Intravenous or intramuscular/subcutaneous naloxone in opioid overdose

Report by Simon Clarke, Specialist Registrar
Checked by Paul Dargan, Specialist Registrar     

Best evidence topic report. Intranasal naloxone in suspected opioid overdose

A short cut review was carried out to establish whether intransasal naloxone is effective in suspected opiate overdose. 596 papers were screened, of which eight presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that it is likely that intranasal Naloxone is a safe and effective first line prehospital intervention in reversing the effects of an Opioid overdose and helping to reduce the risk of needle stick injury. A large, well conducted trial into it's usage is however required to confirm this.     

Adverse events after naloxone treatment of episodes of suspected acute opioid overdose.

OBJECTIVE: An increasing and serious heroin overdose problem in Oslo has mandated the increasing out-of-hospital use of naloxone administered by paramedics. The aim of this study was to determine the frequencies and characteristics of adverse events related to this out-of-hospital administration by paramedics. METHODS: A one-year prospective observational study from February 1998 to January 1999 was performed in patients suspected to be acutely overdosed by an opioid. A total of 1192 episodes treated with naloxone administered by the Emergency Medical Service system in Oslo, were included. The main outcome variable was adverse events observed immediately after the administration of naloxone. RESULTS: The mean age of patients included was 32.6 years, and 77% were men. Adverse events suspected to be related to naloxone treatment were reported in 45% of episodes. The most common adverse events were related to opioid withdrawal (33%) such as gastrointestinal disorders, aggressiveness, tachycardia, shivering, sweating and tremor. Cases of confusion/restlessness (32%) might be related either to opioid withdrawal or to the effect of the heroin in combination with other drugs. Headache and seizures (25%) were probably related to hypoxia. Most events were non-serious. In three episodes (0.3%) the patients were hospitalized because of adverse events. CONCLUSION: Although adverse events were common among patients treated for opioid overdose in an out-of-hospital setting, serious complications were rare. Out-of-hospital naloxone treatment by paramedics seems to save several lives a year without a high risk of serious complications.     

Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting

Prehospital providers are at increased risk for blood-borne exposure and disease due to the nature of their environment. The use if intranasal (i.n.) medications in high-risk populations may limit this risk of exposure. To determine the efficacy of i.n. naloxone in the treatment of suspected opiate overdose patients in the prehospital setting, a prospective, nonrandomized trial of administering i.n. naloxone by paramedics to patients with suspected opiate overdoses over a 6-month period was performed. All adult patients encountered in the prehospital setting as suspected opiate overdose (OD), found down (FD), or with altered mental status (AMS) who met the criteria for naloxone administration were included in the study. i.n. naloxone (2 mg) was administered immediately upon patient contact and before i.v. insertion and administration of i.v. naloxone (2 mg). Patients were then treated by EMS protocol. The main outcome measures were: time of i.n. naloxone administration, time of i.v. naloxone administration, time of appropriate patient response as reported by paramedics. Ninety-five patients received i.n. naloxone and were included in the study. A total of 52 patients responded to naloxone by either i.n. or i.v., with 43 (83%) responding to i.n. naloxone alone. Seven patients (16%) in this group required further doses of i.v. naloxone. In conclusion, i.n. naloxone is a novel alternative method for drug administration in high-risk patients in the prehospital setting with good overall effectiveness. The use of this route is further discussed in relation to efficacy of treatment and minimizing the risk of blood-borne exposures to EMS personnel.     

Intranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdoses

Introduction

This study proposes that intranasal (IN) naloxone administration is preferable to intravenous (IV) naloxone by emergency medical services for opioid overdoses. Our study attempts to establish that IN naloxone is as effective as IV naloxone but without the risk of needle exposure. We also attempt to validate the use of the Glasgow Coma Scale (GCS) in opioid intoxication.

Methods

A retrospective chart review of prehospital advanced life support patients was performed on confirmed opioid overdose patients. Initial and final unassisted respiratory rates (RR) and GCS, recorded by paramedics, were used as indicators of naloxone effectiveness. The median changes in RR and GCS were determined.

Results

Three hundred forty-four patients who received naloxone by paramedics from January 1, 2005, until December 31, 2007, were evaluated. Of confirmed opioid overdoses, change in RR was 6 for the IV group and 4 for the IN group (P = .08). Change in GCS was 4 for the IV group and 3 for the IN group (P = .19). Correlations between RR and GCS for initial, final, and change were significant at the 0.01 level (ρ = 0.577, 0.462, 0.568, respectively).

Conclusion

Intranasal naloxone is statistically as effective as IV naloxone at reversing the effects of opioid overdose. The IV and IN groups had similar average increases in RR and GCS. Based on our results, IN naloxone is a viable alternative to IV naloxone while posing less risk of needle stick injury. Additionally, we demonstrated that GCS is correlated with RR in opioid intoxication.     

