Use of Intranasal Analgesia in Military Setting: a French Cross Sectional Survey

Background For military physicians, practice in tactical and austere environments, particularly during deployments, requires optimized pain management. Several recent studies have shown a denite interest in the intranasal (IN) route for analgesia. Few published series show ecacy and variable times of action depending on the drug used (ketamine, sufentanil and fentanyl), with exceptional side effects. The aim of this study is to evaluate the medical practice of the French Military Health Service (FMHS) physicians. Methods


Results
In all, 259 responses were collected, giving a 33% return rate; 77.6% of physicians reported being familiar with the IN route for analgesia. However, only 18.4% had already used it. Physicians trained in emergency medicine and assigned to highly operational units were more familiar with this route and used it more frequently. The most common drug used was ketamine (51%). Finally, 90% of respondents expressed an interest in training and use of intranasal analgesia.

Conclusions
If a majority of physicians from the FMHS are familiar with IN analgesia, only few use it in practice.
Therefore, speci c training is suitable to improve this knowledge and homogenize guidelines. Having been the subject of numerous studies in progress in civilian and military medicine, the IN route seems to be a promising solution for remote and austere environments.

Background
Pain treatment is a major factor in the overall management of patient care. Yet, almost half of general practitioners (GPs) feel that they have received insu cient training in this domain (1)(2). In military setting, optimum management of analgesia is a key point of combat casualty care (3)(4). A lack of effective analgesia could be correlated with increased morbidity and mortality in combat setting (5). In modern con icts, as the Barkhane Operation in the Sahel-Saharan Strip, the distances (up to 1100km) can be very long and the evacuation to a eld hospital can take many hours (6)(7). In these situations, the appropriate treatment for prehospital analgesia is sometimes limited, or delayed, because of the lack of intravenous (IV) access. To cope with such problems, the intranasal (IN) route appears as a useful one for pain control, being both rapid and non-invasive (8). Although this has long been a recognized technique, it has not been extensively employed.
The nasal mucosa is highly vascular, with numerous capillaries, providing an exchange surface estimated to be 120-150 cm² (9). However, certain factors, such as a severely deviated nasal septum, some vasoconstrictors, or intranasal hemorrhage, could reduce absorption across the mucous membrane. The IN route is also contraindicated in cases of facial trauma (risk of osteo-meningeal breach) (10). When the IN route is used, it is important to deliver high-quality pulverization with good diffusion over the entire nasal mucosa. A posterior spurt with droplets that are too big or a large overall volume both need to be avoided. The optimal droplet size seems to be below 300 microns. In addition, the mucous membrane reaches a saturation point with an administered volume of about 0.5 ml per nostril. A speci c nasal spray is already available (Mucosal Atomization Device ®, MAD Nasal ™, Tele ex., Morrisville, NC, USA). Adapted for use with a syringe, this device provides a ne mist of particles, 30-100 microns in size, and a better bioavailability of the medication (11). The e cacy and speed of the drug activity delivered by the IN route depends on absorption across the nasal mucosa. This is determined by three factors: the size of the droplets (dependent on the device used), the pH, and the liposoluble nature of the molecules administered.
Three substances are of value for intranasal analgesia: ketamine (40%), sufentanil (78%) and fentanyl (90%) (12). Used at low doses, ketamine has a powerful analgesic effect (13). At doses of 0.5-0.75 mg/kg, IN ketamine is considered as a rapid and effective drug for acute pain control (14)(15). With this form of administration, ketamine is detectable in the blood after 2 minutes. A maximum concentration is reached after 30 minutes, and it is estimated to be effective for 3 hours. The average bioavailability of ketamine delivered via the IN route is 40%, within a range of 33-71% (16)(17)(18). The PAIN-K study, randomized controlled trials using a double-blind vs. placebo protocol, demonstrated the e cacy of IN ketamine, at a dose of 0.75 mg/kg, for acute pain control (Numeric Rating Scale [NRS] ≥ 5), without any signi cant adverse effects (19). Sufentanil is a well-known substance used in IN analgesia (20). Several randomized studies have compared IN sufentanil with intravenous (IV) morphine for acute pain control in emergency departments. At doses of 0.7 µg/kg (21)

