Doses Of Naloxone Research Articles

Real-world study of multiple naloxone administration for opioid overdose reversal among bystanders

BackgroundThe increasing prevalence of highly potent, illicitly manufactured fentanyl and its analogues (IMF) in the USA is exacerbating the opioid epidemic which has worsened during the COVID-19 pandemic. Narcan® (naloxone HCl) Nasal Spray has been approved by the US Food and Drug Administration as a treatment for opioid-related overdoses. Due to the high potency of IMF, multiple naloxone administrations (MNA) may be needed per overdose event. It is essential to determine the patterns of naloxone use, including MNA, and preferences among bystanders who have used naloxone for opioid overdose reversal.MethodsA cross-sectional web-based survey was administered to 125 adult US residents who administered 4 mg Narcan® Nasal Spray during an opioid overdose in the past year. The survey asked about the most recent overdose event, the use of Narcan® during the event and the associated withdrawal symptoms, and participant preferences regarding dosages of naloxone nasal spray. An open-ended voice survey was completed by 35 participants.ResultsParticipants were mostly female (70%) and white (78%), while reported overdose events most frequently occurred in people who were males (54%) and white (86%). Most events (95%) were successfully reversed, with 78% using ≥ 2 doses and 30% using ≥ 3 doses of Narcan® Nasal Spray. Over 90% were worried that 1 Narcan® box may not be enough for a successful future reversal. Reported withdrawal symptoms were similar in overdose events where 1 versus ≥ 2 sprays were given. Eighty-six percent of participants reported more confidence in an 8 mg versus a 4 mg naloxone nasal spray and 77% reported a stronger preference for 8 mg over 4 mg.ConclusionsMNA occurred in most overdose events, often involving more sprays than are provided in one Narcan® nasal spray box, and participants predominantly expressed having a stronger preference for and confidence in an 8 mg compared to a 4 mg nasal spray. This suggests the need and desire for a higher dose naloxone nasal spray formulation option. Given that bystanders may be the first to administer naloxone to someone experiencing an opioid overdose, ensuring access to an adequate naloxone supply is critical in addressing the opioid overdose epidemic.

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.

Pharmacology and pharmacokinetics of fentanyl toxicity reversal by anti‐fentanyl monoclonal antibodies in combination with naloxone

AIMWidespread access to illicit fentanyl has contributed to an ongoing epidemic of fatal drug overdoses in the United States. The incidence of fatal overdoses in the United States accelerated during the COVID‐19 pandemic, with over 100,000 deaths recorded by April 2021. Fentanyl‐specific monoclonal antibodies (mAb) offer a prophylactic and therapeutic intervention against opioid overdose by binding and sequestering fentanyl in serum, and reducing distribution to the brain. Here, the kinetics of overdose reversal by anti‐fentanyl mAb alone or in combination with naloxone were explored, and the dose‐response relationship between naloxone and high doses of fentanyl in the presence of mAb was evaluated.METHODSTo evaluate the kinetics of fentanyl reversal, fentanyl 0.1 mg/kg was administered to male Sprague‐Dawley rats, and mAb or naloxone was administered fifteen minutes after exposure. Oxygen saturation was monitored constantly for ten minutes following administration of reversal agent. To evaluate duration and extent of protection from further fentanyl exposures, rats were pre‐treated with mAb, naloxone, or a combination, and challenged with increasing doses of fentanyl up to 0.5 mg/kg. Finally, to determine whether the presence of mAb would increase efficacy of naloxone against a lethal dose of fentanyl, 2.25 mg/kg fentanyl was administered, followed by naloxone 0.01 to 1.0 mg/kg.RESULTSThe most rapid reversal of fentanyl toxicity was achieved by intravenous administration of a combination of anti‐fentanyl mAb and naloxone (&lt;1 min). Intravenous naloxone reversed fentanyl toxicity more quickly than subcutaneous naloxone, and intravenous mAb was effective against fentanyl within 4 minutes, similar to subcutaneous NLX. Against further challenges of fentanyl, both mAb and 0.1 mg/kg naloxone were effective against 0.1‐0.2 mg/kg fentanyl, and the combination of mAb and naloxone was effective against doses of 0.5 mg/kg fentanyl or higher. Prophylactic administration of mAb enhanced efficacy of naloxone in reversing a potentially lethal challenge of 2.25 mg/kg fentanyl. Finally, mAb sequestered high concentrations of both fentanyl and its metabolite norfentanyl in serum, and reduced brain concentrations of fentanyl in pre‐exposure scenarios.CONCLUSIONSThese results support translation of mAb as medical countermeasures to prevent and reverse opioid overdose related to fentanyl and its analogs.

