From the pharmaceutical to the clinical: the case for effervescent paracetamol in pain management. A narrative review

Figures & data

Table 1. Pharmacokinetic studies with effervescent paracetamol formulations in healthy volunteers.

Study	Study design	Formulations/doses compared	Cmax	Tmax^a	AUC0-∞
Rygnestad et al.^37	Open, randomized, Crossover	2 × 500 mg paracetamol Effervescent 2 × 500 mg paracetamol Oral tablets	21.6 mg/L (15.7–23.9)^b 19.8 mg/L (17.8–25.4)^b	27 min (20–34)^b45 min (34–56)^b^*,*	Not reported
Grattan et al.^29	Randomized 5-way Crossover	Paracetamol 500 mg/sodium bicarbonate 400 mg Effervescent	29.8 (9.1) mg/L^c	17.5 min	2647 (478) mg.min/L^c
		Paracetamol 500 mg/sodium bicarbonate 400 mg Effervescent	26.1 (10.7) mg/L^c	22.5 min	2691 (521) mg.min/L^c
		Paracetamol 500 mg/calcium carbonate 375 mg Effervescent	15.4 (5.7) mg/L^c	43.8 min	2545 (521) mg.min/L^c
		Paracetamol 500 mg/sodium bicarbonate 1342 mg Soluble paracetamol	19.9 (6.9) mg/L^c†	20.0 min††	2540 (507) mg.min/L^c†††
		Paracetamol 500 mg Oral tablets	17.0 (6.4) mg/L^c	35.0 min	2477 (459) mg.min/L^c
Sevilla-Tirado et al.^10	Randomized 5-way Crossover	1000 mg paracetamol Effervescent	20.7 (5.8) mg/L^c	0.38 h‡	53.4 (11.7) mg.h/L^c
		2 × 500 mg paracetamol Oral tablets	20.6 (6.9) mg/L^c	0.50 h	55.4 (10.3) mg.h/L^c
		1000 mg paracetamol Powder sachet	20.2 (6.2) mg/L^c	0.25 h	52.6 (12.5) mg.h/L^c
		2 × 500 mg paracetamol Film-coated tablets	18.0 (6.2) mg/L^c	0.50 h	54.8 (14.4) mg.h/L^c
		2 × 500 mg paracetamol Oral tablets^d	19.4 (7.6) mg/L^c	0.50 h	56.3 (14.9) mg.h/L^c
Di Girolamo et al.^1	Open, randomized, Crossover	Paracetamol 500 mg Effervescent	10.0 (3.0) mg/L^c	15.0 min	19.9 (18.1–24.4) mg.h/L^e
		Paracetamol 500 mg Coated tablets	10.9 (5.4) mg/L^c	25.2 min*	20.0 (18.2–23.8) mg.h/L^e*
Fathi et al.^19	Parallel group	500 mg paracetamol Effervescent	15.3 (2.5) mg/L^c*	60 min	53.1 mg.min/L
		1 × 500 mg paracetamol Tablets	11.3 (3.9) mg/L^c	120 min	47.0 mg.min/L
		1 × 500 mg paracetamol Capsules	6.6 (3.2) mg/L^c	Approx 60 min^f	40.6 mg.min/L

C_max: Peak concentration; T_max: time to peak concentration; AUC_0-∞: Area under concentration-time curve extrapolated to infinity.

^aT_max is reported as median values, unless indicated otherwise.

^bMean (95% confidence interval).

^cMean (standard deviation).

^dTwo different proprietary brands were compared in this study.

^eGeometric mean (95% confidence interval).

^fOnly presented graphically: exact value not reported.

^*,**p < 0.05, p < 0.01 tablet versus effervescent formulation.

†p < 0.002 paracetamol 500 mg/sodium bicarbonate 630 mg versus paracetamol 500 mg; p < 0.02 paracetamol 500 mg/sodium bicarbonate 630 mg versus paracetamol 500 mg/sodium bicarbonate 1342 mg, and paracetamol 500 mg/sodium bicarbonate 400 mg versus paracetamol 500 mg.

††p < 0.01 paracetamol 500 mg/sodium bicarbonate 630 mg versus paracetamol 500 mg; p < 0.02 paracetamol 500 mg/calcium carbonate 375 mg versus paracetamol 500 mg/sodium bicarbonate 1342 mg.

†††p < 0.01 paracetamol 500 mg/sodium bicarbonate 400 mg versus paracetamol 500 mg; p < 0.005 paracetamol 500 mg versus paracetamol 500 mg/sodium bicarbonate 1342 mg.

‡p < 0.05 paracetamol 2 × 500 mg/paracetamol 1000/1 × 1000 mg effervescent paracetamol versus paracetamol 2 × 500 mg film-coated tablets.

Figure 1. Kaplan–Meier plot showing time to onset of analgesia in patients with moderate-to-severe pain following dental surgery treated with 1000 mg effervescent paracetamol (solid squares), 1000 mg paracetamol tablets (solid triangles), effervescent placebo (open squares) or tablet placebo (open triangles). Reproduced with permission from Moller PL, et al. ²⁷.

Figure 2. Smoothed estimation of daily drug-related sodium exposure in French participants (n = 281) who reported using effervescent medications within the previous 30 days. Data are presented as a percentage of the World Health Organization (WHO) recommended daily sodium intake of 2 g. Each dot represents a single participant. Reproduced with permission from Perrin et al. ⁶³.

Rygnestad T, Zahlsen K, Samdal FA. Absorption of effervescent paracetamol tablets relative to ordinary paracetamol tablets in healthy volunteers. Eur J Clin Pharmacol. 2000;56(2):141–143.

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Grattan T, Hickman R, Darby-Dowman A, et al. A five way crossover human volunteer study to compare the pharmacokinetics of paracetamol following oral administration of two commercially available paracetamol tablets and three development tablets containing paracetamol in combination with sodium bicarbonate or calcium carbonate. Eur J Pharm Biopharm. 2000;49(3):225–259.

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Sevilla-Tirado FJ, Gonzalez-Vallejo EB, Leary AC, et al. Bioavailability of two new formulations of paracetamol, compared with three marketed formulations, in healthy volunteers. Methods Find Exp Clin Pharmacol. 2003;25(7):531–535.

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Di Girolamo G, Opezzo JA, Lopez MI, et al. Relative bioavailability of new formulation of paracetamol effervescent powder containing sodium bicarbonate versus paracetamol tablets: a comparative pharmacokinetic study in fed subjects. Exp Opin Pharmacother. 2007;8(15):2449–2457.

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Fathi M, Kazemi S, Zahedi F, et al. Comparison of oral bioavailability of acetaminophen tablets, capsules and effervescent dosage forms in healthy volunteers. Curr Issues Pharmacy Med Sci. 2018;31(1):5–9.

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Moller PL, Norholt SE, Ganry HE, et al. Time to onset of analgesia and analgesic efficacy of effervescent acetaminophen 1000 mg compared to tablet acetaminophen 1000 mg in postoperative dental pain: a single-dose, double-blind, randomized, placebo-controlled study. J Clin Pharmacol. 2000;40(4):370–378.

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Perrin G, Berdot S, Thomas F, et al. Evaluation of exposure to effervescent drugs in a large health check-up population in France: a cross-sectional study. BMJ Open. 2018;8(7):e022368.

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