I.V. paracetamol as an adjunct to patient-controlled epidural analgesia with levobupivacaine and fentanyl in labour: a randomized controlled study

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1 British Journal Of Anaesthesia, 117 (5): (2016) doi: /bja/aew311 Obstetrics OBSTETRICS I.V. paracetamol as an adjunct to patient-controlled epidural analgesia with levobupivacaine and fentanyl in labour: a randomized controlled study K. Gupta 1, S. Mitra 1 *, S. Kazal 1, R. Saroa 1, V. Ahuja 1 and P. Goel 2 1 Department of Anaesthesia & Intensive Care, Government Medical College & Hospital, Chandigarh, India and 2 Department of Obstetrics & Gynaecology, Government Medical College & Hospital, Chandigarh, India *Corresponding author. drsmitra12@yahoo.com Abstract Background: Use of i.v. paracetamol for postoperative pain is well documented, but it is unclear if it can reduce the consumption of opioids during patient-controlled epidural analgesia (PCEA) in labouring parturients. Methods: In this randomized, double-blind, placebo-controlled clinical trial conducted in a tertiary care hospital, 80 parturients were randomly assigned to two groups of 40 each, to receive either 1000 mg (100 ml) i.v. paracetamol or 100 ml normal saline as placebo, 30 min before the procedure. After insertion of the epidural catheter, all patients received 10 ml of levobupivacaine 0.1% with 2 lg ml-1 fentanyl, followed by continuous background epidural infusion of 6 ml h-1 with a provision of patient-controlled bolus 5 ml of same drug with a lock-out interval of 12 min. The primary outcome was hourly mean consumption of levobupivacaine and fentanyl mixture (ml.h-1). Secondary outcomes included pain score, sensory and motor block, haemodynamic parameters of mother, duration of second stage of labour, mode of delivery, Apgar scores, foetal heart rate and adverse effects. Results: The hourly mean drug consumption in the Paracetamol group was significantly lower as compared with the Placebo group (7.03 ml.h-1, SD 0.83 vs ml.h-1, SD 1.34; p < 0.001). The mean number of boluses taken were also significantly less in the paracetamol group (1.00, SD 0.93 vs. 1.43, SD 0.90; p ¼ 0.036). Pain scores decreased in both the groups without significant inter-group differences. Conclusions: Use of 1000 mg i.v. paracetamol decreases the mean hourly drug consumption through epidural route. Thus i.v. paracetamol is a safe and effective adjunct to PCEA in labour analgesia. Clinical trial registration: Clinical Trials Registry India ( trial registration number 2013/09/ Key words: administration, intravenous; analgesia; analgesia, epidural; obstetric labour; paracetamol; patient-controlled Accepted: July 6, 2016 VC The Author Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com 617

2 618 Gupta et al. Editor s key points Multimodal analgesia for labour can be used to optimize pain control and reduce opioid consumption. The effects on analgesia and labour of i.v. paracetamol before epidural insertion were studied. I.V. paracetamol reduced epidural fentanyl and levobupivacaine use with similar pain scores. Further studies are needed to explore the role of i.v. paracetamol in labour analgesia. The pain of childbirth is arguably the most severe pain most women will endure in their lifetime. Various responses to pain such as marked stimulation of respiration and circulation, activation of neuroendocrine system and pain-related behaviors, may produce deleterious consequences to both mother and foetus. Many of these responses are mitigated by effective pain relief. 1 Neuraxial techniques are accepted as the gold standard for intrapartum labour analgesia. It has been refined over the past 20 yr to provide higher quality of pain relief, less motor weakness and more control over the administration of pain relief medications. Addition of adjunctive agents (opioids, epinephrine or clonidine) in epidural analgesia, may provide a dose sparing effect, increase the duration and quality of analgesia, but the use of narcotics is limited by adverse effects such as drowsiness, nausea, and vomiting in the mother, and respiratory depression in the neonate. 