Epidural Methadone in Healthy Volunteers

Study Overview
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Brief Summary
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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
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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.

Official Title
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Investigation of Pharmacokinetics and Pharmacodynamics of Epidural Methadone in Healthy Volunteers

Conditions
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Pain, Acute

Intervention / Treatment
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* Drug: Methadone hydrochloride
* Drug: Morphine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18; Body mass index between 18.5 and 30 Good general health with no remarkable medical conditions; Able and willing to provide informed consent. Exclusion Criteria: Known history of hepatic, renal, and cardiac disease; Known history of diabetes mellitus; Chronic pain; A skin or spine condition preventing safe epidural catheter placement; Current pregnancy or lactation; Known coagulopathy or ongoing anticoagulant use which contraindicates epidural catheter placement; Known allergic reactions to opioids or local anesthetics; History of current or prior substance use disorder or positive screen using the 4-question Simple Screening Instrument for Substance Abuse (SSI-SA).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, double-blinded, crossover design in healthy volunteers
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epidural methadone<br>A single 4mg epidural bolus of methadone hydrochloride | Drug: Methadone hydrochloride<br>* Epidural bolus of 4mg of preservative free methadone hydrochloride (4mL of 1mg/mL solution)<br>* Other names: Epidural methadone;|
| Active Comparator: Epidural morphine<br>A single 4mg epidural bolus of morphine sulfate | Drug: Morphine Sulfate<br>* Epidural bolus of 4mg of preservative free morphine sulfate (4mL of 1mg/mL solution)<br>* Other names: Epidural morphine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Selective segmental analgesia for heat pain - methadone | 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. | 0 -12 hours after medication administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Selective segmental analgesia for heat pain - morphine | 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. | 0 -12 hours after medication administration | 
| Selective segmental analgesia for pressure pain - methadone | 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. | 0 - 12 hours after medication administration | 
| Selective segmental analgesia for pressure pain - morphine | 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. | 0 - 12 hours after medication administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methadone, Morphine, Quantitative sensory testing, Epidural