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Intrathecal Hydromorphone and Morphine for Postcesarean Delivery Analgesia: Determination of the ED90 Using a Sequential Allocation Biased-Coin Method

Sviggum, Hans P. MD; Arendt, Katherine W. MD; Jacob, Adam K. MD; Niesen, Adam D. MD; Johnson, Rebecca L. MD; Schroeder, Darrell R. MS; Tien, Michael BS; Mantilla, Carlos B. MD, PhD

doi: 10.1213/ANE.0000000000001229
Obstetric Anesthesiology: Original Clinical Research Report

BACKGROUND: Intrathecal (IT) morphine is considered the “gold standard” for analgesia after cesarean delivery under spinal anesthesia, most commonly administered at a dose of 100 to 200 μg. There is less experience with IT hydromorphone for postcesarean analgesia and limited information on its optimal analgesic dose. We conducted this study to determine the effective analgesic dose for 90% patients (ED90) of IT hydromorphone that provides effective analgesia for women undergoing elective cesarean delivery and its potency ratio to IT morphine.

METHODS: In this dose-finding trial, 80 patients received spinal anesthesia for cesarean delivery. Participants were randomized to receive IT morphine or IT hydromorphone at a dose determined using up–down sequential allocation with a biased-coin design to determine ED90. All patients received standardized multimodal analgesia postoperatively in addition to IT opioid. An effective dose was defined as a numeric response score for pain of ≤3 (scale 0–10) 12 hours after spinal injection.

RESULTS: The ED90 was 75 μg (95% confidence interval [CI], 46–93 μg) for IT hydromorphone and 150 μg (95% CI, 145–185 μg) for IT morphine. At these doses, the 95% CI for the percentage of patients with effective analgesia (numeric rating scale ≤3) was 64% to 100% for hydromorphone and 68% to 100% for morphine. Exploratory findings showed that the incidence of nausea and pruritus was not different among the most commonly used doses of IT hydromorphone (P = 0.44 and P = 0.74) or IT morphine (P = 0.67 and P = 0.38, respectively). When administering IT opioids at ED90 doses or higher, 100% (21/21) of IT hydromorphone and 95% (37/39) of IT morphine patients were satisfied with their analgesia.

CONCLUSIONS: The ratio of IT morphine to IT hydromorphone for effective postcesarean analgesia is 2:1. Patient satisfaction was high with both medications.

Published ahead of print March 11, 2016

From the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.

Accepted for publication January 18, 2016.

Published ahead of print March 11, 2016

Funding: Department of Anesthesiology, Mayo Clinic, Rochester, MN.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Hans P. Sviggum, MD, Department of Anesthesiology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905. Address e-mail to sviggum.hans@mayo.edu.

The effectiveness of intrathecal (IT) morphine as part of a multimodal regimen for postcesarean delivery analgesia is well established. It is generally considered to be the “gold standard” for pain control in this setting.1–3 Its hydrophilic nature allows for broad dermatomal coverage as well as a prolonged duration of action of approximately 14 to 36 hours.3 The optimal dose for postcesarean analgesia has been characterized in a number of studies with successful doses ranging from 0 to 500 μg.4–8 There is a tradeoff, however, between analgesia and opioid side effects. As the dose escalates, IT opioid-induced side effects (nausea, pruritus, sedation, and respiratory depression) escalate as well. Therefore, most providers administer 100 to 200 μg IT morphine dose for cesarean delivery analgesia with excellent analgesic results.4–8

As anesthesia providers have faced national shortages of preservative-free morphine in the recent years or have been unhappy with IT morphine’s side effects, there has been a push to explore the use of IT hydromorphone as a potential alternative for postoperative analgesia after cesarean delivery. IT hydromorphone has routinely been used in pain medicine for >2 decades and is listed as a first-line therapy along with morphine for IT management of chronic pain conditions.9 In addition, its ability to provide postcesarean analgesia when administered in the epidural space has been established.10,11 However, data regarding its efficacy in the IT space for postcesarean analgesia are sparse. Doses of 40 to 100 μg have been reported to provide adequate postoperative analgesia with minimal side effects.12–14 No prospective studies have been conducted to establish the effectiveness or optimal dose of IT hydromorphone for postcesarean analgesia.

