Stable Dose Of Methadone Research Articles

Comparison Between Preoperative Methadone and Buprenorphine Use on Postoperative Opioid Requirement: A Retrospective Cohort Study.

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. A 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, respectively, continued to receive the medications postoperatively. Buprenorphine patients were compared with 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). 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% confidence interval: 46.6%-69.8%, P<0.0001) compared with methadone. Postoperative TWA pain scores for the first 48 hours were 5.0±2.7 (mean±SD), and 5.4±2.3 for buprenorphine and methadone patients, respectively. Preoperative buprenorphine was associated with a 0.37-point lower TWA pain score (95% confidence interval: 0.14-0.61, P=0.002) compared with methadone. Preoperative buprenorphine use was associated with >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 a stable dose of methadone yet.

Acute Experimental Pain Responses in Methadone- and Buprenorphine/Naloxone-Maintained Patients Administered Additional Opioid or Gabapentin: A Double-Blind Crossover Pilot Study

The study objective was to identify the analgesic efficacy of three different pharmacological strategies in patients receiving methadone or buprenorphine as opioid agonist treatment (OAT). The three pharmacological approaches, a) increasing maintenance methadone/buprenorphine dose by 30%, b) adding oxycodone, or c) adding a single dose of gabapentin, were compared with a control condition of the participant's usual OAT dose. A randomized, controlled, double-blinded, double-dummy, within-subject crossover study. Nine participants on stable doses of methadone and eight participants on stable doses of buprenorphine were recruited. An outpatient opioid treatment clinic in inner city Sydney, Australia. The cold pressor tolerance test was used to examine experimental pain threshold and tolerance. Ratings of subjective drug effects and safety measures (physiological and cognitive) were assessed. There was no difference in the primary outcome measures of pain thresholds or tolerance between the conditions examined. Interindividual variability was evident. Differences in some subjective measures were identified, including lower pain recall, lower "bad effects," and higher global satisfaction in the additional methadone condition. In the buprenorphine arm, increased drug liking and "bad effects" were detected with oxycodone administration, while increased subjective intoxication was identified with gabapentin. There was no evidence of an objective improvement in analgesia with any condition compared with control. Further research is required to optimize pain management strategies in this population.

Benzodiazepine withdrawal in pregnant women with opioid use disorders: An observational study of current clinical practices at a tertiary obstetrical hospital

BackgroundAs more patients are admitted for medical complications related to opioid use disorders, physicians are called upon to manage withdrawal from co-occurring substance use disorders. We present an observational study of pregnant women with comorbid opioid and sedative-hypnotic use disorders hospitalized for benzodiazepine withdrawal. ObjectivesOur primary aims were to assess current practices in withdrawal management in the perinatal period in patients admitted to an antepartum unit at a tertiary care setting with comorbid opioid and sedative-hypnotic use disorders; specifically, to identify patterns of withdrawal management, including the type of withdrawal protocol utilized, the total dosage of benzodiazepine used during that protocol, to assess patient variables associated with higher dosing, and to analyze neonatal outcomes. MethodsA chart review of psychiatry consultations for benzodiazepine withdrawal in antepartum women was conducted for patients seen over a 3 year period with manual extraction of patient age, number of pregnancies, modality of benzodiazepine withdrawal management (symptom-triggered versus standing benzodiazepine taper), total amount of benzodiazepine used during the detoxification period, active methadone conversion versus stable methadone dose on admission, and average fetal heart tones during the withdrawal detoxification period. ResultsThe majority of patients (83%) were undergoing methadone conversion or were stable on methadone maintenance. The mean cumulative benzodiazepine dose used was 8.3 ± 10.5 mg in lorazepam equivalents. Women placed on a symptom-triggered protocol received lower mean benzodiazepine doses (2.4 ± 6.9 mg) compared to those on a benzodiazepine taper in conjunction with a symptom-triggered protocol (17.9 ± 20.6 mg; p < 0.001). Women who started methadone during admission tended to receive lower mean lorazepam doses (7.1 ± 10.4) compared to women admitted on stable outpatient doses of methadone (11.5 ± 10.6; p = 0.07). Using t-test and chi-square analyses on a subgroup of women (N = 50), no differences were found between women placed on a taper compared to a symptom-triggered scale alone in neonatal outcomes such as APGARS, NICU admissions, and preterm delivery with low rates of complications in both groups. ConclusionsA symptom-triggered benzodiazepine withdrawal protocol was associated with significantly lower total benzodiazepine use compared to standing taper regimens. Women started on methadone during admission tended to receive lower lorazepam doses compared to women admitted on stable doses of methadone. Preliminary maternal/neonatal outcomes were similar between symptom-triggered and taper groups.

Leaving Hospital Against Medical Advice After Methadone Discontinuation in the Intensive Care Unit: A Case Report

ABSTRACT Methadone is an effective and widely used opioid agonist treatment for reduction and cessation of illicit opioid use. Once a stable dose is achieved, interruptions in treatment are not recommended given the increased risk of relapse and the potential for overdose. Despite comprehensive clinical care guidance on the initiation and administration of methadone in the outpatient setting, there is limited guidance for the continuation of methadone in the hospital or critical care setting. Additionally, little is known about potential morbidity associated with methadone treatment interruption in hospital. This case describes the clinical course of a 58-year-old female who had been on a stable dose of methadone at 120 mg daily. She was admitted to the intensive care unit following the onset of decreased level of consciousness and hypoxia with subsequent respiratory failure. Although intubated in the intensive care unit, her methadone was discontinued. Given the length of time methadone was withheld, she required re-initiation at a dose of 30 mg daily. This led to severe withdrawal symptoms, use of illicit opioids while in hospital, and eventually leaving hospital prematurely against medical advice despite potentially life-threatening active medical issues. This case highlights the potential morbidity of methadone treatment interruption in the hospital setting. Additional research is needed to understand how to manage methadone and potential treatment interruptions during acute medical illness.

Motivational Interviewing Can Facilitate Entry to Matrix Treatment for Methamphetamine Dependence

Background: Methamphetamine dependence on a stable methadone dose is a health problem in Iran (i.e. the most populated Persian Gulf country). However, many Iranian patients are not motivated to enter treatment. Objectives: The study aimed to assess the efficacy of motivational interviewing for entry to matrix treatment for methamphetamine dependence. Methods: A study was conducted on 275 Persian male and female methadone patients who were methamphetamine-dependent, however they reported unwillingness to receive the matrix model. The study was conducted in 20 methadone services in Karaj, Iran during 2014. Addiction severity index was used to collect data on demographics and illicit drug use. Psychological well-being and social functioning were assessed using the Persian versions of the general health questionnaire-28 and the social functioning subscale of the opiate treatment index. Results: The study indicated that 5 sessions of motivational interviewing were significantly efficacious in increasing attendance in the Matrix Model in the treatment group (P < 0.001). Attendance in motivational interviewing was significantly accompanied with increased psychological well-being (P < 0.001) and social functioning (P < 0.001). Conclusions: Motivational interviewing should be provided for those participants who are methamphetamine dependent but are not motivated for change. Conducting randomized controlled trials is suggested.

Impact of SNP-SNP interaction among ABCB1, ARRB2, DRD1 and OPRD1 on methadone dosage requirement in Han Chinese patients.

To evaluate the potential association of the genetic polymorphisms in ABCB1, ARRB2, DRD1 and OPRD1 genes with methadone dosage requirement among Han Chinese opioid-dependent patients. Eight SNPs in ABCB1, ARRB2, DRD1 and OPRD1 genes were selected and genotyped using Sequenom MassARRAY platform among 257 methadone maintenance treatment patients. The required information about stable methadone dose, urine analysis for opioid and socio-demographic characteristics was collected. Generalized multifactor dimensionality reduction method was performed to analyze the SNP-SNP interaction. We found that patients carrying the rs529520TG genotype of OPRD1 probably required higher methadone treatment dosage. A 3-locus SNP-SNP interaction pattern (rs1128503 in ABCB1, rs529520 in OPRD1 and rs1045280 in ARRB2) was significantly associated with the methadone dosage requirement (p=0.029). Our results suggested that specific OPRD1 variants and interaction among polymorphisms in ABCB1, OPRD1 and ARRB2 genes contributes to methadone dosage requirement in Han Chinese opioid-dependent patients.

Clinical Outcomes of Start-Low, Go-Slow Methadone Initiation for Cancer-Related Pain: What's the Hurry?

