Paracetamol (acetaminophen) (Perfusalgan, Bristol Myers Squibb, Braine l’Alleud, Belgium) is one of the most commonly prescribed drugs for acute pain or fever, including during pregnancy and in the postpartum period.1,2 It is frequently administered as part of multimodal analgesia following caesarean delivery, often in combination with NSAIDs, opioids and/or regional techniques.2 Oral paracetamol administration has a slower onset of analgesia and this route may not be appropriate immediately following caesarean delivery. Consequently, intravenous paracetamol is used.
The disposition of many drugs is altered during pregnancy due to physiological changes that involve plasma volume, glomerular filtration rate, hepatic blood flow, cardiac output, gastric emptying and also maternal drug-metabolising enzymes and drug transporters.3–5 Despite the frequent use of paracetamol, there are almost no data on the impact of pregnancy and its covariates on paracetamol pharmacokinetics, and observations were – until recently – limited to oral administration.4,6–8
We recently described intravenous paracetamol loading dose pharmacokinetics following caesarean delivery in 28 patients and reported a significant increase in clearance (median values 20.3 vs. 15.5 l h−1 and 10.9 vs. 9.6 l h−1 m−2, respectively) when compared with observations in healthy non-pregnant adult female volunteers.8,9 Stimulated by the four-fold range of intravenous paracetamol clearance (minimum–maximum 7 to 28.3 l h−1 m−2) following caesarean delivery observed in this initial cohort of 28 patients,8 we explored the covariates of an intravenous paracetamol loading dose (2 g) pharmacokinetics in the same cohort of women, with added participants, who underwent a caesarean delivery at different gestational age or had associated maternal morbidity.
Study registration and ethics
Following registration (EudraCT 2010-020164-37) of this study, ethical approval was provided by the Ethics Committee of the University Hospitals Leuven (Chairperson Professor W. van den Boogaert, 3 June 2010, internal reference study number S52366).
Clinical characteristics and dosing
Anaesthesia for caesarean delivery was based on combined spinal–epidural (CSE) anaesthesia with hyperbaric bupivacaine 7.5 mg and sufentanil 2.5 μg. Subsequent postoperative analgesia used a multimodal approach based on bilateral transverses abdominis plane blocks (0.375% ropivacaine 20 ml per side), together with intravenous ketorolac (30 mg, every 8 h for 24 h) and intravenous paracetamol. The administration of paracetamol (Perfusalgan, Bristol Myers Squibb) started with a loading dose of 2 g over 15 min administered shortly after delivery of the newborn and placental removal.8 Women who were scheduled to undergo a (semi)elective caesarean delivery were recruited for this study after written, informed consent.
Clinical characteristics [gestational age, body weight before pregnancy, body weight at the day of delivery, body height, body surface area (BSA) at delivery, twin pregnancy, associated maternal medical conditions] were recorded. Gestational age was based on early pregnancy ultrasound or was calculated from the last menstrual period. Body weight and height were recorded immediately before the caesarean delivery was performed. BSA was calculated from these data. Associated maternal medical conditions included preeclampsia, as defined by the International Society for the Study of Hypertension during Pregnancy (ISSHP)10 and (pregnancy-related) diabetes mellitus.
Sample collection, sample handling and pharmacokinetics
The time of initiation and duration of intravenous paracetamol administration was recorded. One, 2, 4 and 6 h after the start of intravenous administration, blood samples were collected from a second peripheral venous line dedicated for study related sampling only. The protocol explicitly stated that additional venous punctures were not allowed once this venous access failed.
After centrifugation, plasma samples were stored at −20°C until HPLC analysis to quantify paracetamol concentrations in plasma was performed. The analytical performance, including intra-day and inter-day variation of this HPLC analysis, has been reported earlier.11
Pharmacokinetics were calculated by assuming a linear one-compartment model with instantaneous input and first order output. For every patient, a logarithmic trend line [y = a lognx + b] was calculated from the plasma samples collected when there was at least a 3 h interval between the first and last plasma sample.8 The distribution volume (Vd, l and l kg−1) and concentration [at t = 0 (Cmax0)] were calculated. The slope of the curve [slope = (logCt2 − logCt1)/(t2 − t1)] was used to calculate the time constant K (slope × 2.303), elimination half-life (0.693/K) (t1/2) and clearance (K × Vd).12
Data were reported by mean (SD) (normal distribution evaluated by Kolmogorov–Smirnov test), median (minimum–maximum) or by incidence. Clinical characteristics and individual pharmacokinetic estimates between women who underwent a caesarean delivery at preterm (<37 weeks) or term (≥37 weeks) gestational age, among women with or without medical conditions and among twin or singleton pregnancies were compared using unpaired analysis (MedCalc, Mariakerke, Belgium). A P values less than 0.05 was considered to be significant.
