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

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01943565

Enrollment

Registered

2013-09-17

Start date

2014-12-31

Completion date

2016-08-31

Last updated

2017-06-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy, Pain, Pregnancy

Keywords

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

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.

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.

Interventions

DRUGHydromorphone 25mcg

Intrathecal Hydromorphone 25mcg

DRUGHydromorphone 50mcg

Intrathecal Hydromorphone 50mcg

DRUGHydromorphone 100mcg

Intrathecal Hydromorphone 100mcg

DRUGspinal anesthesia

bupivacaine 0.75% 1.6 mL (12mg)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 40 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

Measure	Time frame	Description
24hr Post-partum IV Opioid Requirement	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

Measure	Time frame	Description
Patients With Nausea and Vomiting Requiring Rescue Medication	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.
Number of Patients With Hypothermia (Body Temperature < 95F/35C)	24hrs post administration of IT hydromorphone	intrathecally administered opioids can cause hypothermia (body temperature \<95F/35C)
Number of Patients With Visual Disturbances	24hrs post administration of IT hydromorphone	IT/IV opioids can create visual disturbances. The number of patients with visual disturbances are reported.
Oxygen Saturation, Need for Supplemental Oxygen	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).
Intraoperative Vasopressor Use: Ephedrine Equivalents	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.
Intraoperative Vasopressor Use: Phenylephrine Equivalents	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.
Number of Patients With Pruritus	24hrs post administration of IT hydromorphone	IT opioids can cause pruritus. Persistent pruritus requiring treatment will be recorded.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Hydromorphone 25mcg The arm will receive 25mcg intrathecal hydromorphone to supplement the spinal anesthesia Hydromorphone 25mcg: Intrathecal Hydromorphone 25mcg spinal anesthesia: bupivacaine 0.75% 1.6 mL (12mg)	11
Hydromorphone 50mcg The arm will receive 50mcg intrathecal hydromorphone to supplement the spinal anesthesia Hydromorphone 50mcg: Intrathecal Hydromorphone 50mcg spinal anesthesia: bupivacaine 0.75% 1.6 mL (12mg)	9
Hydromorphone 100mcg The arm will receive 100mcg intrathecal hydromorphone to supplement the spinal anesthesia Hydromorphone 100mcg: Intrathecal Hydromorphone 100mcg spinal anesthesia: bupivacaine 0.75% 1.6 mL (12mg)	10
Total	30

Baseline characteristics

Characteristic	Hydromorphone 25mcg	Hydromorphone 50mcg	Hydromorphone 100mcg	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	11 Participants	9 Participants	10 Participants	30 Participants
Region of Enrollment United States	11 Participants	9 Participants	10 Participants	30 Participants
Sex: Female, Male Female	11 Participants	9 Participants	10 Participants	30 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	1 / 11	1 / 9	1 / 9
serious Total, serious adverse events	0 / 11	0 / 9	0 / 9

Outcome results

Primary

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.

Time frame: 24hrs after administration of intrathecal hydromorphone

Population: One 25 mcg patient is missing data on this outcome

Arm	Measure	Value (MEAN)	Dispersion
Hydromorphone 25mcg	24hr Post-partum IV Opioid Requirement	3.44 mg	Standard Deviation 3.51
Hydromorphone 50mcg	24hr Post-partum IV Opioid Requirement	3.11 mg	Standard Deviation 2.15
Hydromorphone 100mcg	24hr Post-partum IV Opioid Requirement	4.40 mg	Standard Deviation 3.51

Secondary

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.

Time frame: Intraoperatively (at time of operation)

Population: One 25 mcg patient is missing data on this outcome

Arm	Measure	Value (MEAN)	Dispersion
Hydromorphone 25mcg	Intraoperative Vasopressor Use: Ephedrine Equivalents	60.98 mg	Standard Deviation 26.94
Hydromorphone 50mcg	Intraoperative Vasopressor Use: Ephedrine Equivalents	56.48 mg	Standard Deviation 32.27
Hydromorphone 100mcg	Intraoperative Vasopressor Use: Ephedrine Equivalents	45.48 mg	Standard Deviation 19.78

Secondary

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.

Time frame: Intraoperatively (at time of operation)

Population: One 25 mcg patient is missing data on this outcome

Arm	Measure	Value (MEAN)	Dispersion
Hydromorphone 25mcg	Intraoperative Vasopressor Use: Phenylephrine Equivalents	751.04 mcg	Standard Deviation 331.76
Hydromorphone 50mcg	Intraoperative Vasopressor Use: Phenylephrine Equivalents	695.54 mcg	Standard Deviation 397.42
Hydromorphone 100mcg	Intraoperative Vasopressor Use: Phenylephrine Equivalents	560.11 mcg	Standard Deviation 243.56

Secondary