Paracetamol (acetaminophen) and combinations

General information

More than a century after its introduction, acetylsalicylic acid (aspirin) is by far the most commonly used analgesic, sharing its leading position with the relative newcomer paracetamol (acetaminophen), and notwithstanding the fact that other widely used compounds, such as ibuprofen, have in recent years been introduced in over-the-counter versions. Both are also still prescribed by physicians for mild to moderate pain, fever associated with common everyday illnesses, and disorders ranging from head colds and influenza to toothache and headache. However, they are most commonly used by consumers who obtain them directly from pharmacies, and in many countries outside pharmacies as well, for example in supermarkets.

Perhaps this wide availability and advertising via mass media leads to a lack of appreciation by the lay public that these are medicines with adverse effects. Both have at any rate been subject to misuse and excessive use, leading to such problems as chronic salicylate intoxication with aspirin and severe hepatic damage after paracetamol overdose. Both aspirin and paracetamol have also featured in accidental overdosage (particularly in children) as well as intentional overdosage.

In an investigation of Canadian donors who had not admitted to drug intake, 6–7% of the blood samples taken were found to have detectable concentrations of acetylsalicylic acid and paracetamol [ ].

To offer some protection against misuse of analgesics, many countries have insisted on the use of packs containing total quantities less than the minimum toxic dose (albeit usually the one obtained for healthy young volunteers and thus disregarding the majority of the population), and supplied in child-resistant packaging. Most important, however, is the need to provide education for the lay public to respect such medicines in general for the good they can do, but more especially for the harm that can arise, but can be avoided. There is a definite role for the prescribing physician, since informing the patient seems to prevent adverse events [ ].

The sale of paracetamol or aspirin in dosage forms in which they are combined with other active ingredients offers considerable risks to the consumer, since the product as sold may not be clearly identified as containing either of these two analgesics. Brand names sometimes obscure the actual composition of older formulations that contain one or both of these analgesics in combination with, for example, a pyrazolone derivative and/or a potentially addictive substance. For instance, in Germany, with the EC harmonization of the Drug Law of 1990, the manufacturers of drugs that had been marketed before 1978 had the opportunity of exchanging even the active principles without being obliged to undergo a new approval procedure or to abandon their brand name. Combination formulations are still being promoted and sold, and not exclusively in developing countries. Consequently, the patient who is so anxious to allay all his symptoms that he takes several medications concurrently may without knowing it take several doses of aspirin or paracetamol at the same time, perhaps sufficient to cause toxicity. It is essential that product labels clearly state their active ingredients by approved name, together with the quantity per dosage form [ ].

The antipyretic analgesics share with the non-steroidal anti-inflammatory drugs (NSAIDs) a common mechanism of action, namely inhibition of prostaglandin synthesis from arachidonic acid and their release. More precisely their mode of action is thought to result from inhibition of both the constitutive and the inducible isoenzymes (COX-1 and COX-2) of the cyclo-oxygenase pathway [ ]. However, aspirin and paracetamol are distinguishable from most of the NSAIDs by their ability to inhibit prostaglandin synthesis in the nervous system, and thus the hypothalamic center for body temperature regulation, rather than acting mainly in the periphery. Paracetamol may inhibit COX-3 [ ].

Endogenous pyrogens (and exogenous pyrogens that have their effects through the endogenous group) induce the hypothalamic vascular endothelium to produce prostaglandins, which activate the thermoregulatory neurons by increasing AMP concentrations. The capacity of the antipyretic analgesics to inhibit hypothalamic prostaglandin synthesis appears to be the basis of their antipyretic action. Neither aspirin nor paracetamol affects the synthesis or release of endogenous pyrogens and neither will lower body temperature if it is normal.

While aspirin significantly inhibits peripheral prostaglandin and thromboxane synthesis, paracetamol is less potent as a synthetase inhibitor than the NSAIDs, except in the brain, and paracetamol has only a weak anti-inflammatory action. It is simple to ascribe the analgesic activity of aspirin to its capacity to inhibit prostaglandin synthesis, with a consequent reduction in inflammatory edema and vasodilatation, since aspirin is most effective in the pain associated with inflammation or injury. However, such a peripheral effect cannot account for the analgesic activity of paracetamol, which is less well understood.

