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Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: A mortality assessment study
Abstract
To determine the prevalence of corrected QT interval (QTc) prolongation among patients in opioid maintenance treatment (OMT) and to investigate mortality potentially attributable to QTc prolongation in the Norwegian OMT programme.
Two hundred OMT patients in Oslo were recruited to the QTc assessment study between October 2006 and August 2007. The Norwegian register of all patients receiving OMT in Norway (January 1997-December 2003) and the national death certificate register were used to assess mortality. Mortality records were examined for the 90 deaths that had occurred among 2382 patients with 6450 total years in OMT.
The QTc interval was assessed by electrocardiography (ECG). All ECGs were examined by the same cardiologist, who was blind to patient history and medication. Mortality was calculated by cross-matching the OMT register and the national death certificate register: deaths that were possibly attributable to QTc prolongation were divided by the number of patient-years in OMT.
In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% (n = 8) had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine (n = 27) had QTc results <450 milliseconds. A positive dose-dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. OMT patient mortality, where QTc prolongation could not be excluded as the cause of death, was 0.06/100 patient-years. Only one death among 3850 OMT initiations occurred within the first month of treatment.
Of the methadone patients, 4.6% had QTc intervals above 500 milliseconds. The maximum mortality attributable to QTc prolongation was low: 0.06 per 100 patient-years.
... The most often used reference values for QTc were the ones proposed by the Committee for Proprietary Medicinal Products (CPMP) (14). Nevertheless, many authors used different reference values (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), which made it impossible to produce comprehensive results using the given data. Some authors preferred to measure QTc prolongation as an absolute increase in QTc. ...
... Another cross-sectional study followed patients on medication treatment for addiction with the aim to define the prevalence of QTc prolongation. This study collected data from a registry of all patients on medication treatment for addiction in Norway from 1997 to 2003 for the purpose of discovering mortality that was potentially caused by therapy (28). The cross-sectional study involved 173 patients treated with methadone, and among them, 4.6% (n = 8) had a QTc interval above 500 milliseconds, 15% (n = 26) had a QTc interval above 470 milliseconds, and 28.9% (n = 50) had a QTc interval above 450 milliseconds. ...
... Even though TdP appeared only among patients with QTc values significantly over the threshold known to be high risk for developing TdP, all of these patients also had 2 or more risk factors (31)(32)(33). The most often present risk factors in our research were dose of methadone (23,25,27,28,29,30), co-medication (22,23,27,30 ), and co-morbidity (22,23,27), but also present were gender (23,24,28), age (23,28), misuse of illicit drugs (25,29), therapy length (28,29), and tobacco use (27). ...
Th is paper aimed to collect and unite facts known about the eff ect of methadone treatment on QTc interval prolonga-tion that could determine precipitating factors in the development of heart arrhythmias and their consequences (Tors-ade de Pointes and sudden cardiac death), and to raise the methadone treatment safety level. Studies conducted up to now clearly demonstrate that meth-adone therapy evokes changes in the heart's electrical conduction, but those studies also show that QTc interval prolongation could be precipitated by other factors. Th e most often present risk factors in our research were dose of methadone, co-medication, and co-morbidity, but other relevant risk factors were gender, age, misuse of illicit drugs, therapy length and tobacco use. Active participation in modern treatment processes and implementation of knowledge acquired recently into daily practice, such as setting up reutilized questionnaires and diagnostic methods to expose higher risk for complications and providing broader therapeutic range for cases of drug replacement necessity, will enhance therapy safety level and bring us to the next step of resocialization of these patients, which needs to remain the fi nal goal of treatment.
SAŽETAK Cilj ovog preglednog članka je da prikupi i objedini do sada poznate činjenice, o efektima metadonske tera-pije na produženje QTc intervala, koje mogu da ukažu na predisponirajuće faktore za nastanak srčanih aritmija i nji-hovih posledica (Torsade de Pointes, iznenadna srčana smrt) kao i da unaprede sigurnost prilikom upotrebe ove terapije. Studije sprovedene do sada defi nitivno pokazuju da tera-pija metadonom izaziva promene u električnoj provodlji-vosti srca, ali i da produženje QTc intervala može da bude uslovljeno i drugim faktorima. U najčešće faktore rizika se ubrajaju doza metadona, udružena terapija, ko-morbiditet, pol, starost, zloupotreba ilegalnih droga, dužina terapije i konzumiranje duvana. Aktivno učešće u modernim terapi-jskim procedurama i uključivanje do sada stečenih znanja u rutinsku praksu (putem uvodjenja upitnika i dijagnostičkih metoda) radi utvrđivanja rizika za nastanak komplikacija i obezbedjivanja šireg terapeutskog spectra, će podići nivo sig-urnosti prilikom upotrebe lekova i dovesti nas do sledećeg koraka-resocijalizacije pacijenata, što treba da ostane kra-jnji cilj terapije. Ključne reči: terapija metadonom, produženje QTc in-tervala, Torsade de Pointes, iznenadna srčana smrt
... The benchmark response (BMR) was defined as a 10% change compared to the control. For the QTc, an effect of 10% change over the population baseline of 407 ms, amounting to a QTc of 450 ms is frequently used as a threshold for abnormal QTc prolongation (Anchersen et al. 2009;Chou et al. 2014;ICH 2005b;Mujtaba et al. 2013;Treece et al. 2018). The BMD values resulting in a BMR of 10% with lower and upper 95% confidence limit were defined as BMDL 10 and BMDU 10 . ...
... The predicted BMDL 10 values for methadone-induced cardiotoxicity based on high f u,p values of 0.22 and 0.15 are 1.7-and 2.4-fold higher, respectively, than the recommended initial dose for opioid-native patients (10 mg/day), and the predicted BMDL 10 values based on low f u,p values of 0.055 and 0.034 are 2.2-and 3.6-fold higher, respectively, than the recommended initial dose for opioid users (30 mg/day) (Chou et al. 2014;BCCSU 2017). This indicated that these therapeutic dose levels are below the dose levels predicted to result in 10% change, an effect size that can be used as a threshold to evaluate abnormal QTc prolongation (Anchersen et al. 2009;Chou et al. 2014;ICH 2005b;Mujtaba et al. 2013;Treece et al. 2018). The maintenance dose of 60-120 mg methadone/day (Chou et al. (Esses et al. 2008;Fredheim et al. 2006;Krantz et al. 2002) and other studies as follows: Bart et al. (2017) Table S1 and S2 (color figure online) Fig. 9 Comparison of BMDL values derived from the predicted dose-response curves for human cardiotoxicity of methadone presented in Fig. 8 (lines) and therapeutic dose levels reported in the literature (boxes filled with horizontal lines) 2014; BCCSU 2017) is, however, 0.6-to 7.2-fold higher than the predicted BMDL 10 values in all scenarios, pointing at a potential cardiotoxic effect in especially individuals with relatively lower plasma protein binding (higher f u,p ). ...
... The BMDL 10 values appeared to overlap with the therapeutic dose levels. Given the fact that a BMDL 10 value is generally considered a dose level that is comparable to a no observed adverse effect level (EFSA 2017), and 10% effect is an effect size used as a threshold to evaluate abnormal QTc prolongation (Anchersen et al. 2009;Chou et al. 2014;ICH 2005b;Mujtaba et al. 2013;Treece et al. 2018), doses lower than the predicted BMDL 10 values would be expected to be without an effect on QTc prolongation, which is in line with the observation that the predicted BMDL 10 values based on high f u,p values and low f u,p values are twoto threefold higher than the recommended initial dose for opioid-native patients (10 mg/day) and opioid users (30 mg/ day), respectively (Chou et al. 2014;BCCSU 2017). The fact that the BMDL 10 values obtained with the relatively higher f u,p values are 2.5-to sevenfold lower than the maintenance dose (60 mg/day), may explain the QTc prolongation observed in some methadone maintenance treatment patients given these therapeutic maintenance dose levels. ...
Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.
... Different studies exploring QT interval prolongation have either demonstrated dose dependence [26] or not demonstrated [19,27] a dose response relationship with methadone doses. Previous studies comparing methadone and buprenorphine have found that methadone prolongs the QT but not buprenorphine [16][17][18]28]. Despite this, buprenorphine is on the list of QT drugs at crediblemeds.org ...
... Measurement of the QT interval also varies significantly between previous studies, with some only measuring one lead [28], and others measuring multiple leads but taking the longest, rather than the median measurement of the QT interval [18]. Decades of research into the measurement of the QT interval in the assessment of drug induced QT intervals, recommends using multiple leads and taking the median [36,37]. ...
... Our study supports previous studies of buprenorphine that did not report QT prolongation. A small number of studies directly compared QT interval prolongation in patients prescribed methadone and buprenorphine [16][17][18]28]. A Norwegian study found that 26/173 (15%) patients on methadone had a QTc > 470 ms and eight (4.6%) at QTc > 500 ms, while none in the buprenorphine group had an abnormal QTc [28]. ...
Background:
Methadone is a widely used opioid agonist treatment associated with QT prolongation and torsades des pointes. We investigated the QT interval in patients treated with methadone or buprenorphine using continuous 12-lead holter recordings.
Methods:
We prospectively recorded 24 h holters in patients prescribed methadone or buprenorphine, compared to controls. After their normal dose a continuous 12-lead holter recorder was attached for 24 h. Digital electrocardiograms were extracted hourly from the holter recordings. The QT interval was measured automatically (H-scribe software, Mortara Pty Ltd) and checked manually. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine abnormality. Demographics, dosing, medical history and laboratory investigations were recorded.
Results:
There were 58 patients (methadone[19], buprenorphine[20], control[19]); median age 35y (20-56y); 33 males. Baseline characteristics were similar. Median dose of methadone was 110 mg/d (70-170 mg/d) and buprenorphine was 16 mg/d (12-32 mg/d). Seven participants had abnormal QT intervals. There was a significant difference in the proportion prescribed methadone with abnormal QT intervals, 7/19 (37%;95%CI:17-61%), compared to controls 0/19 (0%;95%CI:0-21%;p = 0.008), but no difference between buprenorphine and controls (0/20). QT versus HR plots showed patients prescribed methadone had higher QT-HR pairs over 24 h compared to controls. There was no difference in dose for patients prescribed methadone with abnormal QT intervals and those without.
Conclusions:
Methadone is associated with prolonged QT intervals, but there was no association with dose. Buprenorphine did not prolong the QT interval. 24 h holter recordings using the QT nomogram is a feasible method to assess the QT interval in patients prescribed methadone.
... Methadone, a synthetic µ-opioid receptor agonist that is widely used in the treatment of heroin dependence and chronic pain, has been associated with drug-induced prolongation of the heart rate-corrected QT interval (QTc) leading to torsades de pointes (TdP) ventricular tachycardia and sudden death in susceptible patients [1][2][3][4][5][6][7][8][9]. In patchclamp experiments, methadone has been shown to block the I Kr current encoded by the human ether-a-go-go related gene (HERG) at clinically relevant concentrations [10], thereby providing a plausible mechanism for QTc prolongation and malignant ventricular tachyarrhythmias observed in susceptible patients taking methadone. ...
... We have previously shown a significant dose-dependent interaction between methadone and QTc in individuals receiving a lower median methadone dose of 40 mg/day (interquartile range: 30-60 mg/day) [27]. For patients receiving a higher daily methadone dose of 100 mg or greater, most previous studies also reported a positive correlation between methadone dose and QTc interval [4][5][6]9,28]. All of these findings indicate a significant association between methadone and QTc interval across a wide therapeutic range of methadone doses among different ethnic populations. Clinically, a QTc interval of ≥500 ms is indicative of a high risk for TdP ventricular tachycardia and sudden death [29,30], which was observed in 2-16% of patients who received methadone at median doses of ≥100 mg/day [4][5][6]. ...
Background: The effects of methadone-induced severe prolongation of the corrected QT interval (QTc) and sudden cardiac death appear unpredictable and sex-dependent. Genetic polymorphisms in the nitric oxide synthase 1 adaptor protein (NOS1AP) have been implicated in QTc prolongation in general populations. We investigated whether common NOS1AP variants interact with methadone in relation to QTc prolongation in patients with heroin dependence. Methods: We genotyped 17 NOS1AP variants spanning the entire gene in heroin-dependent patients who received a 12-lead electrocardiography (ECG) examination both at baseline and during maintenance methadone treatment in Cohort 1 and only during maintenance methadone treatment in Cohort 2. The QT interval was measured automatically by the Marquette 12SL program, and was corrected for heart rate using Bazett’s formula. Results: Cohort 1 consisted of 122 patients (age: 37.65 ± 8.05 years, 84% male, methadone dosage: 42.54 ± 22.17 mg/day), and Cohort 2 comprised of 319 patients (age: 36.9 ± 7.86 years, 82% male, methadone dosage: 26.08 ± 15.84 mg/day), with complete genotyping data for analyses. Before methadone, the QTc intervals increased with increasing age (r = 0.3541, p < 0.001); the age-adjusted QTc showed dose-dependent prolongation in men (r = 0.6320, p < 0.001), but abbreviation in women (r = −0.5348, p = 0.018) in Cohort 1. The pooled genotype-specific analysis of the two cohorts revealed that the QTc interval was significantly shorter in male carriers of the rs164148 AA variant than in male carriers of the reference GG genotype (GG: n = 262, QTc = 423 ± 1.4 ms; AA: n = 10, QTc = 404.1 ± 7 ms, p = 0.009), according to univariate analysis. The QTc remained shorter in male carriers of the rs164148 AA variant compared to GG genotype (423 ± 1.4 ms vs. 405.9 ± 6.9 ms, p = 0.016) in multivariate analysis after adjusting for age and methadone dosage. A cut-off QTc interval of
... In particular, investigating potential effect of opioid agents in causing QT interval prolongation has been of great interest, as it may induce TdP and sudden death. 15 QT interval prolongation has been documented during the administration of methadone, [34][35][36] buprenorphine, 34,37 levomethadyl, 34 oxycodone, 38 and tramadol. 39 Morphine is a less investigated opioid analgesic in this regard. ...
... Methadone contrary to opium might have had a cumulative dose effect on QT interval. 36 Raw opium is a mixture of non-alkaloidal constituents and more than 40 individual alkaloids. 7 Different substances and drugs are added to opium before introducing into the illegal market. ...