Low‐Dose 6β‐Naltrexol Prevents Opioid Dependence Without Affecting Antinociception

We asked whether opioid dependence can be prevented during opioid pain therapy or maintenance therapy of opioid use disorder. We hypothesize that 6β‐naltrexol (6BN) binds to the basally activated μ opioid receptor (MOR) prevalent in dependence and gradually reverts it to its resting state, proposing a novel MOR model (1). Clinical utility of opioid analgesics is compromised by adverse effects and addiction liability, largely mediated by MOR, which displays spontaneous basal activity. It’s upregulation by opioid agonists can contribute to opioid dependence. Acting as inverse MOR antagonists in the dependent state, naltrexone and naloxone cause withdrawal at exceedingly low doses. We had identified 6β‐naltrexol (6BN) as a neutral MOR antagonist, which blocks antinociception and causes withdrawal only at much higher doses, even though its MOR affinity equals that of naltrexone. Weak antagonist potency of 6BN is due to both its neutral antagonism and peripheral selectivity because of slow entry into the brain. Nevertheless, low‐dose 6BN (LD‐6BN; &lt;0.1 mg/kg) potently prevents the development of dependence in adult guinea pigs treated with methadone (6BN IC50=~0.01 mg/kg), presumably a central effect (2). To test whether LD‐6BN establishes meaningful 6BN levels in the brain, we measure blood and brain levels with a highly sensitive mass spectrometry assay. Following an s.c. 6BN dose of 0.02 mg/kg in guinea pigs, blood levels initially exceed brain levels tenfold, consistent with its peripheral selectivity, followed by rapid elimination from blood (t1/2 ~1h). In contrast, 6BN levels increased over 2h and persisted in brain for 8h at 1‐2 nM levels (t1/2 ~5h). Co‐administration of a saturating naloxone dose reduced 6BN brain levels by ~70% at 1‐3h, indicating saturable high affinity binding. The results show that LD‐6BN reaches central opioid receptor sites by slow penetration and long retention in the brain, enabling a possible gradually reversal of upregulated basal MOR activity. LD‐6BN appears to act as a dependence modulator rather than a typical opioid antagonist, accounting for its prevention of opioid dependence during agonist treatment, and possibly other aspects of opioid addiction.1. W. Sadee, J. Oberdick, Z. Wang. Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management. Molecules 25, 4163; doi:10.3390/molecules25184163 (2020)2. A. Safa, A.R. Lau, S., Aten, K. Schilling, K.L. Bales, V. Miller, J. Fitzgerald, M. Chen, K. Hill, K. Dzwigalski, K. Obrietan, M.A. Phelps, W. Sadee, J. Oberdick. Pharmacological prevention of neonatal opioid withdrawal in a pregnant guinea pig model. Front. Pharmacol, DOI: 10.3389/fphar.2020.613328 (2021)

Acute Opioid Withdrawal Following Intramuscular Administration of Naloxone 1.6 mg: A Prospective Out-Of-Hospital Series

