Spinal Morphine vs. Hydromorphone for Pain Control After Cesarean Delivery

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02789410
• Collaborator: (none)
• Enrollment: 134
• Location: 1
• Arms: 2
• Duration (Months): 22.4
• Patients Per Site Per Month: 6

Study Details

Study Description

Brief Summary

Intrathecal (IT) opioids are commonly administered with local anesthetic during spinal anesthesia for post-Cesarean delivery analgesia. Traditionally, IT morphine has been used but the use of IT hydromorphone is growing. A previous study has shown that the effective dose for postoperative analgesia in 90% patients (ED90) for both IT hydromorphone and IT morphine (NCT02009722). These doses were found to be 75 mcg for hydromorphone and 150 mcg for morphine. The current proposed study would compare the duration of analgesia of IT morphine vs IT hydromorphone after elective cesarean delivery. Additionally, the investigators will compare each drug with respect the incidence of nausea and pruritus.

Condition or Disease	Intervention/Treatment	Phase
Analgesia, Obstetrical; Obstetric Surgical Procedures	Drug: Morphine; Drug: Hydromorphone	N/A

Detailed Description

Spinal anesthesia is the most common anesthetic technique used for Cesarean delivery in the United States and across the world. Intrathecal opioids are administered with a local anesthetic during spinal anesthesia post-Cesarean delivery analgesia. The effectiveness of intrathecal morphine for post-Cesarean pain control is well established, and the use of intrathecal hydromorphone in this patient population is growing. No prospective studies have been conducted to specifically compare the efficacy of intrathecal morphine versus hydromorphone for post-Cesarean analgesia.

After intrathecal administration, opioid drug disposition depends on the lipid solubility of the individual drug. Because of its hydrophilic nature, cerebrospinal fluid (CSF) concentrations of morphine decline more slowly than similar doses of lipophilic drugs. This accounts for more rostral spread, greater dermatomal analgesia, and longer duration of action when compared to highly lipophilic opioids like fentanyl and sufentanil. When used for post-cesarean analgesia, intrathecal morphine has a duration of action between 14-36 hours with wide variation between individual patients. While hydromorphone is similar chemically to morphine, it is more lipid soluble. This decreases its spread within the intrathecal space and enhances its penetration into the dorsal horn of the spinal cord where interactions with opioid receptors occur. These differences between the two medications may influence their duration of action. Theoretically, this would reduce the duration of action of intrathecal hydromorphone when compared with intrathecal morphine. Retrospective studies have shown that the analgesic benefit for intrathecal hydromorphone appears to extend at least 12 hours after cesarean delivery and may extend up to 24 hours.

Although effective in reducing pain, intrathecal opioids are associated with side effects including pruritus, nausea, and respiratory depression. A meta-analysis reviewing twenty-eight studies which investigated intrathecal morphine versus placebo demonstrated moderate increases in the incidences of pruritus, nausea and vomiting. In fact the incidence of nausea with IT morphine has been reported to be nearly 33%. The differences in pharmacokinetics between morphine and hydromorphone may also create differences in side effect profiles. Some studies have found that hydromorphone causes less nausea and pruritus than morphine, while others have not. Although opioid-induced respiratory depression is a rare event, studies evaluating intrathecal hydromorphone for post-Cesarean delivery pain have not reported any cases of respiratory depression.

In this study, the investigators aim to compare the duration of analgesia of intrathecal morphine vs. hydromorphone for analgesia after cesarean delivery. Secondarily, the investigators will compare the side effects of each drug, including nausea and pruritus. To achieve the goals of this study, it is important to study equipotent doses of these medications. Previous work by the investigators of this study found that the effective dose for postoperative analgesia in 90% of patients (ED90) is 75 micrograms for intrathecal hydromorphone and 150 micrograms for intrathecal morphine. However, it is not known if these two equipotent medication doses provide a similar duration of analgesia.

The investigators hypothesize that 150 mcg of intrathecal morphine will result in a longer duration of analgesia when compared to 75 micrograms of intrathecal hydromorphone. Additionally, the investigators hypothesize that there will be more pruritus in the intrathecal hydromorphone group early after surgery, and no difference in side effects at 24 hours after surgery.

