Download - Journal of Pain and Symptom Management

706
Journal of Pain and Symptom Management
Vol. 43 No. 4 April 2012
Original Article
Inhaled Fentanyl Citrate Improves Exercise
Endurance During High-Intensity Constant
Work Rate Cycle Exercise in Chronic
Obstructive Pulmonary Disease
Dennis Jensen, PhD, Abdullah Alsuhail, MD, Raymond Viola, MD,
Deborah J. Dudgeon, MD, Katherine A. Webb, MSc, and Denis E. O’Donnell, MD
Department of Kinesiology and Physical Education (D.J.), McGill University, Montreal, Quebec; and
Respiratory Investigation Unit (D.J., K.A.W., D.E.O.), Division of Respirology and Critical Care
Medicine, Department of Medicine, and Palliative Care Medicine Program (A.A., R.V., D.J.D.),
Department of Medicine, Queen’s University and Kingston General Hospital, Kingston, Ontario,
Canada
Abstract
Context. Activity limitation and dyspnea are the dominant symptoms of chronic
obstructive pulmonary disease (COPD). Traditionally, efforts to alleviate these
symptoms have focused on improving ventilatory mechanics, reducing ventilatory
demand, or both of these in combination. Nevertheless, many patients with COPD
remain incapacitated by dyspnea and exercise intolerance despite optimal
therapy.
Objectives. To determine the effect of single-dose inhalation of nebulized
fentanyl citrate (a m-opioid agonist drug) on exercise tolerance and dyspnea in
COPD.
Methods. In a randomized, double-blind, placebo-controlled, crossover study,
12 stable patients with COPD (mean standard error of the mean post-b2-agonist
forced expiratory volume in one second [FEV1] and FEV1 to forced vital capacity
ratio of 69% 4% predicted and 49% 3%, respectively) received either
nebulized fentanyl citrate (50 mcg) or placebo on two separate days. After each
treatment, patients performed pulmonary function tests and a symptom-limited
constant work rate cycle exercise test at 75% of their maximum incremental work
rate.
Results. There were no significant postdose differences in spirometric
parameters or plethysmographic lung volumes. Neither the intensity nor the
unpleasantness of perceived dyspnea was, on average, significantly different at
isotime (5.0 0.6 minutes) or at peak exercise after treatment with fentanyl
citrate vs. placebo. Compared with placebo, fentanyl citrate was associated with
1) increased exercise endurance time by 1.30 0.43 minutes or 25% 8%
(P ¼ 0.01); 2) small but consistent increases in dynamic inspiratory capacity by
Address correspondence to: Dennis Jensen, PhD, Department of Kinesiology and Physical Education, McGill
University, Currie Gymnasium, 475 Pine Avenue West,
Ó 2012 U.S. Cancer Pain Relief Committee
Published by Elsevier Inc. All rights reserved.
Montreal, Quebec H2W 1S4, Canada. E-mail: dennis.
[email protected]
Accepted for publication: May 18, 2011.
0885-3924/$ - see front matter
doi:10.1016/j.jpainsymman.2011.05.007
Vol. 43 No. 4 April 2012
Effect of Inhaled Fentanyl Citrate on Exercise Endurance in COPD
707
w0.10 L at isotime and at peak exercise (both P # 0.03); and 3) no concomitant
change in ventilatory demand, breathing pattern, pulmonary gas exchange, and/
or cardiometabolic function during exercise. The mean rate of increase in
dyspnea intensity (1.2 0.3 vs. 2.9 0.8 Borg units/minute, P ¼ 0.03) and
unpleasantness ratings (0.5 0.2 vs. 2.9 1.3 Borg units/minute, P ¼ 0.06)
between isotime and peak exercise was less after treatment with fentanyl citrate vs.
placebo.
Conclusion. Single-dose inhalation of fentanyl citrate was associated with
significant and potentially clinically important improvements in exercise
tolerance in COPD. These improvements were accompanied by a delay in the
onset of intolerable dyspnea during exercise near the limits of tolerance. J Pain
Symptom Manage 2012;43:706e719. Ó 2012 U.S. Cancer Pain Relief Committee.
Published by Elsevier Inc. All rights reserved.
Key Words
Dyspnea, exercise, COPD, opioids, fentanyl citrate, nebulized, symptom management
Introduction
Activity limitation and exertional dyspnea
(respiratory discomfort) are the dominant
symptoms of chronic obstructive pulmonary
disease (COPD) and contribute importantly to
perceived poor health-related quality of life in
this population.1 It follows that improvement
of exercise tolerance and exertional dyspnea is
among the principal goals of COPD management, i.e., response to therapy.2 Current
approaches to alleviate dyspnea and improve
exercise endurance focus on reducing central
ventilatory drive (e.g., supplemental oxygen,
pulmonary rehabilitation/exercise training,
and opioids); improving dynamic respiratory
mechanical/muscular function (e.g., bronchodilators, heliox, and surgical lung volume reduction); ameliorating the affective dimension
of dyspnea (e.g., sedatives, including opioids,
and anxiolytics); or any combination thereof.2
These conventional approaches yield small
but meaningful symptom improvements; nevertheless, many patients remain incapacitated by
dyspnea despite optimal medications. Under
these circumstances, consideration may be
given to alternative interventions for symptom
relief, such as inhaled nebulized opioids.
As reviewed in detail elsewhere,3e5 only a few
randomized, double-blind, placebo-controlled,
crossover studies have examined the effect of inhaled nebulized opioids on exercise tolerance
and/or exertional dyspnea in patients with
chronic lung disease.6e11 The collective results
of Harris-Eze et al.,6 Masood et al.,8 Beauford
et al.,9 and Leung et al.10 suggest that compared
with placebo, single-dose inhalation of nebulized morphineda m-opioid agonistdat doses
ranging from 1 to 25 mg improves neither
the intensity of exertional dyspnea nor the maximal work rate (Wmax) achieved during
symptom-limited incremental cycle exercise in
patients with COPD and interstitial lung disease. Similarly, Jankelson et al.11 reported no
significant improvement in six-minute walk distance or exertional dyspnea intensity ratings
after treatment with 20 and 40 mg of inhaled
morphine vs. placebo in patients with COPD.
Clearly, these studies do not support the use of
inhaled opioids in the management of chronic
lung disease, which is consistent with the conclusion of a Cochrane review on this topic.12 It
is possible, however, that the lack of effect of
inhaled opioids on exercise tolerance and/or
exertional dyspnea in the above-mentioned
studies may reflect limitations in study design.
In this regard, there is evidence that both incremental cycle exercise and six-minute walk
distance tests are less responsive than highintensity constant work rate (CWR) cycle exercise tests for the purposes of evaluating the
efficacy of a therapeutic intervention, i.e., bronchodilator.13 Indeed, Young et al.7 found that
the mean increase in endurance time during
CWR cycle exercise at 80% of Wmax was significantly greater after treatment with 5 mg of inhaled morphine vs. placebo (þ35% vs. þ1%)
708
Jensen et al.
in symptomatic patients with COPD. The mechanisms of this improvement, however, remain
conjectural because the possible simultaneous
effects of inhaled opioids on detailed ventilatory and perceptual responses to exercise were
not measured.
