- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03893734
Effect of Methadone and Hydromorphone on the QT Interval After Anesthesia and Surgery
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
In the past decade, the single most common cause of withdrawal of the use of drugs that have already been marketed has been the prolongation of the QT interval on the electrocardiogram associated with polymorphic ventricular tachycardia, or torsade de pointes. Without treatment, torsade de pointes can progress to a lethal ventricular arrhythmia. A number of drugs which prolong the QT interval can precipitate torsade de pointes. However, a number of risk factors are often present in patients who develop drug-induced torsade de pointes. These include hypomagnesemia, hypokalemia, female gender, bradycardia, congestive heart failure, rapid rate of drug infusion, and high drug concentrations. Exposure to a drug that prolongs the QT interval, particularly in a susceptible patient, may cause an exaggerated QT prolongation.1 Another reason for the variability in risk for torsade de pointes relates to genetic susceptibility for this arrhythmia. These factors control the duration of the QT interval. At least 6 separate genes, if mutated, can cause the congenital long-QT interval. In particular, the human ether-a-go-go related gene (HERG), which encodes a potassium-channel protein that regulates repolarization potassium currents, has been implicated in increasing the risk of drug-induced torsade de pointes.
A number of drugs used by physicians in the perioperative period effect the QT interval. These include the anti-arrhythmic agents, calcium-channel blockers, antibiotics, antipsychotic drugs, and antiemetic agents like droperidol and haloperidol. Any agent which results in a QT prolongation greater than 500 ms is thought to significantly escalate the possibility of developing this arrhythmia. Drugs which increases that QT interval more than 500 ms should be immediately discontinued (normal values for the QT interval are < 430 ms in males and < 450 ms in females). According to guidelines published by the European Agency for the Evaluation of Medicinal Products, drugs which induce individual changes in the QT of 30 ms are unlikely to raise concerns about arrhythmias, changes of 30-60 ms are thought to potentially increase the risk for arrhythmias, and drug-effects which raise the QT interval more than 60 ms increase concerns about arrythmogenic risk.
Oral methadone is a long acting agent which has been traditionally used to treat opioid addiction. In addition, it is being increasingly used as an important therapy for chronic pain. This agent has a long half-life and can be administered once daily. In addition to its analgesic effects due to its long-acting agonist effect on the µ-receptor, methadone is an antagonist of the N-methyl-D-aspartate (NMDA) receptor. Antagonism of the NMDA receptor may play an important role in treating acute pain and preventing the development of chronic postoperative pain. Furthermore, methadone may prevent reuptake of the neurotransmitters norepinephrine and serotonin and result in improved mood states. In chronic pain patients, methadone may be more effective in treating neuropathic pain and prevent the development of tolerance. Despite these potential advantages, patients receiving chronic methadone therapy are at increased risk of cardiac death. Methadone has been reported to be implicated in 30-40% of opioid-related deaths. Although a number of these deaths may be related to respiratory depression, others may be due to QT prolongation and torsade de pointes. Risk factors in these patients for lethal arrhythmias include dose of methadone, duration of treatment, electrolyte abnormalities, older age, female sex, cirrhosis, genetic susceptibility, and use of other drugs that prolong the QT interval. Studies have demonstrated a mean increase in the QT interval of 15 ms and 34 ms in patients on chronic methadone treatment.
Over the past decade, the use of intravenous methadone in the operating room setting has dramatically increased. An important limitation of the intravenous opioids typically used in the operating room and in the postoperative period for pain management is that the duration of effect of these agents is only 3 to 4 hours. This results in periods of effective pain relief, followed by periods of moderate-to-severe pain in the postoperative period. An alternative strategy for opioid utilization may involve the administration of a very long-acting opioid in the operating room that would provide effective analgesia for the first 24 postoperative hours (which corresponds with the period of the most severe pain after surgery). At the present time, intravenous methadone is the only long-acting opioid available to anesthesiologists. A primary advantage of methadone is its long half-life, which ranges from 25-52 hours when given intravenously in larger doses. Therefore, a single dose given at induction of anesthesia can be used in patients with moderate-to-severe to provide analgesia throughout the perioperative period. In randomized, double-blinded investigations in cardiac and orthopedic surgical patients, subjects randomized to the methadone group reported less pain, required reduced postoperative analgesic medications, and described increased satisfaction with overall pain management when compared to subjects administered a standard opioids.