Compound analgesic formulations

It makes pharmacological sense to combine simple analgesics such as aspirin and paracetamol with opioid analgesics, and various such combinations have been available for some years. These include:

paracetamol + codeine phosphate (co-codamol);
paracetamol + dihydrocodeine tartrate (co-dydramol);
paracetamol + dextropropoxyphene (co-proxamol);
paracetamol + tramadol;
aspirin + codeine phosphate (co-codaprin).

Adverse reactions to these combinations are the same as the adverse reactions to their components. Co-proxamol has been withdrawn in the UK because it was no more effective than paracetamol alone and was associated with a high death rate after overdose [ ]. During the 6 years after the withdrawal of co-proxamol in the UK, there was a major reduction in deaths involving this drug, without an increase in deaths involving other analgesics [ ].

General adverse effects and adverse reactions

Although paracetamol is acceptably safe in usual dosages, there have been reports that in patients with significant hepatic dysfunction or those taking substances that induce hepatic enzymes (for example ethanol, phenobarbital, isoniazid) even these doses may aggravate liver dysfunction, sometimes to the point of causing hepatic failure. The problem of overdosage is substantial. Allergic reactions, including urticaria, are seen occasionally. Anaphylactic shock has been reported. Its interaction with warfarin can be problematic.

Organs and systems

Cardiovascular

Despite the high prevalence of the use of minor analgesics (aspirin and paracetamol) there is little information available on the association between the use of these analgesics and the risk of hypertension. A prospective cohort study in 80 020 women aged 31–50 years has provided some useful information [ ]. The women had participated in the Nurses’ Health Study II and had no previous history of hypertension. The frequency of use of paracetamol, aspirin, and NSAIDs was collected by mailed questionnaires and cases of physician-diagnosed hypertension were identified by self-report. During 164 000 person-years of follow-up, 1650 incident cases of hypertension were identified. Overall, 73% of the cohort had used paracetamol at least 1–4 days/month, 51% had used aspirin, and 77% had used an NSAID. Compared with non-users of paracetamol the age-adjusted relative risk (RR) of hypertension was significantly increased even in women who had used paracetamol for only 1–4 days/month (RR = 1.22; CI = 1.07, 1.39). There seemed to be a dose–response relation, as the RR of hypertension compared with non-users was 2.00 (CI = 1.52, 2.62) in women who had taken paracetamol for 29 days/month or more. For women using aspirin or NSAIDs at a frequency of 1–4 days/month the RRs were 1.18 (CI = 1.02, 1.35) and 1.17 (CI = 1.02, 1.36) respectively. However, after adjusting for age and other potential risk factors, only paracetamol and NSAIDs, but not aspirin, remained significantly associated with a risk of hypertension. In summary, the data from this study support the view that paracetamol and NSAIDs are strongly associated with an increased risk of hypertension in women, the risk increasing with increasing frequency of use. Aspirin did not seem to be associated with an increased risk. This conclusion contrasts with the results of some short-term studies that have shown no effect of paracetamol on blood pressure [ , ].

This study suggests that paracetamol can raise arterial blood pressure in a dose-related fashion, interfere with the actions of antihypertensive drugs, and prompt the need for new antihypertensive therapy. However, these results must be interpreted with caution, as there were some limitations: the assessments of analgesic use and hypertension were made using a self-reported questionnaire; relative risk can be influenced by many potentially confounding variables; the results are relevant only for young women and cannot be extrapolated to the general population.

Respiratory

Paracetamol can aggravate bronchospasm in patients who are sensitive to aspirin and other analgesics [ ]. In severe poisoning, paracetamol depresses respiratory function centrally through metabolic acidosis and coma [ ].

The prevalence of asthma has risen worldwide in recent years, but the reason for this increase is unclear. A number of hypotheses have been formulated, and among them attention has been paid to epidemiological and pathophysiological evidence underlying the hypothesis that paracetamol may be a risk factor for asthma [ ].

In a double-blind, randomized study of ibuprofen in children with febrile illnesses, there was a significant association between increased out-patient visits for asthma and use of paracetamol [ ]. However, the lack of a placebo group in this study made it unclear whether ibuprofen reduced the risk of asthma, paracetamol increased the risk, or a combination of the two.

