Article, Emergency Medicine

The use of intranasal analgesia for acute pain control in the emergency department: A literature review

a b s t r a c t

Background: Traditional routes for administration of pain medications include oral (PO), intravenous (IV), or in- tramuscular routes (IM). When these routes are not feasible, the intranasal (IN) route may be considered. The objectives of this evidence-based review were: to review the literature which compared the safety and efficacy of IN analgesia to traditional routes and to determine if IN analgesia should be considered over traditional routes for Acute pain control in the ED.

Methods: The MEDLINE and EMBASE databases from July 1970 to July 2017 were searched. Randomized con- trolled trials (RCT) that evaluated the use of IN analgesia for acute pain in the ED were included. methodological quality of the trials was assessed using the Grading of Recommendations Assessment, Development, and Evalu- ation criteria.

Results: Eleven randomized controlled trials (RCT) met the inclusion criteria. Four trials found significant reduc- tions in pain scores, favoring IN analgesia. However, in all of the trials, pain relief was not sustained. Three trials reported superior pain reduction with comparators and three trials reported no statistical significance. One trial described effective pain relief with IN analgesia but did not provide data on statistical analysis.

Conclusion: Eleven randomized controlled trials with various methodological flaws revealed conflicting conclu- sions. There is limited evidence to support the use of the IN analgesia over traditional routes for acute pain in the ED. The IN route may be a good alternative in scenarios where IV access is not feasible, patients are refusing injectable medications, or a fast onset of pain relief is needed.

(C) 2017

  1. Introduction

acute pain management in the emergency department (ED) re- quires prompt administration of safe and effective analgesia [1-2]. It has been documented that patients desire analgesia that has a rapid onset and a painless route of delivery [3]. Traditional routes of adminis- tration for analgesia include the oral (PO), intravenous (IV), or intra- muscular (IM) routes. The oral route of administration may not be

feasible in patients who require prompt analgesia or who have a nil per os (NPO) status. On the other hand, administration via the intrave- nous route requires the placement of a catheter so prompt delivery of medications in this scenario depends on the availability of clinical staff to obtain IV access. Lastly, administration via the IM route often results in additional pain at the site of injection for the patient with unpredict- able absorption and delayed onset of analgesia. Successful IM injections may also be difficult in patients who are obese [4]. Administration of

? There were no sources of support in the form of grants, equipment or drugs.

?? The authors have no conflicts of interest to disclose.

* Corresponding author at: Long Island University, Arnold & Marie Schwartz College of Pharmacy & Health Sciences, United States 1 University Plaza, New York, NY, 11201, United States.

E-mail address: [email protected] (B. Sin).

1 PharmD, MBA, BCPS, Assistant Professor of Pharmacy Practice Director, PGY2 Emergency Medicine Pharmacy Residency Program, Arnold & Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, NY. Emergency Medicine Clinical Pharmacy Educator, Department of Pharmacy, Division of Pharmacotherapy Services Director, Emergency Department Clinical Research Program, Department of Emergency Medicine, The Brooklyn Hospital Center, Brooklyn, NY.

https://doi.org/10.1016/j.ajem.2017.11.043

0735-6757/(C) 2017

medications via the IN route has gained popularity as it provides a safe, titratable, effective, painless, and convenient alternative to traditional routes of analgesic administration [5]. Furthermore, a rapid onset of the drug’s Therapeutic effects is observed due to the rich capillary net- work of the respiratory mucosa that is able to transport the drug into systemic circulation [6]. The utility of the IN route may be limited in var- ious circumstances that include: nasal trauma, naso-septal abnormali- ties, or nasal secretions of blood or mucus [6]. It has been postulated that the literature which described the use of intranasal devices for ad- ministration of opioids is limited [6]. However, evidence evaluating the use of the IN route for Administration of analgesia for various types of acute pain has emerged. In the ED, the use of IN analgesia is not a com- mon practice. Its use is often a topic of controversy due to the limited fa- miliarity of medications that may be administered via the IN route, lack of readily available administration devices, and lack of training on spe- cific techniques necessary to use the devices appropriately. The objec- tives of this review were two fold. First, to review the available published literature which evaluated the use of IN analgesia to tradi- tional routes for acute pain control in the ED. Second, from the reviewed literature, to evaluate if IN analgesia should be considered over tradi- tional routes for acute pain control in the ED.

  1. Methods
    1. Criteria for considering studies for inclusion

Randomized controlled trials (RCT) published in the English language that evaluated the use of IN analgesia as the primary analgesic in the ED for humans were selected for the review. The primary out- come of interest in this review was the difference in pain scores from baseline to the cutoff time specified in the original trial between analge- sics administered via the IN route and active comparator or placebo which included administration of analgesia via an alternative route. Secondary outcomes included the incidence of adverse events and rates of Rescue analgesia required by patients who received IN analgesia. Eligible participants included patients of any age range who presented to the ED for acute pain and received at least one dose of intranasal an- algesia in the ED. Case reports, conference papers, narrative reviews, ed- itorials, comments, unpublished papers and letters were excluded. Literature which evaluated patients who received IN analgesia in a set- ting outside the ED or for indications other than analgesia were excluded.

Search methods for identification of studies

This evidence-based review was structured according to the PRISMA statement [7]. A methodological protocol was established a priori by the study investigators (B.S., J.W.) and adhered throughout. A search of the MEDLINE database from July 1970 to July 2017 and EMBASE from July 1970 to July 2017 was conducted. The search strategies are presented in Appendix 1. Additional references were identified from a review of literature citations.

