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Epidural Methadone in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT03525509
Recruitment Status : Completed
First Posted : May 15, 2018
Last Update Posted : September 18, 2019
Sponsor:
Information provided by (Responsible Party):
simon.haroutounian, Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Pain, Acute Drug: Methadone hydrochloride Drug: Morphine Sulfate Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomized, double-blinded, crossover design in healthy volunteers
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: At enrollment, each participant will be assigned a study number, which will match a previously prepared computer-generated list of randomization numbers to determine the interventions. Pharmacy staff who prepares blinded syringes of medications for administration will not be involved in medication administration, outcomes assessment, or statistical analysis. The participants and all other study personnel will be blinded to the treatment allocation.
Primary Purpose: Treatment
Official Title: Investigation of Pharmacokinetics and Pharmacodynamics of Epidural Methadone in Healthy Volunteers
Actual Study Start Date : June 4, 2018
Actual Primary Completion Date : August 28, 2019
Actual Study Completion Date : August 30, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Epidural methadone
A single 4mg epidural bolus of methadone hydrochloride
Drug: Methadone hydrochloride
Epidural bolus of 4mg of preservative free methadone hydrochloride (4mL of 1mg/mL solution)
Other Name: Epidural methadone

Active Comparator: Epidural morphine
A single 4mg epidural bolus of morphine sulfate
Drug: Morphine Sulfate
Epidural bolus of 4mg of preservative free morphine sulfate (4mL of 1mg/mL solution)
Other Name: Epidural morphine




Primary Outcome Measures :
  1. Selective segmental analgesia for heat pain - methadone [ Time Frame: 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 :
  1. Selective segmental analgesia for heat pain - morphine [ Time Frame: 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.

  2. Selective segmental analgesia for pressure pain - methadone [ Time Frame: 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.

  3. Selective segmental analgesia for pressure pain - morphine [ Time Frame: 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03525509


Locations
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United States, Missouri
Washington University in St. Louis
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
simon.haroutounian
Investigators
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Principal Investigator: Simon Haroutounian, PhD Washington University in Saint Louis
Principal Investigator: Yehuda Ginosar, MBBS Washington University in Saint Louis
Publications:
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Responsible Party: simon.haroutounian, Assistant Professor of Anesthesiology, Chief of Clinical Research for Washington University Pain Center, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03525509    
Other Study ID Numbers: 201802099
First Posted: May 15, 2018    Key Record Dates
Last Update Posted: September 18, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by simon.haroutounian, Washington University School of Medicine:
Methadone
Morphine
Quantitative sensory testing
Epidural
Additional relevant MeSH terms:
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Acute Pain
Pain
Neurologic Manifestations
Signs and Symptoms
Morphine
Methadone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antitussive Agents
Respiratory System Agents