Methadone has been shown to be effective for cancer pain. Most published switching methods are complete in less than three days, requiring very close supervision, usually in an inpatient setting. This need for hospitalization is a barrier to access. We present a large retrospective study of slow outpatient methadone starts and describe our starting method. Charts were reviewed of patients referred to the Pain and Symptom Management/Palliative Care clinics at the six BC Cancer Agency's regional centers that underwent initiation of methadone for analgesia over a 14-year period. Patient characteristics, method of start, and outcomes of methadone treatment were recorded. Of the 652 identified patients, we were able to determine outcomes of methadone initiation in 564 (86.5%). Among these, 422 (74.8%) were deemed successful initiations, as determined by whether or not the patient remained on methadone at follow-up with subjective improvement in pain control, on a stable dose of methadone. Of the unsuccessful trials, 97/142 were primarily due to adverse events, 16 of which were considered serious enough to require hospitalization, including two due to sudden cessation of opioid therapy leading to withdrawal. Some of the included adverse events were not necessarily causal from the initiation of methadone, for example, development of bowel obstruction or delirium. Only one death occurred from a deliberate overdose of multiple medications, including methadone. Initiation of methadone for analgesia in ambulatory cancer patients can be done safely in an outpatient setting using a start-low go-slow method, and can be expected to be helpful in ∼75% of patients. Discontinuation is more likely to be for side effects than for inadequate analgesia. Access to methadone therapy can safely be widened by slow initiation, avoiding more dangerous rapid switching protocols and reducing the need for hospitalization.

Opioid Use among Women on a Stable Methadone Dose

Background: Opioid use on a stable methadone dose is a health concern in Iran, the most populous Persian Gulf country. However, the underlying reasons associated with opioid use have not been studied. Objectives: The study aimed to explore the reasons associated with opioid use among a group of Persian methadone-maintained women. The other aim was to explore effective interventions to stop this problem. Methods: The current qualitative study was conducted between June 2008 and December 2009. The study sites included ten large methadone treatment clinics in Tehran. The study employed semi-structured interviews with 50 women. Six roundtable meetings were conducted with nine key informants. NVivo 10 was used to thematically analyze the data. Results: Women were on a stable methadone dose of 45 - 115 mg for at least six months. Opioid availability, an opioid-dependent lifestyle, peer pressure and self-treatment were the reasons of opioid use. The provision of cognitive-behavioral therapy, life skills, observational learning, and mental health services were the suggested interventions to stop opioid use. Conclusions: Opioid use on a stable methadone dose had been facilitated by some factors which should be considered in methadone treatment. The suggested interventions should be considered in increasing methadone treatment outcomes.

Cognitive-Behavioral Therapy for Opiate Users in Methadone Treatment: A Multicenter Randomized Controlled Trial

Background: Opiate use on a stable methadone dose is a health concern in Iran (Persia). Cognitive-behavioral therapy (CBT) is a suggested treatment for this problem. Objectives: The study aimed to assess the CBT effectiveness in the treatment of regular opiate use on a stable methadone dose in Shiraz, near the Persian Gulf of Iran. Methods: The study design was a multicenter randomized controlled trial. The study was conducted at two methadone clinics during 2015. Overall, 118 patients who were regular opiate users were selected. Participants were randomly assigned (1:1) to receive either CBT (n = 59) or remain in a control condition (n = 59). The Opiate Treatment Index, Contemplation Ladder and Severity of Dependence Scale were completed at baseline, post-treatment and a three-month follow-up. The primary outcome was the reduced mean score of regular opiate use. Other outcomes included an increased readiness to reduce opiate use and reduced severity of opiate dependence. Data were analyzed performing intentions-to-treat analyses, independent samples t-tests and Wilcoxon Rank- Sum tests. Results: CBT significantly reduced opiate use (z = 3.73, P = 0.01, d = 0.89) and the severity of opiate dependence (z = 7.36, P = 0.01, d = 0.64) after four weeks of treatment. Readiness to reduce opiate use significantly increased (t (116) = 9.55, P = 0.01, d = 0.81) over the same time. All study results remained stable at three-month follow-up while no significant change was found in the control group. Conclusions: CBT can be used as an effective intervention to reduce regular opiate use on a stable methadone dose. A larger study with more Persian participants and a six-month follow-up is suggested. © 2017, Mazandaran University of Medical Sciences.

Methadone

Methadone

QTc Prolongation in Veterans With Heroin Dependence on Methadone Maintenance Treatment.