Data collection and analysis

Four authors (B.S., J.W., C.C., L.V.) independently screened all titles, abstracts, and full-text articles. Data extraction was performed indepen- dently by two authors (B.S., J.W.) using a standardized electronic data collection form. Articles were eliminated according to the inclusion and exclusion criteria. Duplicate articles, unpublished reports, abstracts, and review articles were not considered. Any disagreement was re- solved by a fifth author (S.M.). The PRISMA checklist was utilized to guide the structure and reporting of the identified literature [7]. An as- sessment of factors (randomization concealment, patient selection, ad- equacy of blinding, and duration of follow-up) that may contribute to risk of bias was conducted independently by two reviewers (B.S., J.W.)

based on the PRISMA statement. In the case of discrepancy, a third re- viewer (C.C.) was consulted. An evaluation on the methodological qual- ity of the evidence based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria [8] was conducted independently by two reviewers (B.S., J.W.). In the case of disagreement, a third reviewer (C.C.) was consulted. An assessment of the risk of bias and level of methodological quality for the identified lit- erature is summarized in Table 2.

  1. Results

The primary search identified a total of 818 publications. The num- ber of citations was reduced, according to their relevance for this review (Fig. 1). The search identified eleven randomized, controlled trials which fulfilled our criteria. We performed our review based on these eleven publications.

Description of included trials

There were eleven randomized trials that met the inclusion criteria. All eleven trials used validated pain scales to measure Analgesic efficacy and incidence of adverse events as a measure of safety. The trials evalu- ated patients who receivED analgesia via the intranasal route against those who received analgesia via intravenous [9-12], intramuscular [13-15] routes, or combination of intranasal with intravenous or intra- muscular routes [16-19]. The characteristics of the eleven trials included in this review are summarized in Table 1.

Risk of bias in includes trials

The trials identified in this review had small sample sizes and var- ious methodological flaws [9-19]. Data on methods used to blind the study investigators was not available in six trials [11,14-18]. None of the trials provided information regarding the procedures for the blinding of data collectors and assessors. Data on the power and sam- ple size necessary to detect a significant difference for the primary outcome were reported in five trials [10-11,13,18-19]. However, two of the five trials did not provide a numerical value that would define the cutoff for significance in their statistical analysis [13,18]. One trial presented its findings of primary outcome in a graphical comparison and did not provide numerical values of the specific pain scores that corresponded to designated time intervals [18]. Three trials did not provide a description of the protocols for the use of rescue analgesia [9,13,18]. Due to the various methodological limitations, the Level of evidence assigned to the eleven individual trials range from very low to moderate.

Patient characteristics

The patient population in the trials included was heterogeneous. Sample sizes of the trials varied widely, ranging from 29 [9] to 404

[13] patients. Six trials evaluated IN analgesia in pediatric patients of b 18 years old [10-11,13-15,18]. Patients received IN analgesia as the primary management for acute pain control due to migraine [9], frac- tures [10,13-15], renal colic [11,16-18], and vaso-occlusive crisis [12].The analgesics administered via IN route in the clinical trials includ- ed desmopressin [16-18], sumatriptan [9], diamorphine [13-14], fenta- nyl [10,12,15], and ketamine [11,19]

Reduction in pain scores

A summary of the primary outcome from the included trials in this review is presented in Table 3. The data collected from a total of 985 pa- tients all revealed conflicting results and conclusions. Significant reduc- tions in pain scores with IN administration of analgesia was found in four trials [12-13,15,19]. However, in all of these trials, the reductions

Fig. 1. The process for selecting studies suitable for inclusion in the final review.

were not sustained. Fein et al. [12] reported greater reduction in pain scores in patients at 20 min after IOT, but not after. Kendall et al. [13] re- ported reduction in pain scores at 5, 10, 20 min after IOT but not at 30 min. Younge et al. [15] reported a significant reduction in pain scores at 10 min following administration of IN analgesia but no difference at 20 min and 30 min after IOT. Shimonovich et al. [19] reported significant pain relief favoring IN ketamine versus IM morphine within 15 min but when compared to IV morphine, pain reduction was significantly less.

Three trials reported greater reduction in pain scores favoring the comparison groups [9,11,17]. In the first trial, although a significant de- crease in pain score with IN sumatriptan was observed at 60 min after IOT, this reduction was lower than that observed with IV ketorolac [9]. The second trial reported that at 5 min after IOT, IV morphine was more effective than IN ketamine but no significant difference was de- tected at 15 and 30 min [11]. In the third trial, patients who received IN desmopressin consistently reported higher pain scores throughout the study’s designated intervals [17].

Adverse events

The incidence of adverse events in patients who received intranasal analgesia is summarized and presented in Table 4. Four out of eleven tri- als did not provide data on the incidence of adverse events [9,13-14,17]. Kendall et al. [13] reported a higher incidence of adverse events in pa- tients who received IN diamorphine compared to patients who received

IM morphine (24% vs. 19%, difference 5.6%, [95% confidence interval:

-2.3% to 13.6%]). Although 84 non-serious adverse events were report- ed, the investigators did not identify what the adverse events were and did not indicate the incidence of each event between the treatment groups [13]. Of the seven trials that reported the incidence of adverse events, Shimonovich et al. [19] reported a lower incidence of dry mouth in patients who received IN ketamine (25%) vs. IM morphine (63%, p = 0.02), and IV morphine (79.2%, p = 0.002). Farnia et al. [11], reported that in patients who received intranasal analgesia, the ad- verse event with the highest incidence was nausea (50%). In this trial, 6 (30%) patients who received Intranasal ketamine also reported of emer- gency phenomenon. Of interest, Hazhir et al. [17] reported two unique adverse events due to IN desmopressin administration that included vertigo (7%) and carpopedal spasm (3%) of the right hand in patients who received IN desmopressin while Fein et al. [12] reported a signifi- cant difference in headache between patients who received Intranasal fentanyl vs. placebo (17% vs. 0, p = 0.05).

