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.

Is pain empathy associated with pain indices and trauma history? A comparison between patients receiving methadone maintenance treatment and healthy controls.

BACKGROUND: To study whether pain empathy and theory of mind (ToM) are related to pain indices and trauma experience, we studied opioid users receiving methadone maintenance treatment (MMT), a population with a history of traumas and a high prevalence of chronic pain. METHODS: MMT patients (n = 53), substance abuse-free, with no impaired cognition (Montreal Cognitive Assessment (MoCA) ≥24), were compared to healthy controls (HC) matched by age and gender (n = 66). All participants were assessed using Reading the Mind in the Eyes (RMET) for ToM, empathy (Interpersonal Reactivity Index [IRI], Empathy Quotient Scale for Adults [EQ60]), and Pain Empathy [PE task]). An algometer was used for pain pressure threshold, and supra-pain threshold was rated using a visual analog scale (VAS). Catastrophizing, McGill pain, Negative life events (NLE), and MoCA questionnaires were administered. Substance abuse was tested in the urine of MMT patients and self-reported by HC. RESULTS: MMT, compared to HC, were less educated with more NLE and a lower RMET (logistic regression). Groups had comparable empathy and pain indices, except for higher supra-threshold VAS rating and catastrophizing in univariate analyses. Pain empathy (PE) correlated with NLE in HC, and in MMT, with catastrophizing, which correlated with NLE, perceived stress, and pain intensity. Higher empathy was observed in 18 participants with a history of sexual abuse (83.3 % belong to the MMT group). CONCLUSIONS: Pain Empathy was found to be associated with personal suffering experience in both groups, as reflected by correlations with NLE in HC and with catastrophizing, which correlates with NLE, stress, and pain intensity, in MMT.

Predictors of treatment retention and survival among methadone-maintained patients: A possible role for a functional delta opioid receptor gene variant.

BACKGROUND: Variants in the delta opioid receptor gene, OPRD1, were associated with opioid use disorder and response to treatment. The study goal was to assess whether OPRD1 variants predict survival and retention in methadone maintenance treatment (MMT). METHODS: Retention and survival time since admission (June 1993 - June 2022) until leaving treatment (for retention), or at the end of follow-up (Dec 2022) (for retention and survival) were analyzed in 488 patients. Vital data was taken from a national registry. Predictors were estimated using Kaplan-Meier and Cox regression models. RESULTS: Longer retention and survival were found for carriers of the T allele of SNP rs204076. This SNP is associated with OPRD1 expression in cortex (GTEx). Carriers of the T allele (n = 251) survived longer compared to non-carriers (24.7 vs. 20.2 years, p = 0.005) and had longer retention (11.2 vs. 8.8 years, p = 0.04). Multivariate analysis identified the T allele as an independent predictor of longer survival time (p = 0.003) and retention (p = 0.009). Additional predictors for survival were no benzodiazepine use after one year in MMT, no hepatitis C, <20 years of opioid usage, and admission at age < 30. Additional predictors for longer retention were no use of other drugs except opioids on admission, and no drugs at one year, as well as methadone dose ≥ 100mg/d at one year and axis I & II DSM-5 psychiatric diagnosis. CONCLUSIONS: The OPRD1 SNP rs204076 and non-genetic predictors contribute to survival time and retention in MMT patients.

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.

Risk and benefit of cannabis prescription for chronic non-cancer pain.

OBJECTIVES: We investigated whether cannabis usage was associated with reduced opioid usage, and the rates of opioid and cannabis use disorders among chronic pain patients who had been prescribed medical cannabis. METHODS: A random sample of chronic pain patients who had license for cannabis use were interviewed by telephone about their lifetime opioid and cannabis usage. Cannabis and opioid use disorders were assessed with Portenoy's criteria. RESULTS: Of the 100 participants aged 18-70 years (compliance 67% (aged >40) and 33% (aged ≤ 40y)), 76 ever used opioids. Of them, 93% decreased or stopped opioids following cannabis initiation. Ten patients (10%), 17.4% of the ≤40 y age group, met the criteria for cannabis use disorder. Compared to those who did not meet the criteria, their lifetime depression was higher (80% vs. 43.2%, respectively, P=.042), and they were less educated (12.2 ± 0.6y vs. 13.5 ± 2.1y, p = 0.05). CONCLUSIONS: Cannabis usage was associated with reduced opioid usage. The prevalence of cannabis use disorder was high among the younger participants who also had a lower study compliance rate, suggesting the higher actual prevalence of cannabis use disorder. While medical cannabis may help reduce opioid use in chronic non-cancer pain patients, younger age, depression, and other risk factors should be carefully evaluated before cannabis is prescribed.

