JINT415
Journal of Internal Medicine 1999; 245: 133–141
A comparison of metoprolol and morphine in the treatment of
chest pain in patients with suspected acute myocardial
infarction – the MEMO study
B. EVERTS 1 , B. KARLSON 2 , N.-J. ABDON 2 , J. HERLITZ 3 & T. HEDNER 1
From the 1Department of Clinical Pharmacology, Sahlgrenska University Hospital; 2Department of Medicine, Central Hospital, Uddevalla; and
3
Division of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden
Abstract. Everts B, Karlson B, Abdon N-J, Herlitz J,
Hedner T (Sahlgrenska University Hospital,
Göteborg, and Central Hospital Uddevalla). A com-
parison of metoprolol and morphine in the treatment
of chest pain in patients with suspected acute
myocardial infarction – the MEMO study. J Intern Med
1999; 245: 133–41.
Objectives. To compare the analgesic effect of meto-
prolol and morphine in patients with chest pain due
to suspected or definite acute myocardial infarction
after initial treatment with intravenous metoprolol.
Design. All patients, regardless of age, admitted to
the coronary care unit at Uddevalla Central Hospital
due to suspected acute myocardial infarction were
evaluated for inclusion in the MEMO study (metopro-
lol–morphine). The effects on chest pain and side-
effects of the two treatments were followed during
24 h. Pain was assessed by a numerical rating scale.
Introduction
Chest pain is the major symptom in patients with
suspected acute myocardial infarction (AMI) [1]. The
severity of chest pain is a reflection of the myocardial
ischaemia and is related to the size of the ischaemic
area [2, 3]. Severe myocardial ischaemia and evolv-
ing AMI cause sympathetic stimulation, which
results in a marked increase in circulating cate-
cholamines [4, 5]. Furthermore, the beta-adrenergic
receptor density in areas of ischaemic myocardium
increases within 30 min of coronary occlusion [5].
Therefore, injured myocardial cells are exposed to an
exaggerated sympathetic activation in the early
stages of AMI.
© 1999 Blackwell Science Ltd
Results. A total of 265 patients were randomized in
this prospective double-blind study and 59% devel-
oped a confirmed acute myocardial infarction. In
both treatment groups, there were rapid reductions
of pain intensity. However, in the patient group treat-
ed with morphine, there was a more pronounced
pain relief during the first 80 min after start of dou-
ble-blind treatment. The side-effects were few and
were those expected from each therapeutic regimen.
During the first 24 h, nausea requiring anti-emetics
was more common in the morphine-treated patients.
Conclusion. In suspected acute myocardial infarc-
tion, if chest pain persists after intravenous beta-
adrenergic blockade treatment, standard doses of an
opioid analgesic such as morphine will offer better
pain relief than increased dosages of metoprolol.
Keywords: acute myocardial infarction, chest pain,
metoprolol, morphine.
The treatment of pain is important, not only for
subjective relief but also because the pain itself can
induce systemic circulatory effects, such as increases
in blood pressure, heart rate and stroke volume [6].
Traditionally, morphine has been used for relief of
chest pain in AMI. Recommended treatment usually
includes an initial bolus dose of 2–4 mg intravenous-
ly, if necessary repeated after 5 min [7].
However, high or repeated morphine doses may
induce unwanted effects such as depressed respira-
tion, although respiratory insufficiency seems to be
rare [8]. Morphine may also induce other symptoms
from the central nervous system, such as nausea in
20–30% of patients [8]. Acute beta-adrenergic
blockade in AMI is a good alternative in pain treat-
133
134 B. E VERTS et al.
ment [9–11]. The therapeutic effects of beta-block-
ade include a reduction in myocardial oxygen con-
sumption through reduction in heart rate and
systolic blood pressure [12, 13]. The effect on
ischaemic pain seems to offer most benefit in patients
with an initial heart rate of more than 60
beats min21 and an initial systolic blood pressure
higher than 120 mm Hg [14].
Other beneficial effects of beta-adrenergic block-
ade in AMI are reductions in mortality and morbidi-
ty, reductions in infarct development and size and
reduction in ventricular dysrhythmias [12, 15]. The
reduction of mortality could be due to an attenua-
tion of the arrhytmogenic and toxic biochemical
effects of catecholamines and also a possible direct
effect on myocardial ventricular fibrillation threshold
[16]. Prolongation of diastole may also improve coro-
nary blood flow to injured, but not irreversibly dam-
aged, myocardium.
Previous clinical trials in AMI have shown a bene-
ficial effect of acute intravenous beta-blockade pro-
viding rapid pain relief, with few side-effects [10–11,
17–19]. Furthermore, the use of beta-adrenergic
blockers reduces the need for opioid analgesics in
such patients [10, 14]. Beta-blockers are also well
suited to be given together with thrombolytic agents
to improve myocardial protection without any
adverse reactions [20, 21].
An optimal treatment strategy, i.e. in what propor-
tions an opioid analgesic such as morphine or a beta-
adrenergic blocker such as metoprolol should be
administered to provide pain relief in suspected AMI,
is not known.
The aim of this study was to compare the effect of
metoprolol and morphine in patients with chest pain
due to suspected AMI after initial treatment with an
intravenous dose of metoprolol.
Patients and methods
Patients randomized in this trial arrived in the
Central Hospital of Uddevalla during the period 1
July 1993 and 31 August 1996. This hospital covers
a catchment area of 120 000 people in western
Sweden.
All patients admitted to the coronary care unit
(CCU) because of symptoms of suspected AMI were
evaluated for inclusion in the study.
The study protocol was approved by the Human
Ethics Committee of the Medical Faculty, University
© 1999 Blackwell Science Ltd Journal of Internal Medicine 245: 133–141
of Göteborg. Both oral and written informed consent
was obtained before inclusion of the patients.
Study design
Eligible for inclusion were male and female patients
of any age with strongly suspected or obvious AMI
on admission, with remaining chest pain > 3 on a
numeric rating scale (NRS) of at least 20 min dura-
tion until 6 h after initial treatment with intravenous
metoprolol. Pain was scored by the patient according
to a numerical rating scale graded from 0 to 10,
where 0 meant ‘no pain’ and 10 meant ‘the most
severe pain’ the patient could imagine.
Due to the beneficial effects of acute intravenous
beta-blockade [10, 15, 17], all eligible patients were
given metoprolol according to the following scheme
before randomization to the double-blind treatments:
1 5 mg 1 5 mg i.v. to patients < 75 years of age
without previous treatment with a beta-blocker;
2 5 mg 1 2.5 mg i.v. to patients . 75 years of age
and without previous treatment with a beta-blocker;
3 2.5 mg 1 2.5 mg i.v. to patients treated with a
beta-blocker regardless of age.
Criteria for exclusion were: heart rate , 40
beats min21, systolic blood pressure , 90 mmHg,
heart failure (pulmonary rales auscultated . 10 cm
above the bases), severe obstructive pulmonary dis-
ease, AV-block II–III or expected poor cooperability.
Trial medication
Patients who fulfiled the inclusion criteria were ran-
domized to double-blind treatment according to A or
B alternative:
A:1 Patients < 75 years of age, an intravenous
injection of 5 mg metoprolol every 5–10 min with a
maximum of six injections.
A:2 Patients . 75 years of age, an intravenous
injection of 2.5 mg metoprolol every 5–10 min with
a maximum of six injections.
B:1 Patients < 75 years of age, an intravenous injec-
tion of 2.5 mg morphine every 5–10 min with a
maximum of six injections.
B:2 Patients . 75 years of age, an intravenous injec-
tion of 2 mg morphine every 5–10 min with a maxi-
mum of six injections.
The double-blind study medication was given dur-
ing the first 2 hours after inclusion until the patient
became free of pain.
After the initial treatment, all patients without

contraindications received oral metoprolol 50 mg
t.i.d. according to clinical routines. The first oral dose
was given 1–6 h after the completion of the double-
blind treatment and evaluation phase.
Concomitant treatment
The patients were treated until they were free of pain
or judged by the physician in charge to require addi-
tional analgesic treatment. Such patients received
nitroglycerin infusion followed by additional intra-
venous morphine 2–5 mg and/or metoprolol 5 mg if
needed. Thrombolysis was given to patients accord-
ing to clinical routines.
If symptomatic bradycardia occurred, at a heart
rate less than 50 beats min21, the patients received
atropine 1 mg intravenously.
Symptoms of obstructive pulmonary disease were
treated with inhaled b2-agonists. Most patients
received aspirin and low-dose i.v. heparin according
to clinical routine at the hospital.
Diagnosis of acute myocardial infarction
Standard medical history and physical examination
were performed by the physician in charge at the
CCU. Serial ECGs (once daily during the first 3 days in
hospital) and blood sampling for aspartate amino
transferase (ASAT) (once daily during the first 3 days
in hospital) and creatine phosphokinase (CKMB) (8
and 15 h after onset of symptoms) were performed.
For the diagnosis of a definite AMI, two of the fol-
lowing criteria had to be fulfiled: (1) chest pain with a
duration of more than 20 min; (2) raised serum
activity of ASAT in at least two of the blood samples
together with elevation of CK-MB; (3) appearance of
Q-waves in at least two leads on a 12-lead standard
ECG.
The patients who did not fulfil the criteria for AMI
as above were classified as follows into four cate-
gories:
1 Possible AMI – chest pain and development of a
Q-wave in only one lead on a 12-lead standard ECG
or chest pain and ASAT or CK-MB above the discrimi-
natory level in only one blood sample.
2 Myocardial ischaemia – chest pain with ST-T
changes but no raised serum enzyme activity.
3 Possible myocardial ischaemia – chest pain,
which was not judged to have been caused by a non-
cardiac disease and when the criteria for AMI, possi-
ble AMI or myocardial ischaemia were not fulfiled.
© 1999 Blackwell Science Ltd Journal of Internal Medicine 245: 133–141
METOPROLOL IN CHEST PAIN 135
4 No myocardial ischaemia – another explanation
for the chest pain was found.
A patient was considered to have congestive heart
failure if there were pulmonary rales, a third heart
sound or other clinical or X-ray signs of congestion
that had to be treated with furosemide. A systolic
blood pressure , 90 mmHg was registered as
hypotension.
Pain scoring
Pain was scored on the NRS at the following times:
before randomization, at 10, 20, 40, 60, 80 and
100 min, and 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18,
20, 22 and 24 h after randomization to the double-
blind treatment regimen.
The maximal pain at home was also retrospective-
ly assessed soon after arrival in the CCU. Lack of reg-
istrations when a patient was asleep were regarded as
missing data.
The primary end-point in the study was pain
intensity scored during the first 2 h after randomiza-
tion. Secondary end-points were pain intensity
scored between 2 and 24 h after randomization, need
of other analgetics, tolerability, morbidity and mor-
tality.
Statistical methods
Mean values and standard error of mean (SEM) are
given. The two treatment groups were compared
using Fisher’s permutation test, which is a non-para-
metric test containing Fisher’s exact test as a special
case. When comparing the two treatment groups
with respect to the time at which the patients became
free of pain, the Mann–Whitney test was used. Two-
sided tests were used. A P-value less than 0.05 was
considered significant.
Results
Study population
During the study period a total of 3044 patients were
hospitalized in the CCU for different reasons. Of these
patients 1093 developed a definite AMI.
A total of 265 patients met the inclusion criteria
and none of the exclusion criteria and were random-
ized in the double-blind MEMO study to receive either
metoprolol (n 5 130) or morphine (n 5 135) treat-
ment for chest pain.
136 B. E VERTS et al.

