British Journal of Clinical DOI:10.1111/j.1365-2125.2010.03700.

Pharmacology

Correspondence
Different effects of Mrs Anne Estrup Olesen MSc (Pharm)
PhD, Mech-Sense, Department of
Gastroenterology, Aalborg Hospital,
morphine and oxycodone in Aarhus University Hospital, Hobrovej
18-22, 9000 Aalborg, Denmark.
Tel.: +45 9932 6243
experimentally evoked Fax: +45 9932 6507
E-mail: [email protected]

hyperalgesia: a human
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Keywords
experimental model, hyperalgesia,

translational study morphine, oxycodone, pain

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Received
11 August 2009
Anne Estrup Olesen,1,2 Camilla Staahl,1,2 Lars Arendt-Nielsen2 & Accepted
Asbjørn Mohr Drewes1,2 31 March 2010

1
Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital and
2
Center for Sensory-Motor Interactions (SMI), Department of Health Science and Technology, Aalborg
University, Aalborg, Denmark

WHAT IS ALREADY KNOWN ABOUT

THIS SUBJECT
• Previous studies using short-lasting AIM
experimental pain stimulations in healthy Similar analgesics may have different analgesic potencies especially in
patients in whom the pain system is sensitized. The aim was to
volunteers have shown differences in opioid
investigate different opioid effects on experimental pain after the
effects regarding visceral pain stimulations. sensitized pain system was mimicked evoking hyperalgesia in healthy
However, these differences can be more volunteers.
pronounced in patients due to a sensitized
pain system. Therefore, the aim of the METHODS
present study was to mimic the clinical Twenty-four healthy volunteers were randomized to treatment with
morphine (30 mg orally) and oxycodone (15 mg orally) or placebo
situation by investigating opioid effects on
in a double-blind crossover study. Hyperalgesia was induced by
experimental pain in healthy volunteers oesophageal perfusion with acid and capsaicin. Several exploratory
after experimentally evoked hyperalgesia. endpoints were studied using skin heat, muscle pressure and
oesophageal mechanical, heat and electrical stimulation. Effects on
pain from deeper structures were considered most important.
WHAT THIS STUDY ADDS? RESULTS
• We now know that morphine and Different analgesic potencies were found. Oxycodone had a greater
oxycodone exerts different effects in the analgesic effect than morphine attenuating pain from: (i) heat
sensitized pain system as we found a stimulation of skin (P = 0.016); difference between the means of 0.39°C,
greater analgesic effect of oxycodone in 95% CI 0.22, 2.09. (ii) muscle pressure (P < 0.001); difference between
response to skin, muscle and oesophageal the means of 11.93kPa, 95% CI 5.4, 18.5. (iii) oesophageal heat
stimulation (P < 0.001); difference between the means of 38.54 cm2,
pain stimulation. This supports clinicians’
95% CI 15.37, 61.71 and (iv) oesophageal electrical stimulation (P =
experiences that oxycodone can be superior 0.016); difference between the means of 6.69mA, 95% CI 1.23, 12.13.
to morphine in the treatment of some pain
conditions. The evoked hyperalgesia CONCLUSION
bridged findings from studies in healthy After sensitization of the pain system different analgesic potencies of
volunteers to patients, and new morphine and oxycodone were found in response to skin, muscle and
oesophageal pain stimulation, in which oxycodone had a greater
fundamental knowledge on different
effect. As similar differential analgesic potencies of the two opioids
analgesic effects in hyperalgesia was found. have been found in patients with chronic pain, the experimental
hyperalgesia model bridged findings from studies in healthy volunteers
to patients.

© 2010 The Authors Br J Clin Pharmacol / 70:2 / 189–200 / 189

Journal compilation © 2010 The British Pharmacological Society
 A. E. Olesen et al.

