High Doses Of Morphine Research Articles

Is buprenorphine maternal dose associated with neonatal opioid withdrawal syndrome severity?

Neonatal opioid withdrawal syndrome (NOWS) is a drug withdrawal syndrome occurring mainly after in utero opioid exposure. Buprenorphine is commonly used for opioid withdrawal. Studies are conflicted about a potential dose effect OBJECTIVE: The aim of our study was to investigate the impact of buprenorphine maternal maintenance therapy on the NOWS based on NOWS duration, birth weight and therapy. We conducted a retrospective study analysing data from infants admitted for NOWS in two Neonatal Intensive Care Unit between January 2010 and December 2020. Nonpreterm infants born to mothers who were treated with buprenorphine or therapy during pregnancy and who had a Lipsitz score of 4 or higher. A total of 75 term newborns were hospitalized for the treatment of NOWS from mother substituted with buprenorphine during the study inclusion period. The duration of NOWS differed significantly between all dose cohorts, with higher doses of maternal buprenorphine maintenance correlating with longer length of NOWS duration. Infants exposed to high doses required 17 days [10; 23], while infants exposed to intermediate doses required 7 days [2; 16] and infants exposed to low doses required 3 days [2; 5], with p-values < .003. Infants exposed to high doses required a longer time to regain their birth weight and higher morphine doses as therapy compared to others. Infants exposed to low doses, intermediate doses, and high doses of buprenorphine demonstrated dose-dependent increases in the durations of hospitalization, respectively. Increased doses of maternal buprenorphine during pregnancy are correlated with NOWS severity. Our study shows that increased doses of maternal buprenorphine during pregnancy are correlated with NOWS severity. Exploring low doses and having different ranges are a new argument to define the impact of maternal buprenorphine consumption.

Impact of chronic opioid on cognitive function and spermatogenesis in rat: An experimental study.

Opioid analgesics like morphine and methadone are widely used for managing severe pain; however, concerns over their potential misuse and adverse effects on the brain and reproductive system are significant. We aimed to investigate their impacts on spermatogenesis and cognitive function in male Norway rats. In this experimental study, 36 male Norway rats (250-300 gr, 6 months old) were divided into 6 groups: low-dose morphine, high-dose morphine, low-dose methadone, high-dose methadone, positive control (received normal saline at 5 mg/kg), and negative control (received no treatment). Morphine and methadone were administered intraperitoneally over 30 days at doses of 3 mg/kg and 7 mg/kg, respectively. Behavioral assessments evaluated anxiety, stress, and short- and long-term memory. Sperm parameters (viability, motility, morphology), hormonal analysis (testosterone, luteinizing hormone, follicle-stimulating hormone, estradiol), and gene expressions (Tp53, CatSper1) were assessed. A significant reduction in rat weight was observed in the high-dose morphine group (p = 0.0045), while testicular weights remained unchanged. Sperm abnormalities were observed with high doses of methadone and morphine. High-dose methadone significantly reduced offspring count (p = 0.0004). Levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol varied significantly across treatment groups. Gene expression was altered in response to treatments (p 0.05). Prolonged exposure to methadone and morphine resulted in memory dysfunction, chronic stress, hormonal disturbances, altered gene expression, and fertility complications. These effects were more pronounced at higher doses, highlighting the importance of careful dosage management in opioid therapy.

Decision Support and Behavioral Health for Reducing High-Dose Opioids in Comorbid Chronic Pain, Depression and Anxiety: Stepped-Wedge Cluster Randomized Trial.

