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Where are we now with paracetamol?

BMJ 2015; 351 doi: (Published 10 July 2015) Cite this as: BMJ 2015;351:h3705

Rapid Response:

Paracetamol Paradox: Distinguish acute and chronic pain; then answers may lie in the pharmacology.

Dear et al write a synopsis of the uncertain status of paracetamol, which is both insightful and engaging. However it is important to draw a clear distinction between acute and chronic pain, so as not to conflate the evidence regarding its respective efficacy in terms of these two complaints.

Meta-analyses and randomised controlled trials show paracetamol is effective at providing pain relief in the acute postoperative setting, irrespective of procedure, and following acute injury(1,2,3,4,5). However its role in chronic pain (back pain and joint osteoarthritis) is less clear(6). In the PACE "acute" back pain trial, cited by the authors patients, which showed a lack of paracetamol efficacy, patients were only excluded if symptoms were greater than 6 weeks in duration(7). In addition on average participants had suffered over 6 previous episodes of back pain; indicating a subacute or acute on chronic phenomenon.

The function of paracetamol appears paradoxical with regard to acute and chronic pain. The mechanism of action of paracetamol remains imperfectly understood, and is only starting to now emerge, over 50 years after the drug's introduction. As the authors correctly state, it has been found to be a strong selective inhibitor of COX-2(8). This is an inducible enzyme and unlike COX-1, is generally only produced during acute inflammation or injury(8). Further the comparative hypoxia at sites of acute inflammation/injury may potentiate the mode of action of paracetamol, which is thought quench free radicals critical to the COX-2 enzyme cycle(8,9). This is consistent with the evidence that supports the efficacy of paracetamol in the acute setting. Intriguingly selective COX 2 inhibitors do not require a specifically inflammatory, post-traumatic or hypoxic (reducing) environment to function(9), perhaps explaining the differing global cardiovascular sequelae of the coxibs and paracetamol. Pharmacology may not be the most popular subject at medical school, however at times it is critical to informing our clinical practice. This is particularly so with paracetamol, where insights into its mode action have occurred long after the inception of clinical use.

(1)Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database Syst Rev. 2008: CD004602.

(2)Bondarsky EE, Domingo AT, Matuza NM, Taylor MB, Thode HC Jr, Singer AJ. Ibuprofen vs acetaminophen vs their combination in the relief of musculoskeletal pain in the ED: a randomized, controlled trial. Am J Emerg Med. 2013:1357-6

(3)Woo WW, Man SY, Lam PK, Rainer TH. Randomized double-blind trial comparing oral paracetamol and oral nonsteroidal antiinflammatory drugs for treating pain after musculoskeletal injury. Ann Emerg Med. 2005; 46:352-61

(4)Shams Vahdati S, Morteza Baghi HR, Ghobadi J, Rajaei Ghafouri R, Habibollahi P. Comparison of paracetamol (apotel®) and morphine in reducing post pure head trauma headache. Anesth Pain Med. 2014:e14903

(5)Deshpande A, Bhargava D, Gupta M. Analgesic efficacy of acetaminophen for controlling postextraction dental pain. Ann Maxillofac Surg. 2014 4:176-7. doi: 10.4103/2231-0746.147117

(6)Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, McLachlan AJ, Ferreira ML. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015 Mar 31;350:h1225

(7)Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial. Lancet2014;384:1586-96.

(8)Hinz, B., Cheremina, O.Brune, K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2008; 22: 383–390

(9)Hinz B, Brune K.m Paracetamol and cyclooxygenase inhibition: is there a cause for concern? Ann Rheum Dis. 2012; 71:20-5.

Competing interests: No competing interests

20 July 2015
Ossie F Uzoigwe
Medical Writer
University of Sheffield
University of Sheffield, UK