Inhaled fentanyl citrate (a m-opioid agonist
drug that is w100 times more potent than morphine and has recently been shown to improve
the perception of breathing at rest in patients
with advanced cancer14) has the potential to
improve exertional dyspnea and exercise tolerance in patients with COPD through a number
of mechanisms, including 1) amelioration of
the sensory intensity and/or affective (i.e.,
unpleasantness) dimension of dyspnea; 2) depression of central ventilatory drive; 3) alteration of afferent inputs from opioid receptors
in the airways and lungs; 4) a bronchodilation
effect; 5) altered central neural processing of
peripheral dyspneogenic stimuli; or 6) any
combination of the above.15e37
Therefore, the purpose of the present study
was, first, to test the hypothesis that inhaled fentanyl citrate would improve exertional dyspnea
and exercise tolerance in symptomatic patients
with COPD and, second, to examine the potential underlying mechanisms of these improvements. To this end, we compared the effects of
inhaled fentanyl citrate 50 mcg (equivalent to
5 mg of inhaled morphine) and placebo on
exercise endurance time (EET) and the intensity
and unpleasantness of perceived dyspnea during
high-intensity CWR cycle exercise. To explore
possible physiological mechanisms of symptom
relief, we measured spirometric parameters
and plethysmographic lung volumes; and performed detailed assessments of ventilatory demand, breathing pattern, dynamic operating
lung volumes, pulmonary gas exchange, and
cardiometabolic function during exercise.
Methods
Subjects
Subjects included 16 stable (i.e., no change
in medication dosage or frequency of administration with no exacerbations or hospitalizations in the preceding six weeks) patients
with a clinical diagnosis of COPD who were
aged 40 years or older with a cigarette smoking
history of $20 pack-years, a post-b2-agonist
Vol. 43 No. 4 April 2012
forced expiratory volume in one second to
forced vital capacity ratio (FEV/FVC) less
than 70%, significant chronic activity-related
dyspnea (Baseline Dyspnea Index focal
score # 638,39 and/or an oxygen cost diagram
rating # 80 mm40), and a body mass index between 18.5 and 30.0 kg/m2. Disease severity
was categorized according to the Global Initiative for Chronic Obstructive Lung Disease
(GOLD) classification system.41 Subjects were
excluded if they had significant diseases other
than COPD that could contribute to activity
limitation and exertional dyspnea; had a clinical
diagnosis of sleep-disordered breathing; had
used either antidepressant or opioid drugs in
the preceding two or four weeks, respectively;
had a history of allergy or adverse reaction to
fentanyl; had a diffusing capacity of the lung
for carbon monoxide (DLCO) value of <40%
predicted; had a history of asthma; used daytime oxygen; experienced exercise-induced
arterial blood oxygen desaturation <80% on
room air; and/or had important contraindications to clinical exercise testing, including
inability to exercise because of neuromuscular
and/or musculoskeletal disease(s).
Study Design
This was a single-center, randomized, doubleblind, placebo-controlled, crossover study (local
ethics approval study code: DMED-1244-09;
ClinicalTrials.gov identifier: NCT00974220).
After giving written informed consent, patients
completed 1) an initial screening visit to determine eligibility for the study and to familiarize
themselves with pulmonary function and exercise tests that would be performed during subsequent treatment visits and 2) two treatment visits
randomized to order, conducted two to 10 days
apart. Visit 1 included a thorough medical
history and clinical assessment; activity-related
dyspnea,38e40 health-related quality of life,42
and anxiety/depression43 evaluation by questionnaires; complete pulmonary function testing; a symptom-limited incremental cycle
exercise test to determine Wmax; and b2-agonist
(400 mcg salbutamol) reversibility testing $30
minutes after incremental exercise testing. After
randomization of treatments (Visits 2 and 3), spirometric and plethysmographic pulmonary
function tests were performed before patients inhaled a 5 mL solution containing either 50 mcg
of fentanyl citrate (10 mcg/mL of 0.9% saline)
Vol. 43 No. 4 April 2012
Effect of Inhaled Fentanyl Citrate on Exercise Endurance in COPD
or 0.9% saline placebo administered by means
of a jet nebulizer (PARI MASTERÒ Compressor
with PARI LC JetÒ Plus Nebulizer; PARI Respiratory Equipment, Inc., Richmond, VA),
with subjects breathing spontaneously through
a mouthpiece with nasal passages occluded by
a noseclip. Exactly 10 minutes after nebulization,
subjects performed spirometric and plethysmographic pulmonary function tests followed
immediately thereafter by a symptom-limited
CWR cycle exercise test at 75% Wmax (i.e., postdose pulmonary function and CWR exercise tests
were completed within a period of w60 minutes
after nebulization).
Before each visit, subjects withdrew from
short- and long-acting b2-agonists (four and 12
hours), short- and long-acting anticholinergics
(six and 24 hours), and short- and long-acting
theophyllines (24 and 48 hours). Subjects also
were required to avoid caffeine and heavy meals
for at least six hours before testing, and alcohol
and major physical exertion entirely on visit
days. All visits were conducted at the same
time of day for each subject.
Randomization, Study Medications, and
Blinding
Randomization, blinding, and dispensing of
study medications were performed by the hospital pharmacist, an unblinded third party who
was not affiliated with either subject recruitment or data collection and analysis.
Efficacy Variables
The primary and secondary efficacy variables
were a priori defined as dyspnea intensity at
a standardized time (isotime) during exercise
and EET, respectively. Additional secondary
efficacy variables included resting pulmonary
function test parameters, and cardiorespiratory
and breathing pattern parameters measured at
rest, isotime, and at end exercise.
Cardiopulmonary Exercise Testing
Symptom-limited exercise tests were conducted on an electronically braked cycle ergometer (Ergoline 800S; SensorMedics, Yorba Linda,
CA) by use of a cardiopulmonary exercise testing
system (Vmax229d; SensorMedics) in accordance with clinical exercise testing guidelines.44,45 Incremental exercise testing was
performed at Visit 1 and consisted of a steadystate resting period of at least six minutes,
709
followed by one minute of unloaded pedaling
and then 10 watt/minute increases in work
rate: Wmax was defined as the highest work
rate that the subject was able to maintain for
$30 seconds. CWR exercise tests performed at
Visits 2 and 3 consisted of a steady-state resting
period of at least six minutes, followed by one
minute of unloaded pedaling and then an immediate stepwise increase in work rate to 75% Wmax
(rounded up to the nearest 5 watts). Pedaling
cadence was maintained between 50 and 70
revolutions/minute, and subjects were verbally
encouraged to cycle to the point of symptom
limitation.
Cardiorespiratory and breathing pattern parameters were collected on a breath-by-breath
basis while subjects breathed through a mouthpiece and a low-resistance flow transducer with
nasal passages occluded by a noseclip. Oxyhemoglobin saturation and heart rate were monitored
by finger pulse oximetry and 12-lead electrocardiogram, respectively. Operating lung volumes
were derived from inspiratory capacity (IC)
maneuvers performed at rest, at the end of every
second minute during exercise, and at end
exercise.46,47
Using Borg’s48 0 to 10 category ratio scale,
subjects provided ratings for the following
questions at rest, within the last 30 seconds
of every second minute during exercise, and
at end exercise: How intense is your sensation
of breathing discomfort (dyspnea) overall?
How unpleasant or bad does your breathing
make you feel? How intense is your sensation
of leg discomfort? Before each exercise test,
the following script was used to distinguish between the intensity and unpleasantness of
breathing sensations to each subject: ‘‘During
cycle exercise, you will be asked to rate various
aspects of your breathing sensations. Some ratings pertain to the intensity, while others pertain to the unpleasantness of your breathing
sensations. You will be asked to separately
rate the intensity and the unpleasantness of
your breathing sensations. The intensity of
the sensation is how much breathing sensation
you feel, while the unpleasantness of the sensation is how bad it makes you feel.’’ All subjects
positively affirmed that they understood the
difference between the intensity and unpleasantness of breathing sensation before exercise
testing. At end exercise, subjects were asked to
1) verbalize their main reason for stopping
710
Jensen et al.