High prevalence of depression or anxiety with opioid use for chronic pain complicates co-management and may influence prescribing behaviors. Compare clinical effectiveness of electronic medical record clinical decision support (EMR-CDS) versus additional behavioral health (BH) care management for reducing rates of high-dose opioid prescriptions. Type 2 effectiveness-implementation hybrid stepped-wedge cluster randomized trial in 35 primary care clinics within a health system in LA, USA. Patients aged 18+ receiving chronic opioid therapy for non-cancer pain with depression or anxiety and matched controls. EMR-CDS included opioid risk mitigation procedures. BH care included cognitive behavioral therapy; depression or anxiety medication adjustments; and case management. Outcomes of interest included difference-in-difference (DID) estimate of changes in probability for prescribing high-dose morphine equivalent daily dose (MEDD ≥50 mg/day and MEDD ≥90), average MEDD, and rates of hospitalization, emergency department use, and opioid risk mitigation. Most participants were female with 3+ pain syndromes. Data analysis included 632 patients. Absolute risk differences for MEDD≥50 and ≥90 decreased post-index compared to pre-index (DID of absolute risk difference [95%CI]: -0.036 [-0.089, 0.016] and -0.029 [-0.060, 0.002], respectively). However, these differences were not statistically significant. The average MEDD decreased at a higher rate for the BH group compared to EMR-CDS only (DID rate ratio [95%CI]: 0.85 [0.77, 0.93]). There were no changes in hospitalization and emergency department utilization. The BH group had higher probabilities of new specialty referrals and prescriptions for naloxone and antidepressants. Incorporation of a multidisciplinary behavioral health care team into primary care did not decrease high-dose prescribing; however, it improved adherence to clinical guideline recommendations for managing chronic opioid therapy for non-cancer pain. ClinicalTrials.gov ID NCT03889418.

Sex differences in morphine sensitivity of neuroligin-3 knockout mice.

Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice, using locomotor activity as a proxy for differences in opioid sensitivity that may be related to the pathophysiology and treatment of autism spectrum disorders. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants.

Use of dexmedetomidine during mechanical ventilation in extremely preterm and extremely low birth weight neonates receiving morphine: A single‐center retrospective study

AbstractAnalgesia and sedation are often provided during mechanical ventilation in extremely preterm neonates. Opioids and benzodiazepines are the most frequently used agents but can have adverse effects. Dexmedetomidine, an alpha‐2 agonist, might be interesting to spare opioid and benzodiazepine use. The objective of this study was to describe a cohort of mechanically ventilated extremely, preterm infants treated with morphine with or without dexmedetomidine. This was a retrospective, observational, single‐center study in the neonatal intensive care unit of Creteil. We included preterm neonates born before 28 weeks of gestation and/or weighting less than 1000 g hospitalized between July 2017 and June 2020, on mechanical ventilation for at least 72 h and who received morphine with or without dexmedetomidine as a second‐ or third‐line treatment. We described morphine and midazolam exposure, respiratory, and digestive outcomes for patients who received dexmedetomidine and those who did not. Twenty nine preterm infants received morphine and dexmedetomidine, and 44 received morphine without dexmedetomidine. Dexmedetomidine was used in patients of 25.7 [25.1–26.7] weeks, 680 [600–750] g and significantly more often in patients with vascular complications during pregnancy (p = 0.008), intrauterine growth restriction (p = 0.01) and in patients who received higher cumulative doses of morphine (p = 0.01). Morphine and midazolam doses tended to decrease after the introduction of dexmedetomidine. Dexmedetomidine was never discontinued because of side effects. In this study, dexmedetomidine, used as a second or third‐line treatment during mechanical ventilation, was associated with a decrease in morphine and midazolam doses after introduction. Dexmedetomidine was used in a specific population of extremely preterm infants, with severe respiratory disease, who required prolonged mechanical ventilation and high morphine doses. This study highlights the need for pharmacokinetic/pharmacodynamic studies in this population, followed by randomized controlled trials and studies on the long‐term effects of dexmedetomidine to determine its place in analgosedation of ventilated preterm infants.

Sex Differences in Morphine Sensitivity of Neuroligin-3 Knockout Mice.

Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants.

Non-linear blood-brain barrier transport and dosing strategies influence receptor occupancy ratios of morphine and its metabolites in pain matrix.

Morphine is important for treatment of acute and chronic pain. However, there is high interpatient variability and often inadequate pain relief and adverse effects. To better understand variability in the dose-effect relationships of morphine, we investigated the effects of its non-linear blood-brain barrier (BBB) transport on μ-receptor occupancy in different CNS locations, in conjunction with its main metabolites that bind to the same receptor. CNS exposure profiles for morphine, M3G and M6G for clinically relevant dosing regimens based on intravenous, oral immediate- and extended-release formulations were generated using a physiology-based pharmacokinetic model of the CNS, with non-linear BBB transport of morphine. The simulated CNS exposure profiles were then used to derive corresponding μ-receptor occupancies at multiple CNS pain matrix locations. Simulated CNS exposure profiles for morphine, M3G and M6G, associated with non-linear BBB transport of morphine resulted in varying μ-receptor occupancies between different dose regimens, formulations and CNS locations. At lower doses, the μ-receptor occupancy of morphine was relatively higher than at higher doses of morphine, due to the relative contribution of M3G and M6G. At such higher doses, M6G showed higher occupancy than morphine, whereas M3G occupancy was low throughout the dose ranges. Non-linear BBB transport of morphine affects the μ-receptor occupancy ratios of morphine with its metabolites, depending on dose and route of administration, and CNS location. These predictions need validation in animal or clinical experiments, to understand the clinical implications.

Fentanyl Analogs Exert Antinociceptive Effects via Sodium Channel Blockade in Mice.

The formalin test is one approach to studying acute pain in rodents. Similar to formalin, injection with glutamate and veratrine can also produce a nociceptive response. This study investigated whether opioid-related compounds could suppress glutamate- and veratrine-induced nociceptive responses in mice at the same dose. The administration of morphine (3 mg/kg), hydromorphone (0.4 mg/kg), or fentanyl (0.03 mg/kg) suppressed glutamate-induced nociceptive response, but not veratrine-induced nociceptive response at the same doses. However, high doses of morphine (10 mg/kg), hydromorphone (2 mg/kg), or fentanyl (0.1 mg/kg) produced a significant reduction in the veratrine-induced nociceptive response. These results indicate that high doses are required when using morphine, hydromorphone, or fentanyl for sodium channel-related neuropathic pain, such as ectopic activity. As a result, concerns have arisen about overdose and abuse if the dose of opioids is steadily increased to relieve pain. In contrast, trimebutine (100 mg/kg) and fentanyl analog isobutyrylfentanyl (iBF; 0.1 mg/kg) suppressed both glutamate- and veratrine-induced nociceptive response. Furthermore, nor-isobutyrylfentanyl (nor-iBF; 1 mg/kg), which is a metabolite of iBF, suppressed veratrine-induced nociceptive response. Besides, the optimal antinociceptive dose of iBF, unlike fentanyl, only slightly increased locomotor activity and did not slow gastrointestinal transit. Cancer pain is a complex condition driven by inflammatory, neuropathic, and cancer-specific mechanisms. Thus, iBF may have the potential to be a superior analgesic than fentanyl.

The reinstatement of the expression phase of morphine-induced conditioned place preference in male Wistar rats under ventral tegmental area stimulation and brief inactivation.

Previous research has found that the electrical stimulation of the ventral tegmental area (VTA) is involved in drug-dependent behaviors and plays a role in reward-seeking. However, the mechanisms remain unknown, especially the effect of electrical stimulation on this area. Therefore, this study aimed to investigate how the electrical stimulation and the temporary inactivation of VTA affect the morphine- dependent behavior in male rats. The adult Wistar male rats were anesthetized with ketamine and xylazine. The stimulation electrode (unilaterally) and the microinjection cannula (bilaterally) were implanted into the VTA, stereotaxically. Then, the rats underwent three-day of repeated conditioning with subcutaneous morphine (0.5 or 5 mg/kg) injections, in the conditioned place preference apparatus, followed by four-day forced abstinence, which altered their conditioning response to a morphine (0.5 mg/kg) priming dose on the ninth day. On that day, rats were given high- or low-intensity electrical stimulation or reversible inactivation with lidocaine (0.5 pL/site) in the VTA. Results showed that the electrical stimulation of the VTA with the high intensity (150 μA/rat), had a minimal effect on the expression of morphine-induced place conditioning in rats treated with a high dose (5 mg/kg) of morphine. However, the reversible inactivation of the VTA with lidocaine greatly increased place preference in rats treated with a low dose (0.5 mg/kg) of morphine. Additionally, the reinstatement of 0.5 mg/kg morphine-treated rats was observed after lidocaine infusion into the VTA. These results suggest that VTA electrical stimulation suppresses neuronal activation, but the priming dose causes reinstatement. The VTA may be a potential target for deep brain stimulation-based treatment of intractable disorders induced by substance abuse.

The effects of chronic high-dose morphine on microgliosis and the microglial transcriptome in rat spinal cord.

Background: Opioids are efficacious and safe analgesic drugs in short-term use for acute pain but chronic use can lead to tolerance and dependence. Opioid-induced microglial activation may contribute to the development of tolerance and this process may differ between males and females. A link is suggested between this microglial activation and inflammation, disturbances of circadian rhythms, and neurotoxic effects. We set out to further delineate the effects of chronic morphine on pain behaviour, microglial and neuronal staining, and the transcriptome of spinal microglia, to better understand the role of microglia in the consequences of long-term high-dose opioid administration. Experimental Approach: In two experiments, we administered increasing subcutaneous doses of morphine hydrochloride or saline to male and female rats. Thermal nociception was assessed with the tail flick and hot plate tests. In Experiment I, spinal cord (SC) samples were prepared for immunohistochemical staining for microglial and neuronal markers. In Experiment II, the transcriptome of microglia from the lumbar SC was analysed. Key Results: Female and male rats had similar antinociceptive responses to morphine and developed similar antinociceptive tolerance to thermal stimuli following chronic increasing high doses of s.c. morphine. The area of microglial IBA1-staining in SC decreased after 2weeks of morphine administration in both sexes. Following morphine treatment, the differentially expressed genes identified in the microglial transcriptome included ones related to the circadian rhythm, apoptosis, and immune system processes. Conclusions: Female and male rats showed similar pain behaviour following chronic high doses of morphine. This was associated with decreased staining of spinal microglia, suggesting either decreased activation or apoptosis. High-dose morphine administration also associated with several changes in gene expression in SC microglia, e.g., those related to the circadian rhythm (Per2, Per3, Dbp). These changes should be considered in the clinical consequences of long-term high-dose administration of opioids.

Predicting favorable response to intravenous morphine in pediatric critically ill cardiac patients.

Analgesia and sedation are integral to the care of critically ill children. However, the choice and dose of the analgesic or sedative drug is often empiric, and models predicting favorable responses are lacking. We aimed to compute models to predict a patient's response to intravenous morphine. We retrospectively analyzed data from consecutive patients admitted to the Cardiac Intensive Care Unit (January 2011-January 2020) who received at least one intravenous bolus of morphine. The primary outcome was a decrease in the State Behavioral Scale (SBS) ≥1 point; the secondary outcome was a decrease in the heart rate Z-score (zHR) at 30 min. Effective doses were modeled using logistic regression, Lasso regression, and random forest modeling. A total of 117,495 administrations of intravenous morphine among 8140 patients (median age 0.6 years [interquartile range [IQR] 0.19, 3.3]) were included. The median morphine dose was 0.051 mg/kg (IQR 0.048, 0.099) and the median 30-day cumulative dose was 2.2 mg/kg (IQR 0.4, 15.3). SBS decreased following 30% of doses, did not change following 45%, and increased following 25%. The zHR significantly decreased after morphine administration (median delta-zHR -0.34 [IQR-1.03, 0.00], p < 0.001). The following factors were associated with favorable response to morphine: A concomitant infusion of propofol, higher prior 30-day cumulative dose, being invasively ventilated and/or on vasopressors. Higher morphine dose, higher zHR pre-morphine, an additional analgosedation bolus ±30 min around the index bolus, a concomitant ketamine or dexmedetomidine infusion, and showing signs of withdrawal syndrome were associated with unfavorable response. Logistic regression (area under the receiver operating characteristic [ROC] curve [AUC] 0.900) and machine learning models (AUC 0.906) performed comparably, with a sensitivity of 95%, specificity of 71%, and negative predictive value of 97%. Statistical models identify 95% of effective intravenous morphine doses in pediatric critically ill cardiac patients, while incorrectly suggesting an effective dose in 29% of cases. This work represents an important step toward computer-aided, personalized clinical decision support tool for sedation and analgesia in ICU patients.

Sex differences in the impact of pain, morphine administration and morphine withdrawal on quality of life in rats

The disruptive effects of pain on quality of life are greater in men than in women, but the disruptive effects of opioid administration and withdrawal tend to be greater in women. These sex differences in pain, acute opioid effects, and opioid withdrawal tend to be opposite to sex differences reported in laboratory rats. We hypothesized that sex differences in humans and rats would more closely align if animal research measured quality of life as opposed to traditional evoked behaviors of pain (e.g., nociceptive reflexes) and opioid withdrawal (e.g., wet dog shakes). The present study assessed quality of life in adult female and male rats by measuring voluntary wheel running in the rat's home cage. Hindpaw inflammation induced by administration of Complete Freund's Adjuvant (CFA) into the right hindpaw caused a greater depression of wheel running in male compared to female rats. Twice daily injections of high morphine doses (5–20 mg/kg) and the subsequent morphine withdrawal caused a greater depression of wheel running in female compared to male rats. These sex differences are consistent with human data that shows the impact of pain on quality of life is greater in men than women, but the negative effects of opioid administration and withdrawal are greater in women. The present data indicate that the clinical significance of animal research would be enhanced by shifting the endpoint from pain and opioid evoked behaviors to measures of quality of life such as voluntary wheel running.

Effect of Exosomal Protein Expression and Electrochemical Nano Interface in Morphine Analgesia Tolerance.

The current understanding of neurons cannot well explain the phenomenon of morphine tolerance, and even if some neuronal drugs are used in combination with morphine, they cannot achieve good results. In recent years, exosomal proteins have been the role of morphine tolerance and morphine-induced hyperalgesia is becoming more and more important. In clinical application, a larger dose is needed to achieve the desired analgesic effect, and large doses of morphine will aggravate the adverse drug reactions. The purpose of this experiment is to explore the role and mechanism of exosomal protein expression and electrochemical nanointerface in morphine analgesic tolerance and provide a theoretical basis for the application of exosomal protein in the clinical prevention and treatment of morphine tolerance. In this paper, adult male rats were randomly divided into groups and analyzed from four aspects: enhancing the analgesic effect of high-dose morphine, preventing morphine tolerance, the effect of morphine-induced hyperalgesia, and changes in mRNA levels of related genes. Experiments have shown that the mRNA levels of exosomal protein-related genes in the spinal cord of morphine-tolerant rats are significantly increased, and the rats given exosome protein inhibitors can prolong morphine analgesia and relieve morphine tolerance and hyperalgesia in behavior. It can inhibit the increase of exosomal protein-related genes. It shows that low-dose long-term morphine treatment can cause spinal endoplasmic reticulum stress, and the exosomal protein inhibitor 4-PBA or TUDCA can enhance the analgesic effect of morphine in neuropathic pain.

Effect of Exosomal Protein Expression and Electrochemical Nano Interface in Morphine Analgesia Tolerance.

The current understanding of neurons cannot well explain the phenomenon of morphine tolerance, and even if some neuronal drugs are used in combination with morphine, they cannot achieve good results. In recent years, exosomal proteins have been the role of morphine tolerance and morphine-induced hyperalgesia is becoming more and more important. In clinical application, a larger dose is needed to achieve the desired analgesic effect, and large doses of morphine will aggravate the adverse drug reactions. The purpose of this experiment is to explore the role and mechanism of exosomal protein expression and electrochemical nanointerface in morphine analgesic tolerance and provide a theoretical basis for the application of exosomal protein in the clinical prevention and treatment of morphine tolerance. In this paper, adult male rats were randomly divided into groups and analyzed from four aspects: enhancing the analgesic effect of high-dose morphine, preventing morphine tolerance, the effect of morphine-induced hyperalgesia, and changes in mRNA levels of related genes. Experiments have shown that the mRNA levels of exosomal protein-related genes in the spinal cord of morphine-tolerant rats are significantly increased, and the rats given exosome protein inhibitors can prolong morphine analgesia and relieve morphine tolerance and hyperalgesia in behavior. It can inhibit the increase of exosomal protein-related genes. It shows that low-dose long-term morphine treatment can cause spinal endoplasmic reticulum stress, and the exosomal protein inhibitor 4-PBA or TUDCA can enhance the analgesic effect of morphine in neuropathic pain.

Effects of cyanocobalamin and its combination with morphine on neuropathic rats and the relationship between these effects and thrombospondin-4 expression.

BackgroundThrombospondin-4 (TSP4) upregulates in the spinal cord following peripheral nerve injury and contributes to the development of neuropathic pain (NP). We investigated the effects of cyanocobalamin alone or in combination with morphine on pain and the relationship between these effects and spinal TSP4 expression in neuropathic rats.MethodsNP was induced by chronic constriction injury (CCI) of the sciatic nerve. Cyanocobalamin (5 and 10 mg/kg/day) was administered 15 days before CCI and then for 4 and 14 postoperative days. Morphine (2.5 and 5 mg/kg/day) was administered only post-CCI. Combination treatment included cyanocobalamin and morphine, 10 and 5 mg/kg/day, respectively. All drugs were administered intraperitoneally. Nociceptive thresholds were detected by esthesiometer, analgesia meter, and plantar test, and TSP4 expression was assessed by western blotting and fluorescence immunohistochemistry.ResultsCCI decreased nociceptive thresholds in all tests and induced TSP4 expression on the 4th postoperative day. The decrease in nociceptive thresholds persisted except for the plantar test, and the increased TSP4 expression reversed on the 14th postoperative day. Cyanocobalamin and low-dose morphine alone did not produce any antinociceptive effects. High-dose morphine improved the decreased nociceptive thresholds in the esthesiometer when administered alone but combined with cyanocobalamin in all tests. Cyanocobalamin and morphine significantly induced TSP4 expression when administered alone in both doses for 4 or 14 days. However, this increase was less when the two drugs are combined.ConclusionsThe combination of cyanocobalamin and morphine is more effective in antinociception and partially decreased the induced TSP4 expression compared to the use of either drug alone.

