Self-harm by single- and multi-agent medication poisoning in a retrospective analysis of a Poison Control Center database from January 2018 to December 2022.

PURPOSE: Medication poisoning is the most common method of self-harm. Longitudinal studies incorporating pre- and post-COVID-19 pandemic data are required to describe the phenomenon and to evaluate the long-term impact on mental health. METHODS: Calls to the Poison Control Center of Policlinico Umberto I Hospital - Sapienza University of Rome, Italy, were analyzed retrospectively for characteristics and clinical presentation of cases of interest from January 2018 to December 2022. RESULTS: A total of 756 cases of self-harm by medication poisonings were recorded in the study period. A reduction in rate of cases in 2020 was followed by a return to pre-pandemic levels by 2021. When separately analyzing single- and multi-agent cases, occurrence of cases involving just one medication increased since early 2021, with a peak in 2022 (7.8% of total calls, 95% CI 6.2-9.5, from 4.9%, 95% CI 4.1-5.8 in 2018). This increase in the rate of cases, mostly of none or mild severity, was driven by youth aged 12-21, in which the relative proportion of single- versus multi-agent cases showed an increasing trend since 2020 (from 42.6% in 2018 to 78.6% in 2022). Acetaminophen was the medication most frequently involved and benzodiazepines the largest class. A psychiatric background was increasingly seen in 2022, especially in age group 12-21. CONCLUSION: Single-agent medication self-harm may be an increasingly prevailing phenomenon. Young adolescents with a psychiatric background might be most vulnerable to this behavior in the COVID-19 pandemic aftermath. Healthcare professionals should expect favorable clinical outcome and improve both counseling and psychotherapy supervision in individuals at risk.

Heroin and its metabolites: relevance to heroin use disorder.

Heroin is an opioid agonist commonly abused for its rewarding effects. Since its synthesis at the end of the nineteenth century, its popularity as a recreational drug has ebbed and flowed. In the last three decades, heroin use has increased again, and yet the pharmacology of heroin is still poorly understood. After entering the body, heroin is rapidly deacetylated to 6-monoacetylmorphine (6-MAM), which is then deacetylated to morphine. Thus, drug addiction literature has long settled on the notion that heroin is little more than a pro-drug. In contrast to these former views, we will argue for a more complex interplay among heroin and its active metabolites: 6-MAM, morphine, and morphine-6-glucuronide (M6G). In particular, we propose that the complex temporal pattern of heroin effects results from the sequential, only partially overlapping, actions not only of 6-MAM, morphine, and M6G, but also of heroin per se, which, therefore, should not be seen as a mere brain-delivery system for its active metabolites. We will first review the literature concerning the pharmacokinetics and pharmacodynamics of heroin and its metabolites, then examine their neural and behavioral effects, and finally discuss the possible implications of these data for a better understanding of opioid reward and heroin addiction. By so doing we hope to highlight research topics to be investigated by future clinical and pre-clinical studies.

Increased heroin intake and relapse vulnerability in intermittent relative to continuous self-administration: Sex differences in rats.

BACKGROUND AND PURPOSE: Studies using intermittent-access drug self-administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent- and continuous-access self-administration on heroin intake, patterns of self-administration and cue-induced heroin-seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites. EXPERIMENTAL APPROACH: Rats were trained to self-administer a palatable solution and then heroin (0.075 mg·kg-1 per inf) either continuously (6 h·day-1 ; 10 days) or intermittently (6 h·day-1 ; 5-min access every 30-min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin-seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test. KEY RESULTS: Intermittent access exacerbated heroin self-administration and was characterized by a burst-like intake, yielding higher brain peaks of heroin and 6-monoacetylmorphine concentrations. Moreover, intermittent access increased cue-induced heroin-seeking during early, but not late abstinence. Heroin-seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle. CONCLUSIONS AND IMPLICATIONS: Intermittent heroin access in rats resembles critical features of heroin use disorder: a self-administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain.

Neuropathic pain (NP) originates from an injury or disease of the somatosensory nervous system. This heterogeneous origin and the possible association with other pathologies make the management of NP a real challenge. To date, there are no satisfactory treatments for this type of chronic pain. Even strong opioids, the gold-standard analgesics for nociceptive and cancer pain, display low efficacy and the paradoxical ability to exacerbate pain sensitivity in NP patients. Mounting evidence suggests that chemokine upregulation may be a common mechanism driving NP pathophysiology and chronic opioid use-related consequences (analgesic tolerance and hyperalgesia). Here, we first review preclinical studies on the role of chemokines and chemokine receptors in the development and maintenance of NP. Second, we examine the change in chemokine expression following chronic opioid use and the crosstalk between chemokine and opioid receptors. Then, we examine the effects of inhibiting specific chemokines or chemokine receptors as a strategy to increase opioid efficacy in NP. We conclude that strong opioids, along with drugs that block specific chemokine/chemokine receptor axis, might be the right compromise for a favorable risk/benefit ratio in NP management.

