Featured new articles related to intranasal drug delivery:
October - December 2013
Andolfatto, G., E. Willman, et al. (2013). "Intranasal Ketamine for Analgesia in the Emergency Department: A Prospective Observational Series." Acad Emerg Med 20(10): 1050-1054.
OBJECTIVES: The objective was to examine the feasibility, effectiveness, and adverse effect profile of intranasal ketamine for analgesia in emergency department (ED) patients. METHODS: This was a prospective observational study examining a convenience sample of patients aged older than 6 years experiencing moderate or severe pain, defined as a visual analog scale (VAS) score of 50 mm or greater. Patients received 0.5 to 0.75 mg/kg intranasal ketamine. Pain scores were recorded on a standard 100-mm VAS by trained investigators at baseline, then every 5 minutes for 30 minutes, and then every 10 minutes for an additional 30 minutes. The primary outcome was the number and proportion of patients experiencing clinically significant reductions in VAS pain scores, defined as VAS reductions of 13 mm or more, within 30 minutes. Secondary outcomes included the median reduction in VAS, the median time required to achieve a 13 mm reduction in VAS, vital sign changes, and adverse events. Continuous data are reported with medians and interquartile ranges (IQRs). The Wilcoxon signed-ranks test was used to assess changes in VAS scores. Adverse effects are reported with proportions and 95% confidence intervals (CIs). RESULTS: Forty patients were enrolled with a median age of 47 years (IQR = 36 to 57 years; range = 11 to 79 years) for primarily orthopedic injuries. A reduction in VAS of 13 mm or more within 30 minutes was achieved in 35 patients (88%). The median change in VAS at 30 minutes was 34 mm (44%). Median time required to achieve a 13 mm VAS reduction was 9.5 minutes (IQR = 5 to 13 minutes; range = 5 to 25 minutes). No serious adverse effects occurred. Minor adverse effects included dizziness (21 patients, 53%; 95% CI = 38% to 67%), feeling of unreality (14 patients, 35%; 95% CI = 22% to 50%), nausea (four patients, 10%; 95% CI = 4% to 23%), mood change (three patients, 8%; 95% CI = 3% to 20%), and changes in hearing (one patient, 3%; 95% CI = 0% to 13%). All adverse effects were transient and none required intervention. There were no changes in vital signs requiring clinical intervention. CONCLUSIONS: Intranasal ketamine reduced VAS pain scores to a clinically significant degree in 88% of ED patients in this series. Adverse effects were minor and transient. Intranasal ketamine may have a role in the provision of effective, expeditious analgesia to ED patients.
Web site Editorial comments:
Here is another IN ketamine article evaluating this drugs effectiveness as an analgesic (not as a sedative). This is the first study on this topic in adults in an emergency room (Johansson also recently published a study for use in the prehospital setting). The authors found this treatment (0.5 to 0.75 mg/kg of intranasal ketamine) to have a clinically significant impact on pain reduction in 88% of patients. The mean pain score reduction was 34 mm on a 100 mm scale. The median time to onset was just under 10 minutes. Side effects were minor. This suggests a potential use for IN ketamine in the setting of acute severe pain in adults – cheap, fast, relatively effective with minimal side effects. Personally I think they used a dose that is a bit low when compared to other studies that used 1 mg/kg, but since this is a relatively new concept, picking a proper first dose can be difficult. Also IN sufentanil may be more compelling for pain control in adults based on recent data showing pain score reductions of 57 mm at 30 minutes (Steenblick). However, there are rare issues with mild respiratory depression using IN sufentanil (especially in the elderly) so it is definitely of higher risk that IN ketamine. The authors specifically mention this issue as the real advantage of IN ketamine – no need for monitoring in a busy or overcrowded department. Perhaps based on the situation either drug would be selected or at times a combination. Hopefully these questions and the ideal dose will be sorted out with further research studies.
