Determination of ED50 and time to effectiveness for intrathecal hydromorphone in laboring patients using Dixon's up-and-down sequential allocation method

Abstract

Background: With the increasing occurrence of drug shortages, understanding the pharmacokinetics of alternative intrathecal opioid administration has gained importance. In particular, additional data are needed to comprehensively evaluate the analgesic properties of intrathecal hydromorphone in the laboring patient. In a phase 2 clinical trial, we set out to determine the median effective dose (ED50) and time to effectiveness for this drug in this population.

Methods: Using Dixon's up-and-down sequential allocation method, twenty women presenting for labor analgesia were prospectively enrolled. A combined spinal-epidural technique was used to deliver the determined dose of intrathecal hydromorphone. Visual analog pain scores were obtained assessing peak pain scores during serial uterine contractions. Effective pain relief was defined as achieving a pain score of less than or equal to 3 out of 10. The dose was deemed to be ineffective if the patient failed to achieve this level of relief after 30 min.

Results: The ED50 of hydromorphone in our population was 10.9 μg (95% confidence interval 5.6-16.2 μg). Amongst patients for whom the dose was effective, the median time to pain relief was 24 min. One patient experienced both nausea and pruritus. No other complications were noted.

Conclusion: Due to the prolonged time to onset, hydromorphone cannot be recommended in favor of substantively better alternatives such as sufentanil and fentanyl.

Trial registration: Clinicaltrials.gov registration number: NCT01598506.

Keywords: Analgesics; Hydromorphone; Intrathecal; Labor; Obstetric; Opioid.

Conflict of interest statement

Ethics approval and consent to participate

Emory University IRB approval (IRB#54701) and an FDA IND (115523) were obtained. The study was registered in Consent for publication

All patients enrolled in this study consented for their data to be published.

Competing interests

All authors declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

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Figures

Fig. 1

Scatter plot demonstrating dosages reported as effective (solid) and ineffective (hollow) for all 20 participants. The horizontal line represents the ED50 and was determined to be 10.9 mcg (95% CI +/−1.2 mcg)