Opioid Concentrations Research Articles

Outside-in hair contamination by blood containing opiates and opioids

Hair analysis for drugs has become extensively used for forensic investigation in recent years. To best interpret hair drug content in post-mortem conditions, the extent of external contamination by biological fluids, such as blood, must be taken into account to avoid false positive results. The present study evaluated opiates and opioids incorporation into hair from blood containing different concentrations of morphine (MOR), 6-mono-acetyl morphine (6-AM), codeine (COD), dihydrocodeine (DHC), tramadol (TRA), oxycodone (OXY), methadone (MET), 2-ethylidene-1,5-dimethyl-3,3- diphenyl pyrrolidine (EDDP), buprenorphine (BUP) and norbuprenorphine (NBUP). The hair strands contaminated by brief soaking into blood were stored at room temperature (RT) or at 4°C during 6 hours, 1, 3, 7 or 14 days. After decontamination by extensive washing, we show that all opiates and opioids were incorporated into hair within a few hours at RT and 4°C, without significant changes over time. The concentrations of opiates and opioids in hair reached the cut-off levels established by the Society of Hair Testing (SoHT) for therapeutic (MET, COD), or toxic or lethal (all other molecules) blood concentrations. The metabolite to parent drug concentration ratios were determined for NBUP/BUP, MOR/6-AM and EDDP/MET and could be helpful as indicators of blood external contamination.

Morphine and hydromorphone pharmacokinetics in human volunteers: population-based modelling of interindividual and opioid-related variability

BackgroundMorphine and hydromorphone have differing onsets, magnitudes, and durations of effects and side-effects. Differences between opioids in their interindividual variabilities in pharmacokinetics and pharmacodynamics might influence rational drug selection. Crossover drug studies can provide more informative interindividual variability data than parallel group studies. Using data from a crossover study of i.v. morphine and hydromorphone in healthy volunteers, we tested the hypothesis that morphine and hydromorphone differ in their interindividual pharmacokinetic variability. MethodsArterial opioid and metabolite concentrations from a randomised crossover study in 51 volunteers receiving a 2-h infusion of hydromorphone (0.05 or 0.1 mg kg−1 i.v.) or morphine (total 0.1 or 0.2 mg kg−1 i.v.) 1–2 weeks apart were evaluated with a three-compartmental model for parent opioid and incorporating glucuronides using population modelling (NONMEM). The primary outcome was interindividual variability in pharmacokinetics, based on the coefficient of variation (%CV) of individual model parameters, calculated as √[exp(ω2)–1]×100 where ω2 is the interindividual variability. ResultsData were analysed per drug and in a combined morphine–hydromorphone model. Both analyses indicate that interindividual variabilities for hydromorphone and morphine were comparable with %CV ranging from 9% to 31% for structural model parameters (combined analysis). Similarly, additive and relative residual errors had comparable variabilities, 20–40% and 72–87%, respectively, for morphine and hydromorphone (combined analysis). ConclusionsMorphine and hydromorphone did not differ in a statistically significant or clinically meaningful manner in their interindividual pharmacokinetic variability. Interindividual pharmacokinetic variability does not appear a meaningful consideration in the choice between these two opioids.

Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone.

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.

Epidural methadone and morphine pharmacokinetics and clinical effects in healthy volunteers: A randomized, crossover-design trial.

Epidural opioids can provide effective analgesia for acute postoperative pain. Due to its unique physicochemical properties and long systemic elimination half-life, epidural methadone may provide lasting analgesia with minimal adverse effects; however, human studies are lacking. The aim of the study was to test the hypothesis that epidural methadone would exhibit greater segmental analgesia (analgesia at the dermatome of injection vs. distant dermatomes) than epidural morphine. In a prospective, randomized, double-blinded, crossover study, thirteen healthy volunteers received a 4-mg epidural bolus of methadone or morphine at L3-L4 and underwent repeated assessment of dermatomal heat pain tolerance and pressure pain threshold at lumbar (L3) and trigeminal (V2) dermatomes, pupil diameter, respiratory parameters and venous opioid concentration for 24 h. The primary outcome was selective (lumbar vs. trigeminal) segmental analgesia for heat pain, as a marker of a spinal analgesic mechanism. The degree of segmental analgesia to heat pain tolerance was not different between morphine and methadone (P =.09), although morphine (P =.0009) but not methadone (P =.81) produced significant analgesia to heat pain at the lumbar vs. trigeminal dermatome over 0-12 h. Morphine overall provided longer lasting analgesia to heat pain vs. methadone (24 vs. 2 h, respectively). Morphine elicited greater systemic effects, including miosis (P =.009) and opioid-related adverse effects (P =.002). These results suggest that, with equal epidural doses, both methadone and morphine produced analgesia and methadone did not produce greater segmental effects than morphine. Epidural methadone provided a more favourable adverse effect profile.

Immune response and cytokine profiles in post-laminectomy pain syndrome: comparative analysis after treatment with intrathecal opioids, oral opioids, and non-opioid therapies.

This study explores the interaction between cytokines, cell-mediated immunity (T cells, B cells, and NK cells), and prolonged morphine administration in chronic neuropathic pain patients without cancer-related issues. Despite evidence of opioid immunomodulation, few studies have compared these interactions. In a cross-sectional and comparative study, 50 patients with chronic low back radicular pain ("Failed Back Surgery Syndrome") were categorized into intrathecal morphine infusion (IT group, n = 18), oral morphine (PO group, n = 17), and non-opioid treatment (NO group, n = 15). Various parameters, including plasma and cerebrospinal fluid (CSF) cytokine concentrations, lymphocyte immunophenotyping, opioid escalation indices, cumulative morphine dose, and treatment duration, were assessed. CSF IL-8 and IL-1β concentrations exceeded plasma levels in all patients. No differences in T, B, and NK lymphocyte numbers were observed between morphine-treated and non-treated patients. Higher plasma IL-5 and GM-CSF concentrations were noted in IT and PO groups compared to NO. CSF IFNγ concentrations were higher in PO and NO than IT. Positive correlations included CD4 concentrations with opioid escalation indices, and negative correlations involved NK cell concentrations, CSF TNFα concentrations, and opioid escalation indices. Positive correlations were identified between certain cytokines and pain intensity in IT patients, and between NK cells and cumulative morphine dose. Negative correlations were observed between CSF IL-5 concentrations and pain intensity in IT and PO, and between opioid escalation indices and CSF cytokine concentrations in PO and IT. Associations between cytokines, cellular immunity, and prolonged morphine treatment, administered orally and intrathecally were identified.

Interactions Between Endocannabinoid and Endogenous Opioid Systems Prospectively Influence Postoperative Opioid Use in Pregnant Patients Undergoing Cesarean Delivery

Both endocannabinoid (EC) and endogenous opioid systems are involved in nociceptive processing and may work together synergistically based on preclinical models. This study evaluated the interactive effects of preoperative beta-endorphin (BE) concentrations (a key analgesic endogenous opioid) in cerebrospinal fluid (CSF) and ECs (CSF and plasma 2-arachidonoylglycerol and plasma anandamide) on postoperative opioid use and pain intensity in a prospective cohort of n = 112 pregnant patients undergoing scheduled cesarean delivery. Maternal blood and CSF samples were collected preoperatively for BE and EC assays. Patients completed measures of outpatient opioid use (number of tablets used and days of use) and average pain intensity at 2 weeks postoperatively. Results of general linear model analyses controlling for maternal age, body mass index at time of delivery, and race revealed significant multiplicative interactions between EC and BE concentrations on number of opioid tablets used (based on pill count), days of opioid use, and total milligram morphine equivalents used in the 2-week follow-up period. Elevated preoperative plasma and CSF 2-arachidonoylglycerol predicted reduced outpatient opioid analgesic use, particularly for patients low in CSF BE. Similar analyses for pain intensity at 2-week follow-up indicated a significant interaction (P < .02) characterized by higher preoperative BE concentrations being associated with lower subsequent pain only for individuals with low preoperative plasma anandamide concentrations. Further exploration of interactions between EC and endogenous opioid inhibitory systems as they influence responses to opioid analgesics in other clinical pain populations may help guide the development of precision pain management approaches. PerspectiveIn the postoperative setting of patients undergoing cesarean delivery, elevated ECs were linked to reduced outpatient opioid analgesic use in individuals who had low endogenous opioid concentrations in CSF. Further exploration of interactions between these 2 inhibitory systems as they impact responses to pain management interventions appears warranted.

