Trends and correlated outcomes in population-level prescription opioid and transdermal fentanyl use in Israel.

BACKGROUND: In the last twenty years, there was a documented increase in prescription opioid procurement in Israel. However, there is still little evidence of the association between opioid procurement rates, health service utilisation in secondary care, and enrollment rates to substance use disorder treatment programmes. In this study, we show trends in the reports of opioid-related hospitalisations, emergency department visits, enrollment to community-based outpatient treatment for Prescription Opioid Use Disorder and opioid-related mortality rates. Additionally, we examine potential correlations between these health service utilisation rates and prescription opioid procurement rates at the population level, with a focus on transdermal fentanyl. METHODS: A longitudinal study at the population level. We used seven-year data on indicators of opioid-related morbidity, prescription opioid procurement data for 2015-2021, and six-year opioid-related mortality data for 2015-2020. We measure the correlation between procurement rates of prescription opioids in Oral Morphine Equivalent per capita, and aggregated rates obtained from hospital administrative data for hospitalisations, emergency department visits, and patient enrolment in specialised prescription opioid use disorder outpatient treatment in the community setting. RESULTS: Between 2015 and 2021, procurement rates in primary care per capita for all prescription opioids increased by 85%, while rates of transdermal fentanyl procurement increased by 162%. We found a significant positive correlation at the population level, between annual opioid procurement rates, and rates per population of opioid-related visits to emergency departments (r = 0.96, p value < 0.01, [CI 0.74-0.99]), as well as a positive correlation with the rates per population of patient enrolment in specialised prescription opioid use disorder outpatient treatment (r = 0.93, p value = 0.02, [CI 0.58-0.99]). Opioid-related mortality peaked in 2019 at 0.31 deaths per 100,000 but decreased to 0.20 deaths per 100,000 in 2020. CONCLUSION: Data shows that all-opioid and transdermal fentanyl procurement has increased yearly between 2015 and 2021. This increase is positively correlated with a growing demand for community-based Prescription Opioid Use Disorder outpatient treatment. Efforts to reduce opioid-related morbidity may require effective approaches toward appropriate prescribing, monitoring, and further increasing access to prescription opioid outpatient treatment.

Why Switch? - Motivations for Self-Substitution of Illegal Drugs.

BACKGROUND: Self-substitution is the conscious switch from one drug to another for reasons such as price, availability, desired effect, or perceived benefit of the substitute drug. Purpose/Objectives: This study aimed to describe drug use patterns and motivations associated with substitution. We examined correlates of lifetime substitution among individuals with substance use disorder. Methods: A cross-sectional study of 771 treatment-enrolled individuals. We used self-report for determining the lifetime prevalence, correlates, and motivations for substitution. Results: Of the 771 respondents, 570 (73.9%) reported ever substituting their preferred substance. The main incentives for substitution were availability (23.7%) and curiosity (20.2%). Among heroin or cannabis preferers, improved effects or less adverse effects of the substitute drug, self-medication, and managing withdrawal symptoms were significant substitution incentives. Increased odds for substitution were observed for past 12 months use of cannabis (OR = 1.51, CI = 1.06-4.52), prescription opioids (OR = 2.86, CI = 1.81-4.52), novel psychoactive substances (OR = 2.68, CI = 1.64-4.36), and repeated admission (OR = 1.50, CI = 1.05-2.14). Older age at onset-of-use was negatively associated with substitution (OR = 0.95, CI = 0.93-0.98). Conclusions: Self-substitution of one substance for another is a highly prevalent behavior among treatment-enrolled patients with substance use disorder. Clinicians caring for substance use disorder patients should be aware of substitution patterns involving the use of highly potent substances, which constitutes a risk to patients. Results underscore the benefit of substitution patterns analyses, as they reveal important information on the characteristics of persons who use drugs and their motivations.

The switch from one substance-of-abuse to another: illicit drug substitution behaviors in a sample of high-risk drug users.

BACKGROUND: Substitution can be defined as the consciously motivated choice to use one drug, either licit or illicit, instead of another, due to perceptions of cost, availability, safety, legality, substance characteristics, and substance attributions. Substitution represents a potential risk to drug users, mainly when substitutes are of higher potency and toxicity. This study offers a basic conceptualization of illicit substitution behavior and describes substitution patterns among users of two highly prevalent drugs of abuse-heroin and cannabis. METHODS: Here, 592 high-risk drug users undergoing pharmacological and psycho-social treatment were interviewed. Patients were asked questions about current drug use, lifetime substitution, and substitution patterns. Descriptive statistics, chi-square tests of independence, and multinomial logistic regressions were used to identify and test correlates of substitution patterns for heroin and cannabis. RESULTS: Of the 592 drug users interviewed, 448 subjects (75.7%) reported having substituted their preferred drug for another illicit substance. Interviews yielded a total of 275 substitution events reported by users of cannabis, and 351 substitution events reported by users of heroin. The most frequently reported substitution substances for responders who preferred heroin were illicit non-prescribed "street" methadone (35.9%), followed by oral and transdermal prescription opioids (17.7%). For responders who preferred cannabis, substitution for synthetic cannabinoid receptor agonists (33.5%) followed by alcohol (16.0%) were the most commonly reported. Age at onset-of-use (p < 0.005), population group (p = 0.008), and attending treatment for the first time (p = 0.026) were significantly associated with reported lifetime substitution. Past-year use of stimulants, heroin, hallucinogens, methylenedioxymethamphetamine (MDMA), and novel psychoactive substances were-at the 95% confidence level-also significantly associated with reported lifetime substitution. In multivariate analysis, the odds for methadone substitution among heroin users were significantly affected by age at onset-of-use, type of treatment center, and education. Odds for substitution for synthetic cannabinoid receptor agonists among cannabis users were significantly affected by age, population group, type of treatment center, and education. CONCLUSION: Self-substitution behavior should be considered by clinicians and policymakers as a common practice among most drugusers. Substitution for street methadone provides evidence for the ongoing diversion of this substance from Opioid Maintenance Treatment Centers, while the prominence of substitution of synthetic cannabinoids among dual-diagnosis patients should be regarded as an ongoing risk to patients that needs to be addressed by clinicians. Analysis of additional substitution patterns should provide further valuable insights into the behavior of drugusers.

