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Use of Oral Methadone as an Analgesic: Review of the Cardiotoxic Side Effects
Abstract
Methadone is a synthetic opiate primarily used in the detoxification and maintenance of patients who are dependent on opiates particularly heroin. Though within last 10-15 years methadone is increasingly used to manage neuropathic and cancer pains. Unfortunately, with increased methadone use for pain is coincided with significant increase in adverse events and fatalities. Cardiotox - icity is one of the major adverse effects reported with the use of oral methadone. The purpose of this paper is to provide an overview of the cardiotoxicity of methadone, when used as an oral analgesic and protocols for safe prescribing of methadone to help physicians recognize situations where this drug offers the greatest advantage as an analgesic.
... It also causes some side effects on central nervous system, skin, gastrointestinal tract, and urogenital and cardiovascular systems (Izadi-Mood et al., 2008). One of the adverse events of methadone is its cardiotoxicity (Kumar, 2010). Indeed, increased QT dispersion, QT interval prolongation, and torsade de pointes (TDP) -a life-threatening arrhythmia-are all reported in patients treated with methadone (Cruciani 2008;Price et al., 2013). ...
... Indeed, increased QT dispersion, QT interval prolongation, and torsade de pointes (TDP) -a life-threatening arrhythmia-are all reported in patients treated with methadone (Cruciani 2008;Price et al., 2013). These cardiovascular side effects were so prominent when a derrivative Levacetyl methadol (LAAM) or Orlaam (Deamer et al., 2001) which caused LAAM was introduced, that it had to be eliminated from European markets (Deamer et al., 2001;Guay, 2009;Kumar, 2010). ...
... Methadone is the drug of choice for the treatment of opioid addiction due to its special pharmacokinetics (Strain, 2002). It is also a good alternative to morphine and other opiate analgesics in the treatment of severe chronic pain (Kumar, 2010). The average bio-availability of methadone (about 80 %) is higher than other opioids and its elimination half-life is long ranging from 7 to 65 hours (Fredheim et al., 2008). ...
Methadone is one of the most popular synthetic opioids in the world with some favorable properties making it useful both in the treatment of moderate to severe pain and for opioid addiction. Increased use of methadone has resulted in an increased prevalence of its toxicity, one aspect of which is cardiotoxicity. In this paper, we review the effects of methadone on the heart as well as cardiac concerns in some special situations such as pregnancy and childhood. Methods: We searched for the terms methadone, toxicity, poisoning, cardiotoxicity, heart, dysrhythmia, arrhythmia, QT interval prolongation, torsade de pointes, and Electrocardiogram (ECG) in bibliographical databases including TUMS digital library, PubMed, Scopus, and Google Scholar. This review includes relevant articles published between 2000 and 2013. The main cardiac effects of methadone include prolongation of QT interval and torsade de pointes. Other effects include changes in QT dispersion, pathological U waves, Taku-Tsubo syndrome (stress cardiomyopathy), Brugada-like syndrome, and coronary artery diseases. The aim of this paper is to inform physicians and health care staff about these adverse effects. Effectiveness of methadone in the treatment of pain and addiction should be weighed against these adverse effects and physicians should consider the ways to lessen such undesirable effects. This article presents some recommendations to prevent heart toxicity in methadone users.
... It also causes some side effects on central nervous system, skin, gastrointestinal tract, and urogenital and cardiovascular systems (Izadi-Mood et al., 2008). One of the adverse events of methadone is its cardiotoxicity (Kumar, 2010). Indeed, increased QT dispersion, QT interval prolongation, and torsade de pointes (TDP) -a life-threatening arrhythmia-are all reported in patients treated with methadone (Cruciani 2008;Price et al., 2013). ...
... Indeed, increased QT dispersion, QT interval prolongation, and torsade de pointes (TDP) -a life-threatening arrhythmia-are all reported in patients treated with methadone (Cruciani 2008;Price et al., 2013). These cardiovascular side effects were so prominent when a derrivative Levacetyl methadol (LAAM) or Orlaam (Deamer et al., 2001) which caused LAAM was introduced, that it had to be eliminated from European markets (Deamer et al., 2001;Guay, 2009;Kumar, 2010). ...
