Anaesthesia, 2010, 65, pages 47

doi:10.1111/j.1365-2044.2009.06109.x
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ORIGINAL ARTICLE

The effect of pre-emptive use of minimal dose fentanyl on

fentanyl-induced coughing
K.-C. Hung,1 C.-W. Chen,2 V. C.-H. Lin,3 H.-C. Weng4 and S.-W. Hsieh1
1 Staff Anesthesiologist, Department of Anesthesiology, 3 Chairman, Department of Urology, E-DA Hospital, Lecturer,
Department of Nursing, 4 Associate Professor, Department of Health Management, I-Shou University, Kaohsiung
County, Taiwan
2 Candidate, Department of Physiology and Masters Program, College of Medicine, Kaohsiung Medical University,
Kaohsiung County, Taiwan
Summary

We performed a randomised, double-blind study to evaluate the effect of the pre-emptive use of
minimal dose intravenous fentanyl (25 lg) on the incidence of cough caused by a larger bolus of
intravenous fentanyl. Six hundred patients were randomly assigned to one of three groups to
receive either 0.5 ml saline 0.9% 1 min before administration of fentanyl 150 lg (3 ml), or
pre-emptive fentanyl 25 lg (0.5 ml) 1 min before administration of fentanyl 125 lg or 150 lg.
The incidence of fentanyl-induced cough was significantly lower in both pre-emptive groups
(7 (3.5%) for 125 lg fentanyl and 15 (7.5%) for 150 lg fentanyl) than in the saline group
(37 (18.5%); p = 0.001). We conclude that pre-emptive use of fentanyl 25 lg, administered 1 min
before bolus injection of fentanyl (125 or 150 lg), can effectively suppress fentanyl-induced cough.
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Correspondence to: Dr Shao-Wei Hsieh

E-mail: billwintw@yahoo.com.tw
Accepted: 15 August 2009

Coughing often occurs after the administration of

intravenous fentanyl to a patient during the induction
of anaesthesia. This unexpected coughing may be
unpleasant for patients and may also disrupt the smooth
induction of anesthesia. In addition, coughing may be
undesirable in certain patient groups e.g. those patients
with increased intracranial, intra-ocular, or intraabdominal pressures. Contrary to the beliefs of some
physicians, fentanyl-induced cough may not always be
harmless [1].
Previous reports have demonstrated that fentanylinduced cough can be reduced with pretreatment of
certain drugs [27]. This may not only be more costly, it
may also be unnecessary. Lin et al. found that a slow
injection of fentanyl may reduce the incidence of
coughing without the need for other drugs [8]. This
slow injection reduces peak drug concentrations, suggesting that fluctuations in plasma fentanyl concentrations
may contribute to the coughing. This possibility led us to
hypothesise that the pre-emptive use of a minimal dose of
fentanyl may prevent coughing when subsequent larger
doses of fentanyl are administered.
4

Methods

Following local ethical approval and written informed

consent, 600 patients, presenting for elective surgery,
were recruited in to the study. All patients were of ASA
physical status 1-2, aged 1875 years and weighed 50
80 kg. We excluded all patients with a history of asthma,
chronic obstructive airway disease, upper respiratory
infection within the 2 weeks leading up to their surgery,
a history of bronchodilator or steroid therapy, or
treatment with angiotensin-converting enzyme inhibitors. As cigarette smoking has been reported to suppress
fentanyl-induced cough [8, 9], the smoking status of all
patients was assessed before fentanyl was administered. A
current smoker was defined as someone who was still
smoking, or had stopped smoking for < 6 months, and a
non-smoker as one who had never smoked, or had
stopped smoking for more than 6 months.
Patients were randomly assigned into three groups
using a computer generated table of random numbers: the
first group receiving 0.5 ml saline 0.9% intravenously
1 min before the administration of fentanyl 150 lg
 2009 The Authors
Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia, 2010, 65, pages 47

