Exploring the Contribution of Pharmacists in Addressing the Opioid Crisis through Naloxone Prescriptions and Pharmacist-Led Interventions

The opioid epidemic in the United States continues to take the lives of many individuals, with overdoses continuing to rise every year. Naloxone is an opioid antagonist that is efficacious in temporarily reversing opioid overdoses. Pharmacists play an important role in the accessibility and education of naloxone in both the community and health system settings. Recent efforts, such as co-dispensing naloxone with opioid prescriptions, naloxone training programs, and approval of naloxone to be over-the-counter, have been implemented in hopes to better control the opioid epidemic. Despite the efforts to make naloxone more accessible, there are still some barriers to overcome such as lack of training, cost, stigma, and patient refusal. This review aims to explore the contributions pharmacists have made thus far and define the barriers that still have to be resolved.

Pharmacokinetics and Absolute Bioavailability of the Sublingual Naloxone Hydrochloride Tablet in Dogs

The pharmacokinetics and absolute bioavailability of the sublingual naloxone tablet were studied with HPLC-electrochemical detection. Eight male dogs received single 5 mg dose of naloxone intravenously, the plasma concentration-time curves could be fitted to two-compartment open model, with 12.0 min of t1/2( , 143.4 min of t1/2( and 7.92 mg(min/L of AUC. The same eight dogs received 5 mg dose of the sublingual naloxone tablet after an interval of a week. The main pharmacokinetic parameters were: t1/2ka = 11.0 min, t1/2( = 15.4 min, t1/2( = 164.1 min, Tmax = 27.7 min, Cmax = 34.2 ng / ml, and AUC = 6.79 mg(min / L, respectively. The plasma concentration-time curves were fitted to the first order absorption two-compartment open model also. The mean absolute bioavailability of the sublingual naloxone tablet was 86.8 ( 10.9%. No statistically significant differences were found with t1/2(, t1/2(, ( and ( between the two routes of administration. These results indicated that the course of disposition for naloxone in dogs was similar for the two routes of administration, and the absolute bioavailability of the sublingual naloxone tablet was high. Thus satisfactory clinical effects could be expected.

Naloxone or Vagotomy Does Not Influence Centrally Octreotide-induced Inhibition of Gastric Acid Secretion in Rats

Summary： To investigate the effect of preceding naloxone injection into the third cerebroventricle or acute subdiaphragmatic vagotomy on the gastric acid secretion inhibited by the somatostatin analogue octreotide given by intracerebroventricular （icv） injection. The third ventricles were cannulated in male Wistar rats anesthetized with sodium pentobarbital. One week later, acute gastric lumen perfusion was carried out. The gastric perfusion samples were collected every 10 min and were titrated by 0.01 mol/L NaOH to neuter. On the basis of subcutaneous injection of pentagastrin （G-5, 160 g/kg）, icv injection of physiological saline （group A, n=20）, icv injection of octreotide （0.05 μ g） （group B, n=20）, icv injection of naloxone （2.5 μ g）＋octreotide （0.05 μg） （group C, n=20）, acute subdiaphragmatic vagotomy＋ icv injection of physiological saline （group D, n=20）, or acute subdia- phragrnatic vagotomy＋icv injection of octreotide （0.05 μg） （group E, n=20） were conducted. Before and after icv injection, 1-h total acid output （TAO） was determined and compared. The experimental data were expressed in change rate （%） of TAO. The change rates （%） of TAO were 4.60 % in group A, -20.35 % in group B, - 18.06 % in group C, 5.01% in group D and -21.59 % in group E, respectively. Comparison of group B or C versus group A showed that P〈0.01 and comparison between the group E versus group D showed that P〈0.01. Whereas the differences between group C and group B, group E and group B were not statistically significant （P〉0.05 for all）. The results indicate that the central inhibition of gastric acid secretion by octreotide may not be mediated by the endogenous opi- ate substance or its receptor and the peripheral pathway for icv injection of octreotide to suppress gastric acid secretion is via extra-vagus route.