... Methadone is the drug of choice for the treatment of opioid addiction due to its special pharmacokinetics (Strain, 2002). It is also a good alternative to morphine and other opiate analgesics in the treatment of severe chronic pain (Kumar, 2010). The average bio-availability of methadone (about 80 %) is higher than other opioids and its elimination half-life is long ranging from 7 to 65 hours (Fredheim et al., 2008). ...
Unlabelled:
Methadone is one of the most popular synthetic opioids in the world with some favorable properties making it useful both in the treatment of moderate to severe pain and for opioid addiction. Increased use of methadone has resulted in an increased prevalence of its toxicity, one aspect of which is cardiotoxicity. In this paper, we review the effects of methadone on the heart as well as cardiac concerns in some special situations such as pregnancy and childhood.
Methods:
We searched for the terms methadone, toxicity, poisoning, cardiotoxicity, heart, dysrhythmia, arrhythmia, QT interval prolongation, torsade de pointes, and Electrocardiogram (ECG) in bibliographical databases including TUMS digital library, PubMed, Scopus, and Google Scholar. This review includes relevant articles published between 2000 and 2013. The main cardiac effects of methadone include prolongation of QT interval and torsade de pointes. Other effects include changes in QT dispersion, pathological U waves, Taku-Tsubo syndrome (stress cardiomyopathy), Brugada-like syndrome, and coronary artery diseases. The aim of this paper is to inform physicians and health care staff about these adverse effects. Effectiveness of methadone in the treatment of pain and addiction should be weighed against these adverse effects and physicians should consider the ways to lessen such undesirable effects. This article presents some recommendations to prevent heart toxicity in methadone users.
... Patients with opioid dependence also tend to have higher rates of mood disorders and other illicit substance abuse, where a combination of these factors may lead to the possibility of central nervous system effects and worsening behavioral symptoms (George et al., 2018). Other potential adverse effects of methadone include nephrotoxicity (Atici et al., 2005;Lentine et al., 2015) and cardiotoxicity (Kumar, 2010 Buprenorphine is an opioid partial agonist that sustains abstinence, delays the time of resumption to opioid use, and retains patients in treatment (Schottenfeld et al., 2005). Buprenorphine has a long half-life of 24-60 h and typical dosages for maintenance treatment are 8-16 mg/day (Walsh et al., 1994;Kampman and Jarvis, 2015). ...
Globally, millions of people suffer from various substance use disorders (SUD), including mono-and polydrug use of opioids and methamphetamine. Brain regions such as the cingulate cortex, infralimbic cortex, dorsal striatum, nucleus accumbens, basolateral and central amygdala have been shown to play important roles in addiction-related behavioral changes. Clinical and pre-clinical studies have characterized these brain regions and their corresponding neurochemical changes in numerous phases of drug dependence such as acute drug use, intoxication, craving, withdrawal, and relapse. At present, many studies have reported the individual effects of opioids and methamphetamine. However, little is known about their combined effects. Co-use of these drugs produces effects greater than either drug alone, where one decreases the side effects of the other, and the combination produces a prolonged intoxication period or a more desirable intoxication effect. An increasing number of studies have associated polydrug abuse with poorer treatment outcomes, drug-related deaths, and more severe psychopathologies. To date, the pharmacological treatment efficacy for polydrug abuse is vague, and still at the experimental stage. This present review discusses the human and animal behavioral, neuroanatomical, and neurochemical changes underlying both morphine and methamphetamine dependence separately, as well as its combination. This narrative review also delineates the recent advances in the pharmacotherapy of mono-and poly drug-use of opioids and methamphetamine at clinical and preclinical stages.
Once used only as third-line therapy in the management of chronic pain states, methadone is now being used as first- and second-line therapy. Most risks and the stigma associated with methadone use have been known for years. Only over the past decade or so have the unique pharmacokinetic-pharmacodynamic properties and methods for conversion from other opioids to methadone been established. Pertinent English-language literature was obtained from MEDLINE/PUBMED and EMBASE searches (1966-June 2009). This paper provides an overview of the cardiotoxicity of oral methadone, with an emphasis on its use as an analgesic. Cardiotoxicity during its use in the maintenance of opioid addiction has also been reviewed due to the wealth of epidemiologic, risk factor, and correlative analytic data contained therein. A series of recommendations are provided to improve the cardiac safety profile of oral methadone used for analgesia. In addition, there is a discussion of settings and patient types which may impact upon these recommendations.
Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)-methadone might be used as target values.
The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I(HERG) in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC50 < 0.1 microM) included lidoflazine, terfenadine, and haloperidol; moderate-potency blockers (0.1 microM < IC50 < 1 microM) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC50 > 1 microM) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC50 > 300 microM) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (<30 min of drug exposure per measurement). Since two of the drugs that were ineffective I(HERG) blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I(HERG).
Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.
Description:
An independent panel developed cardiac safety recommendations for physicians prescribing methadone.
Methods:
Expert panel members reviewed and discussed the following sources regarding methadone: pertinent English-language literature identified from MEDLINE and EMBASE searches (1966 to June 2008), national substance abuse guidelines from the United States and other countries, information from regulatory authorities, and physician awareness of adverse cardiac effects. RECOMMENDATION 1 (DISCLOSURE): Clinicians should inform patients of arrhythmia risk when they prescribe methadone. RECOMMENDATION 2 (CLINICAL HISTORY): Clinicians should ask patients about any history of structural heart disease, arrhythmia, and syncope. RECOMMENDATION 3 (SCREENING): Obtain a pretreatment electrocardiogram for all patients to measure the QTc interval and a follow-up electrocardiogram within 30 days and annually. Additional electrocardiography is recommended if the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures. RECOMMENDATION 4 (RISK STRATIFICATION): If the QTc interval is greater than 450 ms but less than 500 ms, discuss the potential risks and benefits with patients and monitor them more frequently. If the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy. RECOMMENDATION 5 (DRUG INTERACTIONS): Clinicians should be aware of interactions between methadone and other drugs that possess QT interval-prolonging properties or slow the elimination of methadone.
1.1. 1-α-Acetylmethadol (LAAM) and its major metabolites, 1-α-acetylnormethadol (N-LAAM) and 1-α-acetyldinormethadol (DN-LAAM), were shown to exert significant anticholinesterase activity in preparations of guinea pig heart homogenate, guinea pig plasma, purified acetylcholinesterase (EC 3.1.1.7) and purified butyrylcholinesterase (EC 3.1.1.8), P < 0.05.2.2. LAAM and congeners did not decrease heart homogenate cholinesterase activity at low concentrations (5 × 10−6M) which produce bradycardia in vitro that can be blocked completely with atropine.3.3. The data suggest that cholinesterase inhibition does not contribute to the bradycardia effected by lower concentrations of LAAM. However, cholinesterase inhibition may contribute to LAAM-induced bradycardia at higher concentrations.
There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose +/- standard deviation, 69 +/- 29 mg) and buprenorphine (n = 19, mean daily dose 11 +/- 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 +/- 29 mg/day) than methadone subjects without U waves (60 +/- 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 +/- 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 +/- 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.
We report on 8 patients treated with subcutaneous methadone for cancer-related pain at 2 institutions. The success of other subcutaneous agents for pain control has been well demonstrated. It was felt that methadone would be useful due to its low cost. Unfortunately, 7 of the 8 patients experienced adverse reactions at the subcutaneous sites requiring cessation of subcutaneous methadone.
Cardiac muscle contractile responses to six narcotic analgesics (morphine, meperidine, pentazocine, fentanyl, methadone and l-alpha-acetylmethadol), at concentrations from 10(-8) to 10(-4) M, both in the presence and absence of the narcotic antagonist, naloxone, were studied in the isolated, isometric cat right ventricular papillary muscle preparation. Measurements of maximum developed tension (T), maximum rate of tension development (dT/dt) and time to peak tension indicated that no major changes in contractile function occurred with any narcotic at concentrations of 10(-8) to 10(-6) M except for small but significant (P < .05) increases in all three parameters at 10(-6) M fentanyl, and small but significant increases in dT/dt at 10(-8) to 10(-6) M meperidine. At 10(-5) M narcotic, dT/dt was significantly elevated in meperidine-treated muscles (+7%), but significantly reduced in muscles exposed to pentazocine (-8%) or l-alpha-acetylmethadol (-11%). For all six narcotics, the 10(-4) M drug concentration resulted in depression of contractile function that was often associated with nonresponsiveness to electrical stimulation. Pretreatment of muscles with naloxone (10(-4) M) did not prevent this reduction of contractile performance except at the highest concentration (10(-4) M) of meperidine. Following removal of drug, contractile performance improved to varying degrees (recovery to 72-97% of control T), except in l-alpha-acetylmethadol-treated muscles, in which there was no recovery of T. Isoproterenol (0.8 X 10(-7) M) elicited a positive inotropic response whether administered in the presence of 10(-4) M narcotic or following narcotic removal. We conclude that narcotic analgesics in high concentrations exert a direct myocardial depressant effect which is not prevented by naloxone and therefore is not mediated by interaction with opiate receptors. Rather, several effects, including myocardial depression, its reversibility by both drug removal and isoproterenol and decreased muscle excitability are consistent with the hypothesis that narcotic analgesics in high concentrations exert nonspecific, local anesthetic effect on the myocardium.
Fourteen patients with severe cancer pain participated in a trial of methadone given in a fixed dose (10 mg) but at intervals selected by the patients themselves during the loading phase. The aim was to achieve rapid pain relief while avoiding the risk of toxicity from accumulation of methadone. As expected, the dosage intervals increased gradually over the first few days of treatment, the daily dose decreasing from 30-80 mg on the first day to 10-40 mg at the end of the week. Plasma concentrations of methadone varied sevenfold after four to five days (0.24 to 1.75 mumol/1; 7.4 to 54.2 microgram/100 ml). Eleven patients reported complete or almost complete pain relief and elected to continue with methadone after the study. In no case was treatment withdrawn because of intoxication. From these findings a patient-controlled dosage regimen of oral methadone may be an effective and safe alternative to parenteral narcotic medication, adjusting both for individual variation in pain intensity and for pharmacokinetics.
All heroin addicts who registered for methadone treatment in Albuquerque in 1969-1971, 1019 in all, were the subjects of this follow-up study, conducted in 1991-1993. The cohort was almost entirely of Hispanic (Chicano) ethnicity, 86% male, with median age 27 at entry. We located 776, dead or alive, and we were able to interview 243 concerning many aspects of their lives. At least one-third of the original group had died during the 22-year period, representing standard mortality ratios 4.0 for males and 6.8 for females. Drug overdose, violence, alcohol, or suicide accounted for nearly all deaths of which the causes were known. Despite the availability of treatment, including methadone maintenance, both heroin use and criminality continued at a high rate. Of the 428 known survivors, 48% were currently enrolled in a methadone program after 22 years. They were using significantly less heroin, alcohol, and other drugs (except nicotine) than those not on methadone. Similar beneficial effects of methadone maintenance were reported retrospectively at interview. Our findings offer an insight into heroin addiction as a chronic lifelong relapsing disease with a high fatality rate.
To define the dose ratio between morphine and methadone in relation to the previous morphine dose and the number of days needed to achieve the same level of analgesia in a group of patients with advanced cancer with pain who switched from morphine to oral methadone.
A cross-sectional prospective study of 38 consecutive cancer patients who switched from morphine to oral methadone was performed. The intensity of pain before, during, and after the switching period was assessed through a four-point verbal Likert scale. The relationship between previous morphine dose and the final equianalgesic methadone dose, dose ratio between morphine and methadone, and the number of days required to achieve equianalgesia have been examined by means of Pearson's correlation coefficient, scatter plots, and Cuzick's test for trend respectively.
Before the switch, the median oral equivalent daily dose of morphine was 145 mg/d; after the switch, the median equianalgesic oral methadone dose was 21 mg/d. A median time of 3 days (range, 1 to 7 days) was necessary to achieve the equianalgesia with oral methadone; the lower the preswitching morphine dose, the fewer days necessary to achieve equianalgesia with oral methadone (P < .001). Dose ratios ranged from 2.5:1 to 14.3:1 (median, 7.75:1), which indicated that, in most cases, the dose ratio was much higher than that suggested by the published equianalgesic tables. A strong linear positive relationship between morphine and methadone equianalgesic doses was obtained (Pearson's correlation coefficient, 0.91). The dose ratio increased with the increase of the previous morphine dose with a much higher increase at low morphine doses.
