Paracetamol in Older People: Towards Evidence-Based Dosing?

Abstract

Paracetamol is the most commonly used analgesic in older people, and is mainly dosed according to empirical dosing guidelines. However, the pharmacokinetics and thereby the effects of paracetamol can be influenced by physiological changes occurring with ageing. To investigate the steps needed to reach more evidence-based paracetamol dosing regimens in older people, we applied the concepts used in the paediatric study decision tree. A search was performed to retrieve studies on paracetamol pharmacokinetics and safety in older people (> 60 years) or studies that performed a (sub) analysis of pharmacokinetics and/or safety in older people. Of 6088 articles identified, 259 articles were retained after title and abstract screening. Further abstract and full-text screening identified 27 studies, of which 20 described pharmacokinetics and seven safety. These studies revealed no changes in absorption with ageing. A decreased (3.9-22.9%) volume of distribution (Vd) in robust older subjects and a further decreased Vd (20.3%) in frail older compared with younger subjects was apparent. Like Vd, age and frailty decreased paracetamol clearance (29-45.7 and 37.5%) compared with younger subjects. Due to limited and heterogeneous evidence, it was difficult to draw firm and meaningful conclusions on changed risk for paracetamol safety in older people. This review is a first step towards bridging knowledge gaps to move to evidence-based paracetamol dosing in older subjects. Remaining knowledge gaps are safety when using therapeutic dosages, pharmacokinetics changes in frail older people, and to what extent changes in paracetamol pharmacokinetics should lead to a change in dosage in frail and robust older people.

Conflict of interest statement

Paola Mian, Karel Allegaert, Isabel Spriet, Dick Tibboel and Mirko Petrovic declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Figures

Fig. 1

Overview of paracetamol metabolism. CYP2E1 cytochrome-P450 2, GSH glutathione, NAPQI N-acetyl-p-benzoquinone-imine, SULT sulphotransferase, UGT UDP-glucuronosyltransferase

Fig. 2

Paediatric study decision tree [21, 22] applied to paracetamol in older people (grey boxes apply). PD pharmacodynamics, PK pharmacokinetics

Fig. 3

Flowchart of the screening process

Fig. 4

a Volume of distribution (L/kg), b clearance (L/kg/h) values of paracetamol and c formation clearance (L/kg/h) values from paracetamol to its metabolites (in young and older subjects derived from literature). Notes: For Liukas et al. [39], the clearance values of the older subgroups used in their original study (60–70, 70–80, 80–90 years) were pooled to obtain one ‘older people’ clearance value. For Bannwarth et al. [37], Kamali et al. [43] and Miners et al. [38], the volume of distribution was not reported but calculated based on the reported clearance and half-life by study