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Acetaminophen (Paracetamol)

Open AccessPublished:October 14, 2013DOI:https://doi.org/10.1016/j.jpainsymman.2013.08.001
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations

      CNS
      Central nervous system
      COX
      Cyclo-oxygenase
      CSF
      Cerebrospinal fluid
      CYP450
      Cytochrome P450
      INR
      International normalized ratio
      IV
      Intravenous
      IVI
      Intravenous infusion
      LFT
      Liver function test
      NAPQI
      N-acetyl-p-benzoquinoneimine
      NSAID
      Nonsteroidal anti-inflammatory drug
      OTC
      Over the counter (i.e., can be obtained without a prescription)
      PO
      Per os, by mouth
      PR
      Per rectum
      q4h
      Every 4 hours
      q.i.d.
      quarta in die, four times daily
      RCT
      Randomized controlled trial
      rINN
      Recommended International Non-proprietary Name
      WFI
      Water for injection
      There are increasing reports of unintentional overdose of acetaminophen (paracetamol, rINN) resulting in hepatotoxicity. To reduce this risk, the dose of acetaminophen should never exceed the maximum recommended dose, be appropriate for the weight of the patient, and reduced when risk factors for hepatotoxicity exist, e.g., old age, poor nutritional status, fasting/anorexia, concurrent use of drugs that interact with acetaminophen metabolism, and chronic alcohol use.
      For international educational and comparative purposes, this article also refers to formulations not available in the USA, e.g., propacetamol.
      Class: Non-opioid analgesic.
      Indications: PO mild–moderate pain, migraine and tension headache, fever.
      IV short-term treatment of mild–moderate pain, moderate–severe pain (in combination with an opioid) and fever when PO or PR routes not possible.
      Contraindications: IV severe hepatic impairment or severe active liver disease.