(i.e., dyspnea, leg discomfort, combination of
dyspnea and leg discomfort, other) and 2)
quantify the relative contribution of dyspnea
and leg discomfort to exercise cessation.
Analysis of Exercise Endpoints
All breath-by-breath measurements were
averaged in 30-second intervals at rest and during exercise. Three main time points were used
for the evaluation of exercise parameters: preexercise rest, isotime, and peak exercise. Preexercise rest was the steady-state period after
at least three minutes of breathing on the
mouthpiece while seated at rest before the start
of exercise. Isotime was the highest equivalent
exercise time achieved during each of the
CWR tests performed by a given subject,
rounded down to the nearest whole minute.
Peak exercise was the last 30 seconds of loaded
pedaling, whereas EET was the duration of
loaded pedaling.
Pulmonary Function Testing
Routine spirometry (Visits 1e3), constantvolume body plethysmography (Visits 1e3),
DLCO (Visit 1), and maximum inspiratory/
expiratory mouth pressures (Visit 1) were conducted in accordance with recommended
techniques49e53 using automated equipment
(Vmax229d with Vs62j body plethysmograph;
SensorMedics). Measurements were expressed
as percent of predicted normal values;54e58
predicted normal IC was calculated as predicted total lung capacity (TLC) minus predicted functional residual capacity.
Statistical Analysis
Using a paired subject formula (SigmaStatÒ
for Windows Version 3.10; SystatÒ Software,
Inc., San Jose, CA), it was estimated, a priori,
that a minimum sample size of 10 subjects
would provide the power (80%) needed to detect a clinically relevant difference in dyspnea
intensity ratings at isotime of 1 Borg unit,59
assuming a standard deviation of 1 Borg
unit based on values established in our laboratory, a ¼ 0.05 and a two-tailed test of significance. Postdose differences in primary and
secondary efficacy variables were compared
by paired t-tests. A P < 0.05 level of statistical
significance was used for all analyses. Data
are presented as mean standard error of
the mean.
Vol. 43 No. 4 April 2012
Results
Sixteen subjects (nine men and seven
women) with GOLD Stage I to IV COPD were recruited for participation in this study between
February and October 2010. Four subjects
were withdrawn from the study: one female
(GOLD I) and one male (GOLD II) experienced lightheadedness, dizziness, and mild
nausea during and immediately after nebulization of placebo and fentanyl citrate at Visit 2,
respectively; one male (GOLD IV) could not
complete the period of nebulization at Visit 2
(placebo) because of intolerable dyspnea; and
one female (GOLD III) took 200 mcg of salbutamol about one hour before Visit 3 (placebo)
and was excluded from further participation.
Twelve patients (seven men and five women)
with mild-to-severe COPD (GOLD I n ¼ 2;
GOLD II n ¼ 9; GOLD III n ¼ 1), a significant
cigarette smoking history, significant expiratory flow limitation and static lung hyperinflation, poor perceived health-related quality of
life, moderate chronic activity-related dyspnea,
and a relatively reduced symptom-limited peak
aerobic working capacity completed the study
(Table 1). Comorbidities included osteoarthritis (n ¼ 2), osteoporosis (n ¼ 1), osteopenia
(n ¼ 1), controlled Type II diabetes (n ¼ 2),
hypertension (n ¼ 4), hypercholesterolemia
(n ¼ 8), hypothyroidism (n ¼ 1), hypogonadism
(n ¼ 1), and gastroesophageal reflux disease
(n ¼ 2). The use of respiratory medications
included short-acting b2-agonist (n ¼ 5); shortacting anticholinergic (n ¼ 1); long-acting anticholinergic (n ¼ 9); and inhaled corticosteroid
combined with a long-acting b2-agonist (n ¼ 8).
Treatment order was balanced such that five of
12 (42%) subjects were randomized to receive
fentanyl citrate first. On direct questioning,
none of the 12 subjects reported any systemic
side effects (e.g., nausea, sedation, drowsiness,
dizziness, constipation, etc.) after inhalation of
fentanyl citrate or placebo.
Postdose Responses to High-Intensity Constant
Work Rate Cycle Exercise
Neither the intensity nor the unpleasantness
of perceived dyspnea was, on average, significantly different at isotime or at peak exercise
after treatment with fentanyl citrate vs. placebo
(Fig. 1, Table 2). Post hoc analysis of dyspnea
time plots revealed, however, that the mean
Vol. 43 No. 4 April 2012
Effect of Inhaled Fentanyl Citrate on Exercise Endurance in COPD
711
Table 1
Subject Characteristics and Pulmonary Function Test Parameters
Parameter
Male:female, n
Age, years
Height, cm
BMI, kg/m2
Smoking history, no. of pack-years
Duration of COPD, years
Modified Baseline Dyspnea Index focal score 0e12
O2 cost diagram 0e100 mm
VO2peak, mL/kg/minute (% predicteda)
SGRQdtotal score (normal range 5e7)
Symptoms (normal range 9e15)
Activity (normal range 7e12)
Impact (normal range 1e3)
Hospital Anxiety and Depression Scale (normal range 0e7)
7:5
70.5 2.3
167.4 2.3
27.7 1.3
42.2 7.8
6.4 1.7
8.3 0.5
68.2 4.2
18.5 1.0 (74.0 3.8)
27.3 2.8
49.7 5.4
38.0 4.1
14.3 2.6
5.9 1.1
Pulmonary function test parameters
FEV1, L (% predicted)
Post-b2-agonist FEV1, L (% predicted)
FEV1/FVC, % (% predicted)
Post-b2-agonist FEV1/FVC, % (% predicted)
FVC, L (% predicted)
PEFR, L/second (% predicted)
FEF25%e75%, L/second (% predicted)
TLC, L (% predicted)
SVC, L (% predicted)
IC, L (% predicted)
FRC, L (% predicted)
RV, L (% predicted)
sRaw, cm H2O/second (% predicted)
DLCO/VA, mL/minute/mm Hg/L (% predicted)
MIP, cm H2O (% predicted)
MEP, cm H2O (% predicted)
1.48 0.15 (62 4)
1.65 0.18 (69 4)
46.1 2.6 (67 4)
48.8 3.1 (71 4)
3.18 0.19 (93 4)
4.74 0.51 (70 6)
0.48 0.08 (19 3)
6.17 0.33 (105 3)
3.32 0.22 (96 4)
2.35 0.18 (87 4)
3.82 0.22 (120 6)
2.85 0.22 (126 9)
16.9 1.8 (397 38)
3.04 0.16 (68 11)
66.4 5.8 (83 8)
118.9 14.5 (68 9)
BMI ¼ body mass index; VO2peak ¼ symptom-limited peak metabolic rate of oxygen consumption during incremental cycle exercise;
SGRQ ¼ St. George’s Respiratory Questionnaire; FEV1 ¼ forced expiratory volume in one second; FVC ¼ forced vital capacity; PEFR ¼ peak expiratory flow rate; FEF25%e75% ¼ forced expiratory flow between 25% and 75% of FVC; SVC ¼ slow vital capacity; FRC ¼ functional residual capacity;
RV ¼ residual volume; sRaw ¼ specific airways resistance; VA ¼ alveolar volume; MIP ¼ maximal inspiratory mouth pressure; MEP ¼ maximal
expiratory mouth pressure.
Values are means standard error of the mean.
a
Predicted values from Blackie et al.60
rate of increase in dyspnea intensity and unpleasantness ratings between isotime and
peak exercise was less after treatment with fentanyl citrate vs. placebo (Figs. 1 and 2): intensity 1.2 0.3 vs. 2.9 0.8 Borg units/minute
(P ¼ 0.03) and unpleasantness 0.5 0.2 vs.
2.9 1.3 Borg units/minute (P ¼ 0.06). Compared with placebo, fentanyl citrate had no statistically significant effect on 1) the intensity of
perceived leg discomfort at isotime and peak
exercise (Fig. 1, Table 2) and 2) the mean
rate of increase in perceived leg discomfort between isotime and peak exercise (1.0 0.2 vs.
2.7 1.3 Borg units/minute, P ¼ 0.18).
The distribution of reasons for stopping exercise was similar after treatment with fentanyl citrate vs. placebo: nine vs. eight subjects stopped
because of the combination of dyspnea and
leg discomfort, three vs. three subjects stopped
primarily because of dyspnea, and one subject
stopped primarily because of leg discomfort
after placebo. Similarly, the relative contribution of breathing (54% 6% vs. 51% 5%,
P ¼ 0.28) and leg discomfort (46% 6% vs.
49% 6%, P ¼ 0.19) to exercise cessation was
not significantly different after fentanyl citrate
vs. placebo inhalation.
As illustrated in Fig. 2 and Table 2, EET increased by 1.30 0.43 minutes (or 25% 8%) after treatment with fentanyl citrate compared with placebo (P ¼ 0.01). EET increased
by greater than one minute in seven subjects
(2.14 0.49 minutes) and changed by less
than one minute in the remaining five subjects
(0.13 0.34 minutes). In Study Subject 3, EET
increased by 4.85 minutes after treatment with
fentanyl citrate vs. placebo (Fig. 2): mean postdose differences in EET persisted even after
712
Jensen et al.
Dyspnea Intensity (Borg)
6
4
3 “Moderate”
2
0
Dyspnea Unpleasantness (Borg)
Compared with placebo, inhaled fentanyl
citrate had no statistically significant effect on
cardiorespiratory and breathing pattern parameters at rest or during exercise (Fig. 3,
Table 2). Dynamic IC (ICdyn) was modestly
but consistently increased by w0.10 L at isotime and at peak exercise after treatment
with fentanyl citrate vs. placebo (Figs. 2 and
3, Table 2), despite little/no concomitant
change in the volume and timing components
of breathing (Fig. 3, Table 2). Dynamic inspiratory reserve volume increased by w0.08 L
throughout exercise after treatment with fentanyl citrate vs. placebo; however, this difference did not reach statistical significance
(P ¼ 0.08e0.09) (Fig. 3, Table 2).
5 “Severe”
Fentanyl Citrate
1
Placebo
0
1
2
6
3
4
5
6
7
8
Exercise Time (minutes)
9
5 “Severe”
4
3 “Moderate”
Resting Pulmonary Function
There were no statistically significant predose (data not shown) or postdose (Table 3)
differences in spirometric parameters or plethysmographic lung volumes.
2
1
0
0
1
2
3
4
5
6
7
8
9
Exercise Time (minutes)
Discussion
Leg Discomfort (Borg)
6
5 “Severe”
4
3 “Moderate”
2
1
0
Vol. 43 No. 4 April 2012
0
1
2
3
4
5
6
7
8
9
Exercise Time (minutes)
Fig. 1. Mean SEM ratings (modified 10-point
Borg scale) of the intensity and unpleasantness of
perceived dyspnea and the intensity of perceived
leg discomfort during constant work rate cycle exercise at 75% of maximal work rate after inhalation of
fentanyl citrate (50 mcg) or placebo. The rate of increase in dyspnea intensity (1.2 0.3 vs. 2.9 0.8
Borg units/minute, P ¼ 0.03) and unpleasantness
ratings (0.5 0.2 vs. 2.9 1.3 Borg units/minute,
P ¼ 0.06) between isotime and peak exercise was
less after inhaled fentanyl citrate vs. placebo (refer
also to Fig. 2). SEM ¼ standard error of the mean.
this most extreme difference was excluded
from the analysis (0.98 0.31 minutes or
18% 6%, P ¼ 0.01).
The main findings of this study are as follows: 1) treatment with inhaled fentanyl citrate
had no demonstrable effect on either the intensity or unpleasantness of perceived dyspnea
at isotime or at peak exercise; 2) single-dose inhalation of nebulized fentanyl citrate (50 mcg)
was associated with significant acute improvements in EET by an average of 1.30 minutes
or w25% during high-intensity CWR cycle exercise; and 3) the increase in the intensity and
unpleasantness of perceived respiratory discomfort during exercise near the limits of tolerance was less after treatment with fentanyl
citrate vs. placebo.
The patients in this study had airflow limitation and lung hyperinflation ranging in severity
from mild to severe. They had moderate chronic
activity-related dyspnea, poor perceived health
status, and a mean symptom-limited peak metabolic rate of oxygen consumption (VO2) of
only 18.5 mL/kg/minute (or 74% predicted60)
on incremental cycle exercise testing (Table 1).
As expected, all patients experienced ‘‘severe’’
dyspnea at a relatively low exercise intensity
(Fig. 1) and demonstrated a combination of
high ventilatory demand (caused by inefficiency
of pulmonary gas exchange) and abnormal
Vol. 43 No. 4 April 2012
Effect of Inhaled Fentanyl Citrate on Exercise Endurance in COPD
713
Table 2
Mean ± SEM Postdose Cardiorespiratory and Perceptual Responses at Rest, at the Highest Equivalent Isotime,
and at the Symptom-Limited Peak of CWR Cycle Exercise at 75% Wmax (68.3 ± 6.2 watts)
Rest
Isotime
Placebo
Peak
Parameter
Placebo
Fentanyl Citrate
Fentanyl Citrate
Time (minutes)
Dyspnea intensity
(Borg)
Dyspnea
unpleasantness
(Borg)
Leg discomfort
(Borg)
Heart rate (beats/
minute)
O2 pulse (mL O2/
beat)
VO2 (mL/kg/
minute)
VCO2 (mL/kg/
minute)
VE (L/minute)
VT (L)
fR (breaths/minute)
TI (seconds)
TE (seconds)
TI/TTOT (%)
TE/TTOT (%)
VT/TI (L/second)
VT/TE (L/second)
IC (L)
Change in IC from
rest (L)
IRV (L)
VT/IC (%)
VE/VCO2
PETCO2 (mm Hg)
SpO2 (%)
d
0.0 0.0
d
0.0 0.0
5.00 0.58
2.6 0.5
5.00 0.58
2.0 0.5
6.04 0.56
4.6 0.9
0.0 0.0
0.0 0.0
1.6 0.5
1.7 0.6
3.5 0.8
2.8 0.9
0.1 0.1
0.0 0.0
3.3 0.7
3.1 0.6
5.0 0.7
5.0 0.7
76.8 3.7
77.2 3.6
122.6 4.6
122.0 4.4
127.1 4.5
129.9 3.7
3.36 0.35
2.23 0.36
10.6 0.9
10.4 0.9
11.0 0.9
10.6 0.8
3.2 0.2
3.1 0.2
16.5 0.8
16.0 0.8
17.8 0.8
17.5 0.8
2.8 0.2
2.6 0.2
16.5 0.8
16.0 0.9
17.6 0.9
17.5 0.8
12.6 0.9
0.65 0.06
20.2 1.2
1.18 0.07
1.95 0.13
37.9 1.1
62.0 1.1
0.56 0.04
0.34 0.03
2.24 0.20
d
12.0 0.7
0.65 0.06
19.7 1.2
1.23 0.09
2.05 0.16
37.7 1.0
62.2 1.1
0.53 0.03
0.32 0.02
2.32 0.19
d
1.59 0.17
30.0 2.3
59.9 2.9
36.8 1.3
96.5 0.4
1.67 0.16
28.3 1.8
62.0 4.4
36.9 1.0
96.3 0.5
44.6 3.7
43.7 3.4
1.29 0.10
1.32 0.11
35.1 1.3
33.8 1.6
0.71 0.03
0.74 0.03
1.03 0.05
1.07 0.06
41.0 1.4
40.9 1.4
58.7 1.5
58.9 1.4
1.81 0.13
1.78 0.12
1.29 0.12
1.26 0.11
1.75 0.16
1.86 0.18(P <
0.49 0.07 0.46 0.07
0.47 0.09
74.7 2.9
34.8 1.3
43.4 2.1
93.4 1.9
0.54 0.10(P ¼
72.3 3.1
35.2 1.3
43.5 2.1
94.1 0.9
0.01)
0.08)
Placebo
Fentanyl Citrate
7.34 0.70(P ¼
4.2 0.8
47.5 4.0
47.8 4.0
1.30 0.10
1.31 0.10
36.9 1.7
36.6 1.7
0.68 0.03
0.68 0.03
0.99 0.06
0.99 0.06
41.3 1.5
41.2 1.4
59.0 1.3
58.9 1.4
1.91 0.13
1.94 0.15
1.35 0.13
1.36 0.12
1.73 0.16
1.81 0.16(P ¼
0.51 0.08 0.51 0.07
0.44 0.10
76.2 0.2
34.4 1.5
43.7 2.3
94.4 0.9
0.50 0.09(P ¼
73.7 3.1
35.0 1.7
43.8 2.4
93.4 1.2
0.01)
0.03)
0.09)
SEM ¼ standard error of the mean; CWR ¼ constant work rate; Wmax ¼ maximum incremental cycle work rate; VO2 ¼ metabolic rate of oxygen
consumption; VCO2 ¼ metabolic rate of carbon dioxide production; VE ¼ minute ventilation; VT ¼ tidal volume; fR ¼ breathing frequency;
TI ¼ inspiratory time; TE ¼ expiratory time; TI/TTOT ¼ inspiratory duty cycle; TE/TTOT ¼ expiratory duty cycle; VT/TI ¼ mean tidal inspiratory
flow; VT/TE ¼ mean tidal expiratory flow; IC ¼ inspiratory capacity; IRV ¼ inspiratory reserve volume; VE/VCO2 ¼ ventilatory equivalent for
carbon dioxide; PETCO2 ¼ end-tidal partial pressure of carbon dioxide; SpO2 ¼ arterial oxyhemoglobin saturation.
dynamic respiratory mechanical constraints
related, in part, to lung hyperinflation (Fig. 3,
Table 2).
In keeping with the results of Young et al.,7
single-dose inhalation of fentanyl citrate increased EET by an average of w25% compared with placebo (Fig. 2). This is the first
study to demonstrate, however, that improvements in EET occurred in tandem with a delay
in the onset of intolerable dyspnea. The range
of symptom improvement was variable (Fig. 2),
and there was no significant mean reduction
of dyspnea intensity ratings during exercise
after inhalation of fentanyl citrate (Fig. 1).
However, post hoc examination of dyspnea
time plots (Fig. 1) revealed that the mean
rate of increase in dyspnea intensity between
isotime and peak exercise was reduced by
w60% (P ¼ 0.03) after treatment with fentanyl
citrate vs. placebo (Fig. 2). Dyspnea is a complex symptom, and its affective dimension is
believed to reflect neural activation of limbic
and paralimbic sites in the brain in response
to perceived threatened respiratory status.61,62
Unpleasantness ratings fell by w80% (P ¼
0.06) near end exercise after inhalation of fentanyl citrate (Figs. 1 and 2); thus, patients were
able to increase ventilation from isotime to
peak exercise with less perceived unpleasantness of their breathing after treatment with
fentanyl citrate vs. placebo. The intensity of
perceived leg discomfort near end exercise
also was diminished after inhalation of fentanyl citrate vs. placebo (Fig. 1); however, this difference was not statistically significant. We
considered the following possible mechanisms
Jensen et al.
5
0.5
4
0.4
3
2
†
1
Isotime IC dyn (L)
0.2
†
0.1
4
5
6
7
8
9
10
11
12
2
1
0
-1
-2
*
-3
-4
-5
-6
2
3
4
5
6
7
8
9
10
11
12
Subject Number
Mean
-7
1
-0.1
1
2
3
4
5
6
7
8
9
10
11
12
Subject Number
Mean
3
Dyspnea Unpleasantness (Bu/minutes)
2
Mean
1
Subject Number
Dyspnea Intensity (Bu/minutes)
0.3
0.0
0
-1
Vol. 43 No. 4 April 2012
2
0
-2
‡
-4
-6
-8
-10
-12
1
2
3
4
5
6
7
Subject Number
8
9
10
11
12
Mean
EET (minutes)
714
Fig. 2. Individual subject and mean postdose differences in EET, Isotime ICdyn, and the increase in exertional
dyspnea intensity and unpleasantness ratings between isotime and peak exercise after single-dose inhalation of
nebulized fentanyl citrate (50 mcg) vs. placebo. yP # 0.01; *P < 0.05; zP ¼ 0.06. Isotime ICdyn ¼ dynamic inspiratory capacity at isotime; Bu ¼ Borg units; EET ¼ exercise endurance time.
of exertional dyspnea relief and improved exercise tolerance: 1) reduced central ventilatory
drive, 2) improved airway function, 3) altered
perception of dyspnea via central mechanisms,
4) altered peripheral opioid activity, or 5) some
combination thereof.
Ventilatory responses to exercise were similar
after fentanyl citrate and placebo treatments,
with no evidence of respiratory depression
(Fig. 3, Table 2). Thus, reduced central ventilatory drive, which is known to be associated with
exertional dyspnea relief in COPD after oral
morphine administration15 and hyperoxia,63e65
is unlikely to explain exertional dyspnea relief after inhalation of fentanyl citrate. The extent to
which fentanyl citrate was absorbed into the systemic circulation was not quantified in this study.
Worsley et al.66 reported mean peak serum fentanyl concentrations of just 0.04 ng/mL and
0.1 ng/mL, indicating very low systemic bioavailability, after inhalation of 100 mcg and 300 mcg
of nebulized fentanyl, respectively. It is unlikely,
therefore, that the comparatively low dose of inhaled fentanyl citrate (50 mcg) used in our study
resulted in significant systemic absorption. However, one of the 16 patients enrolled in the
present study developed symptoms compatible
with the known side effects of opioid ingestion.
Therefore, we cannot rule out the possibility of
fentanyl citrate-induced alterations of central
nervous system activity (independent of respiratory depression) as a result of systemic absorption of the drug. It is reasonable to assume that
systemic absorption rates of inhaled medications
may be variable across patients with COPD.
Inhaled nebulized opioids selective for the
m-opioid receptor subtype, which have been
identified on vagal afferent nerves in both humans and animals, may have beneficial effects
on the neuromodulation of bronchomotor
tone.17,20e31 We found no evidence of improved
airway function in association with inhalation of
fentanyl citrate; that is, no differences in resting
airway resistance, expiratory flow rates, or plethysmographic lung volumes were observed between the active drug and placebo (Table 3).
Surprisingly, we measured small but consistent
increases in ICdyn by an average of 0.11 L at isotime (P < 0.01) and by 0.08 L at peak exercise
(P ¼ 0.03) after treatment with inhaled fentanyl
citrate compared with placebo (Figs. 2 and 3).
The magnitude of benefit of inhaled fentanyl
Effect of Inhaled Fentanyl Citrate on Exercise Endurance in COPD
55
1.5
50
1.4
45
1.3
Tidal Volume (L)
Ventilation (L/minutes)
Vol. 43 No. 4 April 2012
40
35
30
25
20
Fentanyl Citrate
15
Placebo
1.2
1.1
1.0
0.9
0.8
0.7
0.6
10
0.5
0
1
2
3
4
5
6
7
8
9
0
1
40
2.5
38
2.4
Inspiratory Capacity (L)
Breathing Frequency (bpm)
2
3
4
5
6
7
8
9
Exercise Time (minutes)
Exercise Time (minutes)
36
34
32
30
28
26
24
22
20
2.3
2.2
2.1
*
2.0
*
1.9
1.8
1.7
1.6
1.5
18
0
1
2
3
4
5
6
7
8
0
9
1
2
Exercise Time (min)
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0
1
2
3
4
5
6
3
4
5
6
7
8
9
Exercise Time (minutes)
Inspiratory Reserve Volume (L)
Expiratory Time (seconds)
715
7
8
Exercise Time (minutes)
9
0.0
TLC
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0
1
2
3
4
5
6
7
8
9
Exercise Time (minutes)
Fig. 3. Ventilatory, breathing pattern and operating lung volume responses (mean SEM) to constant work rate
cycle exercise at 75% of Wmax after inhalation of nebulized fentanyl citrate (50 mcg) or placebo. *P < 0.05 fentanyl citrate vs. placebo. SEM ¼ standard error of the mean; TLC ¼ total lung capacity; Wmax ¼ maximum incremental cycle work rate.
citrate on ICdyn is w30% of that reported after
acute administration of various inhaled bronchodilators in patients with COPD.13,46,63,67e69
Improvement of ICdyn during exercise is believed to reflect reduction in dynamic pulmonary hyperinflation, provided TLC remains
unchanged. Increased ICdyn in the later phase
of exercise after inhalation of fentanyl citrate
could not be explained by concurrent alterations in the timing components of breathing
(i.e., prolonged expiratory time or increased
mean tidal expiratory flow rates [Fig. 3,
Table 2]), which facilitate lung emptying.
Increased ICdyn and tidal volume expansion
are well-established effects of lung volume
deflation after bronchodilator therapy in patients with COPD.13,46,63,67e69 Small isolated
increases of ICdyn in association with fentanyl
citrate inhalation in the absence of evidence
of improved airway function or breathing pattern are more difficult to interpret. One possibility is that, in conjunction with increased
tolerance of physical exertion and perceived
respiratory discomfort, patients were able to
generate more effective maximal inspiratory
efforts during the IC maneuver to a slightly
higher TLC after inhalation of fentanyl citrate.
Alternatively, altered vagal afferent nerve activity secondary to topical application of fentanyl
citrate could lead to changes in the behavior
716
Jensen et al.
Table 3
Postdose Pulmonary Function Test Parameters
Parameter
FEV1, L
FEV1/FVC, %
FVC, L
PEFR, L/second
FEF25%e75%, L/second
TLC, L
SVC, L
IC, L
FRC, L
RV, L
sRaw, cm H2O/second
Placebo
Fentanyl
Citrate
P-value
1.44 0.15
45.5 2.3
3.12 0.22
4.5 0.5
0.48 0.09
6.17 0.35
3.16 0.23
2.24 0.19
3.93 0.22
3.01 0.22
22.2 2.8
1.45 0.16
45.8 2.6
3.13 0.23
4.6 0.5
0.49 0.09
6.09 0.35
3.18 0.24
2.24 0.20
3.85 0.23
2.91 0.19
21.3 2.6
0.68
0.67
0.83
0.58
0.59
0.10
0.68
0.95
0.11
0.12
0.34
FEV1 ¼ forced expiratory volume in one second; FVC ¼ forced vital
capacity; PEFR ¼ peak expiratory flow rate; FEF25%e75% ¼ forced
expiratory flow between 25% and 75% of FVC; TLC ¼ total lung
capacity; SVC ¼ slow vital capacity; IC ¼ inspiratory capacity;
FRC ¼ functional residual capacity; RV ¼ residual volume; sRaw ¼
specific airways resistance.
Values are means standard error of the mean.
of dynamic end-expiratory lung volume during exercise.70,71
What could explain the improved symptom tolerance after inhalation of fentanyl citrate in the absence
of any improvement in resting pulmonary function or
ventilatory demand, breathing pattern, pulmonary
gas exchange, and/or cardiometabolic function during exercise? By exclusion, the most likely explanation is 1) a central behavioral effect of the
drug, 2) modulation of peripheral afferent inputs from opioid receptors in the airways and
lungs, or 3) a combination of both. Mahler
et al.16 recently demonstrated that, compared
with placebo, intravenous administration of naloxone (a nonselective opioid receptor antagonist that readily crosses the blood-brain
barrier) decreased EET by w1.7 minutes and
increased dyspnea intensity VO2 slopes by
w35% during high-intensity CWR treadmill exercise in COPD, despite no concomitant change
in the cardiorespiratory response to exercise. It
follows that the improved symptom tolerance
after treatment with the exogenous m-opioid receptor agonist in our study may be due, at least
in part, to altered central neural processing of
dyspneogenic stimuli as a result of systemic absorption of the drug. Indeed, functional magnetic resonance imaging studies have recently
demonstrated an effect of intravenous remifentanil (a m-opioid receptor agonist) administration on neuronal activation of cortical and
subcortical regions of the brain72e74 known
to be involved in respiratory sensation.61,62
Another potential mechanism of symptom
Vol. 43 No. 4 April 2012
relief involves a direct effect of inhaled fentanyl
citrate on opioid receptors localized within
the conducting airways (trachea and main
bronchus) and lung parenchyma of human
and animal lungs.17e19,32e37 In this way, topical
application of fentanyl citrate may have contributed to improvements in EET and exertional
dyspnea by modulating feedback information
from multiple sensory afferents (e.g., pulmonary stretch receptors, bronchopulmonary
C-fibers, juxtapulmonary capillary receptors)
located in the airways and lungs of our patients.
Unfortunately, the ability to quantify possible
central and peripheral influences of inhaled
opioid administration on respiratory sensation
in conscious humans is currently limited.
Limitations
Strictly speaking, this is not a clinical trial but
rather a mechanistic physiological study with
a small sample size (n ¼ 12) that used a rigorous
experimental design to evaluate the efficacy of
inhaled fentanyl citrate on exertional dyspnea
and exercise tolerance in symptomatic patients
with COPD. In this regard, we caution against
the extrapolation of our results to current or potential use of inhaled fentanyl citrate to treat or
manage intractable symptoms in the clinical/
palliative care setting, particularly at rest and/
or in patient populations other than COPD. It
is possible that the lack of salutary effect of inhaled fentanyl citrate on our primary efficacy
variable, dyspnea intensity at isotime, reflects,
at least in part, a Type II statistical error that
more subjects may have overcome. However,
we recruited a sample size from which we could
detect a clinically relevant difference in exertional dyspnea intensity ratings of 1 Borg
unit based on an a priori power calculation. Although consistent within-subject and mean
postdose differences in our secondary efficacy
variable, EET, were observed after treatment
with fentanyl citrate vs. placebo (Fig. 2), we cannot preclude the possibility of a Type I statistical
error. We examined acute responses to a single
dose of inhaled fentanyl citrate and cannot extrapolate these results to regular long-term use
of this medication or its safety. Our dose selection was arbitrary: the optimal dose and the
most effective mode of nebulization of inhaled
opioids are not firmly established and will undoubtedly influence success rates of symptom
alleviation.
Vol. 43 No. 4 April 2012
Effect of Inhaled Fentanyl Citrate on Exercise Endurance in COPD
Summary
In conclusion, single-dose inhalation of
nebulized fentanyl citrate (50 mcg) was associated with significant and potentially clinically
important improvements in exercise endurance during high-intensity CWR cycle exercise
in symptomatic patients with mild-to-severe
COPD. These acute improvements in exercise
tolerance were accompanied by reduced intensity and unpleasantness ratings of exertional
dyspnea near the limits of tolerance. The increased tolerance to the stress of physical exertion and dyspnea occurred in the absence of
alterations in ventilatory demand, breathing
pattern, or dynamic airway function and points
to alternative, but poorly understood, central
and/or peripheral influences of inhaled fentanyl citrate on respiratory sensation. The results of this study, therefore, support the
rationale for future scrutiny of inhaled nebulized fentanyl citrate as a therapeutic intervention to complement existing therapies for the
management of exertional symptoms in selected patients with COPD.
Disclosures and Acknowledgments
Financial support was provided by the Department of Medicine Research Awards Program and the Michael J. Raftis Palliative
Care Development Fund, Queen’s University
and Kingston General Hospital. D. Jensen
was supported by a Canadian Thoracic Society/Canadian Lung Association Post-Doctoral
Research Fellowship Awards and a Queen’s
University Post-Doctoral Fellow Excellence in
Research Award. The funding sources were
not involved in study design or in the conduct of the study or development of the submission. None of the authors have any real or
perceived financial or personal relationships
with individuals, organizations, or companies
to disclose.
References
717
management of chronic obstructive pulmonary diseased2007 update. Can Respir J 2007;14:5Be32B.
3. Brown SJ, Eichner SF, Jones JR. Nebulized morphine for relief of dyspnea due to chronic lung disease. Ann Pharmacother 2005;39:1088e1092.
4. Foral PA, Malesker MA, Huerta G, Hilleman DE.
Nebulized opioids use in COPD. Chest 2004;125:
691e694.
5. Varkey B. Opioids for palliation of refractory
dyspnea in chronic obstructive pulmonary disease.
Curr Opin Pulm Med 2010;16:150e154.
6. Harris-Eze AO, Sridhar G, Clemens RE, et al.
Low-dose nebulized morphine does not improve exercise in interstitial lung disease. Am J Respir Crit
Care Med 1995;152:1940e1945.
7. Young IH, Daviska E, Keena VA. Effect of low
dose nebulised morphine on exercise endurance
in patients with chronic lung disease. Thorax
1989;44:387e390.
8. Masood AR, Reed JW, Thomas SHL. Lack of effect of inhaled morphine on exercise-induced
breathlessness in chronic obstructive pulmonary disease. Thorax 1995;50:629e634.
9. Beauford W, Saylor TT, Stansbury DW, Avalos K,
Light RW. Effects of nebulized morphine sulphate
on the exercise tolerance of the ventilatory limited
COPD patient. Chest 1993;104:175e178.
10. Leung R, Hill P, Burdon J. Effect of inhaled
morphine on the development of breathlessness
during exercise in patients with chronic lung disease. Thorax 1996;51:596e600.
11. Jankelson D, Hosseini K, Mather LE, Seale JP,
Young IH. Lack of effect of high doses of inhaled
morphine on exercise endurance in chronic obstructive pulmonary disease. Eur Respir J 1997;10:
2270e2274.
12. Jennings AL, Davis AN, Higgins JPT, AnzuresCabrera J, Broadley KE. Opioids for the palliation
of breathlessness in terminal illness. Cochrane Database Syst Rev 2001;(4):CD002066.
13. Oga T, Nishimura K, Tsukino M, et al. The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive
pulmonary disease. A comparison of three different
exercise tests. Am J Respir Crit Care Med 2000;161:
1897e1901.
14. Coyne PJ, Viswanathan R, Smith TJ. Nebulized
fentanyl citrate improves patients’ perception of
breathing, respiratory rate, and oxygen saturation
in dyspnea. J Pain Symptom Manage 2002;23:
157e160.
1. Jones PW. Health status measurement in
chronic obstructive pulmonary disease. Thorax
2001;56:880e887.
15. Light RW, Muro JR, Sata SI, et al. Effects of oral
morphine on breathlessness and exercise tolerance
in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989;139:126e133.
2. O’Donnell DE, Aaron S, Bourbeau J, et al.
Canadian Thoracic Society recommendations for
16. Mahler DA, Murray JA, Waterman LA, et al.
Endogenous opioids modify dyspnea during
718
Jensen et al.
treadmill exercise in patients with COPD. Eur
Respir J 2009;33:771e777.
17. Zebraski SE, Kochenash SM, Raffa RB. Lung
opioid receptors: pharmacology and possible target
for nebulized morphine in dyspnea. Life Sci 2000;
66:2221e2231.
18. Krajnik M, Schafer M, Sobanksi P, et al. Local
pulmonary opioid network in patients with lung
cancer: a putative modulator of respiratory function. Pharmacol Rep 2010;62:139e149.
19. Krajnik M, Schafer M, Sobanksi P, et al. Enkephalin, its precursor, processing enzymes, and receptor
as part of a local opioid network throughout the respiratory system of lung cancer patients. Hum Pathol 2010;41:632e642.
20. Belvisi MG, Hele DJ. Cough sensors. III. Opioid
and cannabinoid receptors on vagal sensory nerves.
Handb Exp Pharmacol 2009;187:63e76.
21. Belvisi MG, Stretton CD, Verleden GM, et al.
Inhibition of cholinergic neurotransmission in
human airways by opioids. J Appl Physiol 1992;72:
1096e1100.
22. Patel HJ, Venkatesan P, Halfpenny J, et al. Modulation of acetylcholine release from parasympathetic nerves innervating guinea-pig and human
trachea by endomorphin-1 and -2. Eur J Pharmacol
1999;374:21e24.
23. Johansson IG, Grundstrom N, Andersson RG.
Both the cholinergic and non-cholinergic components of airway excitation are inhibited by morphine in the guinea-pig. Acta Physiol Scand 1989;
135:411e415.
24. Belvisi MG, Stretton CD, Barnes PJ. Modulation
of cholinergic neurotransmission in guinea-pig airways by opioids. Br J Pharmacol 1990;100:131e137.
25. Pype JL, Dupont LJ, Demedts MG,
Verleden GM. Opioids modulate the cholinergic
contraction but not the nonadrenergic relaxation
in guinea-pig airways in vitro. Eur Respir J 1996;9:
2280e2285.
26. Zappi L, Nicosia F, Rocchi D, Song P, Rehder K.
Opioid agonists modulate release of neurotransmitters in bovine trachealis muscle. Anesthesiology
1995;83:543e551.
27. Zappi L, Song P, Nicosia S, Nicosia F, Rehder K.
Inhibition of airway constriction by opioids is different down the isolated bovine airway. Anesthesiology
1997;86:1334e1341.
28. Yu Y, Cui Y, Wang W, et al. Endomorphin1 and
endomorphin2, endogenous potent inhibitors of
electrical field stimulation (EFS)-induced cholinergic contractions of rat isolated bronchus. Peptides
2006;27:1846e1851.
29. Tagaya E, Tamaoki J, Chiyotani A, Konno K.
Stimulation of opioid mu-receptors potentiates
beta adrenoceptor-mediated relaxation of canine
airway smooth muscle. J Pharmacol Exp Ther
1995;275:1288e1292.
Vol. 43 No. 4 April 2012
30. Frossard N, Barnes PJ. Mu-opioid receptors modulate non-cholinergic constrictor nerves in guineapig airways. Eur J Pharmacol 1987;141:519e522.
31. Belvisi MG, Chung KF, Jackson DM, Barnes PJ.
Opioid modulation of non-cholinergic neural bronchoconstriction in guinea-pig in vivo. Br J Pharmacol 1988;95:413e418.
32. Sapru HN, Willette RN, Krieger AJ. Stimulation
of pulmonary J receptors by an encephalin-analog.
