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Introduction: To expand access to naloxone, the state of Illinois implemented a standing order allowing registered pharmacies to dispense the drug without an individual prescription. To participate under the standing order, pharmacies were required to opt in through a formal registration process. In our study we aimed to evaluate the availability and price of naloxone at registered pharmacies.Methods: This was a prospective, de-identified, cross-sectional telephone survey. Trained interviewers posed as potential customers and used a standardized script to determine the availability of naloxone between February–December, 2019. The primary outcome was defined as a pharmacy indicating it carried naloxone, currently had naloxone in stock, and was able to dispense it without anindividual prescription.Results: Of 948 registered pharmacies, 886 (93.5%) were successfully contacted. Of those, 792 (83.4%) carried naloxone, 659 (74.4%) had naloxone in stock, and 472 (53.3%) allowed purchase without a prescription. Naloxone nasal spray (86.4%) was the formulation most commonly stocked. Chain pharmacies were more likely to carry naloxone (adjusted odds ratio [aOR] 3.16, 95% confidence interval [CI] 1.97–5.01, P < 0.01) and have naloxone in stock (aOR 2.72, 95% CI 1.76–4.20, P < 0.01), but no more likely to dispense it without a prescription. Pharmacies in higher population areas (aOR 0.99, 95% CI 0.99–0.99, P < 0.05) and rural areas adjacent to metropolitan areas (aOR 0.5, 95% CI 025–0.98, P < 0.05) were less likely to have naloxone available without a prescription. Associations of naloxone availability based on other urbanicity designations, overdose count, and overdose rate were not significant.Conclusion: Among pharmacies in Illinois that formally registered to dispense naloxone without a prescription, the availability of naloxone remains limited. Additional interventions may be needed to maximize the potential impact of a statewide standing order.

Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

Objectives: This paper outlines the experience developing Addiction Medicine Practice-Based ResearchNetwork (AMNet), which promotes the adoption of patient-reported outcome measures (PROMs) and measurement-based care in outpatient addiction treatment practices and creates a platform for quality improvement and research. Methods: From August 2019 to July 2023, the AMNet team selected patient-reported outcome measures for implementation in the American Psychiatric Association's clinical data registry (PsychPRO), recruited addiction medicine providers, and collected PROMs data. Results: AMNet selected 12 PROMs for implementation in PsychPRO. Through July 2023, 1565 providers expressed interest, of whom 216 of the 929 eligible providers (23%) attended an onboarding call/webinar. Two hundred six providers (95%) from 54 practices returned Participation Agreements. Subsequently, 65 providers (32%) from 39 practices withdrew, resulting in 141 (68%) providers from 15 practices. From November 2020 to July 2023, 38 providers submitted PROMs data using 1 of 3 PsychPRO patient portals. Sixteen of the 53 providers (30%) who signed up for the initial portal collected data from 468 patients. As of July 2023, 83 of the 141 providers (59%) opted to submit PROMs data from their own portal or electronic health record. Conclusions: Next steps will include continued recruitment of providers, addressing barriers to data transfer and integrating data fromproviders' portals into the registry to create a platform for future research. [ABSTRACT FROM AUTHOR]

Women with substance use disorders (SUDs) have been widely reported to face barriers in seeking treatment. We sought to identify barriers that prevented women who use methamphetamine (WWUM) from accessing the decade-old Voluntary Treatment Centers (VTCs) in Malaysia. A total of 153 WWUM who were undergoing rehabilitation for methamphetamine use at a compulsory drug detention center (CDDC) were recruited for this cross-sectional study. Data were collected by canvasing a structured questionnaire through face-to-face meetings. Of the total sample, 131 (86%) were Malays, with a mean age of 32.1 years. The commonly cited treatment barriers were the belief that methamphetamine use was not problematic (42%), not knowing how to seek treatment (38%), feeling embarrassed to seek treatment (33%), the lack of family support (24%), and the long waiting time for enrollment (23%). Logistic analyses indicated that a longer duration of use increased the odds of not acknowledging methamphetamine use as a problem while older participants had lower odds of holding a similar view. A longer duration of use also increased the odds of claiming treatment was not needed but lowered the odds of asserting a lack of confidence in treatment. Furthermore, Malays had higher odds of lacking family support in seeking treatment while being employed lowered the odds of not wanting treatment. Addressing these concerns will hopefully encourage higher participation of WWUM in voluntary treatment programs. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the changes in quality of life (QoL) over a 12-month period among opiate users in Romania, identifying factors that contribute to a worsening of their condition. By examining these dynamics, the research intended to inform targeted interventions and support mechanisms to mitigate the negative outcomes associated with opiate use. Conducted as a longitudinal cohort analysis, this study enrolled 74 participants diagnosed with opioid use disorders from multiple healthcare settings in Romania. The WHOQOL-BREF instrument was utilized to assess QoL, with data collection spanning from 1 January 2023 to 31 December 2023. Ethical compliance with the Declaration of Helsinki was maintained, and participants provided informed consent. Statistical analysis was performed using SPSS, focusing on the impact of demographic and behavioral variables on QoL. Over the 12-month period, significant improvements were observed in all QoL domains: physical (51.68 to 58.39, p < 0.001), psychological (49.34 to 55.32, p < 0.001), social (46.21 to 53.66, p < 0.001), and environmental (47.85 to 54.17, p < 0.001). Methadone compliance significantly influenced positive outcomes across all domains. Compliant participants exhibited higher mean scores compared to non-compliant users, with respective increases in the physical domain from 52.47 to 60.21 (p < 0.001), psychological from 50.93 to 58.32 (p < 0.001), social from 48.36 to 57.14 (p < 0.001), and environmental from 47.82 to 55.79 (p < 0.001). Additionally, education showed a protective effect, particularly enhancing environmental QoL (estimate = 0.33, p = 0.013). Methadone compliance and higher education levels were identified as significant predictors of improved QoL among opiate users, demonstrating the critical importance of adherence to treatment protocols and the supportive role of education in enhancing life quality. These findings highlight the necessity for integrated treatment programs and educational interventions to improve the well-being of individuals battling opioid addiction, advocating for policy enhancements and supportive measures tailored to this demographic. [ABSTRACT FROM AUTHOR]

Background: It is well known that opiates slow gastrointestinal (GI) transit, via suppression of enteric cholinergic neurotransmission throughout the GI tract, particularly the large intestine where constipation is commonly induced. It is not clear whether there is uniform suppression of enteric neurotransmission and colonic motility across the full length of the colon. Here, we investigated whether regional changes in colonic motility occur using the peripherallyrestricted mu opioid agonist, loperamide to inhibit colonic motor complexes (CMCs) in isolated mouse colon. Methods: High-resolution video imaging was performed to monitor colonic wall diameter on isolated whole mouse colon. Regional changes in the effects of loperamide on the pattern generator underlying cyclical CMCs and their propagation across the full length of large intestine were determined. Results: The sensitivity of CMCs to loperamide across the length of colon varied significantly. Although there was a dose-dependent inhibition of CMCs with increasing concentrations of loperamide (10 nM - 1 mM), a major observation was that in the mid and distal colon, CMCs were abolished at low doses of loperamide (100 nM), while in the proximal colon, CMCs persisted at the same low concentration, albeit at a significantly slower frequency. Propagation velocity of CMCs was significantly reduced by 46%. The inhibitory effects of loperamide on CMCs were reversed by naloxone (1 mM). Naloxone alone did not change ongoing CMC characteristics. Discussion: The results show pronounced differences in the inhibitory action of loperamide across the length of large intestine. The most potent effect of loperamide to retard colonic transit occurred between the proximal colon and mid/distal regions of colon. One of the possibilities as to why this occurs is because the greatest density of mu opioid receptors are located on interneurons responsible for neuro-neuronal transmission underlying CMCs propagation between the proximal and mid/distal colon. The absence of effect of naloxone alone on CMC characteristics suggest that the mu opioid receptor has little ongoing constitutive activity under our recording conditions. [ABSTRACT FROM AUTHOR]

Motherhood is a costly life‐history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is associated with decreased pair bond strength, suggesting a trade‐off between parental investment and pair bond maintenance. Neural mechanisms governing pair bonds and maternal bonds overlap, creating possible competition between the two. We measured mRNA expression of genes encoding receptors for oxytocin (oxtr), dopamine (d1r and d2r), mu‐opioids (oprm1a), and kappa‐opioids (oprk1a) within three brain areas processing salience of sociosensory cues (anterior cingulate cortex; ACC), pair bonding (nucleus accumbens; NAc), and maternal care (medial preoptic area; MPOA). We compared gene expression differences between pair bonded prairie voles that were never pregnant, pregnant (~day 16 of pregnancy), and recent mothers (day 3 of lactation). We found greater gene expression in the NAc (oxtr, d2r, oprm1a, and oprk1a) and MPOA (oxtr, d1r, d2r, oprm1a, and oprk1a) following the transition to motherhood. Expression for all five genes in the ACC was greatest for females that had been bonded for longer. Gene expression within each region was highly correlated, indicating that oxytocin, dopamine, and opioids comprise a complimentary gene network for social signaling. ACC‐NAc gene expression correlations indicated that being a mother (oxtr and d1r) or maintaining long‐term pair bonds (oprm1a) relies on the coordination of different signaling systems within the same circuit. Our study suggests the maternal brain undergoes changes that prepare females to face the trade‐off associated with increased emotional investment in offspring, while also maintaining a pair bond. [ABSTRACT FROM AUTHOR]

Objective: In toxicological analyses, a variety of alkaloids and metabolites can be detected in addition to the main drugs or stimulants. The aim of this study is to discuss the diversity, frequency and characteristics of heroin metabolites and alkaloids in postmortem toxicological analyses in the light of the literature. Methods: This study was conducted by retrospectively examining the toxicological examination results after autopsies between January 2020 and April 2022 by Pamukkale University. The cases; were evaluated in terms of sex, age, origin, drug-stimulant substances detected and their diversity. The results were compared with those of similar studies. Detected and their diversity. The findings were compared with the results of similar studies. Results: Drugs or stimulants were found in the toxicological examinations of 45 (4.8%) of 919 deceased examination and autopsy cases. Fourtyone of these cases were male and 4 were female. Methamphetamine and amphetamine-like substances were most commonly found in 26 cases. Opiate derivatives were found in 16 cases, 6-monoacetylmorphine (6-MAM) in 11 cases, meconine in 10 cases and noscapine in 7 cases. Morphine and codeine were detected and the morphine/codeine ratio was greater than 1 in all 8 cases for which quantitative analysis was performed. In addition to these substances, n-ethylamphetamine, norpseudoephedrine, thebaine, acetylcodeine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, methadone, methyldiethanolamine, 3,4-methylenedioxyamphetamine, papaverine, ephedrine/pseudoephedrine and codeine were detected. Conclusion: There may be some difficulties in detecting illegal heroin due to reasons such as codeine found in antitussive drugs being metabolized to morphine and 6-MAM not always being detected due to its short half-life. Detection of alkaloids and metabolites such as acetylcodeine, noscapine, meconin, papaverine and thebaine suggests illicit heroin use. In addition, papaverine, noscapine and their metabolites are found in higher amounts in the composition of heroin produced in Southwest Asia than in Southeast Asia. These detected alkaloids and metabolites may be useful in detecting illegal heroin use and determining the origin of heroin.

Over 50 million Americans endure chronic pain where many do not receive adequate treatment and self-medicate to manage their pain by taking substances like opioids and cannabis. Research has shown high comorbidity between chronic pain and substance use disorders (SUD) and these disorders share many common neurobiological underpinnings, including hypodopaminergic transmission. Drugs commonly used for self-medication such as opioids and cannabis relieve emotional, bothersome components of pain as well as negative emotional affect that perpetuates misuse and increases the risk of progressing towards drug abuse. However, the causal effect between chronic pain and the development of SUDs has not been clearly established. In this review, we discuss evidence that affirms the proposition that chronic pain is a risk factor for the development of opioid and cannabis use disorders by outlining the clinical evidence and detailing neurobiological mechanisms that link pain and drug misuse. Central to the link between chronic pain and opioid and cannabis misuse is hypodopaminergic transmission and the modulation of dopamine signaling in the mesolimbic pathway by opioids and cannabis. Moreover, we discuss the role of kappa opioid receptor activation and neuroinflammation in the context of dopamine transmission, their contribution to opioid and cannabis withdrawal, along with potential new treatments. [ABSTRACT FROM AUTHOR]

Objective: Opioid use disorder is a cause of significant morbidity and mortality. In order to reverse opioid overdose as quickly as possible, many institutions and municipalities have encouraged people with no professional medical training to carry and administer naloxone. This study sought to provide preliminary data for research into the rates of adverse effects of naloxone when administered by bystanders compared to Emergency Medical Services (EMS) personnel, since this question has not been studied previously. Methods: This was a retrospective cohort study performed at an urban, tertiary, academic medical center that operates its own EMS service. A consecutive sample of patients presenting to EMS with opioid overdose requiring naloxone was separated into two groups based on whether naloxone was administered by bystanders or by EMS personnel. Each group was analyzed to determine the incidence of four pre-specified adverse events. Results: There was no significant difference in the rate of adverse events between the bystander (19%) and EMS (16%) groups (OR = 1.23; 95% CI, 0.63 - 2.32; P =.499) in this small sample. Based on these initial results, a study would need a sample size of 6,188 in order to reach this conclusion with 80% power. Similarly, there were no significant differences in the rates of any of the individual adverse events. Secondary analysis of patients' demographics showed differences between the two groups which generate hypotheses for further investigation of disparities in naloxone administration. Conclusions: This preliminary study provides foundational data for further investigation of naloxone administration by bystanders. Adverse events after the prehospital administration of naloxone are rare, and future studies will require large sample sizes. These preliminary data did not demonstrate a statistically significant difference in adverse event rates when comparing naloxone administration by bystanders and EMS clinicians. This study provides data that will be useful for conducting further research on multiple facets of this topic. [ABSTRACT FROM AUTHOR]

Copyright of Bulletin of Legal Medicine / Adli Tıp Bülteni is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BackgroundIt is well known that opiates slow gastrointestinal (GI) transit, via suppression of enteric cholinergic neurotransmission throughout the GI tract, particularly the large intestine where constipation is commonly induced. It is not clear whether there is uniform suppression of enteric neurotransmission and colonic motility across the full length of the colon. Here, we investigated whether regional changes in colonic motility occur using the peripherally-restricted mu opioid agonist, loperamide to inhibit colonic motor complexes (CMCs) in isolated mouse colon.MethodsHigh-resolution video imaging was performed to monitor colonic wall diameter on isolated whole mouse colon. Regional changes in the effects of loperamide on the pattern generator underlying cyclical CMCs and their propagation across the full length of large intestine were determined.ResultsThe sensitivity of CMCs to loperamide across the length of colon varied significantly. Although there was a dose-dependent inhibition of CMCs with increasing concentrations of loperamide (10 nM - 1 μM), a major observation was that in the mid and distal colon, CMCs were abolished at low doses of loperamide (100 nM), while in the proximal colon, CMCs persisted at the same low concentration, albeit at a significantly slower frequency. Propagation velocity of CMCs was significantly reduced by 46%. The inhibitory effects of loperamide on CMCs were reversed by naloxone (1 μM). Naloxone alone did not change ongoing CMC characteristics.DiscussionThe results show pronounced differences in the inhibitory action of loperamide across the length of large intestine. The most potent effect of loperamide to retard colonic transit occurred between the proximal colon and mid/distal regions of colon. One of the possibilities as to why this occurs is because the greatest density of mu opioid receptors are located on interneurons responsible for neuro-neuronal transmission underlying CMCs propagation between the proximal and mid/distal colon. The absence of effect of naloxone alone on CMC characteristics suggest that the mu opioid receptor has little ongoing constitutive activity under our recording conditions.

Objective: To explore the effects of ultrasound-guided serratus anterior plane block (SAPB) and thoracic paravertebral block (TPVB) on opiate dosage and stress response in patients undergoing thoracoscopic radical resection of lung cancer. Methods: A total of 130 patients undergoing elective thoracoscopic radical resection of lung cancer in Changshu Second Peoples Hospital between June 2019 and January 2022 were enrolled. According to the random number table method, they were divided into SAPB group (65 cases, ultrasound-guided SAPB before anesthesia induction) and TPVB group (65 cases, ultrasound-guided TPVB before anesthesia induction). After surgery, all underwent patient-controlled intravenous analgesia with analgesia pumps. The timepoints including preoperative, thoracic closure, and postoperative 2, 6, and 24 hours were set as T1, T2, T3, T4 and T5, respectively, and the intraoperative blood loss and fluid supplement, operation time, intraoperative dosages of sufentanil and propofol, and postoperative cumulative dosages of sufentanil at T3, T4 and T5 in the two groups were recorded. At T3, T4 and T5, pain changes were evaluated by Prince-Henry scores. The levels of prostaglandins E2 (PGE2), norepinephrine (NE) and cortisol (Cor) were detected by enzyme-linked immunosorbent assay. The partial pressure of arterial oxygen was detected by a blood gas analyzer, and oxygenation index (OI) was calculated. The occurrence of postoperative adverse events (PAEs) in the two groups was recorded. Results: From T3 to T5, levels of PGE2, NE, and Cor in SAPB group were significantly lower than those in TPVB group (P＜0.05). OI at T2 to T4 was significantly lower than that at T1, while OI at T5 was significantly higher than that at T2, T3, and T4 in both groups (P＜0.05). From T2 to T4, OI in SAPB group was significantly higher than that in TPVB group (P＜0.05). Compared with TPVB group, the cumulative consumption of sufentanil in SAPB group slightly decreased from T3 to T5, but the differences were not statistically significant (P>0.05). The incidences of nausea and vomiting (6.15% vs 18.46%, χ2=4.561, P=0.033), atelectasis(3.08% vs 12.31%, χ2=3.900, P=0.048) and hypotension (7.69% vs 20.00%, χ2=4.127, P=0.042) in SAPB group were lower than those in TPVB group. Conclusion: Compared with TPVB, ultrasound-guided SAPB can relieve stress response, promote the recovery of pulmonary oxygenation and reduce PAEs in patients undergoing thoracoscopic radical resection of lung cancer, but whether it can significantly reduce the dosage of opiates needs to be further explored.

Abstract Background Number of opiate users worldwide has doubled over the past decade, but not all of them are diagnosed with opioid use disorder. We aimed to identify the prevalence and risk factors for OUD after ten years of follow-up. Methods Among 8,500 chronic opiate users at Golestan Cohort Study baseline (2004–2008), we recalled a random sample of 451 subjects in 2017. We used three questionnaires: a questionnaire about current opiate use including type and route of use, the drug use disorder section of the Composite International Diagnostic Interview lifetime version, and the validated Kessler10 questionnaire. We defined opioid use disorder and its severity based on the DSM-5 criteria and used a cutoff of 12 on Kessler10 questionnaire to define psychological distress. Results Mean age was 61.2 ± 6.6 years (84.7% males) and 58% were diagnosed with opioid use disorder. Starting opiate use at an early age and living in underprivileged conditions were risk factors of opioid use disorder. Individuals with opioid use disorder were twice likely to have psychological distress (OR = 2.25; 95%CI: 1.44–3.52) than the users without it. In multivariate regression, former and current opiate dose and oral use of opiates were independently associated with opioid use disorder. Each ten gram per week increase in opiate dose during the study period almost tripled the odds of opioid use disorder (OR = 3.18; 95%CI: 1.79–5.63). Conclusions Chronic opiate use led to clinical opioid use disorder in more than half of the users, and this disorder was associated with psychological distress, increasing its physical and mental burden in high-risk groups.

This study aimed to evaluate the changes in quality of life (QoL) over a 12-month period among opiate users in Romania, identifying factors that contribute to a worsening of their condition. By examining these dynamics, the research intended to inform targeted interventions and support mechanisms to mitigate the negative outcomes associated with opiate use. Conducted as a longitudinal cohort analysis, this study enrolled 74 participants diagnosed with opioid use disorders from multiple healthcare settings in Romania. The WHOQOL-BREF instrument was utilized to assess QoL, with data collection spanning from 1 January 2023 to 31 December 2023. Ethical compliance with the Declaration of Helsinki was maintained, and participants provided informed consent. Statistical analysis was performed using SPSS, focusing on the impact of demographic and behavioral variables on QoL. Over the 12-month period, significant improvements were observed in all QoL domains: physical (51.68 to 58.39, p < 0.001), psychological (49.34 to 55.32, p < 0.001), social (46.21 to 53.66, p < 0.001), and environmental (47.85 to 54.17, p < 0.001). Methadone compliance significantly influenced positive outcomes across all domains. Compliant participants exhibited higher mean scores compared to non-compliant users, with respective increases in the physical domain from 52.47 to 60.21 (p < 0.001), psychological from 50.93 to 58.32 (p < 0.001), social from 48.36 to 57.14 (p < 0.001), and environmental from 47.82 to 55.79 (p < 0.001). Additionally, education showed a protective effect, particularly enhancing environmental QoL (estimate = 0.33, p = 0.013). Methadone compliance and higher education levels were identified as significant predictors of improved QoL among opiate users, demonstrating the critical importance of adherence to treatment protocols and the supportive role of education in enhancing life quality. These findings highlight the necessity for integrated treatment programs and educational interventions to improve the well-being of individuals battling opioid addiction, advocating for policy enhancements and supportive measures tailored to this demographic.

The United States (US) opioid epidemic is a persistent and pervasive public health emergency that claims the lives of over 80,000 Americans per year as of 2021. There have been sustained efforts to reverse this crisis over the past decade, including a number of measures designed to decrease the use of prescription opioids for the treatment of pain. This study analyzed the changes in federal production quotas for prescription opioids and the distribution of prescription opioids for pain and identified state-level differences between 2010 and 2019. Data (in grams) on opioid production quotas and distribution (from manufacturer to hospitals, retail pharmacies, practitioners, and teaching institutions) of 10 prescription opioids (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol) for 2010 to 2019 were obtained from the US Drug Enforcement Administration. Amounts of each opioid were converted from grams to morphine milligram equivalent (MME), and the per capita distribution by state was calculated using population estimates. Total opioid production quotas increased substantially from 2010 to 2013 before decreasing by 41.5% from 2013 (87.6 MME metric tons) to 2019 (51.3). The peak year for distribution of all 10 prescription opioids was between 2010 and 2013, except for codeine (2015). The largest quantities of opioid distribution were observed in Tennessee (520.70 MME per person) and Delaware (251.45) in 2011 and 2019. There was a 52.0% overall decrease in opioid distribution per capita from 2010 to 2019, with the largest decrease in Florida (−61.6%) and the smallest in Texas (−18.6%). Southern states had the highest per capita distribution for eight of the ten opioids in 2019. The highest to lowest state ratio of total opioid distribution, corrected for population, decreased from 5.25 in 2011 to 2.78 in 2019. The mean 95th/5th ratio was relatively consistent in 2011 (4.78 ± 0.70) relative to 2019 (5.64 ± 0.98). This study found a sustained decline in the distribution of ten prescription opioids during the last five years. Distribution was non-homogeneous at the state level. Analysis of state-level differences revealed a fivefold difference in the 95th:5th percentile ratio between states, which has remained unchanged over the past decade. Production quotas did not correspond with the distribution, particularly in the 2010–2016 period. Future research, focused on identifying factors contributing to the observed regional variability in opioid distribution, could prove valuable to understanding and potentially remediating the pronounced disparities in prescription opioid-related harms in the US. [ABSTRACT FROM AUTHOR]

Objective: To determine if the interaction of opiate misuse and marijuana use frequency is associated with behavioral health outcomes. Setting: Community. Participants: Three thousand seven hundred fifty participants enrolled in the Traumatic Brain Injury Model Systems who completed the Pain Survey and had complete opioid use and marijuana use information. Design: Cross-sectional, secondary analysis from a multisite observational cohort. Main Outcome Measure(s): Clinically significant behavioral health symptoms for posttraumatic stress disorder (PTSD), depression, anxiety, and sleep quality. Results: Three thousand five hundred thirty-five (94.3%) participants did not misuse opiates, 215 (5.7%) did misuse opiates (taking more opioid pain medication than prescribed and/or using nonprescription opioid pain medication); 2683 (70.5%) participants did not use marijuana, 353 (9.3%) occasionally used marijuana (less than once a week), and 714 (18.8%) regularly used marijuana (once a week or more frequently). There was a statistically significant relationship (P < .05) between the interaction of opiate misuse and marijuana use frequency and all behavioral health outcomes and several covariates (age, sex, cause of injury, severity of injury, and pain group category). Pairwise comparisons confirm that statistically significant associations on behavioral health outcomes are driven by endorsing opiate misuse and/or regular marijuana use, but occasional marijuana use was not associated. Conclusions: Higher odds of clinically significant PTSD, depression, anxiety, and poor sleep quality are present in people with traumatic brain injury (TBI) who misuse opiates and/or who use marijuana regularly. In the absence of opiate misuse, regular marijuana use had higher odds of worse behavioral health outcomes than occasional and no use. The interaction of opiate misuse and regular marijuana use yielded the highest odds. Individuals with TBI should be informed of the relationship of substance use and behavioral health outcomes and that current chronic pain may mediate the association. [ABSTRACT FROM AUTHOR]

Background: Number of opiate users worldwide has doubled over the past decade, but not all of them are diagnosed with opioid use disorder. We aimed to identify the prevalence and risk factors for OUD after ten years of follow-up. Methods: Among 8,500 chronic opiate users at Golestan Cohort Study baseline (2004–2008), we recalled a random sample of 451 subjects in 2017. We used three questionnaires: a questionnaire about current opiate use including type and route of use, the drug use disorder section of the Composite International Diagnostic Interview lifetime version, and the validated Kessler10 questionnaire. We defined opioid use disorder and its severity based on the DSM-5 criteria and used a cutoff of 12 on Kessler10 questionnaire to define psychological distress. Results: Mean age was 61.2 ± 6.6 years (84.7% males) and 58% were diagnosed with opioid use disorder. Starting opiate use at an early age and living in underprivileged conditions were risk factors of opioid use disorder. Individuals with opioid use disorder were twice likely to have psychological distress (OR = 2.25; 95%CI: 1.44–3.52) than the users without it. In multivariate regression, former and current opiate dose and oral use of opiates were independently associated with opioid use disorder. Each ten gram per week increase in opiate dose during the study period almost tripled the odds of opioid use disorder (OR = 3.18; 95%CI: 1.79–5.63). Conclusions: Chronic opiate use led to clinical opioid use disorder in more than half of the users, and this disorder was associated with psychological distress, increasing its physical and mental burden in high-risk groups. [ABSTRACT FROM AUTHOR]

Introduction: Opioid withdrawal is one of the most critical complications of opioid use disorder. In this study, we aimed to examine the possible risk of ventricular arrhythmia and sudden cardiac death by calculating electrocardiography (ECG) changes, the markers of ventricular repolarization, in opioid withdrawal. Methods: A total of 90 patients diagnosed with opioid withdrawal who met the inclusion and exclusion criteria were included in the study. QT, QTc, TPe/QT, and TPe/QTc ratios of patients with a Clinical Opiate Withdrawal Scale (COWS) score higher than five and a Framingham heart risk score lower than 10% were measured in 12-lead ECG. Results: A significant difference was found between the patients' heart rate, QT, QTc, and TPe/QT values during withdrawal (entry-first) and after withdrawal (second) (p<0.05). Mean QT First Value (380.69±22.46) was significantly different and higher than Mean QT Second Value (372.82±19.998); Mean QTc First Value (435.41±16.22) was significantly different and higher than Mean QTc Second Value (418.03±17.79); Mean Tpe First Value (81.62±6.009) was significantly different and higher than Mean Tpe Second Value (79.93±5.524); and The Mean Tpe/QT First Value (0.221±0.005) was significantly different and higher than the Mean Tpe/ QT Second Value (0.213±0.004) (p<0.05). Conclusion: The findings of our study show that electrocardiographic QT, QTc, Tpe and Tpe/QTc values, which indicate the risk of sudden cardiac death and ventricular arrhythmia, are significantly higher during opioid withdrawal. In addition to the regulation of addiction treatment during opioid withdrawal, it should be considered that individuals may be at cardiac risk, and the patient should be monitored for cardiac arrhythmia during the withdrawal period. [ABSTRACT FROM AUTHOR]

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We present a case of a 70-year-old male who was brought to the hospital with altered mental status and was found to have 2 serious complications of cocaine use which are Cerebellar Hippocampal and Basal Nuclei Transient Edema with Restricted diffusion (CHANTER) syndrome and mesenteric ischemia. CHANTER syndrome is a recently described constellation of radiologic and clinical findings and has a strong association with opiates, and/or other drugs of abuse, including cocaine. Even though CHANTER has many similarities with other ischemic, anoxic, and/or toxic injuries related to substance abuse such as clinical presentation and restricted diffusion on magnetic resonance imaging (MRI); the typical distribution of affected regions in the brain is helpful in differentiating from other injuries. With this study, we aim to emphasize the clues that separate CHANTER syndrome from other acute neurologic problems in the setting of substance use. Our case also suggests that the obstructive hydrocephalus, a known possible complication of CHANTER, is likely seen in the cases with severe and central cerebellar involvement. Additionally, it is not common to see complications in 2 different systems concurrently and a multisystemic approach is crucial to a patient with cocaine use to prevent missed life-threatening consequences throughout the various body systems.

The actions of endogenous opioids and nociceptin/orphanin FQ are mediated by four homologous G protein-coupled receptors that constitute the opioid receptor family. However, little is known about opioid systems in cyclostomes (living jawless fish) and how opioid systems might have evolved from invertebrates. Here, we leveraged de novo transcriptome and low-coverage whole-genome assembly in the Pacific hagfish (Eptatretus stoutii) to identify and characterize the first full-length coding sequence for a functional opioid receptor in a cyclostome. Additionally, we define two novel endogenous opioid precursors in this species that predict several novel opioid peptides. Bioinformatic analysis shows no closely related opioid receptor genes in invertebrates with regard either to the genomic organization or to conserved opioid receptor-specific sequences that are common in all vertebrates. Furthermore, no proteins analogous to vertebrate opioid precursors could be identified by genomic searches despite previous claims of protein or RNA-derived sequences in several invertebrate species. The presence of an expressed orthologous receptor and opioid precursors in the Pacific hagfish confirms that a functional opioid system was likely present in the common ancestor of all extant vertebrates some 550 million years ago, earlier than all previous authenticated accounts. We discuss the premise that the cyclostome and vertebrate opioid systems evolved from invertebrate systems concerned with antimicrobial defense and speculate that the high concentrations of opioid precursors in tissues such as the testes, gut, and activated immune cells are key remnants of this evolutionary role.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.

Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.

Exposure to severely stressful events during childhood is associated with poor health outcomes in later life, including chronic pain and substance use disorder. However, the mediators and mechanisms are unclear. We investigated the impact of a well-characterized mouse model of early-life adversity, fragmented maternal care (FC) between postnatal day 2 and 9, on nociception, inflammatory hypersensitivity, and responses to morphine. Male and female mice exposed to FC exhibited prolonged basal thermal withdrawal latencies and decreased mechanical sensitivity. In addition, morphine had reduced potency in mice exposed to FC and their development of tolerance to morphine was accelerated. Quantitative PCR analysis in several brain regions and the spinal cords of juvenile and adult mice revealed an impact of FC on the expression of genes encoding opioid peptide precursors and their receptors. These changes included enhanced abundance of 8 opioid receptor transcript in the spinal cord. Acute inflammatory hypersensitivity (induced by hind paw administration of complete Freund's adjuvant) was unaffected by exposure to FC. However, after an initial recovery of mechanical hypersensitivity, there was a reappearance in mice exposed to FC by day 15, which was not seen in control mice. Changes in nociception, morphine responses, and hypersensitivity associated with FC were apparent in males and females but were absent from mice lacking 8 receptors or p-arrestin2. These findings suggest that exposure to early-life adversity in mice enhances 8 receptor expression leading to decreased basal sensitivity to noxious stimuli coupled with accelerated morphine tolerance and enhanced vulnerability to persistent inflammatory hypersensitivity. [ABSTRACT FROM AUTHOR]

The goal of this review is to provide a recent examination of the pharmacodynamics as well as pharmacokinetics, misuse potential, toxicology, and prenatal consequences of buprenorphine. Buprenorphine is currently a Schedule III opioid in the US used for opioid-use disorder (OUD) and as an analgesic. Buprenorphine has high affinity for the mu-opioid receptor (MOR), delta (DOR), and kappa (KOR) and intermediate affinity for the nociceptin (NOR). Buprenorphine's active metabolite, norbuprenorphine, crosses the blood–brain barrier, is a potent metabolite that attenuates the analgesic effects of buprenorphine due to binding to NOR, and is responsible for the respiratory depressant effects. The area under the concentration curves are very similar for buprenorphine and norbuprenorphine, which indicates that it is important to consider this metabolite. Crowding sourcing has identified a buprenorphine street value (USD 3.95/mg), indicating some non-medical use. There have also been eleven-thousand reports involving buprenorphine and minors (age < 19) at US poison control centers. Prenatal exposure to clinically relevant dosages in rats produces reductions in myelin and increases in depression-like behavior. In conclusion, the pharmacology of this OUD pharmacotherapy including the consequences of prenatal buprenorphine exposure in humans and experimental animals should continue to be carefully evaluated. [ABSTRACT FROM AUTHOR]

Morphine is a potent analgesic opiate used to treat chronic pain, mostly in cancer patients. In addition, it is widely used as a drug of abuse. Due to the continuous rise of morphine-associated addiction, there is an urgent need to develop pre-clinical animal models to understand the behavioural pattern of drug dependence and its withdrawal. Recently, the experimental use of zebrafish has attained significance in behavioural neuroscience studies. The literature on zebrafish is conflicting with regard to morphine withdrawal symptoms. Unfortunately, no single model provides comprehensive details to evaluate zebrafish behaviour on opiate exposure. Further, the current models have various limitations, such as short duration, complexity of phenotypes, intricate quantification, and difficulty in studying withdrawal symptoms. Consequently, a firm standardization of the protocol to understand the influence of opiates on physiological and psychological behaviours is required. In this study, we have tried to overcome the shortcomings associated with the existing models and to optimize the protocols involving an array of parameters. We observed that the administration of morphine caused a significant increase in zebrafish behavioural patterns of spiral movements, circular movements, erratic movements, upper transitions, water surface transitions, wall licking, wall licking with upper transitions, wall licking with lower transitions, absolute angle changes, and time spent in the upper compartment. A decline in the freezing bouts and time spent in the lower compartment were noticed. In essence, this study offers a zebrafish model to comprehensively examine changes in behaviour of animals on opiate dependence and its withdrawal. The present study also reported that in zebrafish, the influence of chronic exposure of morphine modulates key gene targets involved in behaviour, neuroinflammation, and autophagy, which directly or indirectly are associated with morphine addiction in a chronic morphine model. [ABSTRACT FROM AUTHOR]

The two-component compound formed by codeine and cyclopentobarbital was produced using grinding techniques and through evaporation from alcoholic solutions. The cocrystal nature of this phase was established unequivocally through single crystal X-ray structure determination. The asymmetric unit contains one formula unit. In the cyclopentobarbital molecule, the cyclopentenyl ring is disordered over two positions related by a rotation of approximately 180° about its C—C bond to the pyrimidine ring. The two NH groups of the cyclopentobarbital molecule form N—H⋯N and N—H⋯O bonds to piperidine and hydroxyl groups, respectively, belonging to different codeine molecules. In addition, the hydroxyl and methoxy groups of neighboring codeine molecules are linked by O—H⋯O interactions, resulting in a H-bonded framework structure of codeine and cyclopentobarbital molecules. The cocrystal was also characterized using thermal analysis, X-ray powder diffraction and IR spectroscopy. [ABSTRACT FROM AUTHOR]

Opioid Use Disorder (OUD) and opioid-related deaths remain a major public health concern in the United States. Both environmental and genetic factors influence risk for OUD. We previously identified Hnrnph1 as a quantitative trait gene underlying the stimulant, rewarding, and reinforcing properties of methamphetamine. Prior work shows that hnRNP H1, the RNA-binding protein encoded by Hnrnph1, post-transcriptionally regulates Oprm1 (mu opioid receptor gene)-the primary molecular target for the therapeutic and addictive properties of opioids. Because genetic variants can exert pleiotropic effects on behaviors induced by multiple drugs of abuse, in the current study, we tested the hypothesis that Hnrnph1 mutants would show reduced behavioral sensitivity to the mu opioid receptor agonist fentanyl. Hnrnph1 mutants showed reduced sensitivity to fentanyl-induced locomotor activity, along with a female-specific reduction in, and a male-specific induction of, locomotor sensitization following three, daily injections (0.2 mg/kg, i.p.). Hnrnph1 mutants also required a higher dose of fentanyl to exhibit opioid reward as measured via conditioned place preference (CPP). Male Hnrnph1 mutants showed reduced fentanyl reinforcement. Hnrnph1 mutants also showed reduced sucrose motivation, suggesting a reward deficit. No genotypic differences were observed in baseline thermal nociception, fentanyl-induced antinociception, physical or negative affective signs of opioid dependence, or in sensorimotor gating. In the context of our prior work, these findings suggest that Hnrnph1 dysfunction exerts a selective role in reducing the addiction liability to drugs of abuse (opioids and psychostimulants), which could provide new biological pathways to improve their therapeutic profiles.

The article discusses the reconsideration of using buprenorphine as the primary analgesic in non-opioid use disorder (OUD) patients in emergency departments post-X-waiver elimination in 2023. Topics include the historical context of the X-waiver program, the pharmacological profile of buprenorphine, and the need for further U.S.-based research to establish guidelines for its appropriate use as a primary analgesic in emergency settings.

The drug screen test on a 12-year-old male patient was positive for opiates by a kinetic interaction of microparticles in solution (KIMS) immunoassay method on the Roche Cobas C502. The positive opiates result was not confirmed by the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. A chart review revealed that the patient had tuberculosis and was on rifampin. We spiked rifampin into drug-free urine and tested opiates with the Cobas method. Once again, a positive result was obtained. This case showed that rifampin can still cause false positive opiate results measured with the KIMS method. We want to stress the importance of confirming positive screen results by more specific methods such as LC-MS/MS.

The two-component compound formed by codeine and cyclopentobarbital was produced using grinding techniques and through evaporation from alcoholic solutions. The cocrystal nature of this phase was established unequivocally through single crystal X-ray structure determination. The asymmetric unit contains one formula unit. In the cyclopentobarbital molecule, the cyclopentenyl ring is disordered over two positions related by a rotation of approximately 180° about its C—C bond to the pyrimidine ring. The two NH groups of the cyclopentobarbital molecule form N—H⋯N and N—H⋯O bonds to piperidine and hydroxyl groups, respectively, belonging to different codeine molecules. In addition, the hydroxyl and methoxy groups of neighboring codeine molecules are linked by O—H⋯O interactions, resulting in a H-bonded framework structure of codeine and cyclopentobarbital molecules. The cocrystal was also characterized using thermal analysis, X-ray powder diffraction and IR spectroscopy.

Opioid overdose remains a problem in the United States despite pharmacotherapies, such as buprenorphine, in the treatment of opioid use disorder. This study characterized changes in buprenorphine use. Using the Drug Enforcement Administration's ARCOS, Medicaid, and Medicare claims databases, patterns in buprenorphine usage in the United States from 2018 to 2020 were analyzed by examining percentage changes in total grams distributed and changes in grams per 100 K people in year‐to‐year usage based on ZIP code and state levels. For ARCOS from 2018 to 2019 and 2019 to 2020, total buprenorphine distribution in grams increased by 16.2% and 12.6%, respectively. South Dakota showed the largest statewide percentage increase in both 2018–2019 (66.1%) and 2019–2020 (36.7%). From 2018 to 2019, the ZIP codes ND‐577 (156.4%) and VA‐222 (−82.1%) had the largest and smallest percentage changes, respectively. From 2019 to 2020, CA‐932 (250.2%) and IL‐603 (−36.8%) were the largest and smallest, respectively. In both 2018–2019 and 2019–2020, PA‐191 had the second highest increase in grams per 100K while OH‐452 was the only ZIP code to remain in the top three largest decreases in grams per 100K in both periods. Among Medicaid patients in 2018, there was a nearly 2000‐fold difference in prescriptions per 100k Medicaid enrollees between Kentucky (12 075) and Nebraska (6). Among Medicare enrollees in 2018, family medicine physicians and other primary care providers were the top buprenorphine prescribers. This study not only identified overall increases in buprenorphine availability but also pronounced state‐level differences. Such geographic analysis can be used to discern which public policies and regional factors impact buprenorphine access. [ABSTRACT FROM AUTHOR]