Background:
Toxicity and side effects of long-term use of opioids are well studied, but little information exists regarding electrophysiological disturbances of opium consumption. While natural opium has been regarded safe to a great extent among traditional communities, concerns are emerging owing to the available evidence of QT prolongation that have been exposed during recent outcome surveillance of patients under opioid use. Potential QT prolonging interactions would raise a higher level of such concern in opium users during COVID pandemic and warrant attention.
Materials and methods:
This study was designed to detect the prevalence of QTc prolongation among opium users and nonusers. Two groups were compared with regard to gender, age, and median QTc interval. Normal and prolonged QTc intervals of user group were compared with respect to age, sex, dose of opium consumption, and duration of opium consumption.
Results:
123 opium users and 39 controls were investigated. Median QTc interval in opium user and non-user group was 460 vs 386 milliseconds, respectively (p value < 0.001). In all, 59.3%, (95% CI: 50.51-67.62%) of cases and none of non-user had prolonged QTc interval (p value < 0.001). There was no significance between normal and prolonged QTc intervals with respect to dose and duration of opium use.
Conclusion:
This study indicated that opium consumption is associated with QTc prolongation. This prolongation does not relate to dose and duration of opium use. Further study is propounded to assess the clinical significance of these results and to determine risk rating of opium compared to other opioids in this regard.
How to cite this article:
Javadi HR, Mirakbari SM, Allami A, Yazdi Z, Katebi K. Opium-associated QT Interval Prolongation: A Cross-sectional Comparative Study. Indian J Crit Care Med 2021;25(1):43-47.
... Previously, QTc interval prolongation and TdP cases have also been described among opioid dependent patients receiving MMT [9][10][11][12][13][14][15][16][17][18][19] . However, the prevalence of QTc interval prolongation among subjects in opioid maintenance treatment varied between studies. ...
... Although several studies on the prevalence of the QTc interval pro- longation in patients receiving MMT have been previously pub- lished [14][15][16][17][18] , data on the QTc interval among opioid naive individuals were not reported in their studies. Our current study is important because it identify the QTc interval in patients on MMT in comparison with the data from sample of opioid naive individuals, which has largely been unstudied. ...
Objective: This study investigated QTc interval among opioid dependent patients on MMT in comparison with opioid naive individuals. Design: This was a cross-sectional observational study conducted at the Clinical Trial Unit (CTU), Hospital USM, Kota Bharu, Kelantan, Malaysia. Materials and Methods: Patients were on the national MMT programme at the MMT clinics in Kelantan, Malaysia. Control subjects were comprised of opioid naive individuals. All participants underwent 12-lead electrocardiogram (ECG). Results: Of the 145 patients who had satisfactory ECG recordings, 29 (20%) had QTc interval prolongation > 450 milliseconds. Four (2.8%) opioid naive individuals had a prolonged QTc interval. No participant had QTc interval > 500 milliseconds. Patients had significantly longer QT and QTc interval compared to opioid naive individuals (p < 0.001). Number of patients with QTc interval prolongation > 450 milliseconds was significantly higher compared to opioid naive individuals (p < 0.001). Conclusion: The results demonstrate clinical evidence of significant longer QTc interval in opioid dependent patients on MMT compared to opioid naive individuals. QTc interval prolongations also occurred in a significant proportion of patients. Methadone therapy may cause QTc interval prolongations and appropriate clinical management measures should be considered to address this challenge.
... Regarding the effect of different doses of buprenorphine, in a cross-sectional study on 450 heroin-dependent who were under BMT (43 patients) or MMT (407 patients), the results showed no association between buprenorphine dose and QTc prolongation, and the patients on BMT had neither QT nor QTc prolongation [34]. In another study, 27 patients out of 173 patients on OMT received buprenorphine and none of them had QTc interval more than 450 ms and there was a relationship between buprenorphine dose and QTc interval [35]. Stallvik et al. [36] studied 80 OMT patients of whom 35 received BMT; they obtained the same result; none of the patients had QTc interval more than 450 ms and no association with serum concentration of buprenorphine was seen. ...
... They demonstrated that oral methadone causes a modest QT prolongation, and also a positive correlation between methadone concentration and magnitude of QT interval was noted [65]. Correspondingly another study on 173 patients receiving methadone showed a positive relationship between methadone dose and QTc interval [35]. Fanoe et al. [34] who found no dose-dependent relationship between buprenorphine and QTc interval, as mentioned above, did find a significant correlation between QTc interval and methadone dose. ...
Objective:
One of the most important side effects of opioids is their influence on the electrical activity of the heart. This review focusses on the effects of opioids on QT interval prolongation and their arrhythmogenic liability.
Methods:
By using various keywords, papers published up to 2018 in different databases were searched and identified. The search terms were opioids names, QTc interval, hERG, torsades de pointes (TdP), cardiac arrhythmias, opioid dependence and other relevant terms. It emphasized the effects of each opioid agent alone on electrocardiogram and some interactions.
Results:
Available data indicate that some opioids such as methadone are high-risk even at low doses, and have potential for prolongation of the QT interval and development of TdP, a dangerous ventricular tachycardia. A number of opioids such as tramadol and oxycodone are intermediate risk drugs and may develop long QT interval and TdP in high doses. Some other opioids such as morphine and buprenorphine are low-risk drugs and do not produce QT interval prolongation and Tdp at least in routine doses. Opium-consumers are at higher risk of supra-ventricular arrhythmias, sinus bradycardia, cardiac block and atrial fibrillation.
Conclusion:
The cardiac arrhythmogenicity of various opioids is different. Methadone has a higher capability to induce long QT interval and dangerous arrhythmias in conventional doses than others. To reduce of arrhythmogenic risk, high doses of opioids must be used cautiously with periodic monitoring of electrocardiogram in high-risk consumers such as patients under opioid maintenance treatment.
... 90,100 Risk of cardiac dysfunction was lower for buprenorphine compared with methadone in an RCT (N=110) 107 and in observational studies (N=890). [108][109][110][111][112] One large observational study (N=21 311) suggested a lower risk of hospitalisation among those receiving methadone than among those receiving buprenorphine. 118 We conducted a series of meta-regressions to explore potential reasons for variability across studies on the primary outcomes, and on the percentage of people retained in treatment with buprenorphine (tables 2, 3). ...
Background:
Opioid dependence is associated with substantial health and social burdens, and opioid agonist treatment (OAT) is highly effective in improving multiple outcomes for people who receive this treatment. Methadone and buprenorphine are common medications provided as OAT. We aimed to examine buprenorphine compared with methadone in the treatment of opioid dependence across a wide range of primary and secondary outcomes.
Methods:
We did a systematic review and meta-analysis in accordance with GATHER and PRISMA guidelines. We searched Embase, MEDLINE, CENTRAL, and PsycINFO from database inception to Aug 1, 2022; clinical trial registries and previous relevant Cochrane reviews were also reviewed. We included all RCTs and observational studies of adults (aged ≥18 years) with opioid dependence comparing treatment with buprenorphine or methadone. Primary outcomes were retention in treatment at 1, 3, 6, 12, and 24 months, treatment adherence (measured through doses taken as prescribed, dosing visits attended, and biological measures), or extra-medical opioid use (measured by urinalysis and self-report). Secondary outcomes were use of benzodiazepines, cannabis, cocaine, amphetamines, and alcohol; withdrawal; craving; criminal activity and engagement with the criminal justice system; overdose; mental and physical health; sleep; pain; global functioning; suicidality and self-harm; and adverse events. Single-arm cohort studies and RCTs that collected data on buprenorphine retention alone were also reviewed. Data on study, participant, and treatment characteristics were extracted. Study authors were contacted to obtain additional data when required. Comparative estimates were pooled with use of random-effects meta-analyses. The proportion of individuals retained in treatment across multiple timepoints was pooled for each drug. This study is registered with PROSPERO (CRD42020205109).
Findings:
We identified 32 eligible RCTs (N=5808 participants) and 69 observational studies (N=323 340) comparing buprenorphine and methadone, in addition to 51 RCTs (N=11 644) and 124 observational studies (N=700 035) that reported on treatment retention with buprenorphine. Overall, 61 studies were done in western Europe, 162 in North America, 14 in north Africa and the Middle East, 20 in Australasia, five in southeast Asia, seven in south Asia, two in eastern Europe, three in central Europe, one in east Asia, and one in central Asia. 1 040 827 participants were included in these primary studies; however, gender was only reported for 572 111 participants, of whom 377 991 (66·1%) were male and 194 120 (33·9%) were female. Mean age was 37·1 years (SD 6·0). At timepoints beyond 1 month, retention was better for methadone than for buprenorphine: for example, at 6 months, the pooled effect favoured methadone in RCTs (risk ratio 0·76 [95% CI 0·67-0·85]; I·=74·2%; 16 studies, N=3151) and in observational studies (0·77 [0·68-0·86]; I·=98·5%; 21 studies, N=155 111). Retention was generally higher in RCTs than observational studies. There was no evidence suggesting that adherence to treatment differed with buprenorphine compared with methadone. There was some evidence that extra-medical opioid use was lower in those receiving buprenorphine in RCTs that measured this outcome by urinalysis and reported proportion of positive urine samples (over various time frames; standardised mean difference -0·20 [-0·29 to -0·11]; I·=0·0%; three studies, N=841), but no differences were found when using other measures. Some statistically significant differences were found between buprenorphine and methadone among secondary outcomes. There was evidence of reduced cocaine use, cravings, anxiety, and cardiac dysfunction, as well as increased treatment satisfaction among people receiving buprenorphine compared with methadone; and evidence of reduced hospitalisation and alcohol use in people receiving methadone. These differences in secondary outcomes were based on small numbers of studies (maximum five), and were often not consistent across study types or different measures of the same constructs (eg, cocaine use).
Interpretation:
Evidence from trials and observational studies suggest that treatment retention is better for methadone than for sublingual buprenorphine. Comparative evidence on other outcomes examined showed few statistically significant differences and was generally based on small numbers of studies. These findings highlight the imperative for interventions to improve retention, consideration of client-centred factors (such as client preference) when selecting between methadone and buprenorphine, and harmonisation of data collection and reporting to strengthen future syntheses.
Funding:
Australian National Health and Medical Research Council.
... A sample size of 316 was calculated using the Kish and Leslie formula, N = Z² (P (1-P)/d²), where: N = sample size, Z=Score for 95% Confidence interval, which is 1.96, P=Prevalence of ECG abnormalities in Methadone assisted clinic in a previous study (7), p=29%, d=Marginal error set at 5%. With a 5% contingency, 16 participants were added to make a final sample size of 332. ...
Background
Patients with opioid use disorder are at a higher cardiovascular risk due to the effect of opioids on the cardiovascular system. Cardiac conduction abnormalities, electrical activity impairment, cardiac arrhythmias, and ventricular hypertrophy are reported in the opioid population.
Objective
This study aimed to assess the prevalence and factors associated with ECG abnormalities among adults with opioid use disorder attending the Itega addiction center for methadone-assisted therapy (MAT).
Methodology
A cross-sectional analytical study was conducted among adult outpatients attending the Itega addiction center in Dodoma. A calculated sample size of 321was attained through a convenience sampling approach. A standard 12-lead ECG was recorded for each participant and interpreted by two independent cardiologists. Univariate and multivariable logistic regression was computed to determine the factors associated with ECG abnormalities. Under adjusted analysis, a p-value of less than 0.05 was considered significant for factors associated with ECG abnormalities after controlling for all the variables with a minimum p-value of 0.2 at univariate analysis.
Results
The majority of 308 (95.95%) of the participants were males, 197 (61.37%) had attained primary education level, and the mean age of the participants was 35.44 ± 6.54 years. The overall prevalence for any ECG abnormalities in this study was 26.47%, with Sinus bradycardia 59(18.4%) being the most observed ECG abnormality, followed by QTc prolongation 27(8.41%). A month's increase in the duration on MAT and being a female were significantly associated with lower odds of ECG abnormalities (AOR =0.85, 95% CI =0.74-0.96 p =0.014) and (AOR = 0.05, 95% CI = 0.01-0.59, p = 0.017) respectively.
Conclusion
The high prevalence of ECG Abnormalities implies high cardiovascular risk among a population with opioid use disorder. Given that majority of the ECG abnormalities are treatable, integrating cardiovascular care in the opioid addiction clinic would be beneficial for this population.
... Methadone is a long-acting opioid used primarily as treatment for opioid use disorder (Bell and Strang, 2020). However, methadone maintenance therapy can be complicated by QT interval prolongation in up to 50% of patients (Fanoe et al., 2007;Anchersen et al., 2009;Fareed et al., 2013;Chowdhury et al., 2015;Titus-Lay et al., 2021), with case reports and pharmacovigilance data describing the potential for ensuing Torsade de Pointes and sudden cardiac death (Chugh et al., 2008;Stringer et al., 2009;Kao et al., 2013;Kao et al., 2015). Risk factors for QT interval prolongation and sudden cardiac death are well described, and include older age, female sex, electrolyte abnormalities, and underlying heart disease (Chugh, 2010;Tisdale et al., 2013;Trinkley et al., 2013). ...
Background: Methadone is associated with ventricular dysrhythmias and sudden death. Serotonin reuptake inhibitors (SRIs) may increase the risk of these events either by inhibiting metabolism of methadone’s proarrhythmic (S)-enantiomer, additive QT interval prolongation, or both. We sought to determine whether certain SRIs were associated with a higher risk of methadone-related ventricular dysrhythmias or sudden death.
Methods: We conducted a nested case-control study of Ontario residents receiving methadone between April 1, 1996 and December 31, 2017. Cases, defined as patients who died of sudden cardiac death or were hospitalized with a ventricular dysrhythmia while on methadone, were matched with up to four controls who also received methadone on age, sex, and a disease risk score. We determined the odds ratio (OR) and p -value functions for the association between methadone-related cardiotoxicity and treatment with SRIs known to inhibit metabolism of (S)-methadone (paroxetine, fluvoxamine, sertraline) or prolong the QT interval (citalopram and escitalopram). Patients who were not treated with an SRI served as the reference group.
Results: During the study period, we identified 626 cases and 2,299 matched controls. Following multivariable adjustment, we found that recent use of sertraline, fluvoxamine or paroxetine (adjusted OR 1.30; 95% confidence intervals [CI] 0.90–1.86) and citalopram and escitalopram (adjusted OR 1.26; 95% CI 0.97–1.63) were associated with small increases in the risk methadone-related cardiac toxicity, an assertion supported by the corresponding p -value functions.
