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Optimal dosing interval for epidural pethidine after Caesarean section
Acute Pain 4 (2002) 27–31
Optimal dosing interval for epidural pethidine after Caesarean section Michael R. Lorimer, MBBS, MRCP, MRCGP, DA, FANZCA∗ , Karen Pedersen, MBBCh, DA, Willem Lombard, MBChB Department of Anaesthesia, National Women’s Hospital, Auckland, New Zealand
Abstract Background: The optimal dosing interval for epidural pethidine after lower segment Caesarean section (LSCS) is unknown. We challenged our current three hourly minimum dosing interval with an hourly dosing interval. Methods: After random assignment, intermittent epidural pethidine (50 mg on demand) was prescribed with a lockout interval of 1 h (group A) or 3 h (group B) for the first day after LSCS. Visual analogue pain scores (VAS 0–100) at rest and on movement were recorded at the time of request and again 30 min after. Side effects and patient satisfaction scores were monitored. Results: Thirty-seven women were enrolled: 18 in group A, 19 in group B. The median (interquartile range) dosing interval was similar in both groups: group A 220 min (178–246 min); group B 233 min (188–241 min). Request for further analgesia occurred at comparable VAS of 26 and 25 at rest and 44 and 43 on movement in groups A and B respectively. Mean pain scores 30 min later were also similar: 5 versus 3 at rest and 13 versus 13 on movement. The pain threshold variability at which analgesia was requested was higher for pain at rest (coefficient of variability, CV, 50%) than for pain with movement (CV 35%). The incidence of troublesome side effects was nausea 16%, pruritus 2.8% and drowsiness 14%. A higher frequency of mild symptoms were reported for pruritus (50%) and drowsiness (57%). Patient satisfaction was high (88%, S.D. 21). Conclusions: Epidural pethidine 50 mg is an effective analgesic after LSCS. A lockout period of 3 h would deny 28% of patient requests. We projected that this denial rate could be reduced to 7% by shortening the lockout period to 2 h. Patient satisfaction scores were high despite frequently reported mild symptoms. Pain on movement is a more reliable indicator of analgesic need than pain at rest. © 2002 Published by Elsevier Science B.V. Keywords: Epidural; Pethidine; Caesarean section; Dose interval; Visual analogue scores; Acute pain assessment
1. Introduction
2. Methods
The use of epidural opioids as sole agents for analgesia after lower segment Caesarean section (LSCS) is well established. The benefit of comparable analgesia to the use of solutions containing local anaesthetics but with preservation of motor function and hemodynamic stability has been demonstrated in a number of studies [1–3]. In this respect, pethidine appears to offer advantages over other opioids [4,5]. Ngan Kee et al. [6,7] have studied both the optimum dose and volume of diluent for epidural pethidine post-LSCS but there have been no clear studies concerning the optimum lockout interval for delivery by bolus or ‘nurse-controlled delivery’. We compared our existing unit policy of a 3 h lockout period with one of 1 h in order to investigate the optimum dose interval as determined by patient request.
The study was designed as a randomised controlled trial and had approval from the Regional Ethics Committee. Fifty ASA 1 and 2 women scheduled for elective Caesarean section under epidural anaesthesia were enrolled. Inclusion criteria required written informed consent and absence of contraindications to epidural anaesthesia/analgesia or the agents used (lignocaine/bupivacaine/fentanyl/pethidine). Patients were given a pre-medication of ranitidine 150 mg orally the night before and again on the morning of surgery. Epidural anaesthesia was established to T4 level via a lumbar epidural catheter using lignocaine 2% or bupivacaine 0.5% and fentanyl (maximum 100 g). No other opioid analgesic or route of administration of fentanyl was permitted. Paracetamol (1 g four hourly) and diclofenac (75 mg 12 hourly) were given to all patients unless contraindicated starting with diclofenac 100 mg and paracetamol 1 g rectally at the completion of surgery. The first dose of epidural pethidine 50 mg (5 mg/ml antimicrobial and antioxidant free) was given by the anaesthetist in the recovery room 30 min before the patient was
∗ Corresponding author. Present address: Department of Anaesthesia, Middlemore Hospital, Otahuhu, Auckland, New Zealand. Tel.: +64-9-276-0000; fax: +64-9-270-4702. E-mail address: [email protected] (M.R. Lorimer).