The purpose of this study was to identify the dose of IT hydromorphone that provided effective analgesia in 90% (ED90) of patients after cesarean delivery using an up–down sequential allocation method with a biased-coin design.15 The up–down sequential allocation method typically identifies a median dose required for the success criterion and is poor at providing reliable estimates beyond this median dose. However, incorporating a biased-coin design allows for a more accurate estimate of the ED90. We hypothesized that the ED90 for IT hydromorphone would range between 40 and 100 μg. In addition, we hypothesized that the ED90 for IT morphine, using this sequential allocation biased-coin method as a validation arm, would range between 100 and 200 μg. Exploratory outcomes included patient satisfaction, rescue opioid consumption, and the occurrence and severity of the following adverse effects: nausea, itching, sedation, and respiratory depression events.

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METHODS

The Mayo Clinic institutional review board approved this study, it was registered at ClinicalTrials.gov (NCT02009722) before patient enrollment, and written consent was obtained from all patients. We included American Society of Anesthesiologists physical status II and III women at term (>37 weeks of gestation) presenting for elective cesarean delivery who were not in labor. Exclusion criteria included contraindications to spinal anesthesia, allergy or idiosyncratic reaction to opioid medications, anticipated fetal anomalies, rupture of membranes, active labor, current opioid use, prepregnancy body mass index >40 kg/m2, performance of concurrent procedures (eg, tubal ligation), or any baseline pain, nausea, or pruritus. Patients in whom the protocol was violated (eg, postoperative data collection not performed) or the study was stopped early (eg, change in fetal or maternal health mandating the use of other anesthetic techniques, inability to initiate spinal anesthesia, withdrawal of subject consent for any reason, or surgical complications resulting in the need for additional procedures) were not included in our analysis.

Subject recruitment was performed by one of the study investigators before the patient underwent elective cesarean delivery at a single tertiary care birthing center. A computer-generated randomization scheme was used to assign each patient to either IT morphine or hydromorphone. This secure system (only accessible by study investigators) also allocated the specific medication dose to be used for each enrolled subject. A physician not involved in patient consent or data collection performed the randomization process and prepared the study medication within 60 minutes of administration. Patients and all outcome assessors were blinded to study group allocation and dose.

The starting doses of IT hydromorphone and morphine were 40 and 100 μg, respectively, as determined by evaluating extant literature5–7 as well as our institution’s prior experience.12 Steps “down” from the starting dose (10 μg IT hydromorphone and 25 μg IT morphine) were smaller than steps “up” because of concern for not providing adequate analgesia (larger decreases would increase the risk of ineffective analgesia) and a desire to more accurately pinpoint an effective dose should it decrease below our starting dose. The steps “up” from the starting dose were designed to reflect common clinical doses used in practice.

The possible doses for IT hydromorphone were as follows (starting dose in italics):

10–20–30–40–50–75–100–150–200–250 μg.

The possible doses for IT morphine were as follows (starting dose in italics):

25–50–75–100–150–200–250–300–400 μg.