Morphine and codeine, two of the most common opioids, are widely used in the clinic for different types of pain. Morphine is one of the most potent agonists for the μ-opioid receptor, leading to the strongest analgesic effect. However, due to their association with serious side effects such as respiratory depression, constriction, euphoria, and addiction, it is necessary for derivatives of morphine and codeine to be developed to overcome such drawbacks. The development of analgesics based on the opiate structure that can be safe, orally active, and non-addictive is one of the important fields in medicinal chemistry. Over the years, morphine and codeine have undergone many structural changes. The biological investigation of semi-synthetic derivatives of both morphine and codeine, especially morphine, shows that studies on these structures are still significant for the development of potent opioid antagonists and agonists. In this review, we summarize several decade-long attempts to synthesize new analogues of morphine and codeine. Our summary placed a focus on synthetic derivatives derived from ring A (positions 1, 2, and 3), ring C (position 6), and N-17 moiety. [ABSTRACT FROM AUTHOR]

Chronic pain conditions create major financial and emotional burdens that can be devastating for individuals and society. One primary source of pain is arthritis, a common inflammatory disease of the joints that causes persistent pain in affected people. The main objective of pharmacological treatments for either rheumatoid arthritis (RA) or osteoarthritis (OA) is to reduce pain. Non-steroidal anti-inflammatory drugs, opioids, and opioid antagonists have each been considered in the management of chronic pain in arthritis patients. Naltrexone is an oral-activated opioid antagonist with biphasic dose-dependent pharmacodynamic effects. The molecule acts as a competitive inhibitor of opioid receptors at high doses. However, naltrexone at low doses has been shown to have hormetic effects and provides relief for chronic pain conditions such as fibromyalgia, multiple sclerosis (MS), and inflammatory bowel disorders. Current knowledge of naltrexone suggests that low-dose treatments may be effective in the treatment of pain perception in chronic inflammatory conditions observed in patients with either RA or OA. In this review, we evaluated the therapeutic benefits of low-dose naltrexone (LDN) on arthritis-related pain conditions. [ABSTRACT FROM AUTHOR]

BackgroundWhoonga is a smoked heroin-based street drug that first emerged in South Africa a decade ago. While previous scientific reports suggest that use is growing and youth are particularly vulnerable, trajectories of initiation are not well characterized.MethodsIn 2015, 30 men undergoing residential addiction treatment for this smoked heroin drug in KwaZulu-Natal, South Africa participated in semi-structured interviews about their experiences using the drug. Interview data were coded using qualitative content analysis.ResultsParticipant trajectories to initiating smoked heroin were "vertical" in the context of marijuana use or "horizontal" in the context of other hard drug use. Participants reporting vertical trajectories began smoking heroin as youth at school or in other settings where people were smoking marijuana. Several participants with horizontal trajectories started smoking heroin to address symptoms of other drug or alcohol addiction. Social influences on initiation emerged as an overarching theme. Members of participants' social networks who were smoking or distributing heroin figured prominently in initiation narratives. Surprisingly, references to injection drug use were absent from initiation narratives. Participants reported people who smoke heroin differ from those who inject heroin by race.ConclusionConsistent with theories implicating social and structural influences on substance use initiation, people who started smoking heroin had social contacts who smoked heroin and frequented places where substance use was common. Smoked heroin initiation for several participants with horizontal trajectories may have been averted if they accessed evidence-based treatments for stimulant or alcohol use disorders. With increasing reports of heroin use across Africa, a coordinated approach to address this growing epidemic is needed. However, because smoked heroin and injection heroin use occur in distinct risk environments, interventions tailored to people who use smoked heroin will be needed to prevent smoked heroin use, prevent transition to injection use, and mitigate other social harms.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.

BackgroundPopulation-based studies show there is a high prevalence of chronic kidney disease (CKD) patients suffering from chronic pain. While opiates are frequently prescribed in non-dialysis-dependent CKD (NDD-CKD) patients, there may be toxic accumulation of metabolites, particularly among those progressing to end-stage renal disease (ESRD). We examined the association of opiate versus other analgesic use during the pre-ESRD period with post-ESRD mortality among NDD-CKD patients transitioning to dialysis.MethodsWe examined a national cohort of US Veterans with NDD-CKD who transitioned to dialysis over 2007-14. Among patients who received ≥1 prescription(s) in the Veterans Affairs (VA) Healthcare System within 1 year of transitioning to dialysis, we examined associations of pre-ESRD analgesic status, defined as opiate, gabapentin/pregabalin, other non-opiate analgesic, versus no analgesic use, with post-ESRD mortality using multivariable Cox models.ResultsAmong 57,764 patients who met eligibility criteria, pre-ESRD opiate and gabapentin/pregabalin use were each associated with higher post-ESRD mortality (ref: no analgesic use), whereas non-opiate analgesic use was not associated with higher mortality in expanded case-mix analyses: HRs (95% CIs) 1.07 (1.05-1.10), 1.07 (1.01-1.13), and 1.00 (0.94-1.06), respectively. In secondary analyses, increasing frequency of opiate prescriptions exceeding 1 opiate prescription in the 1-year pre-ESRD period was associated with incrementally higher post-ESRD mortality (ref: no analgesic use).ConclusionsIn NDD-CKD patients transitioning to dialysis, pre-ESRD opiate and gabapentin/pregabalin use were associated with higher post-ESRD mortality, whereas non-opiate analgesic use was not associated with death. There was a graded association between increasing frequency of pre-ESRD opiate use and incrementally higher mortality.