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.

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.

Measuring anxiety-like behavior in a mouse model of mTBI: Assessment in standard and home cage assays.

Traumatic brain injury (TBI) is a primary global health concern and one of the most common causes of neurological impairments in people under 50. Mild TBI (mTBI) accounts for the majority of TBI cases. Anxiety is the most common complaint after mTBI in humans. This study aims to evaluate behavioral tests designed to assess anxiety-like phenotypes in a mice model of mTBI. ICR mice underwent mTBI using the weight-drop model. Seven days post-injury, mice were subjected to one of five different behavioral tests: Elevated Plus Maze (EPM), Open Field apparatus (OF), Marble Burying test (MBT), Light Dark Box (LDB), and the Light Spot test within the PhenoTyper home cage (LS). In the EPM and OF tests, there were no significant differences between the groups. During the 30-min test period of the MBT, mTBI mice buried significantly more marbles than control mice. In the LDB, mTBI mice spent significantly less time on the far side of the arena than control mice. In addition, the time it took for mTBI mice to get to the far side of the arena was significantly longer compared to controls. Results of LS show significant within-group mean differences for total distance traveled for mTBI mice but not for the control. Furthermore, injured mice moved significantly more than control mice. According to the results, the anxiety traits exhibited by mTBI mice depend upon the time of exposure to the aversive stimulus, the apparatus, and the properties of the stressors used. Therefore, the characterization of anxiety-like behavior in mTBI mice is more complicated than was initially suggested. Based on our findings, we recommend incorporating a variety of stressors and test session lengths when assessing anxiety-like behavior in experimental models of mTBI.

Fire Walk With Me: Posttraumatic Stress Disorder and Pyromania.

Reports of destructive behavior by military personnel after demobilization have become more frequent; however, the pathways that might lead these individuals to commit such acts are not clear enough. This column presents the case of a retired soldier who reported the onset of pyromania after military service, and the relationship between dissociation and reenactment of the trauma is discussed. The main conclusions are that psychotherapy of traumatized patients should focus on helping them create a verbal representation of the trauma and that integrating ceremonies and rituals into treatment is a possible and significant option.

Neural oscillations while remembering traumatic memories in post-traumatic stress disorder.

OBJECTIVE: The current study investigated the oscillatory brain activity of PTSD patients during directed and imaginal exposure to the traumatic memory using magnetoencephalography (MEG), in a paradigm resembling exposure therapy. METHODS: Brain activity of healthy trauma-exposed controls and PTSD participants was measured with MEG as they listened to individualized trauma narratives as well as to a neutral narrative and as they imagined the narrative in detail. Source localization analysis by frequency bands was conducted in order to map neural generators of oscillatory activity. RESULTS: Elicitation of traumatic memories resulted in a distinct neural pattern in PTSD patients compared to healthy trauma-exposed individuals. In response to trauma scripts PTSD patients showed increases in high-gamma band power in visual areas, increased frontal and temporal theta as well as prefrontal alpha and medial temporal beta power relative to neutral scripts. CONCLUSIONS: Results suggest that when recollecting and imagining traumatic memories PTSD patients attempt to engage control or inhibition mechanisms. However, these are either not successfully recruited or inefficient leading to heightened responses and recollection. SIGNIFICANCE: Investigating the oscillatory neural dynamics of PTSD patients can help us better understand the processes underlying trauma re-experiencing.

Hepatitis C Virus Elimination in Methadone-treated Patients: Implementation of Hepatology Clinic in a Methadone Treatment Program.

OBJECTIVES: Patient ignorance and bureaucratic obstacles prevent initiation of hepatitis C virus (HCV) treatment in patients participating in methadone treatment program. Despite high safety and efficacy of currently available oral medications, the rate of patient-initiated treatment remains low. We evaluated the impact of an interventional program on treatment success rate and factors associated with treatment engagement. METHODS: An intervention performed from 2018 to 2020 included an on-site Fibroscan and hepatologist evaluation, anti-viral HCV treatment initiation, and close support and follow-up by a dedicated team. Demographic and medical data were collected and comparison between patients who completed vs. patients who did not complete HCV treatment was done. RESULTS: Fifty-nine out of 74 HCV polymerase chain reaction-positive patients (79.7%) were willing and capable of undergoing on-site hepatologist and Fibroscan evaluations. Twelve (25%) of the participants had cirrhosis, 2 of whom were decompensated. Fifty of the 57 patients that got an anti-viral medication prescription (87%) initiated the treatment. Premature treatment discontinuation was rare (3 patients), intention-to-treat sustain virologic response (SVR) rate was 81% and per-protocol SVR rate was 97%. The rate of treatment initiation during the intervention was significantly higher than the patients' self-initiation rate (44 vs 12 patients). The main factors associated with successful completion of the care cascade was full abstinence from street drugs for 6 months before treatment initiation. CONCLUSIONS: Installing a hepatology clinic in an methadone treatment program center was associated with a 3-fold increase in the HCV treatment, with high adherence to treatment levels, and a high SVR rate. The main factor associated with low engagement to treatment was ongoing street drug use.

Cannabis use is associated with lower retention in methadone maintenance treatment, but not among schizophrenic- and other chronically psychotic patients.

The findings of studies on cannabis use and retention in methadone maintenance treatment (MMT) are inconsistent.To study cannabis use and its relationship to patients' outcomes in MMT with/without lifetime DSM-IV-TR schizophrenia/chronic-psychosis diagnosis.Since June 1993, 877 patients with available lifetime DSM-IV-TR psychiatric diagnosis were followed-up until December 2017. Urine drug screens on admission and after one year were analyzed.Lifetime schizophrenia/psychosis was diagnosed in 50 (5.7%) patients. They did not differ from the other 827 by admission cannabis use (18.0% vs. 12.3%) and had similar 1-year retention rates (76.0% vs.77.0%, respectively). Cumulative retention of the cohort excluding schizophrenia/chronic-psychosis was longer for the 667 patients who did not use cannabis after 1-year (9.1 years, 95%CI 8.4-9.9) compared with the 118 cannabis-users after 1-year (6.0 years, 95% CI 4.8-7.2, p<.001). Among the schizophrenia/chronic-psychosis group, cannabis was not related to retention (38 non-users, 7.9 years 95%CI 5.2-10.5 vs. 9 cannabis-users, 9.9 years, 95% CI 3.8-16.0, p=.5). Survival was shorter for the 41 schizophrenia/chronic-psychosis non-users (15.2 years, 95% CI 12.8-17.7) than for the 719 non-schizophrenia/chronic-psychosis non-users (18.5, 95%CI 17.9-19.2, p = 0.009). However, survival was comparable among the 9 cannabis-users with schizophrenia/chronic-psychosis (20.1, 95% CI 16.2-24.1) and 101 other cohort users (18.6, 95% CI 16.9-20.4).Cannabis use is associated with decreased retention among MMT patients, however the effects of cannabis on schizophrenia/psychosis patients on retention and survival cannot be verified due to the small sample size and the limited data regarding chronicity of cannabis use. Future larger, prospective studies are needed.

No Significant Effects of Cellphone Electromagnetic Radiation on Mice Memory or Anxiety: Some Mixed Effects on Traumatic Brain Injured Mice.

Current literature details an array of contradictory results regarding the effect of radiofrequency electromagnetic radiation (RF-EMR) on health, both in humans and in animal models. The present study was designed to ascertain the conflicting data published regarding the possible impact of cellular exposure (radiation) on male and female mice as far as spatial memory, anxiety, and general well-being is concerned. To increase the likelihood of identifying possible "subtle" effects, we chose to test it in already cognitively impaired (following mild traumatic brain injury; mTBI) mice. Exposure to cellular radiation by itself had no significant impact on anxiety levels or spatial/visual memory in mice. When examining the dual impact of mTBI and cellular radiation on anxiety, no differences were found in the anxiety-like behavior as seen at the elevated plus maze (EPM). When exposed to both mTBI and cellular radiation, our results show improvement of visual memory impairment in both female and male mice, but worsening of the spatial memory of female mice. These results do not allow for a decisive conclusion regarding the possible hazards of cellular radiation on brain function in mice, and the mTBI did not facilitate identification of subtle effects by augmenting them.

False-positive fentanyl screening kit results during treatment with long term injectable risperidone (Risperdal-Consta).

Fentanyl, a highly potent synthetic opioid, is a major cause of overdose deaths in the United States and worldwide. Urine drug immunoassay tests that include fentanyl in their drug panel are the common screening tool. However, false positive results may compromise test accuracy and cause grave clinical outcomes. In this preliminary report we describe 3 cases of patients with schizophrenia, who are treated with long-term injectable risperidone (Risperdal Consta) and were false positively screened for fentanyl by a rapid commercial screening kit. This finding warrants clinical attention to the possibility of inaccurate results regarding fentanyl misuse in multiple clinical settings.

The prevalence of constipation and its relation to sweet taste preference among patients receiving methadone maintenance treatment.

BACKGROUND: Preference for sweet-tasting foods, weight gain, and constipation characterize patients receiving methadone maintenance treatment (MMT). The prevalence of constipation in MMT and its relation to preference for sweet taste and body mass index (BMI) are undetermined. METHODS: A random sample of 83 patients was interviewed for constipation with the Patient Assessment Constipation Quality of Life (PAC-QOL) questionnaire. They rated taste intensity and reward of sweet, salty, and sour solutions by means of a nine-point Likert scale. Data on their BMI, drugs in urine, methadone dose, and serum levels were analyzed. RESULTS: Forty-two patients reported minimum to severe constipation. They characterized as having longer durations of opioid usage before MMT and worse sleep quality than non-constipated patients (logistic regression). Constipation intensity was inversely correlated with duration in MMT and linearly correlated with the Patient Assessment Constipation Quality of Life score. Patients with constipation rated reward to sweet taste significantly higher with no differences in taste intensity compared to non-constipated patients. Patients with high methadone serum levels (≥750 ng/mL) rated taste intensity significantly lower compared to those with normal methadone serum levels (<750 ng/mL), and the lowest rates were reported among patients with no constipation and high methadone serum levels. CONCLUSIONS: Constipation was highly prevalent among MMT patients and associated with poor sleep and lower quality of life. The relation to preference for sweets, as reflected by higher reward rating, strongly supports the need for nutritional intervention to alleviate constipation symptoms and improve quality of life and sleep.

The Effects of the 1st National COVID 19 Lockdown on Emergency Psychiatric Visit Trends in a Tertiary General Hospital in Israel.

OBJECTIVE: To examine whether the 1st COVID-19 lockdown in Israel affected emergency psychiatric presentations in a general hospital. METHOD: We studied files of patients who underwent psychiatric consultation in the emergency-room (ER) at the Tel-Aviv Sourasky Medical Center during a lockdown imposed in 2020. Parallel data were obtained from 2017-2019, as control. RESULTS: The number of psychiatric consultations dropped during the lockdown period; an increased relative number of compulsory psychiatric hospitalizations was documented and a decreased rate of consented psychiatric hospitalizations. DISCUSSION: Less psychiatric patients approached the ER during the lockdown period, pointing to an urgent need to facilitate access to psychiatric care in future times of crisis.

Post-traumatic stress disorder due to sexual abuse and its relation to pain sensitivity among patients in methadone maintenance treatment.

We studied whether post-traumatic stress disorder (PTSD) due to sexual abuse is related to pain indices among methadone maintenance treatment (MMT) patients. Pain threshold was determined, and suprathreshold pain levels were rated among 18 patients with PTSD and sexual abuse, and 38 patients without PTSD (20 with and 18 without sexual abuse). Patients with PTSD had higher proportion of chronic pain and high-perceived stress, and lower pain threshold, with similar supra-threshold ratings. Patients with benzodiazepine in urine had higher pain thresholds and they rated supra-threshold stimuli lower. However, the analgesic effect was not observed among PTSD patients.