Efficacy and safety of controlled-release oxycodone/naloxone versus controlled-release oxycodone in Korean patients with cancer-related pain: a randomized controlled trial

Background: Controlled-release oxycodone/naloxone(OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present study was designed to assess the non-inferiority of OXN-CR to controlled-release oxycodone(OX-CR) for the control of cancer-related pain in Korean patients.Methods: In this randomized, open-labeled, parallel-group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer-related pain [numeric rating scale(NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention-to-treat(ITT) population were randomized(1:1) to OXNCR or OX-CR groups. OXN-CR was administered starting at 20 mg/10 mg per day and up-titrated to a maximum of80 mg/40 mg per day for 4 weeks, and OX-CR was administered starting at 20 mg/day and up-titrated to a maximum of 80 mg/day for 4 weeks.The primary efficacy endpoint was the change in NRS pain score from baseline to week4, with non-inferiority margin of-1.5. Secondary endpoints included analgesic rescue medication intake, patientreported change in bowel habits, laxative intake, quality of life(QoL), and safety assessments.Results: Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN-CR group(n = 58) and the OX-CR group(n = 59)(-1.586 vs.-1.559,P = 0.948). The lower limit of the one-sided 95% confidence interval(-0.776 to 0.830) for the difference exceeded the non-inferiority margin(P < 0.001). The OXN-CR and OX-CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments.Conclusions: OXN-CR was non-inferior to OX-CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in larger populations of Korean patients with cancer-related pain are needed to further investigate the effectiveness of OXN-CR for long-term pain control and constipation alleviation.Trial registration ClinicalTrials.gov NCT01313780, registered March 8。

EFFECTS OF NALOXONE ON THE CHANGES OF PAIN THRESHOLD AND CONTENTS OF MONOAMINE NEUROTRANSMITTERS IN RAT BRAIN INDUCED BY EA

5-HT content in medulla oblongata plus pons and DA level in brain stem obviously increased,while NA concentration in telencephalon markedly decreased in EAA.A previous injection ofnaloxone,a blocker of opiate receptor,could partially inhibit the EAA,abolish the effects ofEA’s increasing the 5-HT content in the medulla oblongata plus pons and the DA level in thebrain stem,and decrease the NA level in the diencephalon after EA.These results indicate thatEA may mediate the metabolism of the central monoamine neurotransmitters partially via opiatereceptor to exert its analgesic effect.

Sodium alginate and naloxone loaded macrophage-derived nanovesicles for the treatment of spinal cord injury

Spinal cord injury(SCI)causes Ca^(2+) overload,which can lead to inflammation and neuronal apoptosis.In this study,we prepared a nanovesicle derived from macrophage membrane(MVs),which encapsulated sodium alginate(SA)and naloxone(NAL)to inhibit inflammation and protect neurons by reducing the free Ca^(2+) concentration at the SCI site.Based on the transmission electron microscopy(TEM)image,the encapsulated sample(NAL–SA–MVs)had a particle size of approximately 134±11 nm and exhibited a sustained release effect.The encapsulation rate of NAL and SA was 82.07%±3.27%and 72.13%±2.61%in NAL–SA–MVs,respectively.Targeting tests showed that the NAL–SA–MVs could accumulate in large quantities and enhance the concentration of SA and NAL at the lesion sites.In vivo and in vitro studies indicated that the NAL–SA–MVs could decrease the concentration of free Ca^(2+),which should further alleviate the inflammatory response and neuronal apoptosis.Anti-inflammation results demonstrated that the NAL–SA–MVs could reduce the pro-inflammation factors(iNOS,TNF-α,IL-1β,IL-6)and increase the expression of antiinflammation factors(IL-10)at the cell and animal level.Concurrently,fluorescence,flow cytometry and western blot characterization showed that the apoptotic condition of the neurons was significantly inhibited.In addition,the motor function of C57 mice were significantly improved after NAL–SA–MVs treatment.In conclusion,it is suggested that the NAL–SA–MVs has tremendous potential in the treatment of SCI.

Effect of Morphine and Naloxone on Release of the Excitatory Amino Acids of Spinal Astrocytes Induced by TNF-α

The effect of morphine and naloxone on release of the excitatory amino acids (EAAs) of spinal astrocytes induced by TNF-α was studied. Astrocytes were purified from 2- to 3-day old SD rats and divided into 8 groups: group 1 (without any stimulatants); group 2 (10 ng/ml TNF-α); group3 (10 ng/ml TNF-α+0.5 μmol/L morphine); group 4 (10 ng/ml TNF-α+1.0 μmol/L morphine); group 5 (10 ng/ml TNF-α+2.0 μmol/L morphine); group 6 (10 ng/ml TNF-α+0.5 μmol/L naloxone); group 7 (10 ng/ml TNF-α+1.0 μmol/L naloxone); group 8 (10 ng/ml TNF-α+2.0 μmol/L naloxone). In group 2, 3, 4 and 5, 0, 0.5, 1.0 or 2.0 μmol/L morphine was added to the cells cultured with serum-free Neurobasal/B27 medium containing 10 ng/ml TNF-α respectively, while in group 6, 7 and 8, 0.5, 1.0 or 2.0 μmol/L naloxone was added respectively to the cells cultured with serum-free Neurobasal/B27 medium containing 10 ng/ml TNF-α. After 30 min incubation, high-pressure liquid chromatography (HPLC) was used to measure the levels of EAAs in all cultured cells. The results showed the level of EAAs in group 2 was significant higher than in group 1 (P<0.01). As compared with group 2, the levels of EAAs in group 3, 4 and 5 were decreased with the difference being significant between group 5 and group 2 (P<0.01) or between group 4 and group 2 (P<0.05). The levels of EAAs in group 6, 7 and group 8 was significantly lower than in group 2 (P<0.05 or P<0.01). It was concluded that TNF-α could promote the release of glutamate and aspartate from astrocytes, and morphine and naloxone might reduce the release of EAAs in cultured spinal astrocytes induced by TNF-α.

Optimal compatible doses and effects of ephedrine and naloxone on neural plasticity in cerebral ischemia/reperfusion rats

BACKGROUND： Ephedrine promotes neural plasticity in rats following cerebral ischemia/reperfusion injury. Ephedrine has been combined with naloxone in some studies, and it has been confirmed that their combination has synergistic effects on increasing neural plasticity following cerebral ischemia/reperfusion injury. OBJECTIVE： To investigate the effects of ephedrine combined with various doses of naloxone on neural plasticity and to find an optimal dose of naloxone in rats after cerebral ischemia/reperfusion injury by analyzing growth associated protein-43 （GAP-43）, synaptophysin and β-endorphin expression in the hippocampal CA3 area. DESIGN, TIME AND SETTING： This immunohistochemical, randomized, controlled, animal experiment was performed at the Chongqing Research Institute of Pediatrics, China from September 2007 to June 2008. MATERIALS： Ephedrine hydrochloride injection and naloxone hydrochloride injection were respectively purchased from Shandong Lvliang Pharmaceutical Factory, China and Sichuan Jingwei Pharmaceutical Co., Ltd., China. A total of 192 healthy adult Sprague Dawley rats were used to establish models of left middle cerebral artery occlusion using the suture occlusion method. METHODS： At 2 hours following cerebral ischemia, the rats were intraperitoneally injected with 1.5 mg/kg/d ephedrine （ephedrine group）, with 0.1, 0.2, or 0.3 mg/kg/d naloxone （low, moderate and high doses of naloxone groups）, with 1.5 mg/kg/d ephedrine ＋ 0.1, 0.2, or 0.3 mg/kg/d naloxone （ephedrine ＋ low, moderate and high doses of naloxone groups）, and with 0.5 mL saline （model group）, respectively. MAIN OUTCOME MEASURES： GAP-43, synaptophysin and β -endorphin expression were detected in the hippocampal CA3 area using immunohistochemistry 1-4 weeks after surgery. Sensorimotor integration in rats was assessed using the beam walking test. RESULTS： GAP-43 and synaptophysin expression was greater in the ephedrine group, and in the ephedrine ＋ moderate and high doses of naloxone groups compared with the model group. GAP-43 and synaptophysin expression was greatest in the ephedrine ＋ high dose of naloxone group at 2 and 3 weeks alter surgery. β -endorphin expression was significantly lower in the ephedrine group, and in the ephedrine ＋ moderate and high doses of naloxone groups compared with the model group （P 〈 0.05）. β -endorphin expression was persistently low in the ephedrine ＋ high dose of naloxone group. At 1-3 weeks after surgery, the beam walking test score was significantly higher in the ephedrine group and ephedrine ＋ various doses of naloxone groups than in the model group （P 〈 0.05）. The score was higher in the ephedrine ＋ moderate and high doses of naloxone groups than in the ephedrine group （P 〈 0.05）. Moreover, the score was increased as the dose of naloxone increased in the ephedrine ＋ various doses of naloxone groups. CONCLUSION： Ephedrine promotes GAP-43 and synaptophysin expression, inhibits /3 -endorphin expression in the hippocampal CA3 area, and improves motor function in rats following cerebral ischemia/reperfusion injury. Naloxone does not have the above-mentioned effects. During combined treatment with ephedrine and naloxone, however, the above-described effects are enhanced with an increased dose of naloxone. The combination of ephedrine （1.5 mg/kg/d） and naloxone （0.3 mg/kg/d） can produce optimal therapeutic efficacy in treatment of cerebral ischemic injury.