Pain intensity was reported by the patient using an 11-point verbal numeric rating scale (NRS) with the anchors “no pain” = 0 and “worst pain ever” = 10.16 IT opioid dose adjustments for subsequent study patients were based on the efficacy of the study drug for the previous patient. Effective analgesia was defined as a verbal NRS score for pain ≤3 at 12 hours after administration of spinal anesthesia. Doses for subsequent patients were adjusted using a biased-coin up–down sequential allocation method described by Durham and Flournoy15 with the aim of estimating the ED90. When ED90 is to be determined (τ = 0.9), the probability (B) = (1 − τ)/τ = (1 − 0.9)/0.9 = 0.1/0.9 ≈ 0.11. If the NRS score for pain was >3 at 12 hours or if the patient required fentanyl patient-controlled analgesia, the dose was increased for the next subject randomized to that same drug. If the NRS score for pain was ≤3 at 12 hours, the next patient randomized to receive that drug received with probability B ≈ 0.11 the next lower dose and with probability 1 − B = 0.89, the same dose as the previous patient. Patients excluded after randomization were removed from the study. The next recruited patient was subjected to random group allocation (IT morphine versus hydromorphone), and the dose assignment was adjusted based on the same biased-coin sequential allocation process as if the excluded patient had not been randomized.

After establishment of IV access in the preoperative area, patients were brought into the operating room. Continuous pulse oximetry, continuous electrocardiography, and noninvasive arterial blood pressure monitors were placed, and initial vital signs were recorded. Spinal medications consisted of 0.75% bupivacaine with 12 mg 8.25% dextrose, 15 μg fentanyl, and either morphine (Medisca Inc., Plattsburgh, NY) or hydromorphone (Akorn Inc., Lake Forest, IL) according to study randomization. The formulation of hydromorphone was preservative-free and was prepared by Mayo Pharmacy Services. The starting concentrations were as follows: 0.1 mg/mL hydromorphone for doses of 100 μg or less, 1 mg/mL hydromorphone for doses higher than 100 μg; and 0.1 mg/mL morphine for doses 100 μg or less, 1 mg/mL morphine for doses higher than 100 μg. Using a sterile technique, an unblinded assistant who had no further clinical or research duties prepared the fentanyl and study drug in separate 1-mL graded tuberculin syringes and the bupivacaine into a 3-mL graded syringe. This assistant then consecutively added the fentanyl and study drug to the 3-mL syringe. Finally, preservative-free normal saline was added to the study solution to achieve a total volume of 3 mL for each mixture. Spinal anesthesia was performed using a standard single injection technique. While receiving an IV bolus of 500-mL lactated Ringer’s solution, patients were placed in the flexed sitting position. Using a sterile technique, the IT space was identified at the L3–4 or L4–5 interspace with a 25-gauge Whitacre spinal needle (BD Medical, Franklin Lakes, NJ), and the full 3 mL volume of prepared solution was injected. All subjects received a prophylactic IV phenylephrine infusion initiated at 0.5 μg/kg/min at the time of spinal injection. Titration of the phenylephrine infusion and further intraoperative arterial blood pressure management were left to the discretion of the anesthesia provider blinded to patient group with the goal of maintaining the patient’s arterial blood pressure at 100% of baseline. Each patient received 0.1 mg granisetron or 4 mg ondansetron intraoperatively after delivery.

Postoperatively, all patients were treated with a standard order set, which provides multimodal analgesia, nausea and pruritus treatment, monitoring, and emergency treatment as needed. Specifically, this order set entails 1000 mg oral acetaminophen and 15 mg IV ketorolac administered every 6 hours. After 3 doses of ketorolac, 600 mg oral ibuprofen was administered every 6 hours. Oral oxycodone was administered every 4 hours as needed for NRS pain scores ≥4, 5 mg for NRS pain scores higher than or equal to 4 and <7, and 10 mg for pain scores >6. Two IV doses of 50 μg fentanyl were allowed for the treatment of breakthrough pain. Granisetron (0.1 mg IV) and/or droperidol (0.625 mg IV) were available as needed for the treatment of nausea. Nalbuphine (5 mg IV every 4 hours as needed) was available to treat pruritus. Naloxone (0.2 mg IV) was given for a respiratory rate of <8 breaths per minute or a Richmond Agitation and Sedation Scale (RASS) of −3, −4, or −5. The RASS is a 10-point scale assessing the level of consciousness with anchors of +4 (combative) and −5 (unarousable).17 A RASS of 0 indicates “alert and calm.” The order set also included continuous pulse oximetry for 24 hours after neuraxial opioid administration as well as assessment of respiratory rate, oxygen saturation, and RASS every hour for the first 12 hours and every 2 hours for the subsequent 12 hours. Any serious adverse event was reported to the Medical Director of Obstetric Anesthesia and/or the Clinical Practice Chair, Rochester Methodist Hospital Anesthesiology.

