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To study the prevalence of perceived high stress among methadone maintenance treatment (MMT) patients, and whether stress can predict outcome, and whether stress may improve during treatment, we studied a sample of 107 MMT patients using Perceived Stress Scale (PSS) questionnaires. We studied if PSS scores on admission predict long-term retention, and we monitored stress indices (PSS, heart rate variability, saliva cortisol) on admission, 6 and 12 months later, to measure changes. Variables included demographic data, history of adverse events, and urine test. A sample of 79 (73.8%) males and 28 (26.2%) females whose age at opioid use onset was 22.1±7.2 years and age at study onset 50.5±10.8 years was studied for PSS. Both high and very-high PSS patients characterized (logistic regression) as abusing benzodiazepine, and with history of depressive symptoms. The very-high PSS group on admission (n=29) had shorter cumulative retention (1.8 years, 95%%CI 1.2-2.4) compared with 50 others (2.8 years, 95%%CI 2.3-3.3, p=0.03). Monitoring stress indices among 25 patients found that no-benzodiazepine and cocaine use on admission, opioid discontinuation after 6 months, and any substance discontinuation after a year were associated with stress reduction. Conclusion: stress level appears to normalize among MMT patients if no other substance is abused., Competing Interests: Declaration of Competing Interest All authors have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: We have previously shown associations between 4 genetic variants in opioid and stress-related genes (OPRM1, NPYR1/NPYR5, NR3C1, and CRHBP) and prolonged abstinence from heroin without methadone maintenance treatment (MMT). We currently assessed the associations between these variants and MMT patients' characteristics., Methods: A non-selective group of 351 patients who stayed at least 1 year in their first admission to MMT were genotyped and their characteristics and substance in urine on admission and after 1 year were studied., Results: The proportions of patients with both cocaine and benzodiazepine abuse were reduced significantly after 1 year in MMT; however, cocaine abuse cessation was significantly associated with the non-carriers of the CRHBP (corticotrophin releasing hormone binding protein) SNP rs1500 minor C allele (GG genotype) (P = 0.0009, PBonferroni = 0.0221). More carriers of the 2 C alleles (CC genotype) than carriers of the GC and GG genotypes abused cocaine on admission (32.3% vs 19.7%, respectively, P = 0.0414, recessive model), and more of the C allele carriers (GC and CC genotypes) than non-carriers (GG genotype) abused cocaine after 1 year in MMT (25.7% vs 15.8%, respectively, P = 0.0334, dominant model). Abusers of benzodiazepine were more prevalent among carriers of the C allele compared with non-carriers on admission (60.6% vs 45.9%, respectively, P = 0.0080, dominant model), as well as after 1 year in MMT (50.9% vs 39.1%, respectively, P = 0.0362)., Conclusions: Reduction in cocaine abuse among MMT patients may be mediated by a genetic effect in a stress-related gene (CRHBP SNP rs1500 minor C allele). Evaluations of larger samples, additional SNPs, and different populations are needed to support these findings.

Background: Drug users reportedly abuse pregabalin, and its combination with opiates was related to fatalities. We aimed to estimate the prevalence of pregabalin misuse and risk factors among patients in methadone maintenance treatment (MMT)., Methods: A cross-sectional study included all current MMT patients (n = 300) after excluding 9 with prescriptions, from a large tertiary medical center university-affiliated MMT clinic in Israel. Pregabalin was tested in one of the routine urine tests for other substances in December 2017. Data on urine results and patients' characteristics were retrieved from the patients' records., Results: Pregabalin was detected among 53 (17.7%) patients. The group had higher depressive symptoms severity score (21-HAM-D) (11.1 ± 8.4 vs. 8.3 ± 7.8, p = 0.03), a higher prevalence of sero-positive HIV (13.7% vs. 4.2%, p = 0.02), sero-positive hepatitis C (66.7% vs. 50.4%, p = 0.04), DSM-IV-TR Axis I psychiatric diagnosis (54.0% vs. 41.7%, p = 0.03), and positive urine for opiates (22.6% vs. 8.9%, p = 0.008), cannabis (39.6% vs. 4.0 p < 0.0005) benzodiazepine (BDZ) (77.4% vs. 18.2%, p < 0.0005) and oxycodone (11.3% vs. 0.4%, p < 0.0005). Logistic regression found pregabalin group as more likely to be urine positive to BDZ (OR = 12.8 95%CI 5.0-32.5) cannabis (OR = 22.7, 95%CI 6.3-81.6) and oxycodone (OR = 43.9, 95%CI 3.6-541.4), with higher 21-HAM-D scores (OR = 1.1, 95%CI 1.04-1.2) and hepatitis C sera-positive (OR = 4.1, 95% CI 1.5-11.4). Unexpectedly, 13.2% of the pregabalin group had take-home dose privileges, which are rewards to non-drug abusers., Conclusions: High prevalence of pregabalin misuse among both BDZ abusers and non-abusers and patients with depressive symptoms supports both the inclusion of routine monitoring for pregabalin and intervention in MMT population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Environmental and social trends and