1 Department of Anaesthetics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 2 Departments of Anaesthesia and Intensive Care Medicine, South Manchester University Hospital, Wythenshawe, UK
* Corresponding author. E-mail: g.a.mcleod{at}dundee.ac.uk
Accepted for publication October 5, 2004.
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Abstract |
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Method. In this double-blind, randomized, prospective study, 62 women in active labour and 5 cm cervical dilatation were recruited to determine whether the mode of action of diamorphine in the epidural space is concentration-dependent. After insertion of a lumbar epidural catheter, patients received epidural diamorphine 3 mg either as a high-volume, low-concentration solution (group A) or a low-volume, high-concentration solution (group B). The concentration of diamorphine was determined by the response of the previous patient in the same group using updown sequential allocation. Pain corresponding to the previous contraction was assessed using a 100-mm visual analogue score and effective analgesia was defined as
10 mm within 30 min of epidural injection.
Results. There was no significant difference in EC50 for diamorphine between the groups: the difference was 15.0 µg ml1 (95% CI 40.3 to 10.3). The EC50 for group A was 237.5 µg ml1 (95% CI 221.2 to 253.8) and the EC50 for group B was 252.5 µg ml1 (95% CI 232.2 to 272.8). The EC50 ratio was 0.95 (95% CI 0.87 to 1.06). The groups exhibited parallelism (P=0.98). The overall EC50 for all data was 244.2 µg ml1 (95% CI 230.8 to 257.2).
Conclusion. We conclude that diamorphine provides analgesia in labour by a concentration-dependent effect.
Keywords: anaesthetic techniques, epidural ; anaesthetic techniques, minimum dose ; analgesics opioid, diamorphine
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Introduction |
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Diamorphine possesses many of the ideal physicochemical characteristics necessary for providing epidural pain relief in labour.1 Principally, it has an intermediate lipid solubility between fentanyl and morphine, enabling passage through both hydrophilic and hydrophobic tissues. Secondly, the free fraction of unionized drug with diamorphine is 11 times greater than that with fentanyl. Thirdly, diamorphine exhibits greater clearance from cerebrospinal fluid compared with morphine, thus reducing the potential for serious side-effects, such as respiratory depression.
Although epidural administration of diamorphine is widespread in the UK for pain relief after abdominal surgery2 and Caesarean section,3 its use in labour has been limited. Epidural administration of bupivacaine and diamorphine mixtures has provided good analgesia for labour as a bolus,4 5 infusion4 6 7 and combined spinal epidural.8 Only one published study has shown that diamorphine alone, albeit with a large (5 mg) dose,9 can provide pain relief in labour equivalent to a combination of diamorphine and bupivacaine. However, unlike local anaesthetics, for diamorphine the influence of volume, mass or concentration on the mode of action remains unknown.
Therefore, the aim of our study was to investigate the use of diamorphine for analgesia in labour using the method of sequential allocation to determine whether the mode of action is concentration-dependent and, if so, to determine its median effective concentration (EC50) and concentrationresponse curve.
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Methods |
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After starting an i.v. crystalloid infusion, and with the patient in the left lateral position, a Touhy needle was inserted at the L 2/3 interspace using loss of resistance to saline and a catheter inserted 3 cm into the epidural space. Saline injection was minimized to <2 ml to avoid dilution of opioid solutions. All epidurals were inserted by a single investigator (B.M.), blinded to the patient group, whose standard technique is to insert epidural catheters caudally at L 2/3. Data from our yearly obstetric anaesthesia audit has regularly shown that caudal epidural catheters, inserted by B.M., have consistently provided good pain relief. Patients were randomized into two groups. All patients received a fixed dose of 3 mg diamorphine. The first group (A) received a high-volume, low-concentration injection starting at 20 ml diamorphine 150 µg ml1 and the second group (B) received a low-volume, high-concentration epidural injection starting at diamorphine 600 µg ml1, 5 ml. No test dose was given and time zero was designated as the time at which the epidural injection was completed.
Pain scoring was conducted by trained midwives, as pain scoring is mandatory for all epidurals in our unit. Pain corresponding to the peak pain associated with the previous contraction was measured every 5 min by the patient with a visual analogue scale (VAS), whereby 0 mm corresponded to no pain and 100 mm to the worst pain imaginable.
Three outcomes resulted from VAS scoring and dictated the concentration of drug given to the next patient, based on a dosing interval of 25 µg ml1. This is termed sequential allocation.
Effective: VAS score 10 mm at any time during the study period. The next patient was given 25 µg ml1 less diamorphine.
Ineffective: VAS score >10 mm at all times during the study period but pain resolved after a bolus of bupivacaine 0.25%, 10 ml. The next patient was given 25 µg ml1 more diamorphine.
Exclude: VAS score >10 mm at all times during the study period but pain did not resolve after a bolus of bupivacaine 0.25%, 10 ml. After an exclusion, the next patient was allocated to the same group and same concentration of solution.