Requirement for rescue analgesia

A summary of the rescue protocols is presented in Table 5. With the exception of the trial by Farnia et al. [11] and Shimonovich et al. [19] all trials reported the use of rescue analgesia. However, only five trials de- scribed the use of a protocol during the study period [10,14-17]. Data on the specific rescue agent used [9,15] and dose of rescue agent used

Table 1

Characteristics of studies included in review.

First author year, country

Sample size

Age range

Inclusion criteria Exclusion criteria Intervention (number of patients assigned)

Comparison (number of patients assigned)

Measured outcome

Meredith 2003,

United States [9]

Borland 2007,

Australia [10]

Farnia 2017,

Iran [11]

Fein 2016, United States [12]

Kendall 2001,

United Kingdom [13]

29

patients

67

patients

40

patients

49

patients

404

patients

18-65

years

7-15

years

15 years old and abovef

3-20

years

3-16

years

History of migraine headache, diagnosed as having migraine headache by the attending emergency physician

Presentation with clinically deformed closed Long-bone fractures

Presented to ED with renal colic, did not need surgical intervention for urolithiasis

Having any SCD genotype, presented to ED with VOC, willingness to receive study drug

Clinical fracture of upper or lower limb

Known allergy to sumatriptan or ketorolac, active Peptic ulcer disease, current use of an ergotamine-containing medication, MAOIs, or antidepressants, hemiplegic or basilar migraine headache, Renal impairment or dialysis dependence, menstruation, pregnancy, or nursing Head injury resulting in impaired judgment, allergy to opiates, blocked or traumatized nose, receiving narcotic analgesic within4 h of arrival to ED, inability to perform pain scoring for any reason

Opioid addition, prior use of analgesics, pregnancy, history of ketamine or morphine hypersensitivity, nasal occlusion, SBP N 180, SBP b 90, respiratory distress, altered mental status, no cooperation Known allergy to fentanyl, daily opiate use, or pregnancy, pain score b 6 on modified WBFPRS, having previously received study drug, hypotension (SBP b 5th percentile for age), oxygen saturation <= 92% on room air, temperature N 102 ?F, respiratory distress, recent trauma, priapism, Isolated headache, isolated abdominal pain, severe rhinorrhea or epistaxis, new neurological signs or symptoms

Not accompanied by a parent or guardian, head injury, need for immediate IV access, blocked nose or upper respiratory tract infection, learning difficulties, blindness or Visual impairment, previous study participation, Opioid analgesia use in the preceding two days, and contraindications to morphine or diamorphine

IN sumatriptan 20 mg (n = 16)

IN fentanyl 1.4 mcg/kg + additional doses of fentanyl 15 mcg to a maximum total intranasal dose (n = 33)

IN ketamine 1 mg/kg (n = 20)

IN fentanyl 2 mcg/kg, max 100 mcg

(n = 24)

IN diamorphine

0.1 mg/kg

(n = 204)

IV ketorolac 30 mg (n = 13)

IV morphine 0.1 mg/kg + additional doses of morphine 1 mg to a maximum total intravenous dose (n = 34)

IV morphine 0.1 mg/kg (n = 20)

IN Normal saline + standard of care (IV morphine 0.1 mg/kg, max 15 mg + IV ketorolac 0.5 mg/kg, max 30 mgd,e or IV hydromorphone 0.015 mg/kg + IV ketorolac 0.5 mg/kg, max 30 mgd,e)

(n = 25)

IM morphine 0.2 mg/kg (n = 200)

Primary: mean decrease in patient-reported 100 mm VAS pain scores Secondary: N/A

Primary: 100 mm VAS pain scores at designated time intervals after medication administration

Secondary: incidence of adverse effects

Primary: mean decrease in patient-reported 10 point VAS pain scores Secondary: adverse events

Primary: median decrease of pain scores at designated time intervals after medication administration Secondary: incidence of adverse events

Primary: distribution of Wong Baker pain scores at designated time intervals after medication administrationa,b Secondary: patient reaction to treatment administration, acceptability of treatment to parent/guardian and staff, incidence of adverse effects

Wilson 1997, United Kingdom [14]

51

patients

3-16

years

Diagnosis of limb fracture Head injury, nasal obstruction,

injury requiring IV access

IN diamorphine

0.1 mg/kg

(n = 30)

IM morphine sulphate 0.2 mg/kg (n = 22)

Primary: Wong-Baker faces pain score at designated time intervals following administration of intervention Secondary: parental acceptability of intervention and incidence of adverse effects

Younge 1999,

Australia [15]

47

patients

3-10

years

Clinical upper or lower limb fractures, accompanied by parents or care giver that could give consent to participate in study

Head injury, blocked nose or rhinorrhea, requiring immediate IV access, intellectual or visual impairment, hepatic or renal disease, allergy to study drugs, receipt of opioid analgesic within previous 24 h, prior participation in study

IN fentanyl 1 mcg/kg

(n = 24)

IM morphine 0.2 mg/kg (n = 23)

Primary: Wong Baker face pain score at designated time intervals following administration of intervention

Secondary: 10 point VAS score by guardians at designated time intervals, tolerance score by guardian at time of administration of intervention, incidence of adverse events

(continued on next page)

Table 1 (continued)

First author year, country

Sample size

Age range

Inclusion criteria Exclusion criteria Intervention (number of patients assigned)

Comparison (number of patients assigned)

Measured outcome

Lopes 2001, Portugal [16]

Kumar 2011,

India [17]

