Chronic Methadone Maintenance Research Articles

Biochemical differences between high and low dose methadone clients on stable maintenance therapy

The methadone dose required to prevent withdrawal symptoms in chronic methadone users varies dramatically from 5 to 300 mg/day, which could be attributed to a number of biochemical factors, including human µ-opioid receptor (hMOR) density, down-stream desensitization, concurrent drug use or P-glycoprotein (P-gp) expression, or other, possibly genetic factors. Here we describe some biochemical changes of patients taking higher versus lower doses in chronic methadone maintenance therapy (MMT). hMOR density was measured in leukocytes from methadone-maintained patients receiving lower dose (<100 mg/day) or higher dose (≥100 mg/day) and naive subjects by flow cytometry. Desensitization of receptor signaling was examined by measuring in vivo and attenuated cyclic AMP (cAMP) levels in response to increasing methadone concentrations. P-gp expression and the presence of other drugs were measured using validated methods.

Modulation of Attentional Bias to Drug and Affective Cues by Therapeutic and Neuropsychological Factors in Patients With Opioid Use Disorder on Methadone Maintenance Therapy.

Objective: Abnormal selective attention to drug cues and negative affect is observed in patients with substance dependence, and it is closely associated with drug addiction and relapse. Methadone maintenance is an effective replacement therapy to treat heroin addiction, which significantly reduces the relapse rate. The present study examines whether the patients with opioid use disorder on chronic methadone maintenance therapy exhibit abnormal attentional bias to drug cues and negative-affective cues. Moreover, its relation to therapeutic and neuropsychological factors is also examined.Methods: Seventy-nine patients with opioid use disorder under chronic methadone maintenance therapy and 73 age-, sex-, and education-matched healthy controls were recruited and assessed for attentional bias to drug cues and negative affect using a dot-probe detection task. Correlational analysis was used to examine the relationships between the attentional bias and the demographic, therapeutic, and neuropsychological factors.Results: No significant overall patient-control group difference is observed in drug-related or negative-affective-related attentional bias scores. In the patient group, however, a significant negative correlation is found between the attentional bias scores to negative-affective cues and the duration of methadone treatment (p = 0.027), with the patients receiving longer methadone treatment showing less attentional avoidance to negative-affective cues. A significant positive correlation is found between the negative affect-induced bias and the impulsivity score (p = 0.006), with more impulsive patients showing higher attentional avoidance to negative affective cues than less impulsive patients. Additionally, the patients detect a smaller percentage of probe stimuli following the drug (p = 0.029) or negative-affective pictures (p = 0.009) than the healthy controls.Conclusion: The results of the present study indicate that the patients under chronic methadone maintenance therapy show normalized attentional bias to drug and negative-affective cues, confirming the involuntary attention of the patients is not abnormally captured by external drug or negative-affective clues. Our findings also highlight that the attentional avoidance of negative-affective cues is modulated by the duration of methadone treatment and the impulsivity level in the patients.

Use of Chronic Methadone Before Total Knee Arthroplasty

BackgroundA subset of patients who undergo total knee arthroplasty (TKA) are on methadone maintenance. They require more and often unpredictable quantities of opioids to function as effective painkillers. This study aims to compare the opioid requirements and the immediate postoperative course for patients on methadone maintenance with those who are not, after a TKA. MethodsA retrospective, case-control study was performed. From 2005 to 2010, 36 patients, who underwent a unilateral TKA, on chronic methadone maintenance were identified. A control group matched for age, gender, and body mass index comprised patients from the same period, who did not self-report taking methadone. Chart review and analysis of patient demographics, type of anesthesia used, preoperative methadone use, inpatient opioid use (converted to oral morphine equivalent doses), need for in-house pain management consult, length of hospital stay, and need for reoperation were performed. ResultsPatients on chronic methadone maintenance used significantly more opioids than patients not on methadone during their entire inpatient stay (P < .001). This was demonstrated by a higher median daily usage of opioids and higher patient-controlled analgesia usage. Patients on methadone maintenance had a significantly longer postoperative inpatient hospitalization (P < .001). Finally, these patients required significantly more inpatient pain management referrals (P = .025). ConclusionThere is a significantly higher opioid requirement, length of stay, and pain management consults in patients on methadone maintenance compared with those who are not after a TKA. These patients may benefit from a nonroutine approach to perioperative care in TKA.

