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

• ClinicalTrials.gov Identifier: NCT01943565
• Recruitment Status: Terminated
• First Posted: September 17, 2013
• Results First Posted: June 19, 2017
• Last Update Posted: June 19, 2017
• Sponsor: Brigham and Women's Hospital
• Information provided by (Responsible Party): Dirk Varelmann, MD, Brigham and Women's Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Healthy; Pain; Pregnancy	Drug: Hydromorphone 25mcg; Drug: Hydromorphone 50mcg; Drug: Hydromorphone 100mcg; Drug: spinal anesthesia	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Intrathecal Hydromorphone for Post-cesarean Delivery Pain - a Dose Finding Study
• Actual Study Start Date: December 2014
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: August 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Hydromorphone 25mcg; The arm will receive 25mcg intrathecal hydromorphone to supplement the spinal anesthesia	Drug: Hydromorphone 25mcg; Intrathecal Hydromorphone 25mcg; Other Name: HM25; Drug: spinal anesthesia; bupivacaine 0.75% 1.6 mL (12mg)
Active Comparator: Hydromorphone 50mcg; The arm will receive 50mcg intrathecal hydromorphone to supplement the spinal anesthesia	Drug: Hydromorphone 50mcg; Intrathecal Hydromorphone 50mcg; Other Name: HM50; Drug: spinal anesthesia; bupivacaine 0.75% 1.6 mL (12mg)
Active Comparator: Hydromorphone 100mcg; The arm will receive 100mcg intrathecal hydromorphone to supplement the spinal anesthesia	Drug: Hydromorphone 100mcg; Intrathecal Hydromorphone 100mcg; Other Name: HM100; Drug: spinal anesthesia; bupivacaine 0.75% 1.6 mL (12mg)

Outcome Measures

Primary Outcome Measures :

1. 24hr Post-partum IV Opioid Requirement [ Time Frame: 24hrs after administration of intrathecal hydromorphone ]
   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.

Secondary Outcome Measures :

1. Oxygen Saturation, Need for Supplemental Oxygen [ Time Frame: 24hrs post administration of IT hydromorphone ]
   Intravenously, and to a lesser extent, intrathecally administered opioids can lead to respiratory depressions. Therefore the subjects' oxygen saturation is measured (standard clinical practice).
2. Patients With Nausea and Vomiting Requiring Rescue Medication [ Time Frame: 24hrs post administration of IT hydromorphone ]
   IV and IT opioids can induce nausea and vomiting. Outcome measure is reported as percentage of patients with nausea and vomiting requiring rescue medication.
3. Number of Patients With Hypothermia (Body Temperature < 95F/35C) [ Time Frame: 24hrs post administration of IT hydromorphone ]
   intrathecally administered opioids can cause hypothermia (body temperature <95F/35C)
4. Number of Patients With Visual Disturbances [ Time Frame: 24hrs post administration of IT hydromorphone ]
   IT/IV opioids can create visual disturbances. The number of patients with visual disturbances are reported.
5. Number of Patients With Pruritus [ Time Frame: 24hrs post administration of IT hydromorphone ]
   IT opioids can cause pruritus. Persistent pruritus requiring treatment will be recorded.
6. Intraoperative Vasopressor Use: Ephedrine Equivalents [ Time Frame: Intraoperatively (at time of operation) ]
   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.
7. Intraoperative Vasopressor Use: Phenylephrine Equivalents [ Time Frame: Intraoperatively (at time of operation) ]

   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Brigham and Women's Hospital

Investigators

• Principal Investigator: Dirk J Varelmann, MD; Brigham and Women's Hospital

More Information

Publications:

Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology. 1979 Feb;50(2):149-51.

Ross BK, Hughes SC. Epidural and spinal narcotic analgesia. Clin Obstet Gynecol. 1987 Sep;30(3):552-65. Review.

Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology. 1999 Feb;90(2):437-44. Erratum in: Anesthesiology 1999 Apr;90(4):1241.

Milner AR, Bogod DG, Harwood RJ. Intrathecal administration of morphine for elective Caesarean section. A comparison between 0.1 mg and 0.2 mg. Anaesthesia. 1996 Sep;51(9):871-3.

Lee YS, Park YC, Kim JH, Kim WY, Yoon SZ, Moon MG, Min TJ. Intrathecal hydromorphone added to hyperbaric bupivacaine for postoperative pain relief after knee arthroscopic surgery: a prospective, randomised, controlled trial. Eur J Anaesthesiol. 2012 Jan;29(1):17-21. doi: 10.1097/EJA.0b013e3283476055.

• Responsible Party: Dirk Varelmann, MD, Instructor of Anaesthesiology, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01943565
• Other Study ID Numbers: 2013P001850; Hydromorphone_IT ( Other Identifier: BrighamHospital )
• First Posted: September 17, 2013
• Results First Posted: June 19, 2017
• Last Update Posted: June 19, 2017
• Last Verified: May 2017

Keywords provided by Dirk Varelmann, MD, Brigham and Women's Hospital:

Pregnancy; Healthy; Intrathecal; Opioids; Spinal; Anesthesia; Pain; Cesarean; Delivery; Human

Additional relevant MeSH terms:

Hydromorphone; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Opioid; Narcotics; Analgesics; Sensory System Agents; Peripheral Nervous System Agents