Effectiveness of Intranasal Analgesia in the Emergency Department

In the Emergency Department (ED), pain is one of the symptoms that are most frequently reported, making it one of the most significant issues for the emergency physician, but it is frequently under-treated. Intravenous (IV), oral (PO), and intramuscular (IM) delivery are the standard methods for administering acute pain relief. Firstly, we compared the safety and efficacy of IN analgesia to other conventional routes of analgesia to assess if IN analgesia may be an alternative for the management of acute pain in ED. Secondly, we analyzed the incidence and severity of adverse events (AEs) and rescue analgesia required. We performed a narrative review-based keywords in Pubmed/Medline, Scopus, EMBASE, the Cochrane Library, and Controlled Trials Register, finding only twenty randomized Clinical trials eligible in the timeline 1992–2022. A total of 2098 patients were analyzed and compared to intravenous analgesia, showing no statistical difference in adverse effects. In addition, intranasal analgesia also has a rapid onset and quick absorption. Fentanyl and ketamine are two intranasal drugs that appear promising and may be taken simply and safely while providing effective pain relief. Intravenous is simple to administer, non-invasive, rapid onset, and quick absorption; it might be a viable choice in a variety of situations to reduce patient suffering or delays in pain management.


Introduction
Acute pain is one of the most frequent symptoms in patients presenting to the Emergency Department (ED), deriving from various conditions, such as trauma, injuries, headache, renal colic, cancer, etc.
Due to its heterogeneity, it frequently represents a challenge for emergency physicians, and data indicate that inadequate pain management is rather typical [1,2].
There are many medications that can be administered, moreover using different routes.The qualities needed in the drugs we want to provide in emergency care are quickness, effectiveness, and safety.The most common routes for acute analgesia are per os (PO), intravenous (IV), and intramuscular (IM).In patients who need quick analgesia or who may have a nihil per os condition, the per os (PO) route may not be the simplest to use.However, even the intravenous administration may not be very convenient because it requires the placement of a peripheral catheter; therefore, the patient must have good venous patrimony, and the hospital requires qualified personnel.
On the other hand, IM administration frequently causes the patient discomfort.Additionally, the medication takes longer to absorb via muscle, delaying the beginning of the analgesic action.
In this scenario, because of its safety, the simplicity of administration, the non-invasive route, the quick effect, and the fact that it does not require a peripheral catheter, the intranasal (IN) method has become increasingly popular [3].Currently, it is regarded as a good substitute for the classic methods of drug administration.Additionally, the nasal mucosa is highly vascularized and rich in capillaries; this results in a more rapid absorption and an early onset of analgesia [3,4].Even this route of administration may have restrictions, for example, in facial trauma, bleeding nose, or white mucus.
The primary goal of the study was to compare the differences in pain scores between IN analgesics and active comparator or placebo from baseline to the time specified in the RCT.Adverse event (AE), frequency and severity, as well as the need for rescue analgesia (if available), were secondary outcomes.
There is little published material regarding opioid IN administration.Due to their difficulty in taking oral or intravenous drugs, most of the studies were conducted on pediatric patients [5,6].Few studies have been performed on adults.
To our knowledge, there is only one review that takes a comprehensive look at the use of intranasal analgesia in emergency care and includes a small number of trials [6].
Probably, the lack of studies is due to the poor habit of using drugs with this route, few devices to use, and poor staff training.In recent years, literature about the effectiveness of intranasal analgesia has increased.

Materials and Methods
We conducted a literature review on the main databases, such as PubMed, the Cochrane Library, Medline, Embase, and Scopus in the timeline 1992-2022, using the keywords: emergency department, intranasal administration, analgesics, migraine, acute pain (MeSH Terms).
We selected all the Randomized controlled trials (RCTs) published in English and evaluated the use of IN analgesia in Emergency Care.
Only adult patients who had received at least one dosage of IN analgesia for acute pain in the Emergency Room and Prehospital Care were the only ones selected for these studies.
The primary search found 126 results.Study protocols, duplicated results, not pertinent articles, and unavailability of full text were excluded.Finally, 20 clinical trials were included in this review (Figure 1), and they were evaluated for the risk of bias assessment.(Table 1 and Figure 1).
In order to assess the effectiveness and impact of the analgesics, validated pain scales were utilized in every trial that was looked at.The frequency of AEs and the requirement for rescue analgesia were also considered by these scales.The inclusion criteria of the patients participating in the trials were as follows: only adults were selected, including patients receiving IN analgesia compared to OS, IV, or a combination of different routes.Pregnant patients were not allowed.Patients were also excluded if they had used analgesics within the previous hours or if they had hemodynamic or respiratory instability or disorientation.Patients who could not provide informed consent (due to clinical impossibilities or the language barrier) were also excluded.Even patients who reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% statistical power.Table 1.Assessment bias of analyzed studies.

Overall
Dodick et al. [7] Medicina 2023, 59, x FOR PEER REVIEW 3 of 13                       In order to assess the effectiveness and impact of the analgesics, validated pain scales were utilized in every trial that was looked at.The frequency of AEs and the requirement for rescue analgesia were also considered by these scales.The inclusion criteria of the patients participating in the trials were as follows: only adults were selected, including patients receiving IN analgesia compared to OS, IV, or a combination of different routes.Pregnant patients were not allowed.Patients were also excluded if they had used analgesics within the previous hours or if they had hemodynamic or respiratory instability or disorientation.Patients who could not provide informed consent (due to clinical impossibilities or the language barrier) were also excluded.Even patients who reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% statistical power.

Results
The results are summarized in Table 2. Below, we list the main pathologies responsible for acute pain management in the ED and the implications of intranasal analgesia in these areas with side effects.In order to assess the effectiveness and impact of the a scales were utilized in every trial that was looked at.The frequ quirement for rescue analgesia were also considered by these s ria of the patients participating in the trials were as follows: o including patients receiving IN analgesia compared to OS, IV, o ent routes.Pregnant patients were not allowed.Patients were a used analgesics within the previous hours or if they had hem instability or disorientation.Patients who could not provide i clinical impossibilities or the language barrier) were also exclu reported an allergy or an intolerance to the trial drug were ineli The sample needed for each RCT was calculated to obta power.

Results
The results are summarized in Table 2. Below, we list the m sible for acute pain management in the ED and the implication in these areas with side effects.In order to assess the effectiveness and im scales were utilized in every trial that was looke quirement for rescue analgesia were also conside ria of the patients participating in the trials wer including patients receiving IN analgesia compar ent routes.Pregnant patients were not allowed.used analgesics within the previous hours or if instability or disorientation.Patients who could clinical impossibilities or the language barrier) w reported an allergy or an intolerance to the trial d The sample needed for each RCT was calc power.

Results
The results are summarized in Table 2. Belo sible for acute pain management in the ED and in these areas with side effects.In order to assess the effectiveness and impact of the analgesics, valida scales were utilized in every trial that was looked at.The frequency of AEs an quirement for rescue analgesia were also considered by these scales.The inclus ria of the patients participating in the trials were as follows: only adults were including patients receiving IN analgesia compared to OS, IV, or a combination ent routes.Pregnant patients were not allowed.Patients were also excluded if used analgesics within the previous hours or if they had hemodynamic or re instability or disorientation.Patients who could not provide informed consen clinical impossibilities or the language barrier) were also excluded.Even pati reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% power.

Results
The results are summarized in Table 2. Below, we list the main pathologie sible for acute pain management in the ED and the implications of intranasal in these areas with side effects.In order to assess the effectiveness and impact of the analgesics, validated pain scales were utilized in every trial that was looked at.The frequency of AEs and the requirement for rescue analgesia were also considered by these scales.The inclusion criteria of the patients participating in the trials were as follows: only adults were selected, including patients receiving IN analgesia compared to OS, IV, or a combination of different routes.Pregnant patients were not allowed.Patients were also excluded if they had used analgesics within the previous hours or if they had hemodynamic or respiratory instability or disorientation.Patients who could not provide informed consent (due to clinical impossibilities or the language barrier) were also excluded.Even patients who reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% statistical power.

Results
The results are summarized in Table 2. Below, we list the main pathologies responsible for acute pain management in the ED and the implications of intranasal analgesia in these areas with side effects.In order to assess the effectiveness and impact of the analgesics, valida scales were utilized in every trial that was looked at.The frequency of AEs an quirement for rescue analgesia were also considered by these scales.The inclus ria of the patients participating in the trials were as follows: only adults were including patients receiving IN analgesia compared to OS, IV, or a combination ent routes.Pregnant patients were not allowed.Patients were also excluded if used analgesics within the previous hours or if they had hemodynamic or re instability or disorientation.Patients who could not provide informed consen clinical impossibilities or the language barrier) were also excluded.Even pati reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% power.

Results
The results are summarized in Table 2. Below, we list the main pathologie sible for acute pain management in the ED and the implications of intranasal in these areas with side effects.In order to assess the effectiveness and im scales were utilized in every trial that was looke quirement for rescue analgesia were also conside ria of the patients participating in the trials wer including patients receiving IN analgesia compar ent routes.Pregnant patients were not allowed.used analgesics within the previous hours or if instability or disorientation.Patients who could clinical impossibilities or the language barrier) w reported an allergy or an intolerance to the trial d The sample needed for each RCT was calc power.

Results
The results are summarized in Table 2. Belo sible for acute pain management in the ED and in these areas with side effects.In order to assess the effectiveness and impact of the analgesics, valida scales were utilized in every trial that was looked at.The frequency of AEs an quirement for rescue analgesia were also considered by these scales.The inclus ria of the patients participating in the trials were as follows: only adults were including patients receiving IN analgesia compared to OS, IV, or a combination ent routes.Pregnant patients were not allowed.Patients were also excluded if used analgesics within the previous hours or if they had hemodynamic or re instability or disorientation.Patients who could not provide informed consen clinical impossibilities or the language barrier) were also excluded.Even pati reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% power.

Results
The results are summarized in Table 2. Below, we list the main pathologie sible for acute pain management in the ED and the implications of intranasal in these areas with side effects.In order to assess the effectiveness and impact of the analgesics, valida scales were utilized in every trial that was looked at.The frequency of AEs an quirement for rescue analgesia were also considered by these scales.The inclus ria of the patients participating in the trials were as follows: only adults were including patients receiving IN analgesia compared to OS, IV, or a combination ent routes.Pregnant patients were not allowed.Patients were also excluded if used analgesics within the previous hours or if they had hemodynamic or re instability or disorientation.Patients who could not provide informed consen clinical impossibilities or the language barrier) were also excluded.Even pati reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% power.

Results
The results are summarized in Table 2. Below, we list the main pathologie sible for acute pain management in the ED and the implications of intranasal in these areas with side effects.In order to assess the effectiveness and im scales were utilized in every trial that was looke quirement for rescue analgesia were also conside ria of the patients participating in the trials wer including patients receiving IN analgesia compar ent routes.Pregnant patients were not allowed.used analgesics within the previous hours or if instability or disorientation.Patients who could clinical impossibilities or the language barrier) w reported an allergy or an intolerance to the trial d The sample needed for each RCT was calc power.