Biliary and pancreatic ductal dilation in patients on methadone maintenance therapy.

To determine whether the diameter of intrahepatic and extrahepatic bile ducts and pancreatic ducts in patients on methadone maintenance therapy is increased when compared with control subjects. Between January 1, 2000 and March 15, 2013, a total of 97 patients (mean age 49.9, range 22-79, 65 male, 32 female) were identified who were receiving chronic methadone maintenance therapy (MMT) when they underwent imaging with abdominal MRI or a contrast-enhanced abdominopelvic CT. A group of 97 consecutive non-MMT control patients (mean age 51.4, range 21-86, 45 male, 52 female) who underwent imaging with abdominal MRI or contrast-enhanced abdominopelvic CT were identified. Patients with known pancreaticobiliary pathology that may confound biliary ductal measurements were excluded. Blinded interpretation was performed, documenting the diameters of the intrahepatic and extrahepatic bile ducts and pancreatic ducts. Descriptive statistics were performed. Patients on MMT demonstrated increased bile duct diameter, with an average increase in duct diameter of 2.39mm for the common bile duct (p <0.001; 95% CI 1.88-2.90mm), 1.43mm for the intrahepatic bile ducts (p <0.001; 95% CI 1.12-1.74mm), and 0.90mm for the pancreatic duct (p <0.001; 95% CI 0.64-1.16mm). No statistically significant correlation was found between ductal diameters and the daily dose of methadone. Patients on methadone maintenance therapy demonstrate significantly increased intra- and extrahepatic bile duct and pancreatic duct diameter when compared with controls. There was no correlation between the dose of methadone and ductal diameter.

QTc Prolongation in Acute Methadone Poisoning

Background:Methadone is considered as a good choice for maintenance treatment program (MMTP) in opioid addicted individuals. QT interval prolongation was reported previously in methadone chronic usersespecially in high dose prescription. QT-interval prolongation predisposes patients to lethal dysrhythmia. This is a report of corrected QT(QTc) prolongation due to acute methadone poisoning. To the best of our knowledge, in review of literatures, there is no previous report of QTc prolongation in cases that are not on chronic methadone therapy. Case Report: The patient was a 20 years old man who has occasionally used opium and ice since 8 month before admission. One night before admission he consumed ice and found psychotic state so he was referred to the addiction treatment center and they put him on methadone maintenance treatment with high dose of methadone. After 40 minutes the patient was drowsy and then hypopnea was started. The patient was referred to the hospital and resuscitation was done after naloxone prescription. After stabilizing general conditions the electrocardiograph shows QTc prolongation which was returned to normal status after 2 days. After 5 days the patient was transferred to psychiatric service with normal sinus rhythm and stable condition. Conclusion:QT interval prolongation in chronic methadone maintenance therapy is defined previously especially in patients on other drugs that interact with the CYP3A4 isoenzyme system and who are on high dose methadone treatment, but it seems that acute methadone intoxication also may prolong the QT interval which should be investigated in future studies.

Investigation of the Interactions between Methadone and Elvitegravir-Cobicistat in Subjects Receiving Chronic Methadone Maintenance

Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.

Cognitive impairment in methadone maintenance patients

Few well-controlled studies have examined psychomotor and cognitive performance in methadone maintenance patients (MMP). In the present study, performance of 18 opioid-dependent MMP was evaluated relative to that of 21 control participants without substance abuse histories. The MMP and control groups were balanced with respect to gender, race, age, years of education, current employment status, current reading level, and estimated IQ score. Recent drug abstinence was verified by urine testing. Participants with a urine screen positive for benzodiazepines or a breathalyzer test positive for alcohol prior to performance testing were excluded. To avoid testing under conditions of acute heroin or cocaine intoxication, but without testing under conditions of acute withdrawal, participants with current use of heroin or cocaine were only required to abstain for 24 h prior to performance testing. MMP exhibited impairment relative to controls in psychomotor speed (digit symbol substitution and trail-making tests), working memory (two-back task), decision making (gambling task), and metamemory (confidence ratings on a recognition memory test); results also suggested possible impairment in inhibitory mechanisms (Stroop color-word paradigm). MMP did not exhibit impairment in time estimation, conceptual flexibility or long-term memory. The wide range of impaired functions is striking, and may have important implications for daily functioning in MMP. Further research is necessary to determine the clinical significance of the impairments in laboratory-based tests for daily performance in the natural environment, as well as to differentiate impairments due to acute methadone dosing, chronic methadone maintenance, chronic poly-drug abuse, and other factors.