Burden of non-fatal opioid overdose hospitalizations on Medicaid

ABSTRACT

Background: The Medicaid population experienced an elevated risk of opioid overdose death. Higher risks of a health condition or worse health outcomes could mean high costs imposed on public sources of insurance. In this study, we compared the length of stay and total charge of hospitalized opioid overdose patients across insurance types to shed light on the financial burden of opioid epidemic across different types of payers. Method: Our sample includes all opioid overdose hospitalizations in the 2012–2013 South Carolina Patient Encounter database. Length of stay and total hospital charge are the two dependent variables. The key independent variable is the insurance status, categorized as: self-pay, commercial insurance, Medicare, Medicaid, and other payers (other government plan and charitable plans). Multilevel models were applied to account for the clustering effect of each hospital. The patients’ age, gender, race/ethnicity, and Charlson Comorbidity Index were used as covariates. Results: A total of 1,262 hospitalizations were included. Medicaid patients stayed longer in hospital (β = 1.815, 95% confidence interval = [0.406–3.224]) and had higher total charge (β = $6,695.2, 95% CI = [215.1–13,175.3) compared with patients with commercial insurance. Conclusion: Medicaid patients’ longer hospitalization and higher hospital charge suggest disparity at the hospital treatment stage.     

Massive hydromorphone dose delivered subcutaneously instead of intrathecally: guidelines for prevention and management of opioid, local anesthetic, and clonidine overdose

Increasing numbers of patients with refractory pain are receiving intrathecal drug delivery systems (IDDS). We describe a case to illustrate the clinical manifestations and management implications of inadvertent overdose with drugs used in IDDS, including opioids, clonidine, baclofen, and local anesthetics. An IDDS patient received a bimonthly dose of intrathecal hydromorphone subcutaneously. The patient received a total of 540 mg hydromorphone into the subcutaneous pocket around the intrathecal pump. She was treated with naloxone intravenously over 12 hours, and had no major adverse sequelae. Such occurrences may happen more frequently with the expanded use of IDDS and clinicians should be prepared to take quick action. Counteracting an opioid with naloxone until the opioid is metabolized and excreted can be done safely. Inadvertent subcutaneous administration of other types of drugs could be more difficult to manage.     

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Intravenous bolus or infusion of naloxone in opioid overdose

Report by Simon Clarke, Specialist Registrar
Checked by Paul Dargan, Specialist Registrar     

A pilot study to compare virtual reality to hybrid simulation for opioid-related overdose and naloxone training

BackgroundIn the midst of the international opioid-related overdose (OOD) crisis, appropriate naloxone training is needed by both healthcare professionals and community members to better leverage its life-saving potential.ObjectivePilot the use of a virtual reality simulation for training student nurses to identify signs and symptoms of an OOD, properly administer intranasal naloxone, and provide immediate recovery care after revival.DesignThis quasi-experimental pretest-posttest study evaluated knowledge and attitudes towards intervening during an opioid-related overdose among student nurses before and after participating in a traditional hybrid simulation or virtual reality simulation.SettingA medium sized urban university's school of nursing in the Northeastern United States.ParticipantsFifty (N = 50) senior Bachelor of Nursing Science (BSN) students.MethodsKnowledge and attitudes were assessed using the Opioid Overdose Knowledge Scale (OOKS) and Opioid Overdose Attitudes Scale (OOAS). Students completed measures 3 weeks prior to training and 3 weeks after. Appropriate t-tests evaluated changes in OOAS and OOKS scores both within and between training groups (e.g. hybrid simulation compared to virtual reality).ResultsSample characteristics were well balanced in both the hybrid simulation group (n = 31) and virtual reality group (n = 19). There were no statistically significant differences in average OOKS and OOAS scores at baseline or at follow up between those receiving hybrid simulation or the virtual reality training. All participants' attitudes scores decreased from baseline to follow up by <2 points. However, there was no difference in the change in knowledge scores between the training groups.ConclusionsIndividuals participating in the virtual reality simulation had similar knowledge retention and attitudes towards responding during an opioid-related overdose and administering intranasal naloxone when compared to individuals participating in hybrid simulation. The lack of significant findings between training groups indicates that the mobile virtual reality training is comparable to the in-person hybrid simulation for training nursing students to appropriately administer naloxone to reverse OOD and provide immediate recovery care after revival.     

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Intravenous or intramuscular/subcutaneous naloxone in opioid overdose

A short cut review was carried out to establish whether intramuscular/subcutaneous naloxone is better than intravenous naloxone in opioid overdose. Altogether 185 papers were found using the reported search, of which two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.     

Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects

Ultralow doses of naloxone (0.001-0.1 microg/kg) produce analgesia in animal models. However, no clinical study has evaluated the combination of ultralow dose naloxone and morphine using patient-controlled analgesia (PCA). This randomized, double blind controlled study sought to determine if the combination of ultralow dose naloxone and morphine in PCA solutions affects opioid requirements, analgesia, and side effects. Two-hundred and sixty-five patients (18-65 years old) undergoing operations were randomized to receive PCA morphine 1 mg/ml (n=129) or PCA morphine 1 mg/ml plus naloxone 0.6 microg/ml (n=136). We evaluated the numbers of supplemental rescue doses, the cumulative dose of each PCA solution, pain intensity, pain relief, and opioid side effects during the first 24 h after surgery. We found that opioid requirements did not differ significantly between groups. The morphine+naloxone group on average required 0.07 mg more morphine (95% CI -1.1 to 1.3) during the 24 h than the morphine group. Pain intensity levels were also similar in both groups. The morphine+naloxone group had 0.06 units lower (95% CI -0.5 to 0.4) pain intensity levels than the morphine group. The morphine+naloxone group had a lower incidence of nausea and pruritus than the morphine group (P=0.01 for both symptoms). However, the incidence of vomiting, time to tolerate fluids, sedation, and urinary retention were similar between groups (all P values >0.1). The combination of ultralow dose naloxone and morphine in PCA does not affect analgesia or opioid requirements, but it decreases the incidence of nausea and pruritus.     

Use of naloxone in valproic acid overdose: case report and review.

We present a case of a mixed ingestion of valproic acid, gabapentin, mexilitine, and ethanol with central nervous system depression that was reversed by naloxone. This report represents the fourth case demonstrating the antidotal efficacy of naloxone in reversing central nervous system depression associated with acute valproic acid overdose. Increasing clinical experience will more fully elucidate indications for, and optimal dosing of, naloxone in valproic acid toxic states.     

Release of opioid peptides in canine hemorrhagic hypotension: Effects of naloxone

Research in Experimental Medicine - Sixteen anesthetized foxhounds were instrumented for hemodynamic measurements. The adrenolumbar vein was cannulated, and hemorrhagic hypotension (MAP=40 mmHg for...     

Use and efficacy of nebulized naloxone in patients with suspected opioid intoxication

ObjectiveTo describe the use and efficacy of nebulized naloxone in patients with suspected opioid intoxication.MethodsThis was an observational study conducted at an inner city emergency department. Patients were eligible if they had self-reported or suspected opioid intoxication and a spontaneous respiratory rate ≥ 6 breaths/minute. Nebulized naloxone (2 mg in 3 mL normal saline) was administered through a standard face mask at the discretion of the treating physician. Structured data collection included demographics, vital signs pre and post naloxone administration and adverse events. The primary outcome was level of consciousness, which was recorded pre and 15 minutes postnaloxone administration using the Glasgow Coma Scale (GCS) and the Richmond Agitation Sedation Scale (RASS).ResultsOf the 73 patients who presented with suspected opioid intoxication and were given naloxone over the study period, 26 were initially treated with nebulized naloxone. After nebulized naloxone administration, median GCS improved from 11 [interquartile range (IQR) 3.5] to 13 (IQR, 2.5), P = .001. Median RASS improved from ? 3.0 (IQR, ? 1.0) to ? 2.0 (IQR, ? 1.5), P < .0001. Need for supplemental oxygen decreased from 81% to 50%, P = .03. Vital signs did not differ pre/post therapy. There were few adverse effects from nebulized naloxone administration: 12% experienced moderate-severe agitation, 8% were diaphoretic and none vomited. Eleven required subsequent administrations of naloxone, nine of whom self-reported using either heroin, methadone or both. Of these, 5 underwent urine drug screening and all 5 tested positive for either opiates or methadone.ConclusionsNebulized naloxone was well-tolerated and led to a reduction in the need for supplemental oxygen as well as improved median GCS and RASS scores in patients with suspected opioid intoxication.     

Rate of patients at elevated risk of opioid overdose visiting the emergency department

Objective

To determine the rate of patients visiting the emergency department who are at risk of opioid overdose.

It's what the community demands: Results of community-based emergency opioid overdose trainings

Objectives

In response to a surge of drug overdoses involving polysubstance use among Atlanta service industry workers that resulted in the deaths of five people in the Atlanta area in the summer of 2021, a local community of harm reductionists and nurses organized opioid education and naloxone distribution (OEND) training sessions specifically customized for service industry workers in Atlanta. After the sessions, the nurses and harm reductionists asked attendants to participate in a study concerning their response to overdoses. The reason nurses and harm reductionists conducted the study was to determine the efficacy of OEND training adapted for those working in the service industries as well as to evaluate and possibly modify the training sessions for future use. This pre-post study examined if and how participants’ knowledge and attitudes toward an opioid-involved overdose changed after engaging with the OEND training. If the study determined that the sessions were successful in teaching service industry workers how to mitigate the immediate and devastating effects of overdose, we recommend expanding and implementing both adaptable training sessions like the OEND training referenced, as well as accompanying studies to improve the training sessions’ effectiveness.

