The Use of the Methadone/Metabolite Ratio (MMR) to Identify an Individual Metabolic Phenotype and Assess Risks of Poor Response and Adverse Effects: Towards Scientific Methadone Dosing.

OBJECTIVES: Significant genetic variability of metabolism confounds reliable clinical use of methadone because physicians have no way of identifying individual patient metabolism. The methadone/metabolite ratio (MMR), the numerical ratio of serum methadone to its inactive metabolite ethylidine-dimethyl-diphenypyrrolidine (EDDP), represents the net expression of the genes controlling metabolism. The MMR has been adapted to four established pharmacogenetic metabolic categories: ultra-rapid (URM), extensive (EM, normal), intermediate (IM), and ultra-slow (USM). METHODS: This study reports on the analysis of 1700 paired peak and trough serum samples for methadone and EDDP. The MMR data were stratified by metabolic category. The reliability of these categories and the relationship of the MMR to 2 other laboratory assessments, a peak/trough ratio (PTR) and a methadone half-life, was tested. Additionally, peak and trough serum levels were analyzed by MMR category. RESULTS: Each category of MMR identified significantly different mean serum levels (peak and trough), peak/trough ratios, and half-lives. When serum levels were analyzed, evidence of subtherapeutic serum levels were found, predominantly in the URM and EM categories. Seventeen percent of peak serum levels were greater than 1000 ng (a level indicating potential toxicity) with a range up to 2384 ng, predominantly in the IM and USM categories. CONCLUSIONS: The MMR measures an individual's phenotype for methadone metabolism. The data suggested underdosing in the URM category, as well as evidence of excessive dosing in IM and USM categories. The MMR provides a guide to safe and effective dosing, an alternative to the pharmacokinetically 'blind' dosing algorithms currently in use.

The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics.

OBJECTIVES: Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. METHODS: Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. RESULTS: The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P = 0.007), and then rose significantly from trimester 3 to postpartum (P = 0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8% to 30% to 38% across trimesters, and decreased to 5% postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. CONCLUSIONS: This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally.

Opioid dependence and pregnancy: minimizing stress on the fetal brain.

Increase in the number of opioid-dependent pregnant women delivering babies at risk for neonatal abstinence syndrome prompted a US Government Accountability Office report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate. There are 3 general sources of dependence: untreated opioid use disorder, pain management, and medication-assisted treatment with methadone or buprenorphine. A survey of methadone patients' experiences when telling a physician of their pregnancy and opioid dependence demonstrated physician confusion about proper care, frequent negative interactions with the mother, and failures to provide appropriate referral. Patients in pain management were discharged without referral when the physician was told of the pregnancy. Methadone and buprenorphine were frequently seen negatively because they "caused" neonatal abstinence syndrome. Most mothers surveyed had to find opioid treatment on their own. How dependence is managed medically is a critical determinant of the level of stress on both mother and fetus, and therefore another determinant of neonatal health. The effects of both opioid withdrawal stress and maternal emotional stress on neonatal and developmental outcomes are reviewed. Currently, there have been efforts to criminalize maternal opioid dependence and to encourage or coerce pregnant women to undergo withdrawal. This practice poses both acute risks of fetal hypoxia and long-term risks of adverse epigenetic programming related to catecholamine and corticosteroid surges during withdrawal. Contemporary studies of the effects of withdrawal stress on the developing fetal brain are urgently needed to elucidate and quantify the risks of such practices. At birth, inconsistencies in the hospital management of neonates at risk for neonatal abstinence syndrome have been observed. Neglect of the critical role of maternal comforting in neonatal abstinence syndrome management is an iatrogenic and preventable cause of poor outcomes and long hospitalizations. Rooming-in allows for continuous care of the baby and maternal/neonatal attachment, often unwittingly disrupted by the neonatal intensive care unit environment. Recommendations are made for further research into physician/patient interactions and into optimal dosing of methadone and buprenorphine to minimize maternal/fetal withdrawal.

The effect of methadone dose regimen on neonatal abstinence syndrome.