Results
The results are summarized in Table 2. Belo sible for acute pain management in the ED and in these areas with side effects.In order to assess the effectiveness and impact of the analgesics, validated pain scales were utilized in every trial that was looked at.The frequency of AEs and the requirement for rescue analgesia were also considered by these scales.The inclusion criteria of the patients participating in the trials were as follows: only adults were selected, including patients receiving IN analgesia compared to OS, IV, or a combination of different routes.Pregnant patients were not allowed.Patients were also excluded if they had used analgesics within the previous hours or if they had hemodynamic or respiratory instability or disorientation.Patients who could not provide informed consent (due to clinical impossibilities or the language barrier) were also excluded.Even patients who reported an allergy or an intolerance to the trial drug were ineligible.
The sample needed for each RCT was calculated to obtain 80% or 90% statistical power.In order to assess the effectiveness and im scales were utilized in every trial that was looke quirement for rescue analgesia were also conside ria of the patients participating in the trials wer including patients receiving IN analgesia compar ent routes.Pregnant patients were not allowed.used analgesics within the previous hours or if instability or disorientation.Patients who could clinical impossibilities or the language barrier) w reported an allergy or an intolerance to the trial d The sample needed for each RCT was calc power.In order to assess the effectiveness and impact of the analgesics, validated pain scales were utilized in every trial that was looked at.The frequency of AEs and the requirement for rescue analgesia were also considered by these scales.The inclusion criteria of the patients participating in the trials were as follows: only adults were selected, including patients receiving IN analgesia compared to OS, IV, or a combination of different routes.Pregnant patients were not allowed.Patients were also excluded if they had used analgesics within the previous hours or if they had hemodynamic or respiratory instability or disorientation.Patients who could not provide informed consent (due to clinical impossibilities or the language barrier) were also excluded.Even patients who reported an allergy or an intolerance to the trial drug were ineligible.In order to assess the effectiveness and im scales were utilized in every trial that was looke quirement for rescue analgesia were also conside ria of the patients participating in the trials wer including patients receiving IN analgesia compar ent routes.Pregnant patients were not allowed.used analgesics within the previous hours or if instability or disorientation.Patients who could clinical impossibilities or the language barrier) w reported an allergy or an intolerance to the trial d  In order to assess the effectiveness and impact of the analgesics, validated pain scales were utilized in every trial that was looked at.The frequency of AEs and the requirement for rescue analgesia were also considered by these scales.The inclusion criteria of the patients participating in the trials were as follows: only adults were selected, including patients receiving IN analgesia compared to OS, IV, or a combination of different routes.Pregnant patients were not allowed.Patients were also excluded if they had used analgesics within the previous hours or if they had hemodynamic or respiratory instability or disorientation.Patients who could not provide informed consent (due to  In order to assess the effectiveness and impact of the a scales were utilized in every trial that was looked at.The frequ quirement for rescue analgesia were also considered by these s ria of the patients participating in the trials were as follows: o including patients receiving IN analgesia compared to OS, IV, o ent routes.Pregnant patients were not allowed.Patients were a used analgesics within the previous hours or if they had hem instability or disorientation.Patients who could not provide i In order to assess the effectiveness and im scales were utilized in every trial that was looke quirement for rescue analgesia were also conside ria of the patients participating in the trials wer including patients receiving IN analgesia compar ent routes.Pregnant patients were not allowed.used analgesics within the previous hours or if instability or disorientation.Patients who could  In order to assess the effectiveness and impact of the analgesics, valida scales were utilized in every trial that was looked at.The frequency of AEs an quirement for rescue analgesia were also considered by these scales.The inclus ria of the patients participating in the trials were as follows: only adults were including patients receiving IN analgesia compared to OS, IV, or a combination  In order to assess the effectiveness and im scales were utilized in every trial that was looke quirement for rescue analgesia were also conside ria of the patients participating in the trials wer including patients receiving IN analgesia compar  In order to assess the effectiveness and impact of the analgesics, validated pain scales were utilized in every trial that was looked at.The frequency of AEs and the requirement for rescue analgesia were also considered by these scales.The inclusion crite-  Banala et al. [25] Medicina 2023, 59, x FOR PEER REVIEW 3 of 13

Results
The results are summarized in Table 2. Below, we list the main pathologies responsible for acute pain management in the ED and the implications of intranasal analgesia in these areas with side effects.There were no significant differences in the incidence of adverse events between the groups