2 4 For over a century, paracetamol has been widely used as an effective antipyretic and analgesic medication with wellestablished tolerability and favorable safety profile, including more recent evidence of its use through the i.v. route in postoperative pain. 5 7 Although paracetamol has been used as an effective and safe analgesic medication, 8 there is a paucity of studies assessing its intrapartum use. The few recently published studies have compared i.v. paracetamol with i.v. pethidine, 9,10 i.m. pethidine, 11 i.m. tramadol, 12,13 i.v. morphine, 14,15 or with saline during Caesarean section under general anaesthesia To the best of our knowledge, no study has compared the role of i.v. paracetamol as an adjunct analgesic agent, to the well established labour analgesia regimes. The combination of a local anaesthetic (levobupivacaine) and an opioid (fentanyl) as patient controlled epidural analgesia (PCEA), is a standard procedure for labouring women in many hospitals including ours. It would be of interest to learn if i.v. paracetamol could have an opioid sparing effect, which could have implications for both the mother and the baby. Thus the present study was designed to evaluate the efficacy of i.v. infusion of 1000 mg of paracetamol as an adjunct and its sparing effect on total consumption of levobupivacaine and fentanyl combination given as patient controlled epidural analgesia in labouring parturients. Methods The study was conducted from June 2013 to June 2014 at a tertiary-care teaching hospital in north India. It was registered with the Clinical Trials Registry of India (the trial was registered in May 2013 with the Trial Reference No. Ref/2013/05/005092, final CTRI Registration number 2013/09/003968). Ethical approval for this study was provided by the Institutional Ethics Committee. After obtaining written informed consent, women requesting analgesia in the first stage of labour were enrolled in this study. The inclusion criteria were: primiparous ASA I and II parturients aged yr, spontaneous onset of labour at term (37 42 weeks gestation), with cervical dilatation of 5 cm, and a single live foetus in cephalic presentation. The exclusion criteria were: refusal by parturient, parturients who had received parenteral opioids in the last four h, any systemic and local sepsis, deranged coagulation profile, multiple pregnancies, premature labour, obstetric complications (e.g., premature rupture of amniotic membranes) and allergy to study drugs (i.e. paracetamol, levobupivacaine and fentanyl). Eighty participants were allocated randomly to two groups by using computer generated random numbers (CONSORT flow chart shown in Fig. 1). Cervical dilatation and patient characteristic data, including age, weight, height and baseline investigations were recorded. The Paracetamol group (n ¼ 40) received a 100-ml i.v. infusion containing 1000 mg of paracetamol (Perfalgan TM, Bristol-Myers Squibb, Mumbai, India) over 15 min, while the placebo group (n ¼ 40) received an i.v. infusion of 100 ml of normal saline (Denis Chem Lab Limited, Gujarat, India) as placebo, 30 min before the procedure. Epidural blocks were sited in a standard manner in all the patients. After shifting the patient to the clean labour room operation theatre, i.v. access was secured and baseline visual analog pain score (VAS based on a 0 10 mm scale, 0 mm ¼ no pain and 10 mm ¼ worst pain imagined) was noted. The patient was continuously monitored for HR, NIBP and SpO 2 throughout the study period. With the parturient in the sitting position, using a disposable 18 g Touhy s needle (Minipack R, Smith UK) the epidural space was identified, by using loss of resistance to saline at either L2-3 or L3-4, using universal aseptic precautions. After noting the distance between the epidural space and skin by using the marking on the epidural needle, 3-4 cm of 20-gauge catheter was inserted in the epidural space from the skin was noted and. The catheter was into the epidural space. The loading dose of 10 ml of 0.1% levobupivacaine with fentanyl 2 lg ml-1 was given after negative aspiration for blood and CSF. Maintenance of PCEA (Master PCA pump, Fresenius Kabi USA) was started after the loading dose, with 6 ml h-1 of 0.1% Levobupivacaine, with fentanyl 2 lg ml-1 as a continuous background infusion and patient controlled boluses of 5 ml of the same drug with a lockout interval of 12 min if needed. Blinding was done by the following means: the drugs were contained in similar looking 100-ml glass bottles obtained from the hospital pharmacy, which were covered by opaque brown papers marked to conceal their identity. The group allocation was done by one investigator (S.M.), the paracetamol or saline infusion bottles were