Effects of Pharmacologic Treatment for Neonatal Abstinence Syndrome on DNA Methylation and Neurobehavior: A Prospective Cohort Study

To determine whether pharmacologic treatment for neonatal abstinence syndrome (NAS) is associated with changes in DNA methylation (DNAm) of the mu-opioid receptor gene (OPRM1) and improvements in neonatal neurobehavior. Buccal swabs were collected from 37 neonates before and after morphine treatment for NAS. Genomic DNA was extracted, and DNAm was examined at 4 cytosine-phosphate-guanine (CpG) sites within the OPRM1 gene. Assessment with the NICU Network Neurobehavioral Scales (NNNS) was also performed before and after NAS treatment. Changes in DNAm (DNAmpost-tx - DNAmpre-tx) and NNNS summary scores (NNNSpost-tx - NNNSpre-tx) were then calculated. Path analysis was used to examine associations among pharmacologic treatment (length of treatment [LOT] and total dose of morphine), changes in DNAm, and changes in NNNS summary scores. DNAm was significantly decreased from pretreatment to post-treatment at 1 of 4 CpG sites within the OPRM1 gene. Neonates also demonstrated decreased excitability, hypertonia, lethargy, signs of stress and abstinence, and increased quality of movement and regulation from pretreatment to post-treatment. Longer LOT and higher morphine dose were associated with greater decreases in DNAm; greater decreases in DNAm were associated with greater decreases in excitability and hypertonia on the NNNS. Pharmacologic treatment of NAS is associated with decreased DNAm of the OPRM1 gene and improved neonatal neurobehavior. Epigenetic changes may play a role in these changes in neonatal neurobehavior.

Evaluating the Antinociceptive Efficacy of Cannabidiol Alone or in Combination with Morphine Using the Formalin Test in Male and Female Mice.

Introduction: Phytocannabinoids have emerged as a potential alternative treatment option for individuals experiencing persistent pain. However, evidence-based research regarding their clinical utility in both males and females remains incomplete. In addition, it is unknown whether combining readily available cannabinoids with opioids has a synergistic or subadditive effect on pain modulation. To begin to fill this knowledge gap, we investigated the antinociceptive effects of the phytocannabinoid, CBD, either alone or in combination with opioids in male and female C57BL/6J mice. Results: Using the formalin test, our results show that CBD (10 mg/kg, i.p.) treatment evoked antinociception in phase I, but not in phase II, of the formalin test in male mice. However, in female mice, CBD showed no significant antinociceptive effect. In addition, a direct sex comparison showed that CBD evoked a significant increase in nociceptive behaviors in female versus male mice during phase I of the formalin test. Furthermore, we show that CBD (10 mg/kg, i.p.) in combination with low-dose morphine (1 mg/kg, i.p.) was ineffective at eliciting a synergistic antinociceptive response in both male and female mice. Lastly, consistent with previous literature, we showed that females treated with a relatively higher dose of morphine (10 mg/kg, i.p.) displayed a significant increase in the variability of nociceptive behaviors compared to morphine-treated male mice. Conclusion: Overall, our results suggest that CBD treatment may have beneficial antinociceptive effects during the acute phase of persistent pain, but these effects are more beneficial to males than females. We provide further pre-clinical support that treatments geared toward reducing nociceptive behaviors differentially affect males and females.