Pubmed link: http://www.ncbi.nlm.nih.gov/pubmed/24127709
Gracia, M. R., L. C. Hortelano, et al. (2013). "Intoxicación accidental por fentanilo intranasal." Anales de Pediatria In press.
The abstract is not available as this was a letter to the editor written in Spanish. Instead we just review the issue in the editorial comments below.
Web site Editorial comments:
This website had previously stated that there are no reports of significant adverse events related to IN fentanyl, but has also stated that sufentanil which is 8-10 times more potent can cause respiratory depression. These statements have been based on many hundreds to thousands of uses of IN fentanyl in pediatric practice using generic fentanyl at concentrations of 50 mcg per ml. Recently, nasal fentanyl has been put on the market as a hospice and chronic pain medication for use in adults. These drugs are extremely highly concentrated – to doses as high several thousand micrograms per ml so that a single 1/10 ml spray may contain hundreds of micrograms of drug. In this situation, overdose is possible and likely in children due to the very high plasma levels that will be obtained despite the slower absorption of the nasal drug and the delayed peak activity. Gracia points this fact out by reporting the respiratory depression and desaturation that occurred when two young boys got a hold of an adult dispenser of this medication and accidentally administered doses to their noses of 400 mcg. Both boys requiring naloxone for recovery – one IN, the other IM.
In our practice we are quite happy with the safety and efficacy (and low cost) of IN fentanyl in the generic formulation (50 mcg/ml). Our experience for over a decade using this medication for acute fractures, burns and other acute painful issues in pediatrics is excellent. We do use IN sufentanil (also at 50 mcg/ml) in adults and do find some mild respiratory depression primarily in the elderly with this more potent opiate (saturations in the 88-90% range at our altitude of 4500 feet – 1500 meters) which we are comfortable with observing until it wears off. I do not see the need in acute care for these more concentrated formulations given the efficacy and safety profiles of the lower concentrations.
Pubmed link: http://www.ncbi.nlm.nih.gov/pubmed/23684172
Mitra, S., S. Kazal, et al. (2013). "Intranasal clonidine vs midazolam as premedication in children: A randomized controlled trial." Indian Pediatr (In press).
Objectives: To compare anxiolysis produced by intranasal clonidine with intranasal midazolam as premedication in children undergoing surgery. Design: Double-blind randomized controlled study. Setting: Tertiary-care hospital, July 2009 to June 2010. Patients: 60 American Society of Anesthesiologists physical status I-II surgical patients 1-10y old. Intervention: The participants were randomly allocated to two groups to receive either intranasal clonidine 4mcg/kg (Group I) or intranasal midazolam 0.3mg/kg (Group II). Outcome measures: The primary outcome measure was proportions of patients with satisfactory anxiolysis at 30 min after drug administration. Secondary outcome measures included satisfactory mask acceptance, times of onset of sedation and anxiolysis, drug acceptance, level of sedation, wake-up score and side effects. Results: All children achieved satisfactory anxiolysis at 30 min. Group I fared significantly better than Group-II on mask acceptance (100% in Group I vs. 80% in Group II; P=0.024), drug acceptance (93% vs. 13%; P<0.001) and proportion of patients with satisfactory wake-up scores (100% vs. 53%; P<0.001). Group II patients had significantly faster onset of sedation (median 10 min vs. 15 min; P<0.05) but not that of anxiolysis compared to Group-I (median 10 min for both groups; P>0.05). Side effects were significantly more frequent in Group II. Conclusions: Though intranasal midazolam produced faster sedation, both the drugs produced satisfactory anxiolysis at 30 min. Mask acceptance and several other secondary outcomes were significantly better with intranasal clonidine.