Opioid/naloxone prolonged release combinations for opioid induced constipation

I read with great interest the recent article by Chen et al in a recent issue of your esteemed journal.The article is highly thought provoking.One emerging therapeutic alternative for opioid induced constipation is the emergence of opioid/naloxone prolonged release combinations.For instance,naloxone when administered in a 1:2 ratio with oxycodone reverses the inhibitory effect of oxycodone on the gastrointestinal tract.The advantage of oxycodone/naloxone prolonged release(OXN) is that while its anti-nociceptive efficacy is equivalent to that of oxycodone prolonged release(OXC),it significantly decreases the "Bowel Function Index" thereby ameliorating symptoms of opioid induced constipation to a large extent.Schutter et al in a recent study have reported a decrease in the bowel function index from 38.2 to 15.1.Similarly,L wenstein et al in another recent study have reported that following a month of therapy,complete spontaneous bowel movements per week is increased from one in OXC therapy to three in OXN therapy.

Effect of naloxone on level of plasma beta-endorphin in neonates with severe asphyxia

β-endorphin is the most actively endogenous substance of cerebral endorphin. When combined with opiate receptor specially, it manifests a strong morphine-like activity and can decrease sensitivity of central nervous system to carbon dioxide so as to inhibit breath. OBJECTIVE： To observe the changes of content of plasma β-endorphin in neonates with severe asphyxia after naloxone treatment in a large dosage. DESIGN： Randomized controlled observation. SETTINGS： Department of Pediatrics, Shenzhen Shajing People＇s Hospital; Center of Pediatrics, Guangzhou Zhujiang Hospital. PARTICIPANTS： A total of 97 neonates with severe asphyxia including 57 boys and 40 girls were selected from Neonatal Intensive Care Unit, Department of Pediatrics, Shenzhen Shajing People＇s Hospital from January 2004 to November 2005. Their gestational age was （38±3） weeks, body mass was （3.2±1.7） kg, and hospitalization duration was （2.8±2.3） hours. All neonates met the diagnostic criteria of with severe asphyxia and all their parents provided the confirmed consent. METHODS： All neonates were treated with inspired oxygen, sedation, stopping terror, decreasing cranial pressure, maintaining a well blood perfusion and normal level of blood glucose （about 5.0 retool/L）. After hospitalization, 0.1 mg/（kg·d） naloxone hydrochloride （Beijing Sihuan Pharmaceutical Technology Co., Ltd.; certification： HI0900021; bullet preparation; 0.4 mg/ampoule） was intravenously dribbled into neonates for 4 - 6 hours, 14 days in total. 2 mL blood was collected from radial artery in neonates at the beginning of hospitalization and at 3 days after naloxone treatment, put in aprotinin-pre-cool tube, mixed evenly, and centrifuged at hypothermia. Plasma was maintained in refrigerator at - 70 ℃. The kit was provided by Neurobiology Department of Shanghai Second Military Medical University of Chinese PLA. Concentration of plasma β-endorphin was measured by using radio-immunity assay.All data were expressed as Mean ± SD and results were compared with paired t test. MAIN OUTCOME MEASURE： Concentration of plasma β-endorphin. RESULTS： All 97 neonates were involved in the final analysis. Concentration of plasma β-endorphin in neonates with severe asphyxia was lower after treatment as compared with that before treatment, and there was significant difference （t = 10.31, P 〈 0.01 ）. CONCLUSION： Naloxone can decrease level of plasma β-endorphin in neonates with severe asphyxia.