Background:QTc prolongation and Torsade de Ppointes have been reported in patients on methadone maintenance.Objectives:In this study, QTc was compared before and after the veteran (n = 49) was on a stable dosage of methadone for 8.72 ± 4.50 years to treat heroin dependence. Risk factors were correlated with the QTc once the veteran was on a stable dose of methadone. Differences in the clinical risk factors in subgroups of veterans with below and above mean QTc change was compared.Patients and Methods:ECG data was obtained from a 12-lead electrocardiogram (pre-methadone and on methadone) on 49 veterans. Data and risk factors were retrospectively collected from the medical records.Results:The mean QTc at baseline (pre-methadone) was 426 ± 34 msec and after being on methadone for an average of 8.72 ± 4.50 years was significantly higher at 450 ± 35 msec. No significant relationships were found between QTc prolongation and risk factors except for calcium. The methadone dosage was significantly higher in veterans with a QTc change above the mean change of ≥ 24 msec (88.48 ± 27.20 mg v.s 68.96 ± 19.84 mg). None of the veterans experienced cardiac arrhythmias.Conclusions:The low complexity of medical co-morbidities may explain the lack of a significant correlation between any risk factor with the QTc except calcium and methadone dosage. The absence of TdP may be explained by the low prevalence of QTc values > 500 msec as well as the retrospective design of the study. During long-term methadone treatment, there was a slight increase in the QTc interval but we did not find evidence of increased cardiac toxicity as a reason for treatment termination.

Reliability of the Beck Depression Inventory in opiate-dependent patients

Background: The prevalence of depressive disorder in opioid-dependent patients in methadone treatment has been found to be between 19 to 74.3%. Beck Depression Inventory (BDI) is commonly used as a screening for depressive symptoms. The objective of this study is assessing BDI in opiate-dependent patients.Methods: A total of 415 patients over 18 years old in a methadone maintenance program that is part of an outpatient drug clinic treated with stable doses of methadone in the last month were assessed using Structured Clinical Interview for Axis I Disorders of the DSM-IV (SCID-I) and BDI.Results: A sample of 118 patients completed the evaluation; 77.96% showed depressive symptoms (N: 92) (BDI scores ≥ 10). Patients who met criteria for depression with SCID-I and BDI (6.7%) showed a higher score in BDI which did not reach significance. Statistical differences were found in the depressive group. Predictive value of BDI was 6.61% with a cut-off point of BDI ≥ 10, growing to 11.7% with a cut-off point of BDI > 30.Conclusions: BDI is not effective for diagnosing depressive disorder. An adequate psychometric tool is needed to improve the detection of depressive symptoms and depressive diagnosis in opiate-dependent patients in order to reduce risk of relapse and improve treatment strategies.

Methadone Toxicity Due to Smoking Cessation—A Case Report on the Drug-Drug Interaction Involving Cytochrome P450 Isoenzyme IA2

To report the potential clinically significant pharmacokinetic interaction that may result from smoking cessation in patients on methadone maintenance therapy. A 46-year-old white man was admitted to the step-down intensive care unit with decreased respirations and altered mental status related to methadone toxicity. The patient had been on a stable dose of methadone for chronic back pain, and he reported a 1 pack per day, 33-year history of cigarette smoking. After methadone was held for 3 days, his mental status improved. It was later revealed that he had initiated smoking cessation. He was discharged home on a reduced dose of methadone with no further complications. While the potential for toxicity exists for patients who are maintained on methadone and decrease the number of cigarettes they smoke, to our knowledge, there is no recent peer-reviewed literature on this interaction. Methadone is a synthetic opioid primarily metabolized by CYP3A4 and, to a lesser degree, by other isoenzymes, including CYP1A2. Polycyclic aromatic hydrocarbons found in tobacco smoke are known CYP1A2 inducers. Decreased intake of cigarette smoke can lead to a reduction in methadone metabolism, resulting in higher serum concentrations. Our case is an example of methadone toxicity secondary to smoking cessation in a patient on methadone maintenance therapy. An objective causality assessment based on the Horn Drug Interaction Probability Scale revealed the interaction to be probable. Patients on methadone should be monitored for signs of methadone toxicity upon the start of smoking cessation, and the dose of methadone should be adjusted accordingly. Additional information and reports cautioning clinicians and patients about this potential interaction would be beneficial.