Table 1 Comparison of baseline characteristics including previous patients in the metoprolol group and 44% in the
history and chronic medication prior to admission to hospital morphine group were on chronic medication with
Metoprolol Morphine beta-blockers (NS). There were no differences
(n 5 130) (n 5 135) between the groups regarding the use of other car-
Age (years; mean 6 SEM) 66.6 6 1.0 66.3 6 1.1
diovascular drugs, including a low dose of aspirin.
Male/female 91/39 90/45 Of the 265 patients who were randomized, 157
History of: developed AMI, four developed possible AMI, 12
Myocardial infarction 42 47 developed myocardial ischaemia and 40 developed
Angina pectoris 71 65
Hypertension 49 47
possible myocardial ischaemia, while 52 were judged
Diabetes mellitus 11 14 not to have myocardial ischaemia. No significant dif-
Congestive heart failure 01 07 ferences were seen between the groups regarding
Smoking previous/current 38/36 43/40 diagnosis or the development of AMI (Tables 2 and
Chronic medication prior to
hospital admission
3).
Beta-blockers 58 59 The groups were also well balanced with respect to
Calcium antagonists 23 25 infarct location. A total of 67 patients had anterior
Long-acting nitrates 24 28 AMI and 65 patients had inferior AMI (Table 3).
Diuretics 27 40
Digitalis 06 12
Anti-arrhythmics 02 02 Treatment of pain
ACE inhibitors 12 12
Aspirin 36 50 Prior to randomization the patients in the two groups
Anticoagulants 07 04 were given 8.2 6 3.5 and 8.7 6 3.0 mg metoprolol
Lipid-lowering drugs 07 03 intravenously, respectively (NS).
Anti-diabetics 06 11
Following randomization, patients were individu-
Psychotropic drugs 05 07
Other medication 58 68 ally titrated according to the protocol to meet the
study end-point. In patients randomized to metopro-
Actual numbers of patients and mean 6 SEM are shown. lol, a mean dose of 26.6 6 0.6 mg (range 10–35 mg)
was given to patients < 75 years and 13.2 6 0.5 mg
The baseline characteristics of the two treatment (range 5–15 mg) to patients . 75 years of age. The
groups are given in Table 1. No major difference total mean dose in the group receiving metoprolol
appeared between the groups. A total of 45% of the was 23.1 ± 0.7 mg (range 5–35 mg).

Table 2 Delay time until randomization and ECG pattern prior to randomization

Metoprolol Morphine
(n 5 130) (n 5 135)

Interval between onset of symptoms

and different points of time (hours; mean 6 SEM)
Admission to hospital 07.75 6 1.16 5.07 6 0.51 (P , 0.05)
Admission to CCU 08.64 6 1.14 5.96 6 0.53 (P , 0.05)
Randomization 10.96 6 1.75 6.55 6 0.58 (P , 0.01)
ECG pattern prior to randomization
Normal 23 27
Pathological but no sign of acute ischaemia 44 41
Acute ischaemia 62 66
ST elevation 45 48
ST depression 26 34
T-wave inversion 12 07
Q-wave 16 15
Localization of myocardial ischaemia
Anterior wall 41 32
Inferior wall 33 38
Lateral wall 15 23
Other place 01 00

Actual numbers of patients are shown.

© 1999 Blackwell Science Ltd Journal of Internal Medicine 245: 133–141

 METOPROLOL IN CHEST PAIN 137

Table 3 Diagnosis during the first 3 days in hospital Thrombolytic agents were given to 38 patients in the
Metoprolol Morphine
metoprolol group and 47 patients in the morphine
group (NS).
Confirmed AMI 76 81
Possible AMI 00 04
Myocardial ischaemia 05 07 Chest pain
Possible myocardial ischaemia 21 19
No myocardial ischaemia 28 24 There was a significant difference in pain relief dur-
Reinfarction 01 01 ing the first 80 min after randomization. A more pro-
Type of ECG changes nounced decrease in pain intensity was seen in the
ST elevation 20 24 group treated with morphine (Fig. 1). After the first
ST depression 17 20
T-wave inversion 39 37 80 min, no further differences in pain intensity were
Q-wave 47 39 observed during the rest of the 24 h period. Figure 2
Localization of myocardial ischaemia shows the percentage of patients in the two groups
Anterior wall 38 29 who reached complete pain relief (i.e. NRS 5 0) in
Inferior wall 31 34
Lateral wall 22 26 relation to time of observation. More patients
Other place 03 02 (P , 0.001) became free of pain in the group treated
with morphine.
Actual numbers of patients are shown.

