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Background: A Zoom-based website was developed in 2020 that offers continuous access to online Narcotics Anonymous (NA) meetings for the first time. This website provides immediate access for persons with substance use disorder to support abstinence from substance-related addictive disorders. Objectives: This study is designed to characterize attendees employing this online format; to evaluate their experiences for gaining support to maintain abstinence; and to compare the 24/7 experience to face-to-face (FF) meetings they attend. Methods: An anonymous 33-item survey was made available on the 24/7 NA website that links to the 24/7 meetings. Persons accessing the site could choose to fill out the survey. Results: 530 respondents completed the survey (64.9% female/35.1% male). Most had stable prior involvement in NA. They had attended more 24/7 meetings (14.9, SD 19.7) than FF meetings (4.6, SD 7.8) in the previous month. 86% had previously attended FF meetings, 48% had served as sponsors, and 92% reported that the 24/7 meetings were more comfortable for them than the FF meetings ( p  < .001, Cohen's d = 0.65) and more supportive of abstinence ( p  < .001, Cohen's d = 0.91). Of the respondents, 8% were still using drugs, of whom 52% had previously completed some of the Twelve Steps. Conclusions: The 24/7 format provides a new and easily accessible way for NA members to gain support for abstinence and is positively rated by attendees seeking support for recovery from substance use disorders. It may serve as a valuable adjunct to the traditional FF format.

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests-thermal gradient ring (5-30 °C, 5-50 °C, 15-40 °C, and 25-50 °C), dynamic cold plate (4 °C to -1 °C at -1 °C/min, -1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)-to measure hyperalgesia in a mouse protocol of heroin dependence. On the thermal gradient ring, mice in the heroin withdrawal group preferred warmer temperatures, and the results depended on the ring's temperature range. On the dynamic cold plate, heroin withdrawal increased the number of nociceptive responses, with a temperature ramp from 4 °C to -1 °C yielding the largest response. On the stable cold plate, heroin withdrawal increased the number of nociceptive responses, and a plate temperature of 2 °C yielded the most significant increase in responses. Among the three tests, the stable cold plate elicited the most robust change in behavior between heroin-dependent and nondependent mice and had the highest throughput. To pharmacologically characterize the stable cold plate test, we used μ-opioid and non-opioid receptor-targeting drugs that have been previously shown to reverse OWIH in mechanical and heat nociception assays. The full μ-opioid receptor agonist methadone and μ-opioid receptor partial agonist buprenorphine decreased OWIH, whereas the preferential μ-opioid receptor antagonist naltrexone increased OWIH. Two N-methyl-d-aspartate receptor antagonists (ketamine, MK-801), a corticotropin-releasing factor 1 receptor antagonist (R121919), a β 2 -adrenergic receptor antagonist (butoxamine), an α 2 -adrenergic receptor agonist (lofexidine), and a 5-hydroxytryptamine-3 receptor antagonist (ondansetron) had no effect on OWIH. These data demonstrate that the stable cold plate at 2 °C yields a robust, reliable, and concise measure of OWIH that is sensitive to opioid agonists., Competing Interests: Conflict of interest The authors report no conflicts of interest related to the content of this work., (Published by Elsevier Inc.)

Background: Pharmacotherapeutic options for the treatment of opioid withdrawal are limited by abuse potential, adverse effects, and lack of availability of existing drugs. The results from previous clinical trials on tramadol are contradictory and non-conclusive; hence the present meta-analysis was conducted to evaluate the efficacy and safety of tramadol in the treatment of opioid withdrawal., Methods: Reviewers extracted data from eight relevant clinical trials after a literature search on MEDLINE/PubMed, Cochrane databases, and clinical trial registries. Quality assessment was done using the risk-of-bias assessment tool, and the random-effects model was used to estimate effect size in frequentist and Bayesian approaches. Subgroup analysis, meta-regression, and sensitivity analysis were done as applicable. PRISMA guidelines were followed in reporting findings., Results: Tramadol significantly reduced opioid withdrawal scale score (SMD: -0.44; 95%CI: -0.76 to -0.13; PI: -1.54 to 0.71; p = 0.006) when all comparators were considered together in the frequentist approach but the reduction was non-significant in Bayesian approach. However, the subgroup analysis revealed no significant difference between tramadol and comparators like placebo (SMD: -1.12; 95%CI: -2.69 to 0.45) buprenorphine (SMD: -0.21; 95%CI: -0.43 to 0.01), clonidine (SMD: -0.26; 95%CI: -0.55 to 0.02) and methadone (SMD: -0.84; 95%CI: -1.78 to 0.10). Meta-regression showed non-significant associations between the SMD in opioid withdrawal score with the duration and dose of tramadol therapy. There were no significant differences in treatment retention at the end of studies between tramadol and comparators. Safety data in the individual studies were inadequate to analyze., Conclusion: Authors conclude that the efficacy of tramadol in reducing opioid withdrawal symptoms is not significantly different from comparators with low certainty of evidence against placebo, moderate against methadone, whereas with high certainty of evidence against buprenorphine and clonidine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Rationale: Super-refractory status epilepticus is a serious illness with high morbidity and mortality, which is defined as an SE that continues or recurs 24 hours or more after the onset of anesthesia. Anesthetic agents can be either pro-convulsant or anticonvulsant or both., Patient Concerns: Epilepsy occurred at the age of 3 years. At the age of 4 years, generalized tonic-clonic seizure occurred for the first time. The patient was hospitalized at the age of 27 and 28 years for treating status epilepticus. At the age of 33 years, antiepileptic drugs were stopped due to poor appetite. In an early morning, the patient was found delirious with reduced speech., Diagnosis: Occasionally, the patient blinked his eyelids, or deflected his eyeballs to 1 side. When propofol was lowered to 10 mL/H, the epileptic wave reduced obviously. Afterwards, the patient opened his eyes autonomously and his consciousness gradually recovered. The patient could answer questions, and the limbs had voluntary movements. The patient breathing also gradually recovered, and his urine gradually returned to pale yellow from green. After anesthetic was stopped for 10 days, the patient lost his consciousness again. The patient eyes turned upward frequently, which was relieved in 1 to 2 seconds with an attack once every 2 to 5 minutes., Interventions: Clonazepam was gradually reduced to 2 mg qn, and the patient gradually woke up during this process. The patient was also treated with levetiracetam 1.5 g bid, oxcarbazepine 0.6 g bid, topiramate 50 mg bid and valproate 0.4 g tid., Outcomes: After 1 month follow-up, status epilepticus did not appear again., Lessons: Propofol aggravated the tonic seizures. As tonic seizures occur during natural sleep and after sleep induced by various narcotic drugs, the decrease of consciousness level induced by excessive sedation of narcotic drugs has been suggested as the reason for poor seizure control., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Opioid misuse has dramatically increased over the last few decades resulting in many people suffering from opioid use disorder (OUD). The prevalence of opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. Coinciding with increases in exposure to opioids, the United States has also observed increases in multiple Narcan (naloxone) administrations as a life-saving measures for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is a main symptom of OUD and opioid withdrawal syndrome, and therefore, should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6 J mice. We find that morphine administration and withdrawal dysregulate sleep, but not equally across morphine exposure paradigms. Furthermore, many environmental triggers promote relapse to drug-seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. Our data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid-induced sleep dysregulation and further validates the construct of this model for opioid dependence and OUD., Competing Interests: Declaration of Competing Interest The authors M. Bedard and Dr. McElligott are sub-contracted by EpiCypher® on a SBIR grant unrelated to the work completed in this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The association of preoperative narcotic use with postoperative outcomes after primary elective total knee arthroplasty (TKA) has remained poorly characterized. The NarxCare platform analyzes patients' state Prescription Drug Monitoring Program records to assign numerical scores that approximate a patient's overall opioid usage. The present study investigated the utility of admission NarxCare narcotic scores in predicting the odds of adverse events (AEs) after primary elective TKA., Methods: Elective primary TKA patients performed at a single institution between October 2017 and May 2020 were evaluated. NarxCare narcotic scores at the time of admission, patient characteristics, 30-day AEs, readmissions, revision surgeries, and mortality were abstracted. Elective TKA patients were binned based on admission NarxCare narcotic scores. The odds of experiencing adverse outcomes were compared., Results: In total, 1136 patients met the criteria for inclusion in the study (Narx Score 0: n = 293 [25.8%], 1 to 99: n = 253 [22.3%], 100 to 299: n = 368 [32.4%], 300 to 499: n = 161 [14.2%], and 500+: n = 61 [5.37%]). By logistic regression, patients with higher admission narcotic scores tended to have a dose-dependent increase in the odds of prolonged length of hospital stay, readmission within 30 days, and aggregated AEs., Discussion: Admission narcotic scores may be used to predict readmission and to stratify TKA patients by risk of AEs., Competing Interests: The following disclosures have been collected and reported per International Committee of Medical Journal Editors (ICMJE) reporting standards. Dr. Grauer or an immediate family member reports personal fees from TIDI Products and the North American Spine Society, outside the submitted work. Dr. Rubin or an immediate family member reports personal fees from DePuy Synthes, ConvaTec, Thompson Surgical Instruments, SLACK Publishers, and Johns Hopkins University Press and other from 3D Surgical, Inc, outside the submitted work. None of the aforementioned disclosures pose relevant conflicts of interest to the current study. None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Background: The appropriate use of narcotics for postoperative pain control is controversial because of potential medication-induced complications. The authors sought to determine the effects of narcotics in the pediatric population following cranial vault remodeling operations., Methods: A retrospective review was performed on 160 consecutive patients who underwent cranial vault remodeling for craniosynostosis., Results: There was a statistically significant difference in total morphine equivalents in the group that experienced no emesis and those with at least one episode of emesis (0.97 morphine equivalents/kg versus 1.44 morphine equivalents/kg; p = 0.05). There was a statistically significant difference in hospital morphine equivalents in the group with documented respiratory events (average, 2.3 morphine equivalents/kg versus 1.3 morphine equivalents/kg in the nonevent group; p = 0.006). The patients who received dexmedetomidine had a trend toward a decrease in hospital narcotic administration with equivalent pain control (1.2 morphine equivalents/kg versus 1.9 morphine equivalents/kg; p = 0.09). There was a statistically significant positive correlation between total morphine equivalents for the hospitalization and hospital stay ( r = 0.27, p = 0.001). The amount of morphine equivalents used in the first 24 hours was also found to be an independent predictor of a respiratory event ( p = 0.002 by multivariate logistic regression). Independent positive predictors of hospital stay were age ( p < 0.001), intensive care unit time ( p < 0.001), and total morphine equivalents for the hospitalization ( p = 0.001) by multivariate analysis with linear regression., Conclusion: The authors' study demonstrates improvement in outcomes with decreased use of narcotics, which establishes that there is a need to further explore postsurgical recovery outcomes with multimodal pain control., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background: Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP., Methods: In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate., Findings: Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80)  = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3)  = 2.41, p = 0.01)., Interpretation: The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse., Funding: National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) has highlighted the scope of heroin dependence and need for evidence-based treatment amongst marginalised people in South Africa. Acute opioid withdrawal management without maintenance therapy carries risks of increased morbidity and mortality. Due to the high costs of methadone, Tshwane's Community Oriented Substance Use Programme (COSUP) used tramadol for opioid withdrawal management during the initial COVID-19 response., Aim: To describe demographics, route of heroin administration and medication-related experiences amongst people accessing tramadol for treatment of opioid withdrawal., Setting: Three community-based COSUP sites in Mamelodi (Tshwane, South Africa)., Methods: A retrospective cross-sectional study was conducted. Data were collected using an interviewer-administered paper-based tool between April and August 2020. Descriptive statistics were used to analyse data., Results: Of the 220 service users initiated onto tramadol, almost half (n = 104, 47%) were not contactable. Fifty-eight (26%) people participated, amongst whom most were male (n = 55, 95%). Participants' median age was 32 years. Most participants injected heroin (n = 36, 62.1%). Most participants experienced at least one side effect (n = 47, 81%) with 37 (64%) experiencing two or more side effects from tramadol. Insomnia occurred most frequently (n = 26, 45%). One person without a history of seizures experienced a seizure. Opioid withdrawal symptoms were experienced by 54 participants (93%) whilst taking tramadol. Over half (n = 38, 66%) reported using less heroin whilst on tramadol., Conclusion: Tramadol reduced heroin use but was associated with withdrawal symptoms and unfavourable side effects. Findings point to the limitations of tramadol as opioid withdrawal management to retain people in care and the importance of access to first-line opioid agonists.Contribution: This research contributes to the limited data around short-acting tramadol for opioid withdrawal management in the African context, with specific focus on the need for increased access to opioid agonists for those who need them, in primary care settings.

Prescribing medicines containing controlled substances (SSC : narcotics and psychotropic substances) can have legal consequences as per the Road Traffic Act. We set forth the physician's duties as well as the risks incurred by the patient. We recommend that rules regarding SSC, which can influence the capacity or the ability to drive, be clarified., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

The aim of the current study was to determine effects of the prenatal exposure to crocin in the expression of withdrawal syndrome on reflexive motor behaviors in mice offspring's. Fourteen male mice and 56 adult female mice were randomly divided into seven groups as: control group (morphine-abstinent male and female); group 2, drug-naïve female and morphine-abstinent male; group 3, drug-naïve male and morphine-abstinent females; group 4, drug-naïve male and female. Groups 5-7, were similar to groups 2-4, except crocin (5 mg/kg) were injected to drug-naïve subjects. Following delivery, 20 pups from each litter were selected and behavior and reflexive motor behaviors were determined. Also, blood samples were taken to determine serum antioxidant activity. According to the results, immobility time significantly increased in offspring of the paternal + maternal exposed to morphine swimming test and tail suspension tests (P < 0.05) and significantly decreased in offspring of paternal + maternal exposed to morphine + crocin group (P < 0.05). Ambulation, surface righting, hind-limb suspension, grip strength and front limb suspension significantly decreased in offspring of the mice exposed to morphine (P < 0.05) and significantly improved in offspring of paternal + maternal exposed to morphine + crocin group (P < 0.05). Hind-limb foot angle and negative geotaxis significantly increased in mice with morphine-exposed offspring's (P < 0.05) while improved in offspring of paternal + maternal exposed to morphine + crocin group (P < 0.05). Prenatal exposure to morphine increased Malondialdehyde while decreased Superoxide dismutase, Glutathione peroxidase and total antioxidant status in mice offspring's (P < 0.05) and these results reversed by prenatal exposure to crocin (P < 0.05). In all studied factors, paternal + maternal exposed to morphine + crocin group had better results compared to the other crocin-received drug-naïve groups (P < 0.05). These results suggested prenatal exposure to crocin decreased morphine-induced adverse effect which paternal and maternal exposed to morphine + crocin had the highest prevention against these effects in mice offspring's., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Bladder cancer disproportionally affects the communities. While it is the ninth most common cancer in the world, in some parts of Iran including Kerman province it is the most common cancer among men. This study aimed to determine potential risk factors of bladder cancer in Kerman province, Iran., Methods: During February to July 2020, in this matched hospital-based case-control study, 100 patients with bladder cancer and 200 healthy individuals (matched in age and sex) were recruited. Socio-demographics status, occupational exposures, common diet, history of drug use and family history of cancer, were collected using a structured questionnaire. Bivariable and multivariable logistic regression were applied and crude and adjusted odds ratios (AOR) along with their 95% confidence intervals (95%CI) were calculated. Data were analyzed using Stata version 14 software., Results: Opium consumption, cigarette smoking and low level of income were associated with increased chance of bladder cancer. Compared to never use, use of opium up to 18000 Gram -year was associated with increased chance of bladder cancer (AOR: 6; 95% CI =2.3, 15.5). The chance was higher among those who used opium more than 18,000 Gram - year (AOR: 11.3; 95% CI =2.3, 15.5). In comparison with never smokers, the chance of bladder cancer increased among those who smoked up to 20 pack-year cigarette) (AOR: 3.4; 95%CI= 1.3, 8.9) and those who smoke ≥ 20 pack-year (AOR: 15.8; 95% CI= 5.9, 42.4)., Conclusions: The observed strong dose-response association between opium consumption, cigarette smoking and bladder cancer highlights the need for extension of harm reduction programs especially in regions with high burden of disease.

Objectives/hypothesis: Children undergoing tonsillectomy for sleep-disordered breathing are at risk for respiratory compromise when narcotics are administered. Severe complications resulting from hypoxia can include neuro-devastation and death. The objective of this prospective study was to evaluate the feasibility, accuracy, and utility of transcutaneous carbon dioxide (tcPCO2) monitoring during and after adenotonsillectomy., Study Design: Prospective, Observational study., Methods: Twenty-nine children with sleep-disordered breathing scheduled for adenotonsillectomy were included in the study. Peri-operative measurements of tcPCO2 were compared against a single venous blood sample (PaCO2) and end-tidal (ET) CO2. The differences between ETCO2, tcPCO2 measures, and PaCO2 were examined using non-paired t-tests and linear regression. Parameters from PSG were recorded and associations with tcPCO2 values were performed using linear regression analysis. Group comparisons were made between pre-, intra-, and post-operative tcPCO2 measurements., Results: Similar to ETCO2, there was good correlation of tcPCO2 to PaCO2. Children with lower oxygen (O2) saturation nadirs had higher peak CO2 levels during surgery and spent a greater proportion of time with CO2 > 50 mmHg in the recovery room (P < .01 and P < .08). Other PSG measures (apnea-hypopnea index, O2 desaturation index, and peak CO2) did not have any significant correlation. Frequent episodes of hypercapnia were noted intra- and post-operatively and mean tcPCO2 values during both periods were significantly higher than baseline (P < .001)., Conclusions: tcPCO2 monitoring is viable in children undergoing adenotonsillectomy and can provide a good estimate of hypoventilation. tcPCO2 measurements may have particular benefit in the post-operative setting and may assist in identifying children at greater risk for respiratory complications., Level of Evidence: 4 Laryngoscope, 131:1410-1415, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Drug-facilitated sexual assault (DFSA) and drug-facilitated crime (DFC) constitute a mode of violence that is generally unknown to the population and may go unnoticed by health professionals. The aim of this systematic review was to analyze the victims of DFC, compiling their sociodemographic characteristics, the toxic substances used and their biological matrices and modes of action, in order to identify the substances that are commonly put to criminal use. The aim would be to establish political and health strategies that inform and warn people about possible criminal social behaviors consequent danger to health. This systematic review was conducted following the PRISMA guidelines. Alcohol, benzodiazepines and cocaine were among the most commonly detected substances. In most of the hospitals, immunoassays, liquid chromatography (LC-MS), or gas chromatography-mass spectrometry (GC-MS) analyses were used to identify the substances, while the most frequently used biological matrices were blood and urine. From a judicial point of view, the instrumental protocols and techniques followed for the detection of toxics in different biological matrices must guarantee the reliability and validity of the results for use in a court of law. The recommendations of international organizations should be followed and must be called upon to strengthen their respective national laws against this chemical submission (CS) phenomenon., (Copyright © 2021 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Using two-sensor electrochemical recordings in freely moving rats, we examined the relationship between physiological and drug-induced oxygen fluctuations in the brain and periphery. Animals chronically implanted with oxygen sensors in the nucleus accumbens (NAc) and subcutaneous (SC) space were subjected to several mildly arousing stimuli (sound, tail-pinch and social interaction) and intravenous injections of cocaine and heroin. Arousing stimuli induced rapid increases in NAc oxygen levels followed by and correlated with oxygen decreases in the SC space. Therefore, cerebral vasodilation that increases cerebral blood flow and oxygen entry into brain tissue results from both direct neuronal activation and peripheral vasoconstriction, which redistributes arterial blood from periphery to the brain. The latter factor could also explain a similar pattern of oxygen responses found in the substantia nigra reticulata, suggesting hyperoxia as a global phenomenon with minor structural differences during early time intervals following the stimulus onset. While arousing stimuli and cocaine induced similar oxygen responses in the brain and SC space, heroin induced a biphasic down-up brain oxygen fluctuation associated with a monophasic oxygen decrease in the SC space. Oxygen decreases occurred more rapidly and stronger in the SC space, reflecting a drop in blood oxygen levels due to respiratory depression.

Chronic prenatal exposure to opioids often causes fetal opioid dependence that leads to neonatal opioid withdrawal syndrome (NOWS) shortly after delivery. Rat models of NOWS often require quantifying neonatal withdrawal behaviors using time-consuming, labor-intensive manual scoring methods. The goal of this study was to automate quantification of opioid withdrawal in neonatal rat pups. Accordingly, we used the animal behavior software Ethovision® XT to analyze archived videos of rat pups subjected to precipitated opioid withdrawal testing on postnatal day 0. We compared results obtained from Ethovision® XT with those previously obtained from manual scoring. Two endpoints reported by Ethovision® XT, Distance Moved (cm) and Movement Duration (s), had strong positive linear relationships with manually derived global withdrawal scores (GWS; R 2  > 0.73). Sensitivity and specificity of each endpoint to discriminate presence and absence of low-grade withdrawal were assessed by receiver operator characteristic curve analysis, which indicated that Distance Moved and Movement Duration had excellent accuracy (AUC > 0.90). Finally, we analyzed main and interaction effects of prenatal treatment (with vehicle or mu opioid receptor full agonists) and postnatal challenge (with saline or an opioid receptor antagonist) on each endpoint and determined they were similar for the manual and automated methods. These results show that Ethovision® XT software can reliably quantify opioid withdrawal in neonatal rat pups with non-inferiority to manual scoring even in videos that were not originally purposed and optimized for Ethovision® XT analysis. This faster and less labor-intensive method of analysis is expected to accelerate progress in preclinical studies of NOWS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species' strengths as model systems and can inform experimental design in studies of opioid withdrawal., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This article examines injectable Opioid Agonist Treatment (iOAT), in which patients suffering from long-term, treatment refractory opioid use disorder (OUD) are prescribed injectable diacetylmorphine, the active ingredient of heroin. While iOAT is part of the continuum of care for OUD in some European countries and in some parts of Canada, it is not an available treatment in the United States. We suggest that one reason for this situation is the belief that a genuine treatment for substance use disorder cannot prescribe the same substance as that used. We examine possible rationales for this belief by considering four combinations of views on the constitutive causal basis of substance use disorders and the definition of effective treatment. We show that all but one combination counts iOAT as a genuine treatment and that there are good reasons to reject the one that does not. Specifically, we claim that medical interventions, such as iOAT, that significantly reduce the severity of a disorder deserve to be categorized as effective treatments and regarded as such in practice.

Background and Objectives: Individuals exposed to fentanyl are at risk of precipitated withdrawal using typical buprenorphine/naloxone induction procedures., Methods: This case series describes buprenorphine/naloxone inductions of four individuals who tested positive for fentanyl., Results: Buprenorphine-precipitated withdrawal was observed in two individuals who completed a conventional buprenorphine/naloxone induction strategy. Two more individuals completed a revised buprenorphine/naloxone induction strategy that did not precipitate withdrawal., Discussion and Conclusion: Using multiple 2 mg doses of buprenorphine/naloxone in patients already in mild/moderate withdrawal improved outcomes., Scientific Significance: Persons who use illicit fentanyl might be less likely to experience precipitated withdrawal from this revised buprenorphine/naloxone induction strategy. (Am J Addict 2021;30:83-87)., (© 2020 American Academy of Addiction Psychiatry.)

Background: Motorcycle drivers are among the most vulnerable road users, accounting for a large proportion of global traffic accidents. This study aimed to investigate the association between the score of adult attention-deficit/hyperactivity (ADHD) traits and risky driving behaviors (RDB) with alcohol intake (AI) and narcotics consumption (NC) among motorcyclists in Iran., Methods: This multi-center cross-sectional study encompassed 1747 motorcyclists from three cities in Iran. A random sampling method was applied in this study, and the required data was collected using three standard questionnaires on ADHD, substance abuse, and RDB. Independent sample t-test, covariance analysis, and quantile regression (QR) were used to analyze the data., Results: The results of t-test and analysis of covariance indicated that AI and NC were significantly associated with ADHD score and RDB among the motorcycle drivers. Additionally, the QR models showed that these effects were significant at all quantiles of ADHD and RDB, even for individuals who were at lower quantiles., Conclusions: Considering the potential dangers of driving after AI and NC, appropriate measures should be adopted before certifying a driving license to screen ADHD as a predisposing factor for substance abuse and RDB. Furthermore, it is essential to equip traffic police with adequate diagnosis kits and establish heavy penalties for the offenders. In this regard, all interventions aimed to reduce traffic accidents among motorcycle drivers should be done considering the interrelationship between ADHD, RDB, and substance abuse.

Background: Extended length of stay (LOS) after surgery is costly to the health care system and can be distressing to the patient and family. Previous studies have shown conflicting data on factors associated with increased LOS and are limited by using multiple different surgeries. Our study seeks to analyze factors that are associated with extended LOS., Objective: The objective of this study was to analyze data from 2 Food and Drug Administration trials of one-level cervical surgery to identify risk factors that are associated with extended LOS in the hospital., Methods: Extended LOS was defined to be >1 day. Patients with LOS ≤1 day were compared with those with LOS >1 day. Data from the BRYAN and Prestige ST Trial (n = 1004) were analyzed. Subjects with LOS ≤1 day were compared with those with LOS >1 day. Variables analyzed for their effect on LOS included demographic characteristics, patient-reported outcome measures, preoperative medical conditions, preoperative neurologic status, and intraoperative factors., Results: A total of 912 patients (90.84%) had an LOS ≤1 day and 92 patients (9.16%) had an extended LOS >1 day. Weak narcotic medication use (P = 0.021; odds ratio [OR], 1.72), Nurick gait (P = 0.019; OR, 1.796), and operative time (P < 0.0001; OR, 2.062) were found to significantly affect LOS., Conclusions: Nurick gait, operative time, and history of weak narcotic use are associated with extended hospital stay. These data may be useful in preoperatively counseling patients, developing quality metrics for hospitals, and helping create financial models for cost/diagnosis-related group reimbursement for single-level anterior cervical surgery., (Published by Elsevier Inc.)

Introduction: Foreign body emboli can lead to acute arterial insufficiency. We present a case report of upper extremity arterial insufficiency in an intravenous (IV) drug user secondary to intra-arterial injection of crushed tablet particles successfully treated with hyperbaric oxygen (HBO2) therapy., Case: A 37-year-old right-hand-dominant male developed pain and swelling of the left hand after attempting to inject crushed hydromorphone tablets into his venous circulation. Angiography revealed incomplete distal filling of the proper digital arteries, princeps pollicis, and radialis indicis branches of the left hand. The patient was treated with HBO2 for acute arterial insufficiency, secondary to these findings. Fluorescence angiography was performed prior to, during and after completion of HBO2, which showed improved perfusion of the hand upon completion of serial imaging. The patient underwent subsequent partial amputation of the left second digit and removal of the thenar and third finger pads., Discussion: Much of the literature on treatment of arterial insufficiency with HBO2 are in relation to chronic problem wounds. However, there is limited data on adjunctive treatment with HBO2 for foreign body embolism. Fluorescence angiography and clinical exam were used to track tissue perfusion and progression throughout course of therapy with HBO2., Conclusion: Acute arterial insufficiency induced by foreign body embolism was successfully treated with HBO2 and provided increased tissue salvage of the patient's hand. The use of fluorescence angiography as a secondary measure of perfusion can provide additional insight regarding qualitative tissue oxygenation and may be a viable tool to track patient progress during HBO2 treatment., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Aim: To identify and evaluate the evidence documenting the association between neonatal morphine and later childhood neuropsychological development., Method: We conducted a systematic literature search of eight electronic databases from inception until June 2019. We included all randomized controlled trials (RCTs) and cohort studies recruiting neonates who received morphine treatment, and measuring neuropsychological development outcomes with a minimum follow-up of 6 months., Results: Twelve separate reports from three RCTs and five cohort studies met our inclusion criteria. Owing to the small number of the included trials and the variable study designs, a meta-analysis was not performed. The findings from this review indicated that neonatal morphine use had no adverse effects on behaviour, cognition, motor, and executive function development at 8 to 9 years and earlier; except for the inconsistent conclusions on internalizing behavioural problems at 5 to 7 years and cognitive and motor developments at 18 months., Interpretation: Why a child needs morphine may have a more profound impact on later neuropsychological development than morphine itself. The small number, high heterogeneity, and limitations of the included studies limit confidence in the result of this systematic review., (© 2020 Mac Keith Press.)

