Nasal Nalbuphine Analgesia in Prehospital Trauma Management by First-Responder Personnel on Ski Slopes in Switzerland

Urs Pietsch (  urs.pietsch@kssg.ch ) Kantonsspital Sankt Gallen https://orcid.org/0000-0001-6957-2638 Yoël Berger Department of Anaesthesiology and Pain Medicine, Inselspital, Bern David Schurter Schutz und Rettung, Zurich Lorenz Theiler Department of Anaesthesiology, Cantonal Hospital Aarau, Aarau Volker Wenzel Department of Anaesthesiology and Intensive Care Medicine Friedrichshafen Lorenz Meuli Department of Vascular Surgery, Cantonal Hospital St. Gallen Andreas Grünenfelder Klinik Gut, St. Moritz Roland Albrecht Swiss Air Ambulance, Zurich


Introduction
Pain is one of the major prehospital symptoms requiring prompt management, in particular in trauma patients. Nevertheless, many colleagues report that analgesia in the eld is insu cient due to multiple reasons (1) (2) (3) (4) (5) (6), one reason being overly long response times of the emergency medical service (EMS). In Switzerland, EMS units are staffed with highly trained paramedics, but due to its mountaineous and alpine terrain the time until arrival at the scene can be prolonged. Therefore, Switzerland has also a long history of helicopter emergency services (HEMS), staffed with a pilot, a paramedic and an emergency physician. Usually, a given HEMS can reach every point in Switzerland within 15 min (7) subject to weather conditions. Winter sports such as downhill skiing or snowboarding attracts > 2. 5

million skiers annually in
Switzerland, with about 76,000 injured skiers requiring treatment (8). First responders (FR) in an accident on a ski slope are usually ski lift employees providing rst aid, but no analgesia. However, analgesia on ski slopes may be achievable with Nalpuphine due to its safety features (mixed agonist / antagonist), ceiling effect regarding respiratory depression, equianalgesic potency to Morphine (9), simple handling, lack of abuse potential, safe in pregnant and lactating women (10) (11) (12), and possible employment by rst responders (FR). (13) (10) (14) (15).
There are several approved routes of Nalbuphine administration including intravenously (IV), intramuscularly (IM), subcutaneously (SC) (10), and nasal due to its high lipophilicity and low molecular weight (14) (16) (17) (18) (19) (20) (21). Because of its simplicity and non-invasive nature, we chose the nasal route to administer Nalbuphine by ski slope rst responders. Our hypothesis was that nasal Nalbuphine would have no effect on pain in victims of ski slope accidents.

Methods
This observational cohort study examined data collected from patients given Nalbuphine analgesia by FR in the prehospital phase. Reporting of the study conforms to the STROBE statement for the report of observational cohort studies.

Study design
All FR received a mandatory theoretical and practical instruction about nasal Nalbuphine using the Mucosal Atomization Device (Tele ex, Wayne, PA, USA). Speci cally, they were instructed about the mechanisms of action, indications and contraindications as well as the potential side effects. Nalbuphine treatment according to an algorithm was required to assure patient safety (Fig. 1). Nalbuphine was restricted to cases when it was highly likely that the waiting time until arrival of an EMS or HEMS team was > 15 min.

Medication, administration, indications and contraindications
Nalbuphine (Nalbuphin OrPha®, OrPha Swiss, Kuesnacht, Switzerland) in a dose of 10 mg/ml in vials containing 2 ml (20 mg) was used. The dosage was according to body weight with a minimal dose of 5 mg for patients of 20-44 kg up to a maximum dose of 20 mg for adults > 75 kg with severe pain (Fig. 1). The total dosage was divided in half to administer a maximum 1 ml in each nostril. Main indication for Nalbuphine was severe pain being de ned as a score of ≥ 5 on a numeric rating scale (NRS) with 0 de ned as absence of pain and 10 being the maximal imaginable pain. If there was evidence of altered consciousness, alcohol consumption or noticeable abnormal vital signs, administration of Nalbuphine by FR was deemed contraindicated. Head trauma regardless of changes in mental status was an absolute contraindication for Nalbuphine to assure that no nasal drug was applied as long as a skull fracture was not excluded. Further Nalbuphine contraindications were known allergy to the drug or its additives, patient refusal, or body weight < 20 kg.