The results of our study confirm that methadone is a potent opioid, more potent than believed. Caution is recommended when switching from any opioid to methadone, especially in patients who are tolerant to high doses of opioids.
Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.
Link: http://www.sciencedirect.com/science/article/pii/S0006295298000884
The aim of this study was to evidence the clinical effects of an abrupt substitution of morphine with methadone using a fixed ratio of 1:5 in patients for whom limiting adverse effects occurred before adequate analgesia was achieved with oral morphine.
A cross-sectional prospective study was carried out on 24 consecutive patients who were switched from oral morphine to oral methadone because they experienced substantial adverse effects that limited further increase in morphine dose. A fixed conversion morphine-to-methadone ratio of 5:1 was chosen. Subsequently, doses were changed according to clinical need, with frequent visits or phone contacts. Pain and symptom intensity, preswitching doses of morphine, initial and subsequent doses of methadone, and survival were recorded.
A significant decrease in pain and symptom intensity was found within 24 hours after the substitution took place. The switching was effective in most patients (19 of 24), although five patients required alternative treatments. No significant changes in methadone dose were reported in the 3 days after switching. Methadone dose was significantly higher in patients who had lower preswitching doses of morphine and vice versa. No relevant complications were reported.
A rapid substitution of morphine with methadone using an initial fixed ratio of 5:1 is a safe and effective method for improving the balance between analgesia and adverse effects in cancer patients with poor morphine response. An appropriate system of patient monitoring is necessary, because further changes in dose may be required according to clinical needs.
In this first clinical report of an idiopathic familial persistently short QT interval (QTI), we describe three members of one family (a 17-year-old female, her 21-year-old brother, and their 51-year-old mother) demonstrating this ECG phenomenon, associated in the 17-year-old with several episodes of paroxysmal atrial fibrillation requiring electrical cardioversion. Similar ECG changes seen in an unrelated 37-year-old patient were associated with sudden cardiac death. Our report also describes other manifestations of abnormal shortening of the QTI and considers the possible arrhythmogenic potential of the short QTI.
A patient undergoing management of heroin dependency with high dosages of the long-acting methadone derivative, levomethadyl acetate HCl (LAAM; ORLAAM) developed a prolonged QTc interval and polymorphic QRS complexes on EKG consistent with torsades de pointes (TdP). The patient was taking other drugs known to prolong the QTc interval (fluoxetine and IV cocaine), and those known to antagonize the activity of the P450 enzymes responsible for the metabolism of LAAM and its active metabolite (fluoxetine, cocaine and marijuana). No previous reports have appeared in the literature attributing this adverse event to LAAM therapy; however, five similar cases have been reported to the manufacturer. Animal studies indicate that LAAM and metabolites prolong the action potential duration of myocardial cells. We propose that predisposed patients on high doses of LAAM may be at risk for developing TdP. Patients being treated with LAAM should receive dosages consistent with guidelines and be evaluated for concomitant diseases, interacting drug therapies, and EKG abnormalities.
In recent years a better understanding of the pharmacologic and pharmacokinetic properties of methadone, including equianalgesic ratios has led to its increased use as a second line opioid for the treatment of pain in patients with cancer. Methadone may be an important alternative for those who have side effects related to the use of other opioids because it has no known active metabolites, is well absorbed by oral and rectal routes, and also has the advantage of very low cost. However, it has a long, unpredictable half-life, which can result in accumulation and toxicity in some patients. In addition, rotation to methadone as a second line agent is more complex than with other opioids because of its increased potency in those patients who are opioid tolerant, particularly those who have been on higher doses of other opioids. Future research should address the use of methadone as a first-line agent in the management of cancer pain, its use in patients with neuropathic pain, and in those who develop rapid tolerance to other opioids. In some patients with cancer the long half-life of methadone offers the advantage of extended dosing intervals to 12 and even 24 hours, further research is also needed in this area.