Interaction between Methadone and Ciprofloxacin

The cytochrome P450 (CYP450) system comprises more than 40 individual enzymes that have been identified in humans. Six major CYP450 isoenzymes are responsible for more than 90% of oxidation of drugs in humans: 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1. Methadone is metabolized by several CYP450 isoenzymes (1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2D6) to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), an inactive metabolite. CYP3A4 is considered the primary isoenzyme responsible for metabolism, followed by CYP2D6. Various drugs may inhibit the CYP450 system. Among the quinolone antibiotics, ciprofloxacin has been demonstrated in vitro to be one of the more potent of these inhibitors, affecting in particular CYP1A2 and CYP3A4. However, the clinical response is sometimes difficult to predict, and the significance of the interaction differs among patients. This report describes a patient who was receiving a stable dose of methadone for treatment of heroin addiction and in whom severe respiratory depression developed after initiation of ciprofloxacin for aspiration pneumonia.

Response to Methadone Maintenance Treatment is Associated with the MYOCD and GRM6 Genes

There is increasing interest in the pharmacogenetic basis for explaining differences between patients in treatment outcome among methadone-treated subjects. Most studies have focused on genetic polymorphisms related to methadone pharmacokinetics and, to a lesser extent, those genes implicated in the pharmacodynamics of methadone. This study aimed to investigate the associations between response to methadone maintenance treatment (MMT) and polymorphisms in genes coding for the OPRM1 opioid receptor, the metabotropic glutamate receptors GRM6 and GRM8, the nuclear receptor NR4A2, the photolyase enzyme cryptochrome 1 (CRY1), and the transcription factor myocardin (MYOCD), which have previously been associated with the risk of opioid dependence disorder. The study used an association, case-control design, conducted in the setting of an MMT program in a drug abuse outpatient center in Barcelona, Spain. We recruited 169 opioid-dependent patients (diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders [4th Edition] criteria) receiving MMT. The inclusion criteria included Caucasian ethnicity, being enrolled in MMT for at least 6 months, and receiving a stable methadone dose for the previous 2 months. The exclusion criteria included language-related barriers, severe cognitive impairment, or any medical disorder that would interfere with the research assessments. Single nucleotide polymorphism (SNP) variants in several candidate genes and regions were genotyped: MYOCD (rs1714984), GRM8 (rs1034576), CRY1 (rs1861591), GRM6 (rs953741), OPRM1 (rs1074287), NR4A2 (rs1405735), and the intergenic variants rs965972 (1q31.2) and rs1867898 (2q21.2). MMT response status was assessed by the number of opioid-positive controls detected by random urinalysis in the previous 2 months. We used the chi-squared test and p-value for the allele frequencies of the eight SNPs in responders versus nonresponders, and multivariate logistic regression analyses to examine associations between genotypes in the responder and ronresponder groups under codominant, dominant, and recessive models of inheritance. A final sample of 116 opioid-dependent patients were included and classified as methadone responders (n = 83) and nonresponders (n = 33), according to illicit opioid use detection in random urinalysis. The responders and nonresponders showed similar demographic and clinical characteristics. All SNPs were in Hardy-Weinberg equilibrium. Subjects carrying the AA genotype at rs1861591 (CRY1; Chr 12: 105941056 G>A) had a higher risk of being nonresponders (odds ratio [OR] = 2.99; 95% CI 1.14, 7.85; p = 0.035), although this difference disappeared with multiple testing corrections. Patients carrying the A allele at rs1714984 (MYOCD; Chr 17: 12558425 G>A) had an increased risk of being nonresponders only if they were also carriers of the AG genotype at rs953741 (GRM6; Chr5: 178262451 A>G) [OR = 10.83; 95% CI 2.52, 46.66; p = 0.006]. A positive association was observed between response to methadone and two variants in the genes MYOCD and GRM6. A pharmacogenetic epistatic effect between SNPs in MYOCD and GRM6 appears to modulate inter-individual variations in MMT response.

Dosing Adjustments in Postpartum Patients Maintained on Buprenorphine or Methadone

Scant scientific attention has been given to examining the need for agonist medication dose changes in the postpartum period. Study objectives were: 1) to determine the need for medication dose adjustments in participants stabilized on buprenorphine or methadone 3 weeks before and 4 weeks after delivery, and 2) to evaluate the need for methadone dose adjustments during the first 7 days in participants transferred from buprenorphine to methadone at 5 weeks postpartum. Participants were opioid-dependent pregnant women who had completed a randomized, double-blind, double-dummy, flexible dosing comparison of buprenorphine to methadone. Participants received a stable dose of methadone (N = 10) or buprenorphine (N = 8) before and 4 weeks after delivery. Buprenorphine-maintained participants were transferred to methadone at 5 weeks postpartum. There were no significant differences predelivery and/or postdelivery between the buprenorphine and methadone conditions in the mean ratings of dose adequacy, "liking," "hooked," and "craving" of heroin or cocaine. Patient response to the conversion from buprenorphine to methadone seems variable. Buprenorphine-maintained participants required dose changes postpartum only after they transferred to methadone. Regardless of type of medication, postpartum patients should be monitored for signs of overmedication.