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.

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.

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.

Trend differences over 20 years between two methadone maintenance clinics, one with and one without cannabis legalization.

BACKGROUND: Although methadone maintenance treatment (MMT) guidelines are well established, patients' characteristics and outcome change over time may be affected by the legality of cannabis. OBJECTIVE: To study trend changes between two clinics over 20 years from Las Vegas (LV) and 27 years from Tel Aviv (TA). METHODS: Patients' characteristics at admission, including drugs in urine at first and 13th month were obtained from their medical charts. Changes by year of admission and cumulative retention were analyzed. RESULTS: The LV MMT clinic (1724 patients) had a lower one-year retention rate compared to the TA MMT clinic (1014 patients) (46.4% vs. 74.4%, respectively, p < 0.0005), and a higher rate of opioid stop after one year (75.9% vs. 68.8%, respectively, p = 0.003). The age at MMT admission and the retention rates decreased in LV and increased in TA. The prevalence of cannabis and benzodiazepine misuse on MMT admission increased in LV with no change recorded in TA. Cocaine on MMT admission decreased in LV and increased in TA, while amphetamine use increased in LV and decreased in TA. Cox models multivariate analyses found cannabis on admission to predict shorter retention in LV (as younger age male and amphetamines), and cannabis after one year in TA (as did cocaine and opiates after one year and BDZ on admission). CONCLUSION: Although cannabis prevalence increased only in LV where it was legalized, it was associated with poor outcomes in both clinics. Younger age, a known poor outcome predictor, may be related to decreased retention in LV.

[STIGMA AND MISINFORMATION ABOUT METHADONE MAINTENANCE THERAPY].

INTRODUCTION: Opioids play a key role in managing acute and chronic pain, but at the same time, opioid abuse is a socio-economic and health problem that has been expanding over the past three decades, causing a high rate of morbidity and mortality. Methadone maintenance therapy is the most effective treatment choice (combined with psychosocial therapy) for opioid addiction. However, only a small proportion of people with opioid addiction turn to this treatment. In addition, patients applying for methadone maintenance treatment do so with great delay, after 10 and even 20 years of addiction. A possible explanation for this phenomenon discussed in the medical literature is stigma and misinformation about methadone maintenance therapy in patients with substance use disorder, society, family of patients, and healthcare professionals.

Polymorphisms in Stress-Related Genes Are Associated with Reduced Cocaine Abuse and Longer Retention in Methadone Maintenance Treatment for Opioid Use Disorder.

BACKGROUND: As CRH-binding protein (CRHBP) SNP rs1500 was associated with reduced cocaine abuse after 1 year in methadone maintenance treatment (MMT) for heroin addiction, we evaluated the association of additional 28 selected SNPs, in 17 stress-related genes, with MMT outcome. METHODS: The distribution of genotypes of each SNP by cocaine abuse after 1 year in MMT was assessed under the dominant and recessive models using χ2. Cumulative retention (up to 26.5 years) was studied using Kaplan-Meier analyses. Logistic regression and Cox model were used for multivariate analyses. RESULTS: Of a nonselective sample of 404 patients, 25 patients with <50% Europeans/Middle Eastern ancestry were excluded. Of the remaining 379 patients, 330 (87.1%) stayed at least 1 year in treatment. Four SNPs were associated with cocaine abuse after 1 year in MMT. A lower proportion of cocaine abusers was found in the groups of subjects with the following genotypes: arginine vasopressin (AVP) SNP rs2282018 CC, CRHBP rs7728378 TT, galanin rs3136541 TT/TC, and neuropeptide Y receptor Y1 (NPY1R) rs4518200 AA. The following independent variables were associated with lack of cocaine in urine after 1 year (multivariate analyses): CRHBP rs7728378 TT, NPY1R rs4518200 AA, no cocaine in urine on admission, as well as opiate and benzodiazepine use after 1 year in MMT. Cumulative retention (n = 379) was longer in carriers of AVP rs2282018 CC (13.7 years, 95% CI 11.1-16.2) versus TT/TC genotypes (10.5, 95% CI 9.4-11.5) (p = 0.0230) Conclusions: The study suggests that a reduction in cocaine abuse and longer retention among MMT patients is mediated in part by variants in stress-related genes and is a step toward precision medicine.

