Nebulized fentanyl is as effective as IV opioids for the treatment of acute pain, however the variations of prepared fentanyl nebulized solution leave a question mark over the ability to deliver consistent doses.

The findings come from a new literature review published in Annals of Pharmacotherapy, examining research from 1945 to May 2016. Databases reviewed were MEDLINE (1966–2016), Web of Science (1945–2016), and Excerpta Medica (1980–2016), using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.

The drug concentration-time profiles for nebulized fentanyl and IV fentanyl were shown to be similar when 100–300μg doses of fentanyl were administered to 15 healthy volunteers via inhalation and intravenous routes (Mather et al, 1998). The effects of fentanyl were reported by patients almost instantly after inhalation and IV administration. However, the time to maximum concentration was significantly longer for nebulized fentanyl (4–9 minutes) vs. IV fentanyl (2–4 minutes). 

In separate studies, the time to maximum concentration for nebulized fentanyl was shown to vary considerably. MacLeod et al (2012) investigated the pharmacokinetics of nebulized and IV fentanyl, and they found that drug efficacy depended on the inhalation device used to deliver the drug to the distal airways (which allows for quicker absorption to systemic circulation) and patient specific factors such as a sealed thoracic wall and sufficient respiratory drive. The time to maximum concentration for the nebulized fentanyl was 20.5 seconds vs. 31.5 seconds for the IV fentanyl.

In a controlled, double-blind, clinical trial, Singh et al (2012) randomized 90 adult patients undergoing lower-abdominal surgery to 3 separate groups: IV fentanyl 2μg/kg, nebulized fentanyl 3μg/kg, and nebulized fentanyl 4μg/kg. Outcomes were measured via visual analogue scale (VAS). Results showed that overall both doses of nebulized fentanyl – based on mean VAS from 5 to 15 minutes – were significantly more effective (P<0.005) compared with baseline. Pain relief duration was also longer with the nebulized group (90 minutes) compared with the IV group (30 minutes).

Other controlled trials found that pain scores with IV fentanyl were less after 15 minutes, but not statistically different from nebulized fentanyl after 30 minutes (Bartfield et al, 2003). In a randomized trial of 73 children aged 4–13 (Furyk et al, 2012), no statistical differences in pain score were observed between IV morphine and nebulized fentanyl treatment groups at 15 or 30 minutes (P=0.34 and 0.081, respectively).

Studies of fentanyl as a liposomal-encapsulated aerosol nebulizer found that the prolonged time to maximum concentration (22.7 minutes for aerosol vs. 3.6 minutes for IV) made it an unsuitable option for the treatment of acute pain.

The authors note that aerosol drug delivery is a complex phenomenon and out of the 4 major types of nebulizer systems available—ultrasonic, jet, vibrating mesh-aperture plate, and breath-enhanced jet nebulizers—it is not known which type of nebulizer would be optimal for fentanyl administration.

The clinical trials found very few adverse effects but the authors note that this may be due to the short duration of these studies. Indeed, a limit to the findings of the review was the small number of 583 total participants involved.

With no current commercial product available, the authors conclude, “Therapeutic efficacy with nebulized fentanyl requires a consistently prepared product and nebulization device that will reliably deliver the drug to the patient’s distal airways.”

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