Narcotic Analgesics and Other Antianginal Drugs

The MIAMI Trial Research Group

The effect of metoprolol on chest pain has been as- sessed in terms of the duration and the use of narcotic analgesics, nitrates and caklum-channel blockers. Fewer metoprdol-treated patients in the- MlAMl trial were glven narcotic analgesii (49% of the placebo patients vs 44% of the metoprolol patients, p <O.OOl), nitrates (55% vs 53%j p = 0.10) and calcium-channel blockers (12% vs 9%, p <O.OOl). A total number of 6,697 dose equivalents of narcotic analgesics were given to the placebo-group compared with 5,493 dose equivalents to the me?oprolol group, a difference of 18% (p <O.OOl). Allean dose eqriva- lents were 2.3 and 1.9, respectively. The analysis of the total use of the 3 types of treatment for ischemk chest pain showed a signifkantly less frequent use of treatment for chest paln in the metoprolol group than in the placebo group (p <0.004). The relative dlffer- ence In the lncldence of drug treatment tended to be more striking for patients with maximal therapy, i.e.,

A variety of pharmacologic and other measures have been used to control chest pain in acute myocardial infarction (AMI) ranging from analgesics or tranquil- izers’ to drugs that act mainly through direct or indi- rect effect on the ischemic myocardium.2 Persistent or recurrent chest pain may induce adverse systemic and coronary circulatory effects via autonomic reflexes, mediated via sympathetic efferent nerves,” but also to some degree via the vagal nerve.4

In order to relieve pain, very large doses of mor- phine-like drugs are sometimes required that may themselves induce unfavorable effects.5-7 Additional approaches to pain control in AM1 are therefore desir- able. Earlier studies have suggested the beneficial ef- fect of metoprolol both in prevention of ischemic chest pain and treatment of pain.slO

The aim of the present analysis was to assess the effect of metoprolol compared with placebo on chest

Address for reprints: ike Hjalmarson, MD, Department of Medicine I, Sahlgren’s Hospital, S-413 45, Gdteborg, Sweden.

receiving high doses of narcotic analgesics, nitrates and calcium-channel blockers. There were 22 % few- er patients receiving 4 or more doses of narcotic analgesks in the metoprokl group than in the placebo group. A multivariate analysts disclosed that site of suspected infarction, delay time, entry systolic blood pressure and metoprolol treatment all had a signlfkant effect on the use of narcotic analgesics. There waSa nonsignlfkant tendency for heart rate to be of impor- tance. In the placebo group the use of narcotic analge- sics increased with decreasing delay time and ln- creasing systolic blood pressure. The use was highest for patients with signs of anterior infarction on electro- cardiogram (ECG) and lowest for patients with normal ECG at entry. The effect of metoprolol was indepen- dent of delay time and systolic blood pressure but varied with ECG classification. The highest effect was seen among patients with signs of anterior Infarction.

(Am J Cardiol 1985;56:3OG-346)

pain as reflected by the duration of treatment with narcotic analgesics, use of analgesics, nitrates and cal- cium-channel blockers. According to the protocol, subgroups were formed with respect to delay time, heart rate and site of infarction.

Patients and Methods All patients (n = 5,778) were included in the analysis. Pain

as such was not measured directly. Instead, the usage and number of doses of narcotic analgesics were used as markers of chest pain, as well as the use of nitrates and calcium- channel blockers. One dose equivalent of any narcotic anal- gesic was defined as the dose equipotent to the analgesic effect of 5 mg of morphine. The duration of pain was defined as the time in hours from randomization to the time of injection of the last dose of narcotic analgesic. This could only be measured during days 0 to 5.

In addition to the subgroup analyses stated in the proto- col, a number of subgroups were formed based on systolic blood pressure, rate-pressure product, age, sex, diuretic us- age and heart failure.

30G

Statistical methods: The general principles of statistical analysis were followed.11

A univariate analysis was performed to see whether there was any influence of the variables defining the subgroups on the use of narcotic analgesics.

