Featured new articles related to intranasal drug delivery:
April- December 2014
Sabzghabaee, A. M., N. Eizadi-Mood, et al. (2014). "Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial." Arch Med Sci 10(2): 309-314.
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.
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.
Karlsen, A. P., D. M. Pedersen, et al. (2014). "Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study." Ann Emerg Med 63(6): 699-703.
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
Tsze, D. S., Y. M. Vitberg, et al. (2014). "Treatment of tetralogy of Fallot hypoxic spell with intranasal fentanyl." Pediatrics 134(1): e266-269.
Abstract: We present the case of a 3-month-old girl who had unrepaired Tetralogy of Fallot who presented to the emergency department with an acute hypoxic episode. The patient was hyperpneic and cyanotic, with an initial oxygen saturation of 56%. She did not respond to knee-to-chest positioning. A single dose of intranasal fentanyl was administered with subsequent resolution of her symptoms and improvement of her oxygen saturation to 78% within 10 minutes. To our knowledge, this is the first report of the successful treatment of a hypoxic episode of Tetralogy of Fallot using intranasal fentanyl.
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I included this as a featured article because it has significant application in a rare but frightening scenario – a hyperecyanotic “Tet Spell.” These children are on a physiologic knife edge and if you frighten them or hurt them they can decompensate severely (or die) with an increase in their right to left shunting of blood in the heart. Traditional treatment includes oxygen administration, knee-chest positioning, calming the patient AND administering IV morphine. Obviously IV starts in these situations are both difficult AND not calming to the child. These authors are the first to publish data on using intranasal opiates rather than IV opiates to calm the child – with no need for establishing IV access in the midst of a dangerous hypercyanotic spell. This therapy will never enter the realm of a randomized controlled trial due to the infrequency of the event so these kinds of case reports are all we have and can assist us in changing practice to better care for these complex but rare conditions.Pubmed link: http://www.ncbi.nlm.nih.gov/pubmed/?term=intranasal+fentanyl+and+tetralogy
Wagner, K. D., P. J. Davidson, et al. (2014). ""I felt like a superhero": the experience of responding to drug overdose among individuals trained in overdose prevention." Int J Drug Policy 25(1): 157-165.
Abstract: BACKGROUND: Overdose prevention programs (OPPs) train people who inject drugs and other community members to prevent, recognise and respond to opioid overdose. However, little is known about the experience of taking up the role of an "overdose responder" for the participants. METHODS: We present findings from qualitative interviews with 30 participants from two OPPs in Los Angeles, CA, USA from 2010 to 2011 who had responded to at least one overdose since being trained in overdose prevention and response. RESULTS: Being trained by an OPP and responding to overdoses had both positive and negative effects for trained "responders". Positive effects include an increased sense of control and confidence, feelings of heroism and pride, and a recognition and appreciation of one's expertise. Negative effects include a sense of burden, regret, fear, and anger, which sometimes led to cutting social ties, but might also be mitigated by the increased empowerment associated with the positive effects. CONCLUSION: Findings suggest that becoming an overdose responder can involve taking up a new social role that has positive effects, but also confers some stress that may require additional support. OPPs should provide flexible opportunities for social support to individuals making the transition to this new and critical social role. Equipping individuals with the skills, technology, and support they need to respond to drug overdose has the potential to confer both individual and community-wide benefits.
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This is one of several articles in the last decade that disproves the commonly held belief that providing naloxone to injection drug users will lead to an increase in risk taking and more drug use. In fact, this study along with others by the same group (2010), by Seal et al (2005)and by Doe-Simkins (2014) all demonstrate no increase in risk taking and often a decrease in risky behavior. This study is particularly interesting from a human relations standpoint: The injection users who were trained in nasal naloxone administration and who used this skill to save someone in their peer community found themselves elevated to a higher social standing and respect in that group and developed a great sense of pride (along with the stress related to this increased responsibility). In many cases this led to less opioid use and even avoidance of high risk settings. So the opposite effect - less use - was conferred by providing this increased sense of worth.Pubmed link: http://www.ncbi.nlm.nih.gov/pubmed/23932166
Weiner, S. G., P. M. Mitchell, et al. (2014). "Use of intranasal naloxone by basic life support providers." Ann Emerg Med 64(4): S52 (Abstract 144).
Abstract: Study Objectives: Intranasal delivery of naloxone to reverse the effects of opioid overdose has been studied by Advanced Life Support (ALS) providers in several out-of-hospital settings. In 2006, in response to the increase in opiate-related overdoses, a special waiver from the state was obtained to allow administration of intranasal naloxone by Basic Life Support (BLS) providers in our city. This study aimed to determine 1) if patients who received a 2 mg dose of nasal naloxone administered by BLS required repeat dosing while in the ED, and 2) the disposition of these patients. Methods: This was an IRB-approved, retrospective, chart review of patients transported by an inner-city municipal ambulance service to one of three academic medical centers. We included patients aged 18 and older who were transported by ambulance between January 1, 2006 and December 12, 2012 and who received intranasal naloxone by BLS providers as per a created protocol. A list of patients, including date of transfer and age of each patient, was provided to each hospital site. Site investigators matched the data to patients from each hospital’s EMR and performed a chart review to confirm that the patient was correctly identified and to record the outcomes of interest. Descriptive statistics were then generated. Results: A total of 793 patients received nasal naloxone by BLS, and 724 (91.3%) were successfully matched to an ED chart. Hospital A received 336 (46.4%) patients, Hospital B received 210 (29.0%) patients and Hospital C received 178 (24.6%) patients. Mean age was 36.2 (SD 10.5) years and 522 (72.1%) were male. 702 (97.1%) were reported to have abused heroin while 21 (2.9%) used other opioids. Nasal naloxone had an effect per the out-of-hospital record in 689 (95.2%) patients. An additional naloxone dose was given in the ED to 64 (8.8%) patients. ED dispositions were: 507 (70.0%) discharged, 105 (14.5%) admitted and 112 (15.5%) other (eg, left against medical advice, left without being seen or transferred). Conclusion: Only a small percentage of patients receiving out-of-hospital administration of nasal naloxone by BLS providers required additional doses of naloxone in the ED and the majority of patients were discharged.
Web site Editorial comments:
While this is not a full article I chose to include this since this concept is such a hot topic right now in the USA with our epidemic of opioid related deaths. This abstract is a call-out for others to introduce both layperson administered naloxone AND BLS fire and Police administered naloxone in appropriate communities. This abstract simply confirms how effective this therapy is and how infrequently any further ALS or ER level care is needed. The risks are minuscule and the benefits are profound for our population.Web link: http://www.annemergmed.com/article/S0196-0644(14)00777-X/abstract
Web site Editorial comments:Pubmed link: