Remifentanil by patient-controlled analgesia compared with intramuscular meperidine for pain relief in labour

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1 British Journal of Anaesthesia 88 (3): 374±8 (2002) Remifentanil by patient-controlled analgesia compared with intramuscular meperidine for pain relief in labour J. A. Thurlow 1 *, C. H. Laxton 1, A. Dick 2, P. Waterhouse 3, L. Sherman 1 and N. W. Goodman 1 1 Department of Anaesthesia, Southmead Hospital, Westbury-on-Trym, Bristol, UK. 2 Department of Anaesthesia, Royal Bournemouth Hospital, UK. 3 Department of Anaesthesia, Frenchay Hospital, Frenchay Park Road, Bristol, UK *Corresponding author: Department of Anaesthesia, Taunton and Somerset Hospital, Musgrove Park, Taunton TA1 5DA, UK Background. The pharmacokinetics of remifentanil suggests that it may be suitable for analgesia during labour. Methods. In an open pilot study, 36 women requesting meperidine for analgesia were recruited early in labour and randomized to receive either meperidine i.m. or remifentanil given as patient-controlled analgesia (PCA). Pain severity, sedation and anxiety were assessed with visual analogue scales and overall effective analgesia was assessed by the woman and midwife. Results. The pain scores were lower in the remifentanil group: median pain score at 60 min was 72 mm for meperidine and 48 mm for remifentanil (P=0.004) and median maximum pain score during the rst 2 h was 82.5 mm for the meperidine group and 66.5 mm for the remifentanil group (P=0.009). Both the midwives' and the women's assessments of overall effective analgesia were higher in the remifentanil group [Likert scale (5 = excellent to 1 = poor): c 2 =12.10, P=0.002 for mothers' assessment; c 2 =12.80, P=0.002 for midwives' assessment]. Conclusion. In this pilot study, remifentanil by PCA gave better pain relief to mothers in labour than intramuscular meperidine. However, remifentanil is a potent respiratory depressant and adequate continuous monitoring is necessary. Br J Anaesth 2002; 88: 374±8 Keywords: analgesics opioid, meperidine; analgesics opioid, remifentanil; analgesia, obstetric Accepted for publication: November 9, 2001 Most women who deliver in modern obstetric units request some form of pharmacological pain relief. There are many treatment options available to relieve the pain of childbirth. Some are more effective than others. Non-pharmacological forms of analgesia, such as breathing exercises and transcutaneous nerve stimulation, can be inadequate for established and augmented labour. Entonox may also be inadequate. Epidural analgesia offers the best pain relief for many women in labour. If an epidural is contraindicated or a woman does not wish to have an epidural, meperidine is the main alternative but, although widely used, it is a poor analgesic and the main effect is sedation. 12 Remifentanil's rapid onset and offset of effect 34 should make it an ideal drug for the intermittent painful contractions of labour. It has been used as an i.v. infusion during non-urgent Caesarean section as an adjunct to epidural anaesthesia. It does cross the placenta (mean uterine vein:maternal artery ratio=0.88) but is rapidly metabolized, redistributed or both (mean uterine artery:uterine vein ratio=0.29), with no clinically adverse effects on the neonate. 5 Patient-controlled analgesia (PCA) techniques are not new to obstetrics: PCA is the standard delivery system for Entonox. Meperidine, 6 butorphanol tartrate, 7 tramadol, 8 nalbuphine 9 and fentanyl have all been given by PCA in labour. Remifentanil may have an advantage compared with these because of its rapid onset time and rate of hydrolysis. There are case reports of remifentanil PCA in labour in parturients with known platelet abnormalities. Intravenous PCA should be better than intermittent i.m. Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2002

