Methadone Group Research Articles

Delivery dose of methadone, but not buprenorphine, is associated with the risk and severity of neonatal opiate withdrawal syndrome

Data on the relationship between the dose of opioid replacement therapy in pregnancy and the risk and severity of neonatal opioid withdrawal syndrome are conflicting and have methodological limitations. To assess the association of methadone and buprenorphine dose at delivery with neonatal opioid withdrawal syndrome in a large cohort. We performed a retrospective cohort study using data from a comprehensive perinatal opioid dependency program from 2000 through 2016. Women with a history of opioid use disorder enrolled in a medication-assisted treatment program were included. Strict neonatal opioid withdrawal syndrome case definition and neonatal treatment guidelines were utilized throughout the study epoch. Comparisons were made between women on methadone and buprenorphine. The dose of opioid replacement at delivery and the risk and severity of neonatal opioid withdrawal syndrome were assessed with univariable analysis and multivariable logistic regression. In all analyses, methadone and buprenorphine dosing were evaluated as a continuous variable. Four hundred eighty two of 709 women (68.0%) met inclusion criteria including 344 on methadone (71.4%) and 138 on buprenorphine (28.6%). Nonopioid polysubstance abuse, body mass index, medication-assisted treatment compliance, birthweight, and other characteristics were similar between groups. Overall, the frequency of neonatal opioid withdrawal syndrome was not significantly different between the methadone and buprenorphine groups (56.8% vs 52.0%, P= .35). Dose at delivery ranged at 0-165 mg for methadone and 0-30 mg for buprenorphine. In a univariable analysis, methadone dose at delivery was associated with neonatal opioid withdrawal syndrome (83.0 ± 34.2 mg vs 71.9 ± 35.8 mg for neonatal opioid withdrawal syndrome vs nonneonatal opioid withdrawal syndrome neonates, P < .001), but buprenorphine dose at delivery was not (8.4 ± 4.4 vs 7.6 ± 4.8 mg for neonatal opioid withdrawal syndrome vs nonneonatal opioid withdrawal syndrome neonates, P= .30). Peak neonatal opioid withdrawal syndrome score, duration of neonatal opioid withdrawal syndrome treatment, and cumulative neonatal morphine exposure were significantly associated with delivery methadone dose but not buprenorphine dose. The association between delivery methadone dose and neonatal opioid withdrawal syndrome persisted in multivariable regression. The dose of methadone at the time of delivery is associated with the frequency and severity of neonatal opioid withdrawal syndrome, with higher doses associated with more severe neonatal opioid withdrawal syndrome when analyzed continuously. These data may inform future prospective studies on methadone dosing in pregnancy. While medication-assisted treatment agent and dose may have an impact on pertinent neonatal outcomes related to neonatal opioid withdrawal syndrome, the provision of medication-assisted treatment in pregnancy should reflect the goal of prevention of recidivism and maternal mortality and utilize an approach that balances fetal and maternal risk to optimize outcomes.

Intraoperative Methadone Reduces Pain and Opioid Consumption in Acute Postoperative Pain: A Systematic Review and Meta-analysis.

Methadone is a potent opioid exerting an analgesic effect through N-methyl-D-aspartate receptor antagonism and the inhibition of serotonin and noradrenaline reuptake. It has also been used in several procedures to reduce postoperative pain and opioid use. This meta-analysis aimed to determine whether the intraoperative use of methadone lowers postoperative pain scores and opioid consumption in comparison to other opioids. Double-blinded, controlled trials without language restrictions were included from MEDLINE, Embase, LILACS, The Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL via EBSCOhost. The included studies tracked total opioid consumption, postoperative pain scores, opioid-related side effects, and patient satisfaction until 72 hours postoperatively. Mean difference (MD) was used for effect size. In total, 476 articles were identified and 13 were considered eligible for inclusion in the meta-analysis. In 486 patients (7 trials), pain at rest (MD, 1.09; 95% confidence interval (CI), 1.47-0.72; P < .00001) and at movement (MD, 2.48; 95% CI, 3.04-1.92; P = .00001) favored methadone 24 hours after surgery. In 374 patients (6 trials), pain at rest (MD, 1.47; 95% CI, 3.04-1.02; P < .00001) and at movement (MD, 2.03; 95% CI, 3.04-1.02; P < .00001) favored methadone 48 hours after surgery. In 320 patients (4 trials), pain at rest (MD, 1.02; 95% CI, 1.65-0.39; P = .001) and at movement (MD, 1.34; 95% CI, 1.82-0.87; P < .00001) favored methadone 72 hours after surgery. A Trial Sequential Analysis was performed and the Z-cumulative curve for methadone crossed the monitoring boundary at all evaluations, additionally crossing Required Information Size at 24 and 48 hours at rest. Methadone group also showed lower postoperative opioid consumption in morphine equivalent dosage (mg) at 24 hours (MD, 8.42; 95% CI, 12.99-3.84 lower; P < .00001), 24-48 hours (MD, 14.33; 95% CI, 26.96-1.91 lower; P < .00001), 48-72 hours (MD, 3.59; 95% CI, 6.18-1.0 lower; P = .007) postoperatively. Intraoperative use of methadone reduced postoperative pain scores compared to other opioids, and Trial Sequential Analysis suggested that no more trials are required to confirm pain reduction at rest until 48 hours after surgery. Methadone also reduced postoperative opioid consumption and led to better patient satisfaction scores through 72 hours postoperatively compared to other opioids.