Large doses of intramuscular (IM) naloxone are commonly used in out-of-hospital settings to reverse opioid toxicity; however, they are used less commonly in hospitals because of concerns about opioid withdrawal, particularly agitation. We aimed to determine the frequency of severe agitation following a single 1.6 mg IM naloxone dose. We undertook a prospective study of adult (>15 years) patients treated by an Australian state ambulance service with 1.6 mg IM administration of naloxone for respiratory depression (respiratory rate <11 breaths/min and/or oxygen saturation <93% in room air) caused by presumed opioid poisoning. The primary outcome was the proportion of presentations with severe agitation (Sedation Assessment Tool score >1) within 1 hour of naloxone administration. Secondary outcomes were the proportion of presentations with acute opioid withdrawal (tachycardia [pulse rate >100 beats/min], hypertension [systolic >140 mm Hg], vomiting, agitation, seizure, myocardial infarction, arrhythmia, or pulmonary edema), and reversal of respiratory depression (respiratory rate >10 breaths/min and saturation >92% or Glasgow Coma Scale score 15). From October 2019 to July 2021, there were 197 presentations in 171 patients, with a median age of 41 years (range, 18 to 80 years); of the total patients, 119 were men (70%). The most common opioids were heroin (131 [66%]), oxycodone (14 [7%]), and morphine (11 [6%]). Severe agitation occurred in 14 (7% [95% confidence interval {CI} 4% to 12%]) presentations. Opioid withdrawal occurred in 76 presentations (39% [95% CI 32% to 46%]), most commonly in the form of tachycardia (18%), mild agitation/anxiety (18%) and hypertension (14%). Three presentations (1.5%) received chemical sedation for severe agitation within 1 hour of naloxone administration. A single 1.6 mg dose of naloxone reversed respiratory depression in 192 (97% [95% CI: 94% to 99%]) presentations. Severe agitation was uncommon following the administration of 1.6 mg IM naloxone and rarely required chemical sedation.

Brief Report: Higher Fentanyl Exposures Require Higher Doses of Naloxone for Successful Reversals in a Quantitative Systems Pharmacology Model

Background: Previously, we reported on an opioid receptor quantitative systems pharmacology (QSP) model to evaluate naloxone Methods: In this study, we extended our model to include higher systemic levels of fentanyl (up to 100 ng/ml) and the newly approved 8mg IN naloxone dose (equivalent to 4 mg) Results: As expected, at the lower peak fentanyl concentrations (25 ng/ml and 50 ng/ml), the simulations predicted that 2 mg, 4 mg, 5 mg, and 10 mg IM doses of naloxone displaced fentanyl and reached below the 50% receptor occupancy within 10 minutes. However, at the concentration of 75 ng/ml, the simulation predicted that the 2 mg dose of naloxone failed to reach below the 50% occupancy within 10 minutes. Interestingly, at the highest peak concentration of fentanyl studied (100 ng/ml), the model predicted that the 4 mg of naloxone IM (equivalent to 8 mg IN) failed to reach below the threshold of 50 % occupancy within 10 minutes or even within 15 minutes (data not shown). In contrast, the model predicted successful reversals when 5 and 10 mg IM doses were utilized. Conclusion: These results support the notion that acutely administered higher doses of naloxone are needed for rapid and adequate clinical reversal, particularly when higher systemic exposure of the potent synthetic opioids occurs.

Naloxone-associated pulmonary edema following recreational opioid overdose.

Describe a series of patients who developed naloxone-associated pulmonary edema after recreational opioid use. Single center retrospective case series of patients who developed pulmonary edema following the prehospital administration of naloxone. Academic, urban safety-net hospital. Adults with recreational opioid overdose who developed naloxone-associated pulmonary edema, defined as the acute onset of respiratory distress, hypoxemia, and radiographic pulmonary edema after naloxone administration for opioid intoxication, provided that gas exchange and chest imaging rapidly improved and pulmonary aspiration of gastric contents was not clinically suspected. Ten adults (median age 23years, 90% male) met our case definition for naloxone-associated pulmonary edema. Implicated opioids were heroin in 8 patients and methadone and oxycodone in 1 patient each. The median total dose of naloxone was 4.25mg (interquartile range [IQR] 3.3-9.8) prior to the onset of clinically-apparent pulmonary edema. Seven patients received invasive mechanical ventilation for a median of two days (IQR 0.8-5), one of whom received veno-venous extracorporeal membrane oxygenation support, and all survived to hospital discharge. Severe acute pulmonary edema may follow naloxone administration after recreational opioid overdose. Acute care clinicians should be aware of this potentially life-threatening adverse effect of naloxone.

As the opioid epidemic takes a turn for the worse, do we need more potent forms of naloxone?

Federal agencies like FDA and CDC have cited the need for higher doses of naloxone to reverse opioid overdoses, especially as fentanyl and other synthetic opioids have crept into illegal drugs, causing overdose deaths to skyrocket.