2 Remifentanil PCA in labour Table 1 Patient details before start of analgesia Variable Meperidine (n=18) Remifentanil (n=18) Median Interquartile range Median Interquartile range Age 29 25± ±32 Weight 64 58± ±78 Height ± ±168 Gestation ± ±41 Dilation 4 3±5 3 3±4 Pain score 68 59± ±82 Sedation 43 15± ±74 Anxiety ± ±77 Systolic blood pressure ± ±140 Diastolic blood pressure 80 70± ±80 Pulse rate ± ±92 Respiratory rate 20 18± ±24 Sa O ± ±98 injections because it avoids the pain of injection and allows better matching of analgesic delivery to the pain. We conducted an open randomized pilot study to compare the analgesic effect of remifentanil given as PCA with i.m. meperidine during labour. Methods After local ethics committee approval, we recruited women aged between 18 and 40 years, of mixed parity, between 38 and 42 weeks gestation in early labour. Women weighing less than 50 kg or more than 100 kg were excluded. After they had given written informed consent, women were assigned randomly to one of two groups by sequentially numbered, sealed opaque envelopes prepared by an independent practitioner. Patients in group M were assigned i.m. meperidine 100 mg and an antiemetic and those in group R were assigned i.v. remifentanil via PCA (20 mg bolus over 20 s, 3 min lockout and no background infusion); full instructions were given to the mother and attending midwife. A dedicated i.v. cannula was sited in a forearm vein in women in group R. A dosing study was conducted before the study proper to ascertain the dose and lockout period required to relieve the pain of labour without obvious clinical side-effects. Starting with a 5 mg bolus, an increasing dose of remifentanil was given at the beginning of each painful contraction until the contraction was painfree, and the time to the next painful contraction was noted. Pain was assessed with a continuous visual analogue scale (VAS; 100 mm, marked `no pain' to `worse pain imaginable'). Women were asked to mark on the line the worst pain they had felt during their last contraction after it had nished. Sedation and anxiety were assessed similarly, using the terms `wide awake' to `very sleepy' for sedation, and `very calm' to `very anxious' for anxiety. Nausea scores and the physiological variables of blood pressure, pulse rate, ventilatory rate and oxygen saturation by pulse oximetry were also measured. Baseline recordings were made and then measurements were taken every 30 min after analgesia was started. Although measurements were recorded every 30 min, all women were observed throughout by their attending midwife, and one of the investigators was available in the delivery suite at all times during the study. All patients were monitored by continuous pulse oximetry. If the assigned analgesia was inadequate for the patient at any time, an alternative was offered and further study recordings were discontinued. The foetus was monitored by continuous cardiotocography and Apgar scores were noted at delivery. All women had access to Entonox at all times. The overall effective analgesia was rated after delivery by the mother and attending midwife within 2 h of delivery on a ve-point verbal scale ranging from excellent to poor (Likert scale: 5=excellent, 4=very good, 3=good, 2=fair, 1=poor). A power calculation was performed at the design stage of the study. We estimated that the probability of a woman who was receiving remifentanil reporting a lower pain score than a woman receiving meperidine was Assuming that the pain scores would be compared using a Wilcoxon rank sum test, for a two-sided 5% level of statistical signi cance and 90% power we estimated that we needed to recruit 30 patients in total, 15 in each group. The overall effective analgesia rating (Likert scale) was analysed using the c 2 test. Fisher's exact test was applied to the nausea and vomiting scores and epidural conversion rates. The combined in uence of drug treatment and other postrandomization events was assessed by analysis of variance. All other non-parametric data were compared using the Wilcoxon rank sum test. Parametric data were analysed with the t-test. Analysis was performed using Stata for Windows (Stata Corporation, Texas, USA) and Microsoft Excel for Windows. Results Forty-one women were asked to take part in the study. Five women refused, stating that they preferred to have 375

3 Thurlow et al. Table 2 Details of labour. *Data incomplete or missing from notes Variable Meperidine (n=18) Remifentanil (n=18) No. % No. % Parity Spontaneous onset of labour 15/17* 88 16/18* 89 Arti cial rupture of membranes 8/16* 50 9/18 50 Syntocinon infusion used 6/17* 35 5/17* 29 Entonox used 13/16* 81 10/18 56 Fetal position OA 9/11* 82 4/12* 33 OP 2/11* 18 4/12* 33 OL 0/11* 0 1/12* 12 T 0/11* 0 3/12* 25 Type of delivery Spontaneous vaginal 16/17* 94 11/18 61 Ventouse 1/17* 6 4/18 22 Caesarean section 0/17* 0 3/18 17 Table 3 Pain scores at 60 min and maximum pain scores during the rst 2 h after analgesia commenced. *Signi cant Meperidine Remifentanil P Median Interquartile range Median Interquartile range At 1 h 72 62± ± * Max. score over 2 h ± ± * meperidine. Thirty-six patients were recruited and there were no withdrawals. Eighteen patients were randomized to each treatment group (Table 1). The number of primigravid patients in each group was similar (13/18 in each group). Details of labour in the two groups are summarized in Table 2. The pain scores at 60 min and the maximum pain scores during the rst 2 h after analgesia commenced were signi cantly lower in the remifentanil group (Table 3). There was no difference in Entonox usage between the two groups (P=0.11). There was no difference between the two groups in the pain scores at 1 h or maximum pain score over the rst 2 h in relation to arti cial rupture of membranes (P=0.86, P=0.31) or Syntocinon usage (P=0.77, P=0.35).The midwives' and mothers' assessments of `overall effective analgesia' were both higher in the remifentanil group (P=0.002) (Figs 1 and 2). There were no other signi cant differences between the two groups. For two women receiving meperidine and seven receiving remifentanil, haemoglobin oxygen saturations of less than or equal to 94% were recorded. The lowest for meperidine was 89% and the lowest for remifentanil 92%. The minimum saturation did not differ signi cantly between the two groups (P=0.08) but the impression was that the overall saturation may have been lower for women receiving remifentanil. Fig 1 Midwife's assessment of overall effective analgesia. Signi cantly better in the remifentanil group (P<0.002). There was no signi cant difference in the recorded minimum ventilatory rate between the two groups (P=0.60), although rates less than 8 between contractions were recorded for three patients receiving remifentanil; these responded quickly to verbal stimulation. All women receiving meperidine were given an antiemetic at the same time (promethazine 25 mg or 376