covered by opaque brown paper and infusion started by another investigator (S.K.), while the assessments were done by a third investigator (K.G.) who was blinded to the group and drug received. The primary outcome of the study was hourly average consumption of levobupivacaine and fentanyl mixture, including both continuous background infusion plus bolus doses (in ml) starting from 1 h after administration of paracetamol or saline, till delivery. The hourly average consumption was considered important so as to correct for the variable duration of labour, and it was calculated as a mean value (ml/h) by dividing the total consumption during the entire course of labour by the duration of labour in h. Secondary outcomes were pain score (VAS), sensory and motor block characteristics (using moist cold wisp of cotton and Bromage score respectively), haemodynamic parameters of mother (using multichannel monitor), foetal heart rate (by cardiotochograph) and adverse effects (assessed

3 I.V. paracetamol as adjunct in labour analgesia 619 Assessed for eligibility (n=92) Excluded (n=12) Enrollment Randomized Not meeting inclusion criteria (n=9) Refused to participate (n=3) Other reasons (n=0) Group 1: i.v. Paracetamol Allocated to intervention (n=40) Received allocated intervention (n=40) Group 2: Placebo Allocated to intervention (n=40) Received allocated intervention (n=40) Lost to follow-up (n=0) Discontinued intervention (n=0) Lost to follow-up (n=0) Discontinued intervention (n=0) Analysed (n=40) Excluded from analysis (n=0) Analysed (n=40) Excluded from analysis (n=0) Fig 1 CONSORT flow diagram. clinically). All these variables were recorded every 5 min for the first 20 min and then every 1 h until delivery. Duration of second stage of labour, mode of delivery, Apgar scores and maternal satisfaction (VAS) were also recorded at the end of labour. Women were questioned regarding their satisfaction for analgesia and future desire to use it in subsequent pregnancies, h after delivery, using separate 100 mm visual linear analogue scales. Sample size calculation We used the primary outcome measure to calculate sample size. From our own previous data on 30 patients undergoing labour epidural analgesia with PCEA in our hospital, it was seen that the mean hourly consumption of levobupivacaine and fentanyl mixture was 15.5 ml h-1, with SD Following the example of Ross and colleagues 19 we decided that a 20% reduction in hourly consumption of neuraxial analgesic combination would be considered as clinically meaningful difference, yielding a value of 12.4 ml h-1 as the mean hourly neuraxial drug consumption in the paracetamol group. Thus, for this study, sample size analysis with the above assumption and with b of 0.20 (i.e. power of 80%) and a of 0.05 demonstrated that a sample size of 36 per group would allow us to detect a 20% difference in total epidural drug combination volume required per h. To allow for slight oversampling, it was decided to have a total sample size of 80 patients, with 40 patients per group. Statistical analysis All data were analysed using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 17.0 for Windows). Means were compared using Student s t-test for independent groups if the data were normally distributed and Mann- Whitney U-test if the data were not normally distributed. Proportions were compared using v 2 or Fisher s exact test whichever was applicable. Two-way repeated-measures

4 620 Gupta et al. Table 1 Comparison of patient characteristics in the two groups Characteristics GROUP I GROUP II (PCM) N ¼ 40 (PLACEBO) N ¼ 40 Age (yr) Range Height (cm) (4.43) (5.21) Mean (SD) Weight (kg) 66 (9.89) (11.79) Mean (SD) ASA I Category 39 (97.5%) 39 (97.5%) n (%) Table 3 Comparison of mode of deliveries (MOD) in the two groups MOD Group I Group II P value (PCM) n¼40 (PLACEBO) n¼40 Normal n (%) 29 (72.5) 30 (75) Forceps assisted n (%) 5 (12.5) 3 (7.5) Caesarean n (%) 6 (15) 7 (17.5) Table 4 Comparison of Apgar scores at 5 min in the two groups Table 2 Comparison of clinical parameters in the two groups. Data are shown as Mean (SD) PARAMETERS GROUP I GROUP II P Value ANOVA were conducted with post-hoc Scheffe s test to conduct pair-wise. Statistical tests were two-sided and performed at a significance level of a ¼ Results (PCM) N ¼ 40 (PLACEBO) N ¼ 40 Hb (g dl-1) (1.62) (1.38) 0.34 Blood sugar (mg dl-1) (15.11) (12.25) 0.56 Prothrombin time (2.90) (3.12) 0.63 index (%) Serum Sodium (3.37) (3.23) 0.43 (meq L-1) Serum Potassium (meq L-1) 4.01 (0.44) 3.94 (0.43) 0.52 A total of 80 parturients were enrolled, 40 in each group. Both the groups were similar with respect to patient characteristics profile and baseline investigations (Tables 1 and 2). Regarding the primary outcome of interest, it was seen that the mean hourly drug consumption was significantly lower in the paracetamol group (7.03 ml, SD 0.83; range ) as compared with the placebo group (8.12 ml, SD 1.34; range ; P <0.001). The paracetamol group also required significantly less total number of boluses (mean 1.00, SD 0.93; interquartile range [IQR] 0-2) than placebo group (mean 1.43, SD 0.90; IQR 1-3; P ¼ 0.036). When hourly bolus consumption rate was compared, statistically significant difference in the bolus consumption was observed at 2 h, with lower bolus consumption in the paracetamol group as compared to placebo group. No significant difference was found in number of boluses taken at the rest of the time intervals over the study period. In our study, time to onset of analgesia was recorded from the time when the bolus drug was injected, to the time when VAS became less than three. The mean onset time was similar in both groups (11.90 min, SD 2.09 in paracetamol group and min, SD 1.93 in placebo group; 95% Confidence Interval [CI] of Difference of Means ; P ¼ 0.82). The mean VAS score before institution of epidural analgesia was comparable in Groups Group I Group II (PCM) n¼40 (PLACEBO) n¼40 APGAR SCORE: 9-10 n (%) 38 (95%) 38 (95%) APGAR SCORE: 6-8 n (%) 2 (5%) 2 (5%) APGAR SCORE: 5 <5 n (%) 0 (0) 0 (0) both the groups (8.97, SD 0.54 in the paracetamol group and 9.00, SD 0.60 in the placebo group; 95% CI of Difference of Means ; P ¼ 0.89). Compared with the pretreatment score, the mean VAS score was lower at subsequent intervals in both the groups. There was no significant difference in the VAS scores in both the groups during the course of labour. The mean duration of second stage of labour was comparable in the groups (65.29 min, SD 23.5 vs min, SD 27.6 for Group I and II respectively; 95% CI of Difference of Means ; P ¼ 0.35). There was no difference in incidence of operative delivery and neonatal outcome as measured by Apgar score in both the groups (Tables 3 and 4). The changes in mean heart rate, systolic and diastolic blood pressure in both groups were minimal and non-significant between the groups (data not shown). Similarly, time to sensory and motor blockade was comparable between the groups (data not shown). No difference in global maternal satisfaction mean score was observed between both the groups (91.78, SD 4.22 vs , SD 4.56; 95% CI of Difference of Means ; P ¼ 0.12). Adverse effects were common but minor in this study and consisted mainly of nausea, vomiting and urinary retention. There were non-significant differences in occurrence of side-effects between the two groups (Table 5). Discussion This randomized, double-blinded, placebo controlled clinical trial demonstrated that i.v. paracetamol is a safe and effective adjunct to PCEA in labour analgesia. A few previous studies have shown the effective use of i.v. paracetamol during intrapartum period Elbohoty and colleagues 9 showed that use of i.v. paracetamol, was as effective as pethidine for intrapartum analgesia during the first stage of labour. In another study done by Abd-El-Maeboud and colleagues 10, it was demonstrated that i.v. infusion of paracetamol was associated with significantly lower VAS score and lower incidence of need for rescue medication as compared with sterile water (placebo) for intrapartum analgesia. In both these studies, and in the recently published studies from Iran, 11 India 12,13 and USA, 14,15 i.v. paracetamol was

5 I.V. paracetamol as adjunct in labour analgesia 621 Table 5 Comparison of incidence of adverse effects in two groups. Data are shown as n (%) Side-effects Group I Group II P value (PCM) n¼40 (PLACEBO) n¼40 Pruritus 1 (2.5) 3 (7.5) 0.11 Nausea 2 (5.0) 1 (2.5) 0.55 Vomiting 3 (7.5) 2 (5.0) 0.64 Urinary retention 3 (7.5) 3 (7.5) 1.00 Fever 0 (0.00) 2 (5.00) 0.15 Hypotension 0 (0.00) 1 (2.5) 0.31 Foetal bradycardia 2 (5.0) 3 (7.5) 0.64 used as the sole intrapartum analgesic. The comparison agents were pethidine, tramadol, or morphine. The use of 1000 mg paracetamol in the present study significantly decreased hourly mean drug consumption and the number of boluses through