Interpretation: Certain SRIs may be associated with a small increase in cardiac toxicity in methadone-treated patients.
... 9,10 Methadone is a full mu-opioid receptor agonist with a long half-life comparable with buprenorphine, which requires a long time to reach steady state resulting in adverse effects such as sedation and respiratory depression, although the toxicity could be seen with single doses. 11 Methadone has dose dependent effect of QT prolongation, 12 which potentially leads to life-threatening arrhythmia. Methadone also possesses N-methyl-D-aspartate receptor antagonist effect, which may mitigate neuropathic pain. ...
Objectives:
Buprenorphine is a partial agonist at mu-opioid receptors and competes for these receptors with other opioids in vitro. Whether patients on buprenorphine maintenance require high doses of opioid analgesics to attain adequate postoperative pain control has not been determined. We evaluated differences in acute postoperative opioid consumption and pain burden between patients taking buprenorphine and those taking methadone preoperatively.
Methods:
Retrospective review of medical records of 928 patients of whom 195 were on buprenorphine and 733 were on methadone preoperatively, was performed. Among methadone and buprenorphine patients, 615 and 89 continued to receive the medications postoperatively. Buprenorphine patients were compared to methadone patients for the first 48-hours postoperatively with regard to acute opioid dose requirements (morphine milligram equivalents (MME) above their baseline buprenorphine and methadone doses) and time-weighted average (TWA) pain scores (using targeted maximum likelihood estimation).
Results:
Opioid dose requirements for 48-hours postoperatively were 150 [22 to 297] (median [interquartile range]) and 220 [90 to 360] MME for buprenorphine and methadone patients respectively. Preoperative buprenorphine was associated with a 59.9% lower postoperative MME (95% CI: 46.6 to 69.8%, P<0.0001) compared with methadone. Postoperative TWA pain scores for the first 48 hours were 5.0±2.7 (mean±standard deviation), and 5.4±2.3 for buprenorphine and methadone patients, respectively. Preoperative buprenorphine was associated with 0.37-point lower TWA pain score (95% CI from 0.14 to 0.61, P=0.0021) compared with methadone.
Discussion:
Preoperative buprenorphine use was associated with more than a 50% reduction in postoperative opioid dose requirement and a statistically significant, though clinically unimportant, reduction in acute pain burden in comparison to methadone. The study is limited by several important factors such as the exclusion of patients requiring intravenous patient controlled analgesia, small number of patients were on higher dose of buprenorphine, and a large percentage of methadone patients were not on stable dose of methadone yet.
... Most studies have demonstrated a dose-dependent association between MTD and QTP [47][48][49][50]; however, some studies were inconclusive [51,52]. ...
Background/Purpose
Mortality associated with prescription opioids has significantly increased over the past few decades and is considered a global pandemic. Prescribed opioids can cause cardiac arrhythmias, leading to fatal outcomes and unexpected death, even in the absence of structural cardiac disease. Despite the extent of cardiac toxicity and death associated with these medications, there is limited data to suggest their influences on cardiac electrophysiology and arrhythmias, with the exception of methadone. The goal of our review is to describe the possible mechanisms and to review the different ECG changes and arrhythmias that have been reported.
Methods
A literature search was performed using Google Scholar, PubMed, Springer, Ovid, and Science Direct to identify studies that demonstrated the use of prescription opioids leading to electrocardiogram (ECG) changes and cardiac arrhythmias.
Results
Many of the commonly prescribed opioid medications can uniquely effect the ECG, and can lead to the development of various cardiac arrhythmias. One of the most significant side effects of these drugs is QTc interval prolongation, especially when administered to patients with a baseline risk for QTc prolongation. A prolonged QTc interval can cause lethal torsades de pointes and ventricular fibrillation. Obtaining an ECG at baseline, following a dosage increase, or after switching an opioid medication, is appropriate in patients taking certain prescribed opioids. Opioids are often used first line for the treatment of acute and chronic pain, procedural sedation, medication opioid use disorders, and maintenance therapy.
Conclusions
To reduce the risk of cardiac arrhythmias and to improve patient outcomes, consideration of accurate patient selection, concomitant medications, electrolyte monitoring, and vigilant ECG monitoring should be considered.
... The methadone formulations available in Canada are racemic mixtures with propensity to increase corrected QT interval (QTc) in a dose-dependent fashion. 4 It has been shown that the (S)-enantiomer of methadone (dextromethadone) is the cause of this dose-related adverse effect. 5 Prolongation of the QTc interval is a marker of the impending possibility of torsade des pointes and sudden death. ...
... 33 Research evidence indicates that the risk of QTc prolongation is less with buprenorphine than it is with methadone, making it a better choice for patients with co-occurring cardiac conditions. [39][40][41] The coadministration of buprenorphine with sedative medications or central nervous system depressants such as alcohol or benzodiazepines can compound its depressant effects, worsening respiratory depression. 42 In addition, the administration of buprenorphine in the presence of other opioids can cause severe precipitated withdrawal symptoms owing to the higher affinity for receptors of buprenorphine compared with other opioids. ...
Opioid use disorder is a critical public health problem that continues to broaden in scope, adversely affecting millions of people worldwide. Significant efforts have been made to expand access to medication therapy for opioid use disorder, in particular buprenorphine. As the emergency department is a critical point of access for many patients with opioid use disorder, the initiation of buprenorphine therapy in the emergency department is increasing, and emergency nurses should be familiar with the care of these vulnerable patients. The purpose of this article is to provide a clinical review of opioid use disorder and opioid withdrawal syndrome, medication treatments for opioid use disorder, best clinical practices for ED-initiated buprenorphine therapy, assessment of withdrawal symptoms, discharge considerations, and concerns for special populations. With expanded understanding of opioid use disorder, withdrawal, and available treatments, emergency nurses will be better prepared to deliver and support life-saving treatments for patients and families suffering from this disease. In addition, emergency nurses are well positioned to play an important role in public health advocacy around opioid use disorder, providing critical support for destigmatization and expanded access to safe and efficacious treatments.
... Some studies noted a dose-dependent increase in QTc with transdermal buprenorphine, but it has not been associated with proarrhythmic effects. [4][5][6] However, despite these advantages, methadone treatment is associated with higher retention rates than buprenorphine, at least in part due to the prerequisite for mild to moderate withdrawal prior to induction and the risk of precipitated withdrawal. 7,8 Sublingual (SL) buprenorphine is an FDA-approved treatment for OUD. ...
Background and objectives:
Buprenorphine's high-binding affinity as a partial µ-opioid agonist displaces preexisting full agonists causing precipitated withdrawal, which requires most individuals starting buprenorphine to endure moderate withdrawal prior to induction to avoid precipitated withdrawal. A novel approach called microinduction has emerged to remove this prerequisite. Our aim is to review the literature on these alternative approaches.
Methods:
Using keywords including buprenorphine, buprenorphine/naloxone, transdermal buprenorphine, suboxone, microinduction, microdosing, rapid induction, buprenorphine-dosing protocol, the authors searched PubMed/Medline, EMBASE, PsycINFO, PsychARTICLES, and Scopus databases from the date of inception through April 30, 2020, which yielded 1726 results, which, in turn, after manual exclusion for irrelevant content and publication in languages other than English, generated a total of 18 papers.
Results:
On the basis of 18 papers included in this review, 63 patients were successfully transitioned to buprenorphine using different microdosing techniques, primarily in the inpatient setting. From the available data, patients were transitioned from a variety of opioids over a range of dosing without significant withdrawal, and initial doses ranged most frequently from 0.2 to 0.5 mg. While the timeframe for the various schedules ranged from 3 to 112 days, most transitioned over a period of 4 to 8 days, and most participants completed the cross titration at 8 to 16 mg.
Discussion and conclusions:
The growing literature demonstrates some initial promise for alternative induction models, specifically targeting patients averse to withdrawal, patients prescribed opioids for chronic pain, patients on high-dose methadone, and patients using illicit or pharmaceutical fentanyl.
Scientific significance:
This manuscript provides a review of the existing literature to help clinicians better understand the approaches to microdosing of buprenorphine in various clinical settings and populations. (Am J Addict 2020;00:00-00).
... Several prospective studies, crosssectional studies, and retrospective reviews have reported QTc prolongation with methadone. [7][8][9][10][11][12][13][14] Many cases of QTc prolongation and TdP have been in patients receiving methadone in large doses (> 100 mg/d); however, incidences have also occurred in those receiving typical doses of methadone for addiction treatment. 8,15,16 Multiple studies have demonstrated that methadone-induced QTc prolongation is dose-dependent. ...
Understanding the effects of methadone on the QTc interval in a veteran patient population using the drug at lower doses for pain may help clinicians develop strategies and protocols for safe use.
... On the contrary, Acherson in 2009 did find an association between methadone dose and QTc prolongation and they concluded that doses 9 120 mg/day would increase the QTcF (Fridericia rate-corrected QT) by 9 20 ms. [23] Other studies have shown similar dose-dependent results. Because of this side effect, one must obtain an EKG prior to initiation of methadone as well as periodically throughout treatment. ...
Purpose of Review
With the increasing age of those born between 1946 and 1965, issues relating to the “baby boomer” generation are more relevant than ever. This review aims to both highlight the importance of screening for substance use disorders in the elderly (specifically in this case, opioid use disorder) and then summarize the available treatment options for this vulnerable population.
Recent Findings
A narrative review of the literature showed surprisingly little research on the treatment of substance use disorders, especially opioid use disorder, in the elderly. None of the three medications that are FDA approved for opioid use disorder in adults (methadone, buprenorphine, and naltrexone) is contraindicated in the elderly. All medications should be used cautiously, keeping in mind that the elderly often have more medical issues (which can include chronic pain) as well as are on multiple medications that can lead to medication interactions.
Summary
Because there is very limited data on treatment of opioid use disorder in later life, current treatment generally follows recommendations for the general/mixed age population. More research into the topic is needed, especially with a larger percentage of the “baby boomer” generation entering the 65+ age range.
... Most of the studies have compared the impact of maintenance therapy with buprenorphine on the QTc interval between methadone and buprenorphine. In the Anchersen study, 29% of the 173 patients, who were treated with methadone, had QTc > 450 msec and 15% had QTc > 470 msec; however, none of the patients treated with buprenorphine had QTc > 450 msec (19). In another study, Sabrina has exclusively investigated the effect of buprenorphine on QTc interval and calculated QTc changes in the follow-up ECG compared to baseline ECG. ...
Background : Methadone, buprenorphine, and opium tincture are effective in the treatment of opioid dependency. Currently, in Iran, these three drugs are used in the maintenance therapy program of opioids. On the other word, there are concerns about the incidence of secondary torsade de point (TdP) arrhythmia caused by the prolonged drug-dependent QTc interval. This cross-sectional study has been designed to evaluate and compare the effects of these three maintenance therapies on the QTc interval.
Methods : The study population included 110 patients (85% male with the mean age of 51.66±13.34) who participated in an opioid maintenance therapy program for at least 6 months. These patients were assigned to three groups of maintenance therapy with methadone (n = 50), buprenorphine (n = 30) and opium tincture (n = 30). For each patient, a 12-lead ECG was acquired and interpreted. The QT interval was corrected based on the QTc = QT + 1/75 (heart rate - 60) formula.
Results : The mean QTc interval was 408.51 ± 25.88 msec in the maintenance therapy group with methadone, 405.58 ± 20.8 msec with buprenorphine and 406.31 ± 16.9 with opium tincture. There was no significant difference between the three groups (P = 0.83). There was only one case with QTc more than 500 msec (511.25 msec) in the maintenance therapy group with methadone.
Conclusions : Methadone, buprenorphine and opium tincture are safe drugs in terms of prolonging the QTc interval and are suitable candidates for maintenance therapy of opioid.
... Despite there have been anecdotal reports of moderate QTc prolongation associated with Buprenorphine, which might become relevant when Buprenorphine is used in a combination with other QTc-prolonging drugs or in individuals with pre-existing long-QT-syndromes, systematic studies have not found clinically relevant QTc-prolongation among patient receiving Buprenorphine as opioid substitution therapy. (Katchman, 2002) (Fanoe, 2007) (Anchersen, 2009) (Athanasos, 2008. ...
... 38,39 So far, cross-sectional studies have been conducted to verify the effects of methadone on QT interval prolongation. 40,41 In a study by Wedam et al (2007), the effect of using methadone, levomethadyl, and buprenorphine on the size of QT was compared, and it has been shown that in methadone and levomethadyl users, QT interval increased significantly from 470 to 490 milliseconds. 41 Methadone, by inhibiting the gene associated with ether-a-go-go, causes the prolongation of the QT complex and the development of torsade de point arrhythmias. ...
Objectives:
Opioid poisoning in children is a common pediatric emergency in Iran. The emergence and spread of new synthetic opioids have come up with new consequences in case of toxicity. In this study, we aimed to evaluate electrocardiographic changes in children with acute opiate poisoning.
Methods:
This cross-sectional study was performed on all children with opioid poisoning admitted to the emergency ward of Vali-e-Asr Hospital, Birjand, Iran, from December 2015 to February 2017. Data (demographics, manifestations, clinical course, and outcome) were collected using a predesigned checklist. An electrocardiogram (ECG) was obtained and evaluated for arrhythmias, corrected QT interval (QTc), and other ECG indices. Data were analyzed using SPSS version 21. A value of P less than 0.05 was considered statistically significant.
Results:
A total of 85 children were enrolled in this study. Most of them were male (51.8%). The mean age of the patients was 3.46 ± 3.36 years. Among these children, 38.8% were poisoned with synthetic opioids (methadone). Mean QTc length was 399 ± 24 milliseconds in nonsynthetic opioid poisoning and 407 ± 66 milliseconds in methadone poisoning, and it was prolonged (>450 milliseconds) in 3.5% of cases. Other ECG changes were limited to 1 U wave formation (1.2%) that was detected in a patient with methadone poisoning.
Conclusions:
Electrocardiogram changes due to acute opioid toxicity in children are not common, although in the case of methadone poisoning, long QT interval and associated arrhythmias should be anticipated. Moreover, because of life-threatening effects of opioids such as respiratory insufficiency and decreased consciousness, it is necessary to be prepared for these conditions.
... Some studies have seen an increased risk in overdose death during the induction of treatment [14,[16][17][18][19], indicating that patients are especially vulnerable during periods of treatment transition [18]. In contrast to this, others have observed very low rates of mortality during the first 2 weeks of OMT [11,20]. Differences in observations may be explained by differences in treatment approaches or characteristics of the at risk population, although this has not been sufficiently explored [21]. ...