1366-0071/02/$ – see front matter © 2002 Published by Elsevier Science B.V. PII: S 1 3 6 6 - 0 0 7 1 ( 0 2 ) 0 0 0 0 7 - 4
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M.R. Lorimer et al. / Acute Pain 4 (2002) 27–31
Table 1 Grading of major side effects (Rx: treatment)
Table 2 Demographics and 24 h co-analgesic consumption (mean values)
0
1
2
3
Pruritus
None
Mild No Rx
Moderate Controlled with Rx
Severe Despite Rx
Nausea
None
Mild No Rx
Moderate Controlled with Rx
Severe Despite Rx
Sedation
None
Awake Mildly drowsy
Asleep Easy to rouse
Asleep Difficult to rouse
discharged to the ward. This was taken as the initiation of the 24 h trial period. Patients were randomised into an experimental group (group A—lockout period 1 h) and a control group (group B—lockout period 3 h) by means of randomly allocated envelopes. Subsequent bolus administration of 50 mg of pethidine via the epidural route was generated by patient request. Rescue analgesia was available in the form of intravenous nurse administered morphine according to the institutional intravenous opiate protocol. All patients received usual ward treatment and observations. In addition, self-assessed visual analogue scores for pain at rest and pain on movement (VAS 0–100 mm; 0 = no pain, 100 = worst imaginable pain) immediately prior to bolus administration and 30 min later were recorded by nursing staff. Side effect profiles for pruritus, nausea and sedation were assessed on a four-point categorical scale at the same intervals (Table 1). Other side effects including respiratory depression were reported on an individual basis only. At the completion of the trial period, patient satisfaction was assessed using a VAS (0–100 mm; 0 = completely dissatisfied, 100 = completely satisfied). Analysis of interval data was by proportional hazards survival of recurrent events using an ‘independent’ framework. In order to correctly account for individuals contributing different amounts of data, consecutive intervals were stratified. To assess analgesic efficacy, a logistic model that allowed for the repeated observations within patients to be correlated with an unstructured correlation matrix was used. This model, which assesses whether the pain score after treatment is less than a fixed value, measures the group effect having controlled for the ‘before’ pain level for each patient at each request. A fixed value analogue score for analgesic success of 25 (VAS 0–100) was chosen. Side effect profiles are presented on a descriptive basis only.
Number Age (years) Weight (kg) Paracetamol (g per day) Diclofenac (mg per day)
Group A
Group B
18 33 82 3.3 108
19 32 93 3.3 130
data, two cases requiring spinal anaesthesia following incomplete epidural blockade, one case of dislodged epidural catheter, and one case of catheter disconnection. In one patient who experienced excessive sedation the dose was reduced to 25 mg. Patient characteristics were comparable including administration of co-analgesics (Table 2). There were no requests for rescue analgesia in either group. The median (interquartile range) dosing interval was similar for both groups: group A 220 min (178–246 min) and group B 233 min (188–241 min; P = 0.68). Fig. 1 shows interval time versus request for the first six demands. There was no significant change in dosing interval between the first and sixth requests in either group (group A, P = 0.66; group B, P = 0.18). In those patients able to receive pethidine hourly (group A) 28% of requests were within the 3 h lockout period of the control group. This is illustrated in Fig. 2, which shows cumulative requests as a percentage of total requests for this group. This curve is generated by ranking all of group A, request intervals in ascending order and plotting this series against total number (%) of requests. Every patient, on each occasion, had a reduction in rest pain within 30 min of delivery of pethidine (P < 0.001). Fig. 3 demonstrates the relationship between mean rest pain and time. Ninety-eight percent of patients had a post-dose rest pain score below a VAS of 25. There was no difference in mean rest pain between groups (P = 0.41). All but one patient, on each occasion, had a reduction in movement pain within 30 min of delivery of pethidine (P < 0.001). There was a single occasion in which a patient
3. Results Thirty-seven data sets were analysed (group A, n = 18; group B, n = 19) from the 50 patients originally enrolled. Reasons for exclusion included eight sets of incomplete
Fig. 1. Interval time vs. sequential request. There was no significant change in dosing interval over time for the first 24 h (six requests).
M.R. Lorimer et al. / Acute Pain 4 (2002) 27–31
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Fig. 2. Cumulative request vs. time. Twenty eight percent of all requests in the trial group occurred under 3 h.
Fig. 3. Mean pain score at rest vs. time. Variation of threshold at request and analgesia achieved at 30 min.
received pethidine when the pre-dose score was already zero accounting for this observation. Fig. 4 shows mean pain on movement versus time. Eighty-four percent of patients had a post-dose movement score below a VAS of 25. There was no difference in mean pain on movement between groups (P = 0.97).
Fig. 4. Mean pain score at rest vs. time. Variation of threshold at request was lower than for pain at rest (Fig. 3); coefficient of variation 35% vs. 50%.
The analgesic threshold was similar between groups for both pain at rest and pain on movement: 26 (S.D. 13) and 25 (S.D. 13) at rest (P = 0.97), and 44 (S.D. 17) and 43 (S.D. 13) on movement (P = 0.57) in groups A and B, respectively. This was consistent throughout the period of the study as illustrated in Figs. 3 and 4. There was lower variability in VAS for pain on movement than pain at rest; coefficient of variability 35% versus 50% suggesting assessment of pain on movement is a more reproducible index of analgesic requirement than pain at rest. Side effect profile was drawn from the combined groups as there was no difference in the frequency of dosing. Reporting was for the entire 24 h period of the study (Fig. 5). Six patients (16%) requested treatment for nausea at some stage during the study period (grade 2 nausea). Of these, only three required more than one dose of antiemetic (two requiring four doses and one requiring two doses). A further four (11%) reported nausea but required no treatment (grade 1). One patient required treatment for ‘moderate’ pruritus (grade 2) during the study period, but a further 18 (50%) reported ‘mild’ pruritus not requiring intervention (grade 1) on at least one occasion.