the epidural route, thus proving the epidural drug dose sparing effect of intrapartum paracetamol. The statistically significant difference in bolus consumption at 2 h between two groups in this study, may be because of occurrence of breakthrough pain in the placebo group, which prompted the patients to take additional bolus at 2 h. The combination of a local anaesthetic (levobupivacaine) and an opioid (fentanyl) as patient controlled epidural analgesia (PCEA), is a standard procedure for labouring women in many hospitals including ours. This study demonstrated that i.v. paracetamol has an opioid sparing effect, which could have implications for both the mother and the baby. A systematic review of 24 trials found that intrathecal opioid in labour, increased the chances of fetal bradycardia (Odds Ratio [OR] 1.8, 95% confidence interval [CI] , number-needed to-harm [NNH] 28). It also found a very high probability of maternal pruritus (OR 29.6, 95% CI , NNH 1.7). 20 Incidence of foetal bradycardia has been reported in 4.7% in epidural analgesia and 8.3% in combined spinal-epidural analgesia. 21 Thus, an opioid sparing effect by i.v. paracetamol, may be a welcome addition to the already existing armamentarium for labour analgesia. As regards the secondary outcome measures, there was no significant difference in VAS scores, maternal haemodynamics and mode of delivery between groups. In both the groups after the initial bolus, maintenance of PCEA was started with a continuous background infusion, with a provision of patient controlled boluses in case breakthrough pain occurs. Higher hourly consumption of drug in placebo group, might be responsible for non-significant difference in VAS score in present study. There was no statistically significant increase in Caesarean section or instrumental delivery in our study. These findings are consistent with Cochrane Database Systemic trials which compared the progress of labour between epidurals discontinued late in labour and continuous epidural infusion during second stage of labour. 22,23 Also, there was no difference in neonatal outcomes in both the groups. Majority of neonates had Apgar score of nine at five min in both the groups. Foetal bradycardia being 15% in both the groups was also comparable. These data confirm the finding of the two previous trials by Elbohoty and colleagues 9 and Abd- El-Maeboud and colleagues, 10 who demonstrated no differences in occurrence of intrapartum foetal distress or neonatal Apgar scores in patients receiving paracetamol. The recent Cochrane meta-analysis, too reports no adverse neonatal outcome in labour epidural deliveries. 22 Non-reassuring foetal heart tones during labour have been reported in 10% to 20% of patients after initiation of neuraxial analgesia, although adverse neonatal outcomes have not been reported. 24 Paracetamol is a frequently used painkiller and antipyretic drug in pregnant women. As compared with other analgesics including opioids, it has an overall favourable safety profile, though one recent commentary 25 and editorial 26 have raised safety concerns regarding the indiscriminate and massive use of paracetamol. In our study no maternal adverse effects have been recorded in the women who received paracetamol, confirming the safety and tolerability of paracetamol reported in other studies. 5,8 In conclusion, providing the perfect combination of effective and safe analgesia during labour has remained an ongoing challenge. Thus, addition of a long-established safe and welltolerated analgesic such as paracetamol, by the i.v. route to the intrapartum labour analgesia regime as above, can have a significant reduction in consumption of the anaesthetic-opioid combination by the epidural route, thereby allowing the use of lower doses of each agent, while minimizing undesirable sideeffects at the same time. Authors contributions Study design/planning: S.M. Study conduct: K.G., S.M., S.K., R.S., P.G. Data analysis: K.G., S.M., S.K. Writing paper: K.G., S.K. Revising paper: all authors Declaration of interest None declared. References 1. Wong CA. Obstetric Pain. In: JC Ballantyne, JP Rathmell, SM Fishman, eds. Bonica s Management of Pain, 4th Edn. Philadelphia: Lippincott Williams & Wilkins, 2011; Lim Y, Sia AT, Ocampo CE. Comparison of intrathecal levobupivacaine with and without fentanyl in combined spinal epidural for labor analgesia. 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