Therapeutic Intranasal Drug Delivery

Abstract: INTRODUCTION: This study was designed to compare the effects of intranasal (IN) and intravenous (IV) administration of naloxone in patients who had overdosed on opioids. MATERIAL AND METHODS: This randomized clinical trial study was conducted in the Department of Poisoning Emergencies at Noor and Ali Asghar (PBUH) University Hospital. One hundred opioid overdose patients were assigned by random allocation software into two study groups (n = 50). Both groups received 0.4 mg naloxone: one group IN and the other IV. Outcomes included change in the level of consciousness (measured using a descriptive scale and the Glasgow Coma Scale (GCS)), time to response, vital signs (blood pressure, heart rate and respiratory rate), arterial blood O2 saturation before and after naloxone administration, side-effects (agitation) and length of hospital stay. RESULTS: Patients who had been administered IN naloxone demonstrated significantly higher levels of consciousness than those in the IV group using both descriptive and GCS scales (p < 0.001). There was a significant difference in the heart rate between IN and IV groups (p = 0.003). However, blood pressure, respiratory rate and arterial O2 saturation were not significantly different between the two groups after naloxone administration (p = 0.18, p = 0.17, p = 0.32). There was also no significant difference in the length of hospital stay between the two groups (p = 0.14). CONCLUSIONS: Intranasal naloxone is as effective as IV naloxone in reversing both respiratory depression and depressive effects on the central nervous system caused by opioid overdose.

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I have recapped the article here due to some missing information in the abstract that is important: Sabzghabaee et al conducted a prospective RCT comparing IN naloxone (0.4 mg) to IV naloxone (0.4 mg) in 100 patients who overdosed on opiates. All patients were delivered the study drug and had their ventilation supported for 5 minutes. After 5 minutes those who failed to respond were administered a second dose – it is not clear from the paper how many patients required redosing. The primary outcome was level of consciousness with secondary outcomes of vital signs (respiratory rate), time to response, oxygen saturation, side effects (agitation) They found both treatment regimens equivalent in reversing both respiratory depression and CNS depression. 100% of the IN group progressed to a state of either lethargy or full consciousness following drug delivery compared to 60% of the IV group (the remaining 40% were obtunded but no longer comatose). The time to response following drug delivery was 2.56 minutes for the nasal route versus 1.48 minutes via the IV route. There was no difference in respiratory rate improvement. Mean arterial saturations increased from 71% to 94% (IN) and 73% to 94% (IV). Agitation was observed in 12 of 50 patients receiving IV naloxone but in no patients receiving IN naloxone. They conclude that IN naloxone is as effective as IV naloxone in reversing both opiate induced respiratory depression and CNS depression, but that the nasal form leads to less severe withdrawal symptoms following delivery and is therefore preferred.

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Editorial note: This is a very important article for those interested in the efficacy, side effects and dosing of nasal naloxone.  All prior studies used a dose of 2 mg for nasal delivery so that was the only evidenced based recommendation possible for dosing. This study used 0.4 mg for the nasal dose and found it equivalent to the IV formulation for the primary goal of delivery – patient arousal and breathing. It would be nice to have at least one additional study to confirm this finding, but if this holds it opens the door to using other formulations of naloxone (that are often less expensive or more readily available) for nasal delivery.  I believe we need another confirmatory study prior to jumping on this concept because there are a number of missing data points (percentage of patients who required redosing) and some findings that don’t seem right (better arousal with IN than with IV drug). Until these are clarified I would be cautious on drawing firm conclusions. Another important point here is the risk of the patient becoming agitated and going into acute narcotic withdrawal. These authors demonstrate what has been reported previously: IN naloxone results in less risk of severe opiate withdrawal. I hypothesize that this is due to the absorption kinetics of the IN route being more prolonged and gentler in terms of arousal than the sudden hit and awakening that occurs with an IV bolus.

Abstract: STUDY OBJECTIVE: Initial out-of-hospital analgesia is sometimes hampered by difficulties in achieving intravenous access or lack of skills in administering intravenous opioids. We study the safety profile and apparent analgesic effect of intranasal fentanyl in the out-of-hospital setting. METHODS: In this prospective observational study, we administered intranasal fentanyl in the out-of-hospital setting to adults and children older than 8 years with severe pain resulting from orthopedic conditions, abdominal pain, or acute coronary syndrome refractory to nitroglycerin spray. Patients received 1 to 3 doses of either 50 or 100 mug, and the ambulance crew recorded adverse effects and numeric rating scale (0 to 10) pain scores before and after treatment. RESULTS: Our 903 evaluable patients received a mean cumulative fentanyl dose of 114 mug (range 50 to 300 mug). There were no serious adverse effects and no use of naloxone. Thirty-six patients (4%) experienced mild adverse effects: mild hypotension, nausea, vomiting, vertigo, abdominal pain, rash, or decrease of Glasgow Coma Scale score to 14. The median reduction in pain score was 3 (interquartile range 2 to 5) after fentanyl administration. CONCLUSION: The out-of-hospital administration of intranasal fentanyl in doses of 50 to 100 mug is safe and appears effective.

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Here is further evidence, in the largest EMS trial published to date, demonstrating both the effectiveness and safety of IN fentanyl for severe acute pain in ambulance patients - primarily adults. The authors demonstrate a high level of understanding of this delivery technique by allowing titration of the drug to effect, a concept that should be mimicked by further researchers. Intranasal medication delivery for painful conditions should be titrated just as IV medications are titrated – the right dose is enough to have clinical effect without significant side effects. They also chose a highly concentrated fentanyl (500-1000 mcg/ml) but data from other studies have demonstrated that this is not required – generic concentrations are adequate and effective especially when titrated.

Pubmed link: http://www.ncbi.nlm.nih.gov/pubmed/24268523

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Tsze, D. S., Y. M. Vitberg, et al. (2014). "Treatment of tetralogy of Fallot hypoxic spell with intranasal fentanyl." Pediatrics 134(1): e266-269.