Effects Of Naloxone Research Articles

Design, synthesis, and evaluation of novel racecadotril-tetrazole-amino acid derivatives as new potent analgesic agents.

Background and purpose:Although pain is one of the most common symptoms of diseases, it is often mismanaged due to limited access to painkillers and ineffectiveness, unacceptable side effects, or the possibility of abuse. However, an alternative approach to existing analgesics is to indirectly increase endogenous pain relief pathways by neprilysin (an enkephalinase) inhibitors. This enzyme breaks down and inactivates enkephalin, dynorphin, endorphins, and their derivatives.Experimental approach:In this project, a new series of racecadotril-tetrazole-amino acid derivatives 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds. 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds.Findings/Results:Most of the synthesized compounds showed moderate to good analgesic effects in hot plat and tail-flick test in comparison to morphine and racecadotril. Compounds 15l and 15j were the most potent compounds. The synergistic analgesic effect of compounds 15l and 15j with morphine and the antagonistic effect of naloxone on the activity of these compounds confirm that the analgesic effect of compounds 15l and 15j could be mediated through the opioidergic system. The negative and high binding energy of docking simulation of the most potent compounds in the catalytic site of neprilysin was also in good agreement with the inhibitory activity of test compounds.Conclusion and implications:Racecadotril-tetrazole-amino acid derivatives, as potential antinociceptive agents, demonstrated moderate to good antinociceptive activities comparable with morphine and higher than racecadotril.

Evaluation of the Effects of Ultra-Low Dose Naloxone on Brachial Plexus Block with Bupivacaine

Introduction: Adjuvants are used in conjunction with local anaesthetics for brachial plexus block to quicken onset, prolong duration and augment the quality of anaesthesia.
 Objectives: The study aims to evaluate the effect of adding ultra-low dose naloxone to bupivacaine on the duration of postoperative analgesia.
 Methodology: A prospective, randomized, double-blind study was conducted including forty American Society of Anesthesiologists Physical Status (ASA PS) I and II patients of either sex between 15 and 65 years of age scheduled for upper limb surgery. They were randomized into two groups. Group BN received a mixture of 0.33% plain bupivacaine with ultra-low dose naloxone (100 ng) and group BS received 0.33% plain bupivacaine with saline. The procedure was standardized in both groups. The onset of sensory and motor block were assessed with pinprick sensation and muscle power respectively. Visual Analogue Score (VAS) was used to assess the pain at 1, 2, 4, 8 and 12 hours postoperatively.
 Result: The patients were comparable with respect to age, sex, ASA PS, baseline hemodynamic and respiratory parameters and duration of surgery. The mean duration of analgesia in group BN was significantly longer (610.7±125.4 mins) as compared to group BS (354.3±59.6 mins) (p<0.001). No complications were noted in both the groups.
 Conclusion: This study demonstrated that 100 ng naloxone, when used with 0.33% plain bupivacaine for supraclavicular brachial plexus block, prolongs postoperative analgesia significantly after upper limb surgeries, without any significant side effects.

Pharmacological mechanisms underlying the efficacy of antibodies generated by a vaccine to treat oxycodone use disorder

Therapeutic vaccines offer a viable strategy to treat opioid use disorders (OUD) complementary to current pharmacotherapies. The candidate Oxy(Gly)4-sKLH vaccine targeting oxycodone displayed pre-clinical proof of efficacy, selectivity and safety, and it is now undergoing clinical evaluation. To further support its implementation in the clinic, this study tested critical in vivo neuropsychopharmacological properties of the Oxy(Gly)4-sKLH vaccine in rats. While repeated immunizations with Oxy(Gly)4-sKLH were necessary to maintain the antibody response overtime, exposure to free oxycodone did not boost oxycodone-specific antibody levels in vaccinated rats, limiting concerns of immune-related side effects. Immunization with Oxy(Gly)4-sKLH achieved sustained antibody titers over a period of five months following initial vaccination, supporting its potential for providing long-lasting protection. In vivo studies of selectivity showed that vaccination prevented oxycodone-induced but not methadone-induced antinociception, while still preserving the opioid antagonist naloxone's pharmacological effects. Vaccination did not interfere with fentanyl-induced antinociception or fentanyl distribution to the brain. These in vivo data confirm the previously reported in vitro selectivity profile of Oxy(Gly)4-sKLH. Vaccination extended oxycodone's half-life up to 25 h compared to control. While vaccination reduced the reinforcing efficacy of oxycodone in an intravenous self-administration model, signs of toxicity were not observed. These rodent studies confirm that active immunization with Oxy(Gly)4-sKLH induces highly specific and long-lasting antibodies which are effective in decreasing the reinforcing effects of oxycodone while preserving the efficacy of medications used to treat OUD and overdose.