Evaluation of performance-enhancing drugs seized by Israeli enforcement agencies 2012-2017: implications for policy and regulatory change.

BACKGROUND: Illicit performance-enhancing substances are used mostly by athletes to enhance performance in sports, and by bodybuilders to gain muscle and body mass. Among performance-enhancing substances, the most common and known substances are anabolic-androgenic steroids, which are associated with a range of short and long-term adverse medical and psychiatric effects. While the sale and distribution of performance-enhancing substances are considered criminal offenses per the Israeli local pharmacy ordinance, the use and personal possession of these substances are not. Presently, the Division of Enforcement and Inspection of the Israel Ministry of Health cooperates with police and customs agents in performance-enhancing substance-related enforcement activities, which chiefly include seizures carried out at suspicious sites. Moreover, the Division of Enforcement and Inspection provides professional guidance, lab analysis services, and expert opinions on the toxicological and pharmaceutical nature of products seized. This paper presents a contemporary sub-analysis of registered seizures of performance-enhancing substances carried-out by Israel enforcement agencies. The main aim of this analysis is to characterize current patterns of performance-enhancing substances, thus providing the possibility of better assessment of current enforcement and health policy. METHODS: A sub-analysis of 712 seizures of performance-enhancing substances seized by Israeli enforcement authorities during a six-year period ranging from January 2012 to December 2017. RESULTS: This study demonstrates that Israel faces a challenge regarding the importation and distribution of illicit performance-enhancing substances. The most common substances seized were anabolic androgenic steroids (N = 539). Most seizures were carried out in the central mail processing sites, (38.4%), followed by seizures in private premises such as homes and warehouses (29.6%). Significant differences were found between anabolic-androgenic steroids and other substances, relating to place and year of seizure. Among seizures with known sources (N = 355), the most frequent geographic region given as the source of substances was Eastern Europe (47.6%), followed by East Asia (24.8%), West Asia (19.4%), and Western Europe (5.9%). Bulgaria was the country with the highest frequency of seizures (N = 71) followed by Jordan (N = 45), Thailand (N = 37) and Moldova (N = 36). Significant regional differences were found based on the variables of gender, place of seizure, and type of substance. The most frequent month of seizures was August (N = 129), followed by July (N = 119), and June (N = 118). CONCLUSIONS: While data analysis focused on the supply side of the performance-enhancing substances market, the high number of seizures of performance-enhancing substances in Israel represents evidence of the existence of a high demand and a large consumer base for these products. Consequently, there is a need for developing further enforcement, treatment, and prevention policies that do not currently exist in Israel. Policymakers should consider prioritizing law enforcement action and incentivizing intelligence sharing to monitor suspected shipment sources and specific points of entry. Additionally, the results demonstrate that there is a need in reforming the penal law to discourage the use of performance-enhancing substances. Similar measures have already been applied in countries like Spain, Italy, and Belgium. Furthermore, policy-makers should consider enhancing health ministry agencies with a higher enforcement capacity by giving them further investigative and inquiry authority. Due to the troubling magnitude of the phenomenon, policymakers should also prioritize educational and prevention strategies.

Recent Use of Synthetic Cannabinoids, Synthetic Opioids, and Other Psychoactive Drug Groups among High-risk Drug Users.