Hazhir 2010,

Iran [18]

Shimonovich 2016,

Israel [19]

61

patients

72

patients

90

patients

75

patients

48.3

yearsc

Not reported in study

16-82

years

18-70

years

Admitted to ED with renal colic caused by lithiasis, received no prior treatment for it

Presenting to the ED with diagnosis of acute renal colic because of stone disease

Presenting to the ED with complaints of renal colic with confirmed presence of Ureteral stone confirmed by ultrasound and KUB

Mild to moderate blunt trauma causing moderate to severe pain (>= 80 mm on 100 mm VAS), GCS of 15,

body weight 50-11 kg, SBP 90-160 mmHg, HR b100

bpm, ASA score 1-2

HTN, coronary disease, rhinitis, influenza, anticoagulant therapy, peptic ulcer, renal or Liver failure, pregnancy

HTN, coronary disease, rhinitis, influenza, anticoagulant therapy, peptic ulcer, renal or liver failure, pregnancy

Allergy to tramadol, being hypertensive, and taking any medication/treatment prior to referral

Head injury, regular use of opiates, analgesia received within prior 3 h, allergy to morphine or ketamine, large meal ingested within previous hour, pregnancy, deviated nasal septum, trauma to the nose, history of psychiatric condition

IN desmopressin 40 mcg (n = 20)

IN desmopressin 40 mcg (n = 24)

IN desmopressin 40 mcg (n = 30)

IN ketamine 1 mg/kg (n = 24)

IM diclofenac 75 mg (n = 19)

IN desmopressin 40 mcg +

IM diclofenac 75 mg (n = 22)

IM diclofenac 75 mg (n = 24)

IN desmopressin 40 mcg +

IM diclofenac 75 mg (n = 24)

IM tramadol 100 mg (n = 30)

IN desmopressin 40 mcg +

IM tramadol 100 mg (n = 30)

IV morphine 0.1 mg/kg slow IV bolus (n = 24) IM morphine 0.15 mg/kg (n = 27)

Primary: 10 cm VAS score at designated time intervals following administration of intervention

Secondary: incidence of adverse events, qualitative assessment of patients pain Primary: 10 cm VAS score at designated time intervals following administration of intervention

Secondary: incidence of adverse events, qualitative assessment of patients pain Primary: 10 point VAS score at designated time intervals following administration of intervention

Secondary: N/A

Primary: time of onset for meaningful pain reliefJPY Secondary: incidence of adverse effect, overall patient satisfaction

Abbreviations: ASA = American Society of Anesthesiologists; ED = emergency department; HTN = hypertension; IM = intramuscular; IN = intranasal; IV = intravenous; GCS = Glasgow Coma Score; HR = heart rate; KUB = abdominal plain film; MAOI = monoamine oxidase inhibitor; N/A = information not available from study article; SBP = systolic blood pressure; SCD = Sickle cell disease; VAS = Visual analogue scale, VOC = vaso-occlusive crisis, WBFPRS = Wong-Baker Faces Pain Rating Scale.

JPY Meaningful pain reduction was defined as time when >15 mm pain decrease on 100mm VAS was observed.

a Original study did not define distribution.

b Specific methods used to calculate distribution numbers were not reported.

c Mean age, age range not provided by original study.

d Ketorolac administered only if no NSAID was taken in the last 6 h.

e All patients received comparison if (morphine or hydromorphone) except if study drug was administered as soon as possible after triage and prior to having an intravenous line placed, parenteral opiates were not administered within 20 min after receiving study drug.

f No ceiling age for inclusion.

[9-10,14-15] were not specified in most studies. The majority of studies offered rescue analgesia at 20 min [13,15], 30 min [10,13-14,16-17] after IOT. In three trials, the percentage of patients requiring rescue analgesia in the IN group was lower as compared to its comparator groups which uti- lized another route of administration [11,13,18]. Farnia et al. [11] concluded that patients who received IN ketamine required less rescue analgesia with- out presenting statistical data. None of the trials described a statistically sig- nificant difference in the number of patients who required rescue analgesia.

  1. Discussion
    1. Findings

As the intranasal route offers clinicians the ability to administer pain medications until a definitive IV access is secured, our review assessed the findings of the literature which evaluated IN analgesia to an analgesia administered via traditional routes. To the best of our knowledge, this is the first evidence-based review that summarizes the evidence for the use of IN analgesia for acute pain in the ED. The literature identified in this re- view reviewed conflicting findings and conclusions. Of the eleven trials in- cluded in this review, only four trials reported significant reductions in pain scores with IN administration of analgesia for vaso-occlusive crisis [12], fractures [13,15], and trauma [19]. However, it is important to note that

significant pain relief was not long lasting with the trials reporting effects not to last beyond 10 min [15], 15 min [19], and 20 min [12-13]. Kendall et al. [13] aimed to evaluate patient’s reported Wong Baker pain score as the primary outcome. Although the study investigators presented data on the distribution of pain scores for patients who received IN diamorphine at 5, 10, 20 min and concluded that IN diamorphine should be preferred, it should be noted that pain scores for patients who received IM morphine were not presented. Hence, an objective analysis, comparison, and evalua- tion of the data was not possible.

Six trials included pediatric patients of b 18 years old [10-11,13-15, 18].Two of the trials reported faster onset of pain relief with intranasal therapy [13,15]. These findings reflect the pharmacokinetics of providing intranasal therapy (quick onset, Short duration of action) and intramus- cular therapy (slow onset, longer Duration of action). Similar to Younge et al. [15], Borland et al. [10] evaluated IN fentanyl exclusively in pediatric patients who had sustained long bone fractures. Interestingly, the study investigators did not report significant differences in pain scores between the treatment groups. There are several possible explanations for this ob- servation. First, the age range of patients studied was different amongst the two studies. Borland et al. [10] included patients aged 7-15 years old while Younge et al. [15] included patients aged 3-10 years old. Sec- ond, Borland et al. [10] allowed for repeat dosing of study interventions while Younge et al. [15] did not. The ability to repeat administration of

Table 2

Assessment of bias risk and assigned level of evidence in the available literature.