Engineering Quick- and Long-acting Naloxone Delivery Systems for Treating Opioid Overdose.

PurposeOpioids have been the main factor for drug overdose deaths in the United States. Current naloxone delivery systems are effective in mitigating the opioid effects only for hours. Naloxone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared as quick- and long-acting naloxone delivery systems to extend the naloxone effect as an opioid antidote.MethodsThe naloxone-PLGA microparticles were made using an emulsification solvent extraction approach with different formulation and processing parameters. Two PLGA polymers with the lactide:glycolide (L:G) ratios of 50:50 and 75:25 were used, and the drug loading was varied from 21% to 51%. Two different microparticles of different sizes with the average diameters of 23 μm and 50 μm were produced using two homogenization-sieving conditions. All the microparticles were critically characterized, and three of them were evaluated with β-arrestin recruitment assays.ResultsThe naloxone encapsulation efficiency (EE) was in the range of 70–85%. The EE was enhanced when the theoretical naloxone loading was increased from 30% to 60%, the L:G ratio was changed from 50:50 to 75:25, and the average size of the particles was reduced from 50 μm to 23 μm. The in vitro naloxone release duration ranged from 4 to 35 days. Reducing the average size of the microparticles from 50 μm to 23 μm helped eliminate the lag phase and obtain the steady-state drug release profile. The cellular pharmacodynamics of three selected formulations were evaluated by applying DAMGO, a synthetic opioid peptide agonist to a μ-opioid receptor, to recruit β-arrestin 2.ConclusionsNaloxone released from the three selected formulations could inhibit DAMGO-induced β-arrestin 2 recruitment. This indicates that the proposed naloxone delivery system is adequate for opioid reversal during the naloxone release duration.

The effects of naloxone, diazepam, and quercetin on seizure and sedation in acute on chronic tramadol administration: an experimental study

BackgroundTramadol is a widely used synthetic opioid. Substantial research has previously focused on the neurological effects of this drug, while the efficacy of various treatments to reduce the associated side effects has not been well studied. This study aimed to evaluate the protective effects of naloxone, diazepam, and quercetin on tramadol overdose-induced seizure and sedation level in male rats.MethodsThe project was performed with 72 male Wistar rats with an average weight of 200–250 g. The rats were randomly assigned to eight groups. Tramadol was administered intraperitoneally at an initial dose of 25 mg/kg/day. On the 14th day, tramadol was injected at 75 mg/kg, either alone or together with naloxone, diazepam, and quercetin (acute and chronic) individually or in combination. The rats were monitored for 6 h on the last day, and the number, the duration, and the severity of seizures (using the criteria of Racine) were measured over a 6-h observation period. The sedation level was also assessed based on a 4-point criterion, ranging from 0 to 3. Data were analyzed in SPSS software using Kruskal–Wallis, Chi-square, regression analysis, and generalized estimating equation (GEE) tests. The significance level was set at P < 0.05.ResultsThe naloxone-diazepam combination reduced the number, severity, and cumulative duration of seizures compared to tramadol use alone and reduced the number of higher-intensity seizures (level 3, 4) to a greater extent than other treatments. Naloxone alone reduced the number and duration of seizures but increased the number of mild seizures (level 2). Diazepam decreased the severity and duration of seizures. However, it increased the number of mild seizures (level 2). In comparison with the tramadol alone group, the acute quercetin group exhibited higher numbers of mild (level 2) and moderate (level 3) seizures. Chronic quercetin administration significantly increased the number of mild seizures. In the GEE model, all groups had higher sedation levels than the saline only group (P < 0.001). None of the protocols had a significant effect on sedation levels compared to the tramadol group.ConclusionThe combined administration of naloxone and diazepam in acute-on-chronic tramadol poisoning can effectively reduce most seizure variables compared to tramadol use alone. However, none of the treatments improved sedation levels.

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System.

