naloxone: IM vs nasal?

naloxone: IM vs nasal?

You forwarded this message on Wed 11/20/2019 7:33 AM

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You forwarded this message on Wed 11/20/2019 7:33 AM

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Geoff A. Modest, M.D.

Wed 11/20/2019 7:31 AM

• Geoff A. Modest, M.D.

JAMA just published a potentially important article from Australia finding that intramuscular naloxone worked more rapidly and effectively than intranasal naloxone for opioid overdose (see opioid OD naloxone IM vs nasal jamaopen2019 in dropbox, or https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2755306 )

Details:

-- 197 patients were randomized to intranasal naloxone 800 µg plus IM placebo vs IM naloxone 800 µg plus intranasal placebo, in the Uniting Medically Supervised Injecting Center in Sydney, Australia, a supervised injecting site

-- 88% male, mean age 34

-- 61% used heroin, 21% pharmaceutical opioids, 12% fentanyl, 5% methadone. 25% had concomitant alcohol use

-- in those with overdose: 35% of patients attributed it to reduced tolerance, 67% had concurrent CNS depressant use, 12% felt they used a higher-quality drug, 8% used higher dose than usual

-- primary outcome: the need for rescue dose of intramuscular naloxone 800µg 10 minutes after the initial dose

-- secondary outcomes: time to adequate respiratory rate >10 breaths/min, and time to Glasgow Coma Scale score of at least 13

Results:

-- need for rescue dose of naloxone, comparing IM vs nasal dosing:

    -- 8.6% with IM vs 23.1% with nasal, 65% fewer with IM dosing, OR 0.35 (0.15-0.66), p=0.002.

        -- Number needed to treat: 7 would need to be given IM naloxone to prevent one additional client needing a rescue dose if all were on nasal naloxone

-- time to respiratory rate of at least 10:

    -- 65% higher with intranasal, HR 1.65 (1.21-2.25), p=0.002

        -- median time to a respiratory rate of at least 10 breaths/min: 8 minutes for intramuscular vs 17 minutes for intranasal

-- time to Glasgow Coma Scale score of at least 13:

    -- 81% higher with intranasal, HR 1.81 (1.28-2.56), p=0.001

        -- median time to a Glasgow Coma Scale score of at least 13: 8 minutes for intramuscular vs 15 minutes for intranasal

-- no major adverse events were reported in either group

Commentary:

-- in this study, it is clear that the IM route was significantly better in all parameters measured. The improved OD recovery time with IM administration of naloxone is particularly important when patients OD in the field, where the 9 minute more rapid respiratory response and the 7 minute more rapid decline in the coma scale may be very important for optimal recovery

-- BUT: this study used naloxone 800 µg intramuscular vs 800 µg intranasal. However, in the US at this point we are using the 4 mg intranasal actuated spray. And, the pharmacokinetics suggest that the 4 mg intranasal spray seem quite good, certainly in comparison to the 400 µg intramuscular dose (see https://www.futuremedicine.com/doi/full/10.2217/pmt-2017-0060 ). This makes it all very hard to interpret this study in the current prescribing climate in the US. [The standard IM naloxone dose is 400 µg to 2mg, though occasionally lower doses are used to avoid acute withdrawal]

    -- Another study of the 2 mg naloxone dose either injected IM or given intranasally found that the IM group had a more rapid response and were more likely to have more than 10 respirations per minute within 8 minutes (82% vs 63%), and the difference in needing rescue medications was twice as high in the nasal group (26% vs 13%) though this did not reach full statistical significance (p=0.056) – see https://onlinelibrary.wiley.com/doi/abs/10.5694/j.1326-5377.2005.tb06550.x . Again, would this be true if using the 4mg dose?? Or, perhaps comparing the 4mg intranasal with 2mg IM?? Should be studied….

-- this current study found that 23% of patients required a rescue dose of naloxone. But another issue potentially affecting its utility/generalizability: this study was done predominantly with patients using heroin. It is important to remember that overdoses related to fentanyl and its various synthetic derivatives (as often seen in the US) may more often require multiple naloxone treatments (see http://gmodestmedblogs.blogspot.com/2017/11/fentanyl-and-opioid-deaths.html). How would this affect the comparisons of IM vs intranasal??

-- one important sidebar to this article is that this Uniting Medically Supervised Injecting Center in Australia allows patients to inject pre-obtained drugs under the supervision of clinically trained staff. During the 4 year study period of this study, there were 249,607 people presenting with intention to inject (comprising 730 individuals per month) and the staff managed 2158 overdose events. It would be really great, and undoubtedly save lives, if our people here had access to this type of supervised setting…. 

So,

-- we as clinicians should try to make sure that patients have multiple intranasal naloxone applicators available, for the situations when more than one are needed

-- I am always concerned when this kind of article comes out, since it might create the impression that nasal naloxone really doesn’t work well and could conceivably dissuade patients, their families/friends, or us clinicians from prescribing it/using it on a regular basis (and, in the couple of quick summaries of this article in the press, there was no comment that the Australian study used a much lower dose of naloxone than we do).

-- this injecting center in Australia is quite impressive, dealing with more than 2000 overdose events in a four-year period, and, one might expect, far fewer fatalities than we might see in the US

bottom line:

given the ease of intranasal naloxone, its documented accuracy of use by non-instructed observers, and its significantly cheaper price as compared to IM autoinjectors, I would not change current practice, though make sure that patients or others around them have sufficient intranasal naloxone. And it really would be useful to have a good study comparing the 4mg dose intranasally vs various doses IM…

geoff​

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