OBJECTIVES: To evaluate the effects of a multiple daily dose methadone regimen in pregnancy on neonatal outcomes. METHODS: Although methadone maintenance has been the standard for the treatment of opioid dependence in pregnancy, there is no consensus on proper dosing. Single daily dosing is the most common strategy. Because of accelerated metabolism of methadone in pregnancy, this regimen may expose mother and fetus to daily episodes of withdrawal and possibly contribute to more severe Neonatal Abstinence Syndrome (NAS). This study reports on a protocol that increased both methadone dose and dose frequency in response to maternal reports of withdrawal. RESULTS: Treatment of NAS was needed in 29% of neonates, compared to a published rate of 60% to 80%. The mean methadone dose was 152 mg at delivery, divided into 2 to 6 doses per day. Ninety-two percent of mothers were free of illicit drug use at delivery. There was no relationship between methadone dose and treatment of NAS. Female babies had a treatment rate of 16% versus 38% for male babies. Beyond abstinence symptoms, cohort outcomes in terms of gestational age, birth weight, prematurity, Caesarian sections, and breastfeeding equaled or approximated US population norms. CONCLUSIONS: The protocol was associated with low rates of treatment of NAS and high rates of maternal recovery. High rates of treatment for NAS reported in methadone-exposed neonates might relate in part to iatrogenic factors and be reduced through the use of divided daily doses and protocols that minimize maternal withdrawal.

Predictors of methamphetamine psychosis: history of ADHD-relevant childhood behaviors and drug exposure.

The goal of this study was to extend our previous research that reported a significant association between Attention Deficit Hyperactivity Disorder (ADHD)-relevant childhood behaviors and the frequency of methamphetamine (MA)-induced psychotic symptoms in an expanded sample. 190 participants who met DSM-IV criteria for MA dependence were administered the Methamphetamine Experience Questionnaire that assessed MA-induced psychosis. Data related to MA exposure, comorbid drug use, education, familial psychiatric history and assessments of ADHD-relevant childhood behaviors as measured by the Wender Utah Rating Scale (WURS) were collected. Although WURS scores did not differ between 145 MAP+ and 45 MAP- subjects, MAP+ subjects with higher WURS scores were significantly more likely to report more frequent psychosis. Although mean daily MA dosage did not differ between the MAP+ and MAP- subjects, MAP+ subjects who consumed larger doses of MA were significantly more likely to experience frequent psychosis. These data suggest that ADHD-relevant childhood behaviors may interact with MA exposure to reflect a neurobiological vulnerability related to the emergence of frequent MA-induced psychotic symptoms. These results may elucidate factors that contribute to the psychiatric sequelae of MA abuse.

Psychiatric comorbidity in methamphetamine dependence.

The primary aim of the present study was to assess the prevalence of psychiatric comorbidity in a large sample of methamphetamine (MA)-dependent subjects using a validated structured clinical interview, without limitation to sexual orientation or participation in a treatment program. The secondary aim was to assess whether the prevalence of psychiatric comorbidities varied by gender. Structured clinical interviews (SCIDs) were administered to 189 MA-dependent subjects and lifetime prevalence of DSM-IV diagnoses was assessed. Across the sample, 28.6% had primary psychotic disorders, 23.8% of which were substance-induced; 13.2% had MA-induced delusional disorders and 11.1% had MA-induced hallucinations. A substantial number of lifetime mood disorders were identified that were not substance-induced (32.3%), whereas 14.8% had mood disorders induced by substances, and 10.6% had mood disorders induced by amphetamines. Of all participants, 26.5% had anxiety disorders and 3.7% had a substance-induced anxiety disorder, all of which were induced by MA. Male subjects reported a higher percentage of MA-induced delusions compared to female abusers. Given the impact of MA psychosis and other drug-induced symptoms on hospitals and mental health services, the description and characterization of comorbid psychiatric symptoms associated with MA use is of paramount importance.

General-medical hospital admissions from a public inpatient psychiatric health facility: a review of medical complications over 30 months.

BACKGROUND: Medical comorbidity and mortality disproportionately affect adults with serious mental illness, as compared with the general population. OBJECTIVE: This study examined the medical diagnoses of patients transferred from a psychiatric health facility to general-medical hospitals. METHOD: The authors retrospectively reviewed the charts of 81 adult patients admitted to an inpatient psychiatric facility who were subsequently transferred to local general-medical hospitals from January 2005 to June 2007. RESULTS: Of 6,688 separate inpatient admissions, 81 patients (2.1%) were admitted to general-medical hospitals a total of 93 times, and had 108 admitting medical diagnoses. The leading admission indications were infections (N=33; 34%), electrolyte or nutritional abnormalities (N=12; 11%), and cardiovascular disorders (N=12; 11%). Iatrogenic causes related to psychiatric medications accounted for a small proportion of medical admissions (N=8; 7.5%). Over 90% of the patients had chronic medical disorders, and 80% of the patients had a psychotic or bipolar disorder. CONCLUSION: Patients with severe mental illness and chronic medical disorders may experience significant acute medical complications during inpatient psychiatric treatment. Given the complex care issues involved, continued vigilance in treating or preventing these conditions is warranted.