4 Remifentanil PCA in labour Fig 2 Mother's assessment of overall effective analgesia. Signi cantly better in the remifentanil group (P<0.002). prochlorperazine 12.5 mg). No antiemetic was given to women receiving remifentanil unless indicated clinically. Ten women receiving meperidine and ve receiving remifentanil experienced nausea and vomiting (P=0.06). Three women receiving remifentanil went on to receive an antiemetic (either promethazine 25 mg or prochlorperazine 12.5 mg). Three women receiving meperidine later received an epidural, while seven receiving remifentanil required additional analgesia and later an epidural (P>0.05). There were more non-spontaneous vaginal deliveries in the remifentanil group (P=0.04). The three Caesarean sections in the women receiving remifentanil were not related in time to the use of remifentanil and all three women needed epidural analgesia because of inadequate pain relief. The time to section after the epidural was sited was between 2 and 8 h. Three of the four ventouse deliveries in the women receiving remifentanil were not related in time to the use of remifentanil and all three women needed epidural analgesia because of inadequate pain relief. The time to ventouse delivery after the epidural was sited was between 3 and 7 h. If this information is taken into account, there would be one non-spontaneous vaginal delivery in each group. The results of ventouse deliveries and Caesarean sections are summarized in Table 2. There were no differences in Apgar scores between the two groups (epidural conversions excluded). Discussion In this pilot study, remifentanil by PCA provided better pain relief to mothers in labour than i.m. meperidine, judged by VAS pain scores and overall assessments by mothers and attending midwives. Although pain scores were recorded every 30 min, the comparative recordings at 60 min were analysed because it was thought that this may be when i.m. meperidine would have its maximum analgesic effect. However, to ensure an effect was not missed, the maximum pain score within the rst 2 h was also analysed. Pain scores after 2 h were not analysed statistically as after this time the analgesic effects of meperidine would begin to wear off, whereas the analgesic effects of remifentanil PCA would continue. This pilot study compared two different pharmacological regimes of analgesic administration, and this may limit the usefulness of its clinical ndings. Using a PCA device can improve satisfaction scores in the clinical setting and itself affect the severity of pain. When visited the following day, almost all women who had received remifentanil commented spontaneously on the controllability of the PCA, which they considered to be an advantage. PCA meperidine and remifentanil have recently been compared in labour, but poor Apgar scores in the meperidine group terminated the study prematurely. 14 Seven women receiving remifentanil went on to have an epidural compared with three women receiving meperidine. This was an unexpected nding as pain scores were signi cantly lower in the remifentanil group. The difference in epidural conversion rate between the two groups was not signi cant, but our sample size was small. Meperidine is a sedative. This may have some in uence on women requesting an epidural. In our pilot study, a xed bolus dose of remifentanil was used. Ideally, the dose should be tailored to the individual patient and adjustments made as necessary with the progression of labour, especially as acute tolerance can develop with prolonged use of remifentanil. 15 More women using remifentanil had lower haemoglobin oxygen saturations and some women had low ventilatory rates. Remifentanil is a potent opioid with potentially serious side-effects. It has a rapid onset, with a time to peak effect of 60±80 s. 3 From clinical observations, we suggest that the mothers must be encouraged to make a demand at the start of contractions rather than when the contractions become painful. If pressed too late, the maximum analgesic effect will occur after the peak of the contraction, along with the side-effects. It is then that ventilatory depression, if it does occur, is more likely. There must be close communication between mother, attending midwife and anaesthetist to ensure proper use of the PCA for best effect with least side-effects. Remifentanil may be an acceptable alternative to meperidine when epidural analgesia is unsuitable. However, it is a potent respiratory depressant and adequate continuous monitoring is advisable. References 1 Olofsson C, Ekman-Ordeberg G, Hjelm A, Irestedt L. Lack of analgesic effect of systemically administered morphine or pethidine on labour pain. Br J Obstet Gynaecol 1996; 103: 968±72 2 Reynolds F, Crowhurst JA. Opioids in labourðno analgesic effect. Lancet 1997: 346: 4±5 3 Glass PSA, Hardman D, Kamiyama Y, et al. Preliminary 377

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