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.

Improvement in Cognitive Performance after One Year of Methadone Maintenance Treatment.

Individuals with substance use disorders are known to suffer from stress, poor sleep, and cognitive impairment. We investigated whether individuals with opioid use disorder would improve cognitive performance following a year of methadone maintenance treatment (MMT). Perceived Stress Scale (PSS), the Pittsburgh Sleep Quality Index (PSQI), and a standardized computerized cognitive battery were administered at admission (T0) to 29 patients, and repeatedly following one year of MMT (T1) by 19 patients. Admission measures did not differ between those who studied once or twice. Patients who perceived very high stress levels (PSS ≥24) at T0 (11, 37.9%) had lower computerized global cognitive scores (67.6±16.2 vs. 90.9±12.5 p≤0.0005). At T1, PSS and PSQI scores improved significantly among 11 patients with no substance abuse, but worsened among 8 with substance abuse (PSS p(interaction)=0.009, p(groups)=0.005, PSQI p(interaction)=0.01, p(groups)=0.04). Global cognitive score improved at T1 for the entire sample (81.8±20.1 to 89.2±13.8, p=0.05). Differentiation by high stress at T0 or by substance abuse at T1 subgroups showed that improvement was observed by those with very low cognitive scores at T0. Patients with poor cognition may improve following one year of MMT, due to stress and substance abuse reduction. Interventions for stress reduction are recommended.

Cognitive state, substance use patterns and outcome after discharge from Kfar Izun, a unique rehabilitation facility.

We studied cognitive performance following discharge from a novel rehabilitation facility, treating individuals with psychosis that developed during trips abroad following mandatory military service. Montreal Cognitive Assessment (MoCA), phonetic and semantic fluency, State-Trait Anxiety, and self-Efficiency were administered before discharge, and 3 and 6 months after discharge. Of the 43 participants (30.2% females), 23(54.8%) had cognitive impairment (MoCA <27), and 15(35.7%) had poor phonetic fluency. Anxiety trait and state were high and inversely correlated with self-efficacy (R=-0.48, p = 0.001) and phonetic fluency (R=-0.43, p = 0.004) and was higher among those who experienced physical exposure, females, and those who served in non-combat army units. Six months after discharge, of 32 participants, 28 were working/studying with a 58.1% reduction in smoking and alcohol consumption, and 16 participants stopped substance use. Phonetic fluency improved among the high anxiety state group with no change among the others. High anxiety levels lowered among those who were still using drugs after six months. The anxiety level lowered and 87.1% of the participants were conducting a productive lifestyle at 6 months after discharge, but half still abused cannabis. Bigger sample and longer follow up would be needed to learn more about the impact of rehabilitation.

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.

Sleeping Patterns in Patients with Opioid Use Disorder: Effects of Opioid Maintenance Treatment and Detoxification.

The aim of the study was to explore whether abstinent patients on recent opioid detoxification or on opioid maintenance treatment suffer from sleeping problems. 199 patients on opioid maintenance treatment (methadone, diacetylmorphine and buprenorphine) or recent opioid detoxification were included in this exploratory cross-sectional study. We used the Pittsburgh Sleep Quality Index (PSQI) and the Regensburger Insomnia Scale (RIS) in order to assess potential sleeping problems. There was a significant effect of the condition "opioid maintenance" or "recent opioid detoxification" on the total score of PSQI and RIS. All opioid maintenance drugs used by the study population were associated with more sleeping problems compared to the detoxification group when calculated with RIS values. Recently abstinent patients (opioid detoxification) displayed significantly fewer sleep disturbances than opioid-maintained patients. Since sleeping problems can seriously impair treatment success and quality of life, screening for sleep disturbances and their subsequent treatment is of pronounced relevance.