All data were collected prospectively by patient interview at 6, 12, and 24 hours after spinal anesthesia administration by blinded study personnel. At each time point, patients reported the following:

  1. NRS score for pain intensity (0–10)
  2. Severity of nausea (0 = none, 1 = mild, 2 = moderate, 3 = severe)
  3. Severity of pruritus (0 = none, 1 = mild, 2 = moderate, 3 = severe)
  4. Overall satisfaction with spinal anesthetic (0 = satisfied, 1 = somewhat satisfied, 2 = neutral, 3 = somewhat unsatisfied, 4 = unsatisfied)

Grading of nausea and pruritus was assessed by the patient’s self-reported perception of severity. Level of sedation was also assessed by RASS at each time point.

The following data were recorded from all women: age, weight, height, ethnicity/race, gestational age, and number of previous cesarean deliveries. The following data were collected from the patient’s electronic medical record: fetal characteristics (eg, birth weight), total opioid consumption within 24 hours of IT opioid administration, medical treatment(s) for nausea or pruritus within 24 hours of IT opioid administration, and hypoventilation events (respiratory rate <8 breaths per minute). Study data were collected and managed using Research Electronic Data Capture (REDCap) (Vanderbilt University, Nashville, TN) tools hosted at the Mayo Clinic.18 REDCap is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources.

The primary outcome was a verbal NRS score for pain at rest 12 hours after spinal administration. Exploratory outcomes included the presence and severity of opioid-related adverse effects at each time point (pruritus, nausea, sedation, and respiratory depression), total opioid consumption within 24 hours from spinal administration, and NRS scores for pain at 6 and 24 hours.

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Statistical Analysis

We chose a sample size of 40 patients in each group (80 total patients). No formal statistical sample size analysis was performed. Simulation studies have suggested that using 20 to 40 patients in up–down sequential allocation trials will provide stable estimates of the target dose for most realistic scenarios. In addition, the nonindependence and unknown distribution of data of an up–down study prevent the development of theoretically rigorous rules to calculate the necessary sample size.19

All analyses were performed separately for morphine and hydromorphone. Isotonic regression using the pooled-adjacent-violators algorithm was used to determine the modified isotonic estimator for the ED90 dose.20 In short, the observed success rate (percentage of patients with NRS pain ≤3) was calculated for each dose. Isotonic regression using the pooled-adjacent-violators algorithm was then used to obtain point estimates for the success rates that were constrained to be monotonic increasing with dose. The modified isotonic estimator for ED90 was then obtained via linear interpolation between the highest dose with an estimated success rate <90% and the lowest dose with an estimated success rate >90%. To provide an interval estimate for ED90, and for the probability of success at the sample estimate for the ED90, a 95% confidence interval (CI) was constructed using the bootstrap approach described by Stylianou et al.21 Bootstrap samples used for the agent-specific ED90 interval estimates were combined, and the potency ratio for each sample was calculated. Using these bootstrap estimates, a bias-corrected bootstrap 95% CI was calculated for the potency ratio of IT morphine to hydromorphone. Supplemental analyses of exploratory endpoints for each study medication were restricted to doses that were used for at least 10 study patients. To account for the repeated-measures study design, NRS scores at 6, 12, and 24 hours were compared across doses using generalized estimating equations. Using a logit link function, generalized estimating equation analyses were also performed to compare the percentage of patients with effective analgesia (NRS ≤3) between dose groups and the frequency of moderate or severe nausea and pruritus between dose groups. The percentage of patients who required treatment for nausea or pruritus during the first 24 hours was compared across doses using the Fisher’s exact test, and opioid consumption over the first 24 hours was compared using the Kruskal-Wallis test. In all cases, 2-tailed tests were performed with P values <0.05 considered statistically significant.