Introduction inflammatory processes and changes in the pain system

that are seen in the clinic [29, 30].
Chronic pain is most often associated with hyperalgesia We hypothesized that an experimental human transla-
which is difficult to treat [1, 2]. Different opioids are used tional pain model including hyperalgesia in volunteers
in chronic pain treatment. However, the clinical signifi- could mimic the sensitized pain system in patients provid-
cance of the potential effects of opiates on inflammatory ing knowledge on the potential analgesic effects of
processes is unclear [3]. Inflammation can effectuate opiates in inflammation. Such a model could bridge find-
changes in the pain systems [4–7]. These changes may ings from experimental pain studies in healthy volunteers
include up-regulation of specific opioid receptors [8–11]. to those in patients. The aims were: (i) to investigate
Animal studies have shown that opioid-binding to whether morphine and oxycodone, compared with
k-receptor sites is increased in inflammation likely caused placebo, had differential analgesic potencies after experi-
by up-regulation of k-receptors in the nervous system [8, mentally induced hyperalgesia and (ii) to validate whether
12]. This may have clinical impact for some opioids, i.e. this effect varied between tissues.
morphine and oxycodone which are thought to have dif-
ferent pharmacological profiles [13]. Hence, morphine
binds to the m-opioid receptor with stronger affinity and Methods
rodent experiments have indicated that oxycodone is a
partial k-agonist [14–18]. This could cause different anal- The study was conducted according to the Declaration of
gesic potencies of morphine and oxycodone in diseases Helsinki. The Ethics Committee for the Region of Northern
with inflammation. Jutland (N-20070025) and the Danish Medicines Agency
Application of experimental pain models in a crossover (2612-3463) approved the study.The study was conducted
study design with appropriate baseline recordings offers a according to the rules of Good Clinical Practice (GCP)
unique opportunity of revealing analgesic effects [19]. It and was monitored by the GCP-unit, Aarhus University
has been recommended to include pain models in various Hospital, Denmark.
tissues, as opioid analgesia can exhibit tissue dissimilarities
[20]. Moreover, different modalities activate distinct pain Subjects and study design
mechanisms, and make it possible to investigate on a The reliability and sensitivity of the experimental tests
mechanistic basis how analgesics work [20]. However, the have been evaluated previously [19]. In a similar study 24
effect on pain from deeper structures (muscle and viscera) healthy volunteers have been sufficient to reveal different
is considered most important as opioid analgesia is more analgesic effects of morphine and oxycodone [21].Thus 24
robust in deep pain [20]. In a previous experimental pain healthy Caucasian (12 females), opioid-naïve volunteers
study in healthy volunteers morphine and oxycodone (mean age 27.8, range 20–48 years) participated in this
were comparable in analgesic potency in the modulation randomized, placebo-controlled, double-blind, three-way
of skin and muscle pain, but oxycodone showed a greater crossover study of Latin square design. The study was
analgesic potency on visceral pain [21]. Chronic pancreati- carried out in the Research Laboratory at ‘Mech-Sense’,
tis is characterized by long lasting inflammation, hyperal- Department of Gastroenterology, Aalborg Hospital,
gesia and pain [22]. Subsequently an experimental pain Denmark. The subjects were informed about the possible
study was performed in patients with chronic pancreatitis risks of the study, gave their informed consent and were
where oxycodone was more potent than morphine in paid for participation. Medical examinations prior to the
attenuating the same experimental skin, muscle and vis- study were normal and all females used contraceptives
ceral pain in patients [23]. This supports the theory of dif- and a pregnancy test was negative in all study periods. All
ferent analgesic potencies of morphine and oxycodone volunteers were trained and familiarized with all pain
when hyperalgesia is present. stimulations on a screening day, which took place at least 1
Pain experienced and reported by healthy volunteers is week before the first study day. Each volunteer fasted for at
different from clinical pain, and in the laboratory it is not least 4 h prior to the study. The subjects were monitored
possible to reproduce the pathophysiology and the full with an electrocardiogram during the entire study.
complexity of the pain experience in patients [4, 24]. On When the subject arrived at the laboratory, blood pres-
the other hand, hyperalgesia, being a hallmark of clinical sure and pulse were registered and a probe designed for
pain, can be evoked experimentally in healthy volunteers multimodal stimulation of the oesophagus was inserted
by sensitizing the oesophagus with capsaicin or acid through the mouth. A bag was mounted on the end of the
[25–27]. Moreover, local sensitization of the oesophagus probe and placed 8 cm proximal to the lower oesophageal
can evoke generalized hyperalgesia reported as increased sphincter. The probe was taped to the chin. The probe has
sensitivity in other organs and tissues than the affected been described in detail previously [26, 31]. The skin and
one [27–29]. However, experimental pain models with muscular pain stimulation devices were positioned.
hyperalgesia are more difficult to control than simple and Figure 1 illustrates the study design. Pain recordings were
short lasting pain stimuli, but may initiate some of the obtained before (baseline, to obtain values before any

190 / 70:2 / Br J Clin Pharmacol

 Opioid analgesia in experimental hyperalgesia

Pain test

Oesophagus
3. Heat
4. Mechanical
5. Electrical

Skin Analgesic effect

1. Heat

Muscle
2. Deep
pressure Pain tests Pain tests Pain tests Pain tests
Baseline 30 60 90 Time (min)
a. Chemical perfusion of oesophagus
b. Drug administration

Figure 1
Flow-chart for the study protocol. A schematic illustration of the pain tests is shown on the left. Pain tests were performed in the order illustrated by the
numbers. The order was similar for all stimulation series and between days and consisted of heat stimulation of the skin, mechanical stimulation of the
muscle and heat, mechanical and electrical stimulation of the oesophagus.The graph (right) shows a schematic illustration of the analgesic effect. Pain tests
were performed at baseline after which hyperalgesia was induced and the drug administered. Pain tests were performed 30, 60 and 90 min after baseline.
Drug administration included either placebo, morphine (30 mg) or oxycodone (15 mg) in randomized order

drug was given) and 30, 60 and 90 min after induction of mixture 2 mg ml-1, Hospital Pharmacies, Denmark) or
hyperalgesia and drug administration. Pain was assessed 15 mg oxycodone (Oxynorm® oral liquid mixture
from skin, muscle and oesophageal stimulations following 10 mg ml-1, Norpharma A/S, Hørsholm, Denmark) or
the same order for all stimulation series as illustrated in placebo in randomized order (all masked in colour by 5 ml
Figure 1. Subjects were blinded to all thresholds measured. orange juice concentrate and diluted with water to a total
This schedule should ensure sufficient testing throughout of 20 ml liquid). The drugs were given immediately after
the opioid absorption phase and the beginning of the baseline pain recordings. The colour of the mixture was
elimination phase without extending the test period too masked in the orange juice and the mixture was infused
much [32, 33]. The degrees of four known adverse effects, through a catheter inside the probe ending in the distal
nausea, dizziness, itching and sweating, were registered as oesophagus.The mixture was handled by a pharmacist not
(1) none, (2) slight, (3) heavy or (4) intolerable and specifi- otherwise involved in the study to ensure blinding of all
cally asked for after each pain test battery. Moreover, the other investigators.
degree of sedation was evaluated after each pain test The dose of morphine was twice that of oxycodone.The
battery by the finger tapping test. If the subject was rationale was that the greater oral bioavailability of imme-
sedated or otherwise feeling unwell during the study, diate release oxycodone compared with morphine, and
blood pressure and pulse were measured again to ensure more rapid onset of analgesia could result in superior
that everything was normal before the study continued. If effects of oxycodone [34]. Thus, we chose a relatively high
the subject felt dizzy, nauseated or otherwise indisposed at dose of morphine to be sure that differences in bioavail-
the end of the study they were observed in the laboratory ability did not favour oxycodone. Furthermore, the two
until the adverse effect ceased and they felt ready to leave. doses have previously showed comparable analgesic
The experiment was repeated three times with at least 1 potencies in experimental skin and muscle pain [21].
week ‘wash-out’ intervals. The randomized order should
deal with periodic effects e.g. learning effects, carry-over Skin stimulation
and interference effects. Hence bias from such effects The cutaneous heat pain tolerance threshold was deter-
would be evenly distributed in the three treatment periods. mined by a computer driven heat pain device (TSA-II Neu-
roSensory Analyzer, Medoc Ltd, Ramat Yishai, Israel). A
Medication thermode with a surface of 25 ¥ 50 mm was applied to the
Each subject was investigated in three separate periods volar surface of the left forearm at 10 cm from the elbow.
and received 30 mg of morphine (morphine oral liquid The temperature increased from 32°C to a maximum of

Br J Clin Pharmacol / 70:2 / 191

 A. E. Olesen et al.

52°C at a rate of 1°C s-1 until the threshold was reached. nomic reactions leading to vomiting of the probe. All data
Three consecutive temperature measurements in °C were were displayed online (Openlab, GMC, Hornslet, Denmark)
noted and the average computed. The threshold was and stored for later analysis.
defined as the highest stimulus intensity the volunteer
could accept. The subjects were told to stop the stimula- Mechanical stimulation For mechanical stimulation the
tion by a click on a button when the pain tolerance thresh- oesophageal bag was distended at a constant infusion rate
old (PTT) was reached. of 15 ml min-1 until ‘moderate pain’ intensity ratings (VAS =
7) were reached. The volumes (ml) in the bag at ‘moderate
Muscle stimulation pain’ were used for further analysis.
Muscle stimulation was done by an electronic cuff algo-
meter consisting of a pneumatic tourniquet cuff, a com- Thermal stimulation A temperature probe (PR Electronics,
puter controlled air compressor, and an electronic 10 cm Rønde, Denmark) monitored the fluid temperature con-
visual analogue scale (VAS) (Aalborg University, Denmark). tinuously in the bag.The heat pain stimuli were performed
The cuff algometer has been described in detail previously by re-circulating water (60°C) in the bag.The infusion chan-
[35, 36].The 0 and 10 cm extremes on the VAS were defined nels in the probe were attached to a specially designed
as‘no pain’and as‘the worst pain imaginable’. The computer pump system. OpenLab software (GMC Aps, Hornslet,
continuously controlled the compression rate to ensure a Denmark) running on a computer was used to control an
linear increase in pressure. A tourniquet cuff was wrapped infusion/withdrawal syringe pump (PHD 2000, Harvard,
around the gastrocnemius muscle. In order to ensure reli- Massachusetts, USA). The pump held two 140 ml syringes
able pressure readings the cuff was fitted tightly around for infusion and withdrawal.The bag volume was kept con-
the limb before each measurement. All recordings were stant by withdrawing the same amount of fluid as infused
made on the right limb with the subject in a supine posi- using the two large lumens. This was done to obtain a
tion. In addition to the hand-held pressure release button linear temperature increase of 1.5°C min-1. The tempera-
the inflation could be terminated both mechanically and ture stimulus did not cause any mechanical stimulation
from the computer program. The cuff was automatically since the amount of fluid in the bag did not change. Previ-
inflated (compression rate 0.50 kPa s-1). The subject was ous to this recirculation 4 ml of water was applied to the
instructed to rate the pain intensity continuously on the bag to ensure sufficient mucosa contact. The subject was
VAS from the first sensation of pain being the pain detec- instructed to rate the intensity continuously on the VAS
tion threshold (PDT). The pressure continued increasing from the first vague perception to the pain detection
and the subject pressed the release button when the cuff threshold. The temperature of the water in the bag at pain
pressure pain tolerance threshold (PTT) was reached. detection threshold was used for analysis.

Oesophageal stimulation Electrical stimulation For electrical stimulation stainless

Before the study all subjects were instructed how to use steel electrodes were mounted on the probe 1 cm proxi-
the 0–10 electronic VAS, for the visceral stimulations, where mal to the bag. A computer-controlled constant current
0 = no perception, 1 = vague perception of mild sensation, stimulator (University of Aalborg, Denmark) delivered a
2 = definite perception of mild sensation, 3 = vague per- 25 ms train-of-five, 1 ms square-wave impulse (perceived
ception of moderate sensation, 4 = definite perception of as a single stimulus), to the oesophagus. Initially the pain
moderate sensation, 5 = the pain threshold (PDT), 6 = mild detection threshold was found with increasing pain stimu-
pain, 7 = moderate pain, 8 = pain of medium intensity, 9 = lations. The current intensity was increased in 1 mA in
intense pain and 10 = unbearable pain.This scale has been increments with random sham stimulations having the
described in detail previously [37] and it has proved to be same or lower intensity until the pain detection threshold
reliable in experimental oesophageal pain in both healthy was found and the corresponding intensity in mA was
volunteers and patients [19, 38–40]. used for analysis.
The subjects were instructed to score the evoked pain
and to differentiate this from unpleasantness in the throat. Induction of hyperalgesia After all the baseline tests in all
The subjects were asked to quantify the referred pain area, tissues the subjects underwent an oesophageal acid + cap-
evoked at the maximal pain intensity by drawing the area saicin perfusion with a 100 ml solution consisting of 90 ml
on transparent paper, which was placed over the skin in HCl 0.1 M (Bie & Berntsen, Rødovre, Denmark) and 1 mg
the region where the pain was felt. The size of the referred capsaicin in 10 ml solvent (0.1 mg·ml-1 in polyoxyethylene
pain area was later calculated and digitized (Trust, 1200 sorbitan mono-oleate, Hospital Pharmacy, Aalborg Hospi-
wireless tablet, Trust International BV, Dordrecht, the Neth- tal, Denmark). The mixture was administered through a
erlands). The visceral stimulations were stopped at moder- perfusion channel in the probe at a rate of 7 ml min-1. If the
ate pain (VAS = 7) for the mechanical and the pain subject reached pain detection threshold (VAS = 5), the
detection threshold (VAS = 5) for thermal and electrical perfusion was stopped for 1 min and then continued until
stimuli stimulations.This was done to prevent severe auto- 100 ml was infused or until it became too unpleasant for

192 / 70:2 / Br J Clin Pharmacol

 Opioid analgesia in experimental hyperalgesia

the subject (pain intensity higher than PDT for more than sixteen sedation, two itching and one sweating. After
1 min). This method has been described previously [41]. administration of oxycodone six volunteers experienced
nausea, sixteen sedation, six itching and four sweating.
Statistics After administration of placebo one volunteer experienced
To eliminate errors relating to differences in baseline pain nausea, two sedation, one itching and three sweating.
recordings, the change in stimulus intensity relative to None of the subjects reported any side effect as intoler-
baseline was used in the statistical analysis [19].The results able. There was no difference in the overall degree of side
are expressed as differences between the means of the effects reported after morphine and oxycodone (P > 0.05).
baseline corrected values and confidence intervals (95%) The finger tapping frequency increased over time in all
unless otherwise indicated. For multiple comparisons the three treatment arms. No difference was found in finger
overall effects were tested by two-way analysis of variance tapping frequency between placebo, morphine and oxyc-
(ANOVA) with the factors: 1) drug (with three levels: placebo, odone (F = 0.1, P = 0.9).
morphine and oxycodone) and 2) time (with three levels:
30, 60 and 90 min). This indicated whether there was a
Skin stimulation
difference in the data obtained in the three drug groups
Compared with placebo, administration of opioids
(placebo, morphine and oxycodone) or in the data
increased PTT to heat stimulation (F = 9.5; P < 0.001)
obtained at the three time points. When an overall signifi-
(Figure 2). In post hoc analysis oxycodone was found to be
cant difference was found, post hoc analyses were done
more effective than placebo (P < 0.001) with a difference
based on a generalized linear model. To evaluate differ-
between the means of 0.69°C (95% CI 1.12, 2.99) and more
ences in drug effects, a total score over the 90 min was
effective than morphine (P = 0.016) with a difference
used in the post hoc analysis. For comparisons of side
between the means of 0.39°C (95% CI 0.22, 2.09).The effect
effects, Friedmans test was used. P < 0.05 was considered
of morphine was not significantly different from placebo
significant. The software package Sigma Stat vs. 3.0 (Systat
(P > 0.05).
Software, San Jose, California, USA) was used for the ANOVA,
whereas the software package STATA version 10.1 (Stata-
Corp LP, College Station, Texas, USA) was used for the post Muscle stimulation
hoc analysis. There was a difference in the effect of opioids and placebo
regarding PDT (F = 3.8; P = 0.02). Post hoc analysis showed
that morphine had a greater analgesic effect than placebo
Results (P = 0.03) with a difference between the means of 9.32 kPa
(95% CI 1.1, 17.6) and oxycodone had a greater analgesic
All volunteers completed the study. The results are shown effect than placebo (P = 0.012) with the difference
in Table 1. The oesophageal perfusion with chemicals between the means of 10.39 kPa (95% CI 2.3, 18.5). No
caused nausea and sweating in all volunteers. After admin- difference was demonstrated between the effect of
istration of morphine two volunteers experienced nausea, morphine and oxycodone (P > 0.05).

Table 1
Results from all experimental pain stimulations given as mean ⫾ CI

Skin Muscle Oesophagus

Heat Pressure Pressure Pressure Pressure Heat Heat Electricity Electricity
PTT (°C) PDT (kPa) PTT (kPa) PTT (ml) RPA (cm2) PDT (°C) RPA (cm2) PDT (mA) RPA (cm2)

Baseline Placebo 47.8 ⫾ 0.8 24.1 ⫾ 3.4 45.2 ⫾ 7.1 27.2 ⫾ 5.0 30.1 ⫾ 21.2 48.0 ⫾ 1.5 30.6 ⫾ 15.4 16.5 ⫾ 3.1 12.9 ⫾ 7.7
Morphine 47.4 ⫾ 0.8 23.3 ⫾ 4.9 43.9 ⫾ 7.3 29.6 ⫾ 5.1 38.8 ⫾ 27.9 50.1 ⫾ 1.7 27.4 ⫾ 11.5 16.7 ⫾ 3.8 9.9 ⫾ 8.5
Oxycodone 47.8 ⫾ 0.7 23.9 ⫾ 4.6 45.2 ⫾ 7.7 28.3 ⫾ 5.1 22.4 ⫾ 12.3 49.4 ⫾ 1.8 32.1 ⫾ 16.7 15.6 ⫾ 3.1 10.7 ⫾ 5.2
30 min. Placebo 47.1 ⫾ 0.9 23.8 ⫾ 4.0 44.9 ⫾ 6.9 26.9 ⫾ 4.6 34.1 ⫾ 23.3 48.1 ⫾ 1.2 37.3 ⫾ 19.1 12.0 ⫾ 1.4 16.2 ⫾ 8.9
Morphine 46.8 ⫾ 0.8 25.4 ⫾ 5.1 46.1 ⫾ 7.5 29.8 ⫾ 5.3 34.6 ⫾ 20.8 48.2 ⫾ 1.4 35.3 ⫾ 19.8 14.2 ⫾ 2.4 9.5 ⫾ 6.3
Oxycodone 47.6 ⫾ 0.7 29.0 ⫾ 6.3 51.8 ⫾ 7.1 30.1 ⫾ 5.0 24.8 ⫾ 16.1 49.2 ⫾ 1.4 21.4 ⫾ 9.1 15.7 ⫾ 2.5 10.7 ⫾ 5.5
60 min. Placebo 47.0 ⫾ 0.7 25.9 ⫾ 4.4 46.1 ⫾ 7.1 29.0 ⫾ 4.7 37.1 ⫾ 21.4 48.3 ⫾ 1.3 45.8 ⫾ 23.7 12.0 ⫾ 1.6 15.4 ⫾ 7.9
Morphine 46.8 ⫾ 0.8 28.6 ⫾ 6.9 48.8 ⫾ 7.7 31.7 ⫾ 5.8 38.4 ⫾ 18.7 49.2 ⫾ 1.7 30.4 ⫾ 11.2 14.1 ⫾ 2.1 11.1 ⫾ 6.7
Oxycodone 47.9 ⫾ 0.7 28.9 ⫾ 5.9 53.2 ⫾ 7.6 29.8 ⫾ 6.1 25.5 ⫾ 11.5 48.7 ⫾ 1.6 24.2 ⫾ 9.5 14.9 ⫾ 2.1 11.7 ⫾ 5.5
90 min. Placebo 47.0 ⫾ 0.9 27.2 ⫾ 4.1 47.8 ⫾ 7.0 30.9 ⫾ 4.9 43.8 ⫾ 25.2 49.3 ⫾ 1.1 43.5 ⫾ 22.3 12.1 ⫾ 1.8 16.1 ⫾ 9.1
Morphine 46.7 ⫾ 0.9 29.1 ⫾ 7.0 49.3 ⫾ 7.7 33.0 ⫾ 6.8 36.3 ⫾ 18.3 49.9 ⫾ 1.1 30.3 ⫾ 10.1 14.0 ⫾ 2.1 12.6 ⫾ 6.1
Oxycodone 47.6 ⫾ 0.8 28.4 ⫾ 6.0 53.9 ⫾ 7.4 30.4 ⫾ 6.0 24.9 ⫾ 9.6 48.2 ⫾ 1.4 24.1 ⫾ 10.1 14.9 ⫾ 2.6 10.6 ⫾ 5.1
Statistical results O>M = P O = M>P O>M>P No difference No difference No difference O>M = P O>M = P No difference

Data were obtained as pain detection thresholds (PDT), pain tolerance thresholds (PTT) or referred pain areas (RPA). The statistical results are summarized as better analgesic effect
(>), equal effect (=) of placebo (P), morphine (M) and oxycodone (O).

Br J Clin Pharmacol / 70:2 / 193

 A. E. Olesen et al.

sensitization
48.5
Temperature (ºC)

48 oxycodone

47.5

placebo
47
1 2
morphine

Baseline 30 60 90
Time (min)

Figure 2
Results from painful skin stimulation. Stimulus intensities evoking skin
pain tolerance threshold to heat stimulation at baseline, 30, 60 and 90 min
after drug administration. Compared with placebo (white) and morphine
(30 mg, grey) administration of oxycodone (15 mg, black) resulted in
higher temperatures. The error bars represent SEM. To eliminate errors
relating to differences in baseline pain recordings (illustrated by a lower
3 4
baseline value for morphine in the figure), the change in stimulus inten-
sity relative to baseline was used in the statistical analysis
Figure 4
Illustration of referred pain areas to painful oesophageal stimulations.The
58 mean of all reported referred pain areas is illustrated at (1) baseline; (2)
56 after perfusion of the oesophagus with acid+capsaicin; (3) after perfusion
oxycodone of the oesophagus with acid + capsaicin and administration of morphine
Pressure (kPa)

54 sensitization and (4) after perfusion of the oesophagus with acid + capsaicin and
52 administration of oxycodone. The referred pain area was drawn immedi-
50 morphine ately after the stimulation. The area reported after electrical stimulation
(white) was often smaller than area reported after mechanical (grey) or
48 thermal stimulation (hatched)
46 placebo
44
phine (P < 0.001) with a difference between the means of
Baseline 30 60 90 11.93 kPa (95% CI 5.4, 18.5). Moreover, there was an overall
Time (min) effect of time on muscle PTT (F = 4.2; P = 0.016).

Figure 3 Oesophageal stimulation

Results from painful muscle stimulation. The stimulus intensities evoking The visceral stimulation resulted in both local and referred
the muscular pain tolerance threshold (PTT) to pressure at baseline, 30, 60 pain. Figure 4 illustrates the average locations and sizes of
and 90 min after drug administration are shown. Administration of both
the referred pain areas.
morphine (30 mg, grey) and oxycodone (15 mg, black) resulted in higher
stimulus intensities to evoke PTT compared with placebo (white). Further-
more, oxycodone was superior to morphine.The error bars represent SEM. Mechanical stimulation Regarding the tolerated volume,
To eliminate errors relating to differences in baseline pain recordings there was no difference between drugs (F = 0.1; P = 0.9).The
(illustrated by a slightly lower baseline value for morphine in the figure), referred pain areas were not affected after administration
the change in stimulus intensity relative to baseline was used in the
of opioids (F = 2.3; P = 0.1).
statistical analysis

Thermal stimulation There was no effect of opioids

Changes in muscle PTT are illustrated in Figure 3. There regarding temperature at PDT (F = 2.1; P = 0.122), but the
was an overall effect of opioids (F = 21.7; P < 0.001). Post hoc referred pain area to heat in the oesophagus decreased (F
analysis showed that morphine had a greater analgesic = 13.7; P < 0.001). Post hoc analysis showed that oxycodone
effect than placebo (P = 0.003) with a difference between had a greater analgesic effect than placebo at decreasing
the means of 9.74 kPa (95% CI 3.3, 16.1) and oxycodone the referred pain area (P < 0.001) with a difference in the
had a greater analgesic effect than placebo (P < 0.001) with means of 60.99 cm2 (95% CI 37.74, 84.24). Moreover, oxyc-
a difference between the means of 21.67 kPa (95% CI 15.2, odone had a greater analgesic effect than morphine (P <
28.2). Oxycodone had a greater analgesic effect than mor- 0.001) with a difference in the means of 38.54 cm2 (95% CI

194 / 70:2 / Br J Clin Pharmacol

 Opioid analgesia in experimental hyperalgesia

60 Morphine showed no significant effect compared with

Referred pain area (cm2)

sensitization placebo (P = 0.051). The referred pain areas to electrical

50
placebo stimulation in the oesophagus were not significantly
affected by drugs (F = 1.7; P = 0.2).
40

morphine
30 Discussion
oxycodone
20 The effects of morphine, oxycodone and placebo were
Baseline 30 60 90 compared in an experimental pain study after hyperalge-
Time (min) sia was evoked in healthy volunteers using acid and cap-
saicin perfusion of the oesophagus. At the doses studied
differences in analgesic potencies were found in various
Figure 5 tissues. Oxycodone attenuated pain to heat stimulation of
Results from painful heat stimulation of the oesophagus. The referred
skin. Both opioids attenuated muscle pain, but oxycodone
pain areas corresponding to pain detection thresholds to heat stimula-
tion of the oesophagus at baseline, 30, 60 and 90 min after drug admin- showed a greater analgesic effect than morphine. Oxyc-
istration are shown. Morphine (30 mg, grey), oxycodone (15 mg, black) odone also showed greater analgesic effect compared
and placebo (white). The effect of oxycodone, but not morphine, was with both morphine and placebo on pain from heat and
better than placebo. The error bars represent SEM. To eliminate errors electrical stimulation of the oesophagus.
relating to differences in baseline pain recordings, the change in stimulus
intensity relative to baseline was used in the statistical analysis
Methodological considerations
A period effect could affect the results, but the randomiza-
sensitization tion of the study ensured that any such effect was equally
19 distributed in all treatment arms. Moreover, previous
studies have demonstrated stable and reproducible pain
recordings in multi-modal, multi-tissue experimental pain
Intensity (mA)

17
studies both within and between days [19, 41].Therefore, a
15
oxycodone period effect was not believed to influence the analysis
significantly in the present study. Another factor, sedation,
morphine could also potentially influence study outcome. Quante
13
et al. investigated this issue after morphine administration
placebo in an experimental pain study in healthy volunteers and
Baseline 30 60 90 found no effect on sedation variables as the experimental
Time (min) pain was likely to increase arousal level thus counteracting
morphine-induced sedation [42]. This could apply to the
present study involving a rather intensive stimulation
Figure 6 paradigm and the increased arousal was supported by an
Results from painful electrical stimulation of the oesophagus. The stimu-
increase in finger tapping frequency in all three treatment
lus intensities in pain detection thresholds to electrical stimulation of the
oesophagus at baseline, 30, 60 and 90 min after drug administration are arms.Thus, it is not likely that sedation influenced the study
shown. Morphine (30 mg, grey), oxycodone (15 mg, black) and placebo outcome.
(white). The effect of oxycodone, but not morphine, was better than In a previous study the current model of oesophageal
placebo. The error bars represent SEM. To eliminate errors relating to sensitization was evaluated and evoked consistent hyper-
differences in baseline pain recordings (illustrated by a slightly lower
algesia in healthy volunteers [41]. Therefore, further inves-
baseline value for oxycodone in the figure), the change in stimulus inten-
sity relative to baseline was used in the statistical analysis tigation of the hyperalgesia was not done in the present
study. Hyperalgesia in chronic pain is often seen as a state
of hypersensitivity of the central nervous system (CNS) that
15.37, 61.71) (Figure 5). Morphine had no significant effect amplifies nociceptive input arising from damaged tissues
compared with placebo (P = 0.056). [4]. Changes in the CNS after peripheral tissue injury have
been shown in animal [43] and human studies [39, 44–47].
Electrical stimulation There was a significant effect of In healthy volunteers experimentally induced peripheral
opioids on the stimulation intensity at PDT (F = 9.7; P < sensitization in muscle and viscera have also evoked both
0.001) (Figure 6). Post hoc analysis showed that oxycodone peripheral and central sensitization [26–28, 30, 48, 49].
attenuated the pain response more than placebo (P < Thus, shorter chemical perfusion of the oesophagus can
0.001) with a difference in the means of 12.10 mA (95% CI induce generalized hyperalgesia with increased sensitivity
6.68, 17.53) and more than morphine (P = 0.016) with a in remote organs and other tissues and act as a transla-
difference in the means of 6.69 mA (95% CI 1.23, 12.13), tional bridge to the clinical situation.

Br J Clin Pharmacol / 70:2 / 195

 A. E. Olesen et al.

When studying analgesic effects on experimental pain do not require any correction for multiplicity [62]. The
it is essential to choose the right dose, dosing regime and unpleasantness of pain is associated with the limbic struc-
time point for testing the analgesia as the kinetic profile tures in the brain, an area where opioids traditionally are
could affect the results [20]. A previous study demon- known to modulate the pain response. As deep pain is
strated similar pharmacokinetic-pharmacodynamic rela- considered more unpleasant than skin type of pain, opioid
tionships for somatic analgesia for morphine and analgesia is more robust in deep pain [20]. Therefore, the
oxycodone [50]. tmax is also comparable for the two opioids results from the deeper structures were considered most
as for both morphine and oxycodone it was previously important. However, results from skin stimulation sup-
found to be 1 h [51, 52]. Moreover, after 30 min both mor- ported results from deeper structures and comparable
phine and oxycodone should be present at the CNS effect results were demonstrated in all tissues which strengthen
sites [50].Therefore, it is not likely that the pharmacokinetic the conclusion.
differences can fully explain the different analgesic effects
between the opioids. A total score over 90 min was found
to be the most appropriate method for the post hoc analy- Different effects of morphine vs. oxycodone
sis as in pain treatment the analgesic effect is also evalu- Skin The skin heat stimulation had a narrow dynamic
ated over time and not at a specific time point. range of a few °C and might not be clinically relevant.
The analgesic potency ratio of oral morphine : oxyc- However, it supports the other results and indicates
odone has been widely discussed [34, 53]. However, it has different anti-hyperalgesic potencies of morphine and
been estimated and found to range from 1:1 to 2.2:1 oxycodone as an induced generalized hyperalgesia
[54–59]. The consensus in the pain management commu- (demonstrated in the placebo arm) was blocked by oxyc-
nity is that oral oxycodone is 1.5 to 2 times as potent as odone, but not significantly by morphine. As the P value for
oral morphine regarding analgesia [60, 61]. In the present the effect of morphine approached significance it could be
study a high dose of morphine was chosen to secure that hypothesized that an increased sample size would be nec-
differences in bioavailability did not favour oxycodone essary to demonstrate an effect of morphine in this experi-
analgesic efficacy. Furthermore, in a previous study the mental pain model of hyperalgesia. Previously, Staahl et al.
doses have showed comparable analgesic potencies in demonstrated equal analgesic potencies of the same
human experimental skin and muscle pain [21]. However, doses of morphine and oxycodone in the skin heat pain
the analgesic potency ratio of oral morphine : oxycodone model [21]. These conflicting results could be due to the
can be different from the non-analgesic pharmacody- effect of the induced generalized hyperalgesia, as this was
namic ratio. Some clinical studies have suggested that believed to affect both the pain system and the opioid
oxycodone produces less severe side effects than mor- system.
phine whereas a study in healthy volunteers suggested
that oral morphine and oral oxycodone have a different Muscle An overall increase in tolerated pressure was
relative potency (closer to 3:1) regarding non-analgesic found over time, most likely due to habituation to the tonic
pharmacodynamics, with oxycodone producing more side stimulation. Thus, no sensitization was found for this
effects [61]. No significant difference in adverse event pro- modality after the induction of generalized hyperalgesia.
files was found in the present study. However there was a This could be due to the fact that nerves from the gastroc-
trend towards more reports of side effects after oxyc- nemius muscle terminate in the lumbar and sacral part of
odone than after morphine. the spinal cord, whereas nerves from the oesophagus and
Opioid side effects could complicate blinding of the the arm are believed to terminate predominantly in the
placebo administration. An inert placebo substance was cervical and thoracic part of the spinal cord. Therefore,
included as the aim was to demonstrate differential effect spinal sensitization caused by acid and capsaicin perfusion
of opioids and not to reveal analgesic efficacy. However, of the oesophagus will not necessarily affect incoming
the inert placebo was to some degree masked by nausea pain signals from the leg. However, the analgesic effect of
and sweating caused by the chemical perfusion of morphine and oxycodone was demonstrated and oxyc-
oesophagus. odone had greater analgesic effect than morphine (and
Numerous endpoints could limit the impact on inter- placebo) in attenuating PTT. Opioids mainly attenuate pain
pretation of the findings by the multiple testing problem. intensities above the PDT [20]. This could explain why a
The two-way ANOVA was chosen for statistical analysis as it differential effect was only found regarding PTT. Staahl
decreases the probability of type 1 errors in multiple et al. also demonstrated differential analgesic effects on
testing. However, the aim was not to investigate whether experimental muscle stimulation in which oxycodone had
all trials were positive. The exploratory endpoints are a greater effect in patients with chronic pancreatitis [23].
thought to provide potentially worthwhile information Conversely, they could not demonstrate differential effects
about the treatment that could serve to generate hypoth- of morphine and oxycodone on pressure evoked muscle
eses for future studies. For this reason, endpoints that are pain in healthy volunteers, when no sensitization was
prespecified in the design of a clinical trial as exploratory induced [21]. A significant effect of morphine was only

196 / 70:2 / Br J Clin Pharmacol

 Opioid analgesia in experimental hyperalgesia

demonstrated on this deep muscle pressure, which could pressure, hyperalgesia might nevertheless have affected
be due to a higher sensitivity and reproducibility of this the variation and a larger sample size would have been
stimulation method. more appropriate to demonstrate the effect of morphine.
However, differential analgesic potencies of morphine and
Oesophagus An analgesic effect of oxycodone using heat oxycodone were demonstrated in all tissues confirming
stimulation of the oesophagus was previously shown in that the sample size was sufficient for the main outcome of
healthy volunteers [21]. In the current study a new method the study.
ensuring linear rise in temperature was used, but no anal- It has been demonstrated in animal studies that oxyc-
gesic effect was demonstrated.This could be related to the odone may interact, at least in part, with a different popu-
faster change in temperature, which could cause uncer- lation of opioid receptors or modulate m-opioid receptor
tainty in pain assessments as it takes some time to rate the signalling in hyperalgesia in a subtly different way from
intensity. As individual differences in reaction time could other opioids [14, 65]. Moreover, the generalized hyperal-
not be excluded this could affect the accuracy of rating. gesia could lead to changes in the opioid system [66, 67].
Therefore, in future studies a slower temperature increase For example a more pronounced up-regulation of
should be recommended. However, the heat evoked k-receptors in inflammation has been speculated [8]. Fur-
referred pain areas were smaller after oxycodone com- thermore, animal studies have shown that binding to
pared with placebo and morphine. This likely reflects the k-receptor sites in the spinal cord are increased to a greater
effects of the drug on spinal or supraspinal changes in the degree than binding to m-receptors during peripheral
pain system after induction of hyperalgesia. The low base- inflammation [12]. It has been proposed from rodent
line value for morphine on referred pain areas from heat experiments that oxycodone is a partial k-agonist [14–18].
stimulation of the oesophagus could not be the reason for Therefore, it could be hypothesized that the differential
lack of significance of morphine effect, as all results were analgesic potencies are caused by different pharmacologi-
baseline corrected for the same reason before analysis. cal profiles of the opioids. Whether the present results are
However, as for the effect of morphine on skin heat pain, due to pharmacology and caused by different affinities for
the P value for the effect of morphine on referred pain area k-opioid receptors cannot be concluded from this or any
from oesophageal heat stimulation approached signifi- other human study as it would require a selective
cance, indicating an effect of morphine. However, in paral- k-antagonist suitable for human administration.
lel with other results the analgesic effect of oxycodone was
greater. In a previous study the opioids attenuated the Translational pain research
response to oesophageal mechanical stimulation in Animal models may provide pharmacodynamic informa-
healthy volunteers [21]. However, no effect was found in tion during drug development, but have limitations mim-
the present study. Acid perfusion causes oesophageal icking human pain conditions. Hence, they are based on
motility changes seen as increasing number and sizes of motor reflexes or behavioural responses, whereas human
contractions [63]. This could lead to squeezing of the pain is a net result of complex sensory, affective and cog-
balloon as well as traction force exerted in the pharynx and nitive processing [68]. Research with patients offers a
therefore the data must be carefully interpreted. means to explore the actual pain states of interest. On the
Electrical stimulation is often the most reliable visceral other hand, they suffer from difficulties in assessment of
stimulus as it is not affected by motility and has a high the pain, due to many confounding factors such as general
dynamic range [64]. Once more, the effect of morphine on malaise, fever, nausea, psychological status, etc [68]. There-
electrically induced pain approached significance, indicat- fore, experimental pain models in healthy volunteers, con-
ing an effect which could be demonstrated with an trolling the pain stimulus and assessment, can act as a
increased sample size. Nevertheless, oxycodone had a translational bridge from studies in animals to humans
greater effect than morphine in attenuating electrically [24]. Traditional models are short lasting and have many
induced pain by blocking the induced hyperalgesia. As the limitations compared with the complex clinical pain con-
electrical stimulation bypasses the peripheral nerves the ditions. However, experimental pain models can include
difference could be related to spinal and supraspinal hyperalgesia and be more consistent with phenomena
changes in the pain system [5–7]. The referred pain area to observed in patients.They may reasonably explain many of
electrical stimulation of the oesophagus increased after the abnormal pain responses typical of chronic pain. This
placebo indicating hyperalgesia. This hyperalgesia was was demonstrated in the current translational study as the
also blocked by the opioids, but non-significantly. The lack differential analgesic potency of morphine and oxycodone
of significance could be due to the high variance in how was comparable with the data previously found in our
subjects reported the referred pain area after electrical group on experimental pain stimulation in patients with
stimulation. chronic visceral pain [23]. Therefore, human experimental
The effect of morphine has previously been proved pain models of hyperalgesia may help to predict analgesic
detectable in 24 healthy volunteers [21]. As the results only potency in a sensitized pain system. Models evoking con-
demonstrated a significant effect of morphine on muscle trolled hyperalgesia have the advantages of experimental

Br J Clin Pharmacol / 70:2 / 197

 A. E. Olesen et al.

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Competing interests different pharmacological profiles: radioligand binding and
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