An analysis was undertaken of the effect of metoprolol on the combined use of nitrates, calcium-channel blockers and single and multiple doses of narcotic analgesics. Narcotic analgesics were considered the strongest and 3 levels were used (no analgesics, 1 to 3 dose equivalents of analgesics and 4 or more dose equivalents of analgesics). Because nitrates could be and were used freely during the entire trial period, calcium-channel blockers were considered “stronger” than nitrates (drug given or not given). Nitrates were ranked lowest and 2 levels were again used (given or not given). Consequently, 12 classes were constructed to describe differ- ent strengths of antianginal and analgesic treatment and perhaps reflect different degrees of ischemic chest pain. In this analysis, the distribution of patients over the 12 classes is described graphically in the 2 treatment groups, and the difference between the treatment groups in these distribu- tions was tested.12 A difference in the distribution between treatment groups would reflect a difference in the combined use of antianginal drugs and hence may suggest an effect on chest pain by metoprolol.

In addition a multivariate model was applied to analyze the importance of different factors for the development of chest pain requiring treatment with narcotic analgesics.

In a logit model, the influence of the following factors on the odds that a patient will be treated with a narcotic analge- sic during days 0 to 15 was analyzed: electrocardiogram (ECG) on admission (anterior infarction, inferior infarction, other locations, pathologic but localization not possible and no abnormalities), delay time from onset of chest pain to randomization (<4,4 to 8 and X3 hours), heart rate (<80,80 to 90 and >90 beats/min), systolic blood pressure on admis- sion (<140,140 to 160 and >160 mm Hg) and drug (placebo or metoprolol).

Results

Narcotic analgesics were given to 49.4% of the pa- tients in the placebo group compared with 44.1% in the metoprolol group, a difference of 11% (p KO.001). Ni- trates were given to 55.3% in the placebo group com- pared with 53.1% in the metoprolol group (p = 0.10). Calcium-channel blockers were used more often in the placebo group (11.8%) than in the metoprolol group (8.80/o), a difference of 25% (p <O.OOl, Fig. 1).

The total number of dose equivalents of narcotic analgesics during days 0 to 15 differed by 18% (p <O.OOl) between the placebo group (n = 6,697) and the metoprolol group (n = 5,493). A mean of 2.31 dose equivalents/patient was given to the placebo group compared with 1.91 in the metoprolol group during days 0 to 15 (p <O.OOl).

Among patients to whom narcotic analgesics had actually been given during days 0 to 15, the mean dose equivalents were 4.69 in the placebo compared with 4.32 in the metoprolol group, a difference of 8% (p = 0.05).

The total pain duration differed by 17% (p <O.OOl) between the placebo group (42,935 hours) and the metoprolol group (35,675 hours). Mean duration of pain for the placebo group was 14.8 hours compared

‘with 12.4 hours for the metop.rolol group (p <0.001). ‘When only the patients who bad received narcotic analgesics were analyzed, no difference in mean pain duration was found; it was 30.8 hours for the placebo group compared with 29.2 hours for the metoprolol group (p KO.2).

Among patients with entry heart rates higher than the median (80 beats/min), narcotic analgesics were given to 52.2% in the placebo group compared with 43.9% in the metoprolol group, a difference of 16% (p <O.OOl, Fig. 2) and the mean dose equivalents in the placebo group were 2.51 compared with 2.0 in the metoprolol group, a difference of 20% (p <O.OOl, Fig. 3).

For patients with entry systolic blood pressure high- er than the median (140 mm Hg) the percentage use of narcotic analgesics was 54% in the placebo group com- pared with 4418% in the metoprolol group, a difference of 17% (p X0.01, Fig. 2) and the mean dose equivalents were 2.64 and 2.0, respectively, a difference of 24% (p <O.OOl, Fig. 3).

The influence of rate-pressure product on the use of narcotic analgesics revealed a similar pattern in the 2 treatment groups.

