Epidural Methadone in Healthy Volunteers

Early Phase 1

Completed

• Conditions: Pain, Acute
• Interventions: Drug: Methadone hydrochloride; Drug: Morphine Sulfate

• Registration Number: NCT03525509
• Lead Sponsor: simon.haroutounian

Brief Summary

Epidurally administered opioid pain medications are important tools for postoperative pain control, but each agent has its own limitations. Methadone's properties suggest that it may provide a long duration of pain control with minimal side effects related to spread to the brain or absorption into the blood stream. In this study, the investigators aim to compare the relative pain relieving effects, markers of side effects, and concentrations in the blood of epidurally administered methadone as compared to another long-acting opioid which is commonly administered epidurally, morphine.

Detailed Description

Acute postoperative pain control remains a major challenge in healthcare, with a need to balance analgesic effectiveness, patient safety, and cost. Excellent analgesia is a universal clinical imperative, but our current approaches are often inadequate. Epidural opioids can be useful tools, but each carries its own strengths and limitations. Bolus morphine is long lasting but exhibits rostral spread in the cerebrospinal fluid, which raises risks of adverse effects, particularly late-onset respiratory depression. Lipophilic opioids such as fentanyl and sufentanil exhibit selective segmental analgesia but are of short duration due to systemic absorption. As such, they require continuous epidural administration via an indwelling epidural catheter and a pump (patient-controlled or continuous infusion), which has implications for nursing, pain management services, and hospital cost. Methadone's physico-chemical properties suggest that epidural methadone administration would be ideal in providing long-duration analgesia with fewer of the adverse effects seen with medications like morphine.

The aim of this study is to compare the effects of two medications given epidurally: morphine and methadone. We will do so using a randomized, double-blinded, crossover design study. During each of two study visits, participants will receive a single epidural bolus of either morphine or methadone. We will examine the ability of the medication to blunt pain from heat or pressure using quantitative sensory testing at both the dermatome of injection (leg) and a distant dermatome (face); in doing so, we will demonstrate relative segmental versus supraspinal or systemic opioid activity. Additionally, we will assess signs and symptoms of supraspinal opioid activity, which may predispose to adverse effects, and blood concentrations of each medication. Each of the aforementioned measurements will be conducted at multiple points over a 24 hour period. Following a washout period, patients will return for a second visit, at which time the protocol will be repeated using the other medication.

Study Timeline

• Study First Submitted: 2018-05-02
• Study First Submitted QC: 2018-05-14
• Study First Posted: 2018-05-15
• Study Start: 2018-06-04
• Primary Completion: 2019-08-28
• Study Completion: 2019-08-30
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-17
• Last Update Posted: 2019-09-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 13

Inclusion Criteria

1. Age ≥18;
2. Body mass index between 18.5 and 30
3. Good general health with no remarkable medical conditions;
4. Able and willing to provide informed consent.

Exclusion Criteria

1. Known history of hepatic, renal, and cardiac disease;
2. Known history of diabetes mellitus;
3. Chronic pain;
4. A skin or spine condition preventing safe epidural catheter placement;
5. Current pregnancy or lactation;
6. Known coagulopathy or ongoing anticoagulant use which contraindicates epidural catheter placement;
7. Known allergic reactions to opioids or local anesthetics;
8. History of current or prior substance use disorder or positive screen using the 4-question Simple Screening Instrument for Substance Abuse (SSI-SA).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Epidural methadone	Methadone hydrochloride	A single 4mg epidural bolus of methadone hydrochloride
Epidural morphine	Morphine Sulfate	A single 4mg epidural bolus of morphine sulfate

Primary Outcome Measures

Name	Time	Method
Selective segmental analgesia for heat pain - methadone	0 -12 hours after medication administration	The analgesia provided by methadone at a given dermatome will be quantified as the area under the curve (AUC) of the heat pain tolerance threshold versus time curve. The selective segmental analgesic effect of methadone will be measured as difference of the AUC for L3 and V2.

Secondary Outcome Measures

Name	Time	Method
Selective segmental analgesia for pressure pain - methadone	0 - 12 hours after medication administration	The analgesia provided by methadone at a given dermatome will be quantified as the area under the curve (AUC) of the pressure pain threshold versus time curve. The selective segmental analgesic effect of methadone will be measured as difference of the AUC for L3 and V2.
Selective segmental analgesia for heat pain - morphine	0 -12 hours after medication administration	The analgesia provided by morphine at a given dermatome will be quantified as the area under the curve (AUC) of the heat pain tolerance threshold versus time curve. The selective segmental analgesic effect of morphine will be measured as difference of the AUC for L3 and V2.
Selective segmental analgesia for pressure pain - morphine	0 - 12 hours after medication administration	The analgesia provided by morphine at a given dermatome will be quantified as the area under the curve (AUC) of the pressure pain threshold versus time curve. The selective segmental analgesic effect of morphine will be measured as difference of the AUC for L3 and V2.

Trial Locations

Locations (1)

Washington University in St. Louis; 🇺🇸 Saint Louis, Missouri, United States