Methamphetamine and paranoia: the methamphetamine experience questionnaire.

Paranoia in methamphetamine (MA) users is not well characterized or understood. To investigate this phenomenon, we created the Methamphetamine Experience Questionnaire (MEQ), and tested its reliability and validity in assessing MA-induced paranoia. We administered the MEQ to 274 MA-dependent subjects. Of the total subjects, 45% (123) first experienced paranoia with MA use; 55% did not. Obtaining or using a weapon while paranoid was common (37% and 11% of subjects with MA-induced paranoia, respectively). Test-retest and inter-rater reliability for MA-induced paranoia showed substantial agreement (kappa = .77, p < .05 and kappa = .80, p < .05, respectively). First episodes of paranoia occurred more often with intravenous use of MA, and subsequent episodes at higher doses. There was modest correlation between paranoia on the MEQ and the Brief Symptom Inventory (BSI) paranoid ideation scale (rho = .27, p < .05). As expected, there was a poor correlation between paranoia on the MEQ and the BSI depression scale (rho = .14, p = .07). The MEQ provides useful information on drug use variables that contribute to paranoia commonly associated with MA use. (Am J Addict 2010;00:1-14).

Drug abstinence and cognitive control in methamphetamine-dependent individuals.

Chronic methamphetamine (MA) abuse is associated with disruption of frontostriatal function as well as deficits in cognitive control. To examine the relationship between drug use patterns and cognitive deficits, we pooled previously published behavioral data with new data collected using the Stroop Attention Test. Subject groups are composed of 38 MA-abusing individuals who recently initiated abstinence (36.1 +/- 8.8 years of age), 27 MA-abusing individuals who had initiated abstinence more than 1 year prior to study (38.7 +/- 7.7 years of age), and 33 non-substance-abusing controls (33.9 +/- 8.5 years of age). The recently abstinent MA-abusing individuals exhibited greater Stroop reaction time (RT) interference compared with both the control group (p = .001) and the long-term abstinent MA-abusing individuals (p = .01). No difference was seen between long-term abstinent MA-abusing individuals and controls (p = .87). Stroop RT interference correlated positively with both duration of drug use (p = .003) and drug abstinence (p = .05). The data in the current study provide evidence that cognitive function may improve with protracted drug abstinence.

Impaired prefrontal cortical function and disrupted adaptive cognitive control in methamphetamine abusers: a functional magnetic resonance imaging study.

BACKGROUND: Methamphetamine (MA) abuse is associated with neurotoxicity to frontostriatal brain regions with deleterious effects on cognitive processes. Deficits in behavioral control are thought to be one contributing factor to the sustainment of addictive behaviors in MA abuse. METHODS: In order to examine patterns of behavioral control relevant to addiction, we employed a fast-event-related functional magnetic resonance imaging design to examine trial-to-trial reaction time (RT) adjustments in 12 MA-dependent subjects and 16 non-substance-abusers. A variant of the Stroop task was employed to contrast the groups on error rates, RT conflict, and the level of trial-to-trial adjustments seen after incongruent trials. RESULTS: The MA abusers exhibited reduced RT adjustments and reduced activation in the right prefrontal cortex compared to controls on conditions that measured the ability to use exposure to conflict situations (i.e., conflict trials) to regulate behavior. The groups did not differ on accuracy rates or within-trial Stroop conflict effects. CONCLUSIONS: The observed deficits in trial-to-trial RT adjustments suggest that the ability to adapt a behavioral response based on prior experience may be compromised in MA abusers. These failures to modify behavior based on prior events may reflect a deficit that contributes to drug-seeking behavior.

Cognitive control and white matter callosal microstructure in methamphetamine-dependent subjects: a diffusion tensor imaging study.

BACKGROUND: Methamphetamine (MA) abuse causes damage to structures within the human cerebrum, with particular susceptibility to white matter (WM). Abnormalities have been reported in anterior regions with less evidence of changes in posterior regions. Methamphetamine abusers have also shown deficits on attention tests that measure response conflict and cognitive control. METHODS: We examined cognitive control with a computerized measure of the Stroop selective attention task and indices of WM microstructure obtained from diffusion tensor imaging (DTI) in the callosal genu and splenium of 37 currently abstinent MA abusers and 17 non-substance abusing control subjects. Measurements of fractional anisotropy (FA), apparent diffusion coefficient (ADC) of callosal fibers, and diffusion tensor eigenvalues were obtained in all subjects. RESULTS: The MA abusers exhibited greater Stroop reaction time interference (i.e., reduced cognitive control) (p = .04) compared with control subjects. After correcting for multiple comparisons, FA within the genu correlated significantly with measures of cognitive control in the MA abusers (p = .04, Bonferroni corrected) but not in control subjects (p = .26). Group differences in genu but not splenium FA were trend significant (p = .09). CONCLUSIONS: Methamphetamine abuse seems to alter anterior callosal WM microstructure with less evidence of change within posterior callosal WM microstructure. The DTI indices within the genu but not splenium correlated with measures of cognitive control in chronic MA abusers.