Normalized Pulse Volume as a Superior Predictor of Respiration Recovery and Quantification of Nociception Anti-nociception Balance Compared to Opioid Effect Site Concentration: A Prospective, Observational Study

Background Quantifying pain and the balance between nociception and anti-nociception (NANB) in sedated patients is challenging. Traditional opioid titration methods overlook individual differences, while existing indices like the Noxious Stimulation Response Index (NSRI) lack correlation with effect-site concentration (Ce). The Normalized Pulse Volume (NPV), used in polygraphs, has potential for pain quantification but is underexplored. This study aimed to assess NPV’s efficacy as a pain monitoring tool compared to Ce and to explore its potential in various clinical settings. Methods The study included 39 patients undergoing surgery under total intravenous anesthesia from July 2013 to May 2014. Selection criteria were an American Society of Anesthesiologists physical status classification system (ASA score) of 1 or 2 and surgeries with minimal fluid resuscitation or blood loss. Exclusion criteria were significant posture changes, massive hemorrhage, and high perfusion index variation. NPV and Ce were measured using the Masimo SET adult SpO2 sensor. Results Out of 39 patients, 9 were excluded. NPV at recovery of spontaneous respiration (RoR) was 2.62 (95% CI: 2.26–2.98) with a coefficient of variation (CoV) of 36.3%, while total Ce was 1.48 ng/ml (95% CI: 1.14–1.84) with a CoV of 62.4%. NPV showed a narrower CoV than Ce (p &lt; 0.05, 1.93*10−5), indicating less variability. NPV outperformed Ce in predicting RoR, suggesting a more accurate reflection of NANB balance. Its superiority in stable measurement underlines its potential as a reliable pain indicator. The study’s limitations include temporal differences in NPV and Ce calculations, affecting comparative analysis. Conclusion NPV demonstrates promise as an objective, reliable indicator of pain or NANB, showing a strong correlation with Ce. Its application could improve pain assessments in clinical settings, optimizing patient care and analgesic administration. Future research should integrate NPV with other vital signs for a comprehensive pain monitoring system.

Prevalence and blood concentrations of benzodiazepines and opioids in opioid-positive death investigations in Ontario, Canada, from 2017 to 2021.

The aim of this study was to investigate the incidence of benzodiazepines in opioid-positive death investigations, including trends in frequency and combination of drugs, as well as demographic data and blood concentrations, where available. Additionally, naloxone concentrations in polysubstance compared to opioid-only cases were analyzed. This was a retrospective study that consisted of all post-mortem toxicology cases in Ontario, Canada, from January 01, 2017, to December 31, 2021, with an opioid finding in any analyzed autopsy specimen. There were 11,033 death investigations identified. The overall rate of benzodiazepine co-involvement was 54.5%. Males accounted for the majority of cases (71%), and the most affected age group was 30- to 39-year-olds. The most frequently detected opioid was fentanyl and the most frequently detected benzodiazepine was etizolam, which was also the most frequently observed opioid/benzodiazepine combination. Findings related to differences in concentrations of opioids when naloxone was also present were mostly non-significant, except for methadone. The rate of benzodiazepine detection with opioids grew faster than opioid detections overall, potentially due to the increasingly toxic drug supply. Detection of novel psychoactive drugs fluctuated more unpredictably than opioids and benzodiazepines associated with clinical use. These findings can help inform policy decisions by public health agencies in exploring harm reduction efforts, for example, education and drug-checking services.