First author year, country

Randomization

RCT

halted early

Provider blinded

Data collector blinded

Data assessor blinded

Duration of

follow-up

Co-intervention

Target sample size attained

Assigned level of evidence

Meredith 2003, United States [9]

Yes

No

Yes

N/A

N/A

60 mins

No

N/A

Very low

Borland 2007, Australia [10]

Yes

No

Yes

N/A

N/A

30 mins

No

Yes

Moderate

Farnia 2017, Iran [11]

Yes

No

Yes

N/A

N/A

30 mins

No

Yes

Moderate

Fein 2016, United States [12]

Yes

No

Yes

N/A

N/A

30 mins

IV morphine 0.1 mg/kg, max 15 mg + IV

ketorolacb or IV hydromorphone 0.015

Yes

Moderate

Kendall 2001, United Kingdom [13]

Yes

No

No

N/A

N/A

30 mins

mg/kg + IV ketorolac 0.5 mg/kg, max 30 mgb

No

Yesa

Low

Wilson 1997, United Kingdom [14]

Yes

No

N/A

N/A

N/A

30 mins

No

N/A

Very low

Younge 1999, Australia [15]

Yes

No

N/A

N/A

N/A

30 mins

No

N/A

Very low

Lopes 2001, Portugal [16]

Yes

No

N/A

N/A

N/A

30 mins

No

N/A

Very low

Kumar 2011, India [17]

Yes

No

N/A

N/A

N/A

60 mins

No

N/A

Very low

Hazhir 2010, Iran [18]

Yes

No

N/A

N/A

N/A

30 mins

No

Yesa

Low

Shimonovich 2016, Israel [19]

Yes

No

No

No

No

60 mins

No

N/A

Very low

Abbreviations: N/A = information regarding sample size was not provided by original study; RCT = randomized controlled trial.

a Numerical value for clinical significance was not defined by original study.

b Ketorolac administered only if no NSAID was taken in the last 6 h.

pain medications could have explained for the lack of difference in pain reduction as dosages of opioids should be titrated upward until satisfacto- ry pain relief is achieved [1]. It has been postulated that antidiuretic hor- mones may provide pain relief in patients with renal colic by decreasing diuresis [20]. Three trials compared IN desmopressin to IM diclofenac [16-17] and IM tramadol [18] for renal colic. Lopes et al. [16] and Kumar et al. [17] utilized similar Inclusion/exclusion criteria, interventions, and evaluated similar outcomes in their studies. Both studies reported superi- or outcomes with the active comparator groups. However, Lopes et al.

[16] reported similar pain relief at 10 min after IOT for both randomized groups. The difference in the findings may have been due to chance as the studies included small sample sizes.

The incidence of adverse events was limited and additional medica- tion intervention was not necessary. Of all trials, Farnia et al. [11] reported nausea in ten out of twenty (50%) patients. This was the highest incidence of nausea observed amongst all trials. This finding was of interest as no other trials which reported of adverse events observed nausea. Fein et al. [12] reported of a significantly higher incidence of headache in patients who received IN fentanyl (17%) versus the comparator (0%), p = 0.05. Al- though headache is a known side effect of fentanyl, this was the only trial which reported of headache with the use of intranasal fentanyl.

Three trials [11,13,18] reported that the percentage of patients requir- ing rescue analgesia in the IN group was lower compared to its compara- tor groups while two trials [13,18] detected no significant differences. It should be noted that in the two of the three trials which reported a lower requirement of rescue analgesia, medications that are not com- monly used in the United States, diamorphine [13] and desmopressin

[18] were utilized intranasally as study interventions. The majority of studies offered rescue analgesia at 20 min [13,15], 30 min [10,13-14, 16-17] after IOT. This finding suggested that clinicians should expect that patients who receive IN analgesia may require receive rescue analge- sia due to the short duration of action. None of the trials presented data on the amount of rescue analgesia consumed by patients. Due to inconsistent use of rescue analgesia, varioUS time points at which rescue was offered, and a lack of data on the amount of rescue analgesia consumed by pa- tients, we were unable to evaluate the potential impact rescue analgesia had on the reported primary outcomes of the trials.

The nasal mucosa is highly vascularized allowing for rapid absorp- tion and onset of medications administered IN. Administration via this route may be a good alternative in clinical scenarios where establishing IV access is not feasible, when patients are refusing medications by the injectable route, or a fast onset of action of pain relief is necessary. When deciding to administer an analgesic medication, it is important

to consider several factors. Prior to Order entry, physicians should con- firm if the medication and certain concentrations of medications are available on their respective hospital’s medication formulary. patient weight is also an important consideration as it affects dosing and, subsequently, the amount of volume that can be administered into the nostrils. Clinicians should use caution when administering volumes greater than 1 mL of volume per nostril as the chances of losing medica- tion to “run-off” increases. Physicians should also take into consider- ation that patients who present with any nasal obstruction, nasal trauma, or nasal-septal abnormalities may not be candidates for IN an- algesia as these factors may affect proper delivery of the analgesic medication. While administering medications via the IN route, patients should be monitored for bad taste in mouth, nasal irritation, and any side effects associated with the analgesic being administered.