The development of alcohol dependence and depression is determined by various genetic and environmental factors. In the presented study, we used high analgesia (HA) and low analgesia (LA) mouse lines, characterized by different endogenous opioid system activity and divergent blood–brain barrier permeability, to determine the influence of cross-fostering of these lines raised by surrogate mothers on ethanol consumption and development of depressive-like behaviors. We also investigated ethanol drinking by biological parents or surrogate mothers. Furthermore, we investigated whether these parental changes would alter the effect of naloxone on ethanol intake and depressive-like behaviors in offspring. Our results reveal that cross-fostering of HA and LA raised by surrogate mothers has a greater impact on depressive-like behaviors than ethanol consumption. Ethanol intake by biological parents substantially affected depressive-like behaviors and ethanol consumption in offspring. Moreover, ethanol intake by biological parents or an adoptive mother modified the effect of naloxone on ethanol consumption and preference and depressive-like behaviors in the HA offspring only. Together, these results indicate that cross-fostering differentially affects the effect of naloxone on alcohol consumption and the development of depression.

Naloxone Injections into the Parabrachial Nucleus/ Kölliker‐Fuse Complex, the preBötzinger Complex and the Caudal Medullary Raphe Reverse Remifentanil‐Induced Respiratory Depression

Background We have shown that naloxone microinjections into the Parabrachial Nucleus/ Kölliker-Fuse (PBN/KF) complex and the preBötzinger Complex (preBC) partially reversed remifentanil-induced respiratory rate depression (1). The magnitude of reversal was dose dependent. The goal of this study was to determine whether additional naloxone injection into the caudal medullary raphe (CMR (2)) could completely reverse the opioid effect. Methods The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4kg) were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the c5 rootlet, time averaged and used to calculate inspiratory and expiratory duration and peak phrenic activity (PPA). Gridwise localized pressure microinjections of AMPA (50 μM, 70 nl) with a multibarrel glass pipette were used to functionally identify the PBN/KF and preBC. The CMR was defined as the area between 2.0mm caudal and 1.5mm rostral to preBC in the midline. We then injected an “apneic” remifentanil IV bolus (12±2mcg), which interrupted inspiratory activity for at least 60 sec. Next, a remifentanil infusion was started at an “analgesic” dose-rate, defined to achieve respiratory rate depression of 50% of control. At steady-state, we sequentially injected naloxone (1mM, 700nl) into the bilateral PBN/KF, the preBC, and the CMR. We repeated the “apneic” remifentanil bolus after naloxone injection into each area. To determine whether injection order affected the naloxone reversal, in separate sets of animals we microinjected naloxone in the reverse order, or solely into the preBC and CMR. Drug effects were compared with Paired t-tests. Results Figure 1 illustrates the effects of sequential naloxone microinjection into the bilateral PBN/KF, preBC, and CMR. At the end of the naloxone injection sequence, respiratory rate depression was completely reversed (A+B) or even increased above baseline (C). Depression of PPA was completely reversed (p=0.756). Conclusion Naloxone injection into the CMR reversed remifentanil-induced respiratory depression in addition to the reversal achieved in the PBN/KF and preBC at “analgesic” and “apneic” remifentanil doses. Further research is needed to determine whether the naloxone effect in the CMR was partially due to reversal of endogenous opioid-receptor activation (see Palkovic B, Endogenous Opioid-Receptor Activation in the Caudal Medullary Raphe Depresses Respiratory Rate in Decerebrate Rabbits, EB 2021). (1) Palkovic et al., Anesthesiology 2020, A3038 (2) Zhang et al., Anesthesiology 2007, 107: 288-97

IND‐enabling studies of vaccines to treat heroin and oxycodone use disorders

To treat opioid use disorder (OUD), a vaccine targeting oxycodone (OXY-sKLH) is currently in a Phase I Clinical Trial and an analogous heroin vaccine (M-sKLH) is being prepared for clinical testing. For both vaccines, key studies were performed to demonstrate the in vivo efficacy and selectivity against their respective target opioids in rats. Sprague Dawley rats were vaccinated with either OXY-sKLH or M-sKLH adsorbed to aluminum adjuvant and compared against controls consisting of either sKLH or aluminum alone. OXY-sKLH protected against oxycodone-induced, but not methadone-induced, antinociception and respiratory depression, compared to controls, while naloxone's reversal effects remained intact. In addition, vaccination with OXY-sKLH did not interfere with fentanyl distribution to serum and brain. M-sKLH similarly protected against heroin-induced effects while maintaining the effects of methadone and naloxone. Distribution of buprenorphine was also unaffected by vaccination with M-sKLH. These in vivo data confirm the previously reported in vitro selectivity of OXY-sKLH and M-sKLH for their targeted opioids. To further support clinical implementation of OXY-sKLH, follow-up studies demonstrated that OXY-sKLH elicited titers that remained high for at least 3-5 months following a final vaccination, increased the half-life of oxycodone 35-fold, and reduced the reinforcing efficacy of oxycodone in an intravenous self-administration model. No evidence of withdrawal was found during self-administration. These data demonstrate that OXY-sKLH produces a long-lasting immune response and extensively alters oxycodone's pharmacokinetics and behavioral effects in rats, supporting its translation to human studies.

