Intrathecal Opioids for Pain Control After Cesarean Delivery: Determining the Optimal Dose

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02009722

Enrollment

Registered

2013-12-12

Start date

2014-01-31

Completion date

2015-04-30

Last updated

2016-07-25

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

Conditions

Analgesia, Obstetrical, Cesarean Section

Keywords

Cesarean Delivery, Intrathecal Morphine, Intrathecal Hydromorphone, Obstetrical Analgesia, Spinal Anesthesia

Brief summary

Both hydromorphone and morphine are administered as part of spinal anesthesia to help improve pain control after cesarean delivery. In this study, the investigators are going to determine the doses of each of those medicines that provides optimal pain control to women undergoing cesarean delivery while limiting side effects related to those medicines. The investigators hypothesize that the doses of hydromorphone and morphine that provide optimal pain control without significant side effects will be 100 micrograms and 150 micrograms, respectively. The investigators further hypothesize that at each respective optimal dose, side effects will be less in the hydromorphone group.

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 along with a local anesthetic during spinal anesthesia for Cesarean delivery to provide postoperative analgesia. The effectiveness of intrathecal morphine for post-Cesarean pain control is well established, but the effectiveness of intrathecal hydromorphone in this patient population is limited to case reports and small retrospective studies. No prospective studies have been conducted to establish the effectiveness of intrathecal hydromorphone for post-Cesarean pain. Hydromorphone has been studied extensively as a substitute for intrathecal morphine in patients with chronic noncancer pain. In fact, a recent consensus article placed hydromorphone as a first line therapy along with morphine for intrathecal pain management. Its ability to treat post-Cesarean pain when administered in the epidural space has been known for quite some time, but its effects in the intrathecal space are less established. In patients undergoing Cesarean delivery, intrathecal doses of 40 to 100 micrograms have been reported to provide good pain scores postoperatively with only minimal side effects. Doses of up to 300 micrograms have been used, leading to excellent pain control without out respiratory depression, but with significant pruritus and nausea. Although 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 33%. While hydromorphone is similar chemically to morphine, it is metabolized differently. Differences in pharmacokinetics may allow for differences in side effect profiles. Hydromorphone is more lipid soluble than morphine. 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. 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. The optimal dose of intrathecal morphine for analgesia following Cesarean delivery is still debated and the efficacy of intrathecal hydromorphone has not been studied extensively in this patient population. The investigators aim to identify the dose of each medication that provides good pain relief without causing significant side effects. The investigators will then perform a comparative analysis of each drug at their optimal dose.

Interventions

DRUGMorphine

Duramorph is administered as part of spinal anesthesia for post-operative pain relief.

DRUGHydromorphone

Hydromorphone (Dilaudid) is administered in the intrathecal space for post-operative pain control

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Women presenting for elective cesarean delivery with no major co-morbidities, including pregnancy induced co-morbidities (e.g. pre-eclampsia) * Singleton gestation at term (37-42 weeks) * Desire to have a spinal anesthesia technique for cesarean delivery

Exclusion criteria

* Current or historical evidence of clinically significant medical disease or condition * Any contraindication to the administration of a spinal technique for anesthesia * History of hypersensitivity or idiosyncratic reaction to opioid medications * Chronic pain syndrome or current regular opioid use * Evidence of anticipated fetal anomalies * Allergy or intolerance to Tylenol, ketorolac, ibuprofen, or oxycodone * BMI \> 40

Design outcomes

Primary

Measure	Time frame	Description
Dose of IT Morphine and IT Hydromorphone for Adequate Analgesia (Pain Score Less Than or Equal to 3) in 90% of Patients	12 hours after administration of spinal anesthesia	Each patient will be interviewed by a member of the study team 12 hours after receiving their spinal anesthetic (which will include either hydromorphone or morphine). Patients will be asked to rate their current level of pain on a scale of 0 (no pain) to 10 (worst pain imaginable). A pain score \<4 will be considered a success. The up-down sequential allocation method will be used to determine the dose (mcg) of IT hydromorphone and IT morphine for subsequent patients

Secondary

Measure	Time frame	Description
Side Effects: Nausea	6 hours after spinal	Patients will be evaluated by a member of the study team at 6 hours after spinal administration. Patients with moderate or severe nausea will be recorded.
Side Effects: Sedation	6, 12, and 24 hours after spinal administration	Patients will be evaluated by a member of the study team at 6, 12, and 24 hours after spinal administration. The presence of sedation will be graded by the Richmond Agitation Sedation Scale. Patients with a score of (-)2 or lower on the Richmond were classified as being positive for sedation.
Pruritus	12 hours after spinal	Patients will be evaluated by a member of the study team at 12 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded.
Side Effects: Pruritus	6 hours after spinal administration	Patients will be evaluated by a member of the study team at 6 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded.
Treatment for Nausea	First 24 hours	number of patients needing medication treatment for nausea in first 24 hours
Treatment for Pruritus	First 24 hours after spinal	The number of patients needing medical treatment for pruritus in first 24 hours after surgery
Nausea	12 hours after spinal	Patients will be evaluated by a member of the study team at 12 hours after spinal administration. The number of patients with moderate or severe nausea will be recorded.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Intrathecal Hydromorphone Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal hydromorphone will be 40 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Hydromorphone: Hydromorphone (Dilaudid) is administered in the intrathecal space for post-operative pain control	40
Intrathecal Morphine Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal morphine will be 100 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Morphine: Duramorph is administered as part of spinal anesthesia for post-operative pain relief.	40
Total	80

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Did not receive intervention	0	1
Overall Study	Protocol Violation	1	2

Baseline characteristics

Characteristic	Intrathecal Hydromorphone	Intrathecal Morphine	Total
Age, Continuous	30.3 years STANDARD_DEVIATION 4.1	30.6 years STANDARD_DEVIATION 4.3	30.5 years STANDARD_DEVIATION 4.2
Sex: Female, Male Female	40 Participants	40 Participants	80 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	29 / 41	26 / 42
serious Total, serious adverse events	0 / 41	0 / 42

Outcome results

Primary

Dose of IT Morphine and IT Hydromorphone for Adequate Analgesia (Pain Score Less Than or Equal to 3) in 90% of Patients

Each patient will be interviewed by a member of the study team 12 hours after receiving their spinal anesthetic (which will include either hydromorphone or morphine). Patients will be asked to rate their current level of pain on a scale of 0 (no pain) to 10 (worst pain imaginable). A pain score \<4 will be considered a success. The up-down sequential allocation method will be used to determine the dose (mcg) of IT hydromorphone and IT morphine for subsequent patients

Time frame: 12 hours after administration of spinal anesthesia

Population: The primary outcome was determining the optimal dose of IT morphine and IT hydromorphone for patients undergoing cesarean delivery. Study was designed to determine the ED90 (effective dose in 90% patients; effective dose meaning a VAS score for pain of 3 or less at 12 hours after spinal placement).

Arm	Measure	Value (NUMBER)
Intrathecal Hydromorphone	Dose of IT Morphine and IT Hydromorphone for Adequate Analgesia (Pain Score Less Than or Equal to 3) in 90% of Patients	75 micrograms
Intrathecal Morphine	Dose of IT Morphine and IT Hydromorphone for Adequate Analgesia (Pain Score Less Than or Equal to 3) in 90% of Patients	150 micrograms

Secondary

Nausea

Patients will be evaluated by a member of the study team at 24 hours after spinal administration. The number of patients with moderate or severe nausea will be recorded.

Time frame: 24 hours after spinal