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RESULTS

Study recruitment took place between January 2014 and November 2014. Four patients were excluded from the study after providing consent (Figure 1). Data from these patients were not included in the analysis. Demographic data for the patients included in the final analysis are shown in Table 1.

Table 1

Table 1

Figure 1

Figure 1

The results of the up–down biased-coin dose allocation are summarized in Figure 2. Isotonic regression analyses revealed an ED90 of 150 μg (95% CI, 145–185 μg) for IT morphine and 75 μg (95% CI, 46–93 μg) for IT hydromorphone. These estimates of the ED90 for postcesarean analgesia produced a ratio (IT morphine/hydromorphone) of 2.0 (95% CI, 1.6–3.6). Of the 21 patients assigned to the dose of 150 μg morphine, 19 met criteria for analgesic efficacy. Of the 10 patients assigned to the dose of 75 μg hydromorphone, 9 met criteria for analgesic efficacy. The 95% CI for the percentage of patients with effective analgesia was 68% to 100% for the dose of 150 μg morphine and 64% to 100% for the dose of 75 μg hydromorphone.

Figure 2

Figure 2

Supplemental analyses were restricted to patients who received 50 (n = 12) versus 75 (n = 10) versus 100 (n = 11) μg hydromorphone and patients who received 150 (n = 21) versus 200 (n = 18) μg morphine. Postoperative oxycodone use over the first 24 hours did not differ significantly among those who received 50 versus 75 versus 100 μg hydromorphone (median 12.5 vs 7.5 vs 15 mg; P = 0.49) or those who received 150 versus 200 μg morphine (median 20 vs 5 mg; P = 0.07). There were no differences in NRS pain scores among dose groups for either medication (P = 0.76 and P = 0.19 for hydromorphone and morphine, respectively; Figure 3, A and B). When including only the calculated ED90 dose or higher, 4 of 21 (19%) patients in hydromorphone group had pain scores >3 at 24 hours, whereas 1 of 18 (6%) patients in the morphine group had pain scores >3 at 24 hours.

Figure 3

Figure 3

The occurrence and treatment of side effects are summarized in Table 2. The incidence of moderate/severe nausea did not differ significantly among dose groups for hydromorphone or morphine. There were also no differences among dose groups for the frequency of moderate/severe pruritus. The percentage of patients receiving hydromorphone who required one or more treatments for nausea or pruritus over the first 24 hours did not differ across doses. Similarly, the percentage of patients receiving morphine who required one or more treatments for nausea over the first 24 hours did not differ between doses. There were no episodes of respiratory depression. No patient experienced any serious adverse events.

Table 2

Table 2

Both IT hydromorphone and IT morphine were well accepted: 90% (36/40) and 95% (38/40) of patients, respectively, described their overall satisfaction with pain control as “satisfied” 24 hours after delivery regardless of dose. When examining only patients receiving the identified ED90 doses or higher, 100% (21/21) of IT hydromorphone and 95% (37/39) of IT morphine patients were satisfied with their pain control.

Seven patients (4 in the hydromorphone group and 3 in the morphine group) received a “rescue” IV fentanyl bolus (25–50 μg) for pain during incision, closure, or in the postanesthesia care unit after their procedure, and all were included in analysis. Of these, 2 patients (both in the hydromorphone group) were analgesic “failures,” whereas the other 5 reported NRS pain scores <3 at 12 hours. One of these 2 analgesic failures (hydromorphone group, 50 μg) received patient-controlled IV fentanyl for refractory postoperative pain.