After the study, pain relief was maintained throughout labour with patient-controlled epidural boluses of bupivacaine 0.1% w/v, 15 ml. Hourly monitoring of maternal heart rate, non-invasive arterial pressure, respiratory rate, itching and nausea and vomiting was undertaken until 2 h after delivery. In addition, mode of delivery was noted and fetal welfare was assessed using continuous cardiotocogram, Apgar scores and umbilical arterial and venous pH.
Statistical analysis
Data are presented as mean (SD) and count and were analysed using Student's t test and Fisher's exact test as appropriate. Median effective concentrations with 95% confidence intervals (CI) were estimated from the sequences using the updown method of Dixon and Massey. The responses at each dose level were also analysed using probit regression to estimate EC50.10 Analyses were carried out using the following software: Microsoft Excel 2000 (Microsoft, Redmond, WA, USA) and Number Cruncher Statistical Systems (NCSS 2001, Kaysville, UT, USA). Bioequivalence was concluded if the 95% confidence interval of the ratio of EC50 was contained within the 0.8 to 1.25 limits. Statistical significance was defined for an overall error at the 0.05 level and P values were two-sided.
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Results |
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Discussion |
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This study also confirms the results of previous research,9 that diamorphine alone can provide good pain relief in labour. All patients receiving more than diamorphine 300 µg ml1 experienced good pain relief in labour of an intensity comparable to that of local anaesthetics in other studies (VAS pain score 10 mm).1012 In contrast, patients receiving high-volume, low-concentration diamorphine, starting at a volume of 20 ml and concentration of 150 µg ml1, had a variable response and oscillation occurred at a median concentration of 237.5 µg ml1.
We consider it important, in studies of analgesics substituting for local anaesthetics in early labour, that the standard of pain relief should be equivalent to that deemed acceptable with local anaesthetics. Therefore, we defined good pain relief as a VAS score 10 mm within 30 min of epidural injection.
Unlike local anaesthetics, epidural diamorphine has not hitherto been studied with respect to the influence of volume, mass or concentration on the clinical efficacy. Several studies have shown that the mode of action of lidocaine,11 bupivacaine,11 levobupivacaine12 and ropivacaine13 is concentration-dependent. The evidence of high-quality pain relief in labour with diamorphine,9 of a magnitude similar to that of the local anaesthetics mentioned above, allowed us to use the method of sequential allocation, used routinely to measure the EC50 of local anaesthetics, in order to estimate the EC50 of diamorphine. Although the EC95 may be regarded as clinically useful, we regard the EC50 as a more sensitive means of comparing drug concentrations as the EC50 represents the point of maximal slope of the cumulative concentrationresponse curve.
We have shown that, like local anaesthetics, diamorphine has a mode of action that is dependent on concentration, but that the volume of diamorphine associated with good clinical efficacy differs from that of local anaesthetics. Small, highly concentrated, volumes of diamorphine provided good pain relief in early labour in this study, whereas local anaesthetics have been shown to require a large volume to fill the discontinuous and segmented14 lumbar epidural space and spread out through the intervertebral foraminae15 in order to block nerve roots.
Provision of good pain relief by high-concentration, low-volume solutions of epidural diamorphine may be attributed to its site of actionopioid receptors within the grey matter of the spinal cord. Bioavailability of diamorphine to the opioid receptors is a balance between the pharmacological properties of the drug (Table 3) and the relative lipid/water solubility and the vascularity of the tissues through which it passes. The intermediate lipid solubility of diamorphine, as indicated by an octanolwater distribution coefficient of 280, lends itself to traversing both hydrophobic and hydrophilic tissue compartments, thus increasing permeability when compared with either morphine or fentanyl.16 17 Furthermore, diamorphine's lower protein binding and lower pKa (and hence lower ionization)18 compared with fentanyl increases bioavailability onto opioid receptors within the spinal cord.
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This study, however, was not designed to answer whether the efficacy of epidural diamorphine is by direct binding to opioid receptors at spinal cord level or by systemic redistribution via subdural blood vessels20 and block of opioid receptors within the spinal cord and brain. A previous study9 suggests that both mechanisms may be pertinent; the concomitant use of epidural epinephrine with diamorphine reduced plasma concentrations of morphine, suggesting that the mode of action of diamorphine is partly systemic. Further studies are necessary to determine whether high-concentration, low-volume diamorphine passing down a steep concentration gradient is associated with less side-effects, lower systemic blood levels and longer duration of action due to a predominantly spinal action.
The clinical advantage of such an epidural solution would be the provision of early pain relief in labour without motor block, thus allowing ambulation. Although the combined spinal epidural technique is popular for initiating pain relief and providing ambulation, many anaesthetists remain reluctant to breach the dura mater in early labour and, instead, provide pain relief with low-concentration, high-volume mixtures of epidural local anaesthetic and fentanyl.
However, before embarking on randomized, controlled outcome studies of the efficacy and side-effects of epidural diamorphine, we are first using the method of sequential allocation to determine whether the addition of local anaesthetics to diamorphine confers any synergistic benefit, and whether epidural diamorphine exhibits any volume dependence.
In conclusion, we have shown that diamorphine provides effective analgesia in early labour and that this effect is concentration-dependent.
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Footnotes |
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References |
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