Methadone versus morphine for postoperative pain in patients undergoing surgery for gynecological cancer: A randomized controlled clinical trial.

The aim of this study was to compare methadone and morphine for the management of postoperative. Open, controlled study. Postoperative recovering area, ward. Sixty-four patients, ASA I-III, undergoing gynecological surgery for cancer. Morphine or methadone 0.15 mg/kg given preoperatively. After operation an intravenous morphine or intravenous methadone infusion at doses of 12 mg/day was started. Pain intensity and opioid consumption. Methadone infusion provided a better analgesia in comparison with morphine infusion on the second day. Opioid consumption was significantly lower in the methadone group. No episodes of relevant desaturation or signs of respiratory depression were recorded. A preoperative bolus of methadone, followed by a continuous infusion of low doses post-operatively, provided a better analgesia, without adding risk of adverse effects, in comparison with morphine.

Intraoperative methadone administration and postoperative pain control: a systematic review and meta-analysis.

Postoperative pain is not adequately managed in greater than 40% of surgical patients and is a high priority for perioperative research. In this meta-analysis, we examined studies comparing postoperative opioid consumption and pain scores in surgical patients who received methadone by any route vs those who received another opioid by any route. Studies were identified from PubMed, Cochrane, Web of Science, EMBASE, and Scopus from January 1966 to November 2018. Pooled odds ratios were calculated for a primary outcome of postoperative opioid consumption and secondary outcomes of time-to-extubation, time-to-first postoperative analgesia request, satisfaction, hospital length-of-stay, and complications. Postoperative pain scores were assessed qualitatively. Ten studies (617 patients) were included. Postoperative opioid consumption at 24 hours was lower in the methadone group vs control (mean difference = -15.22 mg oral morphine equivalents, 95% confidence interval -27.05 to -3.38; P = 0.01). Patients in the methadone group generally reported lower postoperative pain scores in 7 of 10 studies. Meta-analysis revealed greater satisfaction scores with analgesia in the methadone group vs control (0-100 visual analog scale; mean difference = 7.16, 95% confidence interval 2.30-12.01; P = 0.004). There was no difference in time-to-extubation, time-to-first analgesia request, hospital length-of-stay, or complications (nausea, sedation, respiratory depression, and hypoxemia). The results demonstrate that surgical patients who received intraoperative methadone had lower postoperative opioid consumption, generally reported lower pain scores and experienced better satisfaction with analgesia. However, these advantages need to be weighed carefully against dangerous risks with perioperative methadone, specifically respiratory depression and arrhythmia. Future studies should explore logistics, safety, and cost effectiveness.