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DISCUSSION

This double-blind, up–down sequential allocation study with a biased-coin design estimated that the ED90 for postcesarean analgesia for IT hydromorphone is 75 μg (95% CI, 46–93 μg). The estimated ED90 for IT morphine is 150 μg (95% CI, 145–185 μg), which is within the well-established range of effective doses for IT morphine for cesarean delivery,3–6,22 providing validation to the study methodology. Exploratory analyses did not reveal potential differences in rescue opioid consumption, patient satisfaction, or the occurrence and severity of side effects between the most frequent doses within each IT opioid group.

IT morphine is the current gold standard for providing postcesarean delivery analgesia.1–3 It is most effective when used in conjunction with a multimodal analgesic regimen23 and is commonly used effectively in doses of 100 to 200 μg with excellent analgesic results.4–8 The biased-coin up–down sequential allocation methodology of this study has not been used to identify the ED90 of IT opioids for cesarean delivery, but the optimal dose of IT morphine has been established using traditional random allocation dose–response studies. Thus, we included the IT morphine arm to evaluate the methodology in examining effective analgesia after cesarean delivery using IT opioids. The present study confirms previous literature by estimating the ED90 for IT morphine of 150 μg. We believe that this finding validates our study design and supports an estimated ED90 for IT hydromorphone of 75 μg.

Although IT hydromorphone has been studied extensively in the context of chronic noncancer pain,24 reports of the efficacy of IT hydromorphone as part of spinal anesthesia for cesarean delivery are limited to case reports and small retrospective studies.12–14 In a retrospective study performed at our institution, Beatty et al.12 reported that 40 μg IT hydromorphone was comparable in analgesia and side effect profile to 100 μg IT morphine for postcesarean analgesia. However, the Beatty et al. study was limited by its retrospective design, small sample size, potential for selection bias, and a nonstandardized anesthesia protocol.

The relative potency ratio of IV administration of morphine to hydromorphone is approximately 5:1.25 In the present study, estimates of the ED90 of IT hydromorphone and morphine for postcesarean analgesia indicate that the ratio for IT administration of morphine to hydromorphone is 2:1. This novel finding is clinically meaningful because it will assist anesthesiologists in determining dosing conversions with these 2 opioids when administered IT. This estimated 2:1 potency ratio of morphine to hydromorphone is a very important finding given that the incremental dose steps used in the up–down sequential allocation create a degree of uncertainty in the estimates of ED90 (approximately 40 μg width of the 95% CI). Furthermore, the 95% CI for this ratio (1.6–3.6) excludes the reported ratio for IV administration.

Although effective for pain control, IT opioids are associated with adverse effects, including pruritus, nausea, vomiting, sedation, and respiratory depression. A meta-analysis including 28 studies, which investigated IT morphine versus placebo, demonstrated moderate increases in the frequency of pruritus, nausea, and vomiting in the morphine compared with placebo group.26 Although hydromorphone is chemically similar to morphine, it has greater lipid solubility. Differences in drug pharmacokinetics may result in different adverse effect profiles. Some studies have found that hydromorphone causes less nausea and pruritus than morphine,27 but others have not.12 It is unclear whether these studies were comparing equipotent doses of morphine and hydromorphone. The current study was not designed to compare the adverse effect profile of IT hydromorphone to morphine; rather, it was designed as a dose-finding study. Of note, although opioid-induced respiratory depression is a rare event, studies evaluating IT hydromorphone for postcesarean delivery pain have not reported any cases of respiratory depression.12,13 There were no cases of respiratory depression at any dose in this study, and the study population was too small to draw any conclusions regarding differences in safety between the 2 drugs.