Fig. 5. Side effect profile. Grade 1: mild, not requiring treatment. Grade 2: moderate, controlled with treatment.
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M.R. Lorimer et al. / Acute Pain 4 (2002) 27–31
Fourteen percent of patients were assessed as having grade 2 drowsiness (asleep but easy to rouse); 57% were scored with grade 1 drowsiness (awake but drowsy) at the 30 min post-dose assessment. There were no reports of respiratory depression. The 95% confidence interval for patient satisfaction using a VAS (0–100) across the combined groups was 77–98.
4. Discussion We have shown that a 3 h lockout period for delivery of epidural pethidine in the first 24 h post-LSCS produces an unacceptable denial rate for optimum analgesia. Although median duration of analgesia was in the region of 3 h and 30 min to 4 h, this hides a significant proportion requesting earlier analgesia. This has not been highlighted in previous series reporting duration of analgesia with epidural pethidine. The pharmacokinetics of pethidine in the epidural space have been reviewed in previous studies [8,9]. Glynn et al. studied a group of cancer patients with a mixture of post-operative pain and intractable pain who received between 30 and 100 mg of pethidine. In the post-operative patients, median duration of analgesia was 6 h (range 4–20) while in the patients with intractable pain median duration was 8 h (range 4–25). The wide range in duration is not unexpected considering the varying dose, small numbers and heterogeneous nature of the group. Sjöström et al. studying a more homogenous group of patients undergoing major abdominal surgery for inflammatory bowel disease profiled elimination of pethidine from the epidural space after a 30 mg bolus. They demonstrated biexponential elimination kinetics with an early half-life of 71.3 ± 3.1 min and a late half-life from 8 to 12 h post-injection of 982 ± 449 min. They also produced figures for an effect site concentration at the time of further request for analgesia of 1100 ± 310 ng/ml (mean ± S.D.). However, this ranged from 160 to 2000 ng/ml suggesting significant variation in pain thresholds. The mean interval at further request was in the order of 6 h. Brownridge and Frewin [1] studying patients after lower abdominal surgery (including LSCS) have also assessed duration of analgesia with epidural pethidine 50 mg using further request for analgesia as the main indicator. They reported times of 2 h and 30 min to 3 h, although this represented a single bolus in a within patient trial including intramuscular pethidine and epidural bupivacaine. It is apparent, therefore, that variation in dosing interval is a product of both variation in pharmacokinetics and significant variation in thresholds at which analgesia is requested. In this respect, our results concur with previous reports although these have not addressed the significance of the wide variation observed. Using the data we have generated, and a lockout period of 3 h, this degree of spread would lead to a denial rate for delivery of analgesia of 28%. By
studying cumulative request versus time (Fig. 2), it can be seen that reducing the lockout period to 2 h should reduce this to about 7%. This is now the standard at our institution and offers acceptable analgesia while limiting the potential for an increase in side effects associated with a 1 h lockout. It is of interest that over the duration of the study dosing interval and pain scores did not significantly alter which supports previous studies showing pain to be of constant intensity in the first 24 h post-LSCS [10]. Epidural pethidine has compared favourably with other routes of delivery for analgesic efficacy and patient acceptance [1,5,10,11]. Recently studies into the use of VAS for acute pain have reported that clinical significance requires a change of at least 9–13 mm (0–100) [12,13] and the ‘zone of analgesic success’ to lie between 0 and 30 mm (0–100) [14]. Analgesic efficacy was demonstrated in our study producing statistically and clinically significant reductions in pain scores that met both these criteria. The variability in VAS at which analgesia was requested was less for pain on movement. This suggests that pain on movement may be a more reliable index for pain assessment than pain at rest. This has obvious implications for acute pain services with respect to their choice methods of pain assessment. Furthermore, studies by Paech et al. [10] and Ngan Kee et al. [5] have demonstrated the dose sparing effect of the epidural route over the intravenous route while Yarnell et al. [11] found similar phenomenon comparing epidural versus intramuscular pethidine. However, it is unclear whether the particular mode of epidural delivery is important in this respect. Using patient-controlled epidural analgesia (PCEA), median consumption in the first 24 h post-LSCS has been reported to range between 240 and 500 mg [2,6]. Our median consumption of 250 mg would suggest similar advantages with bolus delivery although direct comparisons would require matched populations. We used a categorical scale to document the incidence of common side effects. This included reporting of requirement for intervention, which is frequently omitted from other scoring systems and provides practical information for planning of services. In addition, the occurrence of a side effect on a single occasion over a 24 h period lead to a positive rating thus increasing the sensitivity of reporting. The incidence of nausea was comparable to other studies of epidural pethidine in post-Caesarean section patients [4,10,11]. In these studies, pethidine was given by patientcontrolled device and this appears to confer no advantage over intermittent bolus from this respect. However, a wide range of incidence of nausea has been reported. Smith et al. showed a high overall incidence of nausea (84%) in patients receiving patient-controlled epidural pethidine with a 24 h consumption of 4–500 mg2 . A total of 20% required antiemetic administration. This contrasts with data from Rosaeg and Lindsay [15] who studied Caesarean section patients receiving epidural pethidine in the first 24 h post-operatively. They recorded a
