Paracetamol for pain in adults

Dear Editor,

We read with great interest the review written by Saragiotto et al., « Paracetamol for pain in adults », focused on primary care.

We would like to thank the authors for their effort to try to summarize in a few pages the current scientific evidence about the efficacy and the security of this analgesic in primary care, even if the final result cannot claim to be exhaustive:

• Sore throat pain/upper respiratory tract infections should have been added to clinical contexts mentioned in this report: the analgesic efficacy of a single dose of oral paracetamol versus placebo has already been proven by a few randomized controlled trials (RCTs) in this context [1].

• Results of Cochrane meta-analyses were highlighted by the authors (« Table 1 presents key findings from the Cochrane reviews of paracetamol for pain relief in these conditions »); but they also present results from two non-Cochrane meta-analyses (Hazlewood 2012 [2] and Garcia-Perdomo 2017 [3]) without any justification about this choice*.

• Data concerning acute renal colic pain are also reported, although these data are provided by only one study assessing the efficacy of paracetamol versus placebo, administered by intravenous route, in patients recruited from a hospital emergency department [4].

Furthermore, we think that distinction between acute pain conditions (such as headache) and chronic pain conditions (such as osteoarthritis) should have been pointed out because outcome criteria in RCTs differ in these two conditions:

• In acute pain, RCTs usually assess the efficacy of a single dose of paracetamol within hours after drug administration.

• In chronic pain, RCTs usually assess the efficacy of repeated doses on pain, which is at best rated daily (but often at several weeks apart), and/or on patient functions.

The questions « Will I be relieved within hours after drug intake ? » and « Will this drug relieve my pain in the coming weeks ? », «Will this drug help me move better/function better ? » are different questions which may have different responses, but not necessarily conflicting. To the best of our knowledge, there is no RCT on chronic pain and assessing a single dose of oral paracetamol versus placebo within hours after drug intake, to be able to answer to the patient from the case report.

Finally, this work is one more evidence of the few clinical contexts of primary care where the analgesic effect of paracetamol has been studied, whereas paracetamol is widely prescribed in primary care. Most of efficacy data concerning paracetamol versus placebo on acute pain come from postoperative pain trials, because these situations are well standardized and therefore more able to find a difference, even if it is small, between paracetamol and placebo [5]. But the mechanism of action of paracetamol is still incompletely known, and some data suggest that its action could depend on the inflammatory cellular context [6]. Applying the results obtained in a few clinical pain conditions -- in most cases postoperative pain conditions -- to all pain conditions we usually meet in primary care, cannot be taken for granted. At equal baseline intensity pain level, does an oral dose of paracetamol relieve, regardless of the disease causing pain, and does it always relieve with the same effect size (a little, a lot, or not at all)? This question of a potential interaction between the pharmacological effect of paracetamol and the clinical context is, to our knowledge, remains unanswered.

* Note to Editor : All bibliographic references from Table 1 have been mixed up.

(Thanks to Deep B. for his assistance for translation)

References
1. Gougain M, Moreau A, Boussageon R, Pickering G, Gueyffier F. Acute analgesic effect of paracetamol in primary care : incomplete evidence. Therapie 2017 ; 72(5) : 609-13
2. Hazlewood G, Van der Heijde DM, Bombardier C. Paracetamol for the management of pain in inflammatory arthritis: a systematic literature review. J Rheumatol Suppl 2012;90:11-6. 10.3899/jrheum.120336 22942323
3. García-Perdomo HA, Echeverría-García F, López H, Fernández N, Manzano-Nunez R. Pharmacologic interventions to treat renal colic pain in acute stone episodes: systematic review and meta-analysis. Prog Urol 2017;27:654-65.
4. Bektas F, Eken C, Karadeniz O, Goksu E, Cubuk M, CeteY. Intravenous paracetamol or morphine for the treatment of renal colic: A randomized placebo-controlledtrial. Ann Emerg Med 2009 ; 54 : 568-74
5. Cooper SA, Desjardins PJ, Turk DC, Dworkin RH, Katz NP, Kehlet H, et al. Research design considerations for single-dose analgesic clinical trials in acute pain : IMMPACT recommendations. Pain 2016 ; 157(2) : 288-301
6. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol : therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 2013 ; 21(3) :201-32