Differential Reversal of the Ventilatory‐Depressant Effects of Fentanyl and its Derivatives by Naloxone in Monkeys

Opioid overdose deaths continue to rise with fatalities involving synthetic opioids, such as fentanyl and its derivatives, increasing sharply in 2020 and accelerating further during the COVID‐19 pandemic. Many lives have been saved by administering naloxone to reverse ventilatory depression, the fatal effect of opioids; however, these effects of fentanyl derivatives are reportedly more difficult to reverse with naloxone than those of other opioids like heroin. The current study examined the ability of naloxone to reverse ventilatory depression produced by fentanyl and 2 of its derivatives. Minute volume (VE) was measured using head plethysmography in 4 rhesus monkeys breathing air. On separate occasions, monkeys received saline or naloxone (0.032 mg/kg) 30 min after administration of the smallest dose of fentanyl, 3‐methylfentanyl or carfentanil that decreased VE to <70% of control. Fentanyl and its derivatives dose‐dependently decreased ventilation, although their potency varied markedly; carfentanil was 10‐fold more potent than 3‐methylfentanyl and 100‐fold more potent than fentanyl. For each opioid, the dose that decreased VE varied slightly across individual monkeys (fentanyl: 17.8‐56 µg/kg; 3‐methylfentanyl: 3.2‐5.6 µg/kg; carfentanil: 0.32‐0.56 µg/kg), although those doses reliably decreased ventilation within 30 min such that VE ranged from 57‐63% of control. Ventilatory depression was evident for at least 90 min. Naloxone reversed the ventilatory‐depressant effects of fentanyl and 3‐methylfentanyl with the mean VE increasing to 112% and 120% of control, respectively, within 15 min; however, this attenuation by naloxone did not last long, beginning to wane 30 min after its administration. In contrast, naloxone was not as effective in reversing the ventilatory‐depressant effects of carfentanil; VE was <70% of control 15 min after naloxone and remained <90% at all time points. Thus, reversal of the ventilatory‐depressant effects of fentanyl and 3‐methylfentanyl was similar to each other and to that obtained previously with heroin, supporting the effectiveness of naloxone in attenuating ventilatory depression involving these opioids. Differences between carfentanil and pharmacologically equivalent doses of other opioids suggest that naloxone is not equally potent, and might not be equally effective, in reversing all opioids and underscores the importance of developing novel treatment options for opioid overdose.

Rapid systemic uptake of naloxone after intranasal administration in children

Naloxone has a high affinity for the µ-opioid receptor and acts as a competitive antagonist thus reversing the effects of opioids. Naloxone is often administrated intravenously but there is a growing interest in the intranasal route in treating patients with opioid overdose, and in reversing effects after therapeutic use of opioids. As administration is painless and no intravenous access is needed, the intranasal route is especially useful in children. The aim of this study was to investigate the uptake of naloxone 0,4 mg/mL during the first 20 minutes after administration as a nasal spray in a pediatric population, with special focus on the time to achieve maximum plasma concentration. Twenty children, 6 months to 10 years, were included in the study. The Naloxone dose administered was 20 µg/kg, maximum 0.4 mg, divided into repeated doses of 0.1 mL in each nostril. Venous blood samples were collected at 5, 10, and 20 minutes after the end of administration. All patients had quantifiable concentrations of naloxone in venous blood at 5 minutes and within 20 minutes peak concentration had been reached in more than half of the children. At 20 minutes after intranasal administration the plasma naloxone concentrations were within the range of 2 to 6 nanogram/mL. This study confirms the clinical experience that the rapid effect of naloxone after intranasal administration in children was reflected in rapid systemic uptake to achieve higher peak plasma concentrations than previously reported in adults.