M.R. Lorimer et al. / Acute Pain 4 (2002) 27–31
16% incidence of nausea with only 4% requiring antiemetics. Their 24 h pethidine consumption was 398 ± 106 mg (mean ± S.D.). We recorded a high incidence of mild pruritus (50%) although only one patient required treatment. This compares with previous reports, which have recorded incidences between 10 and 84% [1,2,4,10,11,15]. Similarly, in these instances pruritus has been of minimal clinical impact. Most studies report sedation to be ‘not excessive’. We found drowsiness to be a common side effect though it remains difficult to differentiate mild drowsiness due to drug effects from the fatigue of emotional and physical stress of child birth. Nevertheless, it is likely that assessment at 30 min post-dose is influenced by significant systemic levels of pethidine which would account for the high levels of reporting. This is supported by data from the studies of Sjöström et al. [9] who showed plasma concentration in the first hour post-epidural pethidine 30 mg comparable to those required for analgesia via the intravenous route. The use of placebo doses in the control group within the lockout period could have overcome bias from the lack of blinding. Resultant bias would be maximal where two groups differed widely in their frequency of analgesic consumption. Conversely, where dosing intervals and total consumption are not significantly different across groups, bias should be minimal. This is reflected in our results where pain scores, side effect profiles and patient satisfaction were comparable in both groups. In conclusion, we have confirmed the efficacy of epidural pethidine as an analgesic for post-LSCS pain control. In addition, we have projected that a lockout period of 2 h in our population would satisfy 93% of patient requests and this is now our current standard. Visual analogue scores reliably predicted requirement for further analgesia and showed less variability for pain on movement than for pain at rest. VAS for pain on movement may, therefore, be the better guide to analgesic requirement. Acknowledgements We would like to thank Alistair Stewart from the Department of Community Medicine, Auckland University School of Medicine for his statistical advice, and Dr Brian
31
Anderson for his encouragement and advice in preparation of the manuscript. References [1] P. Brownridge, D.B. Frewin, A comparative study of techniques of postoperative analgesia following Caesarean section and lower abdominal surgery, Anaesth. Intensive Care 13 (1985) 123–130. [2] A.J. Smith, T.K. Haynes, D.E. Roberts, et al., A comparison of opioid solutions for patient-controlled epidural analgesia, Anaesthesia 51 (1996) 1013–1017. [3] R.C. Etches, T.L. Gammer, R. Cornish, Patient-controlled epidural analgesia after thoracotomy: a comparison of meperidine with and without bupivacaine, Anesth. Analg. 83 (1) (1996) 81–86. [4] J.L. Goh, S.F. Evans, T.J.G. Pavy, Patient-controlled epidural analgesia following Caesarean delivery: a comparison of pethidine and fentanyl, Anaesth. Intensive Care 24 (1996) 45–50. [5] W.D. Ngan Kee, K.K. Lam, P.P. Chen, et al., Comparison of patient-controlled epidural analgesia with patient-controlled intravenous analgesia using pethidine or fentanyl, Anaesth. Intensive Care 25 (2) (1997) 126–132. [6] W.D. Ngan Kee, K.K. Lam, P.P. Chen, et al., Epidural meperidine after Caesarean section. A dose-response study, Anesthesiology 85 (1996) 289–294. [7] W.D. Ngan Kee, K.K. Lam, P.P. Chen, et al., Epidural meperidine after Caesarean section: the effect of diluent volume, Anesth. Analg. 85 (1997) 380–384. [8] C.J. Glynn, L.E. Mather, M.J. Cousins, et al., Peridural meperidine in humans, Anesthesiology 55 (1981) 520–526. [9] S. Sjöström, P. Hartvig, P. Persson, et al., Pharmacokinetics of epidural morphine and meperidine in humans, Anesthesiology 67 (1987) 877–888. [10] M.J. Paech, J.S. Moore, S.F. Evans, Meperidine for patient-controlled analgesia after Caesarean section, Anesthesiology 80 (1994) 1268– 1276. [11] R.W. Yarnell, T. Polis, G.N. Reid, et al., Patient-controlled analgesia with epidural meperidine after elective Caesarean section, Reg. Anesth. 17 (1992) 329–333. [12] K.H. Todd, K.G. Funk, R. Bonnacci, Clinical significance of reported changes in pain severity, Ann. Emerg. Med. 27 (4) (1996) 485–489. [13] A.M. Kelly, Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad. Emerg. Med. 5 (11) (1998) 1086–1090. [14] S. Mantha, R. Thisted, J. Foss, et al., A proposal to use confidence intervals for visual analog scale data for pain measurement to determine clinical significance, Anesth. Analg. 77 (1993) 1041–1047. [15] O.P. Rosaeg, M.P. Lindsay, Epidural opioid analgesia after Caesarean section: a comparison of patient-controlled analgesia with meperidine and single bolus injection of morphine, Can. J. Anaesth. 41 (1994) 1063–1068.