Following a loading dose of 2-g intravenous paracetamol, 139 plasma samples were collected from 36 women. Of these, 28 had already been studied for intravenous paracetamol pharmacokinetics after caesarean delivery without further analysis of covariates, including preterm delivery. Individual pharmacokinetic estimates could not be calculated in two of 36 women, because the interval (<3 h) between the first and the last plasma samples was too short in one case, and an extreme paracetamol peak concentration (8.8 mg l−1, mean paracetamol peak value 23.8 mg l−1) in another case.
Women analysed had a mean age of 31 years (5), a mean weight of 80 kg (12.8) and a mean BSA of 1.94 m2 (0.20). Twelve patients delivered preterm, eight women (six preterm, two term) underwent caesarean delivery because of twin pregnancy, one patient (term, singleton) had diabetes mellitus type 1, whereas two (both preterm deliveries, singleton) had mild to moderate preeclampsia. Mean paracetamol concentrations observed 1, 2, 4 and 6 h after administration were 23.8 (5.05), 15.7 (4.3), 7.7 (3) and 3.9 mg l−1 (1.7), respectively. Mean clearance of intravenous paracetamol was 22.4 l h−1 (9.3); mean clearance/BSA was 11.5 l h−1 m−2 (4.0). Median distribution volume was 57.8 l (42.9 to 156). When corrected for weight, mean distribution volume was 0.74 l kg−1 (0.17). Mean elimination half-life was 117 min (22).
The clinical characteristics and pharmacokinetic estimates for the different subgroups are provided in Table 1. Pharmacokinetics after preterm delivery (n = 12, <37 weeks gestational age) were significantly different when compared with observations collected after term delivery (n = 22). Both paracetamol clearance [13.8 (5.7) vs. 10.2 l h−1 m−2 (1.8), P = 0.028] and distribution volume [0.83 (0.25) vs. 0.69 l kg−1 (0.1), P = 0.037] were significantly higher in women who delivered preterm (Table 1, first column). Because of the simultaneous changes in clearance and distribution volume, there was no significant difference in median elimination half-life [112 (28) vs. 119 min (19)]. In contrast, there was no significant difference in pharmacokinetics between twin (n = 8) and singleton (n = 26) pregnancies (Table 1, second column) nor when the analysis was limited to preterm twin patients (n = 6) compared with term singleton cases (n = 20) (Table 1, third column). The impact of preterm delivery on paracetamol pharmacokinetics remained significant when the analysis was restricted to preterm (n = 6) singleton compared with term (n = 20) singleton pregnancies [12.9 (2.3) vs. 10.3 l h−1 m−2 (1.8), P = 0.0131 and 0.81 (0.12) vs. 0.70 l kg−1 (0.1), P = 0.0279] (Table 1, fourth column).
On the basis of high-dose intravenous paracetamol pharmacokinetics calculated in 34 patients immediately following caesarean delivery, we were able to show that individual differences in clearance and distribution volume were explained by preterm delivery. When corrected for size, women who underwent a caesarean delivery before term age (i.e. <37 weeks gestational age) had a higher paracetamol clearance (l h−1 m−2) and a higher distribution volume (l kg−1) compared with those delivered at term. Similar differences were observed when the analysis was restricted to singleton pregnancies. In contrast, these pharmacokinetic estimates were not affected by maternal co-morbidity or twin pregnancy. Table 1 summarised the clinical characteristics and the pharmacokinetic estimates for the different subgroups.