Advantages and Disadvantages of Methadone among Children and Adults: A Systematic Review and Meta-Analysis

Background: Today, an increasing trend to methadone as an alternative maintenance treatment for opiate dependence in adults is observed; children for both intentional and accidental reasons are exposed to serious and fetal effects of methadone. We aimed to investigate effects of methadone on children and sexual functioning among adults in Iranian population. Materials and Methods: An extensive search was done in databases of Medline, EMBASE, Scopus, Cochrane, and Web of Science until August 2018. Two independent researchers screened articles, and categorized them based on the evaluated outcomes and overall effect size was presented. After excluding the duplicated, irrelevant and low-quality articles, eligible ones were enrolled in the meta-analysis. Finally, pooled effect size was presented as standardized mean difference (SMD) or pooled prevalence with 95% confidence interval (95% CI). Results: Methadone was found to be more effective than morphine on neonatal abstinence syndrome. The first four most common symptoms of methadone poisoning were loss of consciousness (81%), sleepiness (72%), meiotic pupils (76%), vomiting (56%), and Apnea (48%). The overall prevalence rate of sexual disorders and erectile dysfunction was 66.3% and 77.5%, respectively. The subjects in methadone group were over 2.5-fold more likely to use condom during intercourse (p<0.001). The methadone therapy could lead to a significant reduction in orgasm functioning (p<0.001), and a significant improvement in libido (p=0.001). The methadone maintenance treatment (MMT) significantly resulted in decreased orgasm function and improved libido in males. Conclusion: Evidence suggests a positive impact of methadone maintenance treatment on risky sexual behaviors. Regarding the methadone poisoning effect on children, people should be informed by health care providers about serious and fetal effects on children.

Use of naltrexone in treating opioid use disorder in pregnancy

The mainstay of the management of opioid use disorder in pregnancy is with methadone or buprenorphine medication-assisted treatment. Methadone and buprenorphine are opioid agonist drugs. Naltrexone, an opioid antagonist, is also a medication-assisted treatment option; however, to date, only a few retrospective studies have reported its use in pregnancy. Our study objective was to evaluate prospectively obstetric and newborn outcomes and the maternal/fetal effects of the use of naltrexone as a medication-assisted treatment in pregnant patients with opioid use disorder. We performed a prospective cohort study collecting data on all pregnant women who were treated with naltrexone medication-assisted treatment compared with pregnant women who were treated with methadone or buprenorphine medication-assisted treatment. Based on a sample size calculation, it was determined that for a power of 90, a minimum of 160 study participants (80 in each group) was needed with an alpha of .01 and an expected 60% rate of newborn infants who were treated for neonatal abstinence syndrome in the methadone or buprenorphine medication-assisted treatment group compared with a 30% rate in the naltrexone medication-assisted treatment group. In a random subset of 20 maternal/newborn dyads, blood levels for naltrexone and 6-beta-naltrexol (an active metabolite) were analyzed at delivery. A total of 230 patients were studied: 121 patients with naltrexone medication-assisted treatment compared with 109 patients with methadone or buprenorphine medication-assisted treatment. No differences between groups were seen regarding demographics, the use of comedications/drugs, or obstetric outcomes. For newborn outcomes, the rate of neonatal abstinence syndrome in neonates >34 weeks gestation was significantly lower in the naltrexone medication-assisted treatment group (10/119 [8.4%] vs 79/105 [75.2%]; P<.0001). Multivariate analysis demonstrated that the only significant factor for the rate of neonatal abstinence syndrome was the form of medication-assisted treatment. Of 87 patients who received naltrexone up to delivery, no neonates experienced symptoms of neonatal abstinence syndrome. No maternal relapses occurred in the 7-day no-treatment window before the initiation of naltrexone therapy. No cases of spontaneous abortion or stillbirth occurred in either group. In 64 patients who started naltrexone therapy at ≥24 weeks gestation, no changes were seen in the fetal heart monitor tracing with drug initiation. The incidence of birth anomalies was no different between the groups. Umbilical cord blood and maternal levels for naltrexone and 6-beta-naltrexol matched; no levels were elevated, and values were undetected if naltrexone was discontinued >60 hours before delivery. These study data demonstrate that, in pregnant women who choose to completely detoxify off opioid drugs during gestation, naltrexone, as a continued form of medication-assisted treatment, is a viable option for some pregnant patients who experience opioid use disorder. Naltrexone crosses the placenta, and maternal and fetal levels are concordant. Because naltrexone clears quickly from the maternal circulation, this rapid clearance needs to be addressed with patients. This is important because maternal relapse could occur in a short time-period if the oral drug is discontinued without the knowledge of their healthcare providers. Nonetheless, the drug is well-tolerated by both mother and fetus, and newborn infants do not experience symptoms of neonatal abstinence syndrome if naltrexone medication-assisted treatment is maintained to delivery.

Concomitant Heroin and Cocaine Use among Opioid-Dependent Patients during Methadone, Buprenorphine or Morphine Opioid Agonist Therapy

Background: Among all the treatment methods developed so far, opioid agonist treatment (OAT) is the most effective therapy for opioid dependence. While methadone (MTD) is the most commonly used, fewer data are available on alternative opioid agonist. The aim of this study was to assess the efficacy of buprenorphine (BUP) and slow-released morphine compared to MTD with regard to the reduction of concomitant heroin and cocaine use. Methods: This cross-sectional study included 105 patients receiving MTD, BUP, or slow-release morphine as opioid agonist therapy at the Psychiatric Hospital of Zurich. Illicit drug use was assessed using a retrospective 3-month hair toxicology analysis to quantify concentrations of heroin degradation products and metabolites, as well as cocaine and cocaine metabolites. We have also collected self-reports, but in the data of the study, only the results of the hair analysis were considered. Results: BUP-treated patients showed lower rates of illicit opiate consumption in comparison to the group treated with MTD or slow-released morphine (p < 0.05). The proportion of heroin-positive hair samples associated with slow-release morphine treatment was similar to the proportion associated with MTD treatment. Neither the MTD vs. slow-released morphine groups nor the BUP vs. MTD groups showed significant differences in the number of patients consuming cocaine although patients in the BUP group had significantly lower concentrations of cocaine in hair testing compared to the patients in the MTD group. Prevalence of cocaine consumption was also significantly lower in the BUP group compared to patients in the slow-release morphine group (p < 0.05). Conclusion: This study suggests that BUP OAT is associated with reduced additional opiate co-use.

Effects of Methadone and Buprenorphine Use During Pregnancy on Neonatal and Maternal Outcomes [4K

INTRODUCTION: The opioid epidemic in continues to be a major public health concern. Opioid use during pregnancy increases risks of adverse neonatal and maternal outcomes, including neonatal abstinence syndrome (NAS). Methadone and Buprenorphine are used as maintenance therapy for opioid dependence during pregnancy. Our objective is to compare effects of Methadone and Buprenorphine on maternal and neonatal outcomes. METHODS: This is a retrospective cohort study that included patients with a singleton pregnancy who received opioid maintenance therapy and delivered at Hurley Medical Center from 2012 - 2017. IRB approval was obtained. Primary outcome was length of neonatal stay. Demographic characteristics, illicit drug use, and tobacco smoking were among variables analyzed in the Methadone and Buprenorphine groups. RESULTS: The study included 228 participants. 47 were on Buprenorphine and 181 on Methadone. Of the neonates, 71% required treatment for NAS. The median length of treatment in days was significantly less in Buprenorphine group (p= 0.001; 10 vs 16), along with median length of stay (p= 0.000001; 12 vs 20). There was no association between Buprenorphine dose and NAS treatment. In the Methadone group, the median dose increased with the level of treatment (p=0.004). After correcting for potential confounders, we noted that gestational age, dose of methadone, and illicit drug use, were associated with higher risk of requiring NAS treatment. CONCLUSION: Neonates exposed to Buprenorphine had significantly lower rates of NAS and shorter NICU stay compared to Methadone. Gestational age at delivery, Methadone dose, and illicit drug use seem to be associated with increased NAS treatment.

Comparison of Analgesic Effects of Nebulized Morphine with Fentanyl Transdermal Patch and Oral Methadone for Cancer Patients in Terminal Stages; a Double-blind Randomized Controlled Study.

Introduction:Recent years have witnessed widespread reports on the effectiveness of nebulized morphine for dyspnea, yet there is no evidence for its effectiveness in analgesic therapy.Objective:This study aims to compare effectiveness and side effects of inhalation morphine with oral methadone and transdermal fentanyl in sequential days in end stage cancer patients.Method:This double-blind, randomized controlled study conducted between April and September 2017. Ninety eligible cancer patients presenting to Sayed al-Shohada Hospital were selected non-randomly according to inclusion criteria and then divided to 3 groups in random order. Pain severity was scored by Visual Analog Scale (VAS). Patients were followed up for 3 days and then data were analyzed by SPSS. The benchmark of success was set as marking 4 or below on VAS and a reduction ratio of 50 percent.Results:Pain severity was equal for 3 groups before the first administration (p>0.05), but it decreased significantly from 8.45 (range 6–10) at baseline to 2.46 (range 1–4) at the end of the 3rd day in the nebulized group. The decrease ratio was equal to 70.8% after three days (p<0.05). Pain severity reduced from 8.45 (range 7–10) to 1.8 (range 1–3) (p<0.05) in the methadone group, and reduced from 8.5 (range 6–10) to 2.13 (range 1–3) in the fentanyl group.Conclusion:Our study showed that nebulized morphine, just like oral methadone and transdermal fentanyl, is effective, safe, and well-tolerated for pain management in patients with cancer.

Buprenorphine and Methadone as Opioid Maintenance Treatments for Heroin-Addicted Patients Induce Oxidative Stress in Blood.

Buprenorphine and methadone are two substances widely used in the substitution treatment of patients who are addicted to opioids. Although it is known that they partly act efficiently towards this direction, there is no evidence regarding their effects on the redox status of patients, a mechanism that could potentially improve their action. Therefore, the aim of the present investigation was to examine the impact of buprenorphine and methadone, which are administered as substitutes to heroin-dependent patients on specific redox biomarkers in the blood. From the results obtained, both the buprenorphine (n = 21) and the methadone (n = 21) groups exhibited oxidative stress and compromised antioxidant defence. This was evident by the decreased glutathione (GSH) concentration and catalase activity in erythrocytes and the increased concentrations of thiobarbituric acid reactive substances (TBARS) and protein carbonyls in the plasma, while there was no significant alteration of plasma total antioxidant capacity (TAC) compared to the healthy individuals (n = 29). Furthermore, methadone revealed more severe oxidant action compared to buprenorphine. Based on relevant studies, the tested substitutes mitigate the detrimental effects of heroin on patient redox status; still it appears that they need to be boosted. Therefore, concomitant antioxidant administration could potentially enhance their beneficial action, and most probably, buprenorphine that did not induce oxidative stress in such a severe mode as methadone, on the regulation of blood redox status.

Intraoperative Methadone in Same-Day Ambulatory Surgery: A Randomized, Double-Blinded, Dose-Finding Pilot Study.

Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery. A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects. Median (interquartile range) methadone doses were 6 (5-6) and 9 (8-9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3-11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1-3.3; P < .001) but not 0.1 mg/kg methadone (5.0 mg, 3.3-8.1; P = .60). Dose-escalation ended at 0.15 mg/kg methadone. Total in-hospital nonmethadone opioid use after short-duration opioid, 0.1 mg/kg methadone, and 0.15 mg/kg methadone was 35.3 (25.0-44.0), 7.1 (3.7-10.0), and 3.3 (0.1-5.8) mg morphine equivalents, respectively (P < .001 for both versus control). In-hospital pain scores and side effects were not different between groups. In the 30 days after discharge, patients who received methadone 0.15 mg/kg had less pain at rest (P = .02) and used fewer opioid pills than controls (P < .0001), whereas patients who received 0.1 mg/kg had no difference in pain at rest (P = .69) and opioid use compared to controls (P = .08). In same-day discharge surgery, this pilot study identified a single intraoperative dose of methadone (0.15 mg/kg ideal body weight), which decreased intraoperative and postoperative opioid requirements and postoperative pain, compared with conventional intermittent short-duration opioids, with similar side effects.

Concomitant abuse of methadone and methamphetamine could impair spatial learning and memory in male rats

Methadone maintenance therapy (MMT) has been considered as an effective medication for opioid dependence. However there are reports of methamphetamine abuse among MMT patients due to greater desired effects and fewer side effects than either substance alone. Little research has been done on the effects of methamphetamine abuse on cognitive behaviors during MMT. In the current study, we investigated spatial learning and memory along with the brain derived neurotrophic factor (BDNF) as important factors in neural plasticity under concomitant use of methadone and methamphetamine in male rats. The animals received administration of methadone (2.5 mg/Kg, SC, twice a day) and methamphetamine (0.5 mg/Kg, SC, once a day) concomitantly or either alone for 21 days. Three hours after each treatment, the rats were trained in eight-arm radial maze for 7 days, and their learning and working memory were evaluated. Moreover, western blotting was performed to evaluate hippocampal BDNF protein levels. The results showed that administration of methadone and methamphetamine concomitantly impaired spatial learning and memory more than methadone alone (P < 0.05). Additional western blotting analysis revealed that BDNF protein levels of hippocampus in the control group was more than the methadone group, while it was less than methamphetamine treated animals (P < 0.05). Our findings suggest that exposure to methamphetamine during methadone maintenance therapy could lead to spatial learning and memory impairments more than mere methadone.

Preoperative oral methadone for postoperative pain in patients undergoing cardiac surgery: A randomized double-blind placebo-controlled pilot

ABSTRACT Background Inadequately controlled sternotomy pain after cardiac surgery can lead to delayed recovery and patient suffering. Preoperative intravenous methadone is effective for reducing both postoperative pain and opioid consumption. Despite ease of administration, the effects of preoperative oral methadone are not well described in the literature. Aims This pilot study investigated the effect of preoperative oral methadone on pain scores, analgesia requirements, and opioid-induced side effects. Methods A randomized double-blind placebo-controlled model was used with sampling of patients undergoing sternotomy for isolated coronary artery bypass graft (CABG) surgery (ClinicalTrials.gov registration no. NCT02774499). Participants were randomized to receive oral methadone (0.3 mg/kg) or oral placebo prior to entering the operating room. The primary outcome was pain scores on a 0–10 Verbal Rating Scale. Secondary outcomes included morphine requirements using patient-controlled analgesia (PCA), time to extubation, level of sedation, and side effects such as nausea, vomiting, pruritus, hypoventilation, and hypoxia over a 72-h monitoring time. Results Twenty-one patients completed the study. Oral methadone did not reduce pain scores in the methadone group (P = 0.08). However, postoperative morphine requirement during the first 24 h was reduced by a mean of 23 mg in the methadone group (mean difference, −23; 99% confidence interval [CI], 37–13 mg; P < 0.005). No reduction in pain scores or PCA morphine was observed beyond 24 h postoperatively. There was no difference in incidence of opioid-related side effects between groups throughout the postoperative period. Conclusions Though preoperative oral methadone did not reduce pain scores, morphine requirements were reduced in the first 24 h post-CABG.

F19ANALYSIS OF BDNF VAL66MET VARIANT AND EXON IV PROMOTER METHYLATION IN AUTISM SPECTRUM DISORDER TRIOS

Heroin addiction is a chronic complex brain disease that contains multiple phenotypes, which vary widely among addicts and may be affected by genetic factors. A total of 801 unrelated heroin addicts were recruited and divided into different subgroups according to eight phenotypes of heroin addiction. Polymorphisms in GAD1 (rs3762555, rs3762556, rs3791878, rs3749034, rs11532313 and rs769395) and GAD2 (rs2839669, rs2839670 and rs2236418) were genotyped using the SNaPshot assay. Associations between genetic variants and the eight phenotypes were mainly assessed by binary logistic regression.We found that the frequencies of G allele of GAD1 rs3749034 and rs3762555 were associated with daily dose of methadone use and memory change after heroin addiction. The C allele frequency of GAD1 rs3762556 was associated with lower daily dose of methadone use. In GAD1, SNPs rs3762556, rs3762555, rs3791878 and rs3749034 had strong linkage, and the frequency of the C-G-C-A haplotype was higher in the lower dose of methadone group. Patients with the TT genotype of rs11542313 were maintained on lower dose of methadone than patients with the CC genotype. The G alleles of rs3762555 and rs3749034 were lower, while the T allele of rs11542313 was higher, in the memory decreased group. The results of association analyses of GAD2 with phenotypes of heroin addiction showed no significant differences.GAD1 polymorphisms were associated with phenotypes of heroin addiction, especially the daily dose of methadone use and memory change in the Han Chinese population. These results may provide individualized guidance for the treatment of heroin addiction.

314: Is opioid maintenance therapy (OMT) associated with placentomegaly and placental dysmaturity?

