Effect of Methadone and Hydromorphone on the QT Interval After Anesthesia and Surgery
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 3/30/2019 |
| Start Date: | May 1, 2018 |
| End Date: | December 23, 2019 |
| Contact: | Lucyna W Klatzco |
| Email: | lklatzco@northshore.org |
| Phone: | 264-364-7272 |
A number of drugs used in the perioperative period may cause prolongation of the QT interval
on the electrocardiogram (EKG). These drugs include inhalational agents, antiemetic agents,
pain medications, and drugs used to reverse the effects of muscle relaxants. Approximately
80% of patients undergoing a general anesthetic will demonstrate significant prolongation of
the QT interval on the EKG in the postanesthesia care unit (PACU) following surgery. The
concern with QT interval prolongation is that it can result in a potentially lethal
ventricular arrhythmia termed torsade des pointes. Despite the concurrent use of several of
these medications in a typical general anesthetic, torsade des pointes is a rare event in the
perioperative period. In the past decade, the use of intravenous methadone as part of a
balanced anesthetic technique has increased significantly. A single dose provided at
induction of anesthesia can provide prolonged (24-48 hours) relief from pain. Studies in
patients receiving long-term treatment with methadone for addiction therapy or chronic pain
have revealed that these patients are at risk for QT prolongation, torsade des pointe, and
cardiac death. However, the effect of a single intravenous dose of methadone used in the
operating room on the QT interval is uncertain. The aim of this randomized clinical trial is
to compare the impact of methadone, when compared to the more commonly-used opioid
hydromorphone, on QT prolongation measured with a 12-lead EKG in the PACU and on
postoperative day 1. We hypothesize that methadone will not result in significant QT
prolongation when used as part of a standardized general anesthetic.
on the electrocardiogram (EKG). These drugs include inhalational agents, antiemetic agents,
pain medications, and drugs used to reverse the effects of muscle relaxants. Approximately
80% of patients undergoing a general anesthetic will demonstrate significant prolongation of
the QT interval on the EKG in the postanesthesia care unit (PACU) following surgery. The
concern with QT interval prolongation is that it can result in a potentially lethal
ventricular arrhythmia termed torsade des pointes. Despite the concurrent use of several of
these medications in a typical general anesthetic, torsade des pointes is a rare event in the
perioperative period. In the past decade, the use of intravenous methadone as part of a
balanced anesthetic technique has increased significantly. A single dose provided at
induction of anesthesia can provide prolonged (24-48 hours) relief from pain. Studies in
patients receiving long-term treatment with methadone for addiction therapy or chronic pain
have revealed that these patients are at risk for QT prolongation, torsade des pointe, and
cardiac death. However, the effect of a single intravenous dose of methadone used in the
operating room on the QT interval is uncertain. The aim of this randomized clinical trial is
to compare the impact of methadone, when compared to the more commonly-used opioid
hydromorphone, on QT prolongation measured with a 12-lead EKG in the PACU and on
postoperative day 1. We hypothesize that methadone will not result in significant QT
prolongation when used as part of a standardized general anesthetic.
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)
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)
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
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