It has been suggested that starting and temporarily discontinuing methadone treatment is related to an increased risk in overdose mortality. This study describes the incidence of overdose mortality in relation to time after (re)entering or leaving treatment.
A dynamic cohort of 5200 Amsterdam methadone clients was observed during treatment and (a maximum of 1 year) after treatment.
Between 1986 and 1998, 29,729 person-years (py) and 68 overdose deaths were recorded, leading to an overdose mortality rate of 2.3/1000 py (2.2 during and 2.4 after treatment). A modest increase was observed during the first 2 weeks after (re)entering treatment; 6.0/1000 py (rate ratio: 2.9; 95% confidence interval 1.4; 5.8). Directly after leaving treatment no increase was observed.
Inhaling heroin, common among Amsterdam heroin users, is thought to account for low OD mortality rates both during and after treatment. Accumulation of methadone, inadequate assessment of tolerance of known clients re-entering treatment and concurrent periods of stress or extreme heroin use when entering treatment are mentioned as possible explanations of the increased risk within the first 2 weeks. An Australian study reported a much higher increase. The modest increase in Amsterdam is explained by low background risk of overdose mortality, low starting dosage and the low threshold to treatment.
l-alpha-acetylmethadol is a long-acting narcotic analgesic that is used in the treatment of opiate addiction. However, the drug has been associated with cases of QT interval prolongation and ventricular arrhythmia. To understand the mechanism underlying these clinical findings, we examined the effects of l-alpha-acetylmethadol on the cloned human cardiac K(+) channels HERG (human ether-a-go-go-related gene), KvLQT1/minK and Kv4.3. Using patch clamp electrophysiology, we found that l-alpha-acetylmethadol inhibited HERG channel currents in a voltage-dependent manner displaying an IC(50) value of 3 microM. The major active metabolite of l-alpha-acetylmethadol, noracetylmethadol, inhibited HERG with an estimated IC(50) values of 12 microM. l-alpha-acetylmethadol had little or no effect on Kv4.3 or KvLQT1/minK K(+) channel currents at concentration up to 10 microM. We conclude that the proarrhythmic effects of l-alpha-acetylmethadol are due to specific blockade of the HERG cardiac K(+) channel and that its active metabolite noracetylmethadol may provide a safer alternative in the treatment of opiate addiction.
The analgesic effectiveness and adverse effect incidence of a daily dose of 10 or 20 mg of oral methadone were evaluated in 18 patients with a diverse range of chronic neuropathic pain syndromes, who had all responded poorly to traditional analgesic regimens. Analgesia was seen after each dose of methadone. As compared with placebo, the 20 mg daily dose (given as 10 mg bd) resulted in statistically significant (P = 0.013-0.020) improvements in patient Visual Analogue Scale ratings of maximum pain intensity, average pain intensity and pain relief, recorded at the same time daily. The analgesic effects extended over 48 hours, as shown by statistically significant (P = 0.013-0.020) improvements in all three outcomes on the rest days instituted between each daily dose. Analgesic effects (lowered maximum pain intensity and increased pain relief, on the day of dosing only) were also seen when the lower daily dose of 10 mg methadone (given as 5 mg bd) was used, but these failed to reach statistical significance (P = 0.064 and 0.065, respectively). Interpatient analysis showed that the analgesic effects were not restricted to any particular type of neuropathic pain. Patient compliance was high throughout the trial. One patient withdrew during the 10 mg and six during the 20 mg methadone treatment periods. This is the first double-blind randomized controlled trial to demonstrate that methadone has an analgesic effect in neuropathic pain.
Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG.
Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers.
We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
Methadone has numerous advantages as an analgesic, which have supported its recent increase in use. However, methadone also has a pharmacological profile as an opioid that differentiates it from other, better known or more widely used opioids. It also has unusual pharmacodynamics, pharmacokinetics, and metabolism that must be considered for safe use of methadone as an analgesic. This review looks at the history of methadone use as an analgesic and its properties that distinguish it as an unusual, and potentially, unstable opioid.
The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2. The present study demonstrates that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene.