To explore the effects of gestational OMT on placental development This is a retrospective cohort study of pregnant patients on OMT (buprenorphine or methadone) between January 2007 and December 2017. ICD codes were used to identify OMT patients. The control group consisted of random non-drug users matched for GA. Patients were excluded if they had gestational diabetes, multiple gestations, positive meconium toxicology results for substances other than methadone or buprenorphine and those without microscopic placental evaluation. Placental weight and histologic evaluation were obtained and compared among the groups. Data analysis was performed using one-way ANOVA with p-value <0.05 significant. 454 cases were reviewed; of which 109 met the inclusion criteria (66 patients were on methadone, 43 were on buprenorphine, and 40 were controls). Gestational age at birth and neonatal birth weight were significantly lower in the methadone group compared to the buprenorphine and control groups . The placenta to neonatal birth weight ratio was significantly higher in the methadone and buprenorphine groups compared to controls (p<0.01). There was no statistically significant difference between methadone and buprenorphine groups (mean ± standard deviation; methadone: 0.19 ± 0.03; buprenorphine: 0.18 ± 0.04; control: 0.15 ± 0.03).The rate ratio of placental dysmaturity (Figure 1) was significantly higher in the methadone and buprenorphine groups compared to control (rate ratio 3.8 and 3.7) Gestational OMT is associated with placentomegaly and placental dysmaturity compared to non- drug users. These findings are correlated with reduced surface area for oxygen diffusion, which may affect neonatal well-being. Further analysis is underway to evaluate the effects of placental dysmaturity on neonatal outcomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

393: Impact of methadone and tobacco exposure on fetal growth

The incidence of small for gestational age (SGA) neonates from mothers taking methadone has been reported to be as high as 30%; however, this could be confounded by tobacco use during pregnancy. Our aim is to evaluate the incidence of intrauterine fetal growth restriction (IUGR) and SGA in fetuses exposed to (1) methadone maintenance therapy alone, (2) methadone and tobacco, (3) tobacco alone. This was a retrospective cohort study of women who delivered a live singleton at Thomas Jefferson Hospital from 2013 to 2017. In the three previously mentioned groups, we evaluated co-morbidities, including diabetes, hypertension, hepatitis infection, smoking history, third trimester fetal growth and delivery outcome. In the group of tobacco alone, women that use other substances were excluded. The primary outcome was incidence of IUGR at third trimester ultrasound and SGA. We included 450 women, 41 in the methadone alone group, 315 in the methadone and tobacco group, and 94 in the tobacco alone group. Medical conditions that may affect fetal growth were not significantly different among the three groups. The smoking cessation program for both groups had similar outcomes. The incidence of IUGR at the third trimester ultrasound was the lowest in the methadone alone group (2.4%), as compared to the methadone and tobacco group (9.8%) and the tobacco alone group (8.6%), this was not significantly different; however the incidence of AC <10th percentile was significantly lower in women in the methadone alone group. The incidence of SGA was the lowest in the methadone alone group (9.7%), as compared to the methadone and tobacco group (23.7%) and the tobacco alone group (30.1%) and this was statistically significant. (Table 1) Fetuses exposed to methadone alone had a lower incidence of IUGR and SGA, compared to methadone and tobacco exposure and tobacco alone. Previously documented rate of SGA in fetuses exposed to methadone likely related to concomitant tobacco exposure rather than methadone exposure alone.

Profiles of visuospatial memory dysfunction in opioid-exposed and dependent populations.

Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p &lt; 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.

Replication of the pharmacogenetic effect of rs678849 on buprenorphine efficacy in African-Americans with opioiduse disorder.

Many patients with opioid use disorder do not have successful outcomes during treatment but the underlying reasons are not well understood. An OPRD1 variant (rs678849) was previously associated with methadone and buprenorphine efficacy in African-Americans with opioid use disorder. The objective of this study was to determine if the effect of rs678849 on opioid use disorder treatment outcome could be replicated in an independent population. Participants were recruited from African-American patients who had participated in previous studies of methadone or buprenorphine treatment at the outpatient treatment research clinic of the NIDA Intramural Research Program in Baltimore, MD, USA between 2000 and 2017. Rs678849 was genotyped retrospectively and genotypes were compared to urine drug screen results from the previous studies for opioids other than the one prescribed for treatment. Genotypes were available for 24 methadone patients and 55 buprenorphine patients. After controlling for demographics, the effect of rs678849 genotype was significant in the buprenorphine treatment group (RR = 1.69, 95% confidence interval (CI) 1.59–1.79, p = 0.021). Buprenorphine patients with the C/C genotype were more likely to have opioid-positive drug screens than individuals with the C/T or T/T genotypes, replicating the original pharmacogenetic finding. The effect of genotype was not significant in the methadone group (p = 0.087). Thus, genotype at rs678849 is associated with buprenorphine efficacy in African-Americans being treated for opioid use disorder. This replication suggests that rs678849 genotype may be a valuable pharmacogenetic marker for deciding which opioid use disorder medication to prescribe in this population.