Epidural Posterior Insular Stimulation Alleviates Neuropathic Pain Manifestations in Rats With Spared Nerve Injury Through Endogenous Opioid System

ObjectivesNeuropathic pain (NP) is defined as constant disabling pain secondary to a lesion or disease of the somatosensory nervous system. This condition is particularly difficult to treat because it often remains resistant to most treatment strategies. Despite the recent diversification of neurostimulation methods, some patients still suffer from refractory pain syndromes. The central role of the posterior insular cortex (PI) in the modulation of pain signaling and perception has been repeatedly suggested. The objective of this study is to assess whether epidural insular stimulation (IS) could reverse NP behavior. Materials and MethodsA total of 53 adult Sprague-Dawley rats received left-sided spared nerve injury (SNI) or Sham-SNI to induce NP symptoms. Afterward, epidural electrodes were implanted over the right PI. After two weeks of postoperative recovery, three groups of SNI-operated rats each received a different stimulation modality: Sham-IS, low-frequency-IS (LF-IS), or high-frequency-IS (HF-IS). Behavioral and functional tests were conducted before and after IS. They comprised the acetone test, pinprick test, von Frey test, and sciatic functional index. An additional LF-IS group received a dose of opioid antagonist naloxone before IS. Intergroup means were compared through independent-samples t-tests, and pre- and post-IS means in the same group were compared through paired t-tests. ResultsWe found a significant reduction of cold allodynia (p = 0.019), mechanical hyperalgesia (p = 0.040), and functional disability (p = 0.005) after LF-IS but not HF-IS. Mechanical allodynia only showed a tendency to decrease after LF-IS. The observed analgesic effects were reversed by opioid antagonist administration. ConclusionThese results suggest a significant reversal of NP symptoms after LF-IS and offer additional evidence that IS might be beneficial in the treatment of resistant NP syndromes through endogenous opioid secretion. Relying on our novel epidural IS model, further fine tuning of stimulation parameters might be necessary to achieve optimal therapeutic effects.

Physiological dependence to mitragynine indicated by a rapid cross-dependence procedure with heroin-dependent mice.

The potential of mitragynine to produce physiological dependence (withdrawal) was assessed using a rapid assessment procedure with male ICR mice exposed to heroin-admixed food followed by naloxone (subcutaneously, s.c.) precipitation of withdrawal. Initial studies indicated that 3 days of exposure to 3.0 mg/g of heroin-admixed food followed by naloxone (0.6 mg/kg) reliably precipitated withdrawal jumping and weight loss. Lower concentrations of heroin-admixed food and lower doses of naloxone produced fewer withdrawal signs. A longer exposure to heroin-admixed food did not produce significantly greater amounts of jumping or weight loss. Further, these withdrawal signs were dose-dependently reversed by s.c. administration of heroin immediately following naloxone administration. Mitragynine (s.c.) also dose-dependently suppressed naloxone-precipitated withdrawal signs. Additionally, both jumping and weight loss were suppressed over a comparable range of mitragynine doses when administered by gavage with a noticeably, but not significantly, higher potency than with s.c. administration. The ED50 values for mitragynine for the suppression of withdrawal by any route (354-911 μmol/kg) were greater than the minimally effective dose that decreased locomotor activity (251 μmol/kg) and from 40- to 104-fold greater than those for heroin. The results suggest inherent opioid dependence liability of mitragynine. The in vivo potency relations between mitragynine and heroin are consistent with a conclusion of dependence-producing effects, indicated by the suppression of withdrawal, comparable to standard opioid μ-receptor agonists, differing primarily in terms of potency. The present paper provides a method for the rapid assessment of physiological dependence liability applicable to other kratom plant constituents or any potential opioid dependence-producing agents.

Low dose naloxone for pruritus in systemic sclerosis: Case series and literature review.

Rationale:Pruritus is a common symptom in patients with systemic sclerosis and has a tremendous effect on the quality of life. Nevertheless, current therapeutic options are limited. The pathogenesis of pruritus in systemic sclerosis is not completely understood; however, opiate-mediated neurotransmission has been postulated to be involved.Patient concerns and diagnosis:We describe 4 female patients with systemic sclerosis suffering from severe pruritus, with an average 5D-itch score of 22.75.Intervention and outcomes:Low-dose oral naloxone was initiated, followed by a significant improvement in the level of pruritus, reaching an average 5D-itch score of 7.5, after 6 and 12 months of treatment. None of the patients experienced side effects.Lessons:Low-dose naloxone plays an important role in the management of pruritus in systemic sclerosis.

