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30 Intrathecal fentanyl and acute tolerancecontaining IT morphine induces acute opioid tolerance,quantified by increased postoperative morphine requirementsand pain scores. The secondary aim was to determineif there is a dose–response associated with thisphenomenon. Our null hypothesis was that the additionof IT fentanyl would not change postoperative analgesicuse or pain scores.MethodsA total of 40 patients were enrolled (10 per group) inthis randomized, double-blinded, controlled, dose-rangingstudy after obtaining Institutional Review Board approvaland written informed consent. We enrolledhealthy women (American Society of Anesthesiologistsphysical status 1 or 2) with term singleton pregnancies(>37 weeks of gestation) undergoing elective cesareandelivery under spinal anesthesia before noon. Patientswere excluded from study participation if they met anyof the following criteria: morbid obesity (body mass index>40 kg/m 2 ), planned postpartum tubal ligation, previousadverse reaction to opioid medications or historyof chronic opioid use.The spinal anesthetic was administered with a 25-gauge Whitacre needle (B. Braun Medical, Bethlehem,PA, USA) at the L2–3 or L3–4 intervertebral space withthe patient in the sitting position. Each participant receivedIT hyperbaric bupivacaine 12 mg and preservative-freemorphine sulfate 200 lg (Astramorph PF,APP Pharmaceuticals LLC, Schaumburg, IL, USA)with an added randomized dose of 0, 5, 10 or 25 lg ITfentanyl (Baxter Healthcare Corporation, Deerfield,IL, USA). Randomization was by computer-generatedrandom-number allocation. The mixture was diluted toa total of 2.5 mL with sterile saline. The investigator,patient, anesthesiologist treating the patient, and allstudy staff remained blinded to the assigned treatment.An anesthesiologist not involved in the study or patientcare prepared the fentanyl doses.Patients were immediately placed supine with leftuterine displacement after the spinal anesthetic wasadministered. The height of the spinal block was assessedby pinprick and touch every 2 min until the blockreached the T4 dermatome bilaterally. Intraoperative vital-signmeasurements included: mean arterial pressuremeasured with a non-invasive blood pressure monitor,heart rate, respiratory rate and oxygen saturation.Ephedrine was given in 5-mg increments to treat systolicarterial pressure

B. Carvalho et al. 31after 12 h. Two patients dropped out because of postoperativepain: one in the fentanyl 5 lg group who hadcomplete data until 8 h, and another in the fentanyl25 lg group who had complete data until 12 h. Therefore,partial data for three patients and complete datafor 37 patients were analyzed. There were no statisticallysignificant differences in the demographics amonggroups with respect to age, height, weight, gestationalage and parity (Table 1).Total postoperative PCA morphine consumption didnot differ among the groups (Fig. 1). Postoperative painscores during the study period are outlined in Fig. 2.There was a significant difference between the postoperativepain AUC with increasing fentanyl doses (Tau0.38, P = 0.003, Kendal correlation test). The median[interquartile range] pain AUC in the fentanyl 0 lg controlgroup was 267 [120–360] mm.h, compared with 487[367–760] mm.h in the fentanyl 5 lg group (P = 0.018),520 [381–647] mm.h in the fentanyl 10 lg group(P = 0.007), and 608 [483–757] mm.h in the fentanyl25 lg group (P = 0.023). There was a poor correlationbetween pain, AUC and total morphine consumption(q = 0.194; P = 0.265).There were no significant differences in postoperativeoxygen saturation or respiratory rate between thegroups. At no time did any patient have an oxygen saturation

