Pain, AcuteEarly Phase 1NCT03525509
Epidural Methadone in Healthy Volunteers
A Early Phase 1 study testing Methadone hydrochloride and Morphine Sulfate in people with Pain, Acute, run by simon.haroutounian at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Pain, Acute
- What is being tested?
- Methadone hydrochloride and Morphine Sulfate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- 4 Jun 2018to 30 Aug 2019
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
Washington University in St. Louis
St Louis, Missouri, 63110
About this study
Official title: Investigation of Pharmacokinetics and Pharmacodynamics of Epidural Methadone in Healthy Volunteers
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.
Read the 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.
- Conditions
- Pain, Acute
- Being tested
- Methadone hydrochloride, Morphine Sulfate
- Keywords
- Methadone, Morphine, Quantitative sensory testing, Epidural
- Medical subject headings
- Acute Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Methadone hydrochlorideDrug
Also called Epidural methadone
Epidural bolus of 4mg of preservative free methadone hydrochloride (4mL of 1mg/mL solution)
Morphine SulfateDrug
Also called Epidural morphine
Epidural bolus of 4mg of preservative free morphine sulfate (4mL of 1mg/mL solution)
| Study group | Role | What they receive |
|---|---|---|
| Epidural methadone | Experimental | A single 4mg epidural bolus of methadone hydrochloride Receives: Drug: Methadone hydrochloride |
| Epidural morphine | Active comparator | A single 4mg epidural bolus of morphine sulfate Receives: Drug: Morphine Sulfate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 0 -12 hours after medication administration
Secondary outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: 0 - 12 hours after medication administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 May 2018
- Study start4 Jun 2018
- Primary completion28 Aug 2019
- Study completion30 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Pain, AcuteStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomized, double-blinded, crossover design in healthy volunteers
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- simon.haroutounian
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, simon.haroutounian, Washington University School of Medicine
- Investigators
- Simon Haroutounian, PhD, Principal investigator, Washington University in Saint LouisYehuda Ginosar, MBBS, Principal investigator, Washington University in Saint Louis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03525509
- Sponsor's protocol ID
- 201802099
- Status last verified
- Sep 2019
- First submitted
- 2 May 2018
- Last updated
- 18 Sep 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Shir Y, Rosen G, Zeldin A, Davidson EM. Methadone is safe for treating hospitalized patients with severe pain. Can J Anaesth. 2001 Dec;48(11):1109-13. doi: 10.1007/BF03020377.
PubMed 11744587Haroutiunian S, Kagan L, Yifrach-Damari I, Davidson E, Ratz Y, Hoffman A. Enhanced antinociceptive efficacy of epidural compared with i.v. methadone in a rat model of thermal nociception. Br J Anaesth. 2014 Jan;112(1):150-8. doi: 10.1093/bja/aet234. Epub 2013 Jul 10.
PubMed 23842610Bernards CM, Shen DD, Sterling ES, Adkins JE, Risler L, Phillips B, Ummenhofer W. Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 1): differences among opioids. Anesthesiology. 2003 Aug;99(2):455-65. doi: 10.1097/00000542-200308000-00029.
PubMed 12883420Gedney JA, Liu EH. Side-effects of epidural infusions of opioid bupivacaine mixtures. Anaesthesia. 1998 Dec;53(12):1148-55. doi: 10.1046/j.1365-2044.1998.00636.x.
PubMed 10193215
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigation of Pharmacokinetics and Pharmacodynamics of Epidural Methadone in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT03525509
- Acronym / sponsor ID
- 201802099
- Conditions
- Pain, Acute
- Keywords
- Methadone, Morphine, Quantitative sensory testing, Epidural
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- simon.haroutounianUniversity, hospital or other
- Study start
- 4 Jun 2018 (actual)
- Primary completion
- 28 Aug 2019 (actual)
- Study completion
- 30 Aug 2019 (actual)
- First posted
- 15 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomized, double-blinded, crossover design in healthy volunteers
| Arm | Type | Receives |
|---|---|---|
| Epidural methadone | Experimental | Drug: Methadone hydrochlorideA single 4mg epidural bolus of methadone hydrochloride |
| Epidural morphine | Active comparator | Drug: Morphine SulfateA single 4mg epidural bolus of morphine sulfate |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (8 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Methadone hydrochlorideAlso: Epidural methadoneEpidural bolus of 4mg of preservative free methadone hydrochloride (4mL of 1mg/mL solution) | Drug | Epidural methadone |
| Morphine SulfateAlso: Epidural morphineEpidural bolus of 4mg of preservative free morphine sulfate (4mL of 1mg/mL solution) | Drug | Epidural morphine |
Primary outcome
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.
3 secondary outcomes
Selective segmental analgesia for heat pain - morphine
Time frame: 0 -12 hours after medication administration
Selective segmental analgesia for pressure pain - methadone
Time frame: 0 - 12 hours after medication administration
Selective segmental analgesia for pressure pain - morphine
Time frame: 0 - 12 hours after medication administration
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2019.
- Background: PubMed 11744587Shir Y, Rosen G, Zeldin A, Davidson EM. Methadone is safe for treating hospitalized patients with severe pain. Can J Anaesth. 2001 Dec;48(11):1109-13. doi: 10.1007/BF03020377.
- Background: PubMed 23842610Haroutiunian S, Kagan L, Yifrach-Damari I, Davidson E, Ratz Y, Hoffman A. Enhanced antinociceptive efficacy of epidural compared with i.v. methadone in a rat model of thermal nociception. Br J Anaesth. 2014 Jan;112(1):150-8. doi: 10.1093/bja/aet234. Epub 2013 Jul 10.
- Background: PubMed 12883420Bernards CM, Shen DD, Sterling ES, Adkins JE, Risler L, Phillips B, Ummenhofer W. Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 1): differences among opioids. Anesthesiology. 2003 Aug;99(2):455-65. doi: 10.1097/00000542-200308000-00029.
- Background: PubMed 10193215Gedney JA, Liu EH. Side-effects of epidural infusions of opioid bupivacaine mixtures. Anaesthesia. 1998 Dec;53(12):1148-55. doi: 10.1046/j.1365-2044.1998.00636.x.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Simon Haroutounian, PhD principal investigator
Washington University in Saint Louis
Yehuda Ginosar, MBBS principal investigator
Washington University in Saint Louis
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Methadone hydrochloride and Morphine Sulfate in people with Pain, Acute, run by simon.haroutounian at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Selective segmental analgesia for heat pain - methadone (time frame: 0 -12 hours after medication administration). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03525509, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2019.