ACTH, cortisol and β-endorphin response to metyrapone testing during chronic methadone maintenance treatment in humans

Normal responses to metyrapone were observed in most steady-state methadone maintained treatment patients. These preliminary studies suggest that in recently detoxified methadone maintained treatment patients, there may be an exaggerated response of the hypothalamic-pituitary-adrenal axis to metyrapone.

Opioid interactions with alcohol.

Concomitant alcohol and narcotic abuse, and also combined addictive disease or narcotic addiction and alcoholism are very common. Interactions of both a pharmacodynamic and also dispositional type may occur between ethanol and either the short-acting exogenous opioids, such as heroin and morphine, or the long-acting exogenous opioid, methadone. Over half of the so-called "overdose" cases in which exogenous opioids (heroin or methadone) are implicated, are in fact cases in which concomitant abuse of alcohol has played a prominent role. Extensive studies have been carried out to determine factors which may alter the disposition of the long-acting exogenous opioid, methadone, which can be used successfully in the maintenance treatment of addiction. Chronic use of methadone, administered orally, can result in a steady state with respect to both drug levels and overall functioning. Many different physiological systems may be altered by acute or chronic use of short-acting narcotics such as heroin or morphine. Normalization of these functions occurs in the chronic steady state of long-term methadone treatment. However, many factors including chronic liver disease and use abuse of other drugs, including alcohol may alter this steady state. Studies have been carried out to determine the dispositional interactions between ethanol and methadone both in humans and in animal models. Also studies have been carried out to determine the effects of liver disease, which may result from alcohol abuse and/or sequelae of viral hepatitis infection on methadone disposition. Any factor which alters exogenous opioid disposition, specifically the steady state which may be achieved during chronic methadone maintenance treatment, may cause drug hunger and therefore drug-seeking behavior. Interactions between ethanol and methadone and also probably between ethanol and heroin may be major factors in contributing to the concomitant addictive diseases of narcotic addiction and alcoholism and also may contribute to persistent illicit drug use of a narcotic or non-narcotic type in patients receiving methadone treatment for heroin addiction. Treatment goals for the future are discussed in this report.

Circadian rhythms and levels of β-endorphin, acth, and cortisol during chronic methadone maintenance treatment in humans

Previous studies have shown alterations of neuroendocrine function in humans receiving any narcotic on short-term basis or short-acting narcotics on a chronic basis. In this study of 16 well-stabilized patients, it was demonstrated that normalization of hypothalamic-pituitary adrenal axis function, as reflected by normal levels and normal circadian rhthm of levels of β-endorphin, ACTH and cortisol, is achieved during long-term steady state methadone maintenance treatment of former heroin addicts.

The Stimulation of Albumin Synthesis by Methadone

Elevated levels of serum albumin have been noted in patients on chronic methadone maintenance and in heroin addicts. This observation was investigated in rabbits maintained on daily methadone 4 mg per kg of body weight after a period of 3 months on increasing dosage to assure drug tolerance. Albumin distribution and metabolism were measured with tested lots of 125I rabbit albumin. Studies were made before and again after the attainment of the methadone maintenance state. Albumin distribution was altered markedly with a shift of intravascular albumin to extravascular sites. Associated with this change, the serum albumin level rose by an average of 0.5 g per 100 ml. Albumin degradation increased by 32% from 248 to 327 mg per kg per day. The total exchangeable albumin pool increased 35%, or 3.6 g. Since the exchangeable albumin pool increased in the face of an increment in albumin degradation, albumin synthesis must have increased even further to account for this change. Although the specific factors responsible for these alterations in albumin metabolism and distribution are not known at present, to date, this hyperalbuminemic hypercatabolic state is not produceable in any other clinical or experimental situation.