32 Intrathecal fentanyl and acute toleranceTable 2Incidence of intraoperative pain and nausea requiring treatment0 lg(n = 10)5 lg(n = 10)Fentanyl dose10 lg(n = 10)Patients requiring treatment for pain 2 0 0 1Patients requiring treatment for nausea 4 * 0 2 0Data are number of patients per group. * There was a significant difference compared to the fentanyl groups combined (P = 0.031).25 lg(n = 10)Table 3Intraoperative hemodynamic data0 lg(n = 10)5 lg(n = 10)Fentanyl dose10 lg(n = 10)25 lg(n = 10)Mean BP (mmHg) 70 ± 5 71 ± 7 77 ± 26 70 ± 15Minimum BP (mmHg) 59 ± 7 57 ± 11 55 ± 9 56 ± 20Ephedrine dose (mg) 17 ± 10 13 ± 11 19 ± 10 19 ± 15Data are mean ± SD. There were no significant differences among the groups. BP: blood pressure.DiscussionOur primary objective was to investigate if clinically significantacute tolerance to opioids developed with theaddition of IT fentanyl to a bupivacaine spinal anestheticsolution containing IT morphine. This was assessed bymeasuring the postoperative i.v. morphine requirementand postoperative pain for patients who had received ITfentanyl in doses 5, 10, and 25 lg compared to a no-fentanylgroup. We expected that if acute tolerance occurred,the amount of morphine consumed and postoperativepain experienced would be greater for the patients whowere given fentanyl versus no fentanyl, assuming subjectsin each group used the PCA to treat their pain to the samelevel. In addition, morphine usage and pain would likelyincrease successively with increasing doses of IT fentanylif there was a dose response associated with IT fentanyldose and acute tolerance.Our study did not find any significant difference inpostoperative morphine usage with increasing fentanyldosages. However, pain scores over the first 24 h aftersurgery, as measured by AUC, were increased in thegroups receiving IT fentanyl. Our assumption that patientswould self-administer the PCA to keep their painlevels the same across groups was incorrect, whichmakes interpretation of the data difficult. Patients whoreceived IT fentanyl, on average, did not treat themselvesto the same pain level as the patients not receivingIT fentanyl. A number of factors may influence morphineuse including side effects such as nausea, patientpreferences for analgesics and concerns for exposure ofmedication to breast-feeding infants. 10 However, wedid not measure or control for these factors and potentialconfounders. In addition, large inter-patient variabilityin PCA use (24-h morphine doses ranged from3 to 68 mg) made opioid consumption data difficult tointerpret. A post-hoc power calculation based on meanPCA use, showed that we would require 170 patients(control group 42: fentanyl group 128) to have enoughpower to have shown a difference in analgesic use (SD10.75 mg, power 0.8, alpha 0.05). Although the higherpostoperative pain scores in patients receiving fentanyldid not result in increased analgesic use, we believe thatthe differences in pain scores suggests that intrathecalfentanyl may induce acute opioid tolerance when ITmorphine is included in the spinal anesthesia solution.One limitation with our study design is that it doesnot allow us to definitively differentiate if IT fentanyl resultsin tolerance to the IT morphine administered in thespinal solution or the i.v. PCA morphine used to treatpostoperative pain. Differentiation between IT and i.v.morphine tolerance could have occurred if only non-opioidswere administered for postoperative analgesia,however, we felt that non-opioids (non-steroidal antiinflammatorydrugs, acetaminophen) would provideinadequate post-cesarean analgesia and could not beethically justified at our institution.Four patients in the control group versus two patientsin all the fentanyl groups combined required treatmentfor intraoperative nausea (P = 0.031). A numberof other studies have shown less intraoperative painand nausea when fentanyl is added to the local anestheticfor spinal anesthesia. 2,11–15 Intrathecal fentanylblunts the noxious input from visceral afferents thatare stimulated by pulling on the peritoneal structuresand exteriorization or manipulation of the uterus. 16These visceral afferent stimuli can manifest clinicallyas nausea, vomiting or cramping and do not appear tobe blocked completely with the local anesthetic blockalone. Even when IT morphine 200 lg was added, asin this study, visceral stimuli appeared to be inadequatelyblocked in the absence of IT fentanyl. Althoughhypotension can cause nausea and be a potential confounder,there was no evidence in our study that patients

B. Carvalho et al. 33treated for nausea had more hypotension than the otherpatients. The intraoperative benefit of using IT fentanylsuggested in this study and a number of previous studiesappears to outweigh the potential for inducing acutepostoperative tolerance.An important message from the data in this study,and other studies of post-cesarean delivery pain 4,17–19is the variability in the postoperative analgesic use andpain scores across all groups. The phenomenon of acutetolerance that we were studying accounted for very littleof the variation in the amount of pain or analgesia required.For example, the range of morphine doses usedby any group was three times the median dose in thegroups. Large inter-patient variability in opioid use isnot unique to this study. 20Although this study was underpowered to show smalldifferences among groups, we found no apparent benefitwith larger IT fentanyl doses. These findings are consistentwith those of Hunt et al., who studied IT fentanyldoses, ranging from 2.5 to 50 lg in combination withIT bupivacaine for cesarean delivery. 21 They found improvedintraoperative analgesia compared to bupivacainealone, but minimal additional benefit beyond ITfentanyl doses of 6.25 lg and interestingly also no differencein postoperative morphine use amongst the groups.Side effects from IT opioids are dose-dependent and largerdoses of fentanyl may increase the risk of respiratorydepression. 11 We did not observe any significant respiratorydepression in the study groups. One patient who receivedfentanyl 25 lg had a decreased respiratory rateintraoperatively for 20 min. Although the patient’srespiratory rate fell below 10 breaths/min, the oxygensaturation remained above 96% and the episode resolvedspontaneously.A potential limitation of this study is the multiplesmall-group comparisons, which were a function of thedose–response design. The strength of this design is thatwe obtain information over a wide range of doses. However,the multi-group design reduces the statisticalpower to show small differences between the groups.Due to the variability in postoperative morphine use,combined with the small sample size and multiplegroups, we lacked power to show a small difference inmorphine use. Although there was a statistically significantdifference in postoperative pain in the fentanylgroups, the clinical effect size was small and did not leadto increased analgesic use despite a five-fold increase infentanyl dose. However, we acknowledge that subtle differencesamong study groups would not have been detecteddue to study design limitations acknowledgedabove.In conclusion, our findings suggest that IT fentanyl indoses from 5 to 25 lg co-administered with IT bupivacaineand morphine for cesarean delivery under spinalanesthesia may induce subtle acute opioid tolerance asevidenced by higher overall pain scores in patientswho received fentanyl compared with the control group.However, this did not result in increased analgesic usepost-cesarean delivery. Therefore the clinical importanceof our findings is uncertain. Future studies with largersample sizes are required to fully elucidate this phenomenonand determine its clinical significance before cliniciansconsider avoid using IT fentanyl for fear ofinducing acute tolerance postoperatively, especially within light of previous studies showing that IT fentanyl resultsin less intraoperative pain and nausea during cesareandelivery.DisclosureThe authors involved in this study and the preparationof the manuscript received no external funding. Thisstudy was financially supported by the Department ofAnesthesia, Stanford University School of Medicine,Stanford, California. We thank Karen Giarrusso, MDfor her valuable help with patient enrollment and datacollection. We would also like to thank Alex McMillan,Human Health and Policy Biostatistics, Stanford University.For his expertise and advice on this analysis.References1. Liu S, Chiu AA, Carpenter RL, et al. Fentanyl prolongs lidocainespinal anesthesia without prolonging recovery. 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