No adverse events directly attributable to methadone were reported in any clinical trials using methadone in the operating room. In particular, no cardiac events, episodes of QT prolongation, or observations of torsade de pointes were reported in any studies. In addition, no case reports of adverse cardiac events related to methadone have been described in the literature. However, none of the previous studies have specifically assessed the effect of methadone on the incidence of QT prolongation or obtained postoperative EKGs. Only two previous investigations have examined the potential effects of a single dose of methadone on the QT interval. In dogs given 0.3 to 1.0 mg/kg doses of intravenous methadone, no significant effect on the QRS duration or QT interval was observed. In a post-hoc analysis of data from a randomized study examining the effect of vitamin treatment and nitrous oxide on cardiovascular events, the impact of various anesthetic agents on the QT interval was examined. EKGs were obtained before anesthesia, 30 minutes after PACU admission, and on postoperative days 1 and 2. Eighty percent of patients had significant QT prolongation in the PACU, whereas no patient had QT prolongation by postoperative day 1. Several drugs were associated with increases in the QT interval, including inhalational agents, ketorolac, antibiotics, vasoactive drugs, and methadone. Fifty-three percent of the patients administered methadone had a QT interval increase of > 30 ms. An important limitation of this investigation is that it was a post-hoc analysis of data from a study in which anesthetic care was not standardized. The data demonstrates, however, that a number of anesthetic agents increase the QT interval. In addition, the stress response to surgery has been demonstrated to increase the QT interval. Despite the frequent use of these agents in the operating room, torsade de pointes is a rare event during or immediately following surgery.
At the present time, no previous randomized trials have assessed the effect of a single dose of methadone, given at induction of anesthesia, on the QT interval as a primary endpoint. The aim of this clinical investigation is to examine the impact of a standard dose of perioperative methadone (0.2 mg/kg ideal body weight (IBW)) on the QT interval, measured with a 12-lead EKG, 30 minutes after PACU admission and on the morning of postoperative day 1. We hypothesize that patients randomized to receive methadone will not have a higher incidence of QT prolongation, when compared to patients given a dose of hydromorphone (the standard intraoperative opioid administered to patients undergoing procedures associated with moderate-to-severe postoperative pain). Secondary endpoints include levels of postoperative pain, analgesic requirements, and any opioid-related complications (level of sedation, episodes of respiratory complications)
Study Type
Enrollment (Anticipated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Lucyna W Klatzco
- Phone Number: 264-364-7272
- Email: lklatzco@northshore.org
Study Locations
-
-
Illinois
-
Evanston, Illinois, United States, 60201
- Recruiting
- NorthShore University HealthSystem
-
Contact:
- Glenn S Murphy, MD
- Phone Number: 847-570-2760
- Email: dgmurphy2@yahoo.com
-
Contact:
- Joseph W Szokol, MD
- Phone Number: 847-570-2760
- Email: szokolmd@gmail.com
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- All patients presenting for elective surgical cases requiring general anesthesia and associated with moderate-to-severe postoperative pain will be eligible for enrollment.