Divided Doses for Methadone Maintenance

Divided Doses for Methadone Maintenance

Intravenous and intranasal heroin‐dependent treatment‐seekers: characteristics and treatment outcome

This study compared the characteristics of intravenous (i.v.) and intranasal (i.n.) heroin users seeking methadone treatment, and their response to treatment. A total of 319 heroin-dependent adults. Participants were assigned randomly to receive interim methadone treatment or to a waiting list control on a 3 : 2 basis. Analyses were conducted by dividing participants into two groups based on their route of heroin ingestion: i.v. or i.n. A methadone clinic in Baltimore City, Maryland. Interim methadone treatment consisted of providing an adequate and stable dose of methadone, but no psychosocial services, to heroin-dependent adults for up to 120 days while they awaited an opening for comprehensive methadone treatment. Addiction Severity Index, Texas Christian University AIDS Risk Assessment, a questionnaire on treatment entry and a urine drug test were collected at baseline and at entry into a comprehensive treatment program, or at 120 days after baseline assessment, whichever came first. At baseline, over 60% of participants were i.n. users and had been for an average of over 12 years; i.v. users, compared to i.n. users, were more likely to have ever used cocaine, to have used cocaine in the past 30 days, to have more medical complications and to report more income generated from criminal behavior. Both i.v. and i.n. users reduced their self-reported days of heroin use, cocaine use and days of criminal activity in response to interim methadone treatment. Despite differences in baseline characteristics, i.n. and i.v. heroin-dependent individuals did not differ in their response to interim methadone treatment.

A combined spectroscopic and functional MRI investigation of the dorsal anterior cingulate region in opiate addiction

Converging neuropsychological and functional neuroimaging evidence indicates that the dorsal anterior cingulate cortex (dACC) is dysfunctional in drug-addicted populations. Few studies, however, have investigated the biochemical and physiological properties of the dACC in such populations. We used proton magnetic resonance spectroscopy ((1)H-MRS) together with functional magnetic resonance imaging (fMRI) to probe dACC biochemistry and physiological activity during performance of a behavioural control task in 24 opiate-dependent individuals (maintained on a stable dose of methadone or buprenorphine at the time of study) and 24 age, gender, intelligence and performance-matched healthy subjects. While both groups activated the dACC to comparable levels, the opiate-using group displayed relatively increased task-related activation of frontal, parietal and cerebellar regions, as well as reduced concentrations of dACC N-acetylaspartate and glutamate/glutamine. In addition, the opiate-using group failed to show the expected correlations between dACC activation and behavioural measures of cognitive control. These findings suggest that the dACC is biochemically and physiologically abnormal in long-term opiate-dependent individuals. Furthermore, opiate addicts required increased, perhaps compensatory, involvement of the fronto-parietal and cerebellar behavioural regulation network to achieve normal levels of task performance/behavioural control. These neurobiological findings may partly underpin key addiction-related phenomena, such as poor inhibitory control of drug-related behaviour in the face of adverse consequences, and may be of relevance to the design of future treatment studies.

Opioid Switching from Morphine to Methadone Causes a Minor But Not Clinically Significant Increase in QTc Time: A Prospective 9-Month Follow-Up Study

Case reports and retrospective studies suggest that methadone causes an increase in QTc (QT time corrected for heart rate) time and risk of torsades de pointes arrhythmia. No prospective studies in pain patients have been conducted, and data on whether a methadone-induced increase in QTc time persists during long-term treatment have not been reported. Eight chronic nonmalignant pain patients experiencing insufficient pain control or intolerable side effects during treatment with oral morphine switched to oral methadone and were included in this study. Electrocardiograms were obtained at baseline and at follow-up 2 weeks, and 3 and 9 months after the opioid switch. Start of methadone caused a minor but statistically significant increase in QTc time, while fluctuations in QTc during treatment with stable doses of methadone were neither clinically nor statistically significant. We observed no episodes of arrhythmias.