The first study to suggest a definitive link between asthma and paracetamol was one using data from the International Study of Asthma and Allergies in Childhood of the European Community Respiratory Health Survey (ECHRIS) [ ]. There was a positive correlation between paracetamol sales and asthma symptoms. For each gram increase in per capita paracetamol sales in 1994–95 the prevalence of wheeze increased by 0.52% among 13- to 14-year-old subjects in this study. Similarly, wheezing rose by 0.26% per gram increase among young adults. Following this report several studies appeared to add supportive evidence.

An association between paracetamol and asthma at the individual level was reported in a large case-control study [ ]. After controlling for potential confounding factors, the odds ratio for asthma compared with newer users of paracetamol was 1.06 (CI = 0.77, 1.45) in infrequent users (less than monthly), 1.22 (CI = 0.87, 1.77) in monthly users, 1.79 (CI = 1.21, 2.65) in weekly users, and 2.38 (CI = 1.22, 4.64) in daily users. The effect was much stronger for severe asthma (OR = 8.2; CI = 2.8, 23). However, the study had limitations, such as selection bias, and did not take into account factors such as respiratory tract infections. Furthermore, the cross-sectional design of the study made it unclear whether the use of paracetamol contributed to asthma or vice versa [ ].

Further evidence came from the Nurses’ Health Study, a prospective cohort study of 121 200 women [ ]. The objective was to examine the relation between paracetamol use and new-onset asthma. During 352 719 person-years of follow-up, 346 participants reported a new diagnosis of asthma. Increasing frequency of paracetamol use was positively associated with newly diagnosed asthma. The multivariate rate ratio for asthma for participants who took paracetamol for more than 14 days/month was 1.65 (CI = 1.11, 2.39) compared with non-users. The positive associations were not affected by the use of aspirin. In a multivariate analysis aspirin was inversely related to newly diagnosed asthma. There was no association with NSAIDs. However, these results cannot be generalized, as the study was conducted in an older, female, and predominantly white population not representative of the general population.

A later study using data from the US-based Third National Health and Nutrition Examination Survey has provided further evidence that use of paracetamol is associated with asthma in a dose-related way (adjusted OR = 1.20; CI = 1.12, 1.28) [ ]. Increased use of paracetamol was also dose-dependently associated with COPD. It should be noted that while absence of dose-relatedness may be evidence against an association, the presence of a dose relationship does not necessarily confirm the association.

In 3000 children aged 6–7 years and 3000 teenagers aged 13–14 years the prevalence of ever wheezing in the younger children who had taken paracetamol in the first year of life was 11% (OR = 1.54; 95% CI = 1.00, 2.38) and the prevalence of ever wheezing in older children who had taken paracetamol at least once a month was 25% (OR = 1.7; 95% CI = 1.43, 2.04) [ ]. Taking more paracetamol during the previous 12 months led to a higher prevalence of dry cough at night and symptoms of rhinitis in the younger children and eczema and rhinitis symptoms in the teenagers.

In a cross-sectional questionnaire study in 3493 children aged 6–7 years old children were classified as cases if they had had wheezing, rhinitis, or eczema either at any time since their neonatal period or in the 12 months before the study [ ]. Paracetamol exposure was considered positive if it had occurred often during the first year of life (first analysis) or in the previous 12 months (second analysis). Paracetamol intake in the first year of life was significantly associated with an increased risk of wheezing (adjusted OR = 1.69; 95% CI = 1.23, 2.34) and rhinitis (adjusted OR = 1.37; 95% CI = 1.20, 1.59) but not eczema (adjusted OR = 1.45; 95% CI = 0.91, 2.32). Frequent paracetamol intake in the previous year increased the risk of wheezing (OR = 3.3; 95% CI = 1.54, 7.18), rhinitis (OR = 1.61; 95% CI = 1.33, 1.95), or eczema (OR = 1.82; 95% CI = 1.24, 2.66).

In a multicenter case-control study of 521 patients with asthma and 507 controls, weekly use of paracetamol, compared with less frequent use, was associated with asthma [ ].