K.-C. Hung et al.
Pre-emptive minimal dose fentanyl and coughing
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(3 ml); the second group receiving pre-emptive fentanyl

25 lg (0.5 ml) 1 min before the administration of
fentanyl 125 lg (2.5 ml); and the third group receiving
the same pre-emptive dose of fentanyl (25 lg), followed
by the administration of fentanyl 150 lg. As a previous
study had reported that the incidence of cough following
fentanyl 1.5 lg.kg)1 was 21.6% [6], we decided to give
fentanyl 25 lg as the pre-emptive dose (0.30.5 lg.kg)1
for our patients), to avoid any possible cough responses.
In order to ensure that neither the patients nor the
observers would know the true dosage of the drug that
each patient was receiving, the total volume of the liquid
in the syringe was kept constant with the use of saline.
Care was also taken to determine the ideal time to
administer the pre-emptive dose of fentanyl. Fentanylinduced cough has been reported to occur within
15 ) 20 s after administration of intravenous fentanyl
[6, 9]. We decided to administer the pre-emptive fentanyl
1 min before the larger bolus dose of fentanyl, to ensure
that the pre-emptive dose had completed one arm-brain
circulation time.
For the current study, once a patient was in the
operating room, intravenous access was first secured and
the cannula connected to a T-connector for drug
injection. All patients were monitored continuously by
electrocardiogram, pulse oximetry and non-invasive
blood pressure measurement throughout the procedure.
General anesthesia was induced after cough cessation, 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 in the 60 s after the fentanyl (125 or 150 lg)
was administered. Any episode of cough was classified as
coughing. Severity of coughing was graded based on the
number of coughs: mild (12); moderate (35); or severe
(> 5 coughs).
In a pilot study, we found that the incidence of
fentanyl-induced cough was 20% (10 50) following a
bolus of fentanyl 150 lg in 50 patients. Therefore, we
assumed that if the incidence of cough decreased to 50%
that of the control group, the effect of pre-emptive
administration of fentanyl may be considered significant.
To achieve 80% statistical power with p < 0.05, each
group would need a minimum of 199 patients. One-way
ANOVA was used to compare the means of continuous
data of all three groups. If group differences were found
by ANOVA to be significant, they were further analysed
by Tukey tests. Categorical data were analysed using chisquared tests with Yates correction or Fishers exact
probability test, as appropriate. The relative magnitudes of
the associations between groups and the likelihood of
fentanyl-induced cough were compared by calculating
crude odds ratio (OR). The precision of the estimated
 2009 The Authors
Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland

OR was assessed by the use of 95% CI. All statistical

operations were performed using SPSS 13.0 for Windows
(Chicago, IL, USA).
Results

There were no differences between the three groups in

terms of patients characteristics and smoking status
(Table 1). As can be seen in Table 2, compared with
saline-fentanyl group the group receiving pre-emptive
fentanyl 25 lg followed by 125 lg coughed less than the
group receiving saline/fentanyl (OR = 0.16; 95% CI
0.070.37, as did the patients in the group receiving preemptive fentanyl 25 lg followed by 150 lg (OR = 0.36;
95% CI 0.190.68). No severe cough was observed in
either pre-emptive group (Table 3). No cough was
observed during the 1 min after the pre-emptive dose
was administered, and before the following larger dose, in
either pre-emptive group. There was no significant
difference in the haemodynamic data among the three
groups before or after fentanyl administration (Table 4).
Discussion

This study found that the incidence of fentanyl-induced

cough could be reduced with a pre-emptive administration
Table 1 Characteristics of patients receiving IV saline + fentanyl
150 lg, fentanyl 25 lg + 125 lg, or fentanyl 25 lg + 150 lg
before induction of anaesthesia. Values are mean (SD) or
number (proportion).
Saline + fentanyl Fentanyl 25 lg + Fentanyl 25 lg +
150 lg
125 lg
150 lg
(n = 200)
(n = 200)
(n = 200)
Age; years
Sex; M F
Weight; kg
Height; cm
ASA 1
ASA 2
Non-smokers
Smokers