Transfer of chemicals to a secondary container, from the introduction of new labelling regulation to COVID-19 lockdown: A retrospective analysis of exposure calls to the Poison Control Centre of Rome, Italy, 2017-2020.

The transfer of a chemical product from its original container to an unlabelled secondary container by consumers is a potential health hazard that may result in unintentional exposures and intoxications. The aim of this study was to describe the pattern of prevalence of exposures to transferred products in Italy from year 2017, when the new European labelling regulation for chemicals became fully operative, to 2020, year of the coronavirus 19 disease first outbreak. Calls to the Poison Control Centre (PCC) of Policlinico Umberto I Hospital - Sapienza University of Rome were analysed retrospectively for characteristics, clinical presentation and circumstances related to the event. We registered 198 cases of interest. There was a reduction in cases from 2017 (4.9%) to 2019 (2.2%), followed by an increased prevalence in 2020 (4.2%) mainly due to the months "post-lockdown." The transferred product was very frequently diluted, and an empty drinking bottle was usually used as secondary container. Exposures were mostly of minor severity, and no deaths occurred. The study highlights the importance of PCCs data in the evaluation of the hazard communication to users through labels and advises for public campaigns to promote safe behaviours during future lockdowns to prevent exposures at a later period.

Factors modulating the incubation of drug and non-drug craving and their clinical implications.

It was suggested in 1986 that cue-induced cocaine craving increases progressively during early abstinence and remains high during extended periods of time. Clinical evidence now supports this hypothesis and that this increase is not specific to cocaine but rather generalize across several drugs of abuse. Investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after abstinence from intravenous drug or palatable food self-administration. Incubation of craving is susceptible to variation in magnitude as a function of biological and/or the environmental circumstances surrounding the individual. During the last decade, the neurobiological correlates of the modulatory role of biological (sex, age, genetic factors) and environmental factors (environmental enrichment and physical exercise, sleep architecture, acute and chronic stress, abstinence reinforcement procedures) on incubation of drug craving has been investigated. In this review, we summarized the behavioral procedures adopted, the key underlying neurobiological correlates and clinical implications of these studies.

How COVID-19 Lockdown in Italy Has Affected Type of Calls and Management of Toxic Exposures: a Retrospective Analysis of a Poison Control Center Database From March 2020 to May 2020.

INTRODUCTION: Between early March 2020 and the end of May 2020, Italy issued strict measures to limit further spread of coronavirus disease 2019 (COVID-19) and became the first European country that imposed a lockdown on the population. The aim of this study was to assess the impact of these restricted conditions on the activity of the Poison Control Center (PCC) of Policlinico Umberto I Hospital-Sapienza University of Rome. METHODS: This was a retrospective analysis of calls received by the PCC during the lockdown period March 9, 2020 through May 31, 2020 compared to the same time period in year 2019 (reference). RESULTS: We observed a reduction in calls from hospitals and emergency departments and an increase in calls from private citizens about exposures to products or intoxications during the lockdown. There were increases in unintentional exposures and exposures to hand and surface sanitizers among household and cleaning products. There was a decrease in calls concerning medications, which were mostly from hospitals and emergency departments. We observed increases in exposures requiring clinical observations among adults and referral to the emergency department among pre-school children. CONCLUSIONS: Public health protection measures against COVID-19 to improve hygiene and maintain clean environments can increase exposures to hazardous products in the domestic environment. We observed an increase in unintentional exposures to household and cleaning products during the lockdown and an increase in ED referrals for pre-school children compared to the previous year. Our data suggest the need for improvements in public campaigns that promote safer handling of household products and prevent unnecessary exposures during a lockdown. The public health promotion activity can benefit the community after the pandemic and prepare the community for lockdowns in the future.

Compulsive-like effects of quinpirole on drinking behavior in rats are inhibited by substituting ethanol for water.

We have previously reported that in rats given the choice between operant and free access to water (contrafreeloading: CFL), repeated administrations of quinpirole, a D2/D3 dopamine receptor agonist, shifted the animals towards the operant access and inhibited water intake. The purpose of the present study was to investigate the influence of substituting different concentrations of ethanol (2, 4, 6%) for water on the effects of repeated daily administrations of vehicle or quinpirole (0.5mg/kg i.p.) in rats that for 6 days were given access to the fluid according to an FR3 schedule of reinforcement and for the following 9 days were given the choice between operant and free access to the fluid. On the first day quinpirole completely suppressed operant behavior, which however progressively increased in the subsequent sessions, approaching control levels by day 6. Ethanol presentation did not alter these effects of quinpirole. When the resource was also freely available, quinpirole produced the expected shift from free to operant access to water (CFL). Substituting ethanol for water resulted in a concentration-related reduction of the over-responding and, consequently, of CFL induced by quinpirole. In vehicle-injected subjects ethanol did not affect responding and only marginally reduced fluid intake. Thus, ethanol appears to prevent perseveration in performing needless instrumental behavior induced by repeated activation of D2/D3 receptors.