Background:
As the effect of opioid maintenance treatment (OMT) on overdose mortality varies both between and within countries, treatment programs need to be evaluated in different treatment settings and over time within settings. We evaluated variations in mortality in a national programme: from the initial rollout as restrictive and low-capacity to its gradual change into more liberal and higher-volume.
Methods:
A 12-year prospective longitudinal cohort study including all persons (n = 6871) applying for and entering OMT in Norway (1997-2009). We followed all patients until 2009 or until death. We used crude mortality rates (CMR) to calculate overdose and all-cause mortality among patients in OMT before, during and after treatment, during a 12-year time-period. We also calculated variations in overdose and all-cause mortality over the course of treatment and after treatment termination. We fitted proportional hazards models with covariates to the data.
Results:
OMT significantly reduces risk of mortality compared to being outside of treatment. The reduction in overdose death was most substantial during the initial phase of the Norwegian OMT-programme, still; we consistently find that overdose deaths were more than halved in all calendar-periods throughout observation. We did not find an elevated risk of overdose death in the first weeks of treatment, nor in the first weeks after treatment cessation.
Conclusion:
In Norway, OMT reduces overall mortality. Reduction in mortality is likely dependent of both treatment delivery and characteristics of the at-risk population.
... 16,27,28 (3) In contrast to methadone, buprenorphine had little or no effect on the corrected QT (QTc) interval, even in high doses used in maintenance therapies. 29,30 (4) While chronic use of opioids has been reported to influence the hypothalamic-pituitary-gonadal axis, buprenorphine appeared less likely to suppress the gonadal axis or gonadal hormone levels than other μ-opioid agonists. [31][32][33] (5) When evaluated in a retrospective study involving patients with cancer and non-cancer pain, buprenorphine in transdermal formulation appeared to produce less analgesic tolerance when compared with transdermal fentanyl. ...
Transdermal buprenorphine (TDB) has demonstrated effectiveness in treating a range of chronic pain conditions, including cancer pain, nociceptive pain, and neuropathic pain and has a favorable safety profile. Worldwide, clinical experience of its use is relatively limited. There is considerable misunderstanding about the pharmacology, mechanism of action, and safety of buprenorphine. There is also limited guidance on the appropriate use of TDB for chronic pain management. This article presents an overview of TDB and also provides practical recommendations for its use as part of a multifaceted strategy in chronic cancer and non-cancer pain.
... In addition, harm reduction -such as electrocardiogram-checks, see Anchersen et al. (2009); medication-reviews, such as to reduce coprescription of benzodiazepines with methadone (Hickman et al., 2018;Pierce et al., 2015b); and moderated alcohol intake -should be prioritized not only to reduce clients' risk of major causes of non-DRDs but to help identify older clients whose methadone-dose may need to be reduced to below 100 mg/day or for whom a switch to buprenorphine may be considered. ...
Background
Opioid drug use is a major cause of premature mortality, with opioid substitution therapy the leading intervention. As methadone-clients age, non-drug-related deaths (non-DRDs) predominate and DRD-risks increase differentially, quadrupling at 45+ years for methadone-specific DRDs.
Methods
36,606 methadone-prescription-clients in Scotland during 2009–2015 were linked to mortality records to end-2015 by their Community Health Index (CHI). Cohort-entry, also baseline quantity of prescribed methadone, were defined by clients’ first CHI-identified methadone-prescription during 2009–2015. National Records of Scotland identified non-DRDs from DRDs; and provided ICD10 codes for underlying and co-present causes of death. Methadone-specific DRD means methadone was implicated in DRD but neither heroin nor buprenorphine.
Results
During 193,800 person-years of follow-up, 1939 non-DRDs (59%) and 1323 DRDs occurred, of which 546 were methadone-specific. Predominant underlying ICD10 chapters for non-DRDs were: neoplasm (377); external causes (341); diseases of digestive (303), circulatory (286) or respiratory (212) system. As methadone-clients aged, the non-DRD proportion of their deaths increased from 54% (717/1318) at 35–44 years to 89% (372/417) at 55+ years.
After allowing for DRDs’ opioid-specificity, age-group and quintile for last-prescribed methadone, there was a significant, positive interaction for co-present circulatory disease between top-quintile for prescribed methadone and 45+ years at death (p = 0.033 after Bonferroni); not for digestive or respiratory co-presence.
Conclusions
Circulatory disease is the co-morbidity most likely implicated in the quadrupling of methadone-specific DRD-risk at 45+ years; followed by digestive disease. Cultural shift is needed in treatment-services because degenerative non-DRDs predominate as methadone-clients age. Future linkage-studies should access hospitalizations and methadone-daily-dose.
... Though relatively safe, buprenorphine should be used cautiously with other QT prolonging medications such as fluoroquinolones (moxifloxacin), macrolides, antipsychotics, tricyclic antidepressants, and selective serotonin receptor antagonists (SSRIs). Evidence has demonstrated the QT prolongation in buprenorphine is less than that of methadone, suggesting buprenorphine may be the optimal maintenance therapy in patients with heart conditions [6,[39][40][41]. ...
Introduction:
Opioid use disorder (OUD) is increasing in prevalence throughout the world, with approximately three million individuals in the United States affected. Buprenorphine is a medication designed, researched, and effectively used to assist in OUD recovery.
Objective:
This narrative review discusses an approach to initiating buprenorphine in the emergency department (ED) for opioid-abuse recovery.
Discussion:
Buprenorphine is a partial mu-opioid receptor agonist with high affinity and low intrinsic activity. Buprenorphine's long half-life, high potency, and 'ceiling effect' for both euphoric sensation and adverse effects make it an optimal treatment alternative for patients presenting to the ED with opioid withdrawal. While most commonly provided as a sublingual film or tablet, buprenorphine can also be delivered via transbuccal, transdermal, subdermal (implant), subcutaneous, and parenteral routes. Prior to ED administration, caution is recommended to avoid precipitation of buprenorphine-induced opioid withdrawal. Following the evaluation of common opioid withdrawal symptoms, a step-by-step approach to buprenorphine can by utilized to reach a sustained withdrawal relief. A multimodal medication-assisted treatment (MAT) plan involving pharmacologic treatment, as well as counseling and behavioral therapy, is essential to maintaining opioid remission. Patients may be safely discharged with safe-use counseling, close outpatient follow-up, and return precautions for continued management of their OUD. Establishing a buprenorphine program in the ED involves a multifactorial approach to establish a pro-buprenorphine culture.
Conclusions:
Buprenorphine is an evidence-based, safe, effective treatment option for OUD in an ED-setting. Though successfully utilized by many ED-based treatment programs, the stigma of 'replacing one opioid with another' remains a barrier. Evidence-based discussions on the safety and benefits of buprenorphine are essential to promoting a culture of acceptance and optimizing ED OUD treatment.
... Although various opioids agonist are known to block the hERG channel, methadone appears to be among the most potent inhibitor of the hERG repolarizing current at therapeutic range [21]. This may explains why these adverse effects (QT prolongation and TdP) mainly affect patients under methadone compared to morphine, heroin or buprenorphine treatments [13,22]. ...
Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors.
Former heroin dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on 5 genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug‐induced QT prolongation. Both SNP‐based and gene‐based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length.
In our sample of 154 patients, current methadone daily dose was associated with QTc length (r Pearson = 0.26; p = 10‐3). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (p = 3.84 x 10‐4; pcorrected= 0.049). Using a gene‐based approach, KCNE1 was also significantly associated with QTc length (p empirical= 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs C; p = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP.
Patients’ genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.
This article is protected by copyright. All rights reserved.
... Buprenorphine was traditionally considered to be a relatively safe drug in regards to developing long QT syndrome [20,21]. However, recent reports indicate that buprenorphine increases the risk of a prolonged QT interval [22,23]. ...
Long QT syndrome is a cardiac repolarization disorder and is associated with an increased risk of torsades de pointes. The acquired form is most often attributable to administration of specific medications and/or electrolyte imbalance. This review provides insights into the risk for QT prolongation associated with drugs frequently used in the treatment of chronic pain. In the field of pain medicine all the major drug classes (i.e. NSAIDs, opioids, anticonvulsive and antidepressant drugs, cannabinoids, muscle relaxants) contain agents that increase the risk of QT prolongation. Other substances, not used in the treatment of pain, such as proton pump inhibitors, antiemetics, and diuretics are also associated with long QT syndrome. When the possible benefits of therapy outweigh the associated risks, slow dose titration and electrocardiography monitoring are recommended.
... The incidence of long QTc is undefined. One prospective study identified it in 4.6% of 173 individuals receiving maintenance methadone ≥ 120 mg/day (and none taking buprenorphine); mortality was merely 0.06 per 100 patient-years (Anchersen, Clausen, Gossop, Hansteen & Waal, 2009). Consensus-based guidelines (Table 5) address concerns and aid prescribing methadone (Chou et al., 2014). ...
Opioid analgesics are the cornerstone of moderate to severe cancer pain management, and do not have ceiling doses unless unmanageable adverse effects occur. Oral, short-acting pure μ agonists such as morphine are most frequently used, but other agents and administration formulations allow finding the right opioid and dose for most patients. In addition, clinicians must understand the metabolism, pharmacokinet-ics, and elimination of particular drugs to individualize opioid selection, select initial doses, and appropriately escalate doses to satisfactory pain relief or uncontrollable toxicity. Anticipation and pro-active management of possible adverse effects, particularly constipation, confusion or delirium, opioid-specific adverse effects, and opioid abuse, are also integral to primary and secondary prophylaxis and management.
Methadone (R,S‐methadone) can prolong the QT interval. R‐methadone inhibits cardiac potassium channel function less than S‐methadone. We tested if switching from methadone to R‐methadone would reduce corrected QT (QTc) intervals in methadone maintenance treatment (MMT) patients. Nine patients, with automatically read QTc intervals ≥450 ms, were required to detect a 20 ms (clinically relevant) reduction in QTc intervals with 15 ms standard deviation (SD) and 90% power. Nine stabilized MMT patients, using median (range) 70 (40–120) mg methadone, were included. Data (ECG recordings, serum samples, and withdrawal symptoms) were collected both before drug intake (C min ) and at 3 h after drug intake (C max ), and were collected on the day before the switch from methadone to equipotent R‐methadone dose and at 14 and 28 days after the switch. A cardiologist calculated QTc intervals retrospectively. Serum electrolytes and methadone concentrations were measured. Mean QTc intervals at C min were 472 ms and 422 ms on methadone (automatically and manually read) and 414 ms on R‐methadone (manually read). Mean (SD) change in QTc intervals was −8 (10) ms ( p = 0.047) at C min but non‐significant at C max . R‐methadone showed a concentration‐dependent relationship with QTc intervals. Switching to R‐methadone reduced QTc intervals, but far less than the 20 ms considered clinically relevant.
Opioids are widely being used for chronic pain management, cough and diarrhea suppressants, anesthetic agents, and opioid de-addiction therapy. Opioid receptors, present in the central nervous system and peripheral tissues, are documented to regulate several cardiac functions through different signaling pathways. Long-acting opioids (LAO) have been successfully evaluated for their beneficial effects in various cardiovascular diseases viz. myocardial infarction, ischemic reperfusion injuries, atherosclerosis etc. However, on the other hand, several research studies pointed towards the harmful effects of LAOs which are mainly associated with QTc prolongation, torsade de pointes, ventricular arrhythmias, and cardiac arrest. This review shall familiarize readers with the benefits as well as the harmful effects of long-acting opioids in cardiovascular diseases. We have also provided an overview of cardiac opioid receptors, endogenous cardiac opioid peptides, and regulation of cardiovascular functions by central and cardiac opioid receptors.
Introduction:
Opioid use disorder (OUD) has become increasingly prevalent among hospitalized patients in the United States and globally. As its prevalence increases, this provides a valuable opportunity for clinicians in the hospital setting to engage and initiate management and treatment of OUD.
Purpose:
This article aims to provide hospitalists and other clinicians working in the hospital with a narrative review of the management of opioid withdrawal and the initiation of medications for opioid use disorder (MOUD) in the hospital and provide an update on a novel low dose approach to buprenorphine induction (also commonly referred to as the 'microinduction' method).
Methods:
Authors performed a narrative review of the literature.
Results:
Management can initially include treating withdrawal symptoms with opioids as well as with a combination of non-opioid medications such as alpha 2 agonists, benzodiazepines, and/or antiemetics as needed. Besides simply managing withdrawal symptoms, clinicians can further improve the care of patients with OUD through initiating maintenance treatment with MOUD, ideally with opioids used in the initial management of withdrawal. Opioid detoxification is an inferior method of primary treatment and is associated with relapse and poor outcomes. In contrast, treatment with MOUD using methadone or buprenorphine is associated with superior treatment outcomes and reduced relapse compared to detoxification alone. Treatment with MOUD using methadone or buprenorphine can be successfully used in the hospital setting. A novel low dose approach to buprenorphine induction may be useful in minimizing precipitated withdrawals in patients who have recently used or received opioids, which makes this an attractive option in the hospital where patients are frequently on opioids for acutely painful conditions. The hospital setting also provides a valuable opportunity for clinicians to address harm reduction in patients with OUD. Finally, clinicians can improve the long-term outcomes of patients with OUD by ensuring a smooth discharge with adequate and timely follow-up.
Conclusion:
Proper management of opioid withdrawal and initiation of MOUD in the hospital can improve outcomes in patients with OUD.
Opiates have a long history of medical use as effective analgesics associated with well‐described side effects, including euphoria, respiratory depression, constipation, bradycardia, and histamine release, among others. The search for opiate analogs that retain effective analgesic qualities without detrimental side effects has yielded numerous compounds, including buprenorphine. Early studies of buprenorphine demonstrated analgesic effectiveness with a favorable safety profile, leading to the approval of formulations for use in humans. Since then, advances in receptor theory and molecular cloning of opioid receptors have led to a deeper understanding of buprenorphine pharmacology. More recent studies of receptor affinity and intrinsic activity have shown that buprenorphine is a μ‐ and κ‐opioid receptor agonist, a nociceptin orphanin peptide agonist, and a δ‐opioid receptor antagonist. Buprenorphine appears to have a primary spinal analgesic mechanism with complex supraspinal actions. It is considered a full agonist for pain but a partial agonist for other clinical endpoints such as respiratory depression. In feline medicine, buprenorphine is approved as low‐ and high‐concentration injectable solutions, in addition to the most recently introduced long‐acting transdermal formulation. Several investigational and compounded formulations have also been evaluated. There are contrasting differentiable features that include pharmacokinetics, onsets‐ and durations‐of‐action, routes of administration, and formulation constituents. Available buprenorphine formulations allow clinicians to select a formulation based on the anticipated duration of pain associated with various surgical procedures, and to provide interventions as needed. In light of the newly approved transdermal buprenorphine solution in cats and progress in buprenorphine pharmacology, the objective of this review is to examine the history and pharmacology of buprenorphine relative to full opioid agonists, where appropriate, integrating these insights into advances within feline medicine.