patients' characteristics may affect predictors for methadone maintenance treatment (MMT) outcome., Methods: We have expanded our previous study of predictors for MMT outcome (from 619 to 890 patients) and the study period (from 15 to 24 years). Survival and retention in MMT since admission to the MMT clinic (6/1993-6/2016) and until death or study closure (6/2017) were compiled and analyzed., Results: Of 890 patients ever admitted (10,146.9 person-years (py)), 237 passed away (116 while in MMT). The mortality rate did not differ between those who stayed or left (2.6 vs. 2.1 per 100 py, p = 0.1), but it was lower among those who stayed ≥1 year during any admission (2.1 vs. 3.3 per 100 py, respectively, p = 0.004). Age <40 years, no hepatitis C or B, no HIV, and no benzodiazepine abuse after one year predicted longer survival (multivariate analyses). No opiate or benzodiazepine abuse after one year, methadone dose ≥100 mg/d, no DSM-IV-TR Axis II diagnosis only, and no direct hospital referral predicted longer retention. Cocaine abuse predicted poor retention and survival among 271 patients admitted during the extended part of the study period., Conclusions: Predictors for retention (associated with MMT outcome) and mortality (associated with pre-treatment comorbidity) after 24 years were similar to those after 15 years. Cocaine abuse as a predictor of both poor retention and poor survival in the later period may reflect the escalating trend for cocaine abuse and should be studied if related to other unmonitored substances., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objectives: Methadone maintenance treatment (MMT) is the gold standard for pregnant women with opioid use disorders. Still, low birth-weights were reported, in particular of mothers who became pregnant before admission to MMT. We studied whether an escalating incentive contingency-management approach may contribute to better newborn birth-weights., Methods: A nationwide controlled randomized trial among all Israeli methadone/buprenorphine maintenance treatment (MBMT), newly or already in treatment pregnant women was performed. A modified contingency-management protocol with coupons of escalating value depending upon reduction of drug use, cigarette smoking, and alcohol consumption was compared to standard care arm. Drugs in urine, smoking (Fagerstrom score), alcohol use, and depression were monitored., Results: Thirty-five women had 46 pregnancies. In their first pregnancy, 19 from the contingency-management and 16 from the standard care arms were studied. Contingency-management group as compared to the standard care arm included more newly admitted women (36.8% vs. 6.3%, p = .05), with benzodiazepine and cannabis onset at a younger age, and higher proportion of any drug abuse while pregnant (100% vs. 68.8%, p = .01). Fifteen of the contingency-management and 14 of the control arm gave birth (78.9% vs. 87.5%, p = .3) with similar proportions of normal (>2,500 g) birth-weight (71.4% vs. 61.5%, p = .8)., Conclusions and Scientific Significance: Newborns' birth-weight was comparable among the two study arms indicating no contribution of the contingency-management approach. Small sample and baseline differences between arms might have influenced results. Intensive intervention should be evaluated on a larger scale of participants. (Am J Addict 2017;26:167-175)., (© 2017 American Academy of Addiction Psychiatry.)

Background: Drug addiction, a leading health problem, is a chronic brain disease with a significant genetic component. Animal models and clinical studies established the involvement of glutamate and GABA neurotransmission in drug addiction. This study was designed to assess if 258 variants in 27 genes of these systems contribute to the vulnerability to develop drug addiction., Methods: Four independent analyses were conducted in a sample of 1860 subjects divided according to drug of abuse (heroin or cocaine) and ancestry (African and European)., Results: A total of 11 SNPs in eight genes showed nominally significant associations (P<0.01) with heroin and/or cocaine addiction in one or both ancestral groups but the associations did not survive correction for multiple testing. Of these SNPs, the GAD1 upstream SNP rs1978340 is potentially functional as it was shown to affect GABA concentrations in the cingulate cortex. In addition, SNPs GABRB3 rs7165224; DBI rs12613135; GAD1 SNPs rs2058725, rs1978340, rs2241164; and GRIN2A rs1650420 were previously reported in associations with drug addiction or related phenotypes., Conclusions: The study supports the involvement of genetic variation in the glutamatergic and GABAergic systems in drug addiction with partial overlap in susceptibility loci between cocaine and heroin addiction., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Methylphenidate, an amphetamine-like prescription medication for attention deficit hyperactivity disorder (ADHD) was suspected as being abused among methadone maintenance treatment (MMT) patients. We tested its presence in the routine urine monitoring of all patients in both Tel Aviv and Las Vegas MMT clinics. Data on demographic and addiction history, ADHD (Wender Utah Rating Scale), cognitive impairment (Mini Mental State Exam), and lifetime DSM-IV-TR psychiatric diagnosis from admission were retrieved, and retention following 6 months. None of the 190 patients in Las Vegas tested positive for methylphenidate, while 14.7% (45/306) did in Tel Aviv. Abusers were less educated (p = 0.01), had higher ADHD scores (p = 0.02), lower cognitive scores (p = 0.05), and a higher benzodiazepine (BDZ) abuse rate (p < 0.0005), with no difference in age, gender, duration in MMT, cannabis, opiates, and cocaine abuse and infectious disease. Of the methylphenidate abuse 42.2% have take-home methadone dose privileges. Not like opiate use, being methylphenidate positive did not relate to 6-months retention. Compared to Tel Aviv, Las Vegas patients were more educated, with lower BDZ, and cocaine abuse. The greater abuse of methylphenidate among ADHD subjects might indicate their using it as self-medication, raising a possible indication for its prescription for that subgroup of MMT patients. The high rate of methylphenidate abuse in Israel needs future study., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Following our finding of high rates of obsessive compulsive disorder (OCD) among methadone maintained (MMT) former opiate addict women with a history of childhood sexual abuse, we compared 68 MMT sexually abused women to 48 women from a Sexual Abuse Treatment Center (SATC) without a history of opiate addiction, for clinical-OCD (Yale-Brown Obsessive Compulsive Scale), dissociation (Dissociative Experiences Scale (DES), complex-post-traumatic stress disorder (PTSD) (Structured Interview for Disorders of Extreme Stress - Non-Other Specify), sexual PTSD (the Clinician-Administered PTSD Scale) and trauma events history (Life Event Inventory). MMT patients were treated for longer periods and were older and less educated. Clinical OCD was more prevalent among the MMT patients (66.2% vs. 30.4%, respectively), while complex-PTSD and high dissociation score (DES≥30) were more prevalent among the non-addicts (46.9% vs. 19.1%, and 57.1% vs. 11.8% respectively). The high rate of OCD among sexually abused MMT women was not found in women who are sexually abused non-addicts. As dissociation was rare among the MMT group, it may just be that the opioids (either as street-drugs or as MMT) serve as an external coping mechanism when the access to the internal one is not possible. Future study about OCD and dissociation before entry to MMT are needed., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The aim of this study was to assess the prevalence of a history of sexual abuse and its relation to psychiatric comorbidity among former opiate addicts currently on methadone maintenance treatment (MMT). We evaluated the history of sexual abuse and current clinical obsessive compulsive disorder (OCD), dissociative identity disorder (DID), and complex posttraumatic distress disorder (cPTSD), and administered the Life Events Inventory Questionnaire among 125 MMT patients (76 females and 49 males). Eighty (64%) patients had experienced sexual abuse, 69 (55.2%) met the criteria for clinical OCD, 20 (16.0%) for cPTSD and 13 (10.4%) for DID. More females had clinical OCD than males (63.2% vs. 42.9%, respectively, p=0.03). Sexually abused patients had higher rates of clinical OCD than their non-abused counterparts (67.5% vs. 33.3%, respectively, p<0.0005) and a higher mean number of negative life events (8.0±2.0 vs. 7.1±1.8, p=0.01). Sexually abused patients showed a trend towards a higher Dissociative Experiences Scale score (17.6±10.1 vs. 14.6±8.1, p=0.08) and rate of DID (13.8% vs. 4.4%, p=0.1), but no significant difference in the rate of cPTSD (17.5% vs. 13.3%, p=0.6) compared to non-abused subjects. The 80 sexually abused patients were mostly female (85%), and 57.5% of them were abused by a family member. In summary, more sexually abused MMT patients were diagnosed with clinical OCD and fewer with cPTSD and DID. Those with cPTSD were characterized by more negative life events, higher dissociation scores, and assaults by a family member. We conclude that sexually abused MMT patients should be screened for clinical OCD., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Methadone maintenance treatment is a chronic treatment for opiate addicts. After having reached full capacity, new admissions to our clinic were delayed (through a waiting list) for all but opiate addicts with HIV and pregnant women. We compared characteristics and outcomes between patients admitted without delay (1993-2002) and those admitted through a waiting list (2003-2009). All 704 patients admitted between June 1993 and June 2009 were followed up until June 2010. There were 470 patients in the early period and 234 in the late period (56 patients were admitted immediately and 178 after 1.1 ± 0.8 years of waiting). Predictors for 1-year retention in treatment (logistic regression model) were if a patient self-referred during the late period, on a waiting list. The waiting list patient group was characterized by older age and self-referral - two known independent predictors of better retention that were attributed to their superior retention rate., (Copyright © 2012 S. Karger AG, Basel.)

Unlabelled: The reports on pain perception among former heroin addicts receiving methadone maintenance treatment (MMT) vary with regard to pain and intolerance threshold, and perception of suprathreshold stimuli has not been previously evaluated. Our aim was to systematically assess perception of threshold and suprathreshold noxious and innocuous stimuli with special attention to the effect of MMT dose and the presence of chronic pain. Noxious and innocuous, thermal and mechanical thresholds and ratings of suprathreshold heat-pain stimuli were measured among 31 MMT subjects receiving high and low MMT dose, with and without chronic pain, and in 17 healthy controls. The characteristics of chronic pain were also evaluated. MMT dose and chronic pain differentially affected pain perception. Whereas MMT dose did not affect thresholds, chronic pain MMT subjects exhibited increased pain threshold and pain-free MMT subjects exhibited decreased pain threshold compared with controls. MMT in general was associated with decreased perception of suprathreshold pain; however, MMT subjects with chronic pain exhibited increased suprathreshold pain ratings. It appears that subjects receiving MMT are hyperalgesic but that chronic pain in these subjects interferes with threshold measurements, inducing an apparent hypoalgesia. On the other hand, chronic pain reduces the analgesic effect of methadone seen in pain-free MMT subjects, amplifying suprathreshold pain perception. Factors such as chronic pain and MMT dose should be taken into account in future studies on pain perception in this population., Perspective: We show that the presence of chronic pain and methadone dose significantly affects perception of pain in former heroin addicts receiving MMT. Studying the alteration in pain perception in these subjects may contribute to understanding the high rates of chronic pain among them and may promote better treatment., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

We have extended our previous 10-year follow-up study of MMT retention for another 5 years and added data on survival of all patients ever admitted to our MMT clinic (6/1993 to 6/2007). Data were calculated from admission to MMT until leaving, death, or study closure (6/2008). Ninety-four of a total of 613 patients (4711.6 person-years [py]) died. Cancer was the primary cause of death for those who remained in treatment, and overdose for those who left MMT. Longer survival (p=0.051) with a trend for a lower mortality rate (p=0.08) was noted among the 464 patients who stayed in treatment > or =1 year (1.8/100 py), compared with the 149 patients who left MMT <1 year (2.6/100 py). Predictors of survival in multivariate analyses were younger age (<40 years) at admission, living with a spouse/partner, being hepatitis B sera-negative, not abusing benzodiazepines on admission (interaction effect), not being referred directly from hospitalization to MMT, and not leaving the MMT program for hospitalization. The two latter variables also predicted longer retention, as did a high methadone dose (> or =100mg/d), no opiate and, no benzodiazepine abuse after 1 year and either having any DSM-IV-TR Axis I, or no Axis I&II psychiatric diagnoses. Unlike retention, mortality was associated with pre-treatment severity and comorbidities thus only partially reflects MMT outcome (opiate abstinence and treatment success). Benzodiazepine abuse reduced both retention and survival, emphasizing the high priority that should be given to stopping it., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the impact of a structured intervention, the "primary intervention for memory structuring and meaning acquisition" (PIMSMA) performed randomly in the emergency department with survivors of suicide bombing attacks, on their medium-term mental health outcome., Design: Follow up and assessment 3-9 months postinjury, and 24 months thereafter., Setting: A tertiary referral general hospital in Tel Aviv, Israel., Participants: Injured survivors of 9 suicide bombing and suicide shooting, men and women aged 16-72 at the time of the incident., Main Outcome Measures: Diagnosis of posttraumatic stress disorder (PTSD) was made using the Hebrew validated version of the DSM-IV SCID-PTSD rating scale. Other psychiatric symptoms were assessed using the following rating scales: impact of event scale (IES), Hamilton rating scale for depression (HAM-D) and for anxiety (HAM-A), and the Pittsburgh sleep quality index (PSQI). Effects of PIMSMA and PTSD level of psychological distress were analyzed using ANOVA and for change over time for continuous variables repeated measured multivariate analyses was performed, and for categorical variables nonparametric-related sample McNemar. Logistic regression for variable associated with PTSD was performed., Results: Out of 213 eligible injured survivors evacuated to our ER, 129 were retrieved 3-9 months after the incident, and 53 were available for assessment 2 years later. Multivariate analyses for being PTSD vs non-PTSD at the first evaluation, being hospitalized OR = 5.6 (95 percent CI 1.1-27.6) and treated OR = 24.5 (95 percent CI 2.8-200) were the only predictors, with no effect (p = 0.9) for PIMSMA vs other supportive intervention. Predictor for PTSD at the second evaluation were IES severity score at first evaluation OR = 1.1 (95 percent CI 1.04-1.2)., Conclusion: The PIMSMA approach is as good as the nonspecific supportive treatment performed routinely in the ED with all survivors of traumatic events of any origin. Further studies are needed to establish valid, evidence-based treatment approaches for the acute aftermath of exposure to severe potentially traumatic events.