Background: The prevalence of substance use, both prescribed and non-prescribed, is increasing in many areas of the world. Substance use by women of childbearing age contributes to increasing rates of neonatal abstinence syndrome (NAS). Neonatal opioid withdrawal syndrome (NOWS) is a newer term describing the subset of NAS related to opioid exposure. Non-pharmacological care is the first-line treatment for substance withdrawal in newborns. Despite the widespread use of non-pharmacological care to mitigate symptoms of NAS, there is not an established definition of, and standard for, non-pharmacological care practices in this population. Evaluation of safety and efficacy of non-pharmacological practices could provide clear guidance for clinical practice., Objectives: To evaluate the safety and efficacy of non-pharmacological treatment of infants at risk for, or having symptoms consistent with, opioid withdrawal on the length of hospitalization and use of pharmacological treatment for symptom management. Comparison 1: in infants at risk for, or having early symptoms consistent with, opioid withdrawal, does non-pharmacological treatment reduce the length of hospitalization and use of pharmacological treatment? Comparison 2: in infants receiving pharmacological treatment for symptoms consistent with opioid withdrawal, does concurrent non-pharmacological treatment reduce duration of pharmacological treatment, maximum and cumulative doses of opioid medication, and length of hospitalization?, Search Methods: We used the standard search strategy of Cochrane Neonatal to search CENTRAL (2019, Issue 10); Ovid MEDLINE; and CINAHL on 11 October 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs), quasi-RCTs, and cluster trials., Selection Criteria: We included trials comparing single or bundled non-pharmacological interventions to no non-pharmacological treatment or different single or bundled non-pharmacological interventions. We assessed non-pharmacological interventions independently and in combination based on sufficient similarity in population, intervention, and comparison groups studied. We categorized non-pharmacological interventions as: modifying environmental stimulation, feeding practices, and support of the mother-infant dyad. We presented non-randomized studies identified in the search process narratively., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. We used the GRADE approach to assess the certainty of evidence. Primary outcomes in infants at risk for, or having early symptoms consistent with, opioid withdrawal included length of hospitalization and pharmacological treatment with one or more doses of opioid or sedative medication. Primary outcomes in infants receiving opioid treatment for symptoms consistent with opioid withdrawal included length of hospitalization, length of pharmacological treatment with opioid or sedative medication, and maximum and cumulative doses of opioid medication., Main Results: We identified six RCTs (353 infants) in which infants at risk for, or having symptoms consistent with, opioid withdrawal participated between 1975 and 2018. We identified no RCTs in which infants receiving opioid treatment for symptoms consistent with opioid withdrawal participated. The certainty of evidence for all outcomes was very low to low. We also identified and excluded 34 non-randomized studies published between 2005 and 2018, including 29 in which infants at risk for, or having symptoms consistent with, opioid withdrawal participated and five in which infants receiving opioid treatment for symptoms consistent with opioid withdrawal participated. We identified seven preregistered interventional clinical trials that may qualify for inclusion at review update when complete. Of the six RCTs, four studies assessed modifying environmental stimulation in the form of a mechanical rocking bed, prone positioning, non-oscillating waterbed, or a low-stimulation nursery; one study assessed feeding practices (comparing 24 kcal/oz to 20 kcal/oz formula); and one study assessed support of the maternal-infant dyad (tailored breastfeeding support). There was no evidence of a difference in length of hospitalization in the one study that assessed modifying environmental stimulation (mean difference [MD) -1 day, 95% confidence interval [CI) -2.82 to 0.82; 30 infants; very low-certainty evidence) and the one study of support of the maternal-infant dyad (MD -8.9 days, 95% CI -19.84 to 2.04; 14 infants; very low-certainty evidence). No studies of feeding practices evaluated the length of hospitalization. There was no evidence of a difference in use of pharmacological treatment in three studies of modifying environmental stimulation (typical risk ratio [RR) 1.00, 95% CI 0.86 to 1.16; 92 infants; low-certainty evidence), one study of feeding practices (RR 0.92, 95% CI 0.63 to 1.33; 49 infants; very low-certainty evidence), and one study of support of the maternal-infant dyad (RR 0.50, 95% CI 0.13 to 1.90; 14 infants; very low-certainty evidence). Reported secondary outcomes included neonatal intensive care unit (NICU) admission, days to regain birth weight, and weight nadir. One study of support of the maternal-infant dyad reported NICU admission (RR 0.50, 95% CI 0.13 to 1.90; 14 infants; very low-certainty evidence). One study of feeding practices reported days to regain birth weight (MD 1.10 days, 95% CI 2.76 to 0.56; 46 infants; very low-certainty evidence). One study that assessed modifying environmental stimulation reported weight nadir (MD -0.28, 95% CI -1.15 to 0.59; 194 infants; very low-certainty evidence) and one study of feeding practices reported weight nadir (MD -0.8, 95% CI -2.24 to 0.64; 46 infants; very low-certainty evidence)., Authors' Conclusions: We are uncertain whether non-pharmacological care for opioid withdrawal in newborns affects important clinical outcomes including length of hospitalization and use of pharmacological treatment based on the six included studies. The outcomes identified for this review were of very low- to low-certainty evidence. Combined analysis was limited by heterogeneity in study design and intervention definitions as well as the number of studies. Many prespecified outcomes were not reported. Although caregivers are encouraged by experts to optimize non-pharmacological care for opioid withdrawal in newborns prior to initiating pharmacological care, we do not have sufficient evidence to inform specific clinical practices. Larger well-designed studies are needed to determine the effect of non-pharmacological care for opioid withdrawal in newborns., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: A wrong traditional belief persists among people that opium consumption beneficially affects cardiovascular disease and its risk factors. However, no evidence exists regarding the effect of opium consumption or cessation on the long-term risk of major adverse cardio-cerebrovascular events after coronary artery bypass grafting. We therefore aimed to evaluate the effect of persistent opium consumption after surgery on the long-term outcomes of coronary artery bypass grafting., Methods: The study population consisted of 28,691 patients (20,924 men, mean age 60.9 years), who underwent coronary artery bypass grafting between 2007 and 2016 at our centre. The patients were stratified into three groups according to the status of opium consumption: never opium consumers ( n  = 23,619), persistent postoperative opium consumers ( n  = 3636) and enduring postoperative opium withdrawal ( n  = 1436). Study endpoints were 5-year mortality and 5-year major adverse cardio-cerebrovascular events, comprising all-cause mortality, acute coronary syndrome, cerebrovascular accident and revascularisation., Results: After surgery, 3636 patients continued opium consumption, while 1436 patients persistently avoided opium use. The multivariable survival analysis demonstrated that persistent post-coronary artery bypass grafting opium consumption increased 5-year mortality and 5-year major adverse cardio-cerebrovascular events by 28% (hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.06-1.54; P  = 0.009) and 25% (HR 1.25, 95% CI 1.13-1.40; P  < 0.0001), respectively. It also increased the 5-year risk of acute coronary syndrome by 34% (sub-distribution HR 1.34, 95% CI 1.16-1.55; P  < 0.0001)., Conclusions: The present data suggest that persistent post-coronary artery bypass grafting opium consumption may significantly increase mortality, major adverse cardio-cerebrovascular events and acute coronary syndrome in the long term. Future studies are needed to confirm our findings.

Background: Environmentally induced epigenetic changes can lead to health problems or disease, but the mechanisms involved remain unclear. Morphine can pass through the placental barrier leading to abnormal embryo development. However, the mechanism by which morphine causes these effects and how they sometimes persist into adulthood is not well known. To unravel the morphine-induced chromatin alterations involved in aberrant embryo development, we explored the role of the H3K27me3/PRC2 repressive complex in gene expression and its transmission across cellular generations in response to morphine., Results: Using mouse embryonic stem cells as a model system, we found that chronic morphine treatment induces a global downregulation of the histone modification H3K27me3. Conversely, ChIP-Seq showed a remarkable increase in H3K27me3 levels at specific genomic sites, particularly promoters, disrupting selective target genes related to embryo development, cell cycle and metabolism. Through a self-regulatory mechanism, morphine downregulated the transcription of PRC2 components responsible for H3K27me3 by enriching high H3K27me3 levels at the promoter region. Downregulation of PRC2 components persisted for at least 48 h (4 cell cycles) following morphine removal, though promoter H3K27me3 levels returned to control levels., Conclusions: Morphine induces targeting of the PRC2 complex to selected promoters, including those of PRC2 components, leading to characteristic changes in gene expression and a global reduction in H3K27me3. Following morphine removal, enhanced promoter H3K27me3 levels revert to normal sooner than global H3K27me3 or PRC2 component transcript levels. We suggest that H3K27me3 is involved in initiating morphine-induced changes in gene expression, but not in their maintenance. Model of Polycomb repressive complex 2 (PRC2) and H3K27me3 alterations induced by chronic morphine exposure. Morphine induces H3K27me3 enrichment at promoters of genes encoding core members of the PRC2 complex and is associated with their transcriptional downregulation.

Background: The prevalence of opiate use among pregnant women can range from 1% to 2% to as high as 21%. Just in the United States alone, among pregnant women with hospital delivery, a fourfold increase in opioid use is reported from 1999 to 2014 (Haight 2018). Heroin crosses the placenta, and pregnant, opiate-dependent women experience a six-fold increase in maternal obstetric complications such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neuro-behavioural problems, increased neonatal mortality and a 74-fold increase in sudden infant death syndrome. This is an updated version of the original Cochrane Review first published in 2008 and last updated in 2013., Objectives: To assess the effectiveness of any maintenance treatment alone or in combination with a psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions alone for child health status, neonatal mortality, retaining pregnant women in treatment, and reducing the use of substances., Search Methods: We updated our searches of the following databases to February 2020: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs)., Selection Criteria: Randomised controlled trials which assessed the efficacy of any pharmacological maintenance treatment for opiate-dependent pregnant women., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane., Main Results: We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow-release morphine. Three out of four studies had adequate allocation concealment and were double-blind. The major flaw in the included studies was attrition bias: three out of four had a high dropout rate (30% to 40%), and this was unbalanced between groups. Methadone versus buprenorphine: There was probably no evidence of a difference in the dropout rate from treatment (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.37 to 1.20, three studies, 223 participants, moderate-quality evidence). There may be no evidence of a difference in the use of primary substances between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.68, two studies, 151 participants, low-quality evidence). Birth weight may be higher in the buprenorphine group in the two trials that reported data MD;-530.00 g, 95%CI -662.78 to -397.22 (one study, 19 particpants) and MD: -215.00 g, 95%CI -238.93 to -191.07 (one study, 131 participants) although the results could not be pooled due to very high heterogeneity (very low-quality of evidence). The third study reported that there was no evidence of a difference. We found there may be no evidence of a difference in the APGAR score (MD: 0.00, 95% CI -0.03 to 0.03, two studies,163 participants, low-quality evidence). Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, may not differ between groups (RR 1.19, 95% CI 0.87 to1.63, three studies, 166 participants, low-quality evidence). Only one study which compared methadone with buprenorphine reported side effects. We found there may be no evidence of a difference in the number of mothers with serious adverse events (AEs) (RR 1.69, 95% CI 0.75 to 3.83, 175 participants, low-quality evidence) and we found there may be no difference in the numbers of newborns with serious AEs (RR 4.77, 95% CI 0.59, 38.49,131 participants, low-quality evidence). Methadone versus slow-release morphine: There were no dropouts in either treatment group. Oral slow-release morphine may be superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants, low-quality evidence). In the comparison between methadone and slow-release morphine, no side effects were reported for the mother. In contrast, one child in the methadone group had central apnoea, and one child in the morphine group had obstructive apnoea (low-quality evidence)., Authors' Conclusions: Methadone and buprenorphine may be similar in efficacy and safety for the treatment of opioid-dependent pregnant women and their babies. There is not enough evidence to make conclusions for the comparison between methadone and slow-release morphine. Overall, the body of evidence is too small to make firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Activity of compound GSB-106, a low-molecular mimetic of loop 4 of the brain neurotrophic factor (BDNF), was studied in experimental morphine withdrawal syndrome simulated in outbred rats. Single and subchronic (5 intraperitoneal injections) administration of GSB-106 in a dose of 0.1 mg/kg significantly reduced the total index of morphine withdrawal syndrome by 55.2 and 45.6%, respectively. GSB-106 reduced the severity of some behavioral signs (piloerection, gnashing of teeth, wet-dog shaking, and runaway attempts), but had no effect on mechanical allodynia formed in the rats with dependence. Subchronic treatment with GSB-106 prevented the increase in the content of ΔFosB (product of early response gene) in the striatum induced by morphine withdrawal. The results confirmed the concept on the involvement of neurotrophins, specifically BDNF and its analogs, in the mechanisms associated with the formation of opiate dependence.