Study Design

• Study Type: Interventional
• Actual Enrollment: 134 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Intrathecal Morphine Versus Intrathecal Hydromorphone for Analgesia Following Cesarean Delivery
• Study Start Date: May 1, 2016
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Mar 15, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Intrathecal hydromorphone Patients will be randomized to receive a one time dose of 75 mcg intrathecal hydromorphone as part of their spinal anesthesia.	Drug: Hydromorphone; Hydromorphone is administered as part of spinal anesthesia for post-operative pain relief.; Other Names: Dilaudid
Active Comparator: Intrathecal morphine Patients will be randomized to receive a one time dose of 150 mcg intrathecal morphine as part of their spinal anesthesia.	Drug: Morphine; Morphine is administered as part of spinal anesthesia for post-operative pain relief.; Other Names: Duramorph

Outcome Measures

Primary Outcome Measures

1. NRS Score for Pain (0-10) With Movement 24 Hours After Spinal Administration [24 hours after administration of spinal anesthesia]

   Each patient will be interviewed by a member of the study team 24 hours after receiving their spinal anesthetic. Patients will be asked to rate their current level of pain on a Numeric Rating Scale (NRS) of 0 (no pain) to 10 (worst pain imaginable).

Secondary Outcome Measures

1. Nausea [24 hours after administration of spinal anesthesia]

   The number of subjects who experienced and self-reported nausea within the first 24 hours after administration of spinal anesthesia.

2. Pruritus [24 hours after administration of spinal anesthesia]

   The number of subjects who experienced and self-reported pruritus within the first 24 hours after administration of spinal anesthesia.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• American Society of Anesthesiologists (ASA) physical status II-III women presenting for elective cesarean delivery

• Term gestation (37-42 weeks)

• Desire to have a spinal anesthesia technique for cesarean delivery

Exclusion Criteria:

• Any contraindication to the administration of a spinal technique for anesthesia

• History of intolerance or adverse reaction to opioid medications

• Chronic pain syndrome or current opioid use >30 oral morphine equivalents/day

• Allergy or intolerance to acetaminophen, ketorolac, ibuprofen, or oxycodone

• Current BMI > 50

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Principal Investigator: Hans P Sviggum, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 21, 2015

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

• Beatty NC, Arendt KW, Niesen AD, Wittwer ED, Jacob AK. Analgesia after Cesarean delivery: a retrospective comparison of intrathecal hydromorphone and morphine. J Clin Anesth. 2013 Aug;25(5):379-383. doi: 10.1016/j.jclinane.2013.01.014. Epub 2013 Aug 17.
• Bucklin BA, Hawkins JL, Anderson JR, Ullrich FA. Obstetric anesthesia workforce survey: twenty-year update. Anesthesiology. 2005 Sep;103(3):645-53.
• Gehling M, Tryba M. Risks and side-effects of intrathecal morphine combined with spinal anaesthesia: a meta-analysis. Anaesthesia. 2009 Jun;64(6):643-51. Review.
• Nortcliffe SA, Shah J, Buggy DJ. Prevention of postoperative nausea and vomiting after spinal morphine for Caesarean section: comparison of cyclizine, dexamethasone and placebo. Br J Anaesth. 2003 May;90(5):665-70.
• 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.
• Rauch E. Intrathecal hydromorphone for cesarean delivery: in search of improved postoperative pain management: a case report. AANA J. 2011 Oct;79(5):427-32.
• Rauch E. Intrathecal hydromorphone for postoperative analgesia after cesarean delivery: a retrospective study. AANA J. 2012 Aug;80(4 Suppl):S25-32.
• Sviggum HP, Arendt KW, Jacob AK, Niesen AD, Johnson RL, Schroeder DR, Tien M, Mantilla CB. Intrathecal Hydromorphone and Morphine for Postcesarean Delivery Analgesia: Determination of the ED90 Using a Sequential Allocation Biased-Coin Method. Anesth Analg. 2016 Sep;123(3):690-7. doi: 10.1213/ANE.0000000000001229.
• Terajima K, Onodera H, Kobayashi M, Yamanaka H, Ohno T, Konuma S, Ogawa R. Efficacy of intrathecal morphine for analgesia following elective cesarean section: comparison with previous delivery. J Nippon Med Sch. 2003 Aug;70(4):327-33.

• Responsible Party: Hans P. Sviggum, M.D., PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02789410
• Other Study ID Numbers: 15-009421
• First Posted: Jun 3, 2016
• Last Update Posted: Apr 25, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Hans P. Sviggum, M.D., PI, Mayo Clinic: Cesarean delivery; Analgesia; Intrathecal opioids
• Additional relevant MeSH terms: Agnosia; Morphine; Hydromorphone