VENTRICAL MICROINJECTING ATROPINE OR NALOXONE REDUCES ANALGESIC EFFECTS PRODUCED BY BRAIN STIMULATION IN THE RAT

Stimulating SmI cortex like needling points produced analgesic effect in rats.Under the background of ventrical microinjecting atropine（10μg/2μl）or naloxone（20μg/20μl）tailflick latency（TEL）remained unchanged after stimulating SmI.Comparing atropine group or naloxone group with normal saline group it was shown that there were a statistical difference in TFL between the two groups respectively.Thus,both ACh and endogenous morphine-like factors may participate in analgesic effect as a neurotransmitter of the corticofugal modulation of pain.

Effect of Shenqi Fuzheng Injection and naloxone and BiPAP ventilator on serum inflammatory factors, immune function and blood gas analysis indexes in patients with AECOPD with type Ⅱ respiratory failure

Objective: To investigate the effect of Shenqi Fuzheng Injection combined with naloxone and BiPAP ventilator on serum inflammatory factors, immune function and blood gas analysis indexes in treatment of AECOPD with type Ⅱ respiratory failure. Methods: A total of 82 patients with AECOPD and type Ⅱ respiratory failure were divided into control group (n=40) and observation group (n=42) according to random data table, patients in the control group received naloxone and BiPAP ventilator therapy, and observation group patients were treated with Shenqi Fuzheng Injection on the basis of control group. The levels of serum inflammatory factors, immune function and blood gas analysis indexes were compared between the two groups before and after treatment. Results: There were no significant difference in levels of CRP, TNF-α, IL-6, CD3+, CD4+, CD8+, CD4+/CD8+, PaO2, PaCO2, SaO2 and pH before and after treatment in the two groups. After treatment, the levels of CRP, TNF-α, IL-6, CD8+and PaCO2 in two groups were significantly lower than those in same group before treatment, moreover observation group was significantly lower than control group;and levels of CRP, TNF-α, IL-6, CD8+ and PaCO2 in the observation group was significantly lower than those of the control group, the difference was statistically significant;When compared with the group before treatment, CD3+, CD4+, CD4+/CD8+, PaO2, SaO2 and pH levels of both groups after treatment were significantly increased, and the level of each index of observation group after treatment were significantly higher than the control group, the difference was statistically significant. Conclusion: The clinical effect of Shenqi Fuzheng Injection Combined with naloxone and BiPAP ventilator in treatment of AECOPD with type II respiratory failure is significant, can effectively reduce the body's inflammatory reaction, improve immune function, regulate blood gas analysis index, with a certain clinical value.

Effects of naloxone hydrochloride on pulmonary function, blood gas changes and inflammatory factors in patients with COPD combined with respiratory failure

