Intrathecal Hydromorphone for Post-cesarean Delivery Pain - a Dose Finding Study

Study Overview
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Brief Summary
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Pain relief after cesarean delivery can be provided in a few ways. Most commonly, certain medications called opioids, such as morphine, are given through the vein or into the muscle. However, a more effective way to give pain relief with fewer side effects (such as nausea and slowing your breathing) is to give opioids in the spinal space as part of the medications given for a cesarean delivery. For many years, the opioid of choice was morphine due to its long anesthetic effect and acceptable side effect profile. A nation-wide disruption in the supply of preservative-free morphine has made it necessary to look for alternatives. Many institutions worldwide have used another opioid, called hydromorphone, in the spinal space for over a decade. This drug has a very good safety and side effect profile and has been used at the investigators' institution for more than a year. Of interest, while a number of different doses of hydromorphone have been used, there have been very few studies to evaluate the best dose for providing good pain relief with minimal side effects. The goal of this study is to find the best dose of spinal hydromorphone for women undergoing cesarean delivery.

Detailed Description
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Intrathecal opioids in have been shown to produce analgesia. Lipid solubility and effect on specific mu opioid receptors in the dorsal horn of the spinal cord primarily determine the analgesic effect of intrathecally injected opioids. Rostral spread of intrathecal opioids causes some of the side effects like pruritus, respiratory depression, nausea and vomiting. In the investigators' institute, during cesarean delivery under spinal anesthesia is usually performed with 1.6-1.8 ml of 0.75% bupivacaine with dextrose (hyperbaric solution) with 10-20mcg of fentanyl. Preservative free intrathecal (IT) morphine100 to 200 mcg is injected at the time of initiation of spinal block for postoperative pain relief. Multiple studies have shown excellent postoperative pain relief following cesarean delivery up to 18hrs with this dosing regimen. However, there has been a national shortage of preservative free morphine since August 2012. Based on the pharmacokinetic and pharmacodynamic profile, intrathecal (IT) preservative free hydromorphone 100 mcg has been used as a substitute. Anecdotal experience during the past 8 months suggest that patients have comparable post partum pain relief, with a similar side-effect profile to IT morphine. There is no published data on the optimal dose of IT hydromorphone for post cesarean analgesia. There are case reports and retrospective case study of use of 100mcg IT hydromorphone. One randomized controlled trial for knee arthroscopy used 2.5-5-10 mcg of IT hydromorphone for postoperative analgesia. Hence it is important to determine the optimal dose of IT hydromorphone for post operative pain management following cesarean delivery in terms of analgesic efficacy, incidence of side effects and the need for treatment interventions This study will aim to determine the optimal dose of intrathecal hydromorphone that would provide adequate postoperative analgesia with minimal side effects.

Official Title
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Intrathecal Hydromorphone for Post-cesarean Delivery Pain - a Dose Finding Study

Conditions
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Healthy, Pain, Pregnancy

Intervention / Treatment
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* Drug: Hydromorphone 25mcg
* Drug: Hydromorphone 50mcg
* Drug: Hydromorphone 100mcg
* Drug: spinal anesthesia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy at-term parturients undergoing elective cesarean delivery under spinal anesthesia Exclusion Criteria: Emergency cesarean delivery Respiratory disease significant comorbidities: preeclampsia, insulin-dependent diabetes mellitus obstructive sleep apnea body mass index > 35kg/m2 <18yrs documented intolerance or allergy to systemic or neuraxial opioids patient with a history of chronic opioid or current use of opioids

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydromorphone 25mcg<br>The arm will receive 25mcg intrathecal hydromorphone to supplement the spinal anesthesia | Drug: Hydromorphone 25mcg<br>* Intrathecal Hydromorphone 25mcg<br>* Other names: HM25;Drug: spinal anesthesia<br>* bupivacaine 0.75% 1.6 mL (12mg)<br>|
| Active Comparator: Hydromorphone 50mcg<br>The arm will receive 50mcg intrathecal hydromorphone to supplement the spinal anesthesia | Drug: Hydromorphone 50mcg<br>* Intrathecal Hydromorphone 50mcg<br>* Other names: HM50;Drug: spinal anesthesia<br>* bupivacaine 0.75% 1.6 mL (12mg)<br>|
| Active Comparator: Hydromorphone 100mcg<br>The arm will receive 100mcg intrathecal hydromorphone to supplement the spinal anesthesia | Drug: Hydromorphone 100mcg<br>* Intrathecal Hydromorphone 100mcg<br>* Other names: HM100;Drug: spinal anesthesia<br>* bupivacaine 0.75% 1.6 mL (12mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24hr Post-partum IV Opioid Requirement | Intrathecal (IT) hydromorphone added to intrathecally administered local anesthetics for spinal anesthesia increases patient comfort by decreasing post-operative pain. This leads to a decrease in the post-operative intravenous hydromorphone requirements. | 24hrs after administration of intrathecal hydromorphone | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen Saturation, Need for Supplemental Oxygen | Intravenously, and to a lesser extent, intrathecally administered opioids can lead to respiratory depressions. Therefore the subjects' oxygen saturation is measured (standard clinical practice). | 24hrs post administration of IT hydromorphone | 
| Patients With Nausea and Vomiting Requiring Rescue Medication | IV and IT opioids can induce nausea and vomiting. Outcome measure is reported as percentage of patients with nausea and vomiting requiring rescue medication. | 24hrs post administration of IT hydromorphone | 
| Number of Patients With Hypothermia (Body Temperature < 95F/35C) | intrathecally administered opioids can cause hypothermia (body temperature <95F/35C) | 24hrs post administration of IT hydromorphone | 
| Number of Patients With Visual Disturbances | IT/IV opioids can create visual disturbances. The number of patients with visual disturbances are reported. | 24hrs post administration of IT hydromorphone | 
| Number of Patients With Pruritus | IT opioids can cause pruritus. Persistent pruritus requiring treatment will be recorded. | 24hrs post administration of IT hydromorphone | 
| Intraoperative Vasopressor Use: Ephedrine Equivalents | IT (intrathecal) applied local anesthetics and opioids can cause arterial and venous vasodilation leading to a decrease in afterload as well as preload. This is typically treated with volume replacement and vasopressors (acutely). Total intraoperative vasopressor use will be reported for ephedrine equivalents. | Intraoperatively (at time of operation) | 
| Intraoperative Vasopressor Use: Phenylephrine Equivalents | IT (intrathecal ) applied local anesthetics and opioids can cause arterial and venous vasodilation leading to a decrease in afterload as well as preload. This is typically treated with volume replacement and vasopressors (acutely). Total intraoperative vasopressor use will be reported for phenylephrine equivalents. | Intraoperatively (at time of operation) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Healthy, Intrathecal, Opioids, Spinal, Anesthesia, Pain, Cesarean, Delivery, Human