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Three Part Question

In [patients acutely intoxicated with opioids] is [intravenous infusion of naloxone better than repeated bolus doses] at reducing [the risk of precipitation of acute withdrawal symptoms]?

Clinical Scenario

A 30 year old male who is a known opioid-addict is brought to the emergency department after an overdose of methadone. He had a GCS of 3, a respiratory rate of 4 breaths per minute, and pinpoint pupils. You are aware that the action of naloxone is shorter than that of methadone and wonder if naloxone infusion is less likely to precipitate acute withdrawal symptoms than repeated bolus doses.

Search Strategy

Medline 1966-02/02 using the OVID interface.
[{exp naloxone OR naloxone.mp} AND {exp infusions, intravenous OR exp injections, intravenous} AND {exp narcotics OR opioid.mp OR opiate.mp OR morphine.mp OR buprenorphine.mp OR codeine.mp OR dextromoramide.mp OR diphenoxylate.mp OR dipipanone.mp OR dextropropoxyphene.mp OR diamorphine.mp OR dihydrocodeine.mp OR alfentanil.mp OR fentanyl.mp OR remifentanil.mp OR meptazinol.mp OR methadone.mp OR nalbuphine.mp OR oxycodone.mp OR pentazocine.mp OR pethidine.mp OR phenazocine.mp OR tramadol.mp}] LIMIT to human AND English.

Search Outcome

188 studies were found of which one addressed the question directly. This is shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Goldfrank L et al, 1986, USA	7 patients attending an ED with symptoms of opioid overdose, given single boluses of naloxone	Observational	Phase one:Serial naloxone levels	Construction of a dosing nomogram from the pharmacokinetic data obtained	Small study with a high drop-out rate (20% in phase two) The revised nomogram has not been tested on a repeated phase two study
			Phase two: Serial naloxone levels; Comparing the measured levels with target levels predicted by the nomogram	Levels measured in phase two were consistenly higher than those predicted by the nomogram; the nomogram was adjusted and tested with a computer simulation

Comment(s)

It was found that there was large variation in factors determining plasma naloxone concentrations between individuals, and the nomogram was constructed to ensure that those who eliminate naloxone rapidly would not experience a reduction in levels and thus risk renarcotisation. This leads to an overestimation of the infusion rate for those who eliminate naloxone more slowly with the theoretical risk of precipitation of acute withdrawal symptoms. A practical regime for titrating naloxone by infusion for opioid overdose has been calculated: 1) titrate the initial bolus of naloxone against clinical effect; 2) start an infusion of naloxone, giving 2/3 of the initial bolus per hour; 3) consider a second bolus (at half of the initial dose) after 15 minutes, if there are signs of reduced respiratory rate or conscious levels. Further research is needed to: Validate the regime against clinical criteria; assess whether it is possible in practice to titrate the patient's response to a "safe" level (eg breathing with a safe airway and a GCS of 14/15 rather than a GCS of 15/15 but agitated and at risk of leaving the ED prematurely) and compare the regime to other routes of administration.

Clinical Bottom Line

A practical regimen for titrating naloxone by infusion for opiod overdose has been calculated.

References

1. Goldfrank L, Weisman RS, Errick JK et al. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 1986;15(5);566-70.