Study population
We carried out an anonymous, multicenter and declared study from January 15, 2020, to April 14, 2020. The study group comprised all the GPs and emergency medicine physicians of the FMHS-727 doctors practicing in France and overseas together with 55 doctors in the emergency departments (EDs) of the eight military training hospitals (MTHs) (Clamart, Saint-Mandé, Toulon, Marseille, Lyon, Metz, Bordeaux and Brest). Physicians without a specialized quali cation in general medicine were excluded.

Data collection
A 16 questions -survey was sent out by the Administration services of Military Medicine (Direction de la médecine des forces), via the "Intradef" network, to French military physicians in different medical centers. For the doctors working in the EDs, the researchers contacted the Head of ED in each hospital.
The questionnaire was prepared on the "JotForm" site (www.jotform.com), and it was rst sent out on January 15, 2020, followed by three reminders by email on February 5, March 5 and April 5, 2020.The physicians involved were offered different ways of returning the completed questionnaires: either access using an Internet link, a "QR code," or the possibility of downloading the questionnaire from the email, as a Word document or PDF, and then sending it back to the researchers by email.
The survey was divided into four parts: biographical details, assessment of related knowledge, the use of IN analgesia, and the relative value of this technique in practice. In addition, for those physicians familiar with the IN technique, ve additional multi-choice questions were added. The latter concerned the rapidity of pain control by the IN route, familiarity with the nasal MAD device, and the bioavailability of the different substances delivered via the IN route (ketamine, sufentanil and fentanyl). A mark out of 5 was attributed each time, according to the answers given (Annex A).
The computerized data collected was then transcribed into a table, using an Excel program (version 10, Redmond, WA).

Statistical analysis
The quantitative variables are shown as average values, with standard deviation and range (x, +/standard deviation, min-max). The quantitative data from the different groups were compared using Student's T-test or the Mann-Whitney U test, provided that the necessary parameters were met.
The qualitative variables are shown as percentages. They were compared using the Chi-squared test or the Fisher's exact test if the theoretical numbers were insu cient. Where several tests were carried out, the "p" value was adjusted using the Bonferroni correction. If, from the numbers collected, it was possible to perform a multivariable data analysis, a stepwise logistic regression was applied using the likelihood ratio test. Subsequently, the goodness-of-t of our logistic regression model was veri ed with the Hosmer-Lemeshow test. All statistical tests were performed using IBM SPPS 25.00 software (IBM Corp. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY).

Description of the sample population
Two hundred and fty-nine responses were collected during the study period, giving a 33% return rate. Only one questionnaire was rejected, because it had been completed by an anesthetist. The nal sample comprised 118 women and 141 men, and the average age was 36.2 years: 35 years (+/-6, 27-57) for the women and 37 years (+/-7, 27-61) for the men.
The majority (65.6%) of respondents had been practicing medicine for < 10 years, and 68.6% of the sample group had followed specialized training courses in emergency medicine. In all, 58.3% of these physicians were on-call in emergency services (EDs or pre-hospital care). Physicians working for the Army accounted for 41.3% of the responses, with 107 completed questionnaires, followed by the Air Force with 33 questionnaires completed (Table 1). Within the FMHS, 305 of the physicians interviewed were working for the Army and we had a 35% response rate; 80 physicians were working for the Air Force and the response rate was 41.2%; and, nally, 98 were working for the Navy and we had a response rate of 19.4%. Hence, our sample group is not signi cantly different from the study population (p = 0.085). However, the number of on-call duties did not seem to affect the extent of this knowledge as much as the number of deployments carried out (p < 0.01). Finally, those physicians who are assigned to highly operational units or units working in austere environments are more familiar with the IN route of analgesia (p < 0.01) ( Table 2). The multivariable analysis that we performed supports these results (Fig. 1). was seldom used (4%). Some physicians have already used ketamine and sufentanil (11%), ketamine/midazolam or sufentanil alone (6%). Furthermore, some physicians have used midazolam alone (9%) (Fig. 2). In the majority of cases, no side effects were observed with ketamine (64.5%) or with the opioids (82%). However, psychodysleptic side effects have been reported by 29% of physicians when administering ketamine by the IN route. Slightly more than half of doctors (52.3%) have stated that additional pain control was necessary after using the IN route. In this case, the analgesic was delivered intravenously by 91.3% of the respondents.
In summary, IN analgesia is more prevalent if the doctor has followed supplementary specialized training in emergency medicine (p < 0.001), has been on-call in a hospital or a pre-hospital context (p < 0.001), or if he/she has been part of a highly operational unit or units working in austere environments (p < 0.01) ( Table 3).