Objective: To investigate the effects of naloxone hydrochloride on pulmonary function, blood gas changes and inflammatory factors in patients with COPD combined with respiratory failure. Methods: According to random data table method, 80 cases of COPD combined with respiratory failure were randomly divided into the control group (n=40) and observation group (n=40), patients in the control group were treated with noninvasive positive pressure ventilation on the basis of routine symptomatic treatment, on the basis of the treatment of the control group, the observation group received naloxone hydrochloride therapy. The levels of pulmonary function, blood gas changes and inflammatory factors were compared in two groups before and after treatment. Results: The levels of serum FEV1, FVC, PEF, PaCO2, PaO2, PaO2/FiO2, TNF-α and PCT in the two groups before treatment were not statistically significant. After treatment, the levels of FEV1, FVC, PEF in the control group and observation group were (70.01±0.36)%, (2.16±0.41) L, (2.98±0.45) L/s and (81.71±0.53)%, (3.65±0.55) L, (4.36±0.43) L/s, which were significantly higher than those in the same group before treatment, and the levels in observation group were significantly higher than those in the control group;the levels of PaCO2, PaO2 and PaO22/FiO2 in the two groups were (59.62±6.47) mmHg, (65.53±7.36) mmHg, (323.89±10.47) and (46.59±6.64) mmHg, (73.65±8.26) mmHg, (398.64±14.06), compared with the same group before treatment, PaCO2 levels were significantly lower in both groups, and the observation group was significantly lower than the control group, PaO2,PaO2/FiO2 levels were significantly increased in both groups, and the observation group was significantly higher than the control group;the levels of TNF-α, PCT in the two groups were (23.28±4.53) pg/mL, (5.22±2.13) ng/mL and (16.61±4.12) pg/mL, (2.07±1.21) ng/mL, which were significantly lower than those in the same group before treatment, moreover, the observation group levels were significantly lower than those in the control group. Conclusion:Treatment of COPD with respiratory failure by naloxone hydrochloride can effectively reduce the level of inflammatory factors, and improved lung function and blood gas levels, which has important clinical value.

Montanide ISA-720 and Naloxone in HBsAg Vaccine Formulation:Cytokine Profiling and Monitoring of Long-Lasting Humoral Immune Responses

Objective This study aimed to investigate the effects of Montanide ISA-720 and Naloxone(NLX)in Hepatitis B surface antigen(HBsAg)vaccine formulation on cytokine and long-lasting antibody responses.Methods First,the HBsAg was formulated in Montanide ISA-720 adjuvant and Naloxone at 5 and 10mg/kg.The experimental mice were immunized three times at a 2-week interval,and then IL-4,IL-2,TNF-α,and IFN-γcytokines;long-lasting IgG antibody responses 220 days after the last shot;and IgG1/IgG2a isotypes were assessed by ELISA.Results The HBsAg-Alum group exhibited the highest IL-4 cytokine response among the experimental groups,whereas NLX in HBsAg-MON720 vaccine formulation did not affect cytokine responses.In addition,NLX in Alum-based vaccine suppressed IL-4 cytokine response and increased the IL-2/IL-4 cytokine ratio.Moreover,HBsAg-MON720 was more potent than HBsAg-Alum in the induction of antibody responses,and NLX in Alum-and MON720-based vaccines induced long-lasting antibody responses.Conclusion NLX in Alum-based vaccine decreased IL-4 cytokine response,increased IL-2/IL-4 cytokine ratio,and improved long-lasting humoral immune responses in both vaccine formulations.Therefore,the adjuvant activity of NLX in the vaccine formulation depends on the type of adjuvant and the nature of the antigen in the vaccine formulation.

Therapeutic effect of naloxone on radiation optic neurapathy Based on rabbit models