Outcomes of neonates conceived on methadone maintenance therapy.

To assess potential risks related to the duration or total amount of fetal methadone exposure during gestation, we compared babies of women who conceived and maintained on methadone throughout pregnancy with babies of women who began methadone treatment during the second or third trimester. Babies conceived on methadone were exposed to the medication for a mean of 37.4 weeks at a mean dose of 110 mg/day, whereas comparison babies were exposed for a mean of 13.1 weeks at a mean dose of 93 mg/day. There were no significant between-group differences in the frequency of treatment of neonatal abstinence, days hospitalized, birth weight, or gestational age. Babies conceived on methadone were significantly less likely to test positive for illicit drugs at delivery as compared with babies conceived off methadone (positive toxicology, 9.1% vs. 34.3%, respectively). Methadone exposure during the entire gestational period was associated with better drug-treatment outcomes but was not associated with more severe neonatal abstinence.

Preliminary evidence of behavioral predictors of recurrent drug-induced psychosis in methamphetamine abuse.

The goal of this study was to examine behavioral characteristics of currently drug-abstinent methamphetamine (MA)-dependent subjects (n=39) who experienced psychotic symptoms associated with MA abuse. All participants completed the Wender Utah Rating Scale (WURS), which retrospectively assesses Attention Deficit Hyperactivity Disorder-relevant childhood behaviors. The results suggest the existence of possible behavioral markers reflecting an early cognitive vulnerability to the development of frequent MA-induced psychotic symptoms as well as increased vulnerability associated with a family history of psychiatric illness.

Findings of preserved implicit attention in methamphetamine dependent subjects.

Long-term methamphetamine (MA) abuse is associated with a wide range of deficits on explicit tasks of selective attention. Less is known however about the effects of MA abuse on implicit measures of attention. Accordingly, we used a computerized spatial priming task to assess implicit attentional processes in 54 MA dependent subjects (mean age=37.04+/-8.9 years) and 32 healthy controls without history of any form of substance abuse (mean age=33.63+/-7.05 years). The MA dependent subjects had been drug-abstinent a minimum of 3 weeks with a mean duration of MA use of 13.27+/-7.75 years. The MA dependent subjects did not differ significantly from controls on either inhibitory priming [p=.37] or facilitory priming) [p=.69]. This result comports with our earlier findings of intact object-based priming in MA dependent individuals and suggests that intact priming effects extend across spatial domains. Further, this pattern of sparing suggests that cortical brain systems typically supporting implicit attentional functioning are relatively intact in long-term MA dependent individuals whereas brain systems supporting explicit attentional processes are affected.

Attentional control and brain metabolite levels in methamphetamine abusers.

BACKGROUND: Methamphetamine abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. METHODS: By using a computerized measure of selective attention and single-voxel proton magnetic resonance spectroscopy, we examined the relationship between attentional control and brain metabolite levels in the anterior cingulate cortex (ACC) and primary visual cortex (PVC) in 36 currently abstinent methamphetamine abusers and 16 non-substance-using controls. RESULTS: The methamphetamine abusers exhibited reduced attentional control (i.e., increased Stroop interference) compared with the controls (p = .04). Bonferroni-adjusted comparisons revealed that ACC levels of N-acetyl aspartate (NAA)-creatine and phosphocreatine (Cr) were lower and that levels of choline (Cho)-NAA were higher in the methamphetamine abusers compared with the controls, at the adjusted p value of .0125. Levels of NAA-Cr, but not of Cho-NAA, within the ACC correlated with measures of attentional control in the methamphetamine abusers (r = -.41; p = .01) but not in controls (r = .22; p = .42). No significant correlations were observed in the PVC (methamphetamine abusers, r = .19; p = .28, controls, r = .38; p = .15). CONCLUSIONS: Changes in neurochemicals within frontostriatal brain regions including ACC may contribute to deficits in attentional control among chronic methamphetamine abusers.