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.

Pregabalin Misuse: Motives, Pattern, and Knowledge about Its Risks among Patients in Methadone Maintenance Treatment.

We examined motives for pregabalin misuse and the relation with knowledge on its risks among patients receiving MMT. A questionnaire was used to assess patients' knowledge before and after an explanatory session. Responses were either "never-use" or "ever-use" (past, occasional, chronic). Pregabalin in urine was tested during 1 month, 4 months before, and 24 months after the explanatory session. Of 231 participants, 72 (31.2%) responded "ever-use" while 46 (19.9%) tested positive for pregabalin (42 (58.3%) of the "ever-use" and 4 (2.5%) of the "never-use" group). The 'occasional' subgroup had the highest proportion of non-prescribed pregabalin (75%), used it for recreational purpose (16.7%) and non-orally (41.7%). A faster dropout (shorter retention in MMT) was observed among patients who used pregabalin not orally (1.4 years, 95%CI 1.2-1.7) vs. (1.7 years, CI 1.6-1.8, p = .02), and those who used it not for pain (p = .024). Knowledge scores were higher among those tested positive for pregabalin (3.5 ± 1.7 vs. 2.9 ± 2.0, p = .04). Pregabalin is highly misused among MMT patients. Those who use it not for its indications, or not orally had a shorter retention in MMT, most likely not as a sole cause. "Ever users" knew more about pregabalin indications and risks. Monitoring and education on pregabalin are recommended.

The Relation between Changes in Vitamin D and Vitamin B12 Levels, Body Mass Index and Outcome in Methadone Maintenance Treatment Patients.

Patients' Body Mass Index (BMI) increase during methadone maintenance treatment (MMT), and both Vitamins D and B12 deficiencies may be associated with BMI. We studied the relations between BMI, these vitamins and treatment outcome in patients with opioid use disorder receiving MMT. Vitamin B12 levels were available for 272 patients and Vitamin D levels were available for 260 patients. Of those 112 and 80 respectively had two measures (at admission or thereafter, and while stabilized or after one year in treatment). Patients' BMI levels and long-term retention were analyzed. Vitamin B12 was lower in patients abusing cocaine/amphetamine on admission. Vitamin D did not change over time, but a significant weight gain could be observed in 38 patients whose vitamin D was elevated compared to 42 whose levels were not, (25.4 ± 4.8 to 28.8 ± 5.2 vs. 24.3 ± 3.7 to 25.5 ± 4.0, p(Time) < 0.0005, p(Group) = 0.03, p(interaction) = 0.02). BMI changes correlated with vitamin D levels change (r = 0.26, p = .04). Longer cumulative retention was observed among the elevated vitamin D group (8.1 years, 95% CI 6.3-9.8) in comparison with the non-elevated group (4.8y 95% CI 3.6-6.1, Kaplan Meier, p = .02). Stimulants misuse was associated with low B12 levels. Vitamin D elevation is associated with weight gain and longer retention in treatment.

Stress indices in methadone maintenance treatment - Cross sectional and follow up study.

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.

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse.

Traumatic brain injury (TBI) has been designated as a signature injury of modern military conflicts. Blast trauma, in particular, has come to make up a significant portion of the TBIs which are sustained in warzones. Though most TBIs are mild, even mild TBI can induce long term effects, including cognitive and memory deficits. In our study, we utilized a mouse model of mild blast-related TBI (bTBI) to investigate TBI-induced changes within the cortex and hippocampus. We performed rapid Golgi staining on the layer IV and V pyramidal neurons of the parietal cortex and the CA1 basilar tree of the hippocampus and quantified dendritic branching and distribution. We found decreased dendritic branching within both the cortex and hippocampus in injured mice. Within parietal cortex, this decreased branching was most evident within the middle region, while outer and inner regions resembled that of control mice. This study provides important knowledge in the study of how the shockwave associated with a blast explosion impacts different brain regions.

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.

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.