A 70-year man presented with idiopathic ventricular fibrillation. Both immediately after the episode and much later, his QT interval was abnormally short without any other physical or electrophysiological anomalies. Analysis of candidate genes identified a g919c substitution in KCNQ1 encoding the K+ channel KvLQT1. Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in I(Ks). When introduced in a human action potential computer model, the modified biophysical parameters predicted repolarization shortening.
We present an alternative molecular mechanism for the short QT-interval syndrome. Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1.
Methadone is a synthetic opioid, used both as an analgesic in severe pain relief and now mainly in the treatment of opiate dependence. Such use of the drug has increased as its advantages have become widely recognized. There are undesirable outcomes from its greater use, including a substantial market in diverted methadone and a high number of deaths where the drug has been implicated. It is important to understand how and why methadone causes death so that such fatalities can be minimized, and to disseminate such information. This paper presents an overview of the chief effects of methadone on the human body, considering its metabolism, drug interactions and tolerance. The principal mechanisms by which methadone causes death are discussed: respiratory depression, aspiration of vomit, pulmonary oedema, bronchopneumonia, cardiac problems and renal failure. Many such deaths are preventable, if drug interactions and polydrug use are avoided, its longer period of metabolism and individuals' tolerance levels are considered. It is hoped that this paper will (a) help guide health professionals in their management and treatment of patients participating in methadone treatment programmes, and (b) provide some basic information for those dealing with individuals who have consumed methadone.
This article reviews the literature pertaining to the metabolism of several of the commonly used opioids, and the known activity of their metabolites. The effect of renal failure on the pharmacokinetics of these drugs and metabolites is then reviewed. Finally, the effect of renal dialysis on opioid drugs and metabolites is reviewed. Based on the review, it is recommended that morphine and codeine are avoided in renal failure/dialysis patients; hydromorphone or oxycodone are used with caution and close monitoring; and that methadone and fentanyl/sufentanil appear to be safe to use. Note is made that the "safe" drugs in renal failure are also the least dialyzable.
The principal aim of this study was to assess the efficacy of quinidine in suppressing IKr in vitro and in modulating the rate dependence of the QT interval in the "SQT1" form of the short QT syndrome.
Graded-intensity bicycle exercise testing was performed off drug in three patients and during oral quinidine in two patients with short QT syndrome and compared to a control group of healthy normal subjects. The in vitro effects of quinidine on currents in patch clamp technique were investigated. Off drugs QTpV3/heart rate correlation is much weaker in patients with short QT syndrome, and QTpV3 shortens less with heart rate increase compared to normal subjects. In addition to prolonging the QT interval into the normal range, quinidine restored the heart rate dependence of the QT interval toward a range of adaptation reported for normal subjects. Data from heterologous expression of wild-type and mutant HERG genes indicate the mutation causes a 20-fold increase in IC50 of d-sotalol but only a 5.8-fold increase in IC50 of quinidine.
Oral quinidine is effective in suppressing the gain of function in IKr responsible for some cases of short QT syndrome with a mutation in HERG and thus restoring normal rate dependence of the QT interval and rendering ventricular tachycardia/ventricular fibrillation noninducible.
Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (I(Kr)) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I(Ks)) channel. Here we identify a new variant, "SQT3", which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I(K1) than the wild-type (P<0.05) at potentials between -75 mV and -45 mV, with the peak current being shifted in the former with respect to the latter (WT, -75 mV; D172N, -65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I(K1) greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients' consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.
Methadone is a synthetic opioid with potent analgesic effects. Although it is associated commonly with the treatment of opioid addiction, it may be prescribed by licensed family physicians for analgesia. Methadone's unique pharmacokinetics and pharmacodynamics make it a valuable option in the management of cancer pain and other chronic pain, including neuropathic pain states. It may be an appropriate replacement for opioids when side effects have limited further dosage escalation. Metabolism of and response to methadone varies with each patient. Transition to methadone and dosage titration should be completed slowly and with frequent monitoring. Conversion should be based on the current daily oral morphine equivalent dosage. After starting methadone therapy or increasing the dosage, systemic toxicity may not become apparent for several days. Some medications alter the absorption or metabolism of methadone, and their concurrent use may require dosing adjustments. Methadone is less expensive than other sustained-release opioid formulations.