      Pharmacology

      Acetaminophen is a synthetic non-opioid analgesic and antipyretic.
      OICPC Therapeutic Highlights
      Paracetamol.
      • Flower R.J.
      • Vane J.R.
      Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol.
      It acts mainly in the CNS, where it has several effects. It is a weak inhibitor of cyclo-oxygenase (COX)-2, an effect that lasts a short time (≤2 h) after a dose,
      • Hinz B.
      • Cheremina O.
      • Brune K.
      Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man.
      • Hinz B.
      • Brune K.
      Paracetamol and cyclooxygenase inhibition: is there a cause for concern?.
      but can also be anti-inflammatory through inhibition of peroxidase regeneration. The latter action, which prevents the oxidation of inactive COX to active COX, can be significant when peroxidase levels are low, e.g., in intact cells in the CNS, but not when peroxidase levels are much higher, e.g., with tissue damage and/or inflammation in the periphery.
      • Mattia A.
      • Coluzzi F.
      What anesthesiologists should know about paracetamol (acetaminophen).
      In addition, acetaminophen has been shown to:
      • interact with L-arginine-nitric oxide, opioid and cannabinoid systems
        • Björkman R.
        • Hallman K.M.
        • Hedner J.
        • Hedner T.
        • Henning M.
        Acetaminophen (paracetamol) blocks spinal hyperalgesia induced by NMDA and substance P.
        • Pini L.A.
        • Vitale G.
        • Ottani A.
        • Sandrini M.
        Naloxone-reversible antinociception by paracetamol in the rat.
      • activate descending serotoninergic inhibitory pain pathways.
        • Mallet C.
        • Daulhac L.
        • Bonnefont J.
        • et al.
        Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia.
        • Dogrul A.
        • Seyrek M.
        • Akgul E.O.
        • et al.
        Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT(7) receptors.
      It is possible that the analgesic effect of acetaminophen is dependent on synergy between some or all these mechanisms.
      • Pickering G.
      • Loriot M.A.
      • Libert F.
      • et al.
      Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism.
      Evidence of synergy between acetaminophen and NSAIDs suggests differing analgesic mechanisms.
      • Miranda H.F.
      • Puig M.M.
      • Prieto J.C.
      • Pinardi G.
      Synergism between paracetamol and nonsteroidal anti-inflammatory drugs in experimental acute pain.
      • Ong C.K.
      • Seymour R.A.
      • Lirk P.
      • Merry A.F.
      Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain.
      Acetaminophen is widely used for acute musculoskeletal pains and acute headache. When used in combination with an opioid to treat postoperative pain, IV acetaminophen has an “opioid-sparing” effect and improves overall analgesia.
      • Tzortzopoulou A.
      • McNicol E.D.
      • Cepeda M.S.
      • et al.
      Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain.
      Postoperative nausea and vomiting also is reduced, but only when the acetaminophen is administered before, during or immediately after surgery. The improvement correlated with the degree of pain relief (but not opioid use), suggesting a possible indirect or direct anti-emetic effect of acetaminophen.
      • Apfel C.C.
      • Turan A.
      • Souza K.
      • Pergolizzi J.
      • Hornuss C.
      Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis.
      Evidence of the efficacy of acetaminophen in combination with an opioid in the treatment of cancer pain is mixed. However, the RCTs that suggested no benefit
      • Axelsson B.
      • Christensen S.
      Is there an additive analgesic effect of paracetamol at step 3? A double-blind randomized controlled study.
      • Israel F.J.
      • Parker G.
      • Charles M.
      • Reymond L.
      Lack of benefit from paracetamol (acetaminophen) for palliative cancer patients requiring high-dose strong opioids: a randomized, double-blind, placebo-controlled, crossover trial.
      were underpowered,
      • Formby F.T.
      Re: lack of benefit from paracetamol (acetaminophen) for palliative cancer patients.
      and another RCT showed a small but clinically important additive effect in about one-third of patients despite the fact that half were already taking an NSAID or a corticosteroid.
      • Stockler M.
      • Vardy J.
      • Pillai A.
      • Warr D.
      Acetaminophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo-controlled cross-over trial.
      Given that an acetaminophen regimen of 650 mg–1 g q.i.d. may pose a considerable pill burden to some patients with cancer, a pragmatic solution might be:
      • to limit the long-term use of acetaminophen to patients in whom definite benefit is seen within 2 days of starting it
      • if already taking acetaminophen with definite past benefit and increasing pain necessitates the addition of an opioid, the ongoing need for acetaminophen should be determined by stopping it after 3–4 days of satisfactory pain relief with both drugs; the acetaminophen is restarted only if the pain returns.
      Single doses of IV acetaminophen provide dose-dependent analgesia in doses up to 2 g.
      • Piguet V.
      • Desmeules J.
      • Dayer P.
      Lack of acetaminophen ceiling effect on R-III nociceptive flexion reflex.
      Increased peak plasma concentrations lead to earlier and higher concentrations of acetaminophen in the CSF, which in turn lead to an earlier onset of action, a longer duration of action, and a greater overall analgesic effect.
      • Jarde O.
      • Boccard E.
      Parenteral versus oral route increases paracetamol efficacy.
      In patients undergoing molar dental extraction, compared with 1 g, 2 g of acetaminophen gave 50% more relief for 50% more time (5 h vs. 3.2 h).
      • Juhl G.I.
      • Norholt S.E.
      • Tonnesen E.
      • Hiesse-Provost O.
      • Jensen T.S.
      Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2 g starting dose following third molar surgery.
      Thus, there may be a place for an initial loading dose when prescribing acetaminophen.
      Parenteral propacetamol, an inactive pro-drug of acetaminophen, is available in some countries (not USA or UK), and is used particularly for orthopedic postoperative pain management.
      • Peduto V.A.
      • Ballabio M.
      • Stefanini S.
      Efficacy of propacetamol in the treatment of postoperative pain. Morphine-sparing effect in orthopedic surgery. Italian Collaborative Group on Propacetamol.
      Propacetamol 2 g yields acetaminophen 1 g.
      • Flouvat B.
      • Leneveu A.
      • Fitoussi S.
      • Delhotal-Landes B.
      • Gendron A.
      Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects.
      Because of a significant risk of sensitization, the manufacturer's protocol must be adhered to.
      Only 2–5% of a therapeutic dose of acetaminophen is excreted unchanged in the urine; the remainder is metabolized mainly by the liver. At therapeutic doses, >80% of acetaminophen is metabolized to glucuronide and sulfate conjugates. About 5–10% is converted by hepatic CYP450 enzymes (mainly CYP2E1 and CYP3A4) to a highly reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI; Fig. 1), which is hepatotoxic. With normal therapeutic doses (i.e., ≤1 g q.i.d.), NAPQI is generally inactivated sufficiently rapidly so as not to cause liver damage.
      In addition to dose, there are other determinants of exposure to NAPQI. For example, metabolism of acetaminophen is gender-dependent (women eliminate the drug more slowly
      • Liukas A.
      • Kuusniemi K.
      • Aantaa R.
      • et al.
      Pharmacokinetics of intravenous paracetamol in elderly patients.
      ) and age-dependent (increased risk of hepatotoxicity in the elderly
      • Mitchell S.J.
      • Kane A.E.
      • Hilmer S.N.
      Age-related changes in the hepatic pharmacology and toxicology of paracetamol.
      ). An 80-year-old may be exposed to 1.5 times the NAPQI concentration as a 20-year-old when given the same dose of IV acetaminophen.
      • Mitchell S.J.
      • Kane A.E.
      • Hilmer S.N.
      Age-related changes in the hepatic pharmacology and toxicology of paracetamol.
      There are also genetic variations in acetaminophen metabolism.
      • Zhao L.
      • Pickering G.
      Paracetamol metabolism and related genetic differences.
      Those with CYP2D6 gene duplication (ultra-rapid metabolizers), have a greater susceptibility to hepatotoxicity because of an increased production of NAPQI.
      • Dong H.
      • Haining R.L.
      • Thummel K.E.
      • Rettie A.E.
      • Nelson S.D.
      Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen.
      Specific drugs also may inhibit glucuronidation or induce the oxidation of acetaminophen to NAPQI (see Box A).
      Risk factors for acetaminophen hepatotoxicity
      • Horsmans Y.
      • Sempoux C.
      • Detry R.
      • Geubel A.P.
      Paracetamol-induced liver toxicity after intravenous administration.
      • Zimmerman H.
      • Maddrey W.
      Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure.
      OldagePoornutritionalstatusFasting/anorexia}lowerglutathionestores