Take-home naloxone programs for suspected opioid overdose in community settings: a scoping umbrella review

BackgroundOpioid related overdoses and overdose deaths continue to constitute an urgent public health crisis. The implementation of naloxone programs, such as ‘take-home naloxone’ (THN), has emerged as a key intervention in reducing opioid overdose deaths. These programs aim to train individuals at risk of witnessing or experiencing an opioid overdose to recognize an opioid overdose and respond with naloxone. Naloxone effectively reverses opioid overdoses on a physiological level; however, there are outstanding questions on community THN program effectiveness (adverse events, dosing requirements, dose-response between routes of administration) and implementation (accessibility, availability, and affordability). The objective of this scoping review is to identify existing systematic reviews and best practice guidelines relevant to clinical and operational guidance on the distribution of THN.MethodsUsing the Arksey & O’Malley framework for scoping reviews, we searched both academic literature and grey literature databases using keywords (Naloxone) AND (Overdose) AND (Guideline OR Review OR Recommendation OR Toolkit). Only documents which had a structured review of evidence and/or provided summaries or recommendations based on evidence were included (systematic reviews, meta-analyses, scoping reviews, short-cut or rapid reviews, practice/clinical guidelines, and reports). Data were extracted from selected evidence in two key areas: (1) study identifiers; and (2) methodological characteristics.ResultsA total of 47 articles met inclusion criteria: 20 systematic reviews; 10 grey literature articles; 8 short-cut or rapid reviews; 4 scoping reviews; and 5 other review types (e.g. mapping review and comprehensive reviews). The most common subject themes were: naloxone effectiveness, safety, provision feasibility/acceptability of naloxone distribution, dosing and routes of administration, overdose response after naloxone administration, cost-effectiveness, naloxone training and education, and recommendations for policy, practice and gaps in knowledge.ConclusionsSeveral recent systematic reviews address the effectiveness of take-home naloxone programs, naloxone dosing/route of administration, and naloxone provision models. Gaps remain in the evidence around evaluating cost-effectiveness, training parameters and strategies, and adverse events following naloxone administration. As THN programs continue to expand in response to opioid overdose deaths, this review will contribute to understanding the evidence base for policy and THN program development and expansion.

\u201cThey\u2019re not doing enough.\u201d: women\u2019s experiences with opioids and naloxone in Toronto

BackgroundAmid increasing opioid overdose deaths in Canada since 2010 and a changing naloxone access landscape, there is a need for up-to-date research on Canadian women’s experiences with opioids. Studies on Canadian take-home naloxone programs are promising, but research beyond these programs is limited. Our study is the first to focus on women’s experiences and perspectives on the opioid crisis in Ontario, Canada’s most populous province, since the opioid crisis began in 2010.ObjectiveOur objective was to address research knowledge gaps involving Canadian women with criminal justice involvement who use opioids, and identify flaws in current policies, responses, and practices. While the opioid overdose crisis persists, this lack of research inhibits our ability to determine whether overdose prevention efforts, especially involving naloxone, are meeting their needs.MethodsWe conducted semi-structured, qualitative interviews from January to April 2018 with 10 women with experience of opioid use. They were recruited through the study’s community partner in Toronto. Participants provided demographic information, experiences with opioids and naloxone, and their perceptions of the Canadian government’s responses to the opioid crisis. Interviews were transcribed verbatim and inductive thematic analysis was conducted to determine major themes within the data.ResultsThematic analysis identified seven major concerns despite significant differences in participant life and opioid use experiences. Participants who had used illicit opioids since naloxone became available over-the-counter in 2016 were much more knowledgeable about naloxone than participants who had only used opioids prior to 2016. The portability, dosage form, and effects of naloxone are important considerations for women who use opioids. Social alienation, violence, and isolation affect the wellbeing of women who use opioids. The Canadian government’s response to the opioid crisis was perceived as inadequate. Participants demonstrated differing needs and views on ideal harm reduction approaches, despite facing similar structural issues surrounding stigma, addiction management, and housing.ConclusionsParticipants experienced with naloxone use found it to be useful in preventing fatal overdose, however many of their needs with regards to physical, mental, and social health, housing, harm reduction, and access to opioid treatment remained unmet.