Discussion
The aim of this study was to assess the level of knowledge of IN analgesia among FMHS physicians. Only a small proportion of the doctors questioned had already used the IN route for pain control and then mainly in pre-hospital medical care and in France. The most frequently used drug is ketamine, alone or in association with midazolam. Ketamine is a substance that is well-known to military physicians, because it is reliable and e cacious in controlling acute pain on the battle eld (28). Ketamine has the effect of stimulating the cardiovascular system (central sympathomimetic action) while having little effect on ventilation (28). In association with midazolam, the psychodysleptic side effects seen with IN ketamine are reduced. However, to our knowledge, no study has yet proven that joint administration of ketamine and midazolam diminishes this side effect. Four of the doctors used midazolam on its own but given that this drug has hypnotic properties it would seem to be more appropriate for sedation (of psychotic patients for instance) rather than pain control.
Despite the more numerous studies on the use of opioids (sufentanil and fentanyl) in IN analgesia, particularly in a pre-hospital context, both drugs are less frequently used by military doctors (23% of use).
These substances are more lipophilic than ketamine and, consequently, the molecules are absorbed better by the nasal mucosa. However, because of their hypotensive properties and certain adverse effects, notably reducing respiration, they merit caution as regards their use for a combat casualty with hemorrhagic shock. On the other hand, an advantage of this class of therapeutics is the possibility of reversing any major adverse effects by the administration of an antidote (naloxone), initially using the same delivery route. The IN administration of this drug is available to non-medical professionals (police, paramedics etc.) in the USA for treating victims of an opioid overdose (29).
In our sample group, the physicians showed a preference, on national territory at least, for using ketamine. In familiarizing themselves with this drug, they will be capable of using it for a combat casualty in a critical state during deployments.
Several procedures are currently being introduced to extend the use of IN analgesia into combat zones. Those military doctors whose role is supporting the National Gendarmerie Intervention Group (GIGN) have put in place a protocol for administering sufentanil and ketamine via the IN route (30). At the moment, the MAD device is only available on demand in exceptional cases during deployments, but it should be available for routine ordering from 2021 onwards.
Finally, a ketamine pulverization device for IN analgesia is being developed currently by the FMHS Central Pharmacy and this could soon be made available as a means of auto-administration for all servicemen and women. The idea is to include this device in the personal kit of each soldier, actually this kit is composed of a morphine syrette (a 10 mg subcutaneous dose) for analgesia (31). It would be interesting to carry out a new study in a few year to assess the impact of introducing both these standardized guidelines and the new injection device on the level of knowledge and application of this method of analgesia.

Limitations
Despite the three reminders made to increase the response rate, the low response rate of 33% could be explained by a signi cant number of military physicians on deployment over our study period. During deployment in overseas military operations, it is more complicated to have access to one's mailbox. Moreover, some physicians may not have been interested in this survey about the IN route and therefore did not respond. Because of this selection bias, it is possible that physicians interested in this technique are over-represented in this study.

Conclusions
In this study, a majority (78%) of physicians from the FMHS reported being familiar with IN analgesia, but only a few (18%) declared using it in practice. Knowledge and use of the IN technique varied according to the dedicated training courses followed previously, whether the physician has been on-call in the hospital or pre-hospital emergency services, and the type of military unit supported. Therefore, speci c training