The Association of Physiological and Pharmacological Anesthetic Parameters With Motor-Evoked Potentials: A Multivariable Longitudinal Mixed Model Analysis.

During spinal surgery, the motor tracts can be monitored using muscle-recorded transcranial electrical stimulation motor-evoked potentials (mTc-MEPs). We aimed to investigate the association of anesthetic and physiological parameters with mTc-MEPs. Intraoperative mTc-MEP amplitudes, mTc-MEP area under the curves (AUC), and anesthetic and physiological measurements were collected retrospectively from the records of 108 consecutive patients undergoing elective spinal surgery. Pharmacological parameters of interest included propofol and opioid concentration, ketamine and noradrenaline infusion rates. Physiological parameters recorded included mean arterial pressure (MAP), bispectral index (BIS), heart rate, hemoglobin O 2 saturation, temperature, and Et co2 . A forward selection procedure was performed using multivariable mixed model analysis. Data from 75 (69.4%) patients were included. MAP and BIS were significantly associated with mTc-MEP amplitude ( P < .001). mTc-MEP amplitudes increased by 6.6% (95% confidence interval [CI], 2.7%-10.4%) per 10 mm Hg increase in MAP and by 2.79% (CI, 2.26%-3.32%) for every unit increase in BIS. MAP ( P < .001), BIS ( P < .001), heart rate ( P = .01), and temperature ( P = .02) were significantly associated with mTc-MEP AUC. The AUC increased by 7.5% (CI, 3.3%-11.7%) per 10 mm Hg increase of MAP, by 2.98% (CI, 2.41%-3.54%) per unit increase in BIS, and by 0.68% (CI, 0.13%-1.23%) per beat per minute increase in heart rate. mTc-MEP AUC decreased by 21.4% (CI, -38.11% to -3.98%) per degree increase in temperature. MAP, BIS, heart rate, and temperature were significantly associated with mTc-MEP amplitude and/or AUC. Maintenance of BIS and MAP at the high normal values may attenuate anesthetic effects on mTc-MEPs.

Investigation of the Effects of Opioids on Microglial Nitrite and Nitric Oxide Synthase (iNOS) Production and Phagocytosis during Inflammation.

This study aimed to investigate how opioids affect phagocytosis and microglial nitrite and nitric oxide synthase (iNOS) production during inflammation. Opioids are a group of chemicals that are naturally found in the opium poppy plant and exert a variety of effects on the brain, including pain alleviation in some cases. They are commonly used in surgery and perioperative analgesia. However, research on the impact of opioids on microglial inflammatory factor production and phagocytosis is limited. This study was designed to investigate the effects of opioids on inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) generation. Moreover, the influence of opioids on the engulfment of C8-B4 microglial cells after stimulation with LPS was also examined. C8-B4 mouse microglial cells were exposed to various concentrations of opioids after stimulation with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Nitrite production was assayed. The iNOS and Cox-2 were determined by Western blotting, and fluorescent immunostaining was performed to assess the percentage of microglia that engulfed fluorescent microspheres in total microglia cultivating with opioids after being activated by LPS. After LPS and IFN-γ stimulation, microglia produced lower amounts of nitric oxide (NO) production with buprenorphine, salvinorin A, and naloxone (P<0.05). When combined with naloxone, no significant differences were found than buprenorphine. It was observed that buprenorphine and salvinorin A could suppress iNOS expression activated by LPS and IFN-γ. Phagocytosis was greatly increased after LPS stimulation, and a significant increase was observed after adding salvinorin A. Buprenorphine and salvinorin A were found to reduce NO production and iNOS induction in microglial cells activated by LPS and IFN-γ. Salvinorin A promoted the phagocytosis of microglia cells treated by LPS.