Study Results

Participant Flow

Arm/Group Title	Intrathecal Hydromorphone	Intrathecal Morphine
Arm/Group Description	Patients will be randomized to receive a one time dose of 75 mcg intrathecal hydromorphone as part of their spinal anesthesia. Hydromorphone: Hydromorphone is administered as part of spinal anesthesia for post-operative pain relief.	Patients will be randomized to receive a one time dose of 150 mcg intrathecal morphine as part of their spinal anesthesia. Morphine: Morphine is administered as part of spinal anesthesia for post-operative pain relief.
Period Title: Overall Study
STARTED	66	68
COMPLETED	66	68
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Intrathecal Hydromorphone	Intrathecal Morphine	Total
Arm/Group Description	Patients will be randomized to receive a one time dose of 75 mcg intrathecal hydromorphone as part of their spinal anesthesia. Hydromorphone: Hydromorphone is administered as part of spinal anesthesia for post-operative pain relief.	Patients will be randomized to receive a one time dose of 150 mcg intrathecal morphine as part of their spinal anesthesia. Morphine: Morphine is administered as part of spinal anesthesia for post-operative pain relief.	Total of all reporting groups
Overall Participants	66	68	134
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.2 (4.4)	31.9 (4.3)	31.5 (4.3)
Sex: Female, Male (Count of Participants)
Female	66 100%	68 100%	134 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	66 100%	68 100%	134 100%

Outcome Measures

1. Primary Outcome

Title	NRS Score for Pain (0-10) With Movement 24 Hours After Spinal Administration
Description	Each patient will be interviewed by a member of the study team 24 hours after receiving their spinal anesthetic. Patients will be asked to rate their current level of pain on a Numeric Rating Scale (NRS) of 0 (no pain) to 10 (worst pain imaginable).
Time Frame	24 hours after administration of spinal anesthesia

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intrathecal Hydromorphone	Intrathecal Morphine
Arm/Group Description	Patients will be randomized to receive a one time dose of 75 mcg intrathecal hydromorphone as part of their spinal anesthesia. Hydromorphone: Hydromorphone is administered as part of spinal anesthesia for post-operative pain relief.	Patients will be randomized to receive a one time dose of 150 mcg intrathecal morphine as part of their spinal anesthesia. Morphine: Morphine is administered as part of spinal anesthesia for post-operative pain relief.
Measure Participants	66	68
Median (Inter-Quartile Range) [score on a scale]	4	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intrathecal Hydromorphone, Intrathecal Morphine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.132
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Nausea
Description	The number of subjects who experienced and self-reported nausea within the first 24 hours after administration of spinal anesthesia.
Time Frame	24 hours after administration of spinal anesthesia

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intrathecal Hydromorphone	Intrathecal Morphine
Arm/Group Description	Patients will be randomized to receive a one time dose of 75 mcg intrathecal hydromorphone as part of their spinal anesthesia. Hydromorphone: Hydromorphone is administered as part of spinal anesthesia for post-operative pain relief.	Patients will be randomized to receive a one time dose of 150 mcg intrathecal morphine as part of their spinal anesthesia. Morphine: Morphine is administered as part of spinal anesthesia for post-operative pain relief.
Measure Participants	66	68
Count of Participants [Participants]	28 42.4%	32 47.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intrathecal Hydromorphone, Intrathecal Morphine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.590
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Pruritus
Description	The number of subjects who experienced and self-reported pruritus within the first 24 hours after administration of spinal anesthesia.
Time Frame	24 hours after administration of spinal anesthesia

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intrathecal Hydromorphone	Intrathecal Morphine
Arm/Group Description	Patients will be randomized to receive a one time dose of 75 mcg intrathecal hydromorphone as part of their spinal anesthesia. Hydromorphone: Hydromorphone is administered as part of spinal anesthesia for post-operative pain relief.	Patients will be randomized to receive a one time dose of 150 mcg intrathecal morphine as part of their spinal anesthesia. Morphine: Morphine is administered as part of spinal anesthesia for post-operative pain relief.
Measure Participants	66	68
Count of Participants [Participants]	27 40.9%	28 41.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intrathecal Hydromorphone, Intrathecal Morphine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.971
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Study treatment follow up was defined as 36 hours following last administration of study treatment.
Arm/Group Title	Intrathecal Hydromorphone		Intrathecal Morphine
Arm/Group Description	Patients will be randomized to receive a one time dose of 75 mcg intrathecal hydromorphone as part of their spinal anesthesia. Hydromorphone: Hydromorphone is administered as part of spinal anesthesia for post-operative pain relief.		Patients will be randomized to receive a one time dose of 150 mcg intrathecal morphine as part of their spinal anesthesia. Morphine: Morphine is administered as part of spinal anesthesia for post-operative pain relief.
All Cause Mortality
	Intrathecal Hydromorphone		Intrathecal Morphine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/66 (0%)		0/68 (0%)
Serious Adverse Events
	Intrathecal Hydromorphone		Intrathecal Morphine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/66 (0%)		0/68 (0%)
Other (Not Including Serious) Adverse Events
	Intrathecal Hydromorphone		Intrathecal Morphine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/66 (0%)		0/68 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.