Optimal dosing interval for epidural pethidine after Caesarean section Michael R. Lorimer, MBBS, MRCP, MRCGP, DA, FANZCA∗ , Karen Pedersen, MBBCh, DA, Willem Lombard, MBChB Department of Anaesthesia, National Women’s Hospital, Auckland, New Zealand
Abstract Background: The optimal dosing interval for epidural pethidine after lower segment Caesarean section (LSCS) is unknown. We challenged our current three hourly minimum dosing interval with an hourly dosing interval. Methods: After random assignment, intermittent epidural pethidine (50 mg on demand) was prescribed with a lockout interval of 1 h (group A) or 3 h (group B) for the first day after LSCS. Visual analogue pain scores (VAS 0–100) at rest and on movement were recorded at the time of request and again 30 min after. Side effects and patient satisfaction scores were monitored. Results: Thirty-seven women were enrolled: 18 in group A, 19 in group B. The median (interquartile range) dosing interval was similar in both groups: group A 220 min (178–246 min); group B 233 min (188–241 min). Request for further analgesia occurred at comparable VAS of 26 and 25 at rest and 44 and 43 on movement in groups A and B respectively. Mean pain scores 30 min later were also similar: 5 versus 3 at rest and 13 versus 13 on movement. The pain threshold variability at which analgesia was requested was higher for pain at rest (coefficient of variability, CV, 50%) than for pain with movement (CV 35%). The incidence of troublesome side effects was nausea 16%, pruritus 2.8% and drowsiness 14%. A higher frequency of mild symptoms were reported for pruritus (50%) and drowsiness (57%). Patient satisfaction was high (88%, S.D. 21). Conclusions: Epidural pethidine 50 mg is an effective analgesic after LSCS. A lockout period of 3 h would deny 28% of patient requests. We projected that this denial rate could be reduced to 7% by shortening the lockout period to 2 h. Patient satisfaction scores were high despite frequently reported mild symptoms. Pain on movement is a more reliable indicator of analgesic need than pain at rest. © 2002 Published by Elsevier Science B.V. Keywords: Epidural; Pethidine; Caesarean section; Dose interval; Visual analogue scores; Acute pain assessment
1. Introduction
2. Methods
The use of epidural opioids as sole agents for analgesia after lower segment Caesarean section (LSCS) is well established. The benefit of comparable analgesia to the use of solutions containing local anaesthetics but with preservation of motor function and hemodynamic stability has been demonstrated in a number of studies [1–3]. In this respect, pethidine appears to offer advantages over other opioids [4,5]. Ngan Kee et al. [6,7] have studied both the optimum dose and volume of diluent for epidural pethidine post-LSCS but there have been no clear studies concerning the optimum lockout interval for delivery by bolus or ‘nurse-controlled delivery’. We compared our existing unit policy of a 3 h lockout period with one of 1 h in order to investigate the optimum dose interval as determined by patient request.
The study was designed as a randomised controlled trial and had approval from the Regional Ethics Committee. Fifty ASA 1 and 2 women scheduled for elective Caesarean section under epidural anaesthesia were enrolled. Inclusion criteria required written informed consent and absence of contraindications to epidural anaesthesia/analgesia or the agents used (lignocaine/bupivacaine/fentanyl/pethidine). Patients were given a pre-medication of ranitidine 150 mg orally the night before and again on the morning of surgery. Epidural anaesthesia was established to T4 level via a lumbar epidural catheter using lignocaine 2% or bupivacaine 0.5% and fentanyl (maximum 100 g). No other opioid analgesic or route of administration of fentanyl was permitted. Paracetamol (1 g four hourly) and diclofenac (75 mg 12 hourly) were given to all patients unless contraindicated starting with diclofenac 100 mg and paracetamol 1 g rectally at the completion of surgery. The first dose of epidural pethidine 50 mg (5 mg/ml antimicrobial and antioxidant free) was given by the anaesthetist in the recovery room 30 min before the patient was
∗ Corresponding author. Present address: Department of Anaesthesia, Middlemore Hospital, Otahuhu, Auckland, New Zealand. Tel.: +64-9-276-0000; fax: +64-9-270-4702. E-mail address: [email protected] (M.R. Lorimer).