J Pharmacol Exp Ther 1981;217:228e234.
33. Willette RN, Sapru HN. Peripheral versus central cardiorespiratory effects of morphine. Neuropharmacology 1982;21:1019e1026.
34. Willette RN, Sapru HN. Pulmonary opiate receptor activation evokes a cardiorespiratory reflex.
Eur J Pharmacol 1982;78:61e70.
35. Willette RN, Gatti P, Gertner SB, Sapru HN. Pulmonary vagal afferent stimulants in the conscious
rat: opioids and phenyldiguanide. Pharmacol Biochem Behav 1982;17:19e23.
36. Bhargava HN, Villar VM, Cortijo J, Morcillo EJ.
Binding of [H3][D-Ala2, MePhe4, Gly-ol5] endkephalin, [H3][D-Pen2, D-Pen5] encephalin, and [H3]U69,593 to airway and pulmonary tissues of normal
and sensitized rats. Peptides 1997;18:1603e1608.
37. Cabot PJ, Dodd PR, Cramond T, Smith MT.
Characterization of non-conventional opioid binding sites in rat and human lung. Eur J Pharmacol
1994;268:247e255.
38. Mahler DA, Weinberg DH, Wells CK,
Feinstein AR. The measurement of dyspnea: contents,
interobserver agreement, and physiologic correlates
of two new clinical indexes. Chest 1984;85:751e758.
39. Stoller JK, Ferranti R, Feinstein AR. Further
specification and evaluation of a new clinical index
for dyspnea. Am Rev Respir Dis 1986;135:
1129e1134.
40. McGavin
CR,
Artvinli
M,
Naoe
H,
McHardy GJR. Dyspnoea, disability, and distance
walked: comparison of estimates of exercise performance in respiratory disease. Br Med J 1978;2:
241e243.
41. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention
of chronic obstructive pulmonary disease: GOLD
executive summary. Am J Respir Crit Care Med
2007;176:532e555.
42. Jones PW, Quirk FH, Baveystock CM,
Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s
Respiratory Questionnaire. Am Rev Respir Dis
1992;145:1321e1327.
43. Zigmond AS, Snaith RP. The Hospital Anxiety
and Depression Scale. Acta Psychiatr Scand 1983;
67:361e370.
44. American Thoracic Society and American College of Chest Physicians. ATS/ACCP statement on
Vol. 43 No. 4 April 2012
Effect of Inhaled Fentanyl Citrate on Exercise Endurance in COPD
cardiopulmonary exercise testing. Am J Respir Crit
Care Med 2003;167:211e277.
45. Roca J, Whipp BJ, Agusti AGN, et al. Clinical exercise testing with reference to lung diseases: indications, standardization and interpretation strategies.
ERS Task Force on Standardization of Clinical Exercise Testing. Eur Respir J 1997;10:2662e2689.
46. O’Donnell DE, Lam M, Webb KA. Measurement
of symptoms, lung hyperinflation and endurance during exercise in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 1998;158:1557e1565.
47. O’Donnell DE, Revill SM, Webb KA. Dynamic
hyperinflation and exercise intolerance in chronic
obstructive pulmonary disease. Am J Respir Crit
Care Med 2001;164:770e777.
48. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377e381.
49. Miller MR, Crapo R, Hankinson J, et al. General
considerations for lung function testing. Eur Respir
J 2005;26:153e161.
50. Miller MR, Hankinson J, Brusasco V, et al.
Standardisation of spirometry. Eur Respir J 2005;
26:319e338.
51. MacIntyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J
2005;26:720e735.
52. American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory
muscle testing. Am J Respir Crit Care Med 2002;
166:518e624.
53. Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur
Respir J 2005;26:511e522.
54. Morris JF, Koski A, Temple WP, Claremont A,
Thomas DR. Fifteen-year interval spirometric evaluation of the Oregon predictive equations. Chest 1988;
92:123e127.
55. Crapo RO, Morris AH, Clayton PD, Nixon CR.
Lung volumes in healthy nonsmoking adults. Bull
Eur Physiopathol Respir 1982;18:419e425.
719
60. Blackie SP, Fairbarn MS, McElvaney GN, et al.
Prediction of maximal oxygen uptake and power during cycle ergometry in subjects older than 55 years of
age. Am Rev Respir Dis 1989;139:1424e1429.
61. Davenport PW, Vovk A. Cortical and subcortical
central neural pathways in respiratory sensations.
Respir Physiol Neurobiol 2009;167:72e86.
62. von Leuopoldt A, Dahme B. Cortical substrates for
the perception of dyspnea. Chest 2005;128:345e354.
63. Peters MM, Webb KA, O’Donnell DE. Combined physiological effects of bronchodilators and
hyperoxia on exertional dyspnea in normoxic
COPD. Thorax 2006;61:559e567.
64. Somfay A, Porzasz SML, Casaburi R. Doseresponse effect of oxygen on hyperinflation and exercise endurance in nonhypoxemic COPD patients.
Eur Respir J 2001;18:77e84.
65. O’Donnell DE, D’Arsigny C, Webb KA. Effects
of hyperoxia on ventilatory limitation during exercise in advanced COPD. Am J Respir Crit Care
Med 2001;163:892e898.
66. Worsley MH, Macleod AD, Brodie MJ,
Asbury AJ, Clark C. Inhaled fentanyl as a method
of analgesia. Anaesthesia 1990;45:449e451.
67. O’Donnell DE, Fl€
uge T, Gerken F, et al. Effects
of tiotropium on lung hyperinflation, dyspnea and
exercise tolerance in COPD. Eur Respir J 2004;23:
832e840.
68. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA.
Effect of salmeterol on the ventilatory response to exercise in COPD. Eur Respir J 2004;24:86e94.
69. Oga T, Nishimura K, Tsukino M, et al.
A comparison of the effects of salbutamol and ipratropium bromide on exercise endurance in patients
with COPD. Chest 2003;123:1810e1816.
70. O’Donnell DE, Sanii R, Anthonisen NR,
Younes M. Effect of dynamic airway compression
on breathing pattern and respiratory sensation in
severe chronic obstructive pulmonary disease. Am
Rev Respir Dis 1987;135:912e918.
56. Burrows B, Kasik JE, Niden AH, Barclay WR. Clinical usefulness of the single-breath pulmonary diffusing capacity test. Am Rev Respir Dis 1961;84:789e806.
71. Pellegrino R, Brusasco V, Rodarte JR, Babb TG.
Expiratory flow limitation and regulation of endexpiratory lung volume during exercise. J Appl
Physiol 1993;74:2552e2558.
57. Briscoe WA, Dubois AG. The relationship between airway resistance, airway conductance, and
lung volumes in subjects of different age and body
size. J Clin Invest 1959;37:1279e1285.
72. Pattinson KTS, Governo RJ, MacIntosh BJ, et al.
Opioids depress cortical centers responsible for the
volitional control of respiration. J Neurosci 2009;29:
8177e8186.
58. Hamilton AL, Killian KJ, Summers E, Jones NL.
Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders.
Am J Respir Crit Care Med 1995;152:2021e2031.
73. Pattinson KTS, Rogers R, Mayhew SD, Tracey I,
Wise RG. Pharmacological FMRI: measuring opioid
effects on the BOLD response to hypercapnia.
J Cereb Blood Flow Metab 2007;27:414e423.
59. Ries AL. Minimally clinically important difference
for the UCSD Shortness of Breath Questionnaire,
Borg Scale, and Visual Analog Scale. COPD 2005;2:
105e110.
74. Leppa M, Korvenoja A, Carlson S, et al. Acute
opioid effects on human brain as revealed by functional magnetic resonance imaging. Neuroimage
2006;31:661e669.