There are almost no data on the impact of pregnancy on paracetamol pharmacokinetics and any observations were – until recently – limited to oral administration.4,6–8 Data on oral paracetamol (650 mg) pharmacokinetics in the first trimester of pregnancy were described by Beaulac-Baillargeon and Rocheleau6 in 18 women (eight pregnant, 10 controls). Compared with non-pregnant controls, median clearance (clearance/f 7.14 vs. 5.22 l h−1 kg−1, P = 0.03) was 37% higher and elimination half-life (1.62 vs. 2.02 h, P < 0.005) 20% lower in the first trimester of pregnancy. Miners et al.7 compared paracetamol disposition after oral administration of 1 g in eight pregnant women in their third trimester of pregnancy with 12 non-pregnant controls. They found that median clearance (CLpo 27.1 vs. 17.1 l h−1) was 58% higher and elimination half-life (1.52 vs. 2.1 h) 28% lower in the third trimester of pregnancy. Two participants studied at the gestational age of 38 weeks had the lowest paracetamol clearance and the longest half-lives, suggesting changes during pregnancy.7 Our observations on high-dose intravenous paracetamol disposition confirm the trend suggested by Miners et al. (decrease at term age) following oral paracetamol administration in the third trimester of pregnancy.7 Interestingly, Nimmo et al.3 were unable to confirm differences in paracetamol elimination half-life during labour at term.4 However, this group were principally concerned with gastric emptying which at term was influenced by narcotic analgesics.
Physiological alterations of pregnancy result in changes in drug disposition.4,5 With regard to paracetamol metabolism, it is well known that in adults this compound is almost exclusively eliminated by the renal route after conjugation mainly to paracetamol glucuronide (47 to 62%) or – to a minor extent – to paracetamol sulfate (25 to 36%) or oxidative metabolites.1 The pattern of an initial progressive increase in clearance with a subsequent decrease in the third trimester of pregnancy results in a still higher clearance at term compared with the non-pregnant status. This probably reflects a pregnancy-related increase in drug glucuronidation activity. Moreover, when compared with other drugs eliminated through glucuronidation, a similar pattern of increased elimination has been seen for propofol (higher clearance at term compared with non-pregnant controls) and lamotrigine (preterm vs. term), as the clearance of lamotrigine also increases up to 32 weeks of gestation, with a subsequent decrease towards term.12,13
The clinical implications of the pharmacokinetic differences during pregnancy for this specific compound are limited when compared with the impact of pregnancy itself. In a regression model, preterm delivery explained 19% (r = 0.43) of the variability in clearance observed within this dataset of pregnant women. In contrast, the difference in median clearance between observations collected at delivery compared with non-pregnant healthy female volunteers (l h−1 + 35%) seems to be more relevant.8 McNicol et al.14 recently published a systematic review on the effects of a single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain in adults. Intravenous paracetamol (1 g) provides around 4 h of effective analgesia (outcome criteria were either pain relief or opioid sparing effect) and the duration of analgesia relates – to a certain extent – to the paracetamol plasma concentration.1,14
Obviously, this pharmacokinetic study has its limitations. First, an unlicensed high-dose approach (2-g intravenous paracetamol) was used. This is at present the routine practice in our hospital for adult postoperative analgesia and is based on its documented tolerance and pharmacokinetics in healthy young adults9 and on its improved analgesia when compared with 1 g in a molar surgery and a hand surgery model in adults.15,16
Second, we explicitly described the multimodal analgesia approach used in our unit. This is because, in theory, the techniques and co-medications used may also have influenced the paracetamol pharmacokinetics of the current cohort that underwent caesarean delivery. In our setting, a low-dose CSE approach was applied. This means that a maximum of 7.5 mg of hyperbaric bupivacaine with no more than 2.5-μg sufentanil is administered intrathecally according to height. This approach results in less pronounced haemodynamic changes and almost no need to administer vasopressors.17 Obviously, this also means that the sensory block is already in regression at the end of surgery. The same holds for other routinely administered compounds such as oxytocin. All co-medication was standardised so that their impact on individuals would have been the same across the group. Although this should have had no significant effect on differences between individuals, it also means that the observations from our setting cannot necessarily be extrapolated to other groups and centres.