Background:
Hemodynamic changes are the most common predicted response after laryngoscopy and intubation during general anesthesia. We compared the efficacy of buprenorphine with fentanyl to attenuate this stress response.
Methods:
One hundred and thirty patients of either sex between the age group of 18-70 years, admitted for the routine surgical procedure under general anesthesia were enrolled in this double blind, randomized, clinical study. Patients were randomly assigned into two equal groups (60 patients in each group): group F received fentanyl 2 μg/kg, and group B received buprenorphine 2.5 μg/kg; both via intravenous route. Each group received a total volume of 10 mL by adding normal saline to the total drug volume, given over 60 seconds, 5 minutes before intubation. Thereafter patients were induced using routine balanced anesthesia technique, and the hemodynamic parameters were observed at baseline (0 minute), 1, 3, and 5 minutes after the administration of the study drug and again at 1, 3, 5, 7, and 10 minutes after intubation. Continuous variables were presented as mean with an 80% confidence interval, and a t-test was applied for comparing the difference of means between two groups after we checked the normality condition. Chi-square test was applied to test the independence of attributes of categorical variables. Repeated measures two-way analysis of variance was performed to compare the outcome variables between the two groups.
Results:
In both groups, mean arterial blood pressure (MAP) and heart rate (HR) were statistically insignificant up to 5 minutes after study drug, thereafter mean HR and MAP at 1, 3, 5, 7, and 10 minutes after intubation, were statistically significant between the two groups, and P value was less than 0.05.
Conclusions:
The dose of 2.5 μg/kg buprenorphine is an effective alternative to fentanyl 2 μg/kg for attenuating the hemodynamic response accompanying laryngoscopy and tracheal intubation without causing any hemodynamic adverse effect.
Many psychiatric medications have the potential to cause QT interval prolongation and increase the risk for torsades de pointes (TdP). While it is challenging to risk-stratify most agents, citalopram is thought to convey greater risk than most antidepressants, and thioridazine, chlorpromazine and ziprasidone are more strongly associated with QT interval prolongation and TdP than are other antipsychotics. Methadone also has the potential to cause significant QT interval prolongation and TdP, and should be used with caution, particularly in patients who may be at higher risk. Psychiatrists should be aware of the potential for medications to prolong the QT interval and TdP, and should think carefully about the need for monitoring and consultation with colleagues in cardiology in certain situations.
Buprenorphin, seit vielen Jahren als Schmerzmittel zugelassen, ist im Jahre 2000 in Deutschland als Substitutionsmittel zugelassen worden und stellt seitdem eine bedeutende Erweiterung der Palette der Medikamente zur Behandlung der Opioidabhängigkeit dar. Bisher sind 7 Medikamente in Deutschland zur Behandlung der Opioidabhängigkeit in verschiedenen Zubereitungen zugelassen (vgl. Abb. 4). Mittlerweile produzieren verschiedene Hersteller Buprenorphinprodukte.
Im November 2018 hat das erste Depot-Buprenorphin die EU-Zulassung erhalten. Mit dem neuen Medikament könnte sich die Substitutionsbehandlung für Buprenorphinpatient*innen künftig vereinfachen, denn das Depot-Buprenorphin erhalten die Opioidabhängigen nur einmal pro Woche oder Monat subkutan injiziert. Damit soll die selbstbestimmte Lebensführung der Substitutionspatienten verbessert und ihre gesellschaftliche Wiedereingliederung erleichtert werden (DAZ 2019).
Die Aufgabe der vorliegenden, aus zwei Teilen bestehenden, Studie, war ein Vergleich des Vergabeaufwandes der im deutschen Justizvollzug bisher verwendeten Substitutionsmittel mit dem neuen Substitutionsmedikament Buvidal®.
Dabei wurde geprüft, ob und in welchem Umfang personelle, sächliche und finanzielle Ressourcen des Justizvollzuges durch den nur noch wöchentlichen bzw. monatlichen Einsatz von Depot-Präparaten eingespart werden können.
Im ersten Teil wurden die für die Substitution benötigten personellen, sächlichen und finanziellen Ressourcen ermittelt. Insbesondere Informationen über:
- den Umfang der tatsächlich im Zusammenhang mit Substitution anfallenden Tätigkeiten als da sind:
o administrative Tätigkeiten
o die eigentliche Substitutionsbehandlung (Vergabe des Substitutionsmittels)
o Kontrollen auf Beikonsum
o Tätigkeiten bei Beginn und am Ende der Substitutionsbehandlung
o Wartezeiten (bedingt durch die besondere Struktur des Justizvollzuges)
- den jeweiligen Zeitbedarf
o für Holen und Zurückbringen der Patient*innen von und zum Haftraum
o für Wartezeiten des medizinischen Personals
o für Einnahmekontrollen und begleitende Diskussionen bei Betrugsversuchen
o für alle im Zusammenhang mit der Substitution anfallenden Tätigkeiten
- den Umfang der Substitution
- das eingesetzte Substitutionsmittel und dessen Häufigkeit
- die durchschnittliche Tagesdosis des eingesetzten Substitutionsmittels
- interne Personalkosten
- externe Personalkosten
Im zweiten Teil ist anhand bestimmter Parameter eine gesundheitsökonomische Modellrechnung vorgenommen worden.
Background:
Methadone is associated with QT interval prolongation and torsades de pointes.
Objectives:
The objective of this study was to i) determine the incidence of QT interval prolongation among patients on maintenance methadone therapy in an urban opioid treatment program (OTP), ii) compare characteristics of patients who developed methadone-associated QT prolongation with those who did not develop QT prolongation, and iii) investigate the relationship between QT interval prolongation and stereospecific serum methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations.
Methods:
Patients (n=93) in an urban OTP underwent a 12-lead electrocardiogram (ECG) prior to initiating methadone and again during steady-state maintenance methadone therapy. In a subset (n=43), blood was obtained to determine serum (S)- and (R)-methadone and (S)- and (R)-EDDP concentrations, which were compared in patients who developed Bazett's-corrected QT (QTc) prolongation [≥ 470 ms (men) or ≥ 480 ms (women) and/or ≥ 60 ms lengthening from pretreatment value] with those who did not have QTc prolongation.
Results:
Mean [± standard deviation (SD)] age was 36±12 years; 73% were female and 74% were white. QTc prolongation occurred in 14 (15.1%) patients. Patients who developed QTc prolongation were older (41±13 versus 35±9 years, p=0.03) and had a longer pre-methadone QTc (429±11 versus 420±20 ms, p=0.02) compared with those who did not have QTc prolongation, respectively. Serum (S)-methadone concentrations were higher in patients with QTc prolongation compared to patients without prolongation (199±81 versus 128±68 ng/mL, respectively, p=0.01), whereas the difference in serum (R)-methadone concentrations between the groups did not reach significance (189±68 versus 125±60 ng/mL, respectively, p=0.08). Serum (R)-methadone concentrations correlated with QTc intervals [R2 = 0.15 (95% confidence interval (CI) 0.11 to 0.62, p=0.0009)]. The correlation between serum (S)-methadone concentrations and QTc did not reach significance [R2 = 0.08 (95% CI -0.01 to 0.54, p=0.06)]. Serum (S)-and (R)-EDDP concentratons were not significantly different between the groups and did not significantly correlate with QTc intervals.
Conclusions:
Approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation. Both serum (S)- and (R)-methadone concentrations, but not (S)- or (R)-EDDP, contribute to methadone-associated QT prolongation.
Opium and morphine have been used for centuries to reduce pain in different clinical conditions including acute heart failure with pulmonary edema or hearth ischemia with infarct. It was soon observed that repeated morphine administration gradually leads to a decrease of the analgesic potency (tolerance) and that, after repeated doses, patients may have difficulties in abandoning morphine or opium use (dependence and withdrawal). Other established morphine side effects such as vomiting, hypotension, respiratory depression, and somnolence suggest careful attention in drug use. In the last few years, most of the literature outline that morphine should not be used in cases of pulmonary edema because of the risk of increased mortality. In patients with infarct, however, morphine is still considered the analgesic of choice, especially when the ischemic pain is not sensitive to nitrates. It has also been suggested that morphine may activate the ischemic tolerance process, thus reducing the ischemic reperfusion damage. Another opioid with significant analgesic action is methadone. In 1965, it was clearly demonstrated that methadone was useful in reducing the problems associated with morphine or heroin misuse. A significant number of patients are now chronically treated with the drug in the methadone treatment programs. In the last 20 years, it has been observed that methadone may cause an increase of the QT interval of the ECG and possibly an increased risk of sudden death. Since methadone is a mixture of two stereoisomers (R and S) and since R-methadone has high affinity for opioid receptors while S-methadone is possibly the main responsible for QT elongation, it has been proposed that the racemic form of the drug should be abandoned and substituted with the stereoselective active R-methadone form.
Objective
Several psychiatric medications have the potential to prolong the QTc interval and subsequently increase the risk for ventricular arrhythmias such as torsades de pointes (TdP). Unfortunately, there is limited guidance for clinicians to inform monitoring for risk and to manage the risks and benefits of treatments.
Methods
After a review of the existing literature, clinical-educators from the Association of Medicine and Psychiatry developed expert consensus guidelines for ECG monitoring of the QTc interval for patients with medical and psychiatric comorbidities who are prescribed medications with the potential to prolong the QTc interval. A risk score was developed based on risk factors for QTc prolongation to guide clinical decision-making.
Results
A baseline ECG may not be necessary for individuals at low risk for arrythmia. Those individuals with a risk score of two or more should have an ECG prior to the start of a potentially QTc-prolonging medication or be started on a lower risk agent. Antipsychotics are not equivalent in causing QTc prolongation. A consensus-based algorithm is also presented for the management of those identified at high (QTc >500 msec), intermediate (males with QTc 450–499 msec or females with QTc > 470–499 msec), or low risk.
Conclusions
The proposed algorithm can help clinicians in determining whether ECG monitoring should be considered for a given patient. These guidelines preserve a role for clinical judgment in selection of treatments that balance the risks and benefits, which may be particularly relevant for complex patients with medical and psychiatric comorbidities. Additional studies are needed to determine whether baseline and serial ECG monitoring reduces mortality.
Patients experiencing the consequences of opioid use often present to the emergency department (ED) at times of crisis, such as following overdose or when in withdrawal. This highlights the important role of the ED in recognizing opioid use disorder and engaging these patients into ongoing treatment. Given the limited ability of the healthcare system to provide timely addiction treatment, initiation of therapy in the ED, with referral to long-term care, is associated with improved outcomes. The primary evidence-based treatment used in EDs for this indication is buprenorphine. Although clinicians may find the initiation of buprenorphine therapy daunting, it is straightforward and well-tolerated, and many of the barriers are surmountable. This article addresses these barriers, which include stigma, complicated pharmacology, and confusing regulations, and provides a basis for the use of buprenorphine in acute care clinical practice.
Extensive 12‐lead ECG monitoring and drug concentrations were obtained during development of BUP‐XR, a monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Matched QT and plasma drug concentrations (11,925) from 1114 subjects were pooled from 5 studies in OUD. A concentration‐QT model was developed, which accounted for confounding factors affecting heart rate and QTc (e.g., co‐medications). Bias‐corrected nonparametric 2‐sided 90% CI were derived for the mean predicted effect of BUP‐XR on QTc (ΔQTc) at therapeutic and supra‐therapeutic doses. Changes in QTc were associated with age, central vs non‐central reading, sex, methadone, and barbiturates. The upper 90% CI of ΔQTc was 0.29, 0.67, and 1.34 msec at the steady‐state Cmax for 100, 300 and 2x300‐mg doses, respectively. An effect of BUP‐XR on QT can be ruled out at therapeutic and supra‐therapeutic doses of BUP‐XR, after accounting for covariates that may influence heart rate and QT interval in OUD. This article is protected by copyright. All rights reserved.
Inappropriate and excessive opioid prescribing practices for treatment of chronic nonmalignant pain contributed to rising rates of opioid related mortality. Effective and widely available opioid addiction treatment resources are needed to ensure successful resolution of the "opioid epidemic". This chapter outlines the basic pathophysiology of addiction as well as principles of opioid addiction management focusing on the pharmacological and nonpharmacological aspects of care. Pharmacological treatment focuses on opioid substitution therapy, with aim at prevention of opioid cravings and opioid withdrawal symptoms. Nonpharmacological treatment involves psychological and supportive approaches to addiction such as group meetings, psychological counseling, and mindfulness training.
Opioid use disorder continues to be a significant source of morbidity and mortality in the USA and the world. Pharmacologic treatment with methadone and buprenorphine has been shown to be effective at retaining people in treatment programs, decreasing illicit opioid use, decreasing rates of hepatitis B, and reducing all cause and overdose mortality. Unfortunately, barriers exist in accessing these lifesaving medications: users wishing to start buprenorphine therapy require a waivered provider to prescribe the medication, while some states have no methadone clinics. As such, users looking to wean themselves from opioids or treat their opioid dependence will turn to alternative agents. These agents include using prescription medications, like clonidine or gabapentin, off-label, or over the counter drugs, like loperamide, in supratherapeutic doses. This review provides information on the pharmacology and the toxic effects of pharmacologic agents that are used to treat opioid use disorder. The xenobiotics reviewed in depth include buprenorphine, clonidine, kratom, loperamide, and methadone, with additional information provided on lofexidine, akuamma seeds, kava, and gabapentin.