Design

The pre-post study used convenience sampling to recruit participants in emergent OEND training. Participants completed an abbreviated version the Opioid Overdose Attitudes Scale (OOAS) which measured how, and to what degree, they changed their attitudes towards overdoses and their responses to them. Participants also completed an abbreviated version of the Opioid Overdose Knowledge Scale (OOKS) which measured how effectively the OEND increased their knowledge when it came to properly responding to an overdose, which included implementing naloxone as part of immediate rehabilitation treatment. Paired nonparametric tests assessed changes in participants' OOAS/OOKS scores.

Results

A total of 161 individuals attended, and 72 consented to be in the study. The sample predominately consisted of white (76.4%) and female (66.7%) adults whose age averaged 34.3 years. Attitude and knowledge score improvements were statistically significant: approximately 11 points (p < .001) and 3 points (p < .001), respectively.

Conclusions

This rapidly implemented training was associated with improving attitudes and knowledge about responding to an opioid-involved overdose. We recommend expanding the scope of studies like these in order to develop and examine effective, dynamic, and targeted OEND training tailored towards specific community groups and situations, such as polysubstance overdose among service industry workers. As the opioid epidemic worsens, it is critical to equip community members themselves with the skills and tools to recognize and respond to opioid overdoses as a frontline prevention to overdose deaths.     

Comparison of lower-dose versus higher-dose intravenous naloxone on time to recurrence of opioid toxicity in the emergency department

Introduction: The initial dose of naloxone administered to patients who present to the emergency department (ED) with opioid overdose is highly variable. The objective of this study was to determine if the initial dose of intravenous (IV) naloxone given to these patients was associated with the time to recurrence of opioid toxicity.

Methods: This was a multicenter retrospective cohort study, conducted at two academic EDs in the United States. Consecutive adults who had a positive response to naloxone for opioid overdose in the ED were included. Patients were categorized into two groups based on initial IV naloxone dose administered: 0.4?mg (lower-dose) or 1–2?mg (higher-dose). The main outcome measure was the time to recurrence of opioid toxicity requiring a second dose of naloxone. Secondary outcomes included the need for naloxone continuous infusion and adverse events.

Results: The study included 84 patients with 42 patients receiving lower-dose and 42 patients receiving higher-dose naloxone. Median time to re-dose of naloxone was similar between the lower-dose (72 [IQR 46–139] minutes) and higher-dose (70 [IQR 44–126] minutes) groups (p=.810). There were 12 patients (29%) in the lower-dose group and 17 patients (41%) in the higher-dose group who subsequently required continuous infusions (p=.359). The proportion of patients with adverse events was similar between lower-dose and higher-dose groups (31% versus 41%, p=.495). There was no difference in the incidence of specific withdrawal related adverse effects.

Conclusions: The initial dose of naloxone given to patients in the ED does not influence the time to recurrence of opioid toxicity.     

Treatment of opioid overdose in a physician-based prehospital EMS: frequency and long-term prognosis

Background

Prehospital treatment of opioid overdose accounts for a significant proportion of the workload of the emergency system in most major cities. Treatment consists of basic life support and administering naloxone. In our physician-manned mobile emergency care unit (MECU), most patients are released and not admitted to hospital. In this study, we aimed to assess the pattern in the number of episodes with opioid overdose treated by MECU in Copenhagen during a 10-year period and to investigate risk factors for mortality of these patients beyond the initial contact.

Methods

Data were collected prospectively in the MECU database covering all cases of opioid overdose in a 10-year period between 1994 and 2003. The pattern in the number of opioid overdose was analysed in Poisson regression models, and mortality was analysed in Kaplan-Meier plots and in Cox regression models.

Results

A total of 4762 episodes of opioid overdose were recorded. Patients were identified in 3245 of these episodes. The annual number of episodes decreased significantly over the data-collection period: from 639 overdoses out of 4520 (14.1%) patients treated in 1994 to 311 out of 7263 patients treated (4.3%) in 2003. A total of 352 patients had cardiac arrest at the scene. The MECU released 2246 patients (69.3%) after treatment, while 675 (20.8%) were admitted to hospital and 322 (9.9%) died. Long-term prognosis was poor with 14% mortality at 1 year. Long-term mortality was significantly related to increasing age, time of the year and if the patient had previous episodes of opioid overdose.

Conclusions

There has been a significant decrease in the number of opioid overdoses during this 10-year-period. Long-term mortality is high in these patients and highest in those with advanced age and numerous episodes of opioid overdose.