Implementation of a Prenatal Naloxone Distribution Program to Decrease Maternal Mortality from Opioid Overdose.

IntroductionMaternal mortality rates have been increasing in the United States for decades. For several years, opioid overdoses have been a leading cause of maternal mortality in several states. New Hampshire (NH) is a particularly severe case, with 50% of all maternal deaths being caused by drug-related overdoses from 2016 to 2017. We report on the implementation of a point-of-care naloxone distribution program for an Ob/Gyn clinic in NH.MethodsNaloxone distribution was tracked to measure program implementation. Proportion of patients screened for naloxone need was calculated monthly. Proportion of patients with which discussions about naloxone took place was calculated quarterly. Patient and provider perspectives on the program were captured periodically. Statistical process control charts monitored change over time and evaluated for special-cause variation.ResultsThe clinic has distributed 12 doses of naloxone since program implementation in April 2020. Despite the challenges posed by the COVID-19 pandemic, screening for naloxone need has remained at pre-pandemic rates (moving average: 73%), except for a decrease in April–May 2020. Patient-provider discussions about naloxone have also remained at pre-pandemic rates (moving average: 51%). Qualitative feedback from patients and providers has indicated that the program has been well-received by both groups.DiscussionThe purpose of this description is to provide a framework for other Ob/Gyn clinics to use in implementing similar naloxone distribution programs. Although too early to determine whether this intervention will result in a significant decrease in maternal mortality due to opioid overdose in our patients, this measure will continue to be tracked annually. Implementation of a naloxone program in the obstetrical context provides an important way to improve outcomes for a vulnerable perinatal population.

Impact of an overdose reversal program in the context of a safe consumption site in Northern Mexico

BackgroundDrug overdoses are prevalent in low- and middle-income countries but are scarcely reported in the literature. We report on an opioid overdose reversal and naloxone distribution program that was instituted at the first safe consumption site in Latin America. MethodsA cross-sectional analysis of witnessed drug overdoses and naloxone distribution between 1 June 2019 and 31 May 2021 in Mexicali, Mexico. Case report forms were entered in an electronic database. Trends in overdose and naloxone distribution were described. Comparisons were made before and after the COVID-19 pandemic was declared in the city. Maps were created to represent the geographic distribution of overdose in the city. ResultsDuring the study period 1,534 doses of naloxone were distributed throughout the community. In addition, there were 464 overdoses reported during this period, of which 4 were fatal. There was a 30% increase in reported overdoses from the period before the COVID-19 pandemic to the period after the pandemic was declared (p = 0.03). Most common substance reported included heroin (93%), sedatives (21%), methamphetamine (16%) and fentanyl (14%). Naloxone was given in 96% of cases (median 1 dose, IQR 1–2 doses) and emergency services were called in 20% of cases. ConclusionsAn opioid overdose reversal program in Mexicali, Mexico was able to distribute naloxone and register drug overdoses between 2019 and 2021 as a harm reduction strategy. This adds to the growing body of literature on the impact of community-based programs on preventing fatal overdoses and the potential for implementation in low-resource settings.

The effect of different doses of naloxone on postoperative hyperalgesia in patients who received high-dose remifentanil during hysterectomy procedures; a double-blind randomized clinical trial

BackgroundHyperalgesia is one of the adverse effects of remifentanil, an opioid drug used for reducing pain in surgical procedures. Naloxone is used for reversing the adverse effects of opioids and can reduce this acute and persistent pain after surgery. In the present study, we aimed to investigate the effect of two doses of naloxone (high and low doses) for reducing hyperalgesia after hysterectomy. MethodsIn this single-blinded randomized clinical trial, 72 patients who underwent hysterectomy with ASA class I and II were randomly divided into three groups of 24 participants. All three groups received an intraoperative infusion of 0.4 micrograms/kg/min of remifentanil.One group received 0.02 µg/kg/min naloxone, the other group received 0.05 µg/kg/min naloxone, and the third group received 0.2 cc/kg normal saline instead of naloxone. The results of the visual analogue scale, Ramsay score, and pressure algometry were completed for all participants half an hour before the surgery, one hour, two, and eight hours after the surgery, pethidine requirement, and postoperative nausea/vomiting and the Ramsay score were recorded. Comparison of variables among the groups was performed using one-way ANOVA and posthoc tests by SPSS software, version 21. ResultsThe mean age of the participants was 48.63±9.85 years. The pressure algometry of the right and left forearms and abdomen was different among the three groups after surgery (P<0.05). There was no difference in mean pethidine requirement at recovery and in general, visual analogue scale score, Ramsay score 1 hour and 8 h after the surgery, and the frequency of postoperative nausea and vomiting among the three groups (P>0.05). ConclusionThe similar efficacy and adverse effects of the two doses indicate that the low dose of naloxone is suggested for reducing remifentanil-induced hyperalgesia after hysterectomy.

Endogenous Insulin: Study on Pain Threshold through Opioid Mechanism in Swiss Albino Mice

<p style="text-align: justify;"><strong>Background:</strong> There is no definitive conclusion on relationship between insulin and pain threshold through opioid mechanism in experimental animal model. The present study investigated the role of endogenous insulin in the modulation of pain using opioid drugs through opioid mechanism and their relationship in experimental animal model. <strong>Methods:</strong> Eight animal groups were used, each group consisting of six mice (Swiss albino). Group 1-treated saline ip; Group 2- administered pentazocine ip; Group 3- treated naloxone in low dose (0.005 mg/kg, ip) 15 min prior to pentazocine treatment; Group 4- administered naloxone in high dose (5 mg/kg, ip)15 min prior to pentazocine treatment. Another four groups of animals (Group 5, 6, 7 and 8) treated saline, pentazocine, low dose and high dose naloxone both administered 15 min prior to pentazocine treatment respectively. Group 1,2,3 and 4 subjected to acetic acid challenge and Group 5,6, 7 and 8 subjected to formalin test. Blood samples were collected and serum insulin was estimated by ELISA and blood glucose was measured by using Ames glucometer. <strong>Results:</strong> Pentazocine significantly increased both serum insulin and antinociceptive response to nociceptive stimuli to acetic acid as well as formalin challenge without significantly affecting plasma glucose in both pain models as compared to saline control. <strong>Conclusion: </strong>The study concluded that possible association between endogenous insulin and pain threshold which is independent of the glycemic status in both the chemically induced nociceptive tests. The relationship between endogenous insulin and pain threshold involves an interaction with opioid system possibly by binding with kappa receptor. <strong>Key words: </strong>Endogenous insulin, Plasma glucose, Pentazocine, Pain thresholds, Mice.

Naloxone Use for Opioid Reversal in Patients with Sickle Cell Disease

Patients with sickle cell disease (SCD) are known to require increased dosing of drugs including opioids due to differences in renal and hepatic metabolism. While it is known that SCD patients require higher opioid doses to achieve the same degree of analgesia, it is not clear if this is associated with a similar increase in drug toxicities. A significant risk of opioid use is respiratory depression, and naloxone is used for rapid reversal of this adverse effect. In the setting of a nationwide opioid shortage in 2018, our institution established a policy requiring the use of patient-controlled analgesia (PCA) rather than intravenous push (IVP) for hospitalized SCD patients. This coincided with a mandate for end tidal carbon dioxide (ETCO) monitoring with PCA use, effectively implementing ETCO in the routine care of this population. In this study, we describe our experience using naloxone for opioid reversal in hospitalized SCD patients.We studied naloxone use in patients admitted to the University of Illinois at Chicago for two 24-month time periods (July 31, 2015 - July 31, 2017 and May 1, 2018 - May 1, 2020). These dates were chosen to compare naloxone use before and after implementation of ETCO monitoring. A pharmacy reporting tool was used to identify every dose of naloxone administered within the hospital during these dates. We isolated patients on the inpatient sickle cell service and compared the proportion of SCD patients between study periods using Fisher's exact test. For SCD patients who received naloxone, we obtained baseline patient characteristics and divided doses into episodes when multiple doses were given within a day. For each episode, we studied analgesic regimens, details of the hospitalization, and laboratory values. Given the small data sample, we used descriptive statistics for analysis.Among 931 total naloxone doses given in the two time periods, 35 were given to SCD patients. Out of 580 total distinct patients, there were 14 patients admitted to the sickle cell service. There were 5 out of 279 (1.8%) SCD patients who received 12 out of 443 (2.7%) doses between July 2015 and July 2017. There were 10 out of 309 (3.2%) SCD patients who received 23 out of 488 (4.7%) doses between May 2018 and May 2020. There was no significant difference in naloxone use by SCD patients before and after implementation of ETCO. For the two time periods combined, there were 14 out of 580 (2.4%) SCD patients who received 35 out of 931 (3.8%) doses. We were able to manually confirm 10 SCD patients and 17 episodes of naloxone use by chart review. Among these, 2 patients who only had 1 episode each received naloxone in the absence of opioid overdose. One patient with multiple episodes had an episode of receiving naloxone for opioid overdose not involving hospital-administered medications. Among the remaining 8 SCD patients who appropriately received naloxone for opioid reversal in the hospital, 100% were black or African American race. Seven (87.5%) out of 8 had Hgb SS genotype, and male-to-female ratio was 1:1. Six out of 14 (42.9%) episodes occurred when patients were not receiving their usual pain regimen. Vaso-occlusive crisis was a diagnosis for 13 out of 14 (92.9%) episodes. A median of 2 doses of naloxone were given per episode. Median creatinine clearance was 20.85 mL/min, and several cases coincided with acute kidney injury. Median sedation scale score prior to naloxone dose was 1 (minimally sedated). One patient was treated with a naloxone continuous infusion.Our study highlights the relatively low use of naloxone in patients with SCD despite generally high usage of opioids. Nearly every patient admitted to the sickle cell service utilizes opioid pain medications, but the proportion of naloxone use in SCD patients is small. There was no significant difference in naloxone use after policy changes instituted the use of ETCO, but this may be due to sample size. The low rates of naloxone use in SCD patients may be related to mechanisms of hyperfiltration that necessitate increased opioid dosing. Our results suggest that the higher observed opioid dosages are not associated with worsened toxicities in SCD patients. With techniques such as ETCO, SCD patients can more safely be treated for pain using opioid medications, and providers should be mindful of pertinent pharmacological factors when caring for this population. DisclosuresSaraf: Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Accidental Opioid Intoxication in Children Treated With Low Doses of Naloxone: A Case of Fentanyl Patch Exposure and a Case of Morphine Tablet Ingestion

Accidental opioid intoxication in children is a rare affection in morocco, its recognition and management must be immediate to avoid its life threatening complications. In a period of two years (September 2019 - September 2021), two cases of severe opioid intoxication in children have been admitted in the intensive care department of the children’s hospital of Rabat. The first case is a 9 years old child admitted for tonic-clonic seizures with acute respiratory distress due to Fentanyl intoxication after being exposed to a skin patch dosed 75 μg/hour, he required mechanical ventilation and was treated with a bolus of 0,8 mg of Naloxone completed with continuous infusion for 48 hours with favorable evolution and hospital release in 5 days. The second case is a 2 years 5 months old child admitted for decreased consciousness with bradypnea due to morphine intoxication after oral ingestion of 5 extended-release morphine tablets dosed 30 mg each, treated with a single bolus of 0,8 mg of Naloxone with rapid improvement.