Opioid use disorder (OUD) is a significant health problem in the United States and many other countries. A combination of issues, most notably increased prescription of opioid analgesics, has resulted in climbing rates of opioid abuse and overdose over the last decade. This ongoing epidemic has produced a growing population of patients requiring treatment for OUD. Medications such as methadone and buprenorphine have well documented success rates in treating the disorder compared with placebo. However, significant percentages of the population still fail to maintain abstinence or reduce illicit opioid use while using such medications. Genetic variation may play a role in this variability in outcome through pharmacokinetic or pharmacodynamic effects on OUD medications, or by affecting the rate of negative side effects and adverse events. This review focuses on the existing literature on the pharmacogenetics of OUD treatment, with specific focus on medication metabolism, treatment outcomes, and adverse events.
Methadone is a synthetic opioid used to treat chronic pain and for maintenance therapy in opiate dependence. Methadone may cause QT prolongation and torsades de pointes, an arrhythmia. Several risk factors predispose patients to the development of this potentially fatal arrhythmia. Careful patient selection, mitigating risk factors, and regular monitoring are recommended to prescribers of methadone. With the increased number of methadone-related deaths, more research is needed to bridge informational gaps regarding its safety.
Background The aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction.
Research design and methods Individuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed.
Results Thirty patients were enrolled. The mean methadone concentration at time points was 177±119 ng/ml and 343±182 ng/ml, while the mean diazepam concentration was 561±437 ng/ml and 1045±933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412±27 ms, 425±18 ms and 424±15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R²=0.239, p=0.018; R²=0.513, p=0.006) was shown, and it remained so if the concentration of diazepam was included (R²=0.347, p=0.026, R²=0.513, p=0.009).
Conclusions The prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue.
Multiple opioid agents with widely varying potencies, metabolic/elimination pathways, durations of action, adverse effect profiles, and abuse and diversion liability exist. The knowledge of different profiles for somatic and psychiatric adverse effects, propensity to confer hyperalgesia, and risk of abuse and diversion is incumbent upon any provider who writes opioid prescriptions. While the generalist certainly does not need to be expert in all of the agents available, the growing scope of the problem of opioid abuse in this country necessitates some familiarity with all of the commonly used agents, regardless of specialty. The old injunction to “know a few agents really well” is certainly reasonable; however, staying abreast of the current knowledge base is essential when prescribing potentially lethal agents and those that can otherwise ruin a life. Basic familiarity with epidemiologic and diversion activity trends is important to the clinician as well.
Objective:
Methadone is associated with prolongation of the electrocardiographic QTc interval. QTc prolongation may be linked to cardiac dysrhythmia and sudden cardiac death. The rate of these events is unknown in methadone-maintained patients.
Methods:
This retrospective cohort study of 749 patients with opioid use disorder receiving methadone maintenance therapy through a single safety-net hospital, queried the electronic health record for electrocardiogram results, demographics, methadone dose, and diagnostic codes consistent with cardiac conduction disorder (International Classification of Disease, Ninth Revision [ICD-9] 426) and cardiac dysrhythmia (ICD-9 427). Factors associated with QTc interval were explored; Cox proportional-hazards regression models were used to analyze time to an event that may predispose to sudden cardiac death.
Results:
One hundred thirty-four patients had an electrocardiogram while on methadone, 404 while off methadone, and 211 both while on and off methadone. Mean QTc interval while on methadone (436 ms, SD 36) was significantly greater than while off methadone (423 ms, SD 33). Age and methadone dose were weakly associated with increased QTc interval (P < 0.01 and P < 0.0005, respectively, adjusted R = 0.05). There were 44 ICD-9 426 and 427 events over 7064 patient-years (6.3 events/1000 patient-yrs). Having a QTc greater than sex-specific cut-off values was significantly associated with time to event (hazard ratio 3.32, 95% confidence interval 1.25-8.81), but being on methadone was not.
Conclusions:
Methadone is associated with QTc prolongation in a nonclinically significant dose-related manner. Cardiac events were rare and the sudden cardiac death rate was below that of the general population. Current recommendations for cardiac risk assessment in methadone-maintained patients should be reconsidered.
Restless legs syndrome (RLS) is a sensorimotor neurologic disorder characterized by an unpleasant urge to move the legs, often accompanied by leg dysesthesias. Symptoms predominate in the evening or at night and often cause significant distress and disruption of sleep. Several non-opioid classes of drugs provide initial relief from the symptoms of RLS. Among these, however, the efficacy of dopamine agonists can wane over time or even paradoxically 'augment' the severity of symptoms during the course of long-term treatment. Opioids can alleviate RLS symptoms, even in patients who have become refractory to, or do not tolerate, other drugs. In a carefully selected group of patients with severe RLS that has not been effectively managed with other therapies, opioids may be an appropriate treatment.
This is the protocol for a review and there is no abstract. The objectives are as follows:
The primary aim of the review is the risk-benefit evaluation of electrocardiograph screening for preventing morbidity and mortality associated with methadone-related QTc interval prolongation in opioid addicts.
The aim of the present study was to assess the incidence of abnormal QTc interval values in a population of subjects on a long-term methadone maintenance treatment, as a single therapy, and with methadone dosages ranging between 10 and 600 mg/daily (mean+/-SD=87+/-76).
Basal ECG recordings were carried out in 83 former heroin addicts on long-term successful methadone maintenance therapy for at least 6 months, while no other known QT-prolonging agent was being administered.
Eighty-three percent of the subjects had a more prolonged QT interval than the reference values for persons of the same sex and age. Only 2 patients displayed a QTc interval of >500 ms. No correlation emerged between QTc values and methadone dosages.
Patients on long-term methadone maintenance treatment show longer than expected QTc interval values. This data, associated with the finding that methadone is a rather potent inhibitor of HERG potassium channels and that it may induce torsade de pointes in predisposed subjects, supports the recommendation that patients entering methadone treatment (MT) are screened for cardiac risk factors. ECG might be considered in ongoing MT patients especially before starting QT-prolonging medications.
Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown.
We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation.
Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function.
QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.
To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals.
Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed.
The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective.
Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses.
Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.
A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use.
Objective.
—To test the hypothesis that female prevalence is greater than expected among reported cases of torsades de pointes associated with cardiovascular drugs that prolong cardiac repolarization.Data Sources.
—A MEDLINE search of the English-language literature for the period of 1980 through 1992, using the terms torsade de pointes, polymorphic ventricular tachycardia, atypical ventricular tachycardia, proarrhythmia, and drug-induced ventricular tachycardia, supplemented by pertinent references (dating back to 1964) from the reviewed articles and by personal communications with researchers involved in this field.Study Selection.
—Ninety-three articles were identified describing at least one case of polymorphic ventricular tachycardia (with gender specified) associated with quinidine, procainamide hydrochloride, disopyramide, amiodarone, sotalol hydrochloride, bepridil hydrochloride, or prenylamine. A total of 332 patients were included in the analysis following application of prospectively defined criteria (eg, corrected QT [QTc] interval of 0.45 second or greater while receiving drug).Data Extraction.
—Clinical and electrocardiographic descriptors were extracted for analysis. Expected female prevalence for torsades de pointes associated with quinidine, procainamide, disopyramide, and amiodarone was conservatively estimated from gender-specific data reported for antiarrhythmic drug prescriptions in 1986, as derived from the National Disease and Therapeutic Index, a large pharmaceutical database; expected female prevalence for torsades de pointes associated with sotalol, bepridil, and prenylamine was assumed to be 50% or less since these agents are prescribed for male-predominant cardiovascular conditions.Results.
—Women made up 70% (95% confidence interval, 64% to 75%) of the 332 reported cases of cardiovascular-drug—related torsades de pointes, and a female prevalence exceeding 50% was observed in 20 (83%) of 24 studies having at least four included cases. When analyzed according to various descriptors, women still constituted the majority (range, 51% to 94% of torsades de pointes cases), irrespective of the presence or absence of underlying coronary artery or rheumatic heart disease, left ventricular dysfunction, type of underlying arrhythmia, hypokalemia, hypomagnesemia, bradycardia, concomitant digoxin treatment, or level of QTc at baseline or while receiving drug. When cases of torsades de pointes were analyzed by individual drug, observed female prevalence was always greater than expected, representing a statistically significant difference (P<.05) for all agents except procainamide.Conclustions.
—These findings strongly suggest that women are more prone than men to develop torsades de pointes during administration of cardiovascular drugs that prolong cardiac repolarization. The pathophysiological basis for, and therapeutic implications of, this gender disparity should be further investigated.(JAMA. 1993;270:2590-2597)
Torsade de pointes is a particular form of polymorphic ventricular tachycardia causing few haemodynamic symptoms, but carries a poor prognosis because of recurrence and sudden death in up to 31% of patients. A wide range of agents have been shown to aggravate and even to cause torsade de pointes by prolonging the QT interval or increasing QT dispersion. For the majority of substances the incidence of torsade de pointes remains unclear, but is of the order of 3 to 15% for a wide range of agents. Elicitation of proarrhythmia by drug-induced QT prolongation is mainly based on increased cellular excitability and/or abnormal dispersion of ventricular repolarisation. Torsade de pointes has been shown to be related to bradycardia-dependent early after-depolarisations and/or increased dispersion of repolarisation. Clinically, patients with predisposing factors prior to medication should be considered at risk of drug-mediated proarrhythmia. Typically, torsade de pointes occurs during the first days of antiarrhythmic therapy. During this phase, QT interval measurement and assessment of the QTc time should be performed frequently. Phases of bradycardia or occurrence of ventricular extra beats with a long coupling interval may be of help to identify patients at high risk of proarrhythmic events.
As a first attempt in managing this arrhythmia, magnesium sulphate has been shown to be effective in many patients. In case of recurrence of torsade de pointes, the use of a temporary pacemaker with pacing at about 100 to 120 beats/min is the therapy of choice until the causative agent has been completely eliminated.
The long QT syndrome (LQTS) is a disorder of cardiac ion channels that affect repolarization. The characteristic manifestations are prolongation of the QT interval and T-wave abnormalities on the ECG and exercise or emotion precipitation of syncope and sudden death, resulting from the ventricular tachyarrhythmia torsade de pointes (TDP) (Fig. 1). The ion-channel dysfunction may be acquired or inherited. The acquired form is more common, usually caused by administration of QT-prolonging drugs Table 1 and Table 2, which for the most part impair the function of the IKr delayed rectifier channel. The inherited form is caused by mutations of genes that encode for cardiac ion channels, principally the IKr and IKs delayed rectifier potassium channels, with a minority of cases caused by mutations of the gene that encodes for the cardiac sodium channel.
Inherited LQTS has become a particularly important entity for several reasons. It is estimated to be present in 1 in 7000 persons in the United States and thus is not a rare disorder. It may cause as many as 3000 unexpected deaths in children and young adults per year. Further, recent discoveries concerning the molecular genetics and pathophysiology of LQTS have provided important insights into the mechanisms of arrhythmias, not only in LQTS but in general. These findings may provide molecular strategies for arrhythmia prevention in some of the estimated 300,000 to 400,000 sudden cardiac deaths100 that occur annually in the United States, including an estimated 7000 to 8000 in young persons.
Background
Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown.Methods
We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation.Results
Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second½ or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function.Conclusions
QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.
Summary Methadone is an effective treatment for opioid dependence- and, until recently, was viewed as a medication without cardiac properties. High-dose therapy has been linked to prolongation of the rate-corrected QT interval (QTc) and torsade de pointes (TdP), a form of ventricular tachycardia requiring QTc prolongation. To date, only one prospective study has demonstrated a modest increase in QTc with methadone. Arrhythmia risk is related to the magnitude of the QTc change from baseline. Clinicians should be aware of methadone's potential cardiovas- cular effects and weigh the benefit-to-risk ratio for each patient, based upon individual risk for arrhythmia.
Aims:
To provide empirically based evaluation data regarding the efficacy of psychopharmacological interventions in opiate substance abuse, the present study employed meta-analytic statistical procedures to determine the effectiveness of methadone hydrochloride as a pharmacotherapeutic agent.
Design:
Empirical research findings from 11 studies investigating the effect of methadone maintenance treatment (MMT) on illicit opiate use, and eight and 24 studies investigating the effect of MMT on HIV risk behaviors and criminal activities, respectively, by individuals in such treatment were addressed.
Findings:
Results demonstrate a consistent, statistically significant relationship between MMT and the reduction of illicit opiate use, HIV risk behaviors and drug and property-related criminal behaviors. The effectiveness of MMT is most apparent in its ability to reduce drug-related criminal behaviors. MMT had a moderate effect in reducing illicit opiate use and drug and property-related criminal behaviors, and a small to moderate effect in reducing HIV risk behaviors.
Conclusions:
Results clarify discrepancies in the literature and are useful in predicting the outcomes of individuals in treatment. The treatment's effectiveness is evident among opiate-dependent individuals across a variety of contexts, cultural and ethnic groups, and study designs.
Methadone is associated with prolongation of the corrected QT interval (QTc) and torsade de pointes in case series, cross sectional studies, a prospective cohort study, and one randomized trial. It has recently been suggested that methadone promoted sudden cardiac death based on the absence of structural heart disease in an autopsy cohort. Given increasing data linking methadone to arrhythmia, clinicians must understand whether the relationship is causal, and if so, anticipate the expected frequency of QTc interval prolongation in their patients. To date has not been well characterized. To assess the impact of methadone on the QTc interval, electrocardiography at baseline and 6 months after methadone induction was evaluated from a previously published prospective cohort study of heroin addicts. Absolute increases above categorical QTc thresholds and the proportion with QTc interval increases exceeding 30 and 60 msec were tabulated. Among 151 subjects, 76% experienced an increase in QTc, whereas 24% had no change or a decrease. The proportion exceeding 450 msec increased from 7% at baseline to 19% at 6 months; those exceeding 500 msec increased from 0% to 2%. Although 18% of subjects had an increase in QTc of 30 msec, only 3% had an increase exceeding 60 msec. Most methadone-treated patients develop QTc prolongation. However, critical QTc prolongation (exceeding 500 msec or increases exceeding 60 msec) occurred infrequently. This highlights the heterogeneity of QTc interval changes and measurement variability but also implies that electrocardiography screening among opioid dependent patients would only occasionally require methadone discontinuation.