Finally, we were unable to control for between individual differences in fluid or weight shifts (e.g. amniotic fluid, newborn, placenta, blood losses) during and following caesarean delivery. We agree that these factors may have contributed to the wider range in individual pharmacokinetic estimates seen when compared with healthy volunteers. At least the data are from a clinically relevant cohort, that is, women following caesarean delivery and in need of adequate analgesia. Moreover, there were no differences in fluid loss between preterm and term.
Individual differences in pharmacodynamic covariates such as the presence of labour, differences in individual thermal pain thresholds, personality characteristics or the duration of surgery18 can all influence individual variability in post-caesarean delivery pain. Despite this, the dose of intravenous paracetamol at caesarean delivery should receive some thought. New dosing regimens after caesarean delivery should be based on both pharmacokinetic and pharmacodynamic information, and researchers should not limit studies to pharmacodynamic aspects only. With a recently published survey on drugs administered for treatment of pain, nausea and pruritus after caesarean delivery in mind,2 we encourage clinicians to consider similar efforts for other compounds given to this group, as it is unlikely that the impact of pregnancy on pharmacokinetics is limited to paracetamol.
Assistance with the study: none declared.
Sources of funding: K.A., J.D. and R.D. are supported by the Fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship 1800209N, 1801207N02 and 1803311N, respectively). A.K. was supported by a JoinEU-SEE scholarship (2009–2010). There were no other sources of financial support or sponsorship.
Conflicts of interest: none declared.
1. Jahr JS, Lee VK. Intravenous acetaminophen. Anesthesiol Clin
2. Marcus HE, Fabian A, Dagtekin O, et al. Pain, postdural puncture headache, nausea, and pruritus after cesarean delivery: a survey of prophylaxis and treatment. Minerva Anestesiol
3. Nimmo WS, Wilson J, Prescott LF. Narcotic analgesics and delayed gastric emptying during labour. Lancet
4. Zajicek A, Giacoia GP. Obstetric clinical pharmacology: coming of age. Clin Pharmacol Ther
5. Parisi MA, Spong CY, Zajicek A, Guttmacher AE. We don’t know what we don’t study: the case for research on medication effects in pregnancy
. Am J Med Genet C Semin Med Genet
6. Beaulac-Baillargeon L, Rocheleau S. Paracetamol pharmacokinetics
during the first trimester of human pregnancy
. Eur J Clin Pharmacol
7. Miners JO, Robson RA, Birkett DJ. Paracetamol metabolism in pregnancy
. Br J Clin Pharmacol
8. Kulo A, van de Velde M, de Hoon J, et al. Pharmacokinetics
of a loading dose of intravenous paracetamol
post caesarean delivery. Int J Obstet Anesth
9. Gregoire N, Hovsepian L, Gualano V, et al. Safety and pharmacokinetics
of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose. Clin Pharmacol Ther
10. Brown MA, Lindheimer MD, de Swiet M, et al. The classification and diagnosis of the hypertensive disorders of pregnancy
: statement from the International Society for the Study of Hypertension in Pregnancy
(ISSHP). Hypertens Pregnancy
11. Allegaert K, Anderson BJ, Naulaers G, et al. Intravenous paracetamol
in term and preterm neonates. Eur J Clin Pharmacol
12. Gin T, Gregory MA, Chan K, et al. Pharmacokinetics
of propofol in women undergoing selective cesarean section. Br J Anaesth
13. Pennell PB, Newport DJ, Stowe ZN, et al. The impact of pregnancy
and childbirth on the metabolism of lamotrigine. Neurology
14. McNicol ED, Tzortzopoulou A, Cepeda MS, et al. Single-dose intravenous paracetamol
or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis. Br J Anaesth
15. Jhul GI, Norholt SE, Tonnesen E, et al. Analgesic efficacy and safety of intravenous paracetamol
(acetaminophen) administered as a 2 g starting dose following third molar surgery. Eur J Pain
16. Cornesse D, Senard M, Hans GA, et al. Comparison between two intraoperative intravenous loading doses of paracetamol on pain after minor hand surgery: two grams versus one gram. Acta Chir Belg
17. Roofthooft E, van de Velde M. Low-dose spinal anaesthesia for caesarean section to prevent spinal-induced hypotension. Curr Opin Anaesthesiol
18. Pan PH, Coghill R, Houle TT, et al. Multifactorial preoperative predictors for postcaesarean section pain and analgesic requirement. Anesthesiology