240 An Investigation into the Link Between Naloxone and Pulmonary Edema

Though naloxone has proven to be an effective opioid reversal agent, the largely unsubstantiated theory that high doses of naloxone can cause pulmonary edema prevents many healthcare providers from initially administering it in high doses. This is especially problematic given high prevalence fentanyl and its analogues, which typically require higher doses of Narcan for reversal. The purpose of this study is to investigate the correlation between naloxone dosages and route and the corresponding rates of development of pulmonary complications. This is a retrospective, observational, cross-sectional study of patients who were treated with naloxone during out-of-hospital transport by Emergency Medical Services (EMS) or in the emergency department (ED) at an urban level 1 trauma center and three associated free-standing EDs over a two year period. For the purpose of this investigation, we defined low doses of naloxone as ≤2 mg, moderate doses of naloxone as >2 mg to ≤4 mg, and high doses of naloxone as >4 mg. Hospital records were scrutinized for naloxone dosing, route of administration (intranasal, intra-osseous, intravenous, mixed, or unknown), and development of pulmonary complications. In total, 639 patients received naloxone and were included in the study. A total of 422 (69.2%) of the patients received low doses of naloxone, 138 (21.6%) received moderate doses of naloxone, and 79 (12.4%) received high doses of naloxone. A total of 13 (2.0%) were ultimately diagnosed with pulmonary complications. Of the patients who were diagnosed with pulmonary complications, six of them were diagnosed with pneumonia, four of them were diagnosed with aspiration pneumonia, and three of them were diagnosed with pulmonary edema. Of the patients who developed pulmonary complications, eight had received a low dose of naloxone, four had received a moderate dose of naloxone, and one had received a high dose of naloxone. There was no significant difference of the development of pulmonary edema, pneumonia, or aspiration pneumonia in the patients who received low, moderate, or high doses of naloxone (p values 0.711, 0.271, and 0.551 respectively). A total of 13 out of the 639 patients who received naloxone for resuscitation developed pulmonary complications. Of the patients who received high-dose naloxone, only one of developed pulmonary complications compared to eight from the low-dose group. There was no significant difference in the development of pulmonary complications between the groups who had received naloxone exclusively through an IV or intranasally (p=0.342). There were no differences in pulmonary edema, aspiration pneumonia or pneumonia between those who received high, medium or low doses of naloxone. Receiving a high dose of naloxone was not associated with a longer hospital stay than the groups who received moderate and low doses.

Role of ultralow dose of naloxone as an adjuvant to fentanyl-bupivacaine in thoracic paravertebral block analgesia after modified radical mastectomy: Randomized controlled trial.

We evaluated the effect of the addition of 100 ng of naloxone to fentanyl-bupivacaine mixture used in thoracic paravertebral block (PVB) on the duration and the quality of post-mastectomy analgesia. A randomized double-blinded trial. Oncology surgery unit. This study included 135 patients, aged 40-60 years of either sex presented for elective unilateral-modified radical mastectomy. Patients were divided randomly into three groups: group I, received 0.3 mL/kg of 0.25 percent bupivacaine; group II, received 0.3 mL/kg of 0.25 percent bupivacaine, fentanyl 50 µg, and naloxone 100 ng; group III, received 0.3 mL/kg of 0.25 percent bupivacaine and fentanyl 50 µg. The visual analog scale was assessed immediately post-operative, every 2 hours till 12 hours, and then every 6 hours for 24 hours; the time of first and total amount of rescue analgesia and side effects during the first 24 hours were recorded. Group II showed a significant prolonged analgesia with a delayed first request of rescue analgesia and lower amount of morphine (592.1 ± 14.9 minutes and 7.28 ± 7.81 mg, respectively) than groups I (127.7 ± 35.1 minutes and 19.84 ± 2.56 mg, respectively) and III (232.2 ± 9.27 minutes and 13.52 ± 1.74 mg, respectively) as p < 0.001. Using naloxone as additives in PVB has been promising and effective in controlling post-mastectomy pain.

Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids.

Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. Widespread clinical use of prescription opioids for moderate to severe pain contributed to the ongoing opioid epidemic with the subsequent emergence of fentanyl-laced heroin. More potent analogues of fentanyl and structurally diverse opioid receptor agonists such as AH-7921 and MT-45 are fueling an increasingly diverse illicit opioid supply. Overdose from synthetic opioids with high binding affinities may not respond to a typical naloxone dose, thereby rendering autoinjectors less effective, requiring higher antagonist doses or resulting in a confusing clinical picture for health care providers. Nonscheduled opioid drugs such as loperamide and dextromethorphan are associated with dependence and risk of overdose as easier access makes them attractive to opioid users. Despite a common opioid-mediated pathway, several opioids present with unique pharmacodynamic properties leading to acute toxicity and dependence development. Pharmacokinetic considerations involve half-life of the parent opioid and its metabolites as well as resulting toxicity, as is established for tramadol, codeine, and oxycodone. Pharmacokinetic considerations, toxicities, and treatment approaches for notable opioids are reviewed.