Acetaminophen is not necessarily safe in childhood and pregnancy. However, acetaminophen is the safest medicine as analgesics for nociceptive pain and antipyretics in childhood and pregnancy. Fever and pain during pregnancy and in childhood themselves are probably associated with adverse gestational and childhood outcomes. Acetaminophen should be used at the lowest effective dosage and for the shortest time. It is reasonable to judge that acetaminophen>2,000 mg/day causes upper gastrointestinal complications. If acetaminophen>2,000 mg/day is administered, gastroprotective agent is probably necessary. Acetaminophen 2,000 mg/day is a gray zone. Proton pump inhibitors cause many serious adverse effects. If proton pump inhibitors are administered with acetaminophen, the advantages of acetaminophen that acetaminophen provides slight and mild adverse effects disappear. Nobody knows which gastroprotective agent is optimal in combination with acetaminophen (>2,000 mg/day). It is reasonable to judge that acetaminophen is ineffective for low back pain and pain due to osteoarthritis. It is true that acetaminophen causes various adverse effects including serious adverse effects. However, it is also true that acetaminophen (<2,000 mg/day) is safer than non-steroidal anti-inflammatory drugs (NSAIDs). If analgesic effects of acetaminophen (<2,000 mg/day) and NSAIDs are the same, NSAID should not be administered. Conversely, when analgesic effects of NSAIDs are stronger than those of acetaminophen, administration of NSAIDs for more than 2 weeks is acceptable.
acetaminophen; adverse effects; paracetamol; non-steroidal anti-inflammatory drugs; adverse effects
Acetaminophen had been believed to be a safe analgesic and antipyretic medication, especially in childhood and pregnancy. According to recent articles, it is not necessarily safe. In this article, advantages, disadvantages, and specific administration method of acetaminophen are shown.
Safety in childhood and in pregnancy
Prenatal exposure to acetaminophen is associated with cerebral palsy, autism spectrum disorder, communication problems, hyperactivity/impulsivity symptoms, attention-deficit/hyperactivity disorder, attention and executive function problems, language delay, lower intelligence quotient, behavioral problems, shorter anogenital distance in male infants, decreased relative numbers of hematopoietic stem cells in cord blood, wheeze, and asthma [1,2]. Acetaminophen use in childhood is associated with autism spectrum disorder [3,4], asthma [5-14], wheezing [15,16], rhinitis [17,18], community acquired pneumonia , obesity [20,21], atopic eczema [22,23], allergic diseases [24,25], hypersensitivity reactions  and acute kidney injury . We should recognize that acetaminophen is danger in childhood and pregnancy . However, acetaminophen is the safest medicine as analgesics for nociceptive pain and antipyretics in childhood and pregnancy [1,2]. Fever and pain during pregnancy and in childhood themselves are probably associated with adverse gestational [1,2] and childhood outcomes. Acetaminophen should be used at the lowest effective dosage and for the shortest time [1,2]. We should use acetaminophen in childhood and pregnancy only when needed and no safer option for pain or fever relief is available [1,2].
Safety of 2 g and more acetaminophen
A small case control study reported that odds ratio (OR) for the risk of upper gastrointestinal (GI) bleeding with was 1.2 (<2,000 mg/day: 95% confidence interval [CI] 1.0-1.4), 1.2 (2,000–3,999 mg/day: 95% CI 0.8-1.7) and 1.0 (≥ 4,000 mg/day: 95% CI 0.5-1.9) . A small case control study reported that acetaminophen was not associated with the risk of upper GI bleeding (multivariate OR 0.8: 95% CI 0.3-1.9) . A systematic review showed that a summary estimate of RR of upper gastrointestinal complications (UGIC) was 1.3 (95% CI 1.2-1.5) . A nested case-control study showed that the relative risk (RR) was 3.6 (95% CI 2.6-5.1) among paracetamol users of more than 2 g daily . A nested case–control study showed an increased risk of UGIC among current users of acetaminophen at doses greater than 2 g (RR 3.7: 95% CI 2.6–5.1) and 2 g (RR 1.9: 95% CI 1.4–2.6) . A retrospective cohort study showed that patients who took higher-dose acetaminophen (2,601–3,250 or>3,250 mg/day) were more likely to experience GI event compared with those who took low-dose acetaminophen (?2,600 mg/day) (RR 1.27: 95% CI 1.13–1.43 and RR 1.34: 95% CI 1.15–1.54, respectively) . A population-based retrospective cohort study showed that the risk of GI hospitalization was 1.20 (95% CI 1.03-1.40) during exposure to acetaminophen (>3g/day) compared with the reference category (acetaminophen ≤3 g/day) . It is reasonable to judge that acetaminophen>2,000 mg/day causes UGIC . If acetaminophen>2,000 mg/day is administered, gastroprotective agent is probably necessary . Acetaminophen 2,000 mg/day is a gray zone . We don’t know which gastroprotective agent is optimal  . Proton pump inhibitors (PPIs) cause many serious adverse effects. If PPIs are administered with acetaminophen, the advantages of acetaminophen that acetaminophen provides slight and mild adverse effects disappear. Acetaminophen (<2,000 mg/day) without gastroprotective agent or acetaminophen (>2,000 mg/day) with effective and safe gastroprotective agent is recommended. Nobody knows what is effective and safe gastroprotective agent [34,35]. Rebamipide is one of candidates, and I administer acetaminophen (>2,000 mg/day) in combination with rebamipide. However, there is no evidence of efficacy and rebamipide can be administered in few countries (Philippines, Thailand, Vietnam, the Republic of Korea, China, Cambodia, Indonesia, Japan, and Egypt).
