Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

The Opioid Interactions of the Antipsychotic Medications Risperidone and Amisulpride in Mice and Their Potential Use in the Treatment of Other Non-Psychotic Medical Conditions.

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. The opioid epidemic in the USA has highlighted the need for alternative treatments for pain. Following reports on the opioid interactions of various antipsychotic medications, we speculated that the involvement of the opioid system in some of the antipsychotics' mechanism of action may suggest their potential use in the treatment of pain. Risperidone is a neuroleptic with a potent dopamine D2 and serotonin 5-HT2 receptor-blocking activity as well as a high affinity for adrenergic and histamine H1 receptors. Amisulpride is a neuroleptic which selectively blocks dopamine D2 and D3 receptors. Both had a potent antinociceptive effect on ICR mice tested with a tail flick assay. That effect on both medications was antagonized by naloxone, indicating that at least some of the antinociceptive effects were mediated by an opioid mechanism of action. Further investigation found that ß-Funaltrexamine hydrochloride (ß-FNA), naloxonazine, and nor-Binaltorphimine dihydrochloride (nor-BNI) reversed the antinociceptive effect of both risperidone and amisulpride. Naltrindole at a dose that blocked [D-Pen2,D-Pen5]enkephalin (DPDPE, δ analgesia) blocked notably amisplride effect and only partially reversed that of risperidone. Risperidone induced an antinociceptive effect, implying involvement of µ and κ-opioid and δ-opioid mechanisms. Amisulpride-induced antinociception was mediated through selective involvement of all three opioid receptor subtypes. These findings emphasize the need for clinical trials to assess the possibility of extending the spectrum of medications available for the treatment of pain.

Different clinical phenotypes of persistent post-traumatic headache exhibit distinct sensory profiles.

INTRODUCTION: Persistent post-traumatic headache remains a poorly understood clinical entity. Although there are currently no accepted therapies for persistent post-traumatic headache, its clinical symptoms, which primarily resemble those of migraine or tension-type headache, often serve to guide treatment. However, evidence-based justification for this treatment approach remains lacking given the paucity of knowledge regarding the characteristics of these two major persistent post-traumatic headache phenotypes and their etiology. METHODS: We compared clinical features and quantitative sensory testing profiles between two distinct cohorts of persistent post-traumatic headache subjects that exhibited symptoms resembling either migraine (n = 15) or tension-type headache (n = 13), as well as to headache-free subjects that had suffered traumatic brain injury (n = 19), and to healthy controls (n = 10). We aimed to determine whether the two persistent post-traumatic headache subgroups could be discriminated based on additional clinical features, distinct quantitative sensory testing profiles, or the interaction of pain severity with the level of post-traumatic stress disorder. RESULTS: Persistent post-traumatic headache subjects with migraine-like symptoms reported that bright light and focused attention aggravated their pain, while stress and nervousness were reported to aggravate the headache in subjects with tension-type headache-like symptoms. Quietness was better in alleviating migraine-like persistent post-traumatic headache, while anti-inflammatory medications provided better relief in tension-type headache-like persistent post-traumatic headache. The two persistent post-traumatic headache subgroups exhibited distinct quantitative sensory testing profiles with subjects exhibiting tension-type headache-like persistent post-traumatic headache displaying a more pronounced cephalic and extracephalic thermal hypoalgesia that was accompanied by cephalic mechanical hyperalgesia. While both persistent post-traumatic headache subgroups had high levels of post-traumatic stress disorder, there was a positive correlation with pain severity in subjects with tension-type headache-like symptoms, but a negative correlation in subjects with migraine-like symptoms. CONCLUSIONS: Distinct persistent post-traumatic headache symptoms and quantitative sensory testing profiles may be linked to different etiologies, potentially involving various levels of neuropathic and inflammatory pain, and if confirmed in a larger cohort, could be used to further characterize and differentiate between persistent post-traumatic headache subgroups in studies aimed to improve treatment.

Drug Abuse and Behavioral Transgressions during Methadone Maintenance Treatment (MMT) are Related to High Psychopathy Levels.

Introduction: Studies which used the Psychopathy Checklist-Revised (PCL-R) among methadone maintenance treatment (MMT) patients focused mostly on methodological issues, without addressing its relationship to patients' misconduct during treatment. This paper tests the hypothesis that high PCL-R scores are related to high rates of drug abuse, and high numbers of behavioral transgressions in MMT during a 7-year period. Material and Methods: 107 MMT patients were recruited from a MMT clinic in Israel, and were administered the PCL-R. The questionnaires results as well as routine drug test findings were recorded between 7/2007 and 11/2007. Seven years later (7/2014), repeated drug test results were analyzed, and the number of behavioral transgressions during the entire period was computed. Results: High levels of psychopathy were related to drug test results indicating any illicit drug use, cocaine use and benzodiazepines misuse at the beginning of study, and limited to benzodiazepines misuse among patients who stayed in treatment at the 7-year follow-up. However, higher scores on different PCL-R facets were significantly associated with different types of drugs. The PCL-R's total score and all but the antisociality facet were positively correlated with a higher number of behavioral transgressions (such as, threats and/or verbal and physical aggression). Conclusions: Administration of the PCL-R during MMT may help identify patients with high illicit drug use levels and a higher chance of committing behavioral transgressions during treatment.

Educational lectures enhance knowledge about the human immunodeficiency virus (HIV) and reduce risky behavior and fear among methadone maintenance treatment patients.

Background: The aim of this study was to characterize human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related knowledge and stigma among methadone maintenance treatment (MMT) patients and evaluate the contribution of an educational lecture in reducing risky behavior and unjustified overprotective behavior due to fear and stigma among MMT patients. Methods: Patients from an MMT clinic within a tertiary medical center were invited to an educational lecture on HIV/AIDS. Seventy participants (of current 330) were chosen by a random sample (December 2015), plus at-risk patients and HIV patients. Attendee compliance and change in scores of questionnaires on knowledge (modified HIV-K-Q-22) and on sexual and injection behaviors were studied. Results: Forty-six patients (65.7% compliance) attended the lecture, and their knowledge and behavior scores improved 2 weeks post-lecture (knowledge: from 14.2 ± 3 to 19.0 ± 2.2 [P < .0005], sexual behavior: from 12.1 ± 2.9 to 8.8 ± 3.0 [P < .0005], and injection behavior: from 7.3 ± 6.2 to 0.2 ± 1.3 [P < .0005]). The unjustified fear of proximity to HIV carriers reported by 50% attendees fell to 35% post-lecture. Eight months post-lecture, the scores on knowledge and risky behavior of 21 randomly chosen attendees were still better than pre-lecture scores (knowledge: 15.4 ± 2.3 vs. 17.2 ± 1.8 [paired t test, P = .001], sexual behavior: 13.2 ± 2.3 vs. 9.7 ± 2.9 [P < .0005], and injection behavior: 9.3 ± 5.6 vs. 2.8 ± 3.1 [P < .0005]). Drug abuse and treatment adherence were not related to intervention and to risky behavior. Conclusions: More knowledge, less fear, and less risky behavior immediately and at 8 months post-lecture reflect the success and importance of the educational intervention. Future efforts are needed in order to reduce ignorance and fear associated with HIV/AIDS.

Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study.

BACKGROUND: Ketamine has been demonstrated to improve depressive symptoms.AimsEvaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD). METHOD: In a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Twenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient. CONCLUSIONS: Repeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.Declaration of interestNone.

Functional effects of synthetic cannabinoids versus Δ9 -THC in mice on body temperature, nociceptive threshold, anxiety, cognition, locomotor/exploratory parameters and depression.