Torsade de pointes is a particular form of polymorphic ventricular tachycardia causing few haemodynamic symptoms, but carries a poor prognosis because of recurrence and sudden death in up to 31% of patients. A wide range of agents have been shown to aggravate and even to cause torsade de pointes by prolonging the QT interval or increasing QT dispersion. For the majority of substances the incidence of torsade de pointes remains unclear, but is of the order of 3 to 15% for a wide range of agents. Elicitation of proarrhythmia by drug-induced QT prolongation is mainly based on increased cellular excitability and/or abnormal dispersion of ventricular repolarisation. Torsade de pointes has been shown to be related to bradycardia-dependent early after-depolarisations and/or increased dispersion of repolarisation. Clinically, patients with predisposing factors prior to medication should be considered at risk of drug-mediated proarrhythmia. Typically, torsade de pointes occurs during the first days of antiarrhythmic therapy. During this phase, QT interval measurement and assessment of the QTc time should be performed frequently. Phases of bradycardia or occurrence of ventricular extra beats with a long coupling interval may be of help to identify patients at high risk of proarrhythmic events. As a first attempt in managing this arrhythmia, magnesium sulphate has been shown to be effective in many patients. In case of recurrence of torsade de pointes, the use of a temporary pacemaker with pacing at about 100 to 120 beats/min is the therapy of choice until the causative agent has been completely eliminated.
To test the hypothesis that female prevalence is greater than expected among reported cases of torsades de pointes associated with cardiovascular drugs that prolong cardiac repolarization.
A MEDLINE search of the English-language literature for the period of 1980 through 1992, using the terms torsade de pointes, polymorphic ventricular tachycardia, atypical ventricular tachycardia, proarrhythmia, and drug-induced ventricular tachycardia, supplemented by pertinent references (dating back to 1964) from the reviewed articles and by personal communications with researchers involved in this field.
Ninety-three articles were identified describing at least one case of polymorphic ventricular tachycardia (with gender specified) associated with quinidine, procainamide hydrochloride, disopyramide, amiodarone, sotalol hydrochloride, bepridil hydrochloride, or prenylamine. A total of 332 patients were included in the analysis following application of prospectively defined criteria (eg, corrected QT [QTc] interval of 0.45 second or greater while receiving drug).
Clinical and electrocardiographic descriptors were extracted for analysis. Expected female prevalence for torsades de pointes associated with quinidine, procainamide, disopyramide, and aminodarone was conservatively estimated from gender-specific data reported for antiarrhythmic drug prescriptions in 1986, as derived from the National Disease and Therapeutic Index, a large pharmaceutical database; expected female prevalence for torsades de pointes associated with sotalol, bepridil, and prenylamine was assumed to be 50% or less since these agents are prescribed for male-predominant cardiovascular conditions.
Women made up 70% (95% confidence interval, 64% to 75%) of the 332 reported cases of cardiovascular-drug-related torsades de pointes, and a female prevalence exceeding 50% was observed in 20 (83%) of 24 studies having at least four included cases. When analyzed according to various descriptors, women still constituted the majority (range, 51% to 94% of torsades de pointes cases), irrespective of the presence or absence of underlying coronary artery or rheumatic heart disease, left ventricular dysfunction, type of underlying arrhythmia, hypokalemia, hypomagnesemia, bradycardia, concomitant digoxin treatment, or level of QTc at baseline or while receiving drug. When cases of torsades de pointes were analyzed by individual drug, observed female prevalence was always greater than expected, representing a statistically significant difference (P < .05) for all agents except procainamide.
These findings strongly suggest that women are more prone than men to develop torsades de pointes during administration of cardiovascular drugs that prolong cardiac repolarization. The pathophysiological basis for, and therapeutic implications of, this gender disparity should be further investigated.
In conclusion, much has been learned in the past several years regarding the molecular biology of LQTS, and this information has been directly applicable to the clinical care of patients with this syndrome. The knowledge also has been of considerable importance for understanding the molecular basis of arrhythmias in general and is providing insights into potential molecular-based therapies for arrhythmias.
LQT2 is one form of the congenital long QT syndrome. It results from mutations in the human ether-a-go-go-related gene (HERG), and more than 80 mutations, usually causing single amino acid substitutions in the HERG protein, are known. HERG encodes the ion channel pore-forming subunit protein for the rapidly activating delayed rectifier K+ channel (I(Kr)) in the heart. This review summarizes current findings about mutations causing LQT2, the mechanisms by which mutations may cause the clinical phenotype of a reduction in I(Kr) and a prolonged QT interval, and how this may be involved in the generation of ventricular arrhythmias.
Medicinal products that, as an unwanted effect, prolong the QT interval of the electrocardiogram (ECG) can trigger episodes of polymorphic ventricular dysrhythmias, called torsades de pointes, which occasionally culminate in sudden death. The accurate measurement of QT interval requires the adoption of appropriate criteria of recording, measurement and data processing. Traditionally, QT interval is standardised to a reference heart rate of 60 beats/min by using the Bazett algorithm. However, this correction method can bias observed QT intervals in either direction. The ECG reflects cardiac electrical currents generated by ions (Na+, K+ and Ca2+) entering and leaving the cytosol mainly via transmembrane channels. Na+ and Ca2+ carry inward depolarising currents (INa, ICa) whereas K+ carries outward repolarising currents (Ito, IKr, IKS and IK1). Sometimes, a prolonged QT interval is a desired drug effect but, more commonly it is not, and reflects abnormalities in cardiac repolarisation heralding torsades de pointes. Furthermore, the potential torsadogenic activity of drugs is favoured by concurrent cardiac risk factors (old age, female gender, bradycardia, electrolyte imbalances, cardiac diseases etc.) which reduce cardiac repolarisation reserve. The evaluation of the cardiac safety of drug candidates can be started by determining their potency as IKr blockers in cloned Human Ether-a-go-go Related Gene (HERG) channels expressed in mammalian cells. Compounds passing successfully this test (desirable cardiac safety index > 30, calculated as ratio of IC50 against IKr over ED50 determined in an efficacy test) should be further investigated in other relevant human cardiac ion currents, in in vitro animal heart preparations and finally in in vivo pharmacodynamic models. The decision as to whether the potential benefit of a new drug outweighs the cardiac risk inherent in its therapeutic use should be made in the light of the condition that it is expected to treat and with reference to alternative drug therapies. If a drug represents a unique therapeutic advance, non-clinical and clinical signals of unsatisfactory cardiac safety may not constitute sufficient grounds to abandon its development. However, if the drug offers only marginal benefits over existing therapies, decisions concerning its possible development should be taken by corporate policy makers.
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.
LAAM and methadone are both full mu opiate agonists and have been shown to reduce dependence on heroin when given continuously under supervised dosing conditions. LAAM has a long duration of action requiring dosing every two or three days compared to methadone which requires daily dosing. LAAM is not as widely available internationally as methadone, and may be withdrawn from the market following ten cases of life-threatening cardiac arrhythmias and an association with QT prolongation.
To compare the efficacy and acceptability of LAAM maintenance with methadone maintenance in the treatment of heroin dependence.
We searched MEDLINE (January 1966 to August 2000), PsycINFO (1887 to August 2000), EMBASE (January 1985 to August 2000), and the Cochrane Controlled Trials Register (Issue 2 2000). In addition we hand searched NIDA monographs until August 2000 and searched reference lists of articles.
All randomised controlled trials, controlled clinical trials and controlled prospective studies comparing LAAM and methadone maintenance for the treatment of heroin dependence and measuring outcomes of efficacy or acceptability were included.
Data on retention in treatment, heroin use, side-effects and mortality were collected by two reviewers independently. A meta-analysis was performed using RevMan. Discrepancies were resolved by consensus.
Eighteen studies, (15 RCTs, 3 Controlled prospective studies) met the inclusion criteria for the review. Three were excluded from the meta-analysis due to lack of data on retention, heroin use or mortality. Cessation of allocated medication (11 studies, 1473 participants) was greater with LAAM than with methadone, (RR 1.36, 95%CI 1.07-1.73, p=0.001, NNT=7.7 (or 8)). Non-abstinence was less with LAAM (5 studies, 983 participants; RR 0.81, 95%CI 0.72-0.91, p=0.0003, NNT=9.1 (or 10)). In 10 studies (1441 participants) there were 6 deaths from a range of causes, 5 in participants assigned to LAAM (RR 2.28 (95%CI 0.59-8.9, p=0.2). other relevant outcomes, such as quality of life and criminal activity could not be analysed because of lack of information in the primary studies.
LAAM appears more effective than methadone at reducing heroin use. More LAAM patients than methadone ceased their allocated medication during the studies, but many transferred to methadone and so the significance of this is unclear. There was no difference in safety observed, although there was not enough evidence to comment on uncommon adverse events.
Methadone is an effective treatment for opioid dependency and chronic pain. A methadone derivative, levacetylmethadol, was withdrawn from the European market after being associated with torsade de pointes. To date, no association between methadone and this arrhythmia has been described.
To evaluate a series of methadone-treated patients experiencing torsade de pointes.
Retrospective case series.
Methadone maintenance treatment programs in the United States and a pain management center in Canada.
17 methadone-treated patients who developed torsade de pointes.
Chart review for concomitant arrhythmia risk factors and quantification of corrected QT interval (QTc).
The mean daily methadone dose was 397 +/- 283 mg, and the mean QTc interval was 615 +/- 77 msec. Fourteen patients had a predisposing risk factor for arrhythmia. A cardiac defibrillator or pacemaker was placed in 14 patients; all 17 patients survived.
This series raises concern that very-high-dose methadone may be associated with torsade de pointes. Given the likely expansion of methadone treatment into primary care, further investigation of these findings is warranted.
Four patients infected with human immunodeficiency virus receiving antiretroviral treatment and high doses of methadone (>200 mg/day) presented with several syncopal episodes. A significant prolongation of the QTc interval was detected in all of them, and in 3 patients, greater than or equal to1 episode of Torsades de Pointes was recorded. The sequence of events in these cases suggests that high doses of methadone caused QT prolongation and provided the substrate for syncope and Torsades de Pointes. (C) 2003 by Excerpta Medica, Inc.
In certain subgroups of patients, prolongation of the QTc interval may increase total and cardiovascular mortality due to life-threatening ventricular arrhythmias and sudden death. Nonetheless, whether modest prolongation of the QTc interval in the general population has clinical importance remains unclear.
We conducted a literature search from 1990 forward to identify all published prospective cohort studies evaluating the association between prolonged QTc interval and risks of total and cardiovascular mortality as well as sudden death. We reviewed each of the studies individually and then conducted a qualitative overview.
The 7 prospective cohort studies identified included 36 031 individuals. There were 2677 (8.7%) individuals with prolonged QTc interval, defined as 440 milliseconds or greater. Whereas 1 study reported no association between prolonged QTc interval and mortality (relative risk, 1.02; 95% confidence interval, 0.70-1.49), the other 6 reported inconsistent associations overall as well as across subgroups defined by various characteristics including age, sex, and comorbidities. The reported associations for both cardiovascular mortality and sudden death were also inconsistent. In the overview, the only consistent findings were for the subgroup of patients with prior cardiovascular disease, in which relative risks ranged from 1.1 to 3.8 for total mortality, from 1.2 to 8.0 for cardiovascular mortality, and from 1.0 to 2.1 for sudden death. Further, in individuals without prior cardiovascular disease, associations were either absent or greatly attenuated; specifically, relative risks ranged from 0.9 to 1.6 for total mortality, from 1.2 to 1.7 for cardiovascular mortality, and from 1.3 to 2.4 for sudden death.
There was no consistent evidence for increased risks of total or cardiovascular mortality or of sudden death, except perhaps for patients with prior cardiovascular disease. In the general population, if QTc interval prolongation is associated with any increase in mortality, that risk is likely to be small and difficult to detect reliably.
Recent reports suggest that methadone may prolong the QTc interval and cause torsades de pointes. This study was conducted to evaluate the prevalence of QTc prolongation during oral methadone therapy and identify factors associated with prolongation. Patients receiving oral methadone as treatment for chronic pain or addiction were eligible for the study. One hundred four patients who were receiving > or = 20 mg methadone per day for > or = 2 weeks underwent electrocardiograms to measure QTc interval duration. Sixty-three (61%) patients were male and 63 (61%) were receiving methadone maintenance for opioid addiction. The mean (+/- SD) age was 45.3 +/- 9.4 years. The median (range) methadone dose was 110 mg/day (20-1200 mg/day); median (range) number of months on methadone was 12.5 months (1-444 months). The median (range) QTc interval was 428 msec (396-494 msec). Thirty-three percent had QTc prolongation (males 40%, females 20%; P=0.03). No patient had a QTc longer than 500 msec. Significant dose response was observed in males on methadone <12 months (rho=0.60, P=0.02). Our study suggests that methadone may prolong the QTc interval in specific subpopulations but poses little risk of serious prolongation.
Torsade de pointes is a rare but potentially fatal ventricular arrhythmia that is often triggered by drugs that prolong the rate-corrected QT (QTc) interval. This arrhythmia has been attributed to levacetylmethadol and methadone, synthetic opioids used to treat heroin addiction. Levacetylmethadol, a derivative of methadone, is being withdrawn from the United States market because its use waned after a black box warning was issued to require electrocardiographic monitoring. Therefore, methadone and buprenorphine are the only opioids available for the treatment of heroin addiction. To our knowledge, the cardiac safety of buprenorphine in patients with methadone-related QTc prolongation has not been described. We report a patient who developed torsade de pointes while receiving high-dose methadone and was successfully inducted onto buprenorphine under close medical supervision. No clinically important QTc prolongation was observed in the acute setting or during follow-up. This observation suggests that buprenorphine may be a safe alternative to oral methadone in patients with opioid addiction who develop torsade de pointes.
QT interval prolongation can lead to torsades de pointes, a potentially fatal arrhythmia. Although research exists on the relationship between QT prolongation and clinical outcome, few studies have described risk factors for prolonged QT interval in the general population.
The Third National Health and Nutrition Examination Survey (NHANES III) collected electrocardiogram interval data on 8561 subjects over 40 years of age and projected results to the US population. QT was corrected for heart rate using Fridericia's formula. Logistic regression analyses were performed to identify factors independently associated with prolonged QTc interval, defined as being in the upper 5% of the population QTc interval distribution. Analyses were conducted separately for women and men as a result of differences in the QT distribution between the sexes and also because of potential effect modification. Analytical variables included age, race/ethnicity, electrolyte measurements, body mass index, the recent use of QT-prolonging drugs and past medical histories of stroke, thyroid disease, hypertension, diabetes and myocardial infarction.
Age, female sex, hypocalcemia (men), hypokalemia (women), and a history of thyroid disease and myocardial infarction (men) were associated with a prolonged QTc interval. In addition, taking QT-prolonging medications in the past month was associated with more than a twofold increase in the odds of prolonged QTc interval in both men and women.