A review of bipolar disorder in adults.

OBJECTIVE: This article reviews the epidemiology, etiology, assessment, and management of bipolar disorder. Special attention is paid to factors that complicate treatment, including nonadherence, comorbid disorders, mixed mania, and depression. METHODS: A Medline search was conducted from January of 1990 through December of 2005 using key terms of bipolar disorder, diagnosis, and treatment. Papers selected for further review included those published in English in peer-reviewed journals, with preference for articles based on randomized, controlled trials and consensus guidelines. Citations de-emphasized original mania trials as these are generally well known. RESULTS: Bipolar disorder is a major public health problem, with diagnosis often occurring years after onset of the disorder. comorbid conditions are common and difficult to treat. Management includes a lifetime course of medication, usually more than one, and attention to psychosocial issues for patients and their families. Management of mania is well-established. Research is increasing regarding management of depressive, mixed and cycling episodes, as well as combination therapy. CONCLUSIONS: Bipolar disorder is a complex psychiatric disorder to manage, even for psychiatrists, because of its many episodes and comorbid disorders and nonadherence to treatment.

High-dose methadone maintenance in pregnancy: maternal and neonatal outcomes.

OBJECTIVE: This study assesses the effect of higher doses of methadone during pregnancy on maternal and fetal outcomes. STUDY DESIGN: We retrospectively reviewed clinical data for 81 mothers who received methadone and their 81 offspring. The cohort was divided into high-dose (>/=100 mg) and low-dose (<100 mg) groups. RESULTS: There were no differences in the rate of medication treatment for neonatal abstinence symptoms or days of infant hospitalization between the high-dose (mean, 132 mg) and low-dose (mean, 62 mg) groups. Despite longer histories of opiate abuse, the high-dose group had less illicit drug use at delivery. The whole cohort, which received an average of 101 mg/d, had an 81% rate of negative toxicology screens at delivery. CONCLUSION: High doses of methadone were not associated with increased risks of neonatal abstinence symptoms but had a positive effect on maternal drug abuse. Arbitrarily limiting methadone dose as a way of minimizing the risks of neonatal abstinence symptoms may be unwarranted.

Measuring teaching effectiveness in a pre-clinical multi-instructor course: a case study in the development and application of a brief instructor rating scale.

BACKGROUND: Despite widespread use, misunderstandings persist about student evaluations of teaching. These evaluations have not been well examined in the common medical school setting of the multi-instructor, preclinical lecture course. PURPOSE: The study evaluated the psychometrics of a brief student evaluation of a teaching instrument developed for a multi-instructor 2nd-year course and described its application. METHODS: An 11-item instrument was developed and administered to 276 students to evaluate 27 lecturers per year in 3 years of an introductory clinical psychiatry course. A fully crossed research design allowed for a thorough analysis of variability in ratings. RESULTS: Generalizability analysis showed good reliability and relatively large Student x Lecturer interactions. Profile analysis generated distinct lecturer teaching profiles. CONCLUSIONS: Judicious use of a psychometrically sound student evaluation of a teaching instrument can be used to assist faculty and course development. Administering the evaluation instrument to an entire class produces no better reliability than administration to randomly selected subgroups of students.

Epidemiology and public health Consequences of methamphetamine use in California's Central Valley.

Methamphetamine use is an increasingly serious public health problem in California and other parts of the country. Despite sensationalistic media attention, however, very little is known about users of this clandestinely consumed drug. Employing methods known as Rapid Assessment and Response, the authors describe the epidemiology and public health implications of methamphetamine use in California's Central Valley, with a focus on Sacramento, which many social indicators suggest has been more severely affected by methamphetamine than any city in the nation. Data sources for this report include interviews with drug users, statistical reports, epidemiologic studies, and local informed expert opinion. In their social demography, methamphetamine users in the Central Valley are in marked contrast to those of coastal cities such as Seattle and San Francisco, being largely heterosexual, and of mixed racial/ethnic heritage. Three-quarters or more initiate their use of the drug while still in their teens, with more than a quarter beginning use before the age of 15. Many of these rapidly gravitate to regular use, and continue using well into their thirties. Methamphetamine users are at much higher risk of infection with HIV than opiate users, particularly if they inject. Partly because methamphetamine enhances libido, users of the drug typically also have many more sexual partners. Not surprisingly, data indicate that methamphetamine users are more likely than heroin users to be HIV-infected. Methamphetamine appears to be less of a street drug than heroin, complicating efforts at street outreach. However, because it is typically used in social settings, a social or diffusion approach to HIV prevention might be particularly promising.