1366-0071/02/$ – see front matter © 2002 Published by Elsevier Science B.V. PII: S 1 3 6 6 - 0 0 7 1 ( 0 2 ) 0 0 0 0 7 - 4
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M.R. Lorimer et al. / Acute Pain 4 (2002) 27–31
Table 1 Grading of major side effects (Rx: treatment)
Table 2 Demographics and 24 h co-analgesic consumption (mean values)
0
1
2
3
Pruritus
None
Mild No Rx
Moderate Controlled with Rx
Severe Despite Rx
Nausea
None
Mild No Rx
Moderate Controlled with Rx
Severe Despite Rx
Sedation
None
Awake Mildly drowsy
Asleep Easy to rouse
Asleep Difficult to rouse
discharged to the ward. This was taken as the initiation of the 24 h trial period. Patients were randomised into an experimental group (group A—lockout period 1 h) and a control group (group B—lockout period 3 h) by means of randomly allocated envelopes. Subsequent bolus administration of 50 mg of pethidine via the epidural route was generated by patient request. Rescue analgesia was available in the form of intravenous nurse administered morphine according to the institutional intravenous opiate protocol. All patients received usual ward treatment and observations. In addition, self-assessed visual analogue scores for pain at rest and pain on movement (VAS 0–100 mm; 0 = no pain, 100 = worst imaginable pain) immediately prior to bolus administration and 30 min later were recorded by nursing staff. Side effect profiles for pruritus, nausea and sedation were assessed on a four-point categorical scale at the same intervals (Table 1). Other side effects including respiratory depression were reported on an individual basis only. At the completion of the trial period, patient satisfaction was assessed using a VAS (0–100 mm; 0 = completely dissatisfied, 100 = completely satisfied). Analysis of interval data was by proportional hazards survival of recurrent events using an ‘independent’ framework. In order to correctly account for individuals contributing different amounts of data, consecutive intervals were stratified. To assess analgesic efficacy, a logistic model that allowed for the repeated observations within patients to be correlated with an unstructured correlation matrix was used. This model, which assesses whether the pain score after treatment is less than a fixed value, measures the group effect having controlled for the ‘before’ pain level for each patient at each request. A fixed value analogue score for analgesic success of 25 (VAS 0–100) was chosen. Side effect profiles are presented on a descriptive basis only.
Number Age (years) Weight (kg) Paracetamol (g per day) Diclofenac (mg per day)
Group A
Group B
18 33 82 3.3 108
19 32 93 3.3 130
data, two cases requiring spinal anaesthesia following incomplete epidural blockade, one case of dislodged epidural catheter, and one case of catheter disconnection. In one patient who experienced excessive sedation the dose was reduced to 25 mg. Patient characteristics were comparable including administration of co-analgesics (Table 2). There were no requests for rescue analgesia in either group. The median (interquartile range) dosing interval was similar for both groups: group A 220 min (178–246 min) and group B 233 min (188–241 min; P = 0.68). Fig. 1 shows interval time versus request for the first six demands. There was no significant change in dosing interval between the first and sixth requests in either group (group A, P = 0.66; group B, P = 0.18). In those patients able to receive pethidine hourly (group A) 28% of requests were within the 3 h lockout period of the control group. This is illustrated in Fig. 2, which shows cumulative requests as a percentage of total requests for this group. This curve is generated by ranking all of group A, request intervals in ascending order and plotting this series against total number (%) of requests. Every patient, on each occasion, had a reduction in rest pain within 30 min of delivery of pethidine (P < 0.001). Fig. 3 demonstrates the relationship between mean rest pain and time. Ninety-eight percent of patients had a post-dose rest pain score below a VAS of 25. There was no difference in mean rest pain between groups (P = 0.41). All but one patient, on each occasion, had a reduction in movement pain within 30 min of delivery of pethidine (P < 0.001). There was a single occasion in which a patient
3. Results Thirty-seven data sets were analysed (group A, n = 18; group B, n = 19) from the 50 patients originally enrolled. Reasons for exclusion included eight sets of incomplete
Fig. 1. Interval time vs. sequential request. There was no significant change in dosing interval over time for the first 24 h (six requests).
M.R. Lorimer et al. / Acute Pain 4 (2002) 27–31
29
Fig. 2. Cumulative request vs. time. Twenty eight percent of all requests in the trial group occurred under 3 h.
Fig. 3. Mean pain score at rest vs. time. Variation of threshold at request and analgesia achieved at 30 min.
received pethidine when the pre-dose score was already zero accounting for this observation. Fig. 4 shows mean pain on movement versus time. Eighty-four percent of patients had a post-dose movement score below a VAS of 25. There was no difference in mean pain on movement between groups (P = 0.97).
Fig. 4. Mean pain score at rest vs. time. Variation of threshold at request was lower than for pain at rest (Fig. 3); coefficient of variation 35% vs. 50%.
The analgesic threshold was similar between groups for both pain at rest and pain on movement: 26 (S.D. 13) and 25 (S.D. 13) at rest (P = 0.97), and 44 (S.D. 17) and 43 (S.D. 13) on movement (P = 0.57) in groups A and B, respectively. This was consistent throughout the period of the study as illustrated in Figs. 3 and 4. There was lower variability in VAS for pain on movement than pain at rest; coefficient of variability 35% versus 50% suggesting assessment of pain on movement is a more reproducible index of analgesic requirement than pain at rest. Side effect profile was drawn from the combined groups as there was no difference in the frequency of dosing. Reporting was for the entire 24 h period of the study (Fig. 5). Six patients (16%) requested treatment for nausea at some stage during the study period (grade 2 nausea). Of these, only three required more than one dose of antiemetic (two requiring four doses and one requiring two doses). A further four (11%) reported nausea but required no treatment (grade 1). One patient required treatment for ‘moderate’ pruritus (grade 2) during the study period, but a further 18 (50%) reported ‘mild’ pruritus not requiring intervention (grade 1) on at least one occasion.