Exclusion Criteria:
- History of arrhythmias, pacemaker, or defibrillator
- Allergy to methadone or hydromorphone
- Preoperative altered mental status
- Abnormal serum electrolyte values
- Existence of significant valvular disease or cardiac rhythm other than sinus
- Significant preoperative pain requiring treatment with opioids or recent history of opioid abuse
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: methadone group
Patients in this group will receive a syringe of methadone at the induction of anesthesia and a syringe of saline at the end of anesthesia.
|
Patients in the methadone group will receive a syringe of methadone at induction of anesthesia and a syringe of saline at the end of anesthesia
|
Placebo Comparator: hydromorphone group
Patients in this group will receive a syringe of saline at induction of anesthesia and a syringe of hydromorphone at the end of anesthesia
|
Patients in the hydromorphone group will receive a syringe of saline at induction of anesthesia and a syringe of hydromorphone at the end of anesthesia
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
QT prolongation on the EKG 30 minutes after postanesthesia care unit admission
Time Frame: 30 minutes after post anesthesia care unit admission
|
EKGs will be obtained 30 minutes after postanesthesia care unit admission
|
30 minutes after post anesthesia care unit admission
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
QT prolongation on the EKG on the morning of postoperative day one
Time Frame: 24 hours after surgery
|
EKGs will be obtained on the morning of postoperative day one
|
24 hours after surgery
|
Level of pain on on a 0-10 scale 30 minutes after postanesthesia care unit admission
Time Frame: 30 minutes after postanesthesia care unit admission
|
Pain will be assessed on a 0-10 scale (0=no pain, 10 worst pain imaginable)
|
30 minutes after postanesthesia care unit admission
|
Level of pain on a 0-10 scale on the morning of postoperative day one
Time Frame: 24 hours after surgery
|
Pain will be assessed on a 0-10 scale (0=no pain, 10 worst pain imaginable)
|
24 hours after surgery
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Heart Diseases
- Cardiovascular Diseases
- Congenital Abnormalities
- Arrhythmias, Cardiac
- Cardiac Conduction System Disease
- Heart Defects, Congenital
- Cardiovascular Abnormalities
- Long QT Syndrome
- Physiological Effects of Drugs
- Central Nervous System Depressants
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Analgesics, Opioid
- Narcotics
- Respiratory System Agents
- Antitussive Agents
- Hydromorphone
- Methadone
Other Study ID Numbers
- EH17-264
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on EKG-QT Prolongation
-
Indiana UniversityPurdue UniversityCompletedQT Interval ProlongationUnited States
-
Peking University Third HospitalUnknown
-
KU LeuvenAgentschap voor Innovatie door Wetenschap en TechnologieCompleted
-
KU LeuvenAgentschap voor Innovatie door Wetenschap en TechnologieCompleted
-
Food and Drug Administration (FDA)Spaulding Clinical Research LLCCompletedPharmacokinetics | Pharmacodynamics | Drug-induced QT ProlongationUnited States
-
Food and Drug Administration (FDA)Spaulding Clinical Research LLCCompletedPharmacokinetics | Pharmacodynamics | Drug-induced QT ProlongationUnited States
-
Food and Drug Administration (FDA)Spaulding Clinical Research LLCCompletedPharmacokinetics | Pharmacodynamics | Drug-induced QT Prolongation
-
Rabin Medical CenterUnknownVoriconazole Induced QT Interval ProlongationIsrael
-
KU LeuvenAgentschap voor Innovatie door Wetenschap en TechnologieCompletedDelirium | QT-prolongationBelgium
Clinical Trials on methadone
-
Pontificia Universidad Catolica de ChileCompletedPain, Postoperative | Opioid Use | Methadone Overdose of Undetermined IntentChile
-
Washington University School of MedicineCompleted
-
University of Southern DenmarkCompletedPain, Postoperative | Pain, Post Operative | Analgesics, Opioid | MethadoneDenmark
-
Washington University School of MedicineCompleted
-
The Miriam HospitalUnknownOpioid-Related DisordersUnited States
-
Johns Hopkins UniversityNational Institute on Drug Abuse (NIDA)RecruitingChronic Pain | Opioid Use Disorder | MethadoneUnited States
-
Washington University School of MedicineNational Institute of Neurological Disorders and Stroke (NINDS)WithdrawnPolyneuropathy | HIV-associated NeuropathyUnited States
-
Washington University School of MedicineCompleted
-
Johns Hopkins UniversityNational Institute on Drug Abuse (NIDA)CompletedOpiate DependenceUnited States
-
University of VirginiaCompleted