Using the TI.VA algorithm to titrate the depth of general anaesthesia: a first-in-humans study

BackgroundThe dose of anaesthetic and opioid drugs must be continuously adjusted after the induction of general anaesthesia to maintain an adequate depth of anaesthesia. The TI.VA algorithm is a multiple-input/multiple-output algorithm designed to optimise the balance between anaesthetic and opioid concentrations during general anaesthesia. It applies vector analysis to a two-dimensional matrix to quantify any inadequacy of the depth of anaesthesia at any given moment and determine any drug dose adjustments required to achieve an adequate depth of anaesthesia. This study aimed to capture preliminary data on the performance and safety of the TI.VA algorithm during total i.v. anaesthesia in patients. MethodsThis prospective study enrolled nine patients with breast cancer scheduled to undergo surgery. General anaesthesia was induced under manual control using propofol and remifentanil. Anaesthesia was guided using the TI.VA algorithm from skin incision until surgical resection was completed. The quality of anaesthesia was assessed through an analysis of performance errors. A bispectral index global score (GSBIS) <50 was considered an acceptable target for algorithm performance. ResultsAll nine procedures were completed without any adverse events and none of the patients recalled any intraoperative event. Overall, we analysed 3417 monitoring points corresponding to 285 min of surgery. All patients presented a GSBIS below the cut-off value of 50. ConclusionsThe TI.VA algorithm provides adequate control of clinical anaesthesia. A more sophisticated prototype needs to be developed before the trial is expanded to include larger patient populations. Clinical trial registrationNCT05199883.

Oxycodone, Morphine, and Fentanyl in Patients With Chronic Pain: Proposal of Dose-Specific Concentration Ranges.

Interpreting opioid concentrations is challenging because of the lack of reference ranges. Therefore, the authors aimed to propose dose-specific concentration ranges in serum for oxycodone, morphine, and fentanyl in patients with chronic pain, based on concentration measurements from a large number of patients and supported by theoretical pharmacokinetic calculations and previously published concentrations. The opioid concentrations in patients undergoing therapeutic drug monitoring (TDM) for various indications (TDM group) and patients with cancer (cancer group) were investigated. Patients were divided based on the daily opioid doses, and the 10th and 90th percentiles of the concentrations in each dose interval were evaluated. In addition, the expected average serum concentrations were calculated for each dose interval based on published pharmacokinetic data, and a targeted literature search for previously reported dose-specific concentrations was performed. The opioid concentrations in 1054 patient samples were included: 1004 in the TDM group and 50 in the cancer group. In total, 607 oxycodone, 246 morphine, and 248 fentanyl samples were evaluated. The authors proposed dose-specific concentration ranges based mainly on 10th-90th percentiles of the concentrations measured in patient samples, whereas the calculated average concentrations and previously published concentrations were used to adjust the ranges. In general, results from calculations and concentrations retrieved from previous literature were within the 10th-90th percentiles of concentrations from patient samples. However, the lowest calculated average concentrations of fentanyl and morphine were below the 10th percentiles of patient samples in all dose groups. The proposed dose-specific ranges may be useful for interpreting steady-state opioid serum concentrations in clinical and forensic settings.

Pharmacogenetics of Lethal Opioid Overdose: Review of Current Evidence and Preliminary Results from a Pilot Study.

There has been a worldwide substantial increase in accidental opioid-overdose deaths. The aim of this review, along with preliminary results from our pilot study, is to highlight the use of pharmacogenetics as a tool to predict causes of accidental opioid-overdose death. For this review, a systematic literature search of PubMed® between the time period of January 2000 to March 2023 was carried out. We included study cohorts, case-controls, or case reports that investigated the frequency of genetic variants in opioid-related post-mortem samples and the association between these variants and opioid plasma concentrations. A total of 18 studies were included in our systematic review. The systematic review provides evidence of the use of CYP2D6, and to a lower extent, CYP2B6 and CYP3A4/5 genotyping in identifying unexpectedly high or low opioid and metabolite blood concentrations from post-mortem samples. Our own pilot study provides support for an enrichment of the CYP2B6*4-allele in our methadone-overdose sample (n = 41) compared to the anticipated frequency in the general population. The results from our systematic review and the pilot study highlight the potential of pharmacogenetics in determining vulnerability to overdose of opioids.