Headache
As known, triptans are frequently used to treat acute migraine; among all, sumatriptan is one of the most used.The oral formulation is the most prescribed, although it has several limitations, such as absorption variation and onset differences that influence the efficacy.Triptans also have well-known side effects that may restrict their effectiveness and tolerability.Few studies have investigated the use of intranasal analgesia for migraine or headache in ED [7,18,27].
A study conducted by Meredith et al. (2003) involved acute migraine.They examined the pain relief using the Visual Analogue Scale (VAS) after the administration of IV Ketorolac versus nasal sumatriptan.The study found that while both medications decreased migrainerelated pain, IV Ketorolac was more efficient.However, this study has several limitations due to the limited sample size and the lack of AEs recorded [8].
Another trial examined the potential for IN Lidocaine to treat migraine; however, it was no more successful than placebo, even in addition to IV Metoclopramide (Avcu et al., 2017).The second outcome of the trial was the requirement for rescue medication, which was IV Fentanyl.Patient pain severity was assessed using the Numeric Rating Scale (NRS).Nevertheless, local discomfort brought on by lidocaine may be a confounding factor in the patient's perceived outcome [9].
Benish et al. released the THINK Trial in 2019 with the aim of comparing the analgesia with IV metoclopramide and diphenhydramine vs. IN ketamine among patients with primary headaches in ED.All 56 of the patients they enrolled were adults.The VAS scale was used to assess changes in pain, and the results showed that standard medication was not superior to ketamine in the recruited patients.However, this RCT had several limitations.For instance, it was a single-blind trial, and patients in the control arm could have received IV Ketorolac or Dexamethasone in addition to the standard therapy, which could have influenced the comparison of analgesic effectiveness.
Savari et al. (2022) compared IN ketamine to IV ketorolac; the group treated with IN ketamine had a greater reduction in pain intensity, but they also had more adverse effects such as fatigue, dizziness, discomfort, nausea, and hypertension [11].

Trauma and Injuries
One of the most frequent causes of pain in ED patients is trauma, which frequently requires a combination of IM and/or IV drugs.Recently, there has been an increase in the use of IN analgesics [12].Shimonovic et al. (2016) compared IN ketamine to IV or IM morphine; despite ketamine has been well studied as an analgesic agent, the IN administration has recently been introduced in ED.Instead, there is a lack of knowledge on the use of morphine in the literature.They enrolled a sample of 90 patients and randomized them into three groups; all three groups showed a similar level of pain relief.The study shows that IN ketamine can be used as an analgesic in emergencies since it demonstrated efficacy and safety comparable to IV and IM Morphine, and no severe AEs were noted [13].
Blancher et al. (2019) compared IN sufentanil versus IV morphine, assessing NRS at 30 min, with 4 h follow-up: they found some severe respiratory AEs (reporting a number needed to harm = 17), questioning the safety of this medication [14].Chew et al. (2017), in a small open-label study, compared IN fentanyl added to IV tramadol and metoclopramide, showing an improvement in VAS score at 10 min, with transient side effects such as lowering in blood pressure and dizziness [15].
In 2019, performed a clinical trial on adult patients with isolated limb injuries, Lemoel et al. [16] examined two analgesic strategies: the usual treatment with IV analgesics, including opioids as rescue, versus a single dose of IV Sufentanyl followed by IV multimodal analgesia.The second approach improved pain relief after 30 min without experiencing any serious AEs, and the need for opioids or IV analgesia decreased.The majority of AEs were mild and temporary; nevertheless, they discovered a significantly high rate of respiratory events when compared to prior studies.This is likely due to ongoing monitoring of the vital signs, which may have detected events without a clinical correlation.
Tongbua et al. ( 2022) recently showed non-inferiority of IN ketamine compared to IV morphine for acute musculoskeletal pain in the elderly, with a quick and sustained effect (up to 120 min), without a significant difference in AEs [17].

Renal Colic
In the Emergency Department, renal colic is a common cause of abdominal discomfort that frequently requires a combination of analgesics, such as non-steroidal antiinflammatory drugs and opiates; one of the most used is ketamine.In fact, numerous randomized trials have compared IN therapies to IV analgesia [28].
Farnia et al. (2017) compared IN ketamine to IV morphine, observing a statistically significant reduction in pain score, although the small sample size suggested the need for larger studies [29].
This conclusion was also supported by the study conducted by Pouraghaei et al. in 2021, which examined these two drugs showing comparable pain relief efficacy in renal colic and no relevant adverse effect [22].
In another study, Desmopressin was suggested as an alternative to the most oftenused medication.The study compared Indomethacin alone versus Indomethacin with IN Desmopressin for the management of renal colic pain.However, Jalili et al.

Breakthrough Cancer Pain
A high percentage of cancer patients experience physical pain, which is frequently a chronic discomfort that ranges from moderate to severe.Breakthrough pain is a term used to describe the exacerbations of this type of pain that often occur in patients who are already receiving analgesic treatment, including opioids.
Considering the challenges associated with getting a venous route in cancer patients, IN analgesia may be helpful in treating cancer patient's pain.
Unfortunately, there are few clinical studies of analgesic therapy for cancer patients in ED.
Only one small non-inferiority open-label RCT (Banala et al., 2020) compared IN fentanyl to IV hydromorphone in patients presenting at the ED with severe breakthrough cancer pain.Two out of three evaluations recommended the use of IN Fentanyl, which also has the benefit of requiring less time to administer.However, due to a protocol deviation (calculated by the researchers presuming that the active arm and the control one were comparable) and lack of blinding, this trial was conducted without knowing the actual pain score at baseline.This RCT might have an important bias [25].

Discussion
Pain control is universally considered an important issue, especially in ED patients; because pain affects a patient's quality of life, it is crucial to obtain the right treatment.Despite the availability of multimodal medications, analgesic therapy is frequently insufficient [30].
IN fentanyl and ketamine have already shown their safety in pharmacokinetics trials.These drugs have a higher bioavailability thanks to their fast absorption via the nasal mucosa and the lack of first-pass effect.It is important to remember IN route restrictions like pathologic changes to the nostrils and a limited amount of administrable volume [4,31,32].
Although there are limited trials available in the ED context, the potential benefits of IN therapies, such as rapid and simple administrations with prompt absorption, may improve pain control in ED and prehospital settings.Subdissociative doses of ketamine were proven to be safe and helpful in patients out-of-hospital, too, by a retrospective large-sample trial [33].
Low-dosage ketamine analgesia in patients with severe acute pain is becoming more and more promising due to its analgesic efficacy (similar to opioids), the potential to maintain circulatory stability and respiratory reflexes, and neuroprotection in patients with acute brain damage [34][35][36].
Opioids are being used extensively to treat acute pain, although they can have side effects that vary on dosage, including weakness, dizziness, nausea, and constipation.Due to this, the importance of multimodal analgesia with opioid-sparing techniques should be considered, especially considering the worrying data about opioid abusers.Ketamine appears to be useful in lowering the demand for opioids [37,38].Due to its sympathomimetic action, the most significant Ketamine contraindication is coronary illness or cardiological pathologies [39].
IN route may help for severe pain requiring quick management (such as trauma or breakthrough cancer pain).The bioavailability of IN opioids depends on the specific molecule, being rather high for fentanyl and sufentanil, thanks to their lipophilic structure [40][41][42].
Regarding the safety profile, most AEs recorded were moderate and did not need medical intervention.According to the literature, dizziness was the most common.Confusion, a brief drop in blood pressure, nausea, and vomiting were also usual AEs.A small percentage of patients receiving opiate-based treatment also occasionally experienced transient bradypnea or oxygen saturation below 90%, necessitating a short-time administration of oxygen therapy.Only a minor number of serious AEs were observed in a few trials (with a small sample size).
For patients presenting with headaches, IN ketamine was found to be more effective than IV ketorolac despite a higher prevalence of side effects [7][8][9][10].
When compared to IV morphine for the treatment of pain due to traumatic injuries, IN ketamine demonstrated a non-inferiority effect; in fact, ketamine has a morphine-sparing effect.Early IN Sufentanyl administration (after triage) can enhance pain management and reduce the need for IV analgesia.For this, adding IN Fentanyl to IV Tramadol resulted in a higher decrease in pain score after 10 min.Only one research reported some significant AEs when IN Sufentanyl was compared to IV Morphine [13,17].However, Ketamine, Fentanyl, and Morphine are thought to be the finest analgesics, per data found in the literature.The fastest onset is achieved with Ketamine and Fentanyl.Similar results on the therapy of traumatic pain were reported by Abu et al. in their review [30].
In small research, IN ketamine was found to be more effective than IV Morphine for patients with renal colic; another trial revealed that IN ketamine and IV morphine were equally beneficial.Although IN fentanyl was proven to be less efficient than IV fentanyl, it may still be used when placing a venous catheter, which could be difficult (such as overcrowding or lack of trained healthcare providers) [19][20][21][22]29].
Given that prehospital treatment is sometimes provided by paramedics, who are only trained to administer certain medications, IN analgesia may aid in the quick delivery of pain relief in this scenario.There is not much research regarding this in the literature, but in this case, IN fentanyl was found to be just as effective as IV morphine, while IN ketamine led to the fastest onset in pain relief [23,24].A recent review (Fernandez et al., 2021) reaffirmed the safety of ketamine used outside of hospitals, with a limited rate of AEs [33].

