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Where are we now with paracetamol?

BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h3705 (Published 10 July 2015) Cite this as: BMJ 2015;351:h3705

Rapid Response:

Intravenous Paracetamol: Wolf in sheep's packaging?

Dear et al raise awareness of the clinical role and potential hazards of the use of paracetamol. Their piece is instructive and timely. Paracetamol is frequently prescribed but many be neither as efficacious nor as entirely anodyne as originally thought. However it is important to take this opportunity to highligh specific dangers peculiar to intravenous paracetamol. Indeed it is many ways a different entity to oral paracetamol with regard to its clinical behaviour and safety profile(1,2,3). Unlike the oral preparation the intravenous dose is weight-dependent. The use of intravenous paracetamol has increased exponentially since first being licensed in 2004. Discussion of paracetamol can not relate exclusively to the oral formulation.
When administered intravenously paracetmaol has 100% bioavailability. This can result in hepatic toxicity, if not titrated to weight, particularly in those with renal impairment. In 2010 The UK Medicines and Healthcare products Regulatroy Agency (MHRA) issued a Drug Saftety Update highlighting the need for caution and vigiliance in the use of intravenous paracetamol(2). Increased awareness to the possibility of iatrogenic paracetamol overdose should have arisen in the UK following a fatal case in Scotland. In 2011 the Fatal Accident enquiry found that
“there existed a prevailing culture of assumed familiarity with the administration of IV paracetamol, a familiarity derived from the common use of oral paracetamol”(1,4).
Following this the MHRA understandably felt the need to issue a further “Safety Memo” emphasising the pressing need to disseminate amongst the medical community the special precautions required in the use of intraveous paracetamol. The MHRA advises that for adults weighing greater than 50mg, the standard dose of 1g of intravenous paracetamol can be administered 4 times a day with a maximum does of 4g in a day. However in those weighing less than 50kg the dose must be tailored to the weight. The safe dose for such patients is 15mg/kg to a maximum dose of 60mg/kg a day. The minimal interval between doses if 4 hours or 6 hours for those with renal impariment(1,2,3).
It is not clear how widely appreciated this guidance is. Both the 2011 NICE and the 2011 Association of Anaesthetists of Great Britain and Ireland guidance on hip fractures recommend the regular and routine use of paracetamol(5,6). Neither makes a distinction between the intravenous and oral paracetamol. However this cohort of patients are frail and elderly. 40% have renal impairment (eGFR<60 ml.min-1.1.73m-1). Surgical patients are at particular risk of the intravenous paracetamol toxicity due to glutathione depletion following fasting(1). This may be compounded by the pre-existing poor nutritional status of hip fracture patiens(1,5,6). Glutathione is sequestered by certain paracetamol metabolites rendering the liver vulnerable to injury. The anaesthetic guidance advises caution in the use of opioids but makes no similar recommendation with respect to pracetamol. Similarly the NICE guidances states that with regard to paracetamol and its adverse effects that “there are virtually none but may decrease blood pressure with [the] iv” preparation. However the document does advise caution in those with renal or hepatic impairment. More may need to be done to raise awareness. Without due clinical diligence intravenous paracetamol can easily become the wolf in sheep's packaging.

(1)http://www.aagbi.org/sites/default/files/intravenousparacetamol.pdf
(2)http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON088171
(3)http://www.medicinesgovernance.hscni.net/download/secondary%20care/Safet....
(4)http://www.scotcourts.gov.uk/opinions/2011FAI7.html
(5)http://www.nice.org.uk/guidance/cg124/evidence/cg124-hip-fracture-full-g...
(6)http://www.aagbi.org/sites/default/files/femoral%20fractures%202012_0.pdf

Competing interests: No competing interests

18 July 2015
Chika E Uzoigwe
Orthopaedics
Sheffield, UK