Synthetic cannabinoids are psychoactive substances designed to mimic the euphorigenic effects of the natural cannabis. Novel unregulated compounds appear once older compounds become illegal. It has been previously reported that synthetic cannabinoids are different than Δ9 -tetrahydrocannabinol (Δ9 -THC) as they have chemical structures unrelated to Δ9 -THC, different metabolism and, often, greater toxicity. This study aimed to investigate the effects of three novel synthetic cannabinoids and pure Δ9 -THC on body temperature, nociceptive threshold, anxiety, memory function, locomotor and exploratory parameters, and depression. We performed a battery of behavioural and motor tests starting 50 minutes post i.p. injection of each drug to adult ICR mice. The synthetic cannabinoids that were used are AB-FUBINACA, AB-CHMINACA and PB-22. All synthetic cannabinoids and Δ9 -THC caused hypothermia, but only Δ9 -THC induced a clear antinociceptive effect. All synthetic cannabinoids and Δ9 -THC caused decreased anxiety levels, spatial memory deficits and decreased exploratory behaviour as measured in the elevated plus maze, Y-maze and staircase paradigm, respectively. However, all synthetic cannabinoids but not Δ9 -THC demonstrated decreased locomotor activity in the staircase test. Moreover, only AB-FUBINACA and Δ9 -THC affected the gait balance and grip strength of the mice as was assessed by the latency time to fall from a rod. In the forced swimming test, PB-22 caused elevated depression-like behaviour while AB-FUBINACA induced a reversed effect. These results suggest varied effects among different synthetic cannabinoids and Δ9 -THC. Further studies are needed to characterize the overall effects and differences between these synthetic cannabinoids and Δ9 -THC.

Outcome of Patients With High Depressive Symptoms on Admission to Methadone Maintenance Treatment.

Objective: Comorbidity of depression among individuals with opioid addiction is highly prevalent, but their outcome in methadone maintenance treatment (MMT) is not well determined.Methods: Characteristics and outcomes (retention until December 2017) of newly admitted and already (5.5 ± 4 years) in MMT patients with available Hamilton Depression Rating Scale (HAM-D) scores on admission were studied.Results: During psychiatric intake on admission, 70 (21.2%) of 330 patients were diagnosed with high depressive symptoms beyond the cutoff (HAM-D scores ≥ 18). Depressed and nondepressed groups had a similar proportion of females (20% and 23.8%) and age at admission (43.0 ± 10.5 and 43.7 ± 10.4 years), but the depressed group had higher Brief Psychiatric Rating Scale (BPRS) scores (21.4 ± 8.6 vs. 7.0 ± 7.3, respectively; p < .0005), a higher proportion of minority (non-Jewish faith; 28.6% vs.15.4%; p =.02), and a higher proportion of positive urine screening results for cocaine (55.7% vs. 34.4%; p = .001) and for benzodiazepines on admission (74.3% vs. 57.5%; p = .01). Retention after 1 year was similar (79% and 80.7%), but depressed patients had higher rates of cocaine (40.8% vs. 25.5%; p = .05) and benzodiazepine use (59.2% vs. 41.8%; p = .04) and a shorter cumulative retention (5.6 years, 95% confidence interval [CI; 4.3, 7.0]) than the nondepressed patients (6.8 years, 95% CI [6.1, 7.5]; p = .05). Of the 263 evaluated while already in MMT, 23.5% were depressed, characterized with more females (43.5% vs. 23.4%) and with a history of rape (34.5% vs. 7.6%).Conclusions: Newly admitted depressed and nondepressed patients succeeded similarly in the first year retention in treatment, despite their cocaine and benzodiazepine co-abuse. The depression was characterized with females and with rape history in those who were already in MMT. Adequate intervention is recommended for both depressed groups to improve long-term retention and outcome.

Newborn birth-weight of pregnant women on methadone or buprenorphine maintenance treatment: A national contingency management approach trial.

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).

Anatomical and functional connectivity in the default mode network of post-traumatic stress disorder patients after civilian and military-related trauma.