Healthcare practitioners should be aware that a prolonged QTc interval is a potential indicator of cardiovascular risk, and should exercise caution in prescribing potentially QT-prolonging medications to certain patients.
The proarrhythmic effects of cocaine may be mediated in part by its effects on cardiac repolarization properties. This study evaluated the acute effects of smoking cocaine 25 mg on the electrocardiograms of 14 habitual cocaine users during a 12-minute observation period. After cocaine administration, heart rate increased by a mean of 22 beats/min (p <0.0001). One patient developed accelerated junctional rhythm, and 5 had nonspecific ST-T-wave abnormalities. The electrocardiograms revealed significant prolongation of the QTc interval (p <0.001) after cocaine administration. In addition, T-wave amplitude decreased and U-wave amplitude increased in response to cocaine use (p <0.05). QRS duration was unchanged by cocaine, whereas the PR interval shortened slightly. The repolarization changes observed after cocaine use were similar to those reported for other sympathomimetic agents and may be a contributing factor in the association between cocaine use and ventricular arrhythmias.
Dynamic instability in cardiac repolarization may contribute to drug-induced arrhythmogenesis. We hypothesized that intravenous cocaine would significantly destabilize repolarization as measured by QT variability.
Twenty-nine cocaine-experienced volunteers not seeking treatment for cocaine addiction received randomized, sequential intravenous infusions of placebo or cocaine (20 and 40 mg). Five-minute epochs of digitized ECG were recorded 10 minutes before, during, and at intervals following the infusions. QT variability was measured using a semiautomated method and expressed as the log ratio of normalized QT variance to normalized heart rate variance (QTVI). Seventeen subjects received a repeat course of cocaine infusions 1 week later. Placebo infusion resulted in a small but significant increase in QTVI, while cocaine caused a highly significant, dose-dependent increase in QTVI that peaked at 10 minutes and dissipated by 45 minutes following infusion (P < 0.0001). The increase in QTVI was reproducible at 1 week (P = 0.8).
Cocaine injection results in a significant dose-dependent increase in QT variability as indexed by QTVI. This destabilizing effect on repolarization may increase vulnerability to reentrant arrhythmias and may partially explain an increased risk of sudden cardiac death associated with cocaine use.
To investigate the relationship between the daily dose of the synthetic opioid methadone and the corrected QT (QTc) interval in a series of methadone-treated patients who developed torsade de pointes.
Retrospective case series analysis.
Outpatient pain management center and methadone maintenance treatment programs.
Seventeen patients who developed torsade de pointes while receiving very high daily doses of methadone.
The QTc intervals were calculated for each patient. The relationship between daily methadone dose and QTc interval was assessed and adjusted for clinical characteristics that may have independently prolonged cardiac repolarization. The mean QTc interval was 615 +/- 77 msec. Multiple linear regression indicated that only the daily methadone dose was predictive of the QTc interval (r = +0.51, p = 0.03). All other variables examined, such as age, sex, presence of hypokalemia or structural heart disease, and presence of QT-prolonging drugs, were not predictive of the QTc interval (minimum p = 0.28).
In this series, the daily methadone dose correlated positively with the QTc interval. This finding supports the possibility that methadone contributed to the development of arrhythmia.
To determine and evaluate QTc intervals in electrocardiograms (ECGs) of former heroin addicts, currently in methadone maintenance treatment (MMT), as previous reports suggest that methadone may prolong QTc intervals, thus possibly increasing the risk for Torsade de pointes (TdP).
Cross-sectional study.
Between January 2003 and September 2004, patients on a steady dose of methadone for at least 2 weeks were studied.
This study is a subset of 153 patients, of whom 151 patients participated in a study of high methadone doses and serum levels. A total of 138 patients in MMT for a minimum of 100 days up to 10.7 years, receiving 40-290 mg/day methadone dose, participated.
Patients had an ECG at the time when blood was drawn for determination of serum methadone levels at around 24 hours after the last oral methadone dose. Corrected-QT intervals (QTc) were calculated using the Bazett formula.
Of 138 patients studied, 98 (71%) were male. Mean QTc interval was 418.3 +/- 32.8 milliseconds (ms). Mean methadone dose was 170.9 +/- 50.3 mg/day and mean serum methadone level was 708.2 +/- 363.1 ng/ml. Methadone dose and serum levels did not correlate with QTc. Three patients had QTc intervals above 500 ms ('prolonged'). After 2 +/- 0.4 years of follow-up, two patients died; they were two of three patients with very prolonged QTc. Causes of death were not attributed to cardiac origin. An additional 19 patients had QTc intervals of between 450 and 499 ms ('possibly prolonged'). None of these QTc > or = 450 ms patients had any cardiac problems. Methadone doses of all 22 patients were > 120 mg/day.
Methadone maintenance is generally safe; however, the possible toxicity of high dose (> 120 mg/day) should be monitored for QTc.
Although many adverse cardiovascular outcomes are mentioned in conjunction with methamphetamine use, a causal relationship between methamphetamine use and arrhythmia or cardiomyopathy has not been demonstrated in man. Clinical experience with methamphetamine users suggested a higher incidence of electrocardiographic abnormalities. This study seeks to quantify that incidence, among subjects enrolled in a study of adults with methamphetamine dependence.
Electrocardiograms obtained during screening in a previous clinical trial were examined. The study population (n = 158) of adults with methamphetamine dependence [Diagnostic and Statistical Manual version IV (DSM IV-TR)] was drawn from five sites across the United States, recruited in the interval 2002-03.
A significant variance from the normal population was noted in the electrocardiograms of the study cohort. Among the abnormalities was a prolongation of the QTc beyond 440 ms in 27.2% of the group. QTc prolongation to this extent poses a particular risk for ventricular arrhythmias, most notably torsades de pointes.
We believe that this is the first demonstration of clinically significant QTc prolongation in a methamphetamine-using population, and that this has implications for the types of arrhythmias for which this population is at risk. It may further provide a marker for risk of cardiomyopathy. The fact of electrocardiographic changes with potential cardiac risks may be useful in a motivational interviewing approach, in challenging the methamphetamine user's basis for continuing use.
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.
Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects.
We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds.
Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group).
Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.
Opioid maintenance treatment (OMT) is generally considered to reduce mortality in opiate dependents. However, the level of mortality reduction is still uncertain. This study investigates mortality reductions in an "intention-to-treat" perspective including all dropouts. The mortality reducing effects of OMT are examined both within treatment and post-treatment. The study separates overdose and total mortality reductions.
The study is a prospective cross-registry study with up to 7 years follow-up. All opiate dependents in Norway who applied for OMT (a total of 3789 subjects) were cross-linked with data from the death registry from Statistics Norway. Date and cause of death were crossed with dates for initiation and termination of OMT, and subjects' age and gender. A baseline was established from the waiting list mortality rate. Intention-to-treat was investigated by analysing mortality among the entire population that started OMT.
Mortality in treatment was reduced to RR 0.5 (relative risk) compared with pre-treatment. In the "intention-to-treat" perspective, the mortality risk was reduced to RR 0.6 compared with pre-treatment. The patients who left the treatment programme showed a high-mortality rate, particularly males.
OMT significantly reduces risk of mortality also when examined in an intention-to-treat perspective. Studies that evaluate effects of OMT only in patients retained in treatment tend to overestimate benefits. Levels of overdose mortality will influence the risk reduction. Cross-registry studies as the current one are an important supplement to other observational designs in this field.
Background:
Buprenorphine maintenance treatment has been evaluated in randomised controlled trials against placebo medication, and separately as an alternative to methadone for management of opioid dependence.
Objectives:
To evaluate buprenorphine maintenance compared to placebo and to methadone maintenance in the management of opioid dependence, including its ability to retain people in treatment, suppress illicit drug use, reduce criminal activity, and mortality.
Search methods:
We searched the following databases to January 2013: Cochrane Drugs and Alcohol Review Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Current Contents, PsycLIT, CORK, Alcohol and Drug Council of Australia, Australian Drug Foundation, Centre for Education and Information on Drugs and Alcohol, Library of Congress, reference lists of identified studies and reviews. We sought published/unpublished randomised controlled trials (RCTs) from authors.
Selection criteria:
Randomised controlled trials of buprenorphine maintenance treatment versus placebo or methadone in management of opioid-dependent persons.
Data collection and analysis:
We used Cochrane Collaboration methodology.
Main results:
We include 31 trials (5430 participants), the quality of evidence varied from high to moderate quality.There is high quality of evidence that buprenorphine was superior to placebo medication in retention of participants in treatment at all doses examined. Specifically, buprenorphine retained participants better than placebo: at low doses (2 - 6 mg), 5 studies, 1131 participants, risk ratio (RR) 1.50; 95% confidence interval (CI) 1.19 to 1.88; at medium doses (7 - 15 mg), 4 studies, 887 participants, RR 1.74; 95% CI 1.06 to 2.87; and at high doses (≥ 16 mg), 5 studies, 1001 participants, RR 1.82; 95% CI 1.15 to 2.90. However, there is moderate quality of evidence that only high-dose buprenorphine (≥ 16 mg) was more effective than placebo in suppressing illicit opioid use measured by urinanalysis in the trials, 3 studies, 729 participants, standardised mean difference (SMD) -1.17; 95% CI -1.85 to -0.49, Notably, low-dose, (2 studies, 487 participants, SMD 0.10; 95% CI -0.80 to 1.01), and medium-dose, (2 studies, 463 participants, SMD -0.08; 95% CI -0.78 to 0.62) buprenorphine did not suppress illicit opioid use measured by urinanalysis better than placebo.There is high quality of evidence that buprenorphine in flexible doses adjusted to participant need,was less effective than methadone in retaining participants, 5 studies, 788 participants, RR 0.83; 95% CI 0.72 to 0.95. For those retained in treatment, no difference was observed in suppression of opioid use as measured by urinalysis, 8 studies, 1027 participants, SMD -0.11; 95% CI -0.23 to 0.02 or self report, 4 studies, 501 participants, SMD -0.11; 95% CI -0.28 to 0.07, with moderate quality of evidence.Consistent with the results in the flexible-dose studies, in low fixed-dose studies, methadone (≤ 40 mg) was more likely to retain participants than low-dose buprenorphine (2 - 6 mg), (3 studies, 253 participants, RR 0.67; 95% CI: 0.52 to 0.87). However, we found contrary results at medium dose and high dose: there was no difference between medium-dose buprenorphine (7 - 15 mg) and medium-dose methadone (40 - 85 mg) in retention, (7 studies, 780 participants, RR 0.87; 95% CI 0.69 to 1.10) or in suppression of illicit opioid use as measured by urines, (4 studies, 476 participants, SMD 0.25; 95% CI -0.08 to 0.58) or self report of illicit opioid use, (2 studies, 174 participants, SMD -0.82; 95% CI -1.83 to 0.19). Similarly, there was no difference between high-dose buprenorphine (≥ 16 mg) and high-dose methadone (≥ 85 mg) in retention (RR 0.79; 95% CI 0.20 to 3.16) or suppression of self-reported heroin use (SMD -0.73; 95% CI -1.08 to -0.37) (1 study, 134 participants).Few studies reported adverse events ; two studies compared adverse events statistically, finding no difference between methadone and buprenorphine, except for a single result indicating more sedation among those using methadone.
Authors' conclusions:
Buprenorphine is an effective medication in the maintenance treatment of heroin dependence, retaining people in treatment at any dose above 2 mg, and suppressing illicit opioid use (at doses 16 mg or greater) based on placebo-controlled trials.However, compared to methadone, buprenorphine retains fewer people when doses are flexibly delivered and at low fixed doses. If fixed medium or high doses are used, buprenorphine and methadone appear no different in effectiveness (retention in treatment and suppression of illicit opioid use); however, fixed doses are rarely used in clinical practice so the flexible dose results are more relevant to patient care. Methadone is superior to buprenorphine in retaining people in treatment, and methadone equally suppresses illicit opioid use.
The association of antipsychotic and antidepressant drugs with Q-T interval prolongation is reviewed.
Prolongation of the Q-T interval can be of particular concern to practitioners when prescribing antidepressants and antipsychotics. Patients may be at a greater risk for developing fatal arrhythmias when taking many of these drugs. In general, antipsychotics cause Q-T interval prolongation at a higher rate than do antidepressants. The typical antipsychotics thioridazine, pimozide, and intravenous haloperidol all have the highest potential for Q-T interval prolongation. The tricyclic antidepressants have a higher rate of Q-T interval prolongation than do selective serotonin-reuptake inhibitors (SSRIs), particularly at higher concentrations and in cases of overdose. In addition, nonpharmacologic risk factors such as existing heart disease, female sex, electrolyte abnormalities, hepatic insufficiency, and stimulant drug abuse contribute to the risk for developing these arrhythmias, as do pharmacologic factors such as multidrug therapy and high dosages of drugs known to prolong the Q-T interval. Risk factors may be identified in the patient's history and demographic information. However, all pharmacists may not have this information readily available to them.
Antipsychotics cause Q-Tc interval prolongation at a higher rate than do antidepressants, and the typical anti-psychotics thioridazine, pimozide, and i.v. haloperidol all have the highest potential for Q-Tc interval prolongation. Tricyclic antidepressants have a higher rate of Q-Tc interval prolongation than do the SSRIs, particularly at higher concentrations and in overdose situations. The frequency of adverse events associated with drug-induced Q-T interval prolongation is unknown.
LAAM mainenance vs. methadone mainte-nance for heroin dependence
- A Whelan
- G Dunlop
- A Ritter
Clark N., Lintzeris N., Gjibers A., Whelan G., Dunlop A., Ritter A. et al. LAAM mainenance vs. methadone mainte-nance for heroin dependence. Cochrane Database Syst Rev 2002; 2: CD002210.
Oslo: Norwegian Centre for Addiction Research
- M B Hansen
- H Kornør
- H Statusrapport
Hansen M. B., Kornør H., Waal H. Statusrapport 2003 (OMT in Norway. Evaluation report 2003). Report no: 1/2003. Oslo: Norwegian Centre for Addiction Research; 2003.
Hypokalemia (review)
- Gennari
Prolonged QTc interval and risks of total and cardiovascular mortality and sudden death in the general population: a review and qualitative overview of the prospective cohort studies
- Montanez
LAAM mainenance vs. methadone maintenance for heroin dependence
- Clark
An analysis of the time‐relation of electrocardiograms
- Bazett H. C.