The extended occurrence of fentanils abuse associated with the dramatic increase in opioid fatal overdoses and dependence strongly emphasizes insufficiencies in opioid addiction treatment. Recently, the growth hormone secretagogue receptor (GHS-R1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in opioid abuse is still unclear. Therefore, the aim of our study was to clarify whether the GHS-R1A antagonist JMV2959 could reduce the fentanyl-induced conditioned place preference (CPP), the fentanyl intravenous self-administration (IVSA), and the tendency to relapse, but also whether JMV2959 could significantly influence the fentanyl-induced dopamine efflux in the nucleus accumbens (NAC) in rats, that importantly participates in opioids' reinforcing effects. Following an ongoing fentanyl self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 minutes before three consequent daily 360-minute IVSA sessions under a fixed ratio FR1, which significantly reduced the number of active lever-pressing, the number of infusions, and the fentanyl intake. Pretreatment with JMV2959 also reduced the fentanyl-seeking/relapse-like behaviour tested in rats on the 12 th day of the forced abstinence period. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of fentanyl-CPP. The fentanyl-CPP development was reduced after the simultaneous administration of JMV2959 with fentanyl during conditioning. The JMV2959 significantly reduced the accumbens dopamine release induced by subcutaneous and intravenous fentanyl. Simultaneously, it affected the concentration of byproducts associated with dopamine metabolism in the NAC. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of fentanyl., (© 2019 Society for the Study of Addiction.)

Background: Opiate exposure during adolescence perturbs the brain's maturation process and potentially confers long-term adverse consequences, not only in exposed individuals but also in their posterity. Here, we investigate the outcomes of adolescent paternal morphine exposure on morphine withdrawal profile in male offspring., Methods: Male Wistar rats were chronically subjected to 10 days of an escalating regimen of morphine during adolescence. After a 20-day washout period, adult males were allowed to copulate with naïve females. The adult male offspring were tested for somatic and affective components of naloxone-precipitated morphine withdrawal using conditioned place aversion. Moreover, electrical activity of the lateral paragigantocellularis (LPGi) nucleus, which is involved in development of opiate dependence, was recorded in response to a challenge dose of morphine via extracellular single-unit recordings., Results: Morphine-sired offspring exhibited augmented expression of naloxone-induced somatic and affective signs of opiate withdrawal compared to the control saline-sired counterparts. In vivo recording revealed that LPGi neurons displayed heterogeneous responses (inhibitory, excitatory, and no change) to acute morphine administration in both morphine- and saline-sired animals. The morphine-induced discharge inhibition was potentiated in morphine-sired offspring. However, the extent of discharge excitation in response to morphine did not reach significance in these subjects. Moreover, the lack of alteration in maternal behavior toward morphine-sired offspring indicates that this is due to germline-dependent transmission of epigenetic traits across generations., Conclusions: Preconception paternal exposure to morphine during adolescence potentiates opiate withdrawal signs in male offspring which is mediated, at least in part, by epigenetic alteration of LPGi-related brain circuitry.

Patients receiving vinca alkaloids for hematological malignancies frequently experience constipation that is unresponsive to laxatives. Research on treatment of vinca alkaloid-induced constipation is limited. This study aimed to determine whether the chloride channel activator lubiprostone ameliorates vinca alkaloid-induced constipation in patients with hematological malignancies. In this retrospective cohort study, vinca alkaloid-induced constipation (grade ≥ 3 using the Common Terminology Criteria for Adverse Events) was investigated in patients treated for hematological malignancies between July 2014 and June 2019 who had already been prescribed osmotic laxatives and additionally received either a stimulant laxative or lubiprostone. Univariate and multivariate analyses were performed to identify the risk factors for persistent constipation after introduction of the second laxative. A propensity score model was used to match 67 patients taking a stimulant laxative and 67 treated with lubiprostone, and the occurrence of intractable constipation was compared between groups. Overall, 203 patients were included, among whom 50 (25%) had constipation. On multivariate analysis, body mass index, opioid use, and addition of lubiprostone were independently associated with constipation. Patients treated with lubiprostone were significantly less likely to experience intractable constipation than did those treated with stimulant laxatives (10% vs. 34%, P = 0.002). Moreover, post-constipation diarrhea was significantly less frequent among patients treated with lubiprostone (42% vs. 63%, P = 0.024). Lubiprostone was more effective than stimulant laxatives at treating vinca alkaloid-induced intractable constipation in patients with hematological malignancies, and its use could enable safe vinca alkaloid chemotherapy.

This study investigated the effects of minocycline microinjections, into the midbrain periaqueductal gray (PAG), on morphine withdrawal and the expression of pannexin-1 (panx1), phosphorylated mammalian target of rapamycin (p-mTOR), protein kinase A (PKA), and cAMP response element-binding protein (CREB). Rats were injected with morphine, intraperitoneally, at increasing doses, twice per day, to establish animal models of morphine exposure. Minocycline was administered into the PAG before the first intraperitoneal (i.p.) injection of morphine each day, on days 1-4. On the last day of the experiment, all rats were injected with naloxone, and morphine withdrawal was observed, and then changes in the expression levels of ionized calcium-binding adaptor molecule 1 (Iba1) and its downstream factors, panx1, p-mTOR, PKA, and CREB were evaluated by western blot and immunohistochemistry analyses. Morphine withdrawal increased microglial activation, whereas minocycline could inhibit microglial activation and withdrawal and the downregulation of panx1, p-mTOR, PKA, and CREB expression, reducing the effects of morphine withdrawal., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A number of recent studies have investigated the optimal dosage and timing of dexamethasone in total hip arthroplasty (THA) but have inconsistent findings. Therefore, we designed the randomized controlled research to look for the optimal intravenous dexamethasone dose for the treatment of early postoperative pain after the THA., Methods: The Declaration of Helsinki principles was followed and the Consolidated Standards of Reporting Trials guidelines for randomized controlled trials was adhered in this study. The First Medical Center in People's Liberation Army General Hospital approved the study (2020-089). After written informed consent was obtained, patients aged between 18 and 80 years with Physical Status I to III of American Society of Anesthesiologists, scheduled for primary unilateral THA, were included in this present work. Randomization is the use of a computer-formed list via a secretary, at a ratio of 1:1:1. The major end points were pain scores at 24 hours, 48 hours, and 72 hours after surgery, with visual analog scale (VAS) utilized at rest, and at 45 degrees passive hip flexion. The secondary outcomes involved the total consumption of morphine, opioid-related side effects, hip range of motion, inflammation markers, and the length of hospital stay., Results: We assumed that the patients who received 3 doses of dexamethasone intravenously possessed the best postoperative results compared to those who received 1 or 2 doses of the dexamethasone., Trial Registration: This study protocol was registered in Research Registry (researchregistry5864).