Management of pharmaceutical and recreational drug poisoning - Expert consensus-based clinical practice guidelines

Poisoning is one of the leading causes of admission to the emergency department and intensive care unit. A large number of epidemiological changes have occurred over the last years such as the exponential growth of new synthetic psychoactive substances. Major progress has also been made in analytical screening and assays, enabling the clinicians to rapidly obtain a definite diagnosis. A committee composed of thirty experts from five scientific societies, the Société de Réanimation de Langue Française (SRLF), the Société Française de Médecine d’Urgence (SFMU), the Société de Toxicologie Clinique (STC), the Société Française de Toxicologie Analytique (SFTA) and the Groupe Francophone de Réanimation et d’Urgences Pédiatriques (GFRUP) evaluated eight fields : – severity assessment and initial triage; – diagnostic approach and role of toxicological analyses; – supportive care; – decontamination; – elimination enhancement; – place of antidotes; – specificities related to recreational drug poisoning; – characteristics of cardiotoxicant poisoning. Population, Intervention, Comparison, and Outcome (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Analysis of the literature and formulation of recommendations were then conducted according to the GRADE® methodology. The SRLF-SFMU guideline panel provided forty-one statements concerning the management of pharmaceutical and recreational drug poisoning. Ethanol and chemical poisoning were excluded from the scope of these recommendations. After two rounds of discussion and various amendments, a strong consensus was reached for all recommendations. Six of these recommendations had a high level of evidence (GRADE 1 ± ) and six had a low level of evidence (GRADE 2 ± ). Twenty-nine recommendations were in the form of expert opinion recommendations due to the low evidences in the literature. The experts reached a substantial consensus for several strong recommendations for optimal management of pharmaceutical and recreational drug poisoning, mainly regarding the conditions and effectiveness of naloxone and N-acetylcystein as antidotes to treat opioid and acetaminophen poisoning, respectively.

Opioids in Post-stroke Pain: A Systematic Review and Meta-Analysis.

Background: Post-stroke pain is one of the most common sequelae of stroke, which stands among the leading causes of death and adult-acquired disability worldwide. The role and clinical efficacy of opioids in post-stroke pain syndromes is still debated. Objectives: Due to the important gap in knowledge on the management of post-stroke pain, this systematic review aimed at assessing the efficacy of opioids in post-stroke pain syndromes. Methods: A literature search was conducted on databases relevant for medical scientific literature, i.e. PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases from databases inception until August 31st, 2020 for clinical trials assessing the effects of opioids and opioid antagonists on pain reduction and pain related symptoms in patients with post-stroke pain syndromes. Studies assessing the effects of other medications (e.g., tricyclic antidepressant, pregabalin) or non - pharmacological management strategies (e.g., neurostimulation techniques) were excluded. The selected studies have been subjected to examination of the risk of bias. Results: The literature search retrieved 83,435 results. After duplicates removal, 34,285 articles were title and abstract screened. 25 full texts were assessed and 8 articles were identified to be eligible for inclusion in the qualitative summary and narrative analysis, of which three were placebo-controlled and two were dose-response. Among placebo-controlled studies, two evaluated the analgesic effect of morphine and one assessed the effects of the opioid antagonist naloxone on patients with central post-stroke pain. With regard to dose-response studies, both were on patients with central post-stroke pain, one assessing the efficacy of levorphanol, and the other on naloxone. Seven out of eight included studies showed an overall slight analgesic effect of opioids, with less consistent effects on other pain-related symptoms (e.g., mood, quality of life). The randomized controlled trials were subjected to meta-analysis and rating of the quality of evidence for the two outcomes considered according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system. The overall results are inconclusive because of the small number of studies and of patients. Conclusions: The limited number of the included studies and their heterogeneity in terms of study design do not support the efficacy of opioids in post-stroke pain and in pain-related outcomes. Large double-blind randomized clinical trials with objective assessment of pain and related symptoms are needed to further investigate this topic.

Evaluation of the Efficacy of Low-Dose Naloxone for the Prevention of Acute Remifentanil-Induced Hyperalgesia in Patients Undergoing General Anesthesia for Laparotomy

