated supratherapeutic ingestion:

• Severe liver damage may occur if an adult takes more than 6 doses in 24 hours or exceeds 4000 mg daily 1, 2
• Repeated supratherapeutic ingestions (>4 g/24h) can lead to hepatotoxicity, hepatic failure, and death 3
• Acute poisoning from self-administered overdoses is potentially lethal, though at recommended therapeutic doses hepatotoxicity is not typically a problem 4
• Risk is increased when taken with 3 or more alcoholic drinks daily or with other acetaminophen-containing products 1, 2
• Patients with liver disease should use caution, with daily doses of 2-3 g generally recommended for those with cirrhosis 3

Cardiovascular Effects

Emerging observational evidence demonstrates dose-dependent cardiovascular risks with chronic paracetamol use:

• All four studies examining cardiovascular adverse events showed a dose-response relationship, with risk ratios for cardiovascular events (myocardial infarction, stroke) increasing from 1.19 (0.81-1.75) at low doses to 1.68 (1.10-2.57) at higher doses 4
• Dose-dependent increase in new cases of hypertension, with a small (~4 mmHg) increase in systolic blood pressure showing particularly strong evidence 4, 5
• In contrast to NSAIDs and COX-2 inhibitors, there are no reports of cardiovascular harm from paracetamol in short-term use, maintaining its favorable cardiovascular safety profile compared to NSAIDs 4

Gastrointestinal Effects

While traditionally considered safer than NSAIDs for gastrointestinal complications, chronic paracetamol use carries some GI risk:

• Meta-analysis of randomized controlled trials showed no more GI symptoms from paracetamol than placebo, avoiding channeling bias 4
• However, observational data shows dose-dependent increase in relative rate of upper GI adverse events (gastroduodenal ulcers and complications including hemorrhage) from 1.11 (1.04-1.18) at low doses to 1.49 (1.34-1.66) at higher doses 4
• Endoscopic studies show no acute mucosal injury from paracetamol 4
• The increased risk of gastrointestinal bleeding with chronic use shows particularly strong evidence and dose dependence 5

Renal Effects

Dose-dependent renal adverse effects emerge with chronic paracetamol use:

• Three of four studies demonstrated dose-response increase in odds ratio of ≥30% decrease in estimated glomerular filtration rate, ranging from 1.40 (0.79-2.48) at low doses to 2.19 (1.4-3.43) at higher doses 4
• Dose-dependent increase in new cases of acute renal failure with chronic use 4
• Evidence for renal toxicity from therapeutic doses is sparse, though concerns have been raised 4

Allergic and Dermatologic Reactions

Severe skin reactions, though rare, represent a serious adverse effect:

• Acetaminophen may cause severe skin reactions including skin reddening, blisters, and rash 1, 2
• If a skin reaction occurs, use should be stopped immediately and medical help sought 1, 2

Mortality Risk

Observational evidence suggests dose-dependent mortality risk with chronic use:

• One study reported dose-response increase in relative rate of all-cause mortality from 0.95 (0.92-0.98) at low doses to 1.63 (1.58-1.68) at higher doses 4
• Another study reported significantly increased standardized mortality ratio for patients prescribed paracetamol compared to those not prescribed paracetamol 4

Important Caveats and Clinical Context

These observational findings must be interpreted with significant caution:

• All long-term adverse effect studies were observational cohort designs with substantial risk of confounding by indication—patients prescribed paracetamol may have higher baseline risk profiles 4
• Many studies relied on self-reported medication use or prescription databases, potentially inaccurately estimating true paracetamol exposure 4
• Channeling bias may lead clinicians to preferentially prescribe paracetamol to patients deemed unsuitable for NSAIDs, creating allocation bias toward higher-risk patients 4
• Short-term use (<14 days) for acute pain in adults with comorbidities is generally safe and appropriate, with putative epidemiologic associations of doubtful relevance to acute use 6

Drug Interactions

Specific interaction requiring monitoring:

• Patients taking warfarin should consult a doctor or pharmacist before using paracetamol 1

Practical Safety Recommendations

To minimize risks while maintaining efficacy:

• For chronic use, consider limiting to 3000 mg or less per day to reduce hepatotoxicity risk 3
• Avoid use for more than 10 days for pain or 3 days for fever unless directed by a physician 1
• Ensure patients are aware of acetaminophen content in combination products (e.g., with opioids) to prevent inadvertent overdose 3
• Monitor for elevated liver enzymes (AST/ALT) as warning signs of potential toxicity 3
• Despite emerging concerns about chronic use, paracetamol remains much safer than NSAIDs for serious GI complications and lacks the cardiovascular toxicity associated with COX-2 inhibitors and traditional NSAIDs 4