In 19 349 adult twins enrolled in the nationwide Danish Twin Registry there was a higher prevalence of asthma in subjects with frequent intake of paracetamol (OR = 2.16; 95% CI = 1.03, 4.53) after adjusting for confounders [ ].

In 205 487 children aged 6–7 years paracetamol used for fever in the first year of life was associated with a higher risk of asthma symptoms at age 6–7 (OR = 1.46; 95% CI = 1.36, 1.56) [ ]. Current use of paracetamol was also associated with a higher risk of asthma symptoms. Moreover, paracetamol use, both in infancy and at age 6–7 years, was associated with rhinoconjunctivitis and eczema.

Despite the evidence, from these and other studies, suggesting a true association, evidence of confounding by indication came from a prospective birth cohort study of 620 children with a first-degree family history of allergic disease, who were followed until age 7 years [ ]. The use of paracetamol was associated (with borderline significance) with a risk of childhood asthma, but the association became clearly non-significant after adjustment for the frequency of respiratory infections. There was no association between the use of paracetamol for non-respiratory causes and asthma.

This suggests that the association of exposure to paracetamol during childhood with apparent increases in the risks of allergic disorders is probably due to confounding by indication and other biases, taking account, for example, of antibiotic use and viral infections in childhood, and in questionnaire studies recall bias [ , ].

Nevertheless studies have continued to appear, with results suggestive of an association, including the following.

In a prospective, longitudinal questionnaire study of a cohort of children of 8176 families, with a 55% response rate, wheeze treated with an inhaled glucocorticoid during the previous year was more likely in those who had had prenatal paracetamol exposure, which was an independent susceptibility factor, although the authors acknowledged the possibility of confounding by maternal indication [ ]. Selection bias was also likely.

In a systematic review and meta-analysis of six studies of the possible association between paracetamol use in pregnancy and subsequent asthma in children aged 30–84 months, the random effects odds ratio, unadjusted for confounders, for the risk of current wheeze was 1.21 (95% CI = 1.02, 1.44) [ ]. Despite the authors’ conclusion, it is likely that adjustment for confounders would have removed the apparent association, which was borderline.

The association between the use of paracetamol and antibiotics in the first year of life and wheezing starting at different times (early, persistent, and late-onset) was studied in SIDRIA-2, a cross-sectional survey of 16 933 children aged 6–7 years [ ]. The use of paracetamol and antibiotics was associated with early wheezing (in the first 2 years of life only; OR = 2.27; 95% CI = 1.98, 2.62 and OR = 3.76; 95% CI = 3.31, 4.27) and with persistent wheezing (first 2 years + last 12 months; OR = 1.77; 95% CI = 1.49, 2.10 and OR = 3.06; 95% CI = 2.60, 3.60), whereas the association with late-onset wheezing (in the last 12 months only) was weak (OR = 1.12; 95% CI = 0.97, 1.31 and OR = 1.18; 95% CI = 1.02, 1.38 for paracetamol and antibiotics respectively). The authors suggested that it is important to take into account different presentations in order to disentangle the association of paracetamol and antibiotics with wheezing.

In a prospective birth cohort study in 1016 children who had been exposed to paracetamol in pregnancy and were re-investigated at 10 years of age, maternal use of paracetamol in the first trimester increased the risk of allergic rhinitis at 10 years (OR = 2.30; CI = 1.06, 4.97) in boys and girls [ ]. Use of paracetamol until 6 months in girls increased the risk of allergic sensitization (OR = 2.20; CI = 1.15, 4.22) and a history of asthma (OR = 2.20; CI = 1.13, 4.30).

In a birth cohort study of wheeze, asthma, and atopy in children who had been exposed to paracetamol between birth and 15 months of age (n = 505) and between 5 and 6 years for all participants (n = 914), odds ratios were adjusted for potential confounders, including the number of chest infections and antibiotic use [ ]. Paracetamol exposure before the age of 15 months was associated with atopy at 6 years (adjusted OR = OR = 3.61; 95% CI = 1.33, 9.77). In contrast, paracetamol exposure between 5 and 6 years showed dose-dependent associations with reported wheeze and current asthma, but there was no association with atopy. Compared with use 0–2 times, the adjusted odds ratios (95% CI) were: wheeze 1.83 (1.04, 3.23) for use 3–10 times, and 2.30 (1.28, 4.16) for use >10 times; current asthma 1.63 (0.92, 2.89) for use 3–10 times and 2.16 (1.19, 3.92) for use >10 times; atopy 0.96 (0.59, 1.56) for use 3–10 times, and 1.05 (0.62, 1.77) for use >10 times.

In a retrospective case-control study of 28 892 cases and 86 676 controls, mean age 43 years, 23% of cases and 18% of controls had paracetamol exposure in the pre-index year, with mean cumulative doses of 79 and 60 g respectively [ ]. There was no significant association between recent exposure and asthma (7 days: OR = 1.02; 30 days: OR = 0.97), but cumulative exposure in the previous year increased the risk (≤ 1 kg: OR = 1.09; >1 kg: OR = 1.60).

In a cross-sectional study in more than 20 000 children aged 6–7 years, after adjusting for sex, BMI, having a cat or dog, maternal education, and parental asthma and smoking, the consumption of paracetamol during the first year of life was associated with wheezing at some time (OR = 2.04; CI = 1.79, 2.31) [ ].

In a prospective birth cohort study of 263 620 children born in 1998 and 9910 children born in 2003, exposure to paracetamol and/or antibiotics and potential confounding factors were analysed; there was a positive relationship between paracetamol and/or antibiotic exposure during the first year of life and subsequent development of atopic eczema asthma and allergic rhinitis in the 1998 birth cohort, but not in the 2003 cohort [ ].

None of these studies convincingly shows an association of paracetamol exposure in childhood with the conditions studied. Confounding by indication and other biases are much more likely to be responsible for the results.

Nervous system

In patients who suffer from recurrent headaches, for example migraine, cluster headache, or tension headache, temporary relief for the constant or intermittent pains is obtained from each analgesic dose, but wears off after a few hours with the arrival of a new episode. The patient gets accustomed to this pattern and may use excessive doses of analgesics. This in turn can cause, worsen, and perpetuate headaches, leading to what is called analgesic-induced or rebound headache. Like migraine, analgesic-induced headache is more likely to occur in women and is associated with depression.

It is postulated that the mechanism by which analgesic abuse transforms a primary headache into a rebound headache involves serotonin: both platelet serotonin concentrations and uptake were lower in patients with analgesic-induced headache compared with migraine sufferers and non-headache sufferers. At the same time, there was upregulation of serotonin receptors on the platelet membrane [ , ]. Extrapolating these findings to the nervous system, it has been suggested that excessive analgesic use suppresses serotonin pathways, contributing to aggravation of headaches. Paracetamol and codeine were the major culprits of the analgesics investigated.

Analgesic-induced headache has also been described in children. One report [ ] described 12 children, aged 6–16 years, who gave a history of headaches on at least 4 days a week, for 3 months to 10 years. Eleven of the children had been taking paracetamol, six in combination with codeine, and one was taking ibuprofen alone. They were taking at least one dose of an analgesic for each headache and eight were taking analgesics every day. The headaches presented with increasing frequency and were related to overuse of analgesics, a typical finding in analgesic-induced headache. The analgesics were withdrawn; in six children the headaches resolved completely, another five children experienced a reduced frequency of headaches, and one resumed analgesic abuse.

A second report [ ] was of a retrospective study of patients seen in a pediatric headache clinic. During 8 months, 98 patients were seen for headache; 46 of them suffered from daily or near daily headache and 30 were consuming analgesics daily. Follow-up information was available in 25. The average number of doses of analgesics per week they consumed was 26. The most commonly used medications were paracetamol and ibuprofen. In addition, a minority were taking combinations that contained aspirin, codeine, caffeine, propoxyphene, or butalbital, or other NSAIDs. Abrupt withdrawal of all analgesics concomitant with the use of amitriptyline 10 mg/day (in 22 patients) prompted a significant reduction in the frequency and severity of headache.

The data from these studies are comparable to previous observations reported in adults [ , ] and suggest that daily use of analgesics can cause daily or near daily headaches in children and adolescents. However, additional controlled prospective studies are needed to address the true frequency of analgesics rebound headache among children and to evaluate possible treatments.

