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doi: 10.4103/2221-6189.248028 ©2018 by the Journal of Acute Disease. All rights reserved.
Intranasal ketamine as an analgesic agent for acute pain management in
emergency department: A literature review
Abdolghader Pakniyat1, Morteza Qaribi2, Dorin Rahnama Hezaveh3, Ali Abdolrazaghnejad4
1Department of emergency Medicine, Faculty of Medicine, Kurdistan University of medical sceinces, Sanandaj, Iran
2Department of Emergency Medicine, School of Medicine, Arak University of Medical Sciences, Arak, Iran
3School of Medicine, Medical University of Lublin, Lublin, Poland
4Department of Emergency Medicine, Khatam-Al-Anbia Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
ARTICLE INFO ABSTRACT
Article history:
Received 5 October 2018
Revision 15 November 2018
Accepted 25 November 2018
Available online 21 December 2018
Keywords:
Administration
Intranasal
Emergency department
Ketamine
Pain management
Review literature
Corresponding author: Ali Abdolrazaghnejad, Department of Emergency Medicine,
Khatam-Al-Anbia Hospital, Zahedan University of Medical Sciences, Zahedan, Iran.
Tel: +989127141399
E-mail: ali.abdorazzagh@gmail.com
1. Introduction
Ketamine is a well-known dissociative anesthetic agent that
mediated its effects mainly via blockade of N-methyl-D-aspartate
and hyperpolarisation-activated-cyclic-nucleotide receptors[1]. For
over 50 years, it has been used in various ways[1-3]. It is likely that
it is a very useful agent for conducting procedural sedation and
analgesia in emergency department (ED)[4-6]. Despite using as an
Ketamine is a well-known dissociative anesthetic agent, and has been used over 50 years.
Intranasal pathway is a mucosal way for absorbing agents to directly affect in brain via
olfactory sheets, bypassing first pass metabolism and the blood brain barrier. The current
uses of intranasal ketamine as an analgesic agent for acute pain management in emergency
department are discussed in this review article. Using “ketamine”, “pain or analgesia”, and
“intranasal” as keywords, a search of google scholar, Pubmed, web of science, and Medline
database from 1970 until 2017 was performed. Finally, from 1 204 papers extracted via
primary search, 1 088 papers were omitted and finally 10 studies were considered for further
assessment. There were four observational studies, one case series and report and 5 clinical
trials. Ketamine was used for acute pain control due to musculoskeletal trauma, burns, and
painful procedures. A total of 390 cases were included in these studies. The studies used
ketamine with doses ranging 0.45-1.25 mg/kg via intranasal pathway. Intranasal ketamine
provides relatively rapid, well tolerated, and clinically significant analgesia for emergency
department patients. Considering the lack of adequate studies and undetermined intranasal
dose, it is better to conduct further high quality investigation in both adults and pediatrics.
J Acute Dis 2018; 7(6): 241-246
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How to cite this article: Pakniyat A, Qaribi M, Hezaveh DR, Abdolrazaghnejad A.
Intranasal ketamine as an analgesic agent for acute pain management in emergency
department: A literature review. J Acute Dis 2018; 7(6): 241-246.
[Downloaded free from http://www.jadweb.org on Monday, December 24, 2018, IP: 10.232.74.22]
242 Abdolghader Pakniyat et al./ J Acute Dis 2018; 7(6): 241-246
analgesic agent in management of chronic pain, but it is not routinely
used for acute pain management of ED due to its potentially side
effects such as dissociation and emergence phenomenon[7,8].
Due to overcrowding and lack of human and facilities resources
in EDs, using a safe drug with minimal side effects is crucial.
Recent evidence proved efficacy of low dose ketamine in this
regards, although it needs further investigation[9-11]. Each drug has
some different pathway of administration. Intranasal pathway is
a mucosal way for absorbing agents to directly affect in brain via
olfactory sheets, bypassing first pass metabolism and the blood brain
barrier[12]. Accordingly, the current uses of intranasal ketamine as an
analgesic agent for acute pain management of ED are discussed in
this review article.
2. Evidence acquisition
All observational and randomized controlled trials that surveyed the
use of intranasal ketamine as an analgesic agent in the emergency
setting were eligible for assessing in this study. Using “ketamine”,
“pain or analgesia”, and “intranasal” as keywords, a search of
google scholar, Pubmed, web of science, and Medline database
from 1970 until 2016 was performed. The searching process
was performed with two independent investigators. All papers
and additional references from their citation were also included.
Initially the abstracts were screened regarding the use of intranasal
ketamine as an analgesic agent for acute pain management in both
prehospital and ED setting. No age limit was considered and both
adult and pediatric studies were included. Papers that used ketamine
through other pathway than intranasal published in non-English
languages, animal studies, and review articles were excluded. Non-
available full text, duplicated studies, and unpublished ones were
eliminated. Evaluation was performed independently by 4 reviewers
and validated scales were using pain measurement tools and also
mentioning side effects were in the studies. The results were
summarized and presents in Tables.
3. Results
Finally, from 1 204 papers extracted via primary search, 1 088
papers were omitted and finally 10 studies were considered for
further assessment. There were four observational studies, one case
series and report and 5 clinical trials including 4 randomized, 1 non-
randomized, 4 blinded, and 1 non-blinded one (Figure 1). Ketamine
was used for acute pain control due to musculoskeletal trauma,
burns, and painful procedures. A total of 631 cases were included in
these studies. The studies used ketamine with doses ranging 0.45 -
1.25 mg/kg via intranasal pathway.
Table 1 shows the characteristics and summery of the clinical
trial studies included in the current review. Clinical trial studies
showed acceptable analgesia with ketamine with no differences
compared with other analgesic agents[13-15]. Table 2 shows the
characteristics and summery of the non-clinical trial studies included
in the current review. The observational studies and case reports
concluded analgesic effect of ketamine without major side effects[19-
22]. Summary of reported side effects in the studies included in the
current review were reported in Table 3. All side effects were minor
and transient.
Figure 1. Fowchart of search strategy and paper extraction in current review.
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243
Abdolghader Pakniyat et al./ J Acute Dis 2018; 7(6): 241-246
Table 1
Characteristics and summery of clinical trial studies in current review.
Ref Design Participants Analgesia agents Outcome Result Conclusion
Graudins et al[14] Randomized,
controlled, double-
blind trial
A total of 80 children
aged 3 to 13 years
and weighing less
than 50 kg, with
isolated limb injury
and pain of more than
6/10.
IN ketamine (1 mg/
kg) or fentanyl (1.5
microgram/kg).
coadministered oral
ibuprofen at 10 mg/
kg
Median pain
reduction at 30
min; pain reduction
at 15 and 60
min, subjective
improvement
and satisfaction,
University of
Michigan Sedation
Score, adverse events,
and rescue analgesia.
Pain reductions of
ketamine vs fentanyl; 45
vs. 40 mm, respectively
(95% CI 10 to 20 mm).
IN fentanyl and
ketamine had similar
analgesic effect in
children with limb
injury. Ketamine had
more minor adverse
events.
Nejati et al[15] Prospective double-
blind randomized
clinical trial
72 stable subjects
aged >18 years
who required NG
tube placement
for diagnostic or
therapeutic purposes
in the ED
Local ketamine
plus water-soluble
lubricating gel
and water-soluble
lubricating gel alone
VAS fallowing of NG
tube placement was
measured; evaluate
the difficulty of the
procedure using a
5-point Likert scale.
VAS of the ketamine vs.
control groups (19.03±
3.56 vs. 33.33±5.31),
not statistically
different between the
two groups (2.39±1.25
vs. 2.78±1.56).
IN ketamine is an
effective agent in
reducing pain during
NG tube insertion
among patients without
serious underlying
illness.
Nielsen et al[16] Prospective
nonrandomized open-
label clinical trial
50 child ≥10 kg
candidate for a
painful procedure
Formulation of IN
sufentanil 0.5 mcg/
kg- ketamine 0.5 mg/
kg
Pain intensity
before and during
the procedure was
measured using age-
appropriate pain
scales.
Procedural pain
intensity scores ≤5
(0-10) in 78% of the
painful procedures.
Sufentanil/ketamine
nasal spray provided
rapid onset of analgesia
for a variety of painful
procedures.
Reynolds et al[17] Randomized
controlled,
87 child (4-17
years old) suspected
isolated fractures
1 mg/kg IN ketamine
vs. 1.5 μg/kg IN
fentanyl
Frequency of
cumulative side
effects and adverse
events within
60 min of drug
administration and
difference in mean
pain score reduction
at 20 min.
Cumulative number
of side effects was 2.2
times higher in the
ketamine group, but
there were no serious
adverse events.
IN ketamine was
associated with more
minor side effects than
IN fentanyl. Pain relief
at 20 min was similar
between groups.
Parvizrad et al[18] Balanced block
randomized
controlled
154 adult patients
with isolated
orthopedic trauma
and VAS ≥60 mm
Ketamine-IN (0.4
mg/kg IN ketamine
and an equal volume
of placebo saline IV
and ketamine-IV (0.2
mg/kg ketamine IV
with 0.5 mL saline
IN)
Patients were
assessed for VAS
measurement and
adverse events At 5,
10, 20, and 30 min.
No difference between
two groups in case of
score change of VAS
and Adverse events in
both groups were mild
and transient.
IN ketamine is may
be used in cases
where there is no need
for venipuncture of
peripheral vessels,
especially in crowded
EDs.
VAS: visual analog scale; IN: Intranasal; IV: intravenously.
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244 Abdolghader Pakniyat et al./ J Acute Dis 2018; 7(6): 241-246
Table 2
Characteristics and summery of non-clinical trial studies in current review.
Ref design Participants Analgesia agents Outcome Result Conclusion
Andolfatto et al[19] Prospective
observational study
40 patients aged >6
years old ( mean
age 47 years) with
primarily orthopedic
injury
0.5 to 0.75 mg/kg
intranasal ketamine
Clinical significant
VAS reduction ( 13
mm) within 30 min,
mean reduction of
VAS, median time
require to achieve at
least 13 mm reduction
of VAS, vital sign
change, side effects.
Median changes in
VAS at 30 min: 34
mm (44%).
Reduced VAS pain
scores to a clinically
significant degree in
88% of ED patients
without major side
effects.
Yeaman et al[20] Prospective,
observational study
72 patients (median
aged 34.5 years) with
severe pain; VAS ≥6.
Ketamine 0.7 mg/
kg intranasal (first
6 mo); 1.0 mg/kg
intranasal (second 6
mo) followed by a
0.5 mg/kg intranasal
(15th min) if no pain
reduction
Change in VAS at 30
min; patients with
clinically significant
VAS reduction in
VAS (≥20 mm) at 30
min; significant pain
reduction dose of
ketamine.
Median reduction
VAS at 30 min was
24 mm (IQR: 2-45).
Significant VAS
reduction ≥20 mm in
40 cases (56%, 95%
CI: 44.0-66.7). Total
median ketamine
dose was 0.94 mg/kg
(IQR: 0.72-1.04).
Intranasal ketamine
of 1 mg/kg, was an
effective analgesic
agent in 56% of
study patients. Needs
further investigation
in adults.
Yeaman et al[21] Observational study 28 patients aged 3-13
years, with moderate
to severe (≥ 6/10) pain
from isolated limb
injury
Ketamine intranasal Change in median
VAS at 30 min.
change in median
pain rating at 60
min, patient/parent
satisfaction, need for
additional analgesia
and side effects.
Median VAS
decreased from
74.5 mm (IQR 60-85)
to 30 mm (IQR 12-
51.5) at 30 min.
An average dose of
1.0 mg/kg intranasal
ketamine result in
adequate analgesia by
30 min.
Shrestha et al[22] Cross sectional,
observational study
39 patients aged > 8
years old with various
acute injuries and
VAS pain score >50
mm
Ketamine 0.7 mg/
kg intranasal with
an additional dose at
15th minutes (0.3 mg/
kg) if VAS >50 mm
Number of patients
achieving ≥ 20 mm
reductions in VAS
at 15 min; median
reduction in VAS
at 15, 30 and 60
min, changes of
vital signs, adverse
events, satisfaction of
patients, and need for
additional ketamine.
VAS reduction from
baseline to 40 mm
(IQR 20–40), 20 mm
(IQR 14–20) and 20
mm (IQR 10–20)
respectively at 15, 30
and 60 min.
Intranasal ketamine
is an analgesic choice
for patients with acute
injury in moderate
to severe pain in an
overcrowded and
resource limited ED.
Johansson et al[23] Case series 9 patients with
trauma in outdoor
winter-conditions
S-Ketamine 0.45-
1.25 mg/kg.
---- Initially median pain-
score from median
10 (interquartile
range 8–10) and
finally median pain-
score after was 3
(interquartile range
2–4).
Nasal administration
of S-ketamine is off
label and as such
we only use it as a
last resource and
propose that the
effect and safety of
the treatment should
be further studied.
VAS: visual analog scale.
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Abdolghader Pakniyat et al./ J Acute Dis 2018; 7(6): 241-246
4. Discussion
Based on the findings of current review, there are acceptable
analgesic effects for intranasal ketamine. However, since all studies
were included without consideration age, clinical situation and
dosage, it would not be possible to determine definite evidence
regarding use of intranasal ketamine as an analgesic agent for acute
pain management of ED.
Bioavailability of ketamine through intranasal pathway is 45%-
55%[13]. It was reported that intranasal ketamine is detectable in
blood 2 min after administration and its maximum concentration
would be at 30 min later, and provides sufficient analgesia up to
1 h[24]. When used in combination with other drugs, low dose
intranasal ketamine could result in reducing the dose of the other
agents. It is particularly useful in opium-addicted patients[14,20,21,25].
Co-administration of other analgesic agents such as in the study of
Graudins et al that patients received ibuprofen, it may be affected on
study results[14].
All studies were conducted on traumatic patients, and supported
intranasal ketamine sufficient analgesic effect 30 min later, although
available data regarding its use in adult is still limited[14-22,16,23].
Clinical trials showed no difference between the studied groups
regarding pain control. Reported side effects were minor and
transient and did not need any intervention[14-16].
Ketamine was used for painful procedural sedation. Nejati et
al showed that intranasal ketamine facilitated nasogastric tube
insertion, without increasing the rate of vomiting[15]. In the study of
Neilsen et al, sufentanil/ketamine nasal spray provided rapid onset of
analgesia for a variety of painful procedures, so intranasal ketamine
is an acceptable choice for suturing, intravenous line insertion and
etc[16].
There were some differences among studies regarding how the
drug was administered into nostril, dripping with a syringe or using
a spray device. Better absorption occurs while the agent is sprayed
into nasal cavity that provided wider mucosal surface area for
absorption[19,22].
Nasal ketamine may be used in cases where there is no need for
venipuncture of peripheral vessels, especially in crowded EDs and in
prehospital situation, where venipuncture is difficult[18,26].
The authors believe that intranasal ketamine is safe and does not
need close monitoring, but in cases with severe pain in crowded
ED it may be not suitable or possible to wait 30 min to achieve
sufficient analgesic effect. Use of ketamine in combination with low
dose of other analgesic agents would be a better decision. Intranasal
pathway is a rapid and needleless approach that decline the risk
of transmission of blood-borne infections in a stressful situation
of out of hospital such as bad weather condition and dangerous
environment, as well in cases that have not an intravenous access or
does not need to insert intravenous line like an isolated orthopedic
trauma, intranasal rout would be preferable.
5. Conclusion
Intranasal ketamine provides relatively rapid, well tolerated, and
clinically significant analgesia for ED patients. Considering the lack
of adequate studies and undetermined intranasal dose, it is better
to conduct further high quality investigation in both adults and
pediatrics.
Conflict of interest statement
The authors report no conflict of interest.
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