Bhattarai B

Kumar Santosh

Shah Rs

Shrestha

Shrestha Sk

CiteSeerX

KATHMANDU UNIVERSITY MEDICAL JOURNAL
Page 16
Preemptive use of Small Dose Fentanyl Suppresses Fentanyl 
Induced Cough
Shrestha SK, Bhattarai B, Shah RS
Department of Anesthesia
Kathmandu University School of Medical Science 
Dhulikhel Hospital, Kathmandu University Hospital 
Dhulikhel Kavre, Nepal
Corresponding author 
Santosh Kumar Shrestha
Department of Anesthesia
Kathmandu University School of Medical Science
Dhulikhel Hospital, Kathmandu University 
Dhulikhel Kavre, Nepal
Email: drsantosh_shrestha@yahoo.com
Citation
Shrestha SK, Bhattarai B, Shah RS. Preemptive use 
of Small Dose Fentanyl Suppresses Fentanyl Induced 
Cough. Kathmandu Univ Med J 2012;10(4):16-19.
ABSTRACT
Background
Fentanyl, a synthetic opioid, is a popular choice amongst anaesthesiologists in 
the operating room. Pre induction intravenous fentanyl bolus is associated with 
coughing in 28 – 65% of patients. Fentanyl induced cough is not always benign and 
can be remarkably troublesome at the most critical moment of anaesthesia when 
airway reflex is lost.
Objectives
To study the effect of pre emptive use of minimal dose fentanyl through the 
peripheral venous cannulae on the incidence of cough by a larger bolus of 
intravenous fentanyl.
Methods
One hundred and fifty patients aged 18 -75 years undergoing elective surgical 
procedures were randomized into three groups of 50 each. The first group received 
0.5 ml saline 0.9 % intravenously one minute prior to the administration of fentanyl 
150µg (3 ml); the second group received pre emptive fentanyl 25µg(0.5ml) prior 
to the administration of fentanyl 125µg(2.5ml); and the third group received 
preemptive fentanyl 25 µg(0.5ml), followed by the administration of fentanyl 
150µg(3ml).. Based on the number of coughs observed, cough severity was graded 
as mild(1-2), moderate (3-5),or severe (>5).
Results
The incidence of fentanyl induced cough was significantly lower in both pre 
emptive group 4(8%) for 125µg fentanyl and 7(14%) for 150µg than in the saline 
group 15(30%).
Conclusion
Pre- emptive use of minimal dose fentanyl 25µg administered one minute before a 
larger bolus dose of fentanyl (125 or 150µg ) can effectively suppress cough.
KEY WORDS
Cough, fentanyl, pre emptive
VOL.10 | NO. 4 | ISSUE 40 | OCT - DEC 2012
Page 17
Original Article
INTRODUCTION
Opioids are used to decrease pain and allay anxiety 
associated with surgery. Fentanyl, a synthetic opioid, is 
widely used during general anesthetic induction because 
of its quick onset, short duration of action, intense 
analgesia, cardiovascular stability, and no histamine 
release.1,2 Reflex cough is often observed after an iv bolus 
of fentanyl during induction, frequency ranging from 28 
– 65%.3-8 Some authors have reported a case of explosive 
coughing after intravenous (IV) fentanyl that produced 
multiple conjunctival and periorbital petechiae.9 Fentanyl 
induced cough is not always benign and is undesirable in 
patients with some pre-existing disease, including cerebral 
aneurysm,brain trauma, open eye injury, dissecting aortic 
aneurysm, pneumothorax, and reactive airway disease.6,8,9
Various interventions has been tried to reduce the incidence 
of fentanyl induced cough by using anaesthetic adjuncts 
and other maneuver. These include β2 receptor agonist, 
epheridine, lidocaine ketamine, clonidine, dexamethasone, 
dexmedetomidine, a huffing manoeuvre prior to induction 
etc.5-8,10-14 All these approaches which are tried are not 
uniformly effective. 
Yu et al found that prolonged injection time of fentanyl 
may reduce the incidence of coughing.15 This slow injection 
time reduces peak drug concentration, suggesting that 
fluctuations in plasma fentanyl concentrations may 
have contributed to coughing. This led us to hypothesize 
that pre–emptive use of small dose fentanyl prior to the 
subsequent larger dose may prevent coughing.
METHODS
After obtaining approval from the institutional ethical 
committee of the hospital and informed consents from 
the patients, 150 adults patients of American society 
of anesthesiologist  physical status I or II, aged 18 – 75 
years and scheduled for elective surgery during general 
anesthesia were enrolled in this randomized, prospective 
double blind placebo control study. The study was 
conducted at Dhulikhel hospital, Kathmandu university 
hospital, between January 2012 and June 2012. 
Exclusion criteria included history of asthma, chronic 
cough, upper respiratory tract infection in the previous two 
weeks, a history of bronchodilator or steroid therapy, or 
medication with angiotensin converting enzyme inhibitor. 
The smoking status of all patients was assessed, as smoking 
has been reported to suppress fentanyl induced cough.16,17
All patients were pre medicated with oral lorazepam 
0.04 mg/kg and pantoprazole 40 mg the night before 
and morning of surgery. Before induction of anesthesia, 
venous access was established with 20gauge cannula on 
the dorsum of the hand. All patients were monitored by 
electrocardiogram, non invasive blood pressure, pulse 
oximetry, end tidal carbon dioxide and temperature.
Patients were randomly assigned into three groups: 
Group 1:  Received 0.5 ml normal saline intravenously 1 
min prior to the administration of fentanyl 150µg (3 ml)
Group 2: Received pre emptive fentanyl 25µg(0.5ml) prior 
to the administration of fentanyl 125µg(2.5ml); 
Group 3: Received preemptive fentanyl 25 µg( 0.5ml), 
followed by the administration of fentanyl 150µg(3ml). 
General anesthesia was induced after the cessation of cough 
if cough occured or 1 min after the end of bolus injection. 
If desaturation was noted, assisted mask ventilation with 
oxygen was applied.
A blind observer recorded the number of coughs that 
occurred after the fentanyl was administered within first 
minute. Based on the number of coughs observed, cough 
severity was graded as mild (1-2), moderate (3-5), or severe 
(>5). Non invasive blood pressure (systolic blood pressure, 
diastolic blood pressure,) and heart rate were recorded one 
minute prior and one minute after fentanyl administration.
All data are reported as mean ± SD or number (proportion).
One way ANOVA was used to compare the means of 
continuous data of all three groups. The relative magnitude 
of the associations between groups and the likelihood of 
fentanyl induced cough were compared by calculating 
adjusted odds ratio (OR). The precision of the estimated 
OR was assessed by the use of 95% confidence interval(CI). 
Statistical analyses were performed using statistical 
package for social sciences ( SPSS) version 17.
 
RESULTS
The groups were similar in demographic characteristics, 
ASA physical status as well as smoking status.(table 1). 
Group 2 patients coughed less than Group 1 patients ( OR 
= 0.197; 95% CI 0.60-0.647), as did the patients in group 3 
(OR = 0.369; CI 0.135 – 1.007)(table 2). Severe cough was 
not observed in either pre emptive group (table 3).There 
was no significant difference in the the haemodynamic 
variable among the three groups before or after fentanyl 
administration (table 4).
Table 1. Demographic Profile of different group of patients prior 
to induction. Values are mean(SD) or number (proportion).
Group I Group II Group III
Age(Years) 42.22(14.10) 40.24(13.45) 39.88(14.99)
Sex:M/F 16/34 17/33 14/36
Weight:Kg 56.22(6.2) 57.96(8.13) 55.80(5.42)
ASA I 35(70%) 41(82%) 40(80%)
ASA II 15(30%) 9(18%) 10(20%)
Smoker 12(24%) 11(22%) 14(28%)
Nonsmoker 38(76%) 39(78%) 36(72%)
KATHMANDU UNIVERSITY MEDICAL JOURNAL
Page 18
DISCUSSION
This study demonstrated that the incidence of fentanyl 
induced cough could be reduced with pre emptive 
administration of fentanyl 25µg prior to the larger bolus 
dose 125µg or 150µg during the induction of anesthesia.
The incidence of cough in the group that didn’t receive 
the pre emptive dose of fentanyl was 30% which is similar 
to the previous study where the reported incidence of 
cough following an intravenous bolus of fentanyl was 28 
–65%.3-7 Fentanyl induced cough is commonly observed 
during induction of anaesthesia. In the study by Bohrer et 
al 45.9% of the patients coughed after receiving 7 µg/kg 
fentanyl through a central venous catheter.3 Another study 
by Lui et al, 43% of patients coughed after receiving 5µg/
kg of fentanyl injected through a peripheral venous line.5 
Phue et al found that fentanyl 1.5µg/kg given through  a 
peripheral venous line elicited cough in 28% of the patients 
and a similar incidence of cough was observed by Agarwal 
et al following 2µg/kg given through peripheral venous 
line over a period of five seconds.4,6 The discrepancy in the 
incidence of cough among these studies can be explained 
by the differences in injection dose, route of administration 
and period of injection.
Lin et al found that there was an age related incidence 
of fentanyl induced cough.7 Another study by Lin et al. 
showed that longer injection time reduces the incidence 
of fentanyl induced cough, and light smoking may be a 
protective factor against fentanyl cough.16 Another study 
by Jung et al showed that priming dose of fentanyl didn’t 
reduce the incidence and severity of fentanyl induced 
cough and former smokers were found to cough more than 
current smokers after injection of fentanyl.18 Contradictory 
to their studies we didn’t find any association between age 
and smoking status on the incidence of cough in any of 
the groups. This may be due to the wide age range of the 
patients studied (18 – 75 years).
Lin et al showed that the threshold for fentanyl induced 
cough may be reached more easily at a larger peak plasma 
concentration; therefore, longer the injection time, less 
frequent is fentanyl induced cough.16 The low incidence 
of fentanyl induced cough in our study may be explained 
by this pharmacokinetic view that the duration of drug 
injection may affect the peak plasma concentration. 
Fentanyl induced cough has been reported to occur within 
15-20 sec after administration of intravenous fentanyl so 
we decided to administer the preemptive fentanyl one 
min before the larger dose of fentanyl, to ensure that the 
preemptive dose had completed one arm brain circulation 
time.17
The mechanisms of fentanyl induced cough are not well 
understood but various theories have been proposed. 
Fentanyl has been shown to inhibit central sympathetic 
outflow causing vagal predominance, which inturn causes 
cough and reflex bronchoconstriction.5,6,19 Effective 
suppression of the cough response from 43% to 3 % 
after terbutaline and salbutamol (selective β2 Agonist) 
inhalation supports the concept of bronchoconstriction.5 
The rapid response of the reflex and efficacy of morphine in 
preventing cough suggests that a pulmonany chemoreflex 
is also the likely mechanism, mediated by either irritant 
receptor or by Vagal C fiber receptors in close proximity to 
pulmonary vessels (juxta capillary receptors). Suppression 
of cough with betamethasone inhalation supports the 
trigger stimulus and bronchial hyperirritability theory.5,6,9 
Inhibition of cough response from 21.6% to 7.2% after 
ketamine pretreatment suggest that NMDA receptor 
has been demonstrated in larynx, lung, and airways, 
and activation of these receptors can trigger airway 
constriction.10 Fentanyl induced muscle rigidity is another 
important causal factor. The α2 adrenoreceptor agonists 
ability to reverse opioid induced muscular rigidity has been 
demonstrated in rats.20 It is possible that α2 adrenoreceptor 
agonist reduce the incidence of fentanyl induced cough 
via reversal of fentanyl induced muscular rigidity and not 
through sedation.21
Many physical methods and drugs havebeen reported 
to prevent fentanyl induced cough, including ephedrine, 
lidocaine, and propofol.7,8,22 A huffing maneuver was 
reported as a useful way to prevent fentanyl induced 
Table 2. Incidence of cough in Group I group II and Group III 
patients. Values are number (proportion) or ( 95% CI).
Group I Group II Group III
Incidence of cough 15(30%) 4(8%) 7(14%)
Odds ratio 1 0.197(0.60-
.647)*
0.369(0.135-
1.007)*
p <0.05 compared with saline fentanyl group (Both are significantly as-
sociated)
Table 4. Haemodynamic variable 1 min prior and 1 min after 
injection in Group I group II and Group III. Values are mean(SD).
Group I Group II Group III p Val-
ue
HR pre per/
min
77.24(7.07) 76.14(5.03) 74.88(5.43) 0.265 NS
HR post 
per/min
74.72(5.85) 73.92(5.15) 73.50(6.54) 0.181 NS
SBP 
pre:mm Hg
121.16(6.
68)
120.32(5.
78)
121.34(5.8) 0.317 NS
SBP 
post;mmHg
116.52(9.
26)
117.34(6.
93)
117.58(7.
47)
0.479 NS
DBP 
pre:mmHg
76.54(4.96) 74.26(7.16) 77.42(6.07) 0.333 NS
DBP 
post:mmHg
73.28(5.07) 72.50(6.85) 74.82(5.36) 0.027 NS
Table 3. Severity of cough in Group I, Group II Group III patients. 
Values are number (proportion).
Group I Group II Group III
Mild 7(46.7) 3(75) 4(57.14)
Moderate 5(33.3) 1(25) 3(42.86)
Severe 3(20) 0 0
VOL.10 | NO. 4 | ISSUE 40 | OCT - DEC 2012
Page 19
Original Article
cough, but some patients who receive midazolam or 
propofol during induction of general anesthesia cannot use 
this maneuver.14
Although the above mentioned medications could reduce 
the incidence of coughing, some unexpected side effects 
may occur during drug administration, such as malignant 
arrhythmia, hypotension, and hypertension. Pretreatment 
with lidocaine can augment the cardiovascular depression of 
induction agents.23 Intravenous ephedrine before fentanyl 
injection can be contraindicated in patients with coronary 
artery disease or moderate to severe hypertension.14 
Using high doses of propofol can be associated with high 
incidence of hypotension.22 Pretreatment with clonidine 
is associated with respiratory depression, drowsiness, and 
severe hypotension.11
All these drugs and maneuver which have been tried to 
attenuate the fentanyl induced cough may not only be 
more costly but it may also be unnecessary. So this study is 
intended and will help to avoid the use of multiple drugs to 
attenuate fentanyl induced cough.
A limitation of this study was that a dose response 
experiment was not performed to determine the optimal 
dose of fentanyl that can reduce the cough prior to the 
larger bolus dose. Although we choose 25µg fentanyl as 
a pre emptive dose we don’t know this dose is effective 
in attenuating cough response elicited by fentanyl at any 
larger dose. Further studies are warranted to determine 
the optimum dose of fentanyl that will suppress fentanyl 
induced cough.
CONCLUSION
Our study suggests that  pre emptive use of minimal dose 
fentanyl 25µg administered 1 min prior to the larger bolus 
dose of fentanyl( 125µg or 150µg) can effectively suppress 
cough and is a simple and cost effective method to prevent 
fentanyl induced coughing.
ACKNOWLEDGEMENT
We would like to thank Mr Roshan Mahato, Department 
of Community Medicine for his assistance in statistical 
analysis.
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Preemptive use of Small Dose Fentanyl Suppresses Fentanyl Induced Cough

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Preemptive use of Small Dose Fentanyl Suppresses Fentanyl Induced Cough

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