Background: Hyperalgesia is a major complication of continuous or intermittent opioid administration. The evidence suggests that concomitant administration of low-dose naloxone could prevent the development of acute opioid-induced hyperalgesia, with no effect on pain control. Objectives: The current study aimed to assess the effects of intraoperative low-dose naloxone, adding to remifentanil infusion on preventing acute postoperative hyperalgesia in patients undergoing general anesthesia for laparotomy. Methods: In this randomized clinical trial, patients undergoing general anesthesia for laparotomic hysterectomy in a tertiary referral teaching hospital from February to December 2019 were randomly assigned to one of three groups of remifentanil-naloxone (remifentanil 0.3 μg/ kg/min with low-dose naloxone 0.25μg/kg /h prepared in 50 mL of normal saline), remifentanil (0.3 μg/kg/min), and control (receiving 50 mL saline infusion), intraoperatively. Patients and researchers were blinded to the type of intervention. The severity of hyperalgesia, as the main outcome, was evaluated by the static Tactile test. The severity of pain was assessed by visual analogous scale 0.5, 2, 6, 12, and 24 hours after surgery. Results: In total, 75 patients were evaluated. The results showed no difference concerning the independent variables (age, body mass index, hypertension, surgery duration, anesthesia duration, and American Society of Anesthesiologists (ASA) class) between the three groups. Heart rate was significantly different in all study time points between the three groups (P &lt; 0.001), but mean arterial pressure and systolic and diastolic blood pressure showed no significant difference (P &gt; 0.05) throughout the study. Assessment of hyperalgesia using the tactile test revealed a higher incidence of hyperalgesia in the remifentanil group in 0.5, 2, 6, 12, and 24 hours after surgery compared to the other two groups, which was statistically significant between the groups at 0.5, 2, and 6 hours after surgery (P &lt; 0.05). Shivering incidence, Morphine dose in 24 hours post-surgery, morphine dose in the recovery room, and VAS for pain were significantly different during the study between the three groups (P &lt; 0.05). Conclusions: This study demonstrated the efficacy of intraoperative low-dose naloxone (0.25 μg/kg/h) added to remifentanil infusion on reducing the frequency and severity of acute postoperative hyperalgesia in patients undergoing general anesthesia for laparotomy hysterectomy.

Naloxone Diminishes the Virulence and Modifies the Cellular Immune Responses of BALB/c Mice Infected with Leishmania major.

Leishmania major-infected BALB/c mice display strong susceptibility to the infection due to the induction of Th2 response. The aim of this study was to assess the effects of naloxone on virulence of L. major in BALB/c mice and the ensued cellular immuneresponse. The effects of injection of a single dose of naloxone in the footpad of L. major-infected BALB/c mice were investigated by evaluating the lesion sizes, the parasite burden, cell proliferation, secreted cytokines (IFN-γ, IL-4, IL-10 and IL-12) and their genes expressions due to naloxone treatment while the untreated mice were used as a control. Significantly lower lesion sizes and less parasite burden were measured in the treated mice. Significantly decreased productions of IFN-γ, IL-12, IL-4, and IL-10 were also observed in the treated mice at week 4 post-infection while the production IL-10 remained significantly hindered till 8weeks post-infection. Our data indicated that although the treatment of L. major-infected BALB/c mice with a single dose of naloxone was unable to improve the cellular immune response, it led to lower virulence, confirmed by significantly reduced lesions and parasite load.

Divergent Electrophysiological Effects of Loperamide and Naloxone in a Sensitive Whole-Heart Model.

Several case reports suggest QT prolongation leading to ventricular arrhythmias with fatal outcome after intoxication with the μ-opioid receptor agonist and anti-diarrheal agent loperamide. The number of cases of loperamide misuse are growing due to its potential stimulating effects. Loperamide intoxications can be treated by naloxone. However, previous reports described a further QT prolongation associated with naloxone administration. Therefore, the aim of this study was to investigate the effects of loperamide and naloxone on the cardiac electrophysiology in a sensitive whole-heart model. Twenty-six hearts of New Zealand White rabbits were retrogradely perfused in a modified Langendorff apparatus. Monophasic action potentials were recorded by endo- and epicardially positioned catheters. Hearts were stimulated at different cycle lengths, thereby obtaining action potential duration at 90% of repolarization (APD90) and QT intervals. Programmed ventricular stimulation was used to assess ventricular vulnerability. Fourteen hearts were perfused with ascending concentrations of loperamide (0.2μM, 0.35μM, and 0.5μM) after obtaining baseline data. Another 12 hearts were treated with naloxone (0.1μM, 0.5μM, 2μM). Loperamide led to a significant increase in QT interval, APD90, and ventricular tachycardia (VT) episodes. In contrast, naloxone led to a decrease in QT interval and APD90. Accordingly, the number of VT episodes was unaltered. To the best of our knowledge, this is the first experimental study that investigated the effects of loperamide and naloxone in a whole-heart model. Loperamide led to a significant increase in action potential duration and QT interval. Simultaneously, the number of ventricular tachycardias was significantly increased. In contrast, naloxone led to a shortening of the action potential duration without altering arrhythmia susceptibility.

