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.

Safety and feasibility of the teaching assistant role of senior surgical residents: a prospective randomized study.

OBJECTIVE: The objective of the study was to assess the teaching assistant role of senior surgical residents. DESIGN: The study was designed in a prospective randomized fashion. All patients undergoing laparoscopic appendectomy were asked for consent. Consenters were assigned randomly to group A (attending directed) or group B (senior resident directed). In group A, all laparoscopic appendectomies were performed by junior residents (PGY-1, -2, or -3) with the attending faculty as the assistant. In group B, all cases were performed by junior residents (PGY-1, -2, or -3) with the chief resident or PGY-4 acting as a teaching assistant. The allocation sequence was generated before the study by random permutations of 120 assignments, 60 to each arm. The study ended after 60 laparoscopic appendectomies were recorded in each arm. SETTING: The study was conducted at San Joaquin General Hospital. This 200-bed, county teaching hospital has sponsored the general surgery residency program for the past 60 years. RESULTS: No significant difference in duration of surgery, hospital stay, postoperative complication, or baseline values was found between group A (attending faculty) or group B (senior resident). CONCLUSIONS: Senior surgical residents can act safely as teaching assistants for junior residents. Under faculty supervision, this teaching role can potentially enhance technical skills acquisition for senior residents in training programs without compromising patient safety.

2011 ACGME duty hour week proposal--a national survey of family medicine residents.

BACKGROUND AND OBJECTIVES: In July 2010, the Accreditation Council for Graduate Medical Education (ACGME) published its proposed duty-hour regulations. We conducted a national online survey to assess current family medicine residents' perceptions of the proposed changes. METHODS: A 27-question survey was used to assess four ACGME proposal domains: resident supervision, 80-duty-hour week, maximum duty-period length, and maximum frequency of in-hospital duty. Additionally, we surveyed opinions on reasonable weekly work hours, under-reporting practice, and residents' activities during hours off, residents' perceptions of their program's ability to comply with future duty-hour regulations, and their overall satisfactions. Members of the Association of Family Medicine Residency Directors (AFMRD) were invited to send the survey Web link to their residents. RESULTS: Out of 720 respondents, 30% supported revision of current duty-hour work rules; 58% disagreed with limiting interns' working hours to 16 hours per day; 48% perceived revision of resident supervision favorably; 26% expressed concern about continuing the current 80-duty-hour week rule; 75% supported limiting night duty to six consecutive nights; 83% agreed that reasonable resident weekly work hours should be 60-80 hours; and 18% admitted under-reporting of duty hours. Residents' hours off activities varied. Only 57% believed that their program will be able to implement the new changes effectively. Overall satisfaction with the future duty-hour rules were mixed: very satisfied (7%), satisfied (24%), somewhat satisfied (27%), unsatisfied (23%), and very unsatisfied (18%). CONCLUSIONS: Support for the proposed ACGME duty-hour regulations was mixed among current family medicine residents. Respondents and residency program directors shared similar concerns about some of the recommended changes.

Directed postgraduate study result in quantitative improvement in American Board of Surgery In-Training Exam scores.

BACKGROUND: The collective study habits of 1 group of residents involved in educationally distinct periods of time in a community-based general surgery residency program were evaluated. METHODS: American Board of Surgery In-Training Exam (ABSITE) score results of 31 residents were calculated during 3 distinctive educational time periods: resident independent, self-directed study; resident-directed study with weekly systematic textbook reviews; and faculty-directed study with additional formal basic science and clinical lectures. RESULTS: Aggregate higher scores were observed when ABSITE results for the directed study period were compared with those observed during the independent study period in mid-level resident years (postgraduate year [PGY] 2 to 4). CONCLUSIONS: With limited faculty resources, community-based surgery residency programs have more challenges in opportunities for resident acquisition of cognitive knowledge and subsequent quantitative improvement in ABSITE scores. This study demonstrated a successful methodology particularly in the face of mandated limitation of weekly resident work hours and diminishing allocated education resources.

Screening preferences for colorectal cancer: a patient demographic study.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death. Screening for colorectal cancer is a rational and cost-effective strategy for reducing the incidence of colorectal cancer and related mortality. Despite endorsement by academic and health care organizations, patient awareness and compliance with screening is low, partly because of patient-related barriers to screening. METHODS: A convenience sample of adults attending the internal medicine and family practice clinics of a community teaching hospital was studied. A description of fecal occult blood testing (FOBT), sigmoidoscopy, and colonoscopy procedures was given in a packet along with a questionnaire. The questionnaire focused on screening procedures followed in our hospital (i.e., yearly FOBT and sigmoidoscopy every 5 years or colonoscopy every 10 years for average-risk individuals). RESULTS: Of the 193 patients who responded, 55% preferred sigmoidoscopy and FOBT, 29% chose colonoscopy, and 16% wanted no screening. Those with knowledge of someone with colon cancer or colon polyps reported a significantly higher preference for screening than those without such knowledge. Catholics were most likely to prefer no screening compared with non-Catholics. Ex-smokers (compared with all others) were more likely to want screening. Catholics were least likely to want colonoscopy. Patients with previous experience of colorectal screening preferred future screening. Those preferring no screening were significantly younger than those who expressed a preference for screening. CONCLUSION: The results of this study demonstrate diversity in patient choices for colorectal cancer screening. A focus on people's preferences rather than on the test itself may help develop and target appropriate intervention for prevention of colorectal cancer.