Acetaminophen is not effective in low back pain and pain due to osteoarthritis
Randomized open-label trial showed that acetaminophen 2,400 mg/day has comparable analgesic effects on acute low back pain (LBP), based on at least a noninferiority margin, compared with loxoprofen 180 mg/day at 4 weeks . A multicenter, double-blind, randomized, clinical trial showed that pain treatment with acetaminophen 4,000 mg/day was not inferior to that with diclofenac 150 mg/day or the combination of acetaminophen 4,000 mg/day and diclofenac 150 mg/day in acute minor musculoskeletal extremity trauma, both in rest and with movement . A retrospective study showed that no difference in analgesic effects between non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen at the latest 2 weeks after injury or surgery . A systematic review and meta-analysis (2006-2016) showed that acetaminophen was found to have a relative (%) changes value close to that of oral NSAIDs .
However, recent systematic review and/or meta-analysis usually showed that acetaminophen was ineffective for LBP and pain due to osteoarthritis (OA). The American College of Physicians developed a guideline for systemic pharmacologic therapies for LBP using a systematic review and reported as follows: New evidence found that acetaminophen was ineffective for acute LBP . Cochrane Database Systetatic Review showed the efficacy and safety of paracetamol for non-specific LBP . It showed as follows: Paracetamol does not produce better outcomes than placebo for people with acute LBP, and it is uncertain if it has any effect on chronic LBP . A systematic review and meta-analysis showed that paracetamol was ineffective in the treatment of LBP and provided minimal short-term benefit for people with OA . A network meta-analysis showed as follows; On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with OA irrespective of dose . A network meta-analysis showed that acetaminophen was likely the least efficacious intervention option on the treatment of knee and/or hip OA . A network meta-analysis showed no role for single-agent paracetamol for the treatment of patients with knee and hip OA irrespective of dose on the basis of the available data .
Acetaminophen is safer than NSAIDs
It is true that acetaminophen causes various adverse effects including serious adverse effects. However, it is also true that acetaminophen (<2,000 mg/day) is safer than NSAIDs. If analgesic effects of acetaminophen (<2,000 mg/day) and NSAIDs are the same, NSAID should not be administered. In this case, acetaminophen (<2,000 mg/day) and NSAIDs may be equally effective, or they may be equally ineffective. In a clinical practice, placebo cannot be administered, therefore, it is impossible to distinguish between true analgesic effects and placebo effects in each medicine. In either case, if analgesic effects of acetaminophen (<2,000 mg/day) and NSAIDs are the same, NSAIDs should not be administered. Conversely, when analgesic effects of NSAIDs are stronger than those of acetaminophen, administration of NSAIDs for more than 2 weeks is acceptable. If analgesic effects of acetaminophen (<2,000 mg/day) and NSAIDs are the same in patients with LBP or OA, should acetaminophen (<2,000 mg/day) be administered? Even if analgesic effect of acetaminophen is placebo effect, acetaminophen with mild adverse effects should be administered, if analgesic effects of acetaminophen and NSAIDs are the same.
Acetaminophen is not necessarily safe. However, it is safer than NSAIDs. If analgesic effects of acetaminophen (<2,000 mg/day) and NSAIDs are the same, acetaminophen should be administered.
Disclosure and Conflicts of Interest
No conflicts of interest
- Toda K (2017) Is acetaminophen safe in pregnancy?Scand J Pain17: 445-446. [crossref]
- Toda K (2018) Acetaminophen is not safe in pregnancy. Obstet Gynecol Res1: 1004.
- Schultz ST, Klonoff-Cohen HS, Wingard DL, Akshoomoff NA, Macera CA, et al. (2008) Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey.Autism12: 293-307. [crossref]
- Bauer AZ, Kriebel D (2013) Prenatal and perinatal analgesic exposure and autism: an ecological link.Environ Health12: 41. [crossref]
- Sheehan WJ, Mauger DT, Paul IM, Moy JN, Boehmer SJ, et al. (2016) Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.N Engl J Med375: 619-630. [crossref]
- Beasley RW, Clayton TO, Crane J, Lai CK, Montefort SR, et al. (2011) Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three. Am J Respir Crit Care Med 183: 171-178. [crossref]
- Lee SH, Kang MJ, Yu HS, Hong K, Jung YH, et al. (2014) Association between recent acetaminophen use and asthma: modification by polymorphism at TLR4.J Korean Med Sci29: 662-668. [crossref]
- Sordillo JE, Scirica CV, Rifas-Shiman SL, Gillman MW, Bunyavanich S, et al. (2015) Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children.J Allergy Clin Immunol135: 441-448. [crossref]
- Magnus MC, Karlstad O, Haberg SE, Nafstad P, Davey Smith G, et al. (2016) Prenatal and infant paracetamol exposure and development of asthma: the Norwegian Mother and Child Cohort Study. Int J Epidemiol 45: 512-522. [crossref]
- Piler P, Åvancara J, Kukla L, Pikhart H, et al. (2018) Role of combined prenatal and postnatal paracetamol exposure on asthma development: the Czech ELSPAC study.J Epidemiol Community Health72: 349-355. [crossref]
- Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, et al. (2009) Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis.Chest136: 1316-1323. [crossref]
- Heintze K, Petersen KU (2013) The case of drug causation of childhood asthma: antibiotics and paracetamol.Eur J Clin Pharmacol69: 1197-1209. [crossref]
- Madani K, Vlaski E, Rennie DC, Sears M, Lawson JA (2018) An international comparison of risk factors between two regions with distinct differences in asthma prevalence. Allergol Immunopathol (Madr) 46: 341-353. [crossref]
- Soto-Martínez ME, Yock-Corrales A, Camacho-Badilla K, Abdallah S, Duggan N, et al. (2018) The current prevalence of asthma, allergic rhinitis, and eczema related symptoms in school-aged children in Costa Rica.J Asthma25: 1-9 [crossref]
- Moraes LS, Takano OA, Mallol J, Solé D (2013) Risk factors associated with wheezing in infants.J Pediatr (Rio J)89: 559-566. [crossref]
- Bercedo-Sanz A, Lastra-Martinez L, Pellegrini-Belinchon J, Vicente-Galindo E, Lorente-Toledano F, et al. (2015) Wheezing and risk factors in the first year of life in Cantabria, Spain. The EISL study. Allergol Immunopathol (Madr) 43: 543-552. [crossref]
- Muc M, Padez C, Pinto AM (2013) Exposure to paracetamol and antibiotics in early life and elevated risk of asthma in childhood.Adv Exp Med Biol788: 393-400. [crossref]
- Kim H, Johnson CC (2014) The association between acetaminophen and asthma: is there anything to learn from the upper airways?Curr Opin Allergy Clin Immunol14: 25-28. [crossref]
- Krenke K, Krawiec M, Kraj G, Peradzynska J, Krauze A, et al. (2018) Risk factors for local complications in children with community-acquired pneumonia.Clin Respir J12: 253-261. [crossref]
- Murphy R1, Stewart AW, Braithwaite I, Beasley R, Hancox RJ, et al. (2015) Association between paracetamol use in infancy or childhood with body mass index.Obesity (Silver Spring)23: 1030-1038. [crossref]
- Mitchell EA, Stewart AW, Braithwaite I, Murphy R, Hancox RJ, et al. (2018) Factors associated with body mass index in children and adolescents: An international cross-sectional study.PLoS One13: e0196221. [crossref]
- Suarez-Varela MM, Garcia-Marcos L, Fernandez-Espinar JF, Bercedo-Sanz A, Aguinaga-Ontoso I, et al. (2013) Is acetaminophen use associated with atopic eczema and other allergic diseases in adolescents? Iran J Allergy Asthma Immunol 12: 115-123. [crossref]
- Pacifici GM, Allegaert K (2014) Clinical pharmacology of paracetamol in neonates: a review.Curr Ther Res Clin Exp77: 24-30. [crossref]
- Amberbir A, Medhin G, Hanlon C, Britton J, Davey G, et al. (2014) Effects of early life paracetamol use on the incidence of allergic disease and sensitization: 5-year follow-up of an Ethiopian birth cohort.PLoS One9: e93869. [crossref]
- Tamay Z, Akcay A, Ergin A, Guler N (2014) Prevalence of allergic rhinitis and risk factors in 6- to 7-yearold children in Istanbul, Turkey.Turk J Pediatr56: 31-40. [crossref]
- Gabrielli S, Langlois A, Ben-Shoshan M (2018) Prevalence of Hypersensitivity Reactions in Children Associated with Acetaminophen: A Systematic Review and Meta-Analysis.Int Arch Allergy Immunol176: 106-114. [crossref]
- Yue Z, Jiang P, Sun H, Wu J (2014) Association between an excess risk of acute kidney injury and concomitant use of ibuprofen and acetaminophen in children, retrospective analysis of a spontaneous reporting system. Eur J Clin Pharmacol 70: 479-482. [crossref]
- Lewis SC, Langman MJ, Laporte JR, Matthews JN, Rawlins MD, et al. (2002) Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Br J Clin Pharmacol 54: 320-326. [crossref]
- Sakamoto C, Sugano K, Ota S, Sakaki N, Takahashi S, et al. (2006) Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan. Eur J Clin Pharmacol 62: 765-772. [crossref]
- González-Pérez A, Rodríguez LA (2006) Upper gastrointestinal complications among users of paracetamol.Basic Clin Pharmacol Toxicol98: 297-303. [crossref]
- Garcia Rodríguez LA, Hernández-Díaz S (2001) The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents.Arthritis Res3: 98-101. [crossref]
- Rahme E, Pettitt D, LeLorier J (2002) Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population. Arthritis Rheum 46: 3046-3054. [crossref]
- Rahme E, Barkun A, Nedjar H, Gaugris S, Watson D (2008) Hospitalizations for upper and lower GI events associated with traditional NSAIDs and acetaminophen among the elderly in Quebec, Canada.Am J Gastroenterol103: 872-882. [crossref]
- Toda K (2018) Acetaminophen (2 g and more) may cause upper gastrointestinal complications. J Anesthesiol Pain Res 1: 1000107.
- Toda K (2013) Is acetaminophen at daily doses of 2,000 mg and higher safe? Comment on the article by Hochberg et al.Arthritis Care Res (Hoboken)65: 325-326. [crossref]
- Miki K, Ikemoto T, Hayashi K, Arai YC, Sekiguchi M, et al. (2018) Randomized open-label non-inferiority trial of acetaminophen or loxoprofen for patients with acute low back pain.J Orthop Sci23: 483-487. [crossref]
- Ridderikhof ML, Lirk P, Goddijn H, Vandewalle E, Schinkel E, et al. (2018) Acetaminophen or Nonsteroidal Anti-Inflammatory Drugs in Acute Musculoskeletal Trauma: A Multicenter, Double-Blind, Randomized, Clinical Trial. Ann Emerg Med 71: 357-368 e358. [crossref]
- Toda K (2018) No difference in analgesic effects between non-steroidal anti-inflammatory drugs and acetaminophen at the latest two weeks after injury or surgery. J Clin Invest Stud 1: 1000104.
- Stewart M, Cibere J, Sayre EC, Kopec JA (2018) Efficacy of commonly prescribed analgesics in the management of osteoarthritis: a systematic review and meta-analysis. Rheumatol Int 176: 106-114.
- Chou R, Deyo R, Friedly J, Skelly A, Weimer M, et al. (2017) Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.Ann Intern Med 166: 480-492. [crossref]
- Saragiotto BT, Machado GC, Ferreira ML, Pinheiro MB, Abdel Shaheed C, et al. (2016) Paracetamol for low back pain.Cochrane Database Syst Rev CD012230. [crossref]
- Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, et al. (2015) Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials.BMJ350: h1225. [crossref]
- Vannacci A, Lombardi N, Simonetti M, Fornasari D, Fanelli A, et al. (2017) Regular use of acetaminophen or acetaminophen-codeine combinations and prescription of rescue therapy with non-steroidal anti-inflammatory drugs: a population-based study in primary care.Curr Med Res Opin33: 1141-1148. [crossref]
- Zhu X, Wu D, Sang L, Wang Y, Shen Y, et al. (2018) Comparative effectiveness of glucosamine, chondroitin, acetaminophen or celecoxib for the treatment of knee and/or hip osteoarthritis: a network meta-analysis.Clin Exp Rheumatol36: 595-602. [crossref]
- da Costa BR, Reichenbach S, Keller N, Nartey L, Wandel S, et al. (2017) Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.Lancet390: e21-21e33. [crossref]