Limitations

This review lacked the qualities of a rigorous systematic review or meta-analysis. Only trials that were written in the English language were included. Nine of the eleven trials were conducted outside of the United States. Medications that are not commonly used as analgesics were utilized in trials that were conducted internationally. Therefore, the findings may not be generalizable to the ED patient population in the United States. The quality of the original articles were inconsistent and poor. This subsequently affected the findings presented in this re- view. Due to significant heterogeneity in the methodology and out- comes assessment of the eleven studies, pooling data and reporting summary results was not possible.

Conclusion

The purpose of this literature review is to review the available publications which compared the use of IN analgesia to traditional routes for acute pain control in the ED. The review consisted of elev- en clinical trials enrolling a total of 985 patients. The level of evidence ranged from very weak to moderate. The data revealed in this review pro- vided conflicting conclusions. The available literature provided limited evidence to support the use of the IN analgesia over traditional routes as the primary management of acute pain in the ED. However, adminis- tration via this route may be a good alternative in clinical scenarios where establishing IV access is not feasible, when patients are refusing medications by the injectable route, or a fast onset of action of pain relief is necessary.

Table 3

Summary of results as specified in the literature.

First author year, country

Measured parameter Result Conclusion

Meredith 2003,

United States [9]

Borland 2007,

Australia [10]

Farnia 2017, Iran

[11]

Fein 2016, United

States [12]

Kendall 2001, United Kingdom [13]

100 mm VAS at 60 min after analgesia administration, mean +- SD

100 mm VAS at 5, 10, 20, and 30 min after administration of study interventions, mean (95% CI)

10 point VAS at 5, 15, 30 min after administration of intervention, mean +- SD

Median decrease in WBS scale at 10, 20, and 30 min after medication administration, median (IQR)

WBS scale at 5, 10, 20, and 30 min after medication administration, mean

IN sumatriptan 61.7 mm +- 35.1 mm (p <= 0.05) vs. IV ketorolac

20.9 mm +- 17.2 mm (p <= 0.05)

5 min: IN fentanyl: 55 vs. IM morphine: 42, difference: -13 (-23

to -3)

10 min: IN fentanyl: 46 vs. IM morphine: 41, difference: -5

(-16-7)

20 min: IN fentanyl: 37 vs. IM morphine: 35, difference: -2

(-13 -10)

30 min: IN fentanyl: 37 vs. IM morphine: 33, difference: -4

(-16-8)

At 5 min AIT: IN ketamine: 6.87 +- 0.47 vs. IV morphine: 6.07 +- 0.47; mean difference: -0.79 (95%CI: -1.48 to -1.04)

At 15 min AIT: IN ketamine: 5.60 +- 0.49 vs. IV morphine: 5.24 +- 0.49; mean difference: -0.36 (95%CI: -1.08-0.34)

At 30 min AIT: IN ketamine: 4.17 +- 0.59 vs. IV morphine: 4.02 +- 0.59; mean difference: -0.15 (95%CI: -1.02-0.71)

At 10 min AIT: results presented in graphical comparison

At 20 min AIT: IN fentanyl: 2(0.5-4) vs. normal saline: 1 (0-2) At 30 min AIT: results presented in graphical comparison

IN diamorphineb

5 min: 4.29 (p = 0.04)

10 min: 8.74 (p = 0.003)

20 min: 9.8 (p = 0.002)

30 min: 1.66 (p = 0.20)

Patients who received IV ketorolac had significant reduction in mean VAS scores No significant difference

At 5 min, IV morphine was more effective than ketamine, no significant difference at 15 and 30 min

Patients who received IN fentanyl had significantly greater reduction in median pain scores (p b 0.05) at 20 min only Patients who received IN diamorphine had significant reduction in mean pain scores at 5, 10, 20 min but not at 30 min

Wilson 1997, United Kingdom [14]

Decrease in Wong Baker face pain scores at 5, 10, 20, and 30 min after administration of intervention, median

Summed decrease: IN diamorphine 9 vs. IM morphine 8 (p = 0.4) No significant difference

Younge 1999,

Australia [15]

Lopes 2001,

Portugal [16]

Kumar 2011, India

[17]

Wong Baker face pain score at baseline, 5, 10, 20, and 30 min after intervention, median

10 cm VAS at baseline and 10, 20, and 30 min after intervention

10 cm VAS at baseline and 10, 30, and 60 min after intervention, median (IQR)

At 10 min AIT: IN fentanyl: 1 vs. IM morphine 2, (p = 0.014) At 20 min AIT: no significant difference observed (p = 0.64) No significant difference observed in other intervalsa,c,d

Scores at 10 and 20 min, pain scores were similar in IM diclofenac, IM diclofenac + IN demopressin groupsa,c

At 30 min, pain scores were lower in IM diclofenac, IM diclofenac

+ IN demopressin groupsc

10 min: IN desmopressin: 80 (50-85) vs. IM diclofenac: 70

(30-90) vs. IN desmopressin + IM diclofenac 70 (60-90)

30 min: IN desmopressin: 75 (40-85) vs. IM diclofenac: 37.5

(10-50) vs. IN desmopressin + IM diclofenac 40 (35-65)

60 min: IN desmopressin: 27.5 (20-50) vs. IM diclofenac: 15

(0-30) vs. IN desmopressin + IM diclofenac: 20 (0-40)

Patients who received IN fentanyl had significant reduction in pain scores at 10 min AIT

IN desmopressin produced effective pain relief at 10 min AIT but efficacy was not sustained beyond 10 min

Patients who received comparative groups had significantly greater reduction in median pain scores (p b 0.05)

Hazhir 2010, Iran

[18]