Posttraumatic stress disorder (PTSD) is characterized by unwanted intrusive thoughts and hyperarousal at rest. As these core symptoms reflect disturbance in resting-state mechanisms, we investigated the functional and anatomical involvement of the default mode network (DMN) in this disorder. The relation between symptomatology and trauma characteristics was considered. Twenty PTSD patients and 20 matched trauma-exposed controls that were exposed to a similar traumatic event were recruited for this study. In each group, 10 patients were exposed to military trauma, and 10 to civilian trauma. PTSD, anxiety, and depression symptom severity were assessed. DMN maps were identified in resting-state scans using independent component analysis. Regions of interest (medial prefrontal, precuneus, and bilateral inferior parietal) were defined and average z-scores were extracted for use in the statistical analysis. The medial prefrontal and the precuneus regions were used for cingulum tractography whose integrity was measured and compared between groups. Similar functional and anatomical connectivity patterns were identified in the DMN of PTSD patients and trauma-exposed controls. In the PTSD group, functional and anatomical connectivity parameters were strongly correlated with clinical measures, and there was evidence of coupling between the anatomical and functional properties. Type of trauma and time from trauma were found to modulate connectivity patterns. To conclude, anatomical and functional connectivity patterns are related to PTSD symptoms and trauma characteristics influence connectivity beyond clinical symptoms. Hum Brain Mapp 37:589-599, 2016. © 2015 Wiley Periodicals, Inc.

ADHD risk alleles associated with opiate addiction: study of addicted parents and their children.

BACKGROUND: Polymorphisms in genes such as DAT1, 5HTTLPR, D4DR4, and MAO-A have been linked to attention deficit hyperactivity disorder (ADHD) and susceptibility for opiate addiction. We investigated in opiate-addicted parents and their children the rate of ADHD and genetic markers that could predict susceptibility to ADHD and/or opiate addiction. METHODS: We studied 64 heroin-addicted, methadone-maintained parents, and their 94 children who had or had not been exposed prenatally to opiates. DNA extracted from mouthwash was assessed for genetic polymorphism for six polymorphic sites of four different genes. Study subjects also filled a variety of questionnaires assessing the rate of ADHD in the parents and children and the children's intelligence quotient. RESULTS: Children of opiate-dependent mothers had a higher rate of ADHD compared to those of the opiate-dependent fathers. Opiate-dependent parents have a high risk of being carriers of most risk alleles examined except DRD4EX3 (allele 7). There was no difference whether the addicted parents had or did not have ADHD. CONCLUSIONS: Serotonergic and dopaminergic risk alleles seem to be mainly related to opiate dependence with no effect on the occurrence of ADHD. People carrying those polymorphisms are susceptible to opioid addiction and not necessarily to ADHD.

Risk factors for weight gain during methadone maintenance treatment.

BACKGROUND: Weight gain was reported during methadone maintenance treatment (MMT). However, its relation to eating habits and specific risk factors, including methadone dose or serum level, was limited. The aims of this study were to characterize risk factors for weight gain and to study current eating habits, food preferences, and nutrition knowledge. METHODS: Patients with available measures of weight and height (body mass index [BMI]) at admission to MMT and at follow-up, when methadone serum levels were determined (after 1 year or when stabilized) (N = 114), were studied (using the Addiction Severity Index [ASI], drugs in urine, methadone doses, and serum levels). In addition, 109 current patients with available earlier (5.8 ± 2.6 years earlier) BMI completed eating behavior rating and nutrition knowledge questionnaires, and their current and earlier BMI were compared. RESULTS: The BMI of 114 newly admitted patients increased from 22.5 ± 3.8 to 24.4 ± 4.3 (P < .0005). Once stabilized on methadone, BMI increased further (24.3 ± 4.5 to 25.6 ± 5.0; P < .0005; n = 74), with no change in methadone doses (125.6 ± 32.5 to 128.0 ± 34.1; F = 1.4, P = .2) or serum levels (495.6 ± 263.7 to 539.8 ± 306.2; F = 1.3, P = .2). Repeated-measures analyses revealed that BMI elevation was higher among 45 hepatitis C virus seronegative and 46 non-benzodiazepine-abusing on-admission patients. Those who scored lower on knowledge about healthy diet and showed a higher sweet-foods preference had a higher BMI. CONCLUSION: BMI increased over time, but independent of methadone dosage and blood levels. As expected, worse diet habits and a desire for sweet foods are related to higher BMI. Paradoxically, healthier status (i.e., hepatitis C seronegative, no benzodiazepine abuse) at admission is predictive of greater weight gain during MMT. Education about nutrition habits is recommended.