Fig. 5. Side effect profile. Grade 1: mild, not requiring treatment. Grade 2: moderate, controlled with treatment.
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Fourteen percent of patients were assessed as having grade 2 drowsiness (asleep but easy to rouse); 57% were scored with grade 1 drowsiness (awake but drowsy) at the 30 min post-dose assessment. There were no reports of respiratory depression. The 95% confidence interval for patient satisfaction using a VAS (0–100) across the combined groups was 77–98.
4. Discussion We have shown that a 3 h lockout period for delivery of epidural pethidine in the first 24 h post-LSCS produces an unacceptable denial rate for optimum analgesia. Although median duration of analgesia was in the region of 3 h and 30 min to 4 h, this hides a significant proportion requesting earlier analgesia. This has not been highlighted in previous series reporting duration of analgesia with epidural pethidine. The pharmacokinetics of pethidine in the epidural space have been reviewed in previous studies [8,9]. Glynn et al. studied a group of cancer patients with a mixture of post-operative pain and intractable pain who received between 30 and 100 mg of pethidine. In the post-operative patients, median duration of analgesia was 6 h (range 4–20) while in the patients with intractable pain median duration was 8 h (range 4–25). The wide range in duration is not unexpected considering the varying dose, small numbers and heterogeneous nature of the group. Sjöström et al. studying a more homogenous group of patients undergoing major abdominal surgery for inflammatory bowel disease profiled elimination of pethidine from the epidural space after a 30 mg bolus. They demonstrated biexponential elimination kinetics with an early half-life of 71.3 ± 3.1 min and a late half-life from 8 to 12 h post-injection of 982 ± 449 min. They also produced figures for an effect site concentration at the time of further request for analgesia of 1100 ± 310 ng/ml (mean ± S.D.). However, this ranged from 160 to 2000 ng/ml suggesting significant variation in pain thresholds. The mean interval at further request was in the order of 6 h. Brownridge and Frewin [1] studying patients after lower abdominal surgery (including LSCS) have also assessed duration of analgesia with epidural pethidine 50 mg using further request for analgesia as the main indicator. They reported times of 2 h and 30 min to 3 h, although this represented a single bolus in a within patient trial including intramuscular pethidine and epidural bupivacaine. It is apparent, therefore, that variation in dosing interval is a product of both variation in pharmacokinetics and significant variation in thresholds at which analgesia is requested. In this respect, our results concur with previous reports although these have not addressed the significance of the wide variation observed. Using the data we have generated, and a lockout period of 3 h, this degree of spread would lead to a denial rate for delivery of analgesia of 28%. By
studying cumulative request versus time (Fig. 2), it can be seen that reducing the lockout period to 2 h should reduce this to about 7%. This is now the standard at our institution and offers acceptable analgesia while limiting the potential for an increase in side effects associated with a 1 h lockout. It is of interest that over the duration of the study dosing interval and pain scores did not significantly alter which supports previous studies showing pain to be of constant intensity in the first 24 h post-LSCS [10]. Epidural pethidine has compared favourably with other routes of delivery for analgesic efficacy and patient acceptance [1,5,10,11]. Recently studies into the use of VAS for acute pain have reported that clinical significance requires a change of at least 9–13 mm (0–100) [12,13] and the ‘zone of analgesic success’ to lie between 0 and 30 mm (0–100) [14]. Analgesic efficacy was demonstrated in our study producing statistically and clinically significant reductions in pain scores that met both these criteria. The variability in VAS at which analgesia was requested was less for pain on movement. This suggests that pain on movement may be a more reliable index for pain assessment than pain at rest. This has obvious implications for acute pain services with respect to their choice methods of pain assessment. Furthermore, studies by Paech et al. [10] and Ngan Kee et al. [5] have demonstrated the dose sparing effect of the epidural route over the intravenous route while Yarnell et al. [11] found similar phenomenon comparing epidural versus intramuscular pethidine. However, it is unclear whether the particular mode of epidural delivery is important in this respect. Using patient-controlled epidural analgesia (PCEA), median consumption in the first 24 h post-LSCS has been reported to range between 240 and 500 mg [2,6]. Our median consumption of 250 mg would suggest similar advantages with bolus delivery although direct comparisons would require matched populations. We used a categorical scale to document the incidence of common side effects. This included reporting of requirement for intervention, which is frequently omitted from other scoring systems and provides practical information for planning of services. In addition, the occurrence of a side effect on a single occasion over a 24 h period lead to a positive rating thus increasing the sensitivity of reporting. The incidence of nausea was comparable to other studies of epidural pethidine in post-Caesarean section patients [4,10,11]. In these studies, pethidine was given by patientcontrolled device and this appears to confer no advantage over intermittent bolus from this respect. However, a wide range of incidence of nausea has been reported. Smith et al. showed a high overall incidence of nausea (84%) in patients receiving patient-controlled epidural pethidine with a 24 h consumption of 4–500 mg2 . A total of 20% required antiemetic administration. This contrasts with data from Rosaeg and Lindsay [15] who studied Caesarean section patients receiving epidural pethidine in the first 24 h post-operatively. They recorded a