To improve surgical pain control through cryoablation of intercostal nerves and reduce narcotic usage in patients undergoing open thoracic or thoracoabdominal aortic aneurysm (TAA or TAAA) repair. From 2012 to 2018, 117 patients underwent open repair of TAA or TAAA. Of those patients, 25 (21%) received cryoablation (2016-2018) of their intercostal nerves and 92 (79%) did not (2012-2018). The primary outcome was pain scores and narcotic usage from extubation day 1 to 10 or the day of discharge. The median age (57 years), demographics, and preoperative comorbidities were not significantly different between the 2 groups. The cryoablation group had significantly more incidences of thoracoabdominal incisions (52% vs 28%), urgent operations (32% vs 11%), and longer duration of chest tubes compared to the noncryoablation group (all P < 0.05). T9-T12 intercostal arteries were selectively reimplanted. Left intercostal nerves were cryoablated from T3 to T9 if 2 thoracotomies were used; or 2 intercostal spaces above and below the thoracotomy if 1 thoracotomy was used. There were no significant differences between the noncryoablation and cryoablation groups in postoperative stroke, paraplegia (5%), pneumonia, and in-hospital mortality (0.9%). However, the average usage of narcotics was significantly reduced in the cryoablation group by 28 measured morphine equivalents (equal to four 5 mg Oxycodone)/patient/day in 10 days after extubation, P = 0.005. With cryoablation of intercostal nerves, the postoperative surgical pain was well controlled and narcotic usage was significantly decreased after TAA or TAAA repair. Cryoablation of intercostal nerves was a safe and effective measure for postoperative pain control in TAA or TAAA repair., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The present opioid epidemic and abuse of fentanyl in the United States has led to an increased risk of exposure to first responders. Law enforcement, fire, and emergency medical services are receiving misinformation on fentanyl health and safety risks and this has led to miscommunication. Understanding the risk perceptions and knowledge of first responders regarding fentanyl can help identify training gaps., Methods: A 15-item 6-point Likert scale online questionnaire was developed and distributed to firefighters, police officers, and emergency medical technicians, regarding perceptions of fentanyl exposure, and additional questions concerning knowledge. The online questionnaire was sent to 15 associations of national and New York State first responders with 3 associations acknowledging and distributing the survey., Results: Of the 247 participants, 187 served New York State; 92 worked in law enforcement; and the other 95 worked in either fire, emergency medical service, or both. New York State first responders generally agreed with expert risk perceptions and knowledge of fentanyl exposure in the pilot study. Items pertaining to using hand sanitizer, selecting glove type, and dermal exposure to fentanyl had lower agreement with expert beliefs., Conclusions: Risk perceptions and knowledge could be used to evaluate fentanyl response training among first responders.

Background: The use of IV narcotic analgesics (IVNA) within the context of vascular procedures is not fully described. We sought to evaluate the burden of IVNA including narcotic analgesia-related adverse drug events (NARADE), associated mortality and hospitalization cost in open and endovascular vascular procedures, and to compare it with nonnarcotic analgesia (IVNNA)., Methods: Retrospective cross-sectional study in hospitals participating in Premier database (2009-2015). Logistic regression analysis was implemented to report the risks of NARADE and in-hospital mortality. Negative binomial regression was used to assess length of stay and generalized linear modeling was used to estimate the hospitalization cost., Results: A total of 171,473 patients were identified. NARADE occurred in 6.2% of the cohort. NARADE group was similar in gender and race but was slightly older (median age 71 vs. 70; P < 0.001). After risk-adjustment, NARADE risk was higher in patients who received IVNA-alone in carotid and lower extremity revascularization (LER) [OR (odds ratio) (95% confidence interval [CI]): 1.17 (1.02-1.34) and 1.31 (1.14-1.50)] or combined with IVNNA [OR (95% CI): 1.34 (1.13-1.59) and 1.81 (1.54-2.13)], respectively. Patients receiving aortic repair benefited from the use of IVNA + IVNNA [OR (95% CI): 0.82 (0.69-0.98)]. Occurrence of NARADE doubled the LOS, amplified mortality risk and increased cost in all domains. NARADE increased the odds of mortality by 24.3, 6.5 (4.9-8.68) and 16.6 times and added $5,368, $12,737 and $11,349 to the cost of carotid, aortic and LER interventions, respectively. In contrast, IVNNA was not associated with NARADE risk, increased LOS or cost and showed a survival benefit in patients undergoing open aortic repair [aOR (95% CI): 0.52 (0.36-0.75)]., Conclusions and Relevance: The use of opioid-based narcotics had increased the risk of NARADE, resources utilization and NARADE-related mortality. Yet the use of nonopioid-based analgesic was safe, did not increase the cost and reduced mortality in open AA repair. This entices shifting the paradigm toward exploring nonopioid-based analgesia options in order to replace or minimize opioid requirements., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Postoperative analgesia in patients undergoing transaxillary thoracic outlet decompression (TATOD) is challenging because of the invasive surgery, the complex innervation of the axillary region, and the preoperative use of opioids by many patients. Commonly, postoperative pain is managed with additional opioids that introduce well-known sideeffects. To investigate the analgesic efficacy of 2 novel regional anesthesia techniques, we performed a retrospective study comparing the combined pectoral block type 1 and erector spinae block (PECS 1 + ESB) and the pectoral block type 2 (PECS 2) and systemic intravenous opioids regimen (no block) in patients undergoing TATOD., Materials and Methods: We performed 10 PECS 1 + ESB and 10 PECS 2 blocks in patients undergoing TATOD. Twenty patients were randomly selected as controls. The primary endpoint was pain. Secondary endpoints were opioid use, nausea, and vomiting., Results: Postoperative maximal numeric rating scale scores on recovery were significantly lower in patients receiving either a PECS 1 + ESB or a PECS 2 block compared with controls without block (no block: median 6.00, interquartile range [IQR] 3.00; PECS 1 + ESB: median 4.50, IQR 4.00; PECS 2: median 4.00, IQR 5.00; P = 0.031). Postoperative intravenous morphine consumption was 43% lower in the PECS 1 + ESB group and 56% lower in the PECS 2 group compared with the group with no block (oral morphine equivalents; no block: mean 16.05 ± SD 6.79 mg; PECS 1 + ESB mean 9.05 ± SD 6.24 mg; PECS 2: mean 7.00 ± SD 6.16; P = 0.03 and P = 0.003, respectively). There was no statistical difference in both nausea and vomitus (no block 45% nausea and 30% vomitus, PECS 1 + ESB 40% nausea and 20% vomitus, PECS 2 10% nausea and 0% vomitus, P = 0.17 and P = 0.14, respectively)., Conclusions: There was a significant reduction in postoperative pain and opioid consumption for patients treated with either the PECS 1 + ESB block or PECS 2., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: For persons with substance use disorders (SUDs), 12-step groups (TSGs) are the most available and used peer-based recovery resource, worldwide. However, disengagement is common, and attrition may partly be due to practices and procedures within these groups that are unacceptable to a portion of the population with SUDs. Our overall aim was to identify problematic issues related to Narcotics Anonymous (NA) participation in Norway, to inform addiction professionals' strategies when referring persons to addiction-related self-help groups (SHGs)., Methods: In this qualitative study, we interviewed ten individuals who had previously participated regularly in NA for at least 6 months, to examine their reasons for disengagement. We interpreted the interviews using thematic analysis., Results: We identified three themes: (1) 'The model did not fit', either the strategies utilized in NA (e.g., meeting format and step working) or NA's explanatory model of addiction, (2) 'Negative experiences spurred frustration', and (3) 'The safe place can become a cage'. The respondents believed that a main aim of recovery was reintegration into society, such that SHG participation should not be an end goal, but rather a platform for normalization back into society. Despite their negative experiences and strong critique, respondents still regarded NA as a valuable recovery resource, but pointed out that one size does not fit all., Conclusion: Addiction professionals should recognize possible problems related to TSG participation, to help prevent negative experiences and possible harms to individuals. Professionals should also inform individuals about alternative support groups, to help them find the recovery resource best suited to them.

Background: Poverty, unemployment and substance abuse are inter-related problems. This study evaluated the effectiveness of abstinence-contingent wage supplements in promoting drug abstinence and employment in unemployed adults in outpatient treatment for opioid use disorder., Methods: A randomised controlled trial was conducted in Baltimore, MD, from 2014 to 2019. After a 3-month abstinence initiation and training period, participants (n=91) were randomly assigned to a usual care control group that received employment services or to an abstinence-contingent wage supplement group that received employment services plus abstinence-contingent wage supplements. All participants were invited to work with an employment specialist to seek employment in a community job for 12 months. Abstinence-contingent wage supplement participants could earn training stipends for working with the employment specialist and wage supplements for working in a community job, but had to provide opiate and cocaine-negative urine samples to maximise pay., Results: Abstinence-contingent wage supplement participants provided significantly more opiate and cocaine-negative urine samples than usual care control participants (65% vs 45%; OR=2.29, 95% CI 1.22 to 4.30, p=0.01) during the 12-month intervention. Abstinence-contingent wage supplement participants were significantly more likely to have obtained employment (59% vs 28%; OR=3.88, 95% CI 1.60 to 9.41, p=0.004) and lived out of poverty (61% vs 30%; OR=3.77, 95% CI 1.57 to 9.04, p=0.004) by the end of the 12-month intervention than usual care control participants., Conclusion: Abstinence-contingent wage supplements can promote drug abstinence and employment., Trial Registration Number: ClinicalTrials.gov NCT02487745., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Both narcotic and psychotropic drugs are more often used to alleviate related multiple physical or mental health problems, but these drugs are very easily addicted to. With the aging of population, abuse of narcotic drugs and psychotropic drugs among the elderly are called for more attention. In this paper, harms caused by the abuse of anesthetic and psychotropic drugs, current situation and causes related to the abuse of anesthetic and psychotropic drugs as well as risk factors and preventive measures regarding the abuse of anesthetic and psychotropic drugs, among the elderly, are reviewed.

Fentanyl has been FDA approval as an analgesic since 1968 and multiple different fentanyl preparations have been developed over the years. Little was known about it is clinical utility defined by risks and benefits until recently. Present commercially available preparations are easily tampered and nonpharmacologic fentanyl has become the major cause of opioid deaths in the United States. This state-ofthe-art review will discuss fentanyl pharmacology, utility, safety and abuse.

Aim: To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. Methods: This post hoc analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received methylnaltrexone subcutaneous injection or placebo. Results: Significantly more patients treated with methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Conclusion: Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. Clinical trial registration numbers: study 301: NCT00401362; study 302: NCT00402038.

Background: The goals of the study were to: (1) evaluate trends in preoperative and prolonged postoperative narcotic use in carpal tunnel release (CTR); (2) characterize risks for prolonged narcotic use; and (3) evaluate narcotic use as an independent risk factor for complications following CTR. Methods: A query of a large insurance database from 2007-2016 was conducted. Patients undergoing open or endoscopic CTR were included. Revision surgeries or patients undergoing median nerve repair at the forearm, upper extremity fasciotomies, or with distal radius fractures were excluded. Preoperative use was defined as narcotic use between 1 to 4 months prior to CTR. A narcotic prescription between 1 and 4 months after surgery was considered prolonged postoperative use. Demographics, comorbidities, and other risk factors for prolonged postoperative use were assessed using a regression analysis. Subgroup analysis was performed according to the number of preoperative narcotic prescriptions. Narcotic use as a risk factor for complications, including chronic regional pain syndrome (CRPS) and revision CTR, was assessed. Results: In total, 66 077 patients were included. A decrease in prescribing of perioperative narcotics was noted. Risk factors for prolonged narcotic use included preoperative narcotic use, drug and substance use, lumbago, and depression. Preoperative narcotics were associated with increased emergency room visits, readmissions, CRPS, and infection. Prolonged postoperative narcotic use was linked to CRPS and revision surgery. Conclusions: Preoperative narcotic use is strongly associated with prolonged postoperative use. Both preoperative and prolonged postoperative prescriptions narcotic use correlated with increased risk of complications. Preoperative narcotic use is associated with a higher risk of postoperative CRPS.

Methadone is an opioid commonly used for acute pain management in burn patients. One adverse effect of methadone is QTc interval prolongation, which may be associated with adverse cardiac outcomes. There is currently a paucity of data regarding risk of QTc prolongation in burn patients taking methadone and a lack of evidence-based recommendations for monitoring strategies in this population. The study objective was to determine the prevalence, risk factors, and cardiac outcomes related to methadone-associated QTc prolongation in adult burn patients. A total of 91 patients were included and were divided into groups according to maximum QTc. QTc prolongation was defined as greater than or equal to 470 ms (males) or 480 ms (females). There were no differences between groups regarding patient-specific risk factors, baseline QTc, or time to longest QTc. Patients in the prolonged QTc group had a higher rate of cardiac events (44% vs 9%; P < .001), higher median (IQR) change from baseline to longest QTc (61 ms [18,88] vs 23 ms [13,38]; P < .001), higher median (IQR) total daily dose of methadone (90 mg [53,98] vs 53 mg [30,75]; P = .004), and longer median (IQR) length of stay (53 [33,82] vs 35 [26,52] days; P = .008). QTc prolongation in burn patients was associated with increased methadone dose and resulted in a higher rate of cardiac events. This study was the first of its kind to look at risk factors and cardiac outcomes associated with methadone use in burn patients., (© American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To examine the school readiness of a regional cohort of prenatally methadone-exposed children across 5 domains and to examine factors contributing to impairment risk., Methods: Data were drawn from a single-center, prospective longitudinal study. One hundred children born to women in methadone maintenance treatment and 110 randomly identified non-methadone-exposed children were studied from birth (2003-2008) to age 4.5 years. At 4.5 years, children underwent comprehensive assessment of their physical/motor development, social-emotional skills, approaches to learning, language development, and cognitive functioning. Predictors of children's overall school readiness were examined, including the extent of prenatal substance exposure (number and quantity of different substances), social risk, maternal mental health, infant clinical factors, and the quality of the home environment at age 18 months Home Observation for Measurement of the Environment (HOME) score., Results: Methadone-exposed children had higher rates of delay/impairment across all outcome domains (odds ratios 4.0-5.3), with 72% impaired in at least 1 domain. Multiple problems were also common, affecting 48% of methadone-exposed children compared with 15% of control children. The mean number of school readiness domains impaired increased, with increasing prenatal substance exposure (rate ratio [RR] = 1.05 [1.01-1.11]), higher social risk (RR = 1.35 [1.20-1.53]), male sex (RR = 1.69 [1.27-2.25]), and lower HOME scores indicating a poorer quality postnatal environment (RR = 0.96 [0.94-0.99])., Conclusion: Children born to opioid-dependent mothers are at high risk of impaired school readiness, with multiple domain problems being common. Impaired school readiness was associated with greater maternal prenatal substance use, higher social risk, male sex, and lower-quality caregiving environments.

Illicit drug use contributes to substantial morbidity and mortality. Drug scheduling, a legal measure in drug enforcement, is often structured as a hierarchy based on addiction tendency, abuse trends, and harm, but may lack data-driven evidence when classifying substances. Our study aims to measure addiction tendency and use trends based on real-world data. We used the open access database of National Police Agency, Ministry of the Interior in Taiwan and analyzed all daily criminal cases of illicit drugs from 2013 to 2017 and monthly illicit drug enforcement data from the same database from 2002 to 2017. We hypothesized that repeat and frequent use despite legal consequence may be a reflection of addictive behavior, and empirical mode decomposition was applied in analysis to calculate addiction tendency indices and intrinsic 15-year use trends. Our analysis showed heroin has the highest addiction index, followed by methamphetamine. 3,4-Methyl enedioxy methamphetamine, marijuana, and ketamine had lower addictive propensities. This result is consistent with most drug scheduling hierarchies. 15-year use trends of substances were consistent with previous epidemiological studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)