Stroop task among patients with obsessive-compulsive disorder (OCD) and pathological gambling (PG) in methadone maintenance treatment (MMT).

OBJECTIVES: To evaluate the impaired attention selection (Stroop interference effect) and general performance [reaction times (RTs)] on the Stroop task among methadone maintenance treatment (MMT) patients with obsessive compulsive disorder (OCD), pathological gambling (PG), both PG/OCD or none, and the influence if having ADHD. METHODS: Eighty-six patients and 15 control subjects underwent the Stroop task, which measured RTs of condition-related words (color, obsessive compulsive disorder, pathological gambling, addiction) and neutral words. RESULTS: MMT patients had longer RTs on the Stroop task compared with controls. RTs were longer among patients with OCD and in those who abused drugs on the study day. The combined PG/OCD group had the longest RTs, but they were also characterized as abusing more drugs, being older, and having worse cognitive status. Stroop color interference differed only among MMT patients with ADHD, and it was higher among those with OCD than those without OCD. The modified condition-related Stroop did not show any interference effect of OCD, addiction, or gambling words. CONCLUSIONS: MMT patients had generally poorer performance, as indicated by longer RTs, that were related to clinical OCD, drug abuse, poor cognitive state, and older age. Patients with both clinical OCD and ADHD had a higher Stroop interference effect, which is a reflection of an attention deficit. In order to improve clinical approach and treatment of MMT patients, OCD and ADHD should be evaluated (and treated as needed).

Trends in substance abuse and infectious disease over 20 years in a large methadone maintenance treatment (MMT) clinic in Israel.

BACKGROUND: The objective was to study substance abuse, infectious disease, and patient outcomes (retention and substance abuse abstinence) over 2 decades in a large methadone maintenance treatment (MMT) facility within a tertiary-referral medical center. METHODS: Prevalence of substance abuse was determined monthly between 1993 (35 patients) and 2013 (350 patients) based on observed random urine tests. On entry, patients were tested for hepatitis C and human immunodeficiency virus (HIV) antibodies. One-year retention and substance abuse abstinence were calculated. RESULTS: At admission, mean age and rate of cocaine and benzodiazepines abuse increased over the years, with no change in the prevalence of hepatitis C (50%) and HIV (<10%). Retention rate increased (P = .008) (range: 42.9%-92.4%; overall: 76.2%) and opiate abstinence also increased (P = .006) (range: 49.1%-85.7%; overall: 68.1%), reflecting outcome improvement over the years. CONCLUSIONS: Outcome improvement could be attributed to the staff's growing experience and improvements in treatment but also to changes in patient characteristics over the past 2 decades.

Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury.

Traumatic brain injury (TBI), either as an isolated injury or in conjunction with other injuries, is an increasingly common event. An estimated 1.7 million injuries occur within the USA each year and 10 million people are affected annually worldwide. Indeed, nearly one third (30.5%) of all injury-related deaths in the USA are associated with TBI, which will soon outpace many common diseases as the major cause of death and disability. Associated with a high morbidity and mortality and no specific therapeutic treatment, TBI has become a pressing public health and medical problem. The highest incidence of TBI occurs in young adults (15-24 years age) and in the elderly (≥75 years of age). Older individuals are particularly vulnerable to these types of injury, often associated with falls, and have shown increased mortality and worse functional outcome after lower initial injury severity. In addition, a new and growing form of TBI, blast injury, associated with the detonation of improvised explosive devices in the war theaters of Iraq and Afghanistan, are inflicting a wave of unique casualties of immediate impact to both military personnel and civilians, for which long-term consequences remain unknown and may potentially be catastrophic. The neuropathology underpinning head injury is becoming increasingly better understood. Depending on severity, TBI induces immediate neuropathologic effects that, for the mildest form, may be transient; however, with increasing severity, these injuries cause cumulative neural damage and degeneration. Even with mild TBI, which represents the majority of cases, a broad spectrum of neurologic deficits, including cognitive impairments, can manifest that may significantly influence quality of life. Further, TBI can act as a conduit to longer term neurodegenerative disorders. Prior studies of glucagon-like peptide-1 (GLP-1) and long-acting GLP-1 receptor agonists have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of chronic neurodegenerative (Alzheimer's and Parkinson's diseases) and acute cerebrovascular (stroke) disorders. In view of the mechanisms underpinning these disorders as well as TBI, we review the literature and recent studies assessing GLP-1 receptor agonists as a potential treatment strategy for mild to moderate TBI.