Co-Administration of Morphine and Naloxone: Histopathological and Biochemical Changes in the Rat Liver

Background: Co-administration of opioid agonists and antagonists at low doses has been reported to significantly enhance and/or prolong the analgesic effects and reduce or prevent tolerance to or dependence on opioids. Objectives: The current study aimed at evaluating the naloxone effect on morphine-induced histopathological and hematologic changes in rats. Materials and Mehods: Thirty mature male Wistar rats were categorized into three groups (n = 10) in a random manner, including the control group receiving normal saline, the morphine-sole group receiving morphine (5 mg/kg/day), and morphine + naloxone group receiving morphine and naloxone (5 and 0.4 mg/kg/day, respectively). After 50 days, the levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), triglyceride (TG), aspartate aminotransferase (AST), cholesterol, and high-density lipoprotein (HDL) were measured in the serum. Moreover, the levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione peroxidase (GPx) were measured to assess the serum antioxidant capacity. Histopathological changes were investigated via hematoxylin and eosin, Masson’s trichrome, and periodic acid-Schiff staining. Inter-group comparisons were made by GraphPad Prism software using one-way ANOVA and Tukey’s test. Results: The animals in the morphine + naloxone group showed higher AST, ALP, ALT, and CAT levels in comparison with the control and morphine-sole groups (P &lt; 0.05). Our findings revealed no changes in the cholesterol, TG, SOD, and GPx levels among the groups (P &gt; 0.05). However, the morphine-sole group exhibited higher serum levels of HDL compared with the controls (P &lt; 0.05). The morphine-sole group showed fibrosis, local necrosis, immune cell infiltration, and diminished intra-cytoplasmic carbohydrate storage. Conclusions: The findings suggest that apart from unchanged serum markers, morphine can potentially induce hepatotoxicity, and at the same time, naloxone is able to ameliorate morphine-induced histopathological damages.

Epidural Naloxone Attenuates Fentanyl Induced PONV in Patients Undergoing Lower Limb Orthopaedic Surgeries. a Prospective Randomized Double-Blind Comparative Study.

Background and aimEpidural administration of opioids with local anaesthetics is a popular choice for perioperative pain relief. But opioid induced side effects limit their use for postoperative analgesia. Hence, this study was designed to evaluate the effectiveness of epidural naloxone, an opioid receptor antagonist, in reducing PONV in patients receiving epidural fentanyl.MethodsAfter obtaining the Institutional Ethics Committee approval and written informed consent, 46 patients, between 18–80 years, of either sex, with ASA physical status 1–3, undergoing lower limb orthopaedic surgeries were enlisted for this prospective, randomized, double blind comparative study. Subjects were allocated to one of the two groups and received epidurally, either fentanyl with bupivacaine (Group C, n = 23) or fentanyl with bupivacaine and naloxone 2 mcg (Group N, n = 25), for reducing postoperative pain. PONV score and Wong Bakers Scale (WBS) for pain score were recorded at 6, 12 and 18hrs, postoperatively.ResultsAll patients were comparable with respect to age, gender, ASA PS, height, body weight as well as duration of surgery. A statistically significant decrease in PONV score was observed in Group N at 6 and 12 hours, postoperatively. The patients who required rescue antiemetic were also significantly lower in Group N at 6 and 12 hours. The mean WBS score for pain also showed significant reduction in Group N at 6 hours, postoperatively.ConclusionConcomitant use of low dose epidural naloxone and fentanyl is effective in attenuating PONV, besides enhancing analgesia in the earlypostoperative period.

Complete essential oils of Laurus nobilis inducing antinociceptive action by opioid mechanism in C-Reflex and spinal Wind-Up model in rat

The essential oil of Laurus nobilis L. was used to test their antinociceptive efficacy. It was applied intraperitoneally (i.p.) to rats subjected to a nociception test (C reflex and spinal wind-up). The results showed that the essential oil applied at higher doses (0.06 mg/Kg) causes a complete abolition of the spinal wind-up, while the C reflex was unchanged, indicating a clear antinociceptive effect. At lower concentrations (0.012 mg/Kg), there was a lowering in the wind-up by 85% within ten minutes of the essential i.p. oil application. Interestingly, there was an effect of naloxone (0.08 mg/Kg i.p.) When applied, a change occurs that almost entirely reversed the antinociception caused by the essential oil from Laurus nobilis. We conclude that there is a significant antinociceptive effect of the essential oil of Laurus nobilis subjected to electric nociception. In addition, it was observed that naloxone reversed the antinociceptive effect (windup) produced by Laurus nobilis.