Marjorie Meyer

Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society

UNLABELLED Methadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain. As part of the guideline development process, the American Pain Society commissioned a systematic review of various aspects related to safety of methadone. After a review of the available evidence, the expert panel concluded that measures can be taken to promote safer use of methadone. Specific recommendations include the need to educate and counsel patients on methadone safety, use of electrocardiography to identify persons at greater risk for methadone-associated arrhythmia, use of alternative opioids in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation, careful dose initiation and titration of methadone, and diligent monitoring and follow-up. Although these guidelines are based on a systematic review, the panel identified numerous research gaps, most recommendations were based on low-quality evidence, and no recommendations were based on high-quality evidence. PERSPECTIVE This guideline, based on a systematic review of the evidence on methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge in use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias.

Characteristics of vascular smooth muscle in the maternal resistance circulation during pregnancy in the rat.

OBJECTIVE Our purpose was to determine if pregnancy results in a decrease in arterial sensitivity to receptor-independent stimuli and a change in vascular smooth muscle membrane potential. STUDY DESIGN Mesenteric resistance arteries from late pregnant (n = 19) and age-matched virgin control (n = 20) Sprague-Dawley rats were studied in a pressurized arteriograph system or isometric myograph. RESULTS Arteries from pregnant rats were less sensitive to membrane depolarization by K+ than were those from nonpregnant rats (mean effective concentration that produced a 50% response 49 vs 39 mmol/L, pregnant vs nonpregnant, p < 0.05). Arterial basal tone and the myogenic response to increasing pressure steps were also reduced in arteries from pregnant rats compared with nonpregnant controls. The vascular smooth muscle membrane of the arteries from the pregnant rats was hyperpolarized compared with that from the control rats (-64 mV from pregnant rats vs -57 mV from nonpregnant rats, p < 0.01). This was associated with a reduction in vasomotion in the arteries from the pregnant rats (10% for pregnant rats vs 45% from nonpregnant rats, p < 0.01). CONCLUSION Pregnancy results in alterations of the vascular smooth muscle, including changes in the regulation of membrane potential and a reduced sensitivity to receptor-independent stimuli.

Gestation increases nitric oxide–mediated vasodilation in rat uterine arteries☆☆☆★★★

OBJECTIVE The purpose of this study was to determine the influence of endothelium-released nitric oxide on uterine arterial tone and reactivity during pregnancy. STUDY DESIGN The effects of pregnancy on endothelial function were evaluated in isolated pressurized rat uterine arteries from late-pregnant rats (day 19 to 20) versus age-matched nonpregnant controls. The effects of nitric oxide synthase inhibition (N(omega)-nitro-L-arginine) on arterial tone and reactivity under basal and activated (phenylephrine) conditions were determined, as was arterial reactivity to endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators, by evaluating changes in lumen diameter. RESULTS (1) Maximal constriction to N(omega)-nitro-L-arginine was significantly enhanced under basal (nonstimulated) conditions in arteries from late-pregnant versus nonpregnant rats (changes in lumen diameter 37% +/- 8% vs 9.3 +/- 6.2%, respectively, p < 0.05). (2) Nitric oxide synthase blockade with 1 nmol/L N(omega)-nitro-L-arginine significantly increased phenylephrine sensitivity in arteries from late-pregnant animals (median effective concentration 115 +/- 23 nmol/L vs 33 +/- 8 nmol/L, control vs treated vessels, p < 0.05) but was without statistically significant effect on arteries from nonpregnant animals (control 255 +/- 164 nmol/L, treated 250 +/- 102 nmol/L, p > 0.05). (3) The threshold concentration of acetylcholine required to elicit endothelium-dependent dilation was significantly lower in late-pregnant versus nonpregnant arteries (1.4 +/- 0.2 nmol/L vs 12.2 +/- 3.8 nmol/L, p < 0.05). (4) Vascular smooth muscle sensitivity to an exogenous nitrodilator (sodium nitroprusside) was identical in late-pregnant versus nonpregnant vessels. CONCLUSION Endothelial vasodilator influences are augmented during pregnancy under basal, activated (phenylephrine), and chemically provoked (acetylcholine) conditions in uterine arteries by enhanced release of nitric oxide.