10 point VAS at 10, 20, and 30 min after administration of intervention

Results shown in graphic comparisona No significant difference

Shimonovich 2016,

Israel [19]

time of onset for meaningful pain reliefe, minutes (95%CI)

IN ketamine: 14.3 (9.8-18.8) vs. IV morphine: 8.9 (6.6-11.2) vs. IM morphine: 26 (20.3-31.7)f,g

Patients who received IN ketamine had faster pain relief vs. IM morphine but not IV morphine

Abbreviations: AIT = after initial treatment; CI = confidence interval; IM = intramuscular; IN = intranasal; IQR = interquartile range; IV = intravenous; mm = millimeter; NRS = nu- meric rating scale; SD = standard deviation; VAS = visual analogue scale; WBS = Wong Baker Face Scale.

a Study presented data in graphical chart and did not provide detailed numerical results.

b Study did not provide results to intramuscular morphine group.

c p-Value not provided by study.

d Numerical data for 5 min and 30 min after intervention was not presented.

e Meaningful pain reduction was defined as time when >=15 mm pain decrease on 100 mm VAS was observed.

f Statistical significance detected between IN ketamine vs. IV morphine.

g Statistical significance detected between IN ketamine vs. IM morphine.

Appendix 1. Search strategy for MEDLINE and EMBASE.

MEDLINE EMBASE

#1 “intranasal” [Mesh] 1. intranasal.tw

#2 emergency medicine [tw] 2. analgesia.tw

#3 emergency department [tw] 3. pain.tw

#4 clinical study [tw] 4. exp analgesia

#5 “Acute Pain” [Mesh] 5. exp intranasal

#6 “Analgesia” [Mesh] 6. emergency department.tw

#7 randomized [tiab] 7. intranasal&.ti,ab.

#8 controlled [tiab] 8. random$.ti,ab.

#9 trial [tiab] 9. randomi#e$.ti,ab

#10 randomized controlled trial [pt] 10. /and 1-3

#11 intravenous [tw] 11. /or 1-4

(continued)

MEDLINE EMBASE

#12 versus [tw] 12. /or 4-5

#13 #1 AND #2 13. /or 5-6

#14 #1 AND #3 14. /or 7-8

#15 #1 AND #2 AND #4 AND #5 15. /and 10-14

#16 #1 AND #5 AND #2 16. randomized trial.tw

#17 #1 AND #5 AND #2 17. clinical trial/

#18 #1 AND #3 AND #5 AND #6 18. randomized controlled trial.sh

#19 #1 AND #3 AND #6 19. /or 15-17

#20 #11 AND #12 AND #1 AND #6 20. 15 and 18

#21 #1 AND #6 AND #7 AND #8 AND #9 21. 15 and 19

#22 #1 AND #6 AND #10

Table 4

Number (%) of patients who reported experiencing adverse events after Intranasal administration of medication.

First author year, country

Adverse events

Vomiting Bad taste in mouth

Dry mouth

Nausea

Postural hypotension

Vertigo

Carpopedal spasm

Meredith 2003, United States [9]

Incidence not reported

Borland 2007, Australia [10]

1 (3%)a 3 (9%)a

0

0

0

0

0

Farnia 2017, Iran [11]

0 0

0

10 (50)a

0

0

0

Fein 2016, United States [12]

0 0

0

0

2 (8.3)a

0

0

Kendall 2001, United Kingdom [13]

Incidence not reported

Wilson 1997, United Kingdom [14]

Younge 1999, Australia [15]

Incidence not reported

1 (2%)a 0

0

0

0

0

0

Lopes 2001, Portugal [16]

1 (2%) 0

0

0

0

0

0

Kumar 2011, India [17]

Hazhir 2010, Iran [18]

Incidence not reported

0 0

0

0

0

2 (7%)a

1 (3%)a

Shimonovich 2016, Israel [19]

0 0

0

0

0

0

0

Abbreviations: F = fentanyl group, K = ketamine group.

a Significance not reported by original study.

Table 5

Summary of rescue protocols utilized in identified literature.

First author year, country

Rescue protocol per original reference

Rescue agent and dose utilized

Number of patients (%) requiring rescue analgesia

Mean dose utilized

Meredith 2003, United States [9]

Details on protocol not presented

N/A

IN sumatriptan: 4 (25%) vs. IV Ketorolac: 2 (15%)e

N/A

Borland 2007, Australia [10]

by original study

30 min AIT, rescue analgesia was

IV Morphine to titrationa

2 (3%) patients received rescue analgesiac

N/A

Farnia 2017, Iran [11]

provided

The use of rescue analgesia was

N/A

No numerical data presentedg

N/A

not mentioned

Fein 2016, United States [12]

The use of rescue analgesia was

N/A

N/A

N/A

left to the discretion of the

prescriber

Kendall 2001, United Kingdom [13]

If attending physician decided

patient was still experiencing

IM Morphine 0.2 mg/kg

20 min AIT: IN diamorphine 9 (4%) vs. IM

morphine: 10 (5%)f

N/A

severe pain 20-30 min after

treatment, rescue analgesia was

30 min AIT: IN diamorphine 11 (5%) vs. IM

morphine: 10 (5%)f

offered to the patient. No protocol

Wilson 1997, United Kingdom [14]

was described

30 min AIT, rescue analgesia was

Morphine IMa

IN diamorphine: 1 (3.3%) vs. IM morphine: 1 (4.5%)e

N/A

Younge 1999, Australia [15]

provided

20 min AIT, rescue analgesia was

N/A

IN fentanyl: 1 (2%) vs. IM morphine: 0 (0%)e

N/A

provided

Lopes 2001, Portugal [16]