Web site Editorial comments:
This study randomized 60 children to either IN midazolam 0.3 mg/kg (5 mg/ml generic solution) or IN clonidine 4 mcg/kg (150 mcg/ml solution) plus 0.6 mg of atropine. The primary outcome was adequate sedation at 30 minutes. Secondary outcomes were crying after drug delivery and mask acceptance in the operating suite. All 60 patients (30 per group) achieved adequate sedation by 30 minutes though it was faster onset (20 minutes) with midazolam. The clonidine group had better acceptance of the drug with less crying and they had better mask acceptance and calmer awakening. The authors conclude: “intranasal clonidine has been shown to produce comparable level of sedation as effective anxiolysis as nasal midazolam after 30 min, but with a better mask acceptance and recovery profile.”
There are some quite serious flaws in the study design which in 2013 are really not excusable given the easy access to data via the internet and the huge database that is 20 years old showing that midazolam sedation requires a dose of more than 0.3 mg/kg nasally. Another flaw is that the well known downside of burning upon application that can be mitigated by combining it with a topical anesthetic. Furthermore they delivered the drug in a recumbent position with a dropped syringe – which tends to lead to a lot of runoff into the hypopharynx (i.e. oral drug) and loss of any true nasal absorption further limiting the drugs effectiveness. Never the less, the study is interesting in that someone finally did a moderate sized trial on a very inexpensive Alpha-2 agonist – Clonidine – and showed it is very effective at preoperative anxiolysis and sedation without the issue of burning upon application. This has been hinted at by prior case reports of intranasal clonidine and by many trials of a more expensive alpha-2 agonist dexmedetomidine. In the era of health care cost concerns, it might be time to further investigate this very inexpensive sedation option – nasal clonidine, delivered by an atomizer. Good efficacy and safety data on this medication might be compelling enough to convince many clinicians to switch from midazolam to clonidine or to actually even consider nasal medication for sedation and anxiolysis for minor procedures.
Internet link for free article: http://www.indianpediatrics.net/Epub05092013/RP-00299.pdf
Sharma, R. and R. Harish (2013). "Comparative study of the efficacy of intranasal midazolam vs intravenous midazolam in convulsing neonates and children." RRJMHS 2(4): 54-57.
To compare the efficacy of intranasal midazolam in relation to intravenous midazolam for control of seizures. To observe variability if any amongst the two groups in terms of heart rate, respiratory rate, blood pressure and oxygen saturation. A Prospective Randomized study conducted on 100 patients of 0-19 years of age hospitalized in emergency ward and NICU in a convulsing state. They were divided into two groups. GP-I was given intranasal midazolam @ 0.3 mg/ kg and GP-II was given intravenous midazolam @ 0.3 mg/ kg. Outcome was measured in terms of: Time taken from physician contact to drug administration. Time taken from drug administration to cessation of seizures. Mean time from physician contact to drug administration was significantly shorter with intranasal midazolam as compared to intravenous midazolam viz [ 0.40+ 0.10min vs 1.06+0.40+min) [p< 0.05 ].Mean time from drug administration to cessation of seizures was comparable in both the groups 1.0 + 0.31 min and 1.0+0.32 min (p> 0.05). However this difference was statistically insignificant. The readings for oxygen saturation and vital parameters did not show a statistically significant difference amongst the groups. Seizure control was more prompt with intranasal midazolam as compared to intravenous midazolam. As time needed for drug administration was lesser. Intranasal midazolam is a rapid, efficacious, easy to administer and socially more acceptable route of drug administration. It can be used not only in hospital setting but also for home management of seizures after proper instructions to parents.
Web site Editorial comments:
Here is our 4th or 5th prospective randomized trial comparing intranasal benzodiazepines to the gold standard intravenous benzodiazepines for the treatment of status epilepticus. As in every other prospective trial on the topic the two treatment are equivalent in terms of efficacy: In this study both were successful at stopping seizures 94% of the time with a single dose. The intranasal route was also slightly faster likely due to the delays associated with IV line establishment. Unique to this study was the inclusion of neonates: There were 7 neonates in this study and an additional 26 children under the age of 1 year.
Internet link to free article: (click for link to free article)
Web site Editorial comments: