3.2 Primary outcome
Sensory block up to the T6 dermatome was achieved in all patients. Parturients in the FM group required additional analgesics less often intraoperatively than those in the M group (P < .01, relative risk 0.06, 95% CI 0.004–1.04; Table 2). Noninferiority of the new treatment (FM) was confirmed on the basis of mean cumulative patient-controlled pethidine consumption in the 24 hours postoperatively. The 95% CI for the difference between treatment means ranged from −10.0 to 45.7 mg, and was below the prespecified boundary of 50 mg (Table 2, Fig. 2). Postoperative PCA is shown in Fig. 3A.
3.3 Secondary outcomes
During the first postoperative time interval (1–12 hours), patients in the FM group required on average more than double the dose of pethidine when compared with the M group (P = .02; Table 2). During the second postoperative time interval (13–24 hours), mean cumulative patient-controlled pethidine consumption remained at similar levels in both groups (P = .78; Table 2). Duration of effective analgesia and mean VAS scores did not differ between the groups (Fig. 3B, Table 2).
The number of patients experiencing PONV was higher in the FM group (P = .01, relative risk 10.3, 95% CI 1.4–74.5; Table 3). The incidence of pruritus was relatively high, but did not differ between the groups. Oversedation and respiratory depression did not occur in any of the patients, and mean oxygen saturation levels were similar (Table 3). There was no difference in Apgar scores between the groups and no clinically important hemodynamic changes occurred in either group intraoperatively or postoperatively.
Our study demonstrates that a combination of intrathecal lipophilic and hydrophilic opioids, such as fentanyl and morphine, can improve perioperative analgesia in patients undergoing CS, but at a cost of more postoperative PONV. Improvement in analgesia was clearly seen intraoperatively. Intrathecal morphine alone, according to some authors, reduces intraoperative discomfort,[10,24] whereas others believe it only starts to work postoperatively. Intraoperative pain has been reported in 18% to 29% of cases after administration of spinal morphine at a dose of 0.1 to 0.2 mg.[5,6,11,25,31] More detailed studies have shown the onset of action of morphine to be 30 to 60 minutes after intrathecal administration in obstetrics and other types of surgery. Given that the duration of CS is usually shorter than 1 hour, the onset of action of morphine during surgery or postoperatively determines the indications for use of spinal fentanyl. The results of our study indicate that morphine does not have an intraoperative analgesic effect, given that 25% of women needed additional intraoperative analgesia. However, the time interval between induction of anesthesia and skin incision in our study was 10 minutes on average. Thus, in the event of a short time interval between spinal anesthesia and the start of surgery, we recommend a combination of the 2 opioids. Other researchers have reached a similar conclusion, and a decrease in intraoperative pain was seen in many studies,[26–28] including in the present study. A search of the literature concerning use of spinal fentanyl in CS revealed that doses much smaller than those used in our study have been equally effective for intraoperative analgesia.[6,8,25,33] This phenomenon was not observed in nonobstetric patients, and a study in an animal model suggested an escalating influence of progesterone on the analgesic effect of lipophilic spinal opioids during pregnancy. In many studies, abolition of intraoperative visceral pain was observed in almost all patients who received spinal fentanyl in doses higher than 10 μg[7,9,10,24,33,35]; doses below 10 μg were considered adequate by some authors, but not by others.
The mean cumulative patient-controlled pethidine consumption and average VAS scores were not significantly different between the 2 groups in the 24 hours after CS, indicating an overall benefit of combined intrathecal opioids in CS. In contrast, a similar study by Carvalho et al reported no difference in postoperative opioid consumption, but higher VAS scores in the group that received a combination of fentanyl and morphine. However, in our study, when we divided the postoperative period into 2 time intervals, we found a higher demand for patient-controlled pethidine in the FM group during the first 1 to 12 hours, which has been defined previously as the time when the requirement for analgesics after CS is greatest. Sibilla et al similarly noted that only 30% of women who received spinal morphine required additional analgesia during the first 12 hours after CS, whereas 60% of women receiving fentanyl and morphine required additional analgesia in the same time interval. This observation could be explained by the occurrence of acute spinal opioid tolerance. It has been reported that a small dose of spinal fentanyl during CS can result in an increased postoperative demand for intravenous opioids.[6,37] It has also been suggested that an increase in transmission of pain could be linked to 3 mechanisms, that is, reduction of opioid activity at spinal opioid receptors, a reduced effect of endogenous spinal opioids, and an influence on descending pain control pathways. Other mechanistic theories for this phenomenon include the widely held assumption that whereas the onset of action of spinal fentanyl is rapid, the onset of action of morphine administered via the spinal route is slow (which is debatable), such that fentanyl binds to a proportion of spinal opioid receptors before morphine is able to reach them. By the time that the fentanyl is released from these receptors, the proportion of morphine molecules that could potentially bind with them has already been absorbed into the systemic circulation. The remaining concentration of morphine is therefore lower than it would be if morphine was the only substance in the solution from the outset.
The phenomenon of increased demand for opioids after spinal fentanyl was noticed also in the duration of effective analgesia, which was reduced from approximately 12 to 8 hours when opioids were combined. Although this difference was not significant, the trend was quite clear and the result was close to statistical significance (P = .07). A similarly short duration of effective analgesia (4–14 hours) when using a combination of fentanyl and morphine has been observed in other studies.[10,26,27] In contrast, the average duration of effective analgesia was 18 to 22 hours in studies when morphine 100 μg was used alone.[10,27,38–40]
The mechanism for intrathecal opioid-induced PONV is thought to involve cephalad migration of the opioid in cerebrospinal fluid to opioid receptors in the area postrema. The likelihood of PONV after administration of spinal fentanyl[8,41] or morphine[21,22,42] alone for obstetric purposes has been reported to be relatively low in previous studies, and is consistent with our findings (3.6% for spinal morphine). However, some researchers have reported a higher incidence of PONV after spinal morphine.[24,40,43,44] Unexpectedly, we noted that the incidence of PONV was 37% in patients who received both intrathecal opioids, which is similar to the incidence of 20% to 35% reported elsewhere for use of a combination of opioids.[3,10,26,27,45] One study that reported an increase in PONV when intrathecal opioids were combined suggested that a change in baricity of the opioid solution resulting in hypobaricity, and more cephalad migration of the mixture, might be responsible for the increased incidence of this side effect.
A review of the literature shows that addition of morphine to a local anesthetic agent results in an increased incidence of pruritus in the order of 40% to 63%,[10,24,31,38,39,42] which is consistent with our results (36%). A combination of intrathecal opioids, according to some studies, results in an even greater increase in pruritus (67%–87%),[10,26,45] but in other studies, including our present study, the incidence of pruritus was relatively low (37%–48%).[3,28,45]
Severe respiratory depression has not been observed after intrathecal administration of morphine at doses of 0.1 to 0.2 mg for CS,[10,26,38–40] and was not seen in our study either. Reviews and other studies on this topic report that respiratory depression after intrathecal opioids is rare and mild in the obstetric population, and that the risk is no higher than after parenteral opioid administration.[13,24,46] It is not clear how a combination of opioids influences the risk of respiratory depression. There has been a report of 1 severe case, which was considered to be associated more with the effect of morphine and not fentanyl, given that it occurred late after administration.
There was no relationship between intrathecal opioid administration and neonatal Apgar scores in our study, and this finding is in agreement with other reports.[8,10,11,31,33]
In summary, the main contribution of this study to the literature is the finding that a combination of morphine and fentanyl as a supplement to spinal anesthesia for CS provides better intraoperative and postoperative analgesia than does spinal morphine without fentanyl. We have included both periods in our analysis because we believe that the quality of intraoperative analgesia is as important as effective postoperative pain management.
We made several assumptions at the beginning of this study. First, we assumed a noninferiority margin of 50 mg on the basis of statistical and clinical reasoning. From the perspective of the intrathecal morphine group, it is almost as high as the mean total pethidine consumption over 24 hours postoperatively. However, the postoperative pethidine requirement in the relevant CS studies has been reported to be 360 to 680 mg in patients who received placebo (ie, no intrathecal opioids).[48,49] In light of these results, our margin of 7% to 14% of this requirement appears to be reasonable. If we have decreased the noninferiority margin to 40 mg, the sample size of 24 patients per group would not exceed the number of patients that we have studied, but the inference of the noninferiority trial would be inconclusive. In this situation, our recommendations about the use of the 2 spinal opioids would have to be weaker. Second, based on the previous studies mentioned earlier in this section, we assumed the difference in occurrence of intraoperative pain between the groups to be 25%. Decreasing the proportion of patients experiencing intraoperative pain in group M to 15% would have increased our sample size by about half of the number of patients that we studied (44 parturients per group). That assumption would mean that our sample size was relatively small. However, sample sizes in comparable studies, also focusing on use of a combination of intrathecal opioids in CS, ranged from 20 to 31 patients per group.[10,25–28,45] Moreover, most studies assessing intraoperative analgesia after addition of spinal fentanyl in CS have used groups containing as few as 5 to 20 patients,[6–8,33,35,36,50] and very few have included greater numbers of patients (29 per group).[9,10]
The combination of intrathecal fentanyl and morphine provides better perioperative analgesia than intrathecal morphine alone and may be recommended in situations where the time from induction of anesthesia to skin incision is short. However, the increase in side effects (PONV) and possibility of acute spinal opioid tolerance after adding intrathecal fentanyl indicates a need for further studies using the same study design and outcome measures, but with lower doses of fentanyl. The practical application of the results of this study could be the use of a combination of lipophilic and hydrophilic spinal opioids as an addition to a local anesthetic agent in spinal anesthesia for CS to increase the patient's comfort level. Based on our results, and those of others, we would recommend using morphine 100 μg and fentanyl 10 to 15 μg.
We are grateful to Professor Jacek Koronacki, Director of the Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland, for his constructive comments concerning the statistical analysis. We would like to thank Professor Ewa Mayzner-Zawadzka, MD, PhD, DSc, Department of Anesthesiology and Intensive Care, University of Warmia and Mazury, Poland, for mentoring and supervision during the research. We would also like to thank Editage (www.editage.com) for English language editing.
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Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
acute opioid tolerance; hydrophilic and lipophilic opioids; patient-controlled analgesia (PCA); post-caesarean pain management; spinal anesthesia; spinal opioids; superiority and noninferiority trial