To determine an ED90 for postcesarean analgesia, the present study used an up–down biased-coin method of sequential allocation of IT morphine and hydromorphone. This study design allows for a wide range of doses to be administered, allows the estimation of a dose at a chosen quantile (eg, ED90) without the need for unverified extrapolations from an ED50 dose, and allows for results to be obtained in a relatively small (20–40) number of patients.19 This study design yields reliable and efficient estimates of the optimal analgesic dose compared with studies examining 2 or more doses in a standard fashion. We used a fixed sample size stopping rule consistent with other anesthesiology studies using up–down methodology.19 Some studies using up–down study designs use different stopping rules to prevent needlessly exposing subjects and using resources during a trial. However, we elected to use a fixed sample size stopping rule because oversampling did not pose a clinical risk to patients in our study, and we wanted to collect exploratory data on all subjects.

In the setting of multimodal analgesia, this up–down biased-coin sequential allocation study effectively answers the clinical question as to the amount of IT drug needed to provide effective postoperative analgesia to 9 of 10 patients presenting for elective cesarean delivery. Most studies using up–down sequential allocation methods try to identify the ED50 of a certain drug. However, in most instances, anesthesiologists concerned about providing postoperative analgesia are more interested in the ED90 or ED95 of a drug. Unfortunately, the ED50 determined with up-and-down methodology often times cannot provide reliable insight into the upper tail of the distribution, and extrapolation from this point to a higher quantile should not be attempted.19

This study has limitations. Although the up–down sequential allocation method permits estimating a medication dose at a certain quantile, it does not guarantee that the determined effect dose will be appropriate for all patients. Certainly, there is individual patient variability in analgesic responses. Even without considering patient variability, an ED90 dose means that approximately 1 in 10 patients will experience “ineffective” analgesia. Analgesic outcome was determined by NRS score for pain at 12 hours; however, it could be argued that a different time point or different outcome would better assess postcesarean analgesic success. Specifically, this study was not designed to compare the duration of analgesia between the 2 medications. In addition, we chose to include patients who received a bolus of IV fentanyl during incision closure or in the postanesthesia recovery unit. Although the use of IV fentanyl in this setting could be viewed as an anesthetic failure, we felt that its use did not alter assessment of our primary outcome, pain at 12 hours postoperatively. A further limitation is that patients who requested treatment for pruritus received nalbuphine, which is a mixed opioid agonist–antagonist. Theoretically, this practice could have influenced patients’ analgesia in the postoperative period. Lastly, it is important to note that although patients were randomly allocated to the IT hydromorphone or morphine groups, this study was not designed to compare analgesic efficacy between IT hydromorphone and IT morphine. Future research is needed to specifically compare adverse effect profiles at equipotent doses of these 2 medications and to determine whether hydromorphone provides a similar duration of analgesia to morphine.

In conclusion, through an up–down sequential allocation method using a biased-coin design, the estimated potency ratio of IT morphine to hydromorphone for postcesarean analgesia was 2:1. We estimated that the ED90 for analgesia 12 hours after cesarean delivery for IT morphine is 150 μg, which compares favorably to extant literature. In addition, the estimated ED90 for analgesia 12 hours after cesarean delivery for IT hydromorphone is 75 μg. Exploratory analysis showed high patient satisfaction with both medications and that there does not appear to be a large difference in the adverse effect profiles of either medication at the doses used. These results support the use of either medication when combined with a multimodal analgesic regimen in the setting of cesarean delivery under spinal anesthesia.

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DISCLOSURES

Name: Hans P. Sviggum, MD.

Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.

Name: Katherine W. Arendt, MD.

Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.

Name: Adam K. Jacob, MD.

Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.

Name: Adam D. Niesen, MD.

Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.

Name: Rebecca L. Johnson, MD.

Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.

Name: Darrell R. Schroeder, MS.

Contribution: This author helped design the study, analyze data, and prepare the manuscript.

Name: Michael Tien, BS.

Contribution: This author helped collect data, analyze data, and prepare the manuscript.

Name: Carlos B. Mantilla, MD, PhD.

Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.

This manuscript was handled by: Cynthia A. Wong, MD.

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