Intranasal naloxone for the treatment of suspected heroin overdose

AIMS: This paper reviews available literature regarding the effectiveness, safety and utility of intranasal (i.n.) naloxone for the treatment of heroin overdose. METHODS: Scientific literature in the form of published articles during the period January 1984 to August 2007 were identified by searching several databases including Medline, Cinahl and Embase for the following terms: naloxone, narcan, intranasal, nose. The data extracted included study design, patient selection, numbers, outcomes and adverse events. RESULTS: Reports of the pharmacological investigation and administration of i.n. naloxone for heroin overdose are included in this review. Treatment of heroin overdose by administration of i.n. naloxone has been introduced as first-line treatment in some jurisdictions in North America, and is currently under investigation in Australia. CONCLUSION: Currently there is not enough evidence to support i.n. naloxone as first-line intervention by paramedics for treatment of heroin overdose in the pre-hospital setting. Further research is required to confirm its clinical effectiveness, safety and utility. If proved effective, the i.n. route may be useful for drug administration in community settings (including peer-based administration), as it reduces risk of needlestick injury in a population at higher risk of blood-borne viruses. Problematically, naloxone is not manufactured currently in an ideal form for i.n. administration.     

Take-home naloxone to reduce heroin death

BACKGROUND: This paper reviews the relevant literature related to the distribution of take-home naloxone. METHODS: A Medline search was conducted on articles published between January 1990 and June 2004 to identify scientific literature relevant to this subject. Those publications were reviewed, and from them other literature was identified and reviewed. RESULTS: The prevalence, pathophysiology and circumstances of heroin overdose, and also bystander response are included in this review. Naloxone peer distribution has been instituted to varying degrees in the United States, Italy, Spain, Germany and the United Kingdom. CONCLUSION: At this point the evidence supporting naloxone distribution is primarily anecdotal, although promising. Although the distribution of naloxone holds promise for further reducing heroin overdose mortality, problems remain. Naloxone alone may be insufficient in some cases to revive the victim, and cardiopulmonary resuscitation (CPR), especially rescue breathing, may also be needed. A second dose of naloxone might be necessary. Complications following resuscitation from overdose may infrequently need in-hospital care. Mortality from injecting without anyone else present will be unaffected by take-home naloxone. Take-home naloxone should be studied in a rigorous scientific manner.     

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study

Background and Aims

Take‐home naloxone can prevent death from heroin/opioid overdose, but pre‐provision is difficult because naloxone is usually given by injection. Non‐injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability.

Design

Open‐label, randomized, five‐way cross‐over PK study.

Setting

Clinical trials facility (Croydon, UK).

Participants

Thirty‐eight healthy volunteers (age 20–54 years; 11 female).

Intervention and comparator

Three doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone.

Measurements

Regular blood samples were taken, with high‐frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration.

Findings

Mean peak concentration (C_max) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15–30 minutes (T_max). For comparison, the i.m. reference reached T_max at 10 minutes. Mean bioavailability was 47–51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3‐minute intervals showed that comparable plasma naloxone concentrations would be anticipated.

Conclusions

Concentrated 2 mg intranasal naloxone is well‐absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post‐dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.     

Distinguishing signs of opioid overdose and indication for naloxone: an evaluation of six overdose training and naloxone distribution programs in the United States

AIMS: This study assessed overdose and naloxone administration knowledge among current or former opioid abusers trained and untrained in overdose-response in the United States. DESIGN AND PARTICIPANTS: Ten individuals, divided equally between those trained or not trained in overdose recognition and response, were recruited from each of six sites (n = 62). SETTING: US-based overdose training and naloxone distribution programs in Baltimore, San Francisco, Chicago, New York and New Mexico. MEASUREMENTS: Participants completed a brief questionnaire on overdose knowledge that included the task of rating 16 putative overdose scenarios for: (i) whether an overdose was occurring and (ii) if naloxone was indicated. Bivariate and multivariable analyses compared results for those trained to untrained. Responses were also compared to those of 11 medical experts using weighted and unweighted kappa statistics. FINDINGS: Respondents were primarily male (72.6%); 45.8% had experienced an overdose and 72% had ever witnessed an overdose. Trained participants recognized more opioid overdose scenarios accurately (t(60) = 3.76, P < 0.001) and instances where naloxone was indicated (t(59) = 2.2, P < 0.05) than did untrained participants. Receipt of training and higher perceived competency in recognizing signs of an opioid overdose were associated independently with higher overdose recognition scores. Trained respondents were as skilled as medical experts in recognizing opioid overdose situations (weighted kappa = 0.85) and when naloxone was indicated (kappa = 1.0). CONCLUSIONS: Results suggest that naloxone training programs in the United States improve participants' ability to recognize and respond to opioid overdoses in the community. Drug users with overdose training and confidence in their abilities to respond may effectively prevent overdose mortality.     

Comparative toxicology of fatal heroin overdose cases and morphine positive homicide victims

AIMS: To compare the blood toxicology of heroin overdose cases and morphine positive homicide victims. DESIGN: Analysis of coronial cases. SETTING: Sydney, Australia. Cases A total of 705 cases of death due to opioid toxicity and 28 morphine positive homicide cases (1 January 1998-31 December 2002). FINDINGS: There was no significant difference between the median morphine concentrations of the overdose and homicide groups (0.50 versus 0.45 mg/l). The overdose group was more likely to have blood alcohol (OR 3.21) present, but less likely to have methadone (OR 0.26) and cannabis (OR 0.04). There was a significant negative correlation between blood morphine and alcohol concentrations among the overdose group (rho = -0.32), but not among the homicide group (rho = -0.03). Independent predictors of a higher blood morphine concentration were a lower alcohol concentration and a higher methadone concentration. CONCLUSIONS: Morphine concentrations per se are not diagnostic of overdose. The study confirms the salience of concomitant alcohol consumption in such events.     

The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers

Aims Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. Design A randomized, double‐blind, placebo‐controlled, cross‐over study. Setting An in‐patient research unit at the University of Kentucky. Participants Healthy adults (n = 10) abusing, but not physically dependent on, intranasal opioids. Measurements Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject‐ and observer‐rated measures were collected before and for up to 72 hours after drug administration. Findings Both formulations produced time‐ and dose‐dependent increases on subjective and physiological mu‐opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time–course were observed. Buprenorphine bioavailability was 38–44% and T_max was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. Conclusions It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non‐dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine/naloxone administration may deter the likelihood of intranasal misuse of buprenorphine/naloxone, but not buprenorphine, in opioid‐dependent individuals.