Articles You May Have Missed.

Background: Buprenorphine is a partial opioid agonist with a reported “ceiling effect” for respiratory depression. Despite implied safety, it has been associated with significant overdoses. Conflicting data exist regarding the response to naloxone. Research Question: How do the clinical characteristics and response to naloxone following buprenorphine overdose compare with those of heroin and methadone overdose? Methods: Consecutive patients admitted to two teaching hospitals with Glasgow Coma Score (GCS) <12 and at least two of the following three criteria were included in this 4year prospective. Observational Study: History suggestive of opioid overdose, pinpoint pupils, or initial respiratory rate <12/min. Demographics, intent, initial GCS, respiratory rate, oxygen saturation (SpO2), and vital signs were collected. Urine toxicological screening was performed and only overdoses involving the exclusive presence of 6-monoacetylmorphine, buprenorphine, or methadone were included. Cases involving multiple opioids were excluded, but cases with benzodiazepine coingestion were allowed. Patients were treated with naloxone and/or flumazenil. Antidote dose and order were at the discretion of the attending physician. Response to naloxone was considered “positive” if full awakening occurred or intubation avoided. Results: During the study, 160 patients were admitted for opioid overdose and 84 met inclusion criteria. These 84 were divided into three groups: heroin (n=26), buprenorphine (n=39), and methadone (n=19). Initial GCS, respiratory rate, SpO2, and blood gas analysis were similar between groups. Benzodiazepine coingestion was more common in the buprenorphine vs heroin group and suicide more common in the methadone vs buprenorphine group. Naloxone was administered in 65% of 84 patients. Buprenorphine-poisoned patients did not respond to 0.4– 0.8 mg intravenous naloxone (0/19). Conclusion: Buprenorphine overdose induced a typical opioid syndrome that was not reversed with naloxone. Critique: The strength of the study was a large number of patients and confirmation of toxins. Weaknesses include lack of data on pinpoint pupils (an inclusion criteria), subjective endpoints, preponderance of benzodiazepine co-ingestions, and lack of detailed naloxone dosing information. Implication for Toxicologists: This study gives further evidence that buprenorphine overdose produces a typical opioid toxidrome. If naloxone is used to treat suspected buprenorphine overdose, doses of 0.4 to 0.8 mg may be insufficient to reverse the clinical effects. Benzodiazepines are common coingestants.

Intraoperative use of methadone improves control of postoperative pain in morbidly obese patients: a randomized controlled study

ObjectivesSurgical patients still commonly experience postoperative pain. With the increasing prevalence of obesity, there is a growing demand for surgical procedures by this population. Intraoperative use of methadone has not been well assessed in this population.Materials and methodsPatients with a body mass index of 35 kg/m2 or more undergoing bariatric surgery were randomly assigned to receive either fentanyl (group F) or methadone (group M) in anesthesia induction and maintenance. The primary outcome was morphine consumption during the first 24 hours after surgery through a patient-controlled analgesia device. Secondary outcomes were pain scores at rest and while coughing, opioid related side effects, and patient satisfaction. The patients were also evaluated 3 months after surgery for the presence of pain, dysesthesia, or paresthesia at surgical site.ResultsPostoperative morphine consumption was significantly higher for patients receiving fentanyl than methadone during the postoperative period at 2 hours (mean difference [MD] 6.4 mg; 95% CI 3.1–9.6; P<0.001), 2–6 hours (MD 11.4 mg; 95% CI 6.5–16.2; P<0.001), 6–24 hours (MD 10.4 mg; 95% CI 5.0–15.7; P<0.001), and 24–48 hours (MD 14.5 mg; 95% CI 3.9–25.1; P=0.01). Patients from group F had higher pain scores until 24 hours postoperatively, higher incidence of nausea and vomiting, lower satisfaction, and more evoked pain at surgical scar at the 3-month postoperative evaluation than group M.ConclusionIntraoperative methadone can safely lower postoperative opioid consumption and improve postoperative pain scores compared with fentanyl in morbidly obese patients.