30 min AIT, rescue analgesia was

IN desmopressin group: IM

First rescue analgesia: IN desmopressin: 13 (65%)

N/A

administered. If adequate

analgesia was not achieved, a

diclofenac 75 mg

IM diclofenac group: IN

vs. IM diclofenac: 7 (37%) vs. IN desmopressin + IM

diclofenac: 2 (9%)e

second dose of rescue analgesia

was providedd

desmopressin 40 mcg

IN desmopressin + IM

Second rescue analgesia: IN desmopressin: 5 (25%)

vs. IM diclofenac: 1 (5%)e

diclofenac group: tramadol

or pethidinea,b

Kumar 2011, India [17]

30 min AIT, rescue analgesia was

IN desmopressin group: IM

IN desmopressin: 24 (100%) vs. IM diclofenac: 2

N/A

provided. If pain persisted after 30

min, IM penthidine 100 mg was

diclofenac 75 mg

IM diclofenac group: IN

(8%) vs. IN desmopressin + IM diclofenac: 3

(12.5%)e

provided

desmopressin 40 mcg

No patients required IM penthidine

IN desmopressin + IM

diclofenac group: IM

Hazhir 2010, Iran [18]

Details on protocol not presented

tramadol 50 mg

Pethidinea,b

IM tramadol: 15 (50%) vs. IN desmopressin: 10

N/A

by original study

(33.3%) vs. IM tramadol + IN desmopressin: 14

(46.7%)f

Shimonovich 2016, Israel [19]

The use of rescue analgesia was

N/A

N/A

N/A

not mentioned

Abbreviations: AIT = after initial treatment; IM = intramuscular; IN = intranasal; IV = intravenous; N/A = information not available from study.

a Dose not reported.

b Route not reported.

c Study did not specify whether the patient who received rescue was randomized to receive intranasal or intravenous therapy.

d Study did not specify timeframe for the administration of second rescue analgesia.

e Analysis to detect significant difference not conducted.

f Significance not detected by original study.

g Study investigators concluded that the need for rescue analgesia was less in intranasal ketamine without providing statistical data.

References

  1. Motov SM, Nelson LS. Advanced concepts and controversies in emergency depart- ment pain management. Anesthesiol Clin 2016;34(2):271-85.
  2. Sokoloff C, Daoust R, Paquet J, Chauny JM. Is adequate pain relief and time to analge- sia associated with emergency department length of stay? A retrospective study. BMJ Open 2014;4(3):e004288.
  3. Borland M, Jacbos I, King B, O’Brien D. A randomized controlled trial comparing in- tranasal fentanyl to Intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med 2007;49(3):335-40.
  4. Nisbet AC. Intramuscular gluteal injections in the increasing obese population: retro- spective study. BMJ 2006;332(7542):637-8.
  5. Corrigan M, Wilson SS, Hampton J. Safety and efficacy of intranasally administered medications in the emergency department and prehospital settings. Am J Health Syst Pharm 2015;72(18):1544-54.
  6. Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain manage- ment in adults. Acta Anaesthesiol Scand 2002;46(7):759-70.
  7. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analysis: the PRISMA statement. J Clin Epidemiol 2009;62(10):1006-12.
  8. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the qual- ity of evidence. J Clin Epidemiol 2011;64(4):401-6.
  9. Meredith JT, Wait S, Brewer KL. A prospective double-blind study of nasal sumatrip- tan versus IV ketorolac in migraine. Am J Emerg Med 2003;21(3):173-5.
  10. Borland M, Jacobs I, King B, O’Brien D. A randomized controlled trial comparing in- tranasal fentanyl to IV morphine for managing acute pain in children in the emer- gency department. Ann Emerg Med 2007;49(3):335-40.
  11. Farnia M, et al. Comparison of intranasal ketamine versus IV morphine in reducing pain in patients with renal colic. Am J Emerg Med 2017;35(3):434-7.
  12. Fein DM, Avner JR, Scharbach K, Manwani D, Khine H. Intranasal fentanyl for initial treatment of vaso-occlusive crisis in sickle cell disease. Pediatr Blood Cancer 2017;

64(6). https://doi.org/10.1002/pbc.26332.

  1. Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical features. BMJ 2001;322(7281):261-5.
  2. Wilson JA, Kendall JM, Cornelius P. Intranasal diamorphine for paediatric analgesia assessment of safety and efficacy. J Accid Emerg Med 1997;14(2):70-2.
  3. Younge PA, Nicol MF, Kendall JM, Harrington AP. A prospective randomized pilot comparison of intranasal fentanyl and intramuscular morphine for analgesia in chil- dren presenting to the emergency department with clinical features. Emerg Med (Fremantle) 1999;11(1):90-4.
  4. Lopes T, et al. An assessment of the clinical efficacy of intranasal desmopressin spray in the treatment of renal colic. BJU Int 2001;87(4):322-5.
  5. Kumar S, et al. A comparative assessment of the clinical efficacy of intranasal desmopressin spray and diclofenac in the treatment of renal colic. Urol Res 2011; 39(5):397-400.
  6. Hazhir S, Badr YA, Darabi JN. Comparison of intranasal desmopressin and intramus- cular tramadol versus pethidine in patients with renal colic. Urol J 2010;7(3): 148-51.
  7. Shimonovich S, Gigi R, Shapira A, Sarig-Meth T, Nadav D, Rozenek M, et al. Intranasal ketamine for acute traumatic pain in the emergency department: a prospective, ran- domized clinical trial of efficacy and safety. BMC Emerg Med 2016;16(1):43.
  8. Masoumi K, et al. The efficacy of intranasal desmopressin as an adjuvant in the acute renal colic pain management. Pain Res Treat 2014;2014(1):320327.

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