      Concurrent use of glucuronidation inhibitors and/or CYP2E1-inducing drugs, e.g., phenobarbital, primidone, probably isoniazid, and possibly St. John's wort
      Chronic alcohol use

      Unintentional and deliberate overdose and NAPQI-induced hepatotoxicity

      An overdose of acetaminophen overwhelms its normal metabolism, shifting more acetaminophen into the NAPQI pathway. NAPQI is normally inactivated by conjugation with glutathione but, in overdose, the body's glutathione store becomes exhausted and the accumulation of NAPQI leads to liver parenchymal cell death.
      Although overdose is traditionally associated with ingestion of a large single dose of acetaminophen as a deliberate suicide attempt, reports of unintentional overdose from its analgesic use are increasing.

      MHRA. Intravenous paracetamol (Perfalgan): risk of accidental overdose especially in infants and neonates. Drug Saf Update July 2010;3:2. Available from www.mhra.gov.uk//Safetyinformation.

      • Larson A.M.
      • Polson J.
      • Fontana R.J.
      • et al.
      Acute Liver Failure Study Group
      Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.
      A man aged 43 with Crohn's colitis and weighing 30 kg died of hepatic failure after taking 4 g/24 h for only 4 days.
      • Claridge L.C.
      • Eksteen B.
      • Smith A.
      • Shah T.
      • Holt A.P.
      Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults.
      Indeed, there are numerous reports of hepatotoxicity associated with chronic use of 5–7.5 g/24 h.
      • Krenzelok E.P.
      The FDA Acetaminophen Advisory Committee Meeting - what is the future of acetaminophen in the United States? The perspective of a committee member.
      Thus, the dose of acetaminophen must always be appropriate for the weight and circumstances of the patient, and the maximum recommended dose not exceeded.
      Repeated suprathreshold ingestion over a time period of >8 h (“staggered overdose”) produces a higher risk of liver and multi-organ failure, and a lower unassisted survival rate, than single time point overdose. About two-thirds of staggered overdoses relate to medicinal use rather than attempted suicide.
      • Craig D.G.
      • Bates C.M.
      • Davidson J.S.
      • et al.
      Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity.
      The likelihood of an unintentional/staggered overdose is greater in patients with one or more risk factors for acetaminophen hepatotoxicity (Box A).
      A single time point overdose of acetaminophen below 125 mg/kg (7.5 g or 15 tablets in a 60 kg person) is unlikely to result in liver damage. At twice this dose, the probability of liver damage is around 50%, but the individual may remain well. A dose of 500 mg/kg (30 g or 60 tablets in a 60 kg person) is almost certain to produce life-threatening liver damage. Acetaminophen overdose also can lead to acute renal failure, although this is often reversible without the need for dialysis.
      • von Mach M.A.
      • Hermanns-Clausen M.
      • Koch I.
      • et al.
      Experiences of a poison center network with renal insufficiency in acetaminophen overdose: an analysis of 17 cases.
      Overdose, whether deliberate or unintentional, can be treated with a glutathione precursor, e.g., IVI acetylcysteine (Box B)

      MHRA. Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine. Drug Safety Update September 2012;6: A1. Available from www.mhra.gov.uk//Safetyinformation.

      Acetadote (acetylcysteine) Package Insert. Available from http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021539s012lbl.pdf. Accessed September 27, 2013.

      or PO methionine.

      British National Formulary Emergency treatment of poisoning. London: BMJ Group and Pharmaceutical Press. Available from www.bnf.org. Accessed March 15, 2013.

      • Ferner R.E.
      • Dear J.W.
      • Bateman D.N.
      Management of paracetamol poisoning.
      If given within 15 h of the overdose, acetylcysteine prevents NAPQI from reacting with liver cell proteins. Further, because it has a protective effect against apoptosis (programmed cell death), acetylcysteine can help to a lesser extent if given for ≤3 days after the overdose.
      Use of acetylcysteine
      A total dose of 300 mg/kg is given by three separate IVI over a total of 21 h. The recommended volume of diluent varies according to the weight of the patient. For those weighing 41–100 kg:
      • loading dose: 150 mg/kg diluted in 200 mL, given over 1 h
      • second dose: 50 mg/kg diluted in 500 mL, given over 4 h
      • third dose: 100 mg/kg diluted in 1000 mL, given over 16 h.
      For those weighing 21–40 kg, use half the volume of diluent. For patients whose weight falls outside of these ranges, see Prescribing Information.
      5% dextrose in water, 0.45% sodium chloride or WFI can be used as diluent.
      Acute alcohol intake does not increase the risk of hepatotoxicity. Indeed, because alcohol and acetaminophen compete for the same oxidative enzymes, acute alcohol consumption at the time of an acetaminophen overdose may be protective. However, because alcohol consumption induces the production of the relevant enzymes, if chronic alcohol use suddenly stops, acetaminophen will be metabolized more rapidly, and could lead to hepatotoxicity.
      • Gómez-Moreno G.
      • Guardia J.
      • Cutando A.
      Interaction of paracetamol in chronic alcoholic patients. Importance for odontologists.
      In any case, some alcoholics are more susceptible to acetaminophen toxicity, possibly because of their poor nutritional status.
      • Riordan S.M.
      • Williams R.
      Alcohol exposure and paracetamol-induced hepatotoxicity.
      To reduce the chance of unintentional overdose, the United States Food and Drug Administration has recommended that:

      FDA. Liver injury related to the use of acetaminophen in both over-the-counter and prescription products. Advisory Committe Meeting (transcript). 2009. Available from www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm.

      FDA. Prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. Drug Saf Commun 2011. Available from http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm. Accessed September 27, 2013.

      • the amount of acetaminophen in a prescription tablet, capsule, or other dosage unit is limited to a maximum of 325 mg by the end of 2013
      • the maximum single dose is lowered to 650 mg
      • a boxed warning is added highlighting the potential for severe liver injury
      • patients should not exceed a total daily dose of 4 g.
      Implementation is in process and “extra strength” products containing 500 mg/dose unit remain available. However, over-the-counter products now recommend a maximum dose of 2.6–3 g/24 h, which patients should not exceed unless directed by a doctor.
      Bioavailability 60% after 500 mg PO, 90% after 1 g PO; PR is about two-thirds of PO, but is higher with two 500 mg suppositories than with one 1 g suppository.
      Onset of action 15–30 min PO; 5–10 min IV (pain relief), 30 min IV (antipyretic effect).
      Time to peak plasma concentration widely variable PO, e.g., 20 min in fasting state but 1–2 h if delayed gastric emptying;
      • Prescott L.F.
      Paracetamol (acetaminophen): A critical bibliographic review.
      15 min IVI (this is synchronous with the end of a 15 min infusion).
      Plasma half-life 1.25–3 h PO;
      • Prescott L.F.
      Paracetamol (acetaminophen): A critical bibliographic review.
      2–3 h IV.
      Duration of action 4–6 h PO and IV.

      Cautions

      Severe hepatic impairment or severe active liver disease (IV use contraindicated in this setting), particularly if associated with alcohol dependence and malnutrition. In severe renal impairment (creatinine clearance <30 mL/min), the dose interval should ≥6 h.
      Most dispersible or effervescent acetaminophen-containing tablets (alone or combined with an opioid) have a Na+ content of ≥14 mmol/tablet. Thus, a dose of 8 tablets/24 h would exceed the recommended maximum daily dietary Na+ intake of 100 mmol (6 g of sodium chloride). Dispersible or effervescent formulations should thus be avoided in patients with hypertension or renal impairment, particularly if already on a salt-restricted diet. In contrast, non-soluble formulations contain negligible Na+.

      UK Medicines Information. What is the sodium content of medicines? Q&As. 145.4. 2012. Available from www.evidence.nhs.uk. Accessed September 27, 2013.

      Acetaminophen can be taken by at least two-thirds of patients who are hypersensitive to aspirin or other NSAID.
      • Szczeklik A.
      Analgesics, allergy and asthma.
      • Settipane R.A.
      • Schrank P.J.
      • Simon R.A.
      • et al.
      Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects.
      In people with a history of aspirin/NSAID-induced asthma, give a test dose of 250 mg (half a tablet) and observe for 2–3 h. If no undesirable effects occur, acetaminophen can safely be used in standard doses.
      • Shin G.Y.
      • Dargan P.
      • Jones A.L.
      Paracetamol and asthma.

      Drug Interactions

      Concurrent use of glucuronidation inhibitors and/or CYP2E1-inducing drugs, e.g., phenobarbital, primidone, probably isoniazid, and possibly St. John's wort may increase the risk of acetaminophen toxicity (Box A).
      Concurrent use of the 5HT3-receptor antagonists tropisetron and granisetron can completely block the analgesic effect of acetaminophen,
      • Pickering G.
      • Loriot M.A.
      • Libert F.
      • et al.
      Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism.
      but ondansetron may be safe in this respect.
      • Jokela R.
      • Ahonen J.
      • Seitsonen E.
      • Marjakangas P.
      • Korttila K.
      The influence of ondansetron on the analgesic effect of acetaminophen after laparoscopic hysterectomy.
      Concurrent use with warfarin: a regular daily intake of acetaminophen ≥1300 mg for one week may increase the INR to >6,
      • Bell W.
      Acetaminophen and warfarin: undesirable synergy.
      • Hylek E.M.
      • Heiman H.
      • Skates S.J.
      • Sheehan M.A.
      • Singer D.E.
      Acetaminophen and other risk factors for excessive warfarin in anticoagulation.
      but a total weekly dose of acetaminophen of ≤2 g has no effect. The underlying mechanism is not clear, but may relate to interference with the hepatic synthesis of factors II, VII, IX and X. A recent post-mortem series found that concurrent acetaminophen increases the risk of a bleed with warfarin 2.7 times.
      • Launiainen T.
      • Sajantila A.
      • Rasanen I.
      • Vuori E.
      • Ojanperä I.
      Adverse interaction of warfarin and paracetamol: evidence from a post-mortem study.

      Undesirable Effects

      Very common (>10%): dyspepsia, elevated liver enzymes (Box C).
      Acetaminophen and elevated liver enzymes
      • Watkins P.B.
      • Kaplowitz N.
      • Slattery J.T.
      • et al.
      Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.
      • Dart R.C.
      • Bailey E.
      Does therapeutic use of acetaminophen cause acute liver failure?.
      The plasma levels of various liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase, γ-glutamyl transferase) can increase with normal doses of acetaminophen.
      For example, ALT increased >3 times the upper limit of normal in 40% of young healthy volunteers receiving 4 g/day, with the highest increase 14–16 times greater. The rise was evident after 72 h, and persisted for a median of one week after discontinuation.
      These changes are probably unimportant in the absence of functional or synthetic liver impairment (e.g., indicated by an increase in plasma bilirubin or a reduction in clotting factors, respectively) and possibly improve with ongoing use, although this is poorly documented.
      Awareness of this phenomenon may aid interpretation of abnormal LFTs, and help avoid the erroneous assumption that rapidly worsening LFTs must indicate rapidly worsening disease within the liver, e.g., from liver metastases.
      Rare (<0.1%, >0.01%): PO cholestatic jaundice,
      • Waldum H.L.
      • Hamre T.
      • Kleveland P.M.
      • Dybdahl J.H.
      • Petersen H.
      Can NSAIDs cause acute biliary pain and cholestasis?.
      • Wong V.
      • Daly M.
      • Boon A.
      • Heatley V.
      Paracetamol and acute biliary pain with cholestasis.
      acute pancreatitis, thrombocytopenia, agranulocytosis, anaphylaxis.
      • Leung R.
      • Plomley R.
      • Czarny D.
      Paracetamol anaphylaxis.
      • Mendizabal S.
      • Gomez M.D.
      Paracetamol sensitivity without aspirin intolerance.
      • Morgan S.
      • Dorman S.
      Paracetamol (acetaminophen) allergy.
      IV malaise, hypotension.
      Chronic acetaminophen use increases the risk of renal impairment 2.5 times; and the risk is related to dose and cumulative exposure over a lifetime.
      • D'Arcy P.
      Paracetamol.
      • Fored C.M.
      • Ejerblad E.
      • Lindblad P.
      • et al.
      Acetaminophen, aspirin, and chronic renal failure.
      The risk is higher in diabetics, and when renal impairment is associated with systemic vasculitis.
      The use of acetaminophen in pregnancy and early childhood increases the risk of a child developing asthma.
      • Holgate S.T.
      The acetaminophen enigma in asthma.
      However, there is no hard evidence that acetaminophen precipitates asthma in established asthmatics.
      • Shin G.Y.
      • Dargan P.
      • Jones A.L.
      Paracetamol and asthma.
      • Shaheen S.O.
      • Sterne J.A.
      • Songhurst C.E.
      • Burney P.G.
      Frequent paracetamol use and asthma in adults.