Conclusions
These findings suggest that it might be a viable choice in a variety of situations to reduce patient suffering or delays in pain management or when accessing an intravenous route may be challenging due to clinical circumstances or a shortage of qualified healthcare professionals.In particular, in busy EDs, a standardized protocol for early analgesic administration may aid in pain treatment.
Analgesia needs to be tailored to each patient's features, type of pain, and clinical environment.IN Fentanyl and Ketamine look promising and may be administered easily and safely while providing effective pain relief.
For this review, we could not find randomized trials including patients presenting with alteration of mental status and respiratory or hemodynamic instability, probably because of the potential impact of narcotics on breath or arterial blood pressure; none of the studies included pregnant women.This could be a major limitation, considering that in Emergency Care, pain and respiratory or hemodynamic instability often coexist.
The absence of follow-up in this evaluation (just one research included a follow-up at 48-72 h) makes it impossible to determine if these patients need additional medications in the hours or days that followed or the frequency of subsequent adverse events (AEs).The fact that patient recruitment was completed only when researchers were available and without knowledge of the full population and the characteristics of patients who presented with pain to the ED raises the possibility of bias.Some of the trials included were conducted on a small sample.There were few studies from Europe and Oceania; most trials were conducted in Asia or America, and no trials were undertaken in Africa.Only a small number of RCTs from Iran included patients who were 15 years old or older, whereas all the other studies included participants who were 18 years old or older.The risk of local irritation or side effects, as well as the comparison of the IN medication to placebo with a difference in pain control following the injection of analgesic or saline solution, were other possible sources of bias.In some cases (such as breakthrough cancer pain), only open-label trials were found [43].
Moreover, an optimal rescue therapy or analgesia could help hospitals out with the never-ending issue of overcrowding [44,45].
did not find IN Desmopressin to be more efficient than Indomethacin alone when compared to IN Ketamine [19].In a comparison between IN Ketamine and IV Fentanyl, Mozafari et al. (2020) discovered that ketamine was less efficient than fentanyl and was more likely to cause side effects [20].Nazemian et al. (2020) compared IN to IV fentanyl added to IV ketorolac.They found IN fentanyl effective in pain control, though significantly less than IV fentanyl; they concluded that this option could be considered in situations where obtaining an IV route could lead to a delay in pain control, such as overcrowded ED [21].

3. 4 .
Other Situations 3.4.1.Prehospital To our knowledge, two RCTs have assessed IN analgesia in a prehospital setting.Rickard et al. (2007) compared IN fentanyl to IV morphine, demonstrating a similar VAS reduction without a significant difference in AEs; a limitation of this trial was the lack of blindings [23].Andolfatto et al. (2019) compared IN ketamine to a placebo when added to standard care (Nitrous Oxide), finding an improvement in pain control without severe AEs [24].

3. 4 . 3 .
Acute Pain (Back and Abdominal Pain) Sin et al. (2019) compared IN sufentanil to IV morphine in the treatment of abdominal and low back pain, finding equal improvement in NRS and AEs; the study's limitations include a small sample size and lack of data on IV morphine rescue analgesia [26].