Efficacy of Perioperative Administration of Intravenous Parecoxib on Postoperative Morphine Consumption after Video-Assisted Thoracoscopic Surgery

Background: Morphine is commonly used to relief pain after video-assisted thoracoscopic surgery (VATS), however high dose morphine is usually related with many complications. Parecoxib is a potent cyclo-oxygenase inhibitor for parenteral administration that has a role in acute pain management addition to opioid protocol. Objective: To investigate the potential benefits of intravenous parecoxib for relieving postoperative pain after VATS. Materials and Methods: The present study was a randomized controlled trial that assigned 22 patients undergoing VATS into two groups to received either parecoxib 40 mg as P group with 11 patients, or placebo using 2 mL of Normal Saline Solution as C group with 11 patients with an intravenous administration at 30 minutes prior to surgery and then 12 hours later. In the postoperative period, all patients received intravenous patient-controlled analgesia (PCA) with morphine. The primary outcome was the total morphine consumption for 24 hours postoperatively. The secondary outcomes were pain score at 2, 6, 12, and 24 hours postoperatively, using a numeric rating scale (NRS, 0 to 10) and the incidence of side effects. Results: The total morphine consumption was significantly lower in P group (26.64±4.41 mg) than C group (39.82±3.87 mg) at 24 hours postoperatively (p&lt;0.001). The NRS pain score at rest and on coughing at 24 hours postoperatively between P group compared with C group were 1.09±1.04 versus 4.45±0.69 (p&lt;0.001) and 2.91±0.83 versus 5.36±0.81 (p&lt;0.001), respectively. The incidences of nausea and vomiting were found in both groups at 2, 6, and 12 hours, postoperatively, but there was no statistically significant difference between both groups (p&gt;0.05). Other adverse events such as sedation, pruritus, dyspepsia, headache, hypotension, and respiratory depression were not found. Conclusion: Perioperative administration of parecoxib was safe and effectively decrease postoperative morphine consumption and pain score at rest and on coughing within 24 hours postoperatively after VATS. Keywords: Intravenous parecoxib; Video-assisted thoracoscopic surgery; Acute postoperative pain

Sodium chloride injection to treat opioid overdose; Does it work? A preclinical study

Opioid overdoses (ODs) are increasing in Mexico's northern border. Because naloxone is usually not available, witnesses inject common salt (NaCl) into a vein of OD victims in an attempt to help them regain consciousness. Despite this widespread practice, no preclinical studies have addressed the efficacy of NaCl as an opioid antidote. Here we tested saline solutions at different concentrations. Because the highest (31.6 %) caused tail necrosis, we selected 17.7 % as a hypertonic saline solution (HSS) to determine if it could prevent the lethal effect of morphine (Mor), fentanyl (Fen), or Mor + Fen in adult Wistar male rats. We also evaluated if NaCl could modify the opioid antagonist effect of naloxone. Our results show that HSS: a) sensitizes animals to thermal but not mechanical stimuli; b) does not prevent mortality caused by high morphine or fentanyl doses; c) decreases the latency to recovery from the sedative effects caused by low doses of morphine or fentanyl; and d) increases naloxone's efficacy to prevent the lethality produced by Mor or Fen, but not by Mor + Fen. These results suggest that HSS is marginally effective in shortening the recovery time from nonfatal opioid ODs and increases naloxone's efficacy to counteract opioid-induced ODs.

Profiling the Effects of Repetitive Morphine Administration on Motor Behavior in Rats.

Efficient repetitive clinical use of morphine is limited by its numerous side effects, whereas analgesic tolerance necessitates subsequent increases in morphine dose to achieve adequate levels of analgesia. While many studies focused on analgesic tolerance, the effect of morphine dosing on non-analgesic effects has been overlooked. This study aimed to characterize morphine-induced behavior and the development and progression of morphine-induced behavioral tolerance. Adult male Sprague–Dawley rats were repetitively treated with subcutaneous morphine for 14 days in two dose groups (A: 5 mg/kg/day (b.i.d.) → 10 mg/kg/day; B: 10 mg/kg/day (b.i.d.) → 20 mg/kg/day). Motor behavior was assessed daily (distance traveled, speed, moving time, rearing, rotation) in an open-field arena, before and 30 min post-injections. Antinociception was measured using tail-flick and hot-plate assays. All measured parameters were highly suppressed in both dosing groups on the first treatment day, followed by a gradual manifestation of behavioral tolerance as the treatment progressed. Animals in the high-dose group showed increased locomotor activity after 10 days of morphine treatment. This excitatory phase converted to an inhibition of behavior when a higher morphine dose was introduced. We suggest that the excitatory locomotor effects of repetitive high-dose morphine exposure represent a signature of its behavioral and antinociceptive tolerance.