Mapping the Evidence for Opioid-Mediated Changes in Malignancy and Chemotherapeutic Efficacy: Protocol for a Scoping Review.

Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a "physiologic range" to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. PRR1-10.2196/38167.

Policies Affecting Pregnant Women with Substance Use Disorder

Policies Affecting Pregnant Women with Substance Use Disorder

Endogenous Opioid Imbalance as a Potential Factor Involved in the Pathogenesis of Chronic Kidney Disease-Associated Pruritus in Dialysis Patients.

Chronic pruritus is one of the most common symptoms of dermatological diseases. It may occur in the course of other disorders, such as kidney disease. Chronic kidney disease-associated pruritus (CKD-aP) most often affects people with end-stage renal disease. The etiology of this condition is still not fully understood, but researchers are currently focusing on a thorough analysis of the association between disturbed opioid balance and increased neuronal signaling leading to pruritus. The aim of this study is to assess the concentration of endogenous opioids in dialysis patients with and without pruritus and in the control group, and to determine the correlation between the concentration of these substances and the occurrence and severity of itching. The study involved 126 dialysis patients and 50 healthy controls. Patients were divided into groups with pruritus (n = 62) and without pruritus (n = 64). The severity of pruritus was assessed using the NRS scale. The concentration of endogenous opioids was determined using the ELISA. The concentration of met-enkephalin was higher in the group of patients with pruritus compared to the control group. Moreover, significantly lower levels of β-endorphin and dynorphin A were observed in the group of dialysis patients compared to the control group. In addition, a statistically significant difference was seen between the β-endorphin concentration in the group of dialysis patients with pruritus compared to the group without pruritus. The ratio of β-endorphin/dynorphin A concentrations was significantly lower in the group of patients with pruritus compared to patients without pruritus and the control group. No correlations were found between serum level of studied opioids and the severity of pruritus. The concentrations of the studied opioids did not correlate with the severity of pruritus. Observed opioid imbalance may affect the occurrence of CKD-aP in dialysis patients, but a thorough understanding of the mechanism of action of these substances in the sensation of pruritus is necessary to assess the possibility of finding a new therapeutic target.

Can nociception monitors be used to titrate remifentanil with a stable low noxious stimulation response index (NSRI)?

Purpose: Opioids blunt autonomic nervous system (ANS) responses to noxious stimuli. Nociception monitors analyze the same ANS responses and thus might prove useful to guide opioid dosing. However, concomitantly administered hypnotics also blunt ANS responses and may thus jeopardize the usefulness of nociception monitors to guide intra-operative opioid dosing. We therefore studied the PK (prediction probability) of 3 nociception monitors (NOL index, qNOX and SPI) for the prevailing opioid concentration while maintaining the NSRI (noxious stimulus response index) at a low constant value with a range of opioids and inhaled agent combinations. Methods: In 24 consenting ASA I-II patients undergoing robotic assisted radical prostatectomy, anesthesia was maintained with desflurane in O2/air and remifentanil (target controlled infusion). During the dissection phase, the remifentanil effect site concentration (Ce) in each patient was maintained at 1, 3, or 5 ng/mL for 20 min while the end-expired desflurane concentration (FET) was adjusted to keep the noxious stimulus response index (NSRI) at 5; the sequence in which each patient received each of the three remifentanil Ce was randomized. After stabilization, during each 20 min study period, the following data were collected: NSRI, NOL Index, SPI, qNOX, and FETdes. For each parameter, the prediction probability (PK) for Ce remifentanil was calculated. Results: All patients remained hemodynamically stable. Surgery was finished before the last data collection period in 5 patients with a remifentanil Ce = 5 ng/mL, and in 1 patient with a remifentanil Ce = 1 ng/mL. All other data have been included in the data analysis. The prediction probability (PK) calculated for NOL Index, qNOX and SPI for Ce remifentanil was 0.519, 0.470, and 0.477, respectively. Conclusion: Nociception monitoring becomes useless to titrate opioids when the concomitantly administered hypnotic is adjusted to maintain a low NSRI, presumably because suppression of movement to laryngoscopy also ensures suppression of the sympathetic nervous system response to the noxious stimulus present during intra-abdominal resection of the prostate. Both the hypnotic/opioid ratio and stimulus intensity of the stimulus/response pair need to be considered when attempting to use nociception to guide opioid administration.