47.7 (13.8)
104 96
64.9 (8.3)
161.9 (8.0)
108 (54.0%)
92 (46.0%)
155 (77.5%)
45 (22.5%)

46.9 (14.5)
101 99
64.1 (9.0)
162.8 (8.8)
115 (57.5%)
85 (42.5%)
148 (74.0%)
52 (26.0%)

45.1 (13.1)
102 98
65.9 (9.0)
162.4 (8.2)
109 (54.5%)
91 (45.5%)
146 (73%)
54 (27%)

Table 2 Incidence of cough in patients receiving IV saline +

fentanyl 150 lg, fentanyl 25 lg + 125 lg, or fentanyl 25 lg +
150 lg. Values are number (proportion) or (95% CI).

Incidence
of cough
Odds ratio

Saline + fentanyl
150 lg
(n = 200)

Fentanyl 25 lg +
125 lg
(n = 200)

Fentanyl 25 lg +
150 lg
(n = 200)

37 (18.5%)

7 (3.5%)*

15 (7.5%)

0.16 (0.070.37)

0.36 (0.190.68)

*p < 0.001 compared with saline-fentanyl group.

K.-C. Hung et al.

Pre-emptive minimal dose fentanyl and coughing
Anaesthesia, 2010, 65, pages 47
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of fentanyl 25 lg 1 min before a bolus injection of

fentanyl 125 or 150 lg during the induction of anesthesia.
The incidence of cough in the group that did not
receive the pre-emptive dose of fentanyl was 18.5%, a
finding similar to that reported previously (1865%)
[28]. One previous study suggested that the discrepancy
in the incidence of cough between various studies may be
due to the different doses of fentanyl used and also the
different routes of administration. Furthermore, age may
also be a confounding factor that affects frequency of
cough [5]. Lin et al. found that only light smoking, not
heavy smoking, could decrease the frequency of fentanylinduced cough, but the association between age and
incidence of cough was not observed in their study [8]. In
a cohort study from 1311 adult patients, these authors
reported that increasing age, cigarette smoking, prior
epidural injection of lidocaine or a priming dose of
vecuronium were associated with a decreased risk of
fentanyl-induced cough [9]. In our study, we found no
association of age or smoking status on the incidence of
cough in any of the groups. The reason for this difference
in findings is unclear. The incidence of cough was
significantly reduced from 18.5% to 3.5% in the preemptive group that received fentanyl 25 lg followed by
125 lg, compared to the saline group. Lin et al. proposed
that the threshold for fentanyl-induced cough was easily
reached by a larger peak plasma concentration. A slower
injection time resulted in a smaller peak concentration,
and consequently a lower incidence of fentanyl-induced
cough [8]. Therefore, the low incidence of cough in this
pre-emptive group in our study might be attributed to
this pharmacokinetic mechanism. Although the preemptive group receiving fentanyl 25 lg followed by
150 lg had a larger peak plasma concentration of fentanyl,
they also had a lower frequency of cough than the saline
group (7.5% and 18.5% respectively). This finding adds
further credence to the possibility that fentanyl-induced
cough might be associated with a relative fluctuation in
plasma fentanyl concentration. In addition, opioid receptors are located at nerve terminals, and on stimulation,

cause a reduction, the release of a neurotransmitter [10].