Characteristics and outcome of minority group patients in methadone maintenance treatment.

Abstract Minority status is associated with mental and physical morbidity, substance dependence, and poor outcomes. To compare characteristics and treatment outcomes between patients from two minority groups in Israel (Christians and Muslims) and patients from the majority population (Jews) in methadone maintenance treatment (MMT), we prospectively studied all patients admitted to our clinic between 1993 and 2012 and followed up until 2013; 655 Jews, 67 Christians, and 37 Muslims. Christian patients differed from Jews and Muslims by younger age at admission to MMT, greater prevalence of drug injectors, and a higher proportion of Hepatitis-C and HIV sera positive. Muslims had comparatively less education and a lower proportion of females. The three groups had similar rates of one-year retention (75.9%) and opiate abstinence (68.1%). They also did not differ in long-term retention (up to 20 years): Muslims 5.5 years (95%CI 3.6-7.4), Christians 7.5 years (95%CI 6-9.1), and Jews 7.6 years (95%CI 7-8.2, p = .3). The Hepatitis-C incidence, however, was higher among the 21 admitted Hepatitis-C seronegative minorities (5.0/100 person years) than the 207 Hepatitis-C seronegative non-minority patients (1.7/100 person years, p=0.03). All groups had good treatment outcomes, except for Hepatitis-C seroconversion, which necessitates a specific preventive intervention among the minority groups.

The relationship between vulnerable attachment style, psychopathology, drug abuse, and retention in treatment among methadone maintenance treatment patients.

The relationship between vulnerable attachment style, psychopathology, drug abuse, and retention in treatment among patients in methadone maintenance treatment (MMT) was examined by the Vulnerable Attachment Style Questionnaire (VASQ), the Symptom Checklist-90 (SCL-90), and drug abuse urine tests. After six years, retention in treatment and repeated urine test results were studied. Patients with vulnerable attachment style (a high VASQ score) had higher rates of drug abuse and higher psychopathology levels compared to patients with secure attachment style, especially on the interpersonal sensitivity, anxiety, hostility, phobic anxiety, and paranoid ideation scales. Drug abstinence at baseline was related to retention in treatment and to higher rates of drug abstinence after six years in MMT, whereas a vulnerable attachment style could not predict drug abstinence and retention in treatment. Clinical Implications concerning treatment of drug abusing populations and methodological issues concerning the VASQ's subscales are also discussed.

Fentanyl abuse proportion in methadone maintenance treatment, and patients' knowledge about its risks.

INTRODUCTION: Fentanyl is not yet routinely monitored among methadone maintenance treatment (MMT) patients in Israel. We aimed 1. to evaluate urine fentanyl proportion changes over 3 years and characterize patients' characteristics 2. To study patients' self-report on fentanyl usage, and compare knowledge about fentanyl risk, before and following brief educational intervention. METHODS: Fentanyl in the urine of all current MMT patients was tested every 3 months year between 2021 and 2023, and patients with positive urine fentanyl were characterized. Current patients were interviewed using a fentanyl knowledge questionnaire (effects, indications, and risks) before and following an explanation session. RESULTS: Proportion of fentanyl ranged between 9.8 and 15.1%, and patients with urine positive for fentanyl (September 2023) were characterized as having positive urine for pregabalin, cocaine, and benzodiazepine (logistic regression). Of the current 260 patients (87% compliance), 78(30%) self-reported of fentanyl lifetime use ("Ever"), and 182 "never" use. The "Ever" group had higher Knowledge scores than the "Never", both groups improved following the explanatory session (repeated measure). The "Ever" group patients were found with urine positive for cannabis and benzodiazepine on admission to MMT, they were younger, did not manage to gain take-home dose privileges and had a higher fentanyl knowledge score (logistic regression). CONCLUSIONS: In the absence of routine fentanyl tests, a high knowledge score, shorter duration in MMT, benzodiazepine usage on admission, and current cannabis usage, may hint of the possibility of fentanyl abuse.