BACKGROUND： Radiation therapy is widely used to treat tumor of brain; however, irradiation of radiation into eye tissues may easily cause ischemia and hypoxia in retina and optic nerve tissue so as to induce radiation optic neurapathy. Noloxone is a specific antagonist of opiate receptor, and it can change injured effect of f3 -endorphin. OBJECTIVE： To observe the axoplasmic transport of optic nerve at various phases after radiation injury so as to investigate the mechanism and regularity of optic nerve injury; meanwhile, to verify the therapeutic effects of naloxone on radiation optic neurapathy. DESIGN： Randomized controlled animal study. SETTINGS： Medical College of Qingdao University, Changzhi Medical College. MATERIALS： A total of 40 healthy adult New Zealand rabbits, weighing 2 - 2.5 kg, of either gender, were checked by using slit lamp and ophthalmoscop before radiation in order to exclude eye diseases. FCC-7000 vertical kilocurie ^60Co therapeutic machine was made in Yantai, China; in addition, naloxone was provided by Beijing Sihuan Pharmaceutical Factory. METHODS： The experiment was carried out in the Animal Experimental Laboratory, Medical College of Qingdao University from January 2005 to December 2006. The experimental rabbits were randomly divided into radiation group （n =16）, treatment group （n =16）, blank control group （n=4） and injured control group （n=4）. Except blank control group, rabbits in other three groups were irradiated in as the center of optic chiasma including the area of optic nerve by using ^60Co therapeutic machine. Radioactive source was 85 cm away from head, and the size of operative field was 5 cm × 5 cm. The radiation was performed once a day with the dosage of 3 Gy for 8 days in total. The total dosage was 24 Gy. When radioactive dosage reached 24 Gy, 2 mg/kg naloxone was dropped into ear vein of rabbits in the treatment group once a day for 10 days in total. Rabbits in the injured control group were only irradiated but not given any drugs. MAIN OUTCOME MEASURES： At 1, 10, 30 and 60 days after 24-Gy radiation, anterogradely labeled horseradish peroxidase （HRP） was used to measure optical density mean （OPTDM） in the radiation group and the treatment group; while, OPTDM was directly measured in the blank control group, and OPTDM was directly measured after radiation in the injured control group. RESULTS： All 40 experimental rabbits were involved in the final analysis. There were significant differences in OPTDM at various phases between radiation group and blank control group （P 〈 0.05）; in addition, there was significant difference in OPTDM in the treatment group at 1, 10, 30 and 60 days after 24-Gy radiation （P 〈 0.05）; otherwise, at 30 and 60 days after 24-Gy radiation, there was significant difference in OPTDM between radiation group and treatment group （P 〈 0.05）. CONCLUSION： Naloxone may improve optic nerve axoplasmic transport disorder induced by radiation so as to protect optic nerve.

Effects of microinjection of morphine and naloxone into the medial area of nucleus retrofacialis on respiration in rats

Experiments were performed on SD rats. The animals were anesthetized with urethane (1. 0 g/kg, i. p. ). The diaphragmatic electric activity and intratracheal pressure were monitored. Morphine (4 mg/kg, i. v. ) caused marked respiratory inhibition. The respiratory frequency (RF), integrated diaphragmatic electric activity (IDEA) and diaphragmatic minute activity (DMA) were decreased. The respiratory depression effect of morphine was almost completely eliminated by pretreatment with naloxone injected into the medial areas of the nucleus retrofacialis (mNRF). Bilateral microinjection of morphine (5 μg) into mNRF might result in apnea in all animals. This effect could be fully prevented by injection of naloxone into mNRF in advance. The results suggest that there might be morphine receptors in the mNRF and they might play an important role in the respiratory inhibition induced by systemic administration of morphine.

An LC-MS Method for Evaluating Photostability of Naloxone Hydrochloride I.V. Infusion

Naloxone is a well-known opioid antagonist indicated for the treatment of CNS （central nervous system） and respiratory depression induced by natural or synthetic opioid in adults and neonates whose mothers have received opioids. While it has been reported that an injection of 0.2 mg/mL of naloxone hydrochloride is physically and chemically stable, data on photostability on continuous i.v. infusion of 0.2 mg/mL of naloxone hydrochloride has not been reported. Therefore, a method was required for assessment of naloxone hydrochloride photostability. A high performance LC-MS （liquid chromatography/mass spectrometry） method was established to evaluate the photostability of naloxone hydrochloride. Injections of naloxone hydrochloride in 0.9% sodium chloride were exposed to artificial light and stored at room temperature （22 ~C） and 37 ~C. Naloxone losses up to 9.79% of its initial concentration when exposed to light at room temperature for 192 h, but the degradation increased up to 14.91% as the storage temperature increase. The disappearance of naloxone hydrochloride was correlated with the appearance of nor-oxymorphonedegradant. Naloxone hydrochloride is photosensitive and degradation increased at highly temperature and light intensity. Therefore, naloxone i.v. infusion solutions should either be protected from light and/or be frequently replaced when being administered to patients.