Statement of the American Society Of Addiction Medicine Consensus Panel on the use of buprenorphine in office-based treatment of opioid addiction.

Objectives:Opioid addiction affects over 2 million patients in the United States. The advent of buprenorphine and the passage of the Drug Addiction Treatment Act in 2000 have revolutionized the opioid treatment delivery system by granting physicians the ability to administer office-based opioid treatment (OBOT), thereby giving patients greater access to treatment. The purpose of this consensus panel was to synthesize the most current evidence on the use of buprenorphine in the office-based setting and to make recommendations that will enable and allow additional physicians to begin to treat opioid-addicted individuals. Methods:Literature published from 2000 to 2009 was searched using the PubMed search engine and yielded over 375 articles published in peer-reviewed journals, including some that were published guidelines. These articles were submitted to a consensus panel composed of researchers, educators, and clinicians who are leaders in the field of addiction medicine with specific expertise in the use of OBOT. The panel discussed results and agreed upon consensus recommendations for several facets of OBOT. Results:On the basis of the literature review and consensus discussions, the panel developed a series of findings, conclusions, and recommendations regarding the use of buprenorphine in office-based treatment of opioid addiction. Conclusions:Therapeutic outcomes for patients who self-select office-based treatment with buprenorphine are essentially comparable to those seen in patients treated with methadone programs. There are few absolute contraindications to the use of buprenorphine, although the experience and skill levels of treating physicians can vary considerably, as can access to the resources needed to treat comorbid medical or psychiatric conditions–-all of which affect outcomes. It is important to conduct a targeted assessment of every patient to confirm that the provider has resources available to meet the patients needs. Patients should be assessed for a broad array of biopsychosocial needs in addition to opioid use and addiction, and should be treated, referred, or both for help in meeting all their care needs, including medical care, psychiatric care, and social assistance. Current literature demonstrates promising efficacy of buprenorphine, though further research will continue to demonstrate its effectiveness for special populations, such as adolescents, pregnant women, and other vulnerable populations. Since the time of this review, several new studies have provided new data to continue to improve our understanding of the safety and efficacy of buprenorphine for special patient populations.

Estrogen Replacement Increases β-Adrenoceptor-Mediated Relaxation of Rat Mesenteric Arteries

The purpose of the present study was to determine whether estrogen replacement in ovariectomized rats could modulate arterial diameter responses to beta-adrenoceptor activation. Under relaxed conditions (0.1 mM papaverine) there were no differences in the lumen diameter of isolated, pressurized (50 mm Hg) mesenteric arteries from nontreated (191.7 +/- 13.8 microns; n = 19) versus those from estrogen-treated (190.1 +/- 11 microns; n = 14) ovariectomized Sprague-Dawley rats. In arteries precontracted with noradrenaline (0.3-1 microM), isoprenaline (0.01-10 microM)-induced relaxation was significantly increased in arteries from ovariectomized estrogen-treated rats (52.4 +/- 2% of the maximal relaxation induced by 0.1 mM papaverine, vs. 33.3 +/- 6.5%; p < 0.01). The half-maximal concentration value was 0.04 +/- 0.05 microM in estrogen-treated rats and 0.4 +/- 0.1 microM in nontreated rats (p < 0.01). This response was inhibited by propranolol (1 microM) in both groups to a comparable extent (61.5%), and was unaffected by endothelial removal. Forskolin (0.01-10 microM) induced similar concentration-dependent vasodilation in arteries of both groups of rats with no differences in sensitivity or maximal response. These results suggest that isoprenaline acts through beta-adrenoceptors present on vascular smooth muscle and that estrogen replacement enhances the relaxant responses induced by beta-adrenoceptor activation by an endothelium-independent mechanism.