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16% incidence of nausea with only 4% requiring antiemetics. Their 24 h pethidine consumption was 398 ± 106 mg (mean ± S.D.). We recorded a high incidence of mild pruritus (50%) although only one patient required treatment. This compares with previous reports, which have recorded incidences between 10 and 84% [1,2,4,10,11,15]. Similarly, in these instances pruritus has been of minimal clinical impact. Most studies report sedation to be ‘not excessive’. We found drowsiness to be a common side effect though it remains difficult to differentiate mild drowsiness due to drug effects from the fatigue of emotional and physical stress of child birth. Nevertheless, it is likely that assessment at 30 min post-dose is influenced by significant systemic levels of pethidine which would account for the high levels of reporting. This is supported by data from the studies of Sjöström et al. [9] who showed plasma concentration in the first hour post-epidural pethidine 30 mg comparable to those required for analgesia via the intravenous route. The use of placebo doses in the control group within the lockout period could have overcome bias from the lack of blinding. Resultant bias would be maximal where two groups differed widely in their frequency of analgesic consumption. Conversely, where dosing intervals and total consumption are not significantly different across groups, bias should be minimal. This is reflected in our results where pain scores, side effect profiles and patient satisfaction were comparable in both groups. In conclusion, we have confirmed the efficacy of epidural pethidine as an analgesic for post-LSCS pain control. In addition, we have projected that a lockout period of 2 h in our population would satisfy 93% of patient requests and this is now our current standard. Visual analogue scores reliably predicted requirement for further analgesia and showed less variability for pain on movement than for pain at rest. VAS for pain on movement may, therefore, be the better guide to analgesic requirement. Acknowledgements We would like to thank Alistair Stewart from the Department of Community Medicine, Auckland University School of Medicine for his statistical advice, and Dr Brian
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Anderson for his encouragement and advice in preparation of the manuscript. References [1] P. Brownridge, D.B. Frewin, A comparative study of techniques of postoperative analgesia following Caesarean section and lower abdominal surgery, Anaesth. Intensive Care 13 (1985) 123–130. [2] A.J. Smith, T.K. Haynes, D.E. Roberts, et al., A comparison of opioid solutions for patient-controlled epidural analgesia, Anaesthesia 51 (1996) 1013–1017. [3] R.C. Etches, T.L. Gammer, R. Cornish, Patient-controlled epidural analgesia after thoracotomy: a comparison of meperidine with and without bupivacaine, Anesth. Analg. 83 (1) (1996) 81–86. [4] J.L. Goh, S.F. Evans, T.J.G. Pavy, Patient-controlled epidural analgesia following Caesarean delivery: a comparison of pethidine and fentanyl, Anaesth. Intensive Care 24 (1996) 45–50. [5] W.D. Ngan Kee, K.K. Lam, P.P. Chen, et al., Comparison of patient-controlled epidural analgesia with patient-controlled intravenous analgesia using pethidine or fentanyl, Anaesth. Intensive Care 25 (2) (1997) 126–132. [6] W.D. Ngan Kee, K.K. Lam, P.P. Chen, et al., Epidural meperidine after Caesarean section. A dose-response study, Anesthesiology 85 (1996) 289–294. [7] W.D. Ngan Kee, K.K. Lam, P.P. Chen, et al., Epidural meperidine after Caesarean section: the effect of diluent volume, Anesth. Analg. 85 (1997) 380–384. [8] C.J. Glynn, L.E. Mather, M.J. Cousins, et al., Peridural meperidine in humans, Anesthesiology 55 (1981) 520–526. [9] S. Sjöström, P. Hartvig, P. Persson, et al., Pharmacokinetics of epidural morphine and meperidine in humans, Anesthesiology 67 (1987) 877–888. [10] M.J. Paech, J.S. Moore, S.F. Evans, Meperidine for patient-controlled analgesia after Caesarean section, Anesthesiology 80 (1994) 1268– 1276. [11] R.W. Yarnell, T. Polis, G.N. Reid, et al., Patient-controlled analgesia with epidural meperidine after elective Caesarean section, Reg. Anesth. 17 (1992) 329–333. [12] K.H. Todd, K.G. Funk, R. Bonnacci, Clinical significance of reported changes in pain severity, Ann. Emerg. Med. 27 (4) (1996) 485–489. [13] A.M. Kelly, Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad. Emerg. Med. 5 (11) (1998) 1086–1090. [14] S. Mantha, R. Thisted, J. Foss, et al., A proposal to use confidence intervals for visual analog scale data for pain measurement to determine clinical significance, Anesth. Analg. 77 (1993) 1041–1047. [15] O.P. Rosaeg, M.P. Lindsay, Epidural opioid analgesia after Caesarean section: a comparison of patient-controlled analgesia with meperidine and single bolus injection of morphine, Can. J. Anaesth. 41 (1994) 1063–1068.