Metabolism

Hypoglycemia has been recorded with paracetamol, particularly in children [ ].

Acid–base balance

Acidosis without liver damage, a rare presentation, has been reported in a case of paracetamol poisoning in a child [ ].

A previously healthy 27-month-old girl started vomiting and became somnolent without a history of drug exposure. She was intubated and given activated charcoal. The serum paracetamol concentration was 5.3 mmol/l (804 μg/ml) 2.5 hours after the onset of symptoms. The pH was 7.32, PaCO ₂ 4.6 kPa, PaO ₂ 46 kPa, and bicarbonate 17 mmol/l. The lactate was 4.6 mmol/l. The serum aminotransferase activities were not raised. A urine toxicology screen was negative, and the aspirin concentration was less than 20 mg/l. Four hours after the development of symptoms, she was given intravenous N-acetylcysteine, which was continued for 36 hours, until the paracetamol concentration was undetectable. Her liver function tests remained normal, the acidosis resolved, and her mental status returned to normal.

Hematologic

Agranulocytosis was recorded in a series in France [ ], but does not appear to have been a significant clinical problem elsewhere.

Two patients developed immune thrombocytopenia attributed to metabolites of paracetamol [ ].

A 30-year-old man and a 66-year-old woman had taken paracetamol 1 g intermittently for headaches and other non-specific indications. Routine blood testing showed thrombocytopenia (50 × 10 ⁹ /l and 45 × 10 ⁹ /l respectively). They both stopped taking paracetamol, and their platelet counts rose to normal within 7–10 days. Their sera contained antibodies (IgG or IgA) that recognized normal platelets in the presence of the metabolite paracetamol sulfate.

This suggests that in patients with drug-induced immune thrombocytopenia, tests for metabolite-dependent antibodies can be helpful in identifying the responsible agent.

A hemolytic crisis has been recorded in a patient with glucose-6-phosphate dehydrogenase deficiency [ ].

Gastrointestinal

The association between paracetamol and upper gastrointestinal complications has been investigated in a nested case-control study using the UK General Practice Research Database and a systematic review of 12 twelve studies [ ]. Paracetamol was associated with a small increased risk of upper gastrointestinal complications (RR = 1.3; 95% CI = 1.1, 1.5). The relative risk was 3.6 (95% CI = 2.6, 5.1) among paracetamol users of more than 2 g/day, whereas smaller doses did not increase the risk. Among the 12 studies identified in the systematic review, estimates were 0.2–2.0, with a summary estimate of 1.3 (95% CI = 1.2, 1.5). These findings suggest that paracetamol does not greatly increase the risk of upper gastrointestinal complications.

Liver

Paracetamol is directly hepatotoxic and can cause severe hepatic damage in dosages over 6–10 g (12–20 tablets).

Liver damage due to paracetamol is usually associated with suicidal overdosage. However, it has been suggested that the use of paracetamol in children with acute febrile illnesses can cause fulminant hepatic failure [ ]. In a case-control study 25 children with fulminant hepatic failure were compared with 33 age-matched controls. All of the former and none of the latter had taken supratherapeutic doses of paracetamol (mean 145 mg/kg/day). The mean paracetamol concentration was 1.78 mmol/l. There was no serological evidence of hepatitis A, hepatitis B, or dengue. Three children died.

In an analysis of alanine aminotransferase activity in seven controlled clinical trials involving the use of paracetamol alone 1950–4000 mg/day for 4 weeks up to 12 months, there were no reports of hepatotoxicity or hepatic failure in 1530 patients [ ]. While they were taking long-term paracetamol, 181 of 1039 patients (17%) had an alanine aminotransferase activity that exceeded the upper limit of the reference range, but none was more than three times the upper limit of the reference range in conjunction with a serum bilirubin over the upper limit of the reference range, and no patient had an alanine aminotransferase activity more than 10 times the upper limit of the reference range. All the changes were transient.

Biliary tract

Acute biliary pain with cholestasis is an occasional complication [ , ].

Pancreas

Pancreatitis has been reported, but only in overdose [ ].

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