In the morphine group, the corresponding doses
were 10.7 6 0.5 mg (range 1.5–17.5 mg) and
9.3 6 0.5 mg (range 2.0–12.0 mg) in
patients < 75 years and . 75 years of age,
respectively. The total mean dose in the group
receiving morphine was 10.3 6 0.4 mg (range
1.5–17.5 mg).
Additional morphine treatment was 1.5 mg in the
metoprolol group and 0.9 mg in the morphine group
(NS) during the 24 h period. Additional metoprolol
medication was given in the metoprolol group
(2.5 6 0.6 mg) and in the morphine group
(4.6 6 0.8 mg) (P , 0.05). Nitroglycerin infusion
was given to 68 and 63 patients, respectively (NS).
Mortality
There were no significant differences between the
groups in respect to mortality in hospital (three
patients died in the metoprolol group and six patients
in the morphine group) or at 6 months’ follow-up
(six patients died in the metoprolol group and six
patients in the morphine group).
Complications
The incidence of various adverse reactions noted
prior to randomization, during the first 24 h and
from the first 24 h to discharge are shown in Table 4.
Nausea occurred more frequently during the first
24 h in patients who received morphine (P , 0.05)

Fig. 1 Pain intensity in patients

with suspected AMI expressed
according to the numerical rating
scale (NRS) in relation to time. The
effect in patients receiving double-
blind metoprolol (n 5 130) or
morphine (n 5 135) is shown. Data
are means 6 SEM. *P , 0.05,
**P , 0.01, ***P , 0.001.

© 1999 Blackwell Science Ltd Journal of Internal Medicine 245: 133–141

138 B. E VERTS et al.

Fig. 2 Percentage of patients

reaching complete relief of pain
(pain score 5 0 on the NRS) at
various times after randomization.
The effect in relation to time after
administration of double-blind
metoprolol (n 5 130) or morphine
(n 5 135) to patients with chest
pain due to suspected or definite
AMI is shown.

Table 4 In-hospital complications and adverse reactions

After randomization
——————————————————————————–––
Prior to randomization 0–24 h . 24 h
———————————— ———————————–— ——————————–—––
Metoprolol Morphine Metoprolol Morphine Metoprolol Morphine

Ventricular fibrillation 00 00 01 02 00 01
Treated ventricular tachycardia 00 00 02 03 02 02
Supraventricular tachycardia 01 03 06 08 07 07
Bradycardia 04 03 17 20 08 07
Hypotension 02 01 19 19 06 05
AV-block-II 00 00 01 00 03 01
AV- block-III 00 00 01 01 02 00
Congestive heart failure 10 11 22 29 17 25
Symptoms of airway obstruction 01 01 03 01 01 03
Nausea 08 06 31 49 (P , 0.05) 07 00 (P , 0.05)
Confusion 00 00 02 09 00 02
Other major adverse events
Urticaria 00 01
Stroke 01 00

Actual numbers of patients are shown.

Table 5 Concomitant treatment

After randomization
——————————————————————————––
Prior to randomization 0–24 h . 24 h
———————————— ———————————— ———————————––
Metoprolol Morphine Metoprolol Morphine Metoprolol Morphine

Anti-emetics 01 03 23 41 (P , 0.05) 03 02
Beta-agonists 00 01 02 01 00 01
Atropine 03 03 11 11 03 00
Treatment for congestive heart
failure 13 13 33 45 23 26
Other therapy 04 11 41 53 44 60

Actual numbers of patients are shown.