Intrapartum and Postpartum Analgesia for Women Maintained on Methadone During Pregnancy

OBJECTIVE: To determine whether methadone maintenance alters intrapartum or postpartum pain or medication requirements. METHODS: Sixty-eight patients treated with methadone for opiate dependence during pregnancy (vaginal n=35; cesarean n=33) were matched retrospectively to control women. Analgesic medication and pain scores (0–10) were extracted from the medical record. The primary endpoint was opiate use postpartum (oxycodone equivalents). The secondary endpoints were pain scores and intrapartum analgesia. RESULTS: There were no differences in intrapartum pain or analgesia. After vaginal birth, methadone-maintained women experienced increased pain (methadone, 2.7 [1.9–5.0]; control, 1.4 [0.5–3.0], P=.001) but no increase in opiate use ([mean±standard deviation] methadone 12.7±32.1; control 6.8±12.7 mg/24 h, P=.33); after cesarean delivery both pain (methadone, 5.3 [4.1–6.0]; control, 3.0 [2.2–3.9], P=.001) and opiate use (methadone, 91.6±51.8; control, 54.0±18.6 mg/24 h, P=.001) increased. CONCLUSION: Methadone-maintained women have similar analgesic needs and response during labor, but require 70% more opiate analgesic after cesarean delivery. LEVEL OF EVIDENCE: II

Intolerance to volume expansion: a theorized mechanism for the development of preeclampsia

We present a theorized mechanism for the development of preeclampsia, suggesting that one important underlying pathophysiologic mechanism is intolerance to volume expansion. The stage is set for this intolerance by chronic volume constriction, which leads to a requirement for increased basal peripheral vasoconstrictor tone to maintain blood pressure and allow for continued perfusion of the upright hominid head. In pregnancy, volume expansion signaled by the placenta cannot be accommodated by the constricted vascular system. The inability of the normally adaptive endothelial vasodilatory mechanisms to overcome the chronic vasoconstrictor tone leads to endothelial damage, exacerbation of vasoconstriction, and clinical hypertension. Disease resolution, characterized by diuresis, occurs with the elimination of the placenta-derived drive to retain volume. The reason preeclampsia does not recur uniformly with subsequent pregnancy is permanent restructuring of the maternal cardiovascular system with pregnancy that allows for greater plasma volume expansion in future gestations.

Labor induction with a prenatal diagnosis of fetal macrosomia

Since our institution has a low cesarean rate (14%), it was our hypothesis that the rate of cesarean delivery in patients who underwent induction for macrosomia would be similar to the cesarean rate in patients with similar birth weights who entered labor spontaneously. A retrospective analysis of cases seen from December 1993 to July 1995 revealed 53 nondiabetic patients who underwent induction for fetal macrosomia. These study patients were matched to the next nondiabetic patient delivering a child of equal or greater birth weight who entered labor spontaneously. Maternal demographics, labor characteristics, and neonatal outcome data were reviewed. There were no differences between the induction and spontaneous labor groups in maternal age, gestational age, rate of nulliparity, incidence of shoulder dystocia, Apgar scores, or vaginal birth after prior cesarean delivery. The cesarean delivery rate was higher in the induction group when compared to the spontaneous labor group (36% vs. 17%, P < 0.05) despite a lower birth weight in the induction group (4,102 +/- 374 g vs. 349 g, P < 0.05). Regional analgesia was administered more frequently in the induction group (38% vs. 53%, P < 0.05). An increased risk of cesarean delivery was observed in subjects undergoing induction for the indication of fetal macrosomia. These data support a plan of expectant management when fetal macrosomia is suspected.

Intrapartum and postpartum analgesia for women maintained on buprenorphine during pregnancy

Objective: To determine whether buprenorphine maintenance alters intrapartum or postpartum pain or medication requirements.

Methadone and buprenorphine for opioid dependence during pregnancy: a retrospective cohort study.

Objectives:To compare maternal characteristics, prenatal care, and newborn outcomes in a cohort of opioid-dependent pregnant women treated with methadone versus buprenorphine. Methods:In a retrospective cohort study, 609 pregnant, opioid-dependent women were treated with methadone (n = 248) or buprenorphine (n = 361) between 2000 and 2012 at a single institution. Results:Mothers treated with buprenorphine were more likely to start medication before or earlier in pregnancy, had longer gestation, and gave birth to larger infants. Newborns of buprenorphine- versus methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration. Conclusions:These data suggest pregnancy outcomes with buprenorphine to treat opioid dependence during pregnancy in clinical practice are as good and often better than outcomes with methadone. These results are consistent with efficacy data from randomized clinical trials and further support the use of buprenorphine for the treatment of opioid dependence during pregnancy.