      Dose and Use

      In palliative care, typical PO doses for adults generally range from 500 mg–1 g q.i.d.
      • Stockler M.
      • Vardy J.
      • Pillai A.
      • Warr D.
      Acetaminophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo-controlled cross-over trial.
      However, in patients with risk factors for acetaminophen hepatotoxicity (Box A), it is safer to opt for a submaximal dose. Further, despite the lower PR bioavailability, in practice the rectal dose is generally the same as the PO dose.

      IV

      IV acetaminophen (1 g in 100 mL) is given by infusion over 15 min. There have been case reports of massive inadvertent iatrogenic IV overdose leading to hepatic failure, sometimes fatal, particularly in children.
      • Dart R.C.
      • Rumack B.H.
      Intravenous acetaminophen in the United States: iatrogenic dosing errors.
      The available IV solution contains 10mg/mL. When written up just as mg, it has occasionally been misread and given as mL, with the result that the patient has received 10 times the prescribed dose. To minimize the chance of this happening, a prescription for IV acetaminophen should be written in terms of both mg and mL, not just as mg.
      IV acetaminophen can be used when administration PO or PR is not possible. The dose depends on body weight and the presence/absence of risk factors for acetaminophen hepatotoxicity:
      • adults and children >50 kg, 1 g up to q4 h, maximum recommended dose 4 g/24 h
      • adults and children >50 kg plus any risk factors, restrict maximum dose to 3 g/24 h
      • adults and children 10–50 kg, 15 mg/kg up to q4 h, maximum recommended dose 60 mg/kg/24 h.

        British National Formulary. London: BMJ Group and Pharmaceutical Press. Available from: www.bnf.org. Accessed March 15, 2013.

      Supply

      Acetaminophen (generic)

      Tablets 325 mg, 28 days @ 650 mg q.i.d. = $15.
      Tablets 500 mg, 28 days @ 1 g q.i.d. = $15.
      Caplets (capsule-shaped tablets) and Geltabs 500 mg are available OTC; many patients find these easier to swallow.
      Oral suspension 160 mg/5 mL, 1 g/30 mL, 28 days @ 1 g q.i.d. = $168.

      Tylenol® (McNeil)

      Tablets 325 mg, 28 days @ 650 mg q.i.d. = $21.
      Tablets (Caplets) 500 mg, 28 days @ 1 g q.i.d. = $22.
      Oral suspension 160 mg/5 mL, 28 days @ 1 g q.i.d. = $178; cherry, grape or bubble gum flavor; available OTC.

      Sustained-release

      Tablets ER (Caplets) 650 mg, 28 days @ 650 mg q.i.d. = $19.

      Tylenol® Arthritis Relief (McNeil)

      Tablets ER (Caplets) 650 mg, 28 days @ 650 mg q.i.d. = $19.

      Rectal Preparations

      Suppositories 120 mg, 325 mg, 650 mg, 28 days @ 1 q.i.d. = $66, $74 and $79, respectively.

      Ofimev® (Cadence)

      Injection (for IV infusion) 10 mg/mL, 100 mL vial (1 g) = $15.
      This is not a complete list; oral acetaminophen is also available in several combination products with weak opioids or oxycodone.

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