Cold nociception as a measure of hyperalgesia during spontaneous heroin withdrawal in mice.

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 ß2-adrenergic receptor antagonist (butoxamine), an α2-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.

Lennox-Gastaut syndrome characterized by super-refractory status epilepticus treated with high-dose anesthetics: A case report.

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.

Efficacy and safety of tramadol in the treatment of opioid withdrawal: A meta-analysis of randomized controlled trials.

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.

Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice.

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.

Managing acute opioid withdrawal with tramadol during COVID-19 lockdown in a peri-urban setting.

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.

The effect of a methadone-initiated memory reconsolidation updating procedure in opioid use disorder: A translational study.

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).

Pediatric Outcomes following Cranial Vault Remodeling with Restricted Use of Postoperative Narcotics: A Retrospective Review.

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.

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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.

Prescrire des médicaments contenant des substances soumises à contrôle (SSC : stupéfiants et substances psychotropes) peut avoir des conséquences en matière de circulation routière. Nous présentons ici les devoirs du médecin et les risques encourus par la personne en traitement, avant de plaider pour une clarification s'agissant de médicaments pouvant influer sur la capacité ou l'aptitude à la conduite.

Admission NarxCare Narcotic Scores Are Associated With Increased Odds of Readmission and Prolonged Length of Hospital Stay After Primary Elective Total Knee Arthroplasty.

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.

Effects of the prenatal exposure to crocin in the expression of withdrawal syndrome on reflexive motor behaviors in mice offspring's.

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.

Opium and Cigarette Smoking are Independently Associated with Bladder Cancer: The Findings of a Matched Case - Control Study.

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.

Can Treatment for Substance Use Disorder Prescribe the same Substance as that Used? The Case of Injectable Opioid Agonist Treatment.

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.

Hyperbaric oxygen therapy and fluorescence angiography in arterial insufficiency secondary to injection of crushed hydromorphone.

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.

Relationships between oxygen changes in the brain and periphery following physiological activation and the actions of heroin and cocaine.

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.

The association between the score of adult attention-deficit/hyperactivity traits and risky driving behaviors with alcohol intake and narcotics consumption among Iranian motorcyclists.

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.

Drug-facilitated sexual assault and other crimes: A systematic review by countries.

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.

Automated quantification of opioid withdrawal in neonatal rat pups using Ethovision® XT software.

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; R2 > 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.

Morphine use in the neonatal period and later neuropsychological development: a systematic review.

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.