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
[15]onovic et al.[13]Blancher et al.[14]Chew et al.[15]

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Shimonovic et al.[13] Blancher et al.[14] Chew et al.[15] Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection o Reported sults
Shimonovic et al.[13] Blancher et al.[14] Chew et al.[15] Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studie

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Shimonovic et al.[13] Blancher et al.[14] Chew et al.[15] Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studie

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studie

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 . Cont. First Author Randomization Process Deviation from Intended Intervention Missing Outcome Data Measurement of the Outcome Selection of the Reported Results Overall Blancher et al. [14] Figure 1. -
FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 2 .
Description of the study analyzed with adverse events.
Headache reduction at 15 min, 30 min, 1 h, 2 h Response rate superior in zolmitriptan (66,2%) vs. placebo (35,0%) p < 0.001 Adverse events (dysgeusia and nasal irritation overall) more frequent in the Zolmitriptan group h ] IN zolmitriptan vs. IV ketorolac for headache 16 sumatriptan, 13 ketorolac Headache reduction at 1 h Both achieved significant pain reduction; however, ketorolac was superior in reducing VAS Not reported Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studie

Table 2 .
Description of the study analyzed with adverse events.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 2 .
Description of the study analyzed with adverse events.

Table 1 .
Assessment bias of analyzed studies.

thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 2 .
Description of the study analyzed with adverse events.

Table 2 .
Description of the study analyzed with adverse events.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 2 .
Description of the study analyzed with adverse events.

Table 1 .
Assessment bias of analyzed studies.

thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measuremen the Outcom
Figure 1.-FLOWCHART of analyzed studie

Table 1 .
Assessment bias of analyzed studie

First Au- thor Randomization Process Deviation from In- tended Intervention Missing Ou come Data
Figure 1.-FLOWCHART

Table 1 .
Assessment bias of analyzed studies.

thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studie

First Au- thor Randomization Process Deviation from In- tended Intervention Missing Ou come Data
Figure 1.-FLOWCHART

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measuremen the Outcom
Figure 1.-FLOWCHART of analyzed studie

Table 1 .
Assessment bias of analyzed studie

First Au- thor Randomization Process Deviation from In- tended Intervention Missing Ou come Data
Figure 1.-FLOWCHART

First Au- thor Randomization Process Deviation from In tended Interventio
Medicina 2023, 59, x FOR PEER REVIEW

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome
Medicina 2023, 59, x FOR PEER REVIEW 4 of 13

Table 1 .
Assessment bias of analyzed studie

First Au- thor Randomization Process Deviation from In- tended Intervention Missing Ou come Data
Medicina 2023, 59, x FOR PEER REVIEW

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome
Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measuremen the Outcom
Medicina 2023, 59, x FOR PEER REVIEW

Table 1 . Assessment bias First Au- thor Randomization Process Deviation from In tended Interventio
Medicina 2023, 59, x FOR PEER REVIEW

Table 1 .
Assessment bias of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measuremen the Outcom
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studie

Table 1 .
Assessment bias of analyzed studie

First Au- thor Randomization Process Deviation from In- tended Intervention Missing Ou come Data
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART

Table 1 . Assessment bias First Au- thor Randomization Process Deviation from In tended Interventio
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection o Reported sults
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 . Assessment bias First Au- thor Randomization Process Deviation from In tended Interventio
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection of the Reported Re- sults Overall
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Au- thor Randomization Process Deviation from In- tended Intervention Missing Out- come Data Measurement of the Outcome Selection o Reported sults
Medicina 2023, 59, x FOR PEER REVIEW Figure 1.-FLOWCHART of analyzed studies.

Table 1 .
Assessment bias of analyzed studies.

Table 1 . Assessment bias First Au- thor Randomization Process Deviation from In tended Interventio
Medicina 2023, 59, x FOR PEER REVIEW

Table 2 .
Description of the study analyzed with adverse events.