Occurrence of hypertension among patients with opioid use disorder in methadone maintenance treatment.

BACKGROUND: Patients in methadone maintenance treatment (MMT) may develop age-related medical problems, but hypertension (HTN) proportion and its occurrence during MMT have not been studied yet. We aimed to evaluate changes in blood pressure (BP) during MMT and characterize current HTN. METHODS: Of all 1098 ever admitted MMT patients, those with ≥2 BP follow-up measures were included ( n  = 516), of them all current patients ( N  = 245) tested for HTN (systolic BP ≥140 mmHg or diastolic BP ≥90 were detected twice (one week apart) were considered as affected with HTN. Current and earliest during the first, and latest year in MMT of body mass index (BMI), BP, methadone dose and serum level, and drugs in urine were analyzed. RESULTS: HTN was detected in 89(36.3%) of the current patients. The HTN and non-HTN groups did not differ by sex ( P  = 0.6), age ( P  = 0.2), and duration in MMT ( P  = 0.6), but had higher BMI (27.9 ±â€Š5.2 vs. 25.6 ±â€Š5.2, respectively, P  = 0.001) and fewer had positive urine test findings for any substance (31.5% vs. 44.9%, P  = 0.04). Comparing their earliest measures (before 11.9 ±â€Š5.8 years), BP and BMI increased more among the hypertensive group, independent of methadone dose and serum levels, which significantly reduced over the years. No drug abuse was associated with increased BMI and BP. CONCLUSIONS: Weight gain was associated with BP elevation and characterized patients who succeeded in drug abstinence during MMT. Healthy nutrition education at admission to MMT may reduce the incidence of weight gain and HTN, therefore identifying HTN and offering treatment for this highly prevalent life-threatening condition among middle-age and older patients in MMT is recommended.

Different characteristics but comparable hypertension rates between two MMT "twin" clinics.

BACKGROUND: Patients in methadone maintenance treatment (MMT) may develop age-related medical problems. Objective: To compare hypertension prevalence and its risk factors between two MMT clinics, having similar treatment guidelines, but different characteristics, one from Tel Aviv (TA) and one from Las Vegas (LV). METHODS: Prevalence of hypertension (systolic ≥140 and or diastolic ≥90 mmHg BP) among all current 291 MMT patients in TA and 180 patients in LV were studied, including body mass index (BMI), drugs in urine, sociodemographic, and addiction history data. RESULTS: Hypertension prevalence was comparable in TA (35.4%) and LV (34.4%), however TA patients were older (55.9 ± 9.5 vs. 45.5 ± 13.3, p < 0.001), with fewer females (22 vs. 42.2%, p < 0.001), fewer obese (BMI ≥30) (24 vs. 40.9%, p < 0.001), higher cocaine (21 vs. 7.8%, p < 0.001), and lower cannabis (14.1 vs. 32.4%, p < 0.001) and amphetamines (0 vs. 33.5%) users. Logistic regression found higher BMI to characterize hypertension in both clinics, but in TA also negative urine cocaine, benzodiazepine, and opioids screen, while in LV older age (≥50 y), male gender, and negative urine cannabis screen. CONCLUSIONS: While TA was characterized with older patients, LV patients had a comparable hypertension rate, as obesity was more prevalent. No drug use was accompanied by higher BMI in TA and therefore associated with hypertension. Weight reduction, hypertension detection and treatment are recommended.