Depletion of neurotransmitter in the nerve fibers from
stimulation by the pre-emptive use of fentanyl may be
another plausible explanation.
Fentanyl-induced cough has been attributed to various
possible mechanisms. The rapid cough response elicited
by bolus fentanyl suggests that the pulmonary chemoreflex resulting from stimulaton of C-fiber receptors
(J receptors) may play a role in fentanyl-induced cough
[11]. As fentanyl has been reported to trigger tracheal
smooth muscle constriction [12], stimulation of irritant
receptors (rapidly adapting receptors) from deformation of
the tracheobronchial wall is another possible mechanism.
Selective b2-adrenergic bronchodilators (terbutaline and
salbutamol) or NMDA antagonists (ketamine) have been
reported to reduce the incidence of fentanyl-induced
cough [3, 4, 6], further supporting the possible role of
bronchoconstriction. Another possible mechanism may
be the release of histamine from lung mast cells, as
inhalation of metered doses of sodium cromoglicate,
(which is known to inhibit degranulation of mast cells),
has been shown to decrease the incidence of cough [4].
A further mechanism may be the sudden adduction of the
vocal cords or supraglottic obstruction by soft tissue
caused by opioid-induced muscle rigidity [13].
There are two limitations in our study. Firstly, the
bolus dose of fentanyl used in our study was 125 or
150 lg. We do not know whether the pre-emptive use of
fentanyl 25 lg would be effective in attenuating the
cough response elicited by fentanyl at doses > 150 lg.
Secondly, one may argue that the anti-tussive effect of
pre-emptive fentanyl may be related to the centrallyacting effect of the drug. Opioids may inhibit the cough
reflex by directly affecting the cough centre in the
medulla, at doses lower than required for analgesia.
Table 4 Haemodynamic variables 1 min before saline or
fentanyl 25 lg (pre), and 1 min after fentanyl 125 lg or 150 lg
(post), in patients receiving saline + fentanyl 150 lg, fentanyl
25 lg + 125 lg, or fentanyl 25 lg + 150 lg. Values are mean
(SD).

Table 3 Severity of cough in patients receiving saline + fentanyl

150 lg, fentanyl 25 lg + 125 lg, or fentanyl 25 lg + 150 lg.
Values are number (proportion).
Severity
of cough*

Saline + fentanyl
150 lg
(n = 200)

Fentanyl 25 lg +
125 lg
(n = 200)

Fentanyl 25 lg +
150 lg
(n = 200)

Mild
Moderate
Severe

19 (51.4)
11 (29.7)
7 (18.9)

6 (85.7)
1 (14.3)
0

7 (46.7)
8 (53.3)
0

*Number of coughs observed in 1 min: mild (12); moderate (35); and

severe (> 5).

SBP pre; mmHg

SBP post; mmHg
DBP pre; mmHg
DBP post; mmHg
HR pre; beats.min)1
HR post; beats.min)1

Saline +
fentanyl
150 lg
(n = 200)

Fentanyl
25 lg +
125 lg
(n = 200)

Fentanyl
25 lg +
150 lg
(n = 200)

136.6
135.4
77.9
77.6
76.4
76.7

138.8
138.6
78.9
76.8
75.3
74.8

136.9
136.2
79.0
78.3
74.7
74.8

(19.1)
(19.2)
(11.2)
(11.3)
(14.6)
(14.8)

(20.1)
(21.0)
(11.8)
(11.5)
(13.8)
(14.4)

(20.1)
(20.5)
(10.9)
(11.3)
(14.8)
(14.9)

ns
ns
ns
ns
ns
ns

SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart
rate.
 2009 The Authors
Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia, 2010, 65, pages 47

K.-C. Hung et al.
Pre-emptive minimal dose fentanyl and coughing
. ....................................................................................................................................................................................................................

However, as peak brain concentration is achieved at

6 min after intravenous administration of fentanyl [14],
the centrally-acting effect of pre-emptive fentanyl to
reduce the cough response elicited by a larger dose
fentanyl may be unlikely.
In conclusion, pre-emptive use of minimal dose fentanyl 25 lg administered 1 min before a larger bolus dose of
fentanyl (125 or 150 lg) can effectively suppress cough.
This may be as a result of fluctuations in plasma concentrations of fentanyl during induction of anaesthesia.
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