Data collection and statistical analysis
The study was performed in six different ski resorts in the canton of Graubuenden, Switzerland (Arosa, Jakobshorn Davos, Lenzerheide, Marguns Engadin, Parsenn and Weisse Arena Laax). Observation period was from November 2017 until April 2020. Data collection was performed directly by FR using an online questionnaire with prede ned endpoints. Apart from age and gender, no further personal data was recorded to ensure de-identi cation of patients. Also, no personal data of the FR on scene was collected so no conclusion about the rescuer could be drawn during later analysis.

Statistical analysis
Patient´s characteristics were summarized and presented by tables. Continuous variables were summarized by mean ± standard deviation if normally distributed or by median and the interquartile range if skewed. Normality was tested using the Shapiro-Wilk test. Categorical variables were summarized with counts and percentages for each level of the variable. Wilcoxon-Mann-Whitney-U Test was used to assess differences in pre-vs. post Nalbuphine NRS. To further elaborate factors that are potentially associated with the effectiveness of Nalbuphine, a multiple linear regression model was built including the variables sex, age in categories and initial pain level in a complete-case-analysis. To adjust for difference in absolute pain reduction for depending on the initial reported pain level, the same regression model was built on a calculated relative pain reduction variable (i.e. percentage of NRS from initial NRS). Dose of Nalbuphine applied was excluded from the model due to multicollinearity of this variable, and the initial pain level. Location of injury was not included in the model due to the low number of patients per injury location, and the substantial proportion of missing data in this variable.

Patient characteristics
During the observation period, a total of 267 patients (male gender, 61.1%; age, 33.3 ± 18.2 years) were treated with nasal Nalbuphine by FR (Table 1). Injuries were located on the upper extremity (44.2%), with more than the half of these involving the shoulder (23.6% of all injuries). Lower extremities were injured in 35.2%, with a majority of knee and lower leg injuries (12% and 14.6% of total injuries, respectively). The remaining 20.6% were injuries of the trunk including back, thorax and abdominal injuries. From 28 patients, (10.5%) there was no data available about the site of injury (Table 1).   (Table 1, Fig. 2). The multivariate regression model showed that pain reduction was more pronounced in patients with higher initial pain level. This effect decreased, but remained statistically signi cant in the second multivariate model using a relative scale for pain reduction (Table 2). Nalbuphine was less effective in patients aged 20-60 years compared to the adolescent population where Nalbuphine was more effective. The same tendency was observed for the elderly population (i.e. ≥60 years of age). However, there were only 20 patients in this age group and the difference was not statistically signi cant. The level of pain reduction was similar for both genders ( Table 2, Fig. 2). In 41 (15.3%) patients, a dissatisfaction of the treatment was documented. Complete-case analysis: Included observations n = 244, 19 missing observations. Estimate = Difference in NRS reduction after application of nasal Nalbuphine according to either level of the factor variable or initial pain level (absolute difference or relative difference in percentage respectively). 95% C.I. = 95% con dence interval of the estimate. Male sex and Age < 20 years served as the reference groups in both models.
Side effects were reported in 5.6% (n = 11) of patients. Three patients (1.1%) complained of nausea and eight patients (3.0%) reported an uncomfortable feeling in the nose during and after Nalbuphine administration, or disliked the bitter taste. No major adverse event was observed.

Discussion
In our study, the majority of the patients reported a mean reduction of 3 points on the NRS without any major adverse events after Nalbuphine administration.
The reported pain relief in our study is consistent with the literature, where a decrease of more than 2 points on the NRS was deemed a good pain relief after (22). A study with out-of-hospital use of nasal Fentanyl showed also an average reduction of 3 points on the NRS, concluding that nasal Fentanyl is effective for analgesia in the pre-hospital phase (23). Only few studies evaluated analgesia with Nalbuphine in the prehospital setting, however with con icting results. When given by paramedics out-ofhospital, IV or IM Nalbuphine reduced pain by 5 points on the NRS (24), while the same strategy resulted in excessive Morphine requirements after hospital admission in a case series. That study even reported less decline in pain scores after further administration of analgesics in the emergency department in prehospital Nalbuphine patients (25), which is in accordance with a case review that described increased opioid requirements after Nalbuphine (15). In fact, this is expected because the mixed agonist / antagonist effects of Nalbuphine, with agonistic effects on the κ-receptors and antagonistic effects on the µ-receptor (9). Therefore, if analgesia is continued with pure µ-receptor agonists, an increased dose is needed to overcome the antagonistic effect exerted by Nalbuphine. Our study could not follow up patients after hand-over to EMS / HEMS personnel. Another possible disadvantage of mixed opioid agonist / antagonists is a limited analgesic effect or ceiling effect (9). This could explain that no patient was completely free of pain after Nalbuphine with a minimal NRS of one after treatment.
We did not nd any signi cant differences between genders regarding pain intensity before or after Nalbuphine, regardless of the administered dose. There is some evidence that Nalbuphine has a pain facilitating effect in males, at least if it is administered in small doses of 5 mg (26), an effect we did not observe. There was a predominance of males in our study (58.8% vs 41.2%) which is consistent with the average distribution of injured people on Swiss ski slopes (56.6% male vs 43.4% female) (27). We observed only a few minor side effects. Although unlikely, the risk of respiratory depression exists also following Nalbuphine (9) (13) (14), but this was not reported in our study. Interestingly, in our study only 15% reported a bad satisfaction with Nalbuphine even though the number of patients who reported a good analgesic effect was high (60.0%). This phenomenon was already described in labouring women treated with Nalbuphine; only 54-57% of the parturient women experienced good pain relief but 78% were willing to have the same treatment in a subsequent birth (12). This could possibly be explained by a reported feeling of relaxation, more than pain relief (12). There is also evidence that satisfaction with opioid treatment seems to be in uenced, at least in part, by a rapid onset (13). Nasally administered drugs are normally well absorbed and show a rapid onset of action due to the rich blood supply and large surface of the mucosa, bypassing of a rst-pass-effect and, maybe at least in part bypassing the bloodbrain-barrier (18).
Our study has some limitations. We mainly observed traumatic shoulder and knee injuries, which is expected with the predominance of our study sites being in Swiss ski resorts (27). There could be a bias in data collection because it was performed directly by FR. If a patient felt sympathies for his rescuer, it is possible that the answers have been whitewashed, in particular regarding qualitative outcomes such as overall satisfaction. Although the qualitative pain reduction from each patient was reported, there were missing NRS values after Nalbuphine 10.5% (n = 28) of the patients, which is to be expected in an observational study in the pre-hospital setting. There was also a predominance of the male gender; this could have had an in uence on the described pain reduction. We observed only a few minor side effects with Nalbuphine. However, we did not follow up the patients, and we cannot prove that Nalbuphine administration is always safe.

Conclusion
In conclusion, nasal Nalbuphine by FR was a noninvasive pain management strategy that provided safe and effective analgesia in prehospital, acutely injured patients. This may be an alternative method especially in circumstances of severe pain and prolonged time between arrival of the FR and arrival of EMS / HEMS personnel on scene.
List Of Abbreviations Availability of data and supporting materials section: Not applicable.
Funding: No external funding.
Competing interests: The authors declare that they have no competing interests.
Authors' contributions: R.A., D.S. and U.P. developed the original idea for the manuscript and helped write it. Y.B., L.T., L.M., V.W. helped to write the manuscript, gathered additional data, and made important recommendations. All authors read and agreed to the nal version of the manuscript. Figure 1 Treatment algorithm that had to be followed by the lay rescuers to assure drug administration only if indicated. NRS = numeric rating scale. GCS = Glasgow coma scale.