The therapeutic potential of ultra-short-acting β-receptor antagonists in perioperative analgesic: Evidence from preclinical and clinical studies.

Perioperative multimodal analgesia can reduce the side effects of a high concentration of opioids, improving the comfort of the patient. However, insufficient analgesia of this model has prompted researchers to explore new adjuvant analgesics. Recently, an increasing number of studies have found a low-grade analgesic effect in the clinical application of ultra-short-acting β-adrenergic receptor antagonists, which are conventionally used as pharmacologic agents in the cardiovascular system. The mechanism by which ultra-short-acting β-antagonists exert antinociceptive effects has not been clarified yet. In this review, we intend to address its potential reasons from the side of neurotransmitters, inflammatory cytokines, and signaling pathways, providing theoretical proof for the application of β-adrenergic receptor antagonists in analgesia.

Quantitative and rapid detection of morphine and hydromorphone at the point of care by an automated giant magnetoresistive nanosensor platform.

Opioids, such as morphine and hydromorphone, are common pain management drugs with a high risk for addiction and adverse effects when delivered in large doses or administered too frequently. Point-of-care (POC) tools provide a solution to combat these negative outcomes through active monitoring of opioid concentrations in clinical settings. We demonstrate that giant magnetoresistive (GMR) nanosensors offer a quantitative, sensitive, and rapid solution for low-cost, sample-to-answer opioid detection at the POC. We show the robust nature of GMR nanosensors by developing a competitive morphine assay and characterizing it in saliva, blood, and plasma. We then implemented the assay on a fully automated POC GMR platform and demonstrated its duality to detect either morphine or hydromorphone using only 180μL of direct saliva without the need for pre-processing. In 35min from sample addition to result, the automated platform was controlled via smartphone and had seamless transmission of results via Bluetooth. The fully automated POC assay had a limit of detection of 3.43ng/mL for morphine and 3.49ng/mL for hydromorphone. The low-cost, 80-plex GMR nanosensor array coupled with the automated POC platform enables future development of multiplexed drug screening tools that can be deployed in clinical settings using a wide variety of non-invasive matrices.

Concentrations of psychoactive substances in blood samples from non-fatal and fatal opioid overdoses.

AimThe primary aim was to compare concentrations of psychoactive substances in blood in non‐fatal and fatal opioid overdoses. The secondary aim was to assess the concentration levels of naloxone in blood in non‐fatal overdoses and the association between naloxone findings and concomitantly detected drugs.Method DesignCase‐control study.SettingNorway. Fatal overdoses from 2017 and non‐fatal overdoses from February 2018 to September 2019.CasesThirty‐one non‐fatal and 160 fatal opioid overdose cases. Data from the non‐fatal overdoses were collected from hospital records and blood samples, and data from the fatal overdoses were collected from autopsy reports. Concentrations of psychoactive substances (including ethanol) in blood samples were collected at the time of hospital admission for the non‐fatal overdoses and during autopsy for the fatal overdoses.ResultsThe median number of different substances detected was four for fatal and five for non‐fatal overdoses. The fatal overdoses had higher pooled concentrations of opioids (188 vs 57.2 ng/mL, P < .001), benzodiazepines (5467 vs 2051 ng/mL, P = .005) and amphetamines (581 vs 121 ng/mL, P < .001) than the non‐fatal overdoses. A linear relationship between naloxone and concomitant pooled opioid concentrations was found (95% confidence interval = 0.002‐0.135, P < .05).ConclusionThe total load of drug concentrations was associated with the fatal outcome of an overdose, while the number of drugs used, to a lesser extent, differentiated between those who survived and those who died from an overdose. Higher opioid concentrations were associated with treatment with higher naloxone doses.