The Place of Community Rescue Naloxone in a Public Health Crisis of Opioid Overdose

The recent large increase in deaths involving opioids (whether prescription or illicit, pure or adulterated, alone or in combination with other drugs) is the manifestation of a complex, and multifaceted problem consisting of psychological, psychosocial, medical, legal, regulatory, economic, cultural, and political components, among others. Because the problem involves issues related to both supply and demand, the solution is not obvious, simple, or quick. There is no easy fix. Preventing and treating opioid misuse and abuse requires a comprehensive, time-intensive, and expensive intervention supported by public policy and support through coordinated medical, regulatory, legal, and financial guidelines and practice. But until the long-term problems can be fixed, the immediate crisis of overdose deaths can be ameliorated by making available an opioid receptor antagonist to reverse the respiratory depression that is the cause of death to those who are in the best position to administer it in time (professionals, untrained bystanders, and even fellow drug abusers). The statistics overwhelmingly demonstrate that this is a life-saving medical intervention. Yet, there is still uncertainty about this intervention, and even some opposition to it. We describe the scientific basis for the approach and the issues surrounding its use to treat accidental or intentional overdose by pain patients, recreational opioid users, and addicts. We also describe the calls to limit the number of times it should be available to a user and the limitations of its effectiveness—mainly that it only addresses the acute death crisis, not the underlying problems that led to it.

Paroxetine Augments while Naloxone Abolishes the Analgesic Effect of Paracetamol in Acute Nociceptive Pain in Mice

The mechanism(s) of analgesic action of paracetamol (acetaminophen;N-acetyl-p-aminophenol) remains controversial. Previous studies on rats suggested that the antinociceptive action of paracetamol might involve the central descending inhibitory pain pathways recruiting both a serotoninergic and an opioidergic system. This study explores this issue in mice using paroxetine, the most potent selective serotonin re-uptake inhibitor, and the nonselective opioid pure antagonist naloxone. Animals were divided into two main groups for two separate experiments, each subdivided into 3 subgroups. In both experiments;the first group served as control, the second group received paracetamol (200 mg/kg, i.p). In one experiment, the third group received paroxetine (20 mg/kg p.o for 7 days) before paracetamol. In the other experiment, animals of the third group were pretreated with naloxone (5 mg/kg, i.p) 30 min before paracetamol. The antinociceptive effect of paracetamol was tested using the hot plate test. Paracetamol displayed a significant antinociceptive activity that was augmented by pretreatment with paroxetine as was shown by maintenance of its effect beyond that shown by paracetamol alone. On the other hand, pretreatment with naloxone abolished paracetamol’s antinociceptive activity in the hot-plate test. These results extended the previous observation in rats that the antinociceptive effect of paracetamol involved activation of a central descending pain inhibitory pathway with serotonin and opioidergic peptides being potential mediators recruited.

Evaluation of Opioid Reversal with Naloxone before and after Implementation of a Computerized Physician Order Entry System at a Tertiary Medical Center

Objectives： Opioid medications consistently rank among the drugs most frequently associated with adverse events. We reviewed cases of naloxone administration to assess our opioid prescribing and administration practices before and after implementation of a computerized provider order entry （CPOE） system. Our primary measure was the rate of opioid reversal with naloxone in the two time periods. Methods： We systematically reviewed all cases of naloxone administration at our institution from March 2016 through May 2016 （before period） compared with cases from October 2017 through December 2017 （after period）. Results： In the before period, 0.58% of patients who received an opioid required reversal with naloxone compared with 0.16% in the after period （p 〈 0.001）. Subject demographics such as age, sex, BMI, and serum creatinine were not significantly different between the two groups. Similarly large proportions of patients in the before and after groups had at least 2 risk factors for over-sedation （79.5% and 75%, respectively, p = 0.17）. More than 84% and 61% of patients in the before and after groups, respectively, did not have documentation of an opioid on the admission medication history, suggesting they were opioid-naYve （p= 0.10）. Per our institution＇s policy on range orders, nurses should begin with the lowest prescribed opioid dose; this policy was followed in 58.3% in the before period and 69.2% in the after period （p = 0.36）. Conclusions： Doses of naloxone that were required for opioid reversal were significantly reduced after implementation of a CPOE system. Our opioid-reversal rate was comparable to similar studies; however, secondary endpoints indicate that opioid prescribing and administration habits may not account for patient-specific risk factors for over-sedation.