We have evaluated the ability of various opioid agonists, including methadone, L-alpha-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K(+) current (I(HERG)) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I(HERG), with IC(50) values in the 1 to 10 microM range. The other drugs tested were far less potent with respect to I(HERG) inhibition. Compared with the reported maximal plasma concentration (C(max)) after administration of therapeutic doses of these drugs, the ratio of IC(50)/C(max) was highest for codeine and morphine (>455 and >400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I(HERG). In contrast, the lowest ratios of IC(50)/C(max) were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I(HERG) was rapid, with steady-state inhibition achieved within 1 s when applied at its IC(50) concentration (10 microM) for I(HERG) block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although approximately 10% of the available HERG K(+) channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I(HERG) in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.
This topical review addresses methadone's pharmacology, its application in malignant and non-malignant pain conditions, practical issues related to methadone for the treatment of pain and its influence on QTc time.
Relevant papers were identified in PubMed and EMBASE.
Methadone is advocated by experts as a second line opioid when first line opioids fail to provide a satisfactory balance between pain control and side effects (opioid switching). Although randomized-controlled studies are lacking, current evidence suggests that switching to methadone in this situation reduces pain intensity. However, interindividual variability in its pharmacokinetics make its application challenging and metabolism by CYP 3A4 and 2B6 implies a substantial risk of drug-drug interactions. Several ways of switching to methadone have been presented, with a gradual switch during 3 days or 'stop and go' as the dominating strategies. Episodes of torsade de pointes arrhythmia during methadone treatment have been reported in patients with other risk factors for arrhythmia, while small prospective studies have reported a small, lasting and stable increase in QTc time. The extensive use of methadone for opioid replacement in addicts has added additional patient barriers to its use for pain control.
In spite of challenges related to the variable pharmacokinetics and concerns regarding increase in QTc time, current evidence indicates that opioid switching to methadone improves pain control in a substantial proportion of patients who are candidates for opioid switching. Measures must be instituted to secure that patients receiving methadone for pain are not considered opioid addicts.
Case presentation: A previously healthy 20-year-old man arrives at the emergency department for a consultation for mild fever. During his initial interview, he complains of palpitations to the triage nurse and therefore he undergoes an ECG, which is placed in the chart. A few minutes later, while awaiting his turn to be seen, he goes into cardiac arrest. The patient does not respond to resuscitation and dies in the emergency department. The autopsy reveals no cardiac structural abnormalities or evidence of myocarditis. The cause of death is determined as sudden unexplained cardiac death. The ECG from the emergency department revealed ST-segment elevation in the right precordial leads consistent with a Brugada ECG pattern.
The Brugada syndrome is a heterogeneous genetic disease that predisposes to life-threatening ventricular tachyarrhythmias and sudden cardiac death (SCD). The syndrome is usually identified by a characteristic Brugada-type ECG that consists of ST elevation of a coved type in the precordial leads V1 to V3, although affected individuals may have a normal ECG.1,2 Because patients with Brugada syndrome usually become symptomatic at a relatively young age, early diagnosis is crucial to prevent SCD in those with a higher risk of developing an arrhythmic event.3
Approximately one fourth of the cases of Brugada syndrome are caused by loss of function mutations in the cardiac sodium channel SCN5A. Several nongenetic factors have been mentioned in the literature as possible inductors of the ECG pattern resembling Brugada syndrome.2 As such, a Brugada-type ECG may appear in some patients during febrile states …
come back from the dead? Addiction
- Jh Jaffe
- Laam Can
Jaffe JH. Can LAAM, like Lazarus, come back from the dead? Addiction.
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Opioid switching to improve pain relief and drug tolerability. The Cochrane database of systematic reviews
- C Quigley
Quigley C. Opioid switching to improve pain relief and drug tolerability.
The Cochrane database of systematic reviews. 2004; CD004847.
Increase in death due to methadone in North Carolina
- M F Ballesteros
- D S Dudnitz
- C P Sanford
- J Gilchrist
- G A Agyekum
- J Butts
Ballesteros MF, Dudnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J.
Increase in death due to methadone in North Carolina. JAMA. 2003;290:40-5.