© 1999 Blackwell Science Ltd Journal of Internal Medicine 245: 133–141


and these patients required more anti-emetic treat-
ment (P , 0.05). The concomitant treatment is
shown in Table 5. The incidence of ventricular fibril-
lation and treated ventricular tachycardia was simi-
lar in the both groups.
Congestive heart failure was seen in 17 and 21%
in the metoprolol and morphine groups, respectively
(NS), during the first 24 h.
Subgroup analyses
Among patients with a confirmed AMI who were
randomized to receive morphine, there was a signifi-
cant decrease in chest pain during the first hour of
randomization compared with the metoprolol group
(P , 0.001). Such differences were also found in sub-
groups of younger patients (P , 0.001), among
females (P , 0.01) and among patients with a Q-
wave infarction (P , 0.01). However, in other sub-
groups, such as males, elderly patients (. 75 years),
patients with diabetes mellitus or patients with non-
Q-wave infarction, there were no or borderline differ-
ences between the two treatment groups in reduction
of pain intensity.
Discussion
The present study shows that intravenous adminis-
tration of morphine results in a more extensive
reduction of chest pain compared with intravenous
metoprolol in patients with suspected or definite AMI
when added to a standard dose of metoprolol as a
baseline anti-ischaemic regimen. If traditional con-
traindications are borne in mind, there is a good tol-
erance to beta-adrenergic blockade in traditional
doses in the acute phase of AMI [10, 14, 15].
The management of chest pain in patients during
the first hours after the onset of myocardial infarc-
tion is of importance for short-term as well as long-
term outcome [22]. Several studies have shown that
intravenous beta-adrenergic blockade will cause an
immediate, although not complete, relief of chest
pain if administered during the early phase of
myocardial infarction [17]. This is in line with recent
data from our group showing that high doses of
intravenous metoprolol can be safely administered to
provide a beneficial effect on chest pain, especially in
patients with myocardial ischaemia and those with-
out Q-wave infarction [11].
From a pharmacological point of view, beta-adren-
© 1999 Blackwell Science Ltd Journal of Internal Medicine 245: 133–141
METOPROLOL IN CHEST PAIN 139
ergic blocking drugs do not belong to the group of
analgesic drugs. There are, however, several possible
mechanistic explanations for the pain-relieving
effects of beta-blockade in AMI. Firstly, a limitation of
the infarct size might, by itself, result in a lower pain
intensity. Further, an anti-ischaemic effect, not
always related to infarct limitation but rather to a
reduction of the rate–pressure product, may be a
possible mechanism [23]. Finally, the decreased
myocardial contractility by beta-adrenergic blockade
might reduce pain intensity due to a reduction of the
oxygen consumption.
Opioid analgesics still remain the first-line treat-
ment for chest pain in AMI patients in most coun-
tries. Morphine has generally been considered the
drug of choice, due to its potent effect and advanta-
geous or neutral haemodynamic profile. However,
opioid analgesia alone in patients with acute chest
pain may be insufficient. Several studies have report-
ed unsatisfactory pain relief in subgroups of patients
given morphine [24, 25].
The time-lag between administration of opioid
analgesics and maximal relief of pain has not yet
been sufficiently evaluated. Delayed analgesia up to
20 min after intravenous morphine administration
has been reported [26]. The duration of opioid anal-
gesia is difficult to estimate due to the considerable
variability between patients in the natural course of
pain in AMI [3]. There is also a lack of controlled
studies with placebo or an active comparator. In an
observational study on a large patient cohort, a
mean morphine dose of 6.7 mg was given to patients
with chest pain due to suspected AMI [27]. A sub-
stantial proportion of patients (44.5%) had only one
pain attack, whilst 21.1% had two to three, and
34.4% had four or more pain attacks.
Little is known about the optimal dose of intra-
venous morphine in suspected myocardial infarction
since there is as yet no study evaluating the
dose–response relationship. From experience gener-
ated from clinical practice, it has been suggested that
an intravenous morphine dose of 10 mg (70 kg)21 is
an optimal dose to provide sufficient analgesia in
AMI patients [28].
In the present study the mean morphine consump-
tion following randomization was 10.3 6 0.4 mg.
This may be lower than expected in AMI patients
[29]. However, potential confounders may be that
initial administration of a beta-blocker reduced the
requirement of morphine [10], or that only patients
140 B. E VERTS et al.
with an uncomplicated AMI and moderate pain were
included in the study.
Due to the beneficial effects of acute intravenous
beta-blockade, all eligible patients were given intra-
venous metoprolol prior to randomization. The more
favourable outcome with respect to pain in the mor-
phine group could then be a result of the additive
effect of low-dose metoprolol followed by morphine.
Clinical implications
In patients with acute chest pain due to suspected
AMI, both intravenous morphine and metoprolol
induce rapid relief of pain. However, after an initial
dose of beta-adrenergic blockade, a more extensive
pain relief was observed in the morphine group,
indicating that adding intravenous morphine
remains the preferred strategy of pain management
in patients with acute chest pain due to suspected
AMI.
Acknowledgements
This study was supported by grants from the Swedish
Medical Research Council (project no. 8642), the
Medical Faculty, University of Göteborg (LUA),
Bohuslandstinget and ASTRA-Hässle AB. We greatly
acknowledge valuable assistance from the staff at the
CCU, Uddevalla Hospital, and from Gabriella Salén.
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Received 23 February 1998; accepted 14 May 1998.
Correspondence: Bernt Everts MD, Dept of Clinical Pharmacology,
Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.