The use of synthetic cannabinoids receptor agonists (SCRA) and synthetic opioids is associated with significant morbidity and mortality. This study examined the patterns-of-use of prescription oral opioids or transdermal fentanyl formulations, and SCRA, among 342 patients enrolled in treatment for drug-dependence in Israel. 16.1% of participants reported recent (past-12 months) SCRA use, while 24.9% reported recent use of prescription oral opioids, transdermal fentanyl patches, or both. Odds of reporting recent use of SCRA were positively and significantly associated with reporting recent use of cannabis (Adjusted Odds Ratio [AOR] 9.86, 95% Confidence Interval [CI] 4.44-21.90) and synthetic cathinones (AOR 5.47, CI 2.50-11.96). Recent use of prescription oral opioids or transdermal fentanyl formulations use was positively and significantly associated with recent use of gabapentinoids (AOR 14.33, CI 7.10, 28.90), stimulants (AOR 7.12, CI 3.82,13.28), heroin (AOR 5.81, CI 3.39,9.97), benzodiazepines (AOR 4.63, CI 2.74,7.84), synthetic cathinones (AOR 4.12, CI 1.95, 8.70), and hallucinogens (AOR 2.48, CI 1.24, 2.96). Clinicians should be informed about the extent of prescription oral opioids or transdermal fentanyl formulations and SCRA use among high-risk drug users, and the associated higher odds of concomitantly using other psychoactive substance, for they represent actual risk to patients and complicate treatment.

A Case of Hepatotoxicity Induced by Adulterated "Tiger King", a Chinese Herbal Medicine Containing Sildenafil.

Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in "100% natural" or "herbal" supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated "Chinese herbal" supplement "Tiger King" for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was "possible" and "probable" respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient's clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of "Tiger king" in particular, and other counterfeit medications or herbal supplements of unknown origin.

[The illegal synthetic cannabinoid drug market in Israel - evolution and new challenges].

INTRODUCTION: This article represents a short review of the current knowledge on the abuse of synthetic cannabinoids from the perspective of the Division of Enforcement and Inspection of the Israeli Ministry of Health - a body in charge of providing professional assistance to law enforcement bodies in the fields of drug abuse. We describe the principal changes observed in the synthetic cannabinoid market and the Israeli legislators' and enforcement bodies' attempts to cope with these phenomena. These changes relate to the types of synthetic cannabinoids being trafficked, with many structural variations between substances, and a new legal framework which allows for the rapid, temporary scheduling of synthetic cannabinoids using both individual and generic definitions. Despite changes in legislation, we are currently witnessing the adaptation of the synthetic cannabinoid drug market to the new legal reality and enforcement practices. A considerable part of synthetic cannabinoid trafficking is carried out using phone orders, or has moved to the internet and social networks, thus making its detection difficult for enforcement bodies. Current trafficking practices represent a growing challenge for enforcement bodies. Hence, there is a need for cooperation between enforcement bodies, the Israeli Ministry of Health and health practitioners in identifying new substances, and characterizing their harms.

[Synthetic cannabinoids--the new "legal high" drugs].

Recently, a new Law, named the "derivative law" (first addition, schedule drug change--2010), was accepted in the Israeli parliament. It will mean that dangerous substances that are closely related structurally to a drug that is listed in the dangerous drugs ordinance will automatically enter the dangerous drugs ordinance. The dangerous drugs that were sold in kiosks were related to 4 major groups: Amphetamines, methamphetamines, cathinone and methcathinone. Over 90% of the substances known as "legal highs" or "hagigat" belong to these groups. Before the law was accepted, merchandisers and clandestine Laboratories took advantage of a state in which every small molecular change in a controlled substance of amphetamines, methamphetamines, cathinone and methcathinone required a long legal process in order to include the new substance in the controlled substance law. During this process, we believe that public health was endangered. The chemists and merchandisers found a new solution to "legally" bypass the "derivative law", by marketing a new group of substances named "synthetic cannabinoids". The synthetic cannabinoids do not resemble the chemical structure of tetrahydrocannabinol (THC] which appears in marijuana or hashish, but affects the body in the same manner and according to the literature, are five times more potent. The synthetic cannabinoids are sold in Israel under different nicknames such as: "Mabsuton", "Mr. Nice Guy", "Spice", "Sabbaba" and "Lemon Grass". The substance can be used in different ways such as smoking, inhaling or swallowing. The use of synthetic cannabinoids causes side effects that include: euphoria, dizziness, headache, thirst, paranoia, insomnia, fatigue and disturbed vision. Cases of hospital admission in Israel due to the use of these substances have been reported. The symptoms included psychiatric disturbances. In an urgent meeting of the multi-ministry committee on psychotropic substances held in December 2010 in the Israel Anti-Drug Authority, it was decided to recommend to the Minister of Health to insert an inclusive group of "synthetic cannabinoids" into the control drug list in Israel. On April 5, 2011, after receiving the approval of the health and welfare committee in the Israeli parliament, the dangerous drugs ordinance (new version)--5732-1973 was amended with the addition of an inclusive group of "synthetic cannabinoids". These include: JWH-018, JWH-133, JWH-073, CP 47, 497, CP 55, 940, HU-331, HU-210, HU-211, HU-250.

Matrix metallo-proteinase (MMP-2) organoboronate inhibitors.

Novel organoboronate derivatives consisting of BB, BC(R(1)R(2))B, BCCB, CBC, Department of Medicinal RBC=CBB, and RBC=CBP structures were synthesized and have been investigated in vitro as MMP-2 inhibitors. We discovered that most of the boronate derivatives (those not containing phosphorus) showed significant activity against MMP-2. The trisboronate 14 proved to be a potent MMP-2 inhibitor at 5 and 10 microM. Structure activity relationships (SARs) data for the compounds were investigated and are discussed.