In all the remaining subgroups of patients in whom entry heart rate, systolic blood pressure or rate-pres- sure product was lower than the median, there was a consistently less pronounced and nonsignificant dif- ference in favor of metoprolol between the treatment groups for all variables (Fig. 2 and 3).

Neither age, sex nor acute heart failure on admis- sion, defined as administration of diuretics before ran- domization, had any association with the use of nar- cotic analgesics.

The analysis of the total use of the 3 types of treat- ment for ischemic chest pain showed a significantly different distribution in the 2 treatment groups (p <0.004). The difference in the percentage use of drug

L31 1 1269 / 1602 1 1527 252 / narcot,c analgesics “itMt-2S calclml blockers

FIGURE 1. Number and percentage of patients given narcotic analge- sics, nitrates and calcium-channei blockers during days 0 to 15. 0 = placebo patients: ITI = metoprolol patients.

MIAMI: Metoprolol In Acute Myocerdial Infarction

treatment tended to be more pronounced for patients with maximal therapy, i.e., those receiving high doses of narcotic analgesics, nitrates and calcium-channel blockers. Although this was only a small group, 42% fewer patients received the maximal treatment in the metopiolol group compared with placebo (Fig. 4). The difference for all patients receiving 4 or more doses of narcotic analgesics, constituting one-fourth of all pla- cebo patients, was 22%. Thus, patients who seem to benefit most from metoprolol are those who suffered the most pain, as reflected by the high use of narcotic analgesics with or without combined treatment with nitrates and calcium-channel blockers.

The multivariate analysis disclosed that site of in- farction, delay time and systolic blood pressure had a significant effect on the use of narcotic analgesics. There was a nonsignificant tendency for heart rate to be of importance.

In the placebo group the use of narcotic analgesics increased with decreasing delay time and increasing systolic blood pressure. Furthermore, the use was most frequent for patients with signs of anterior in- farction on ECG and lowest for patients with normal ECG.

The drug effect did not vary significantly with delay time and systolic blood pressure, but varied signifi- cantly with ECG classification at entry. The highest effect was seen among patients with signs of anterior infarction. For patients with signs on ECG classified as “inferior”, “ pathological” or “normal”, only a minor drug effect was observed (Table I).

Discussion

The present MIAMI trial confirmed previous find- ings of a reduced’use of narcotic analgesics in the early

Rate pressure product

%

! 6 HR z-80

FIGURE 2. Number and percentage of patients receiving narcotic analgesics during days 0 to 15 among those hav- ing entry heart rate (HR), systolic blood pressure (SBP) and rate-pres- sure product (RPP) below and above median values, respectively. 0 = pla- cebo patients; tE = metoprolol pa- tients.

tiRs80 Whl40 sBp=+l40

mm& RPPsl12 RPP>112

hr*mmHg 100

beats/mm

Heart rate Systolic Blood Pressure

FIGURE 3. Mean dose of narcotic an- algesics during days 0 to 15 among those having entry heart rate (HR), systolic blood pressure (SBP), and rate-pressure product (RPP) below and above median values, respective- ly. 0 = placebo patients; q = meto- prolol patients.

SBPS 140 SBP,140

rnrn”Q

RPPS 112 RPPZ112

hr x mmliq 100

beatslmin

TABLE I Estimated Expected Proportions of Patients (76) agit -__-

Signs on Electrocardiogram (ECG) of Site of Suspected Infarction at Entry ____rn--

SBP Delay Anterior Inferior Others Abnormal ECG Normal ECG

(mm Hg) (hours) P M P M P M P M P M

<4 68.6 56.6 57.3 56.3 55.2 48.7 45.1 42.0 36.1 34.7 <140 4-8 84.0 51.5 52.2 51.2 50.0 43.6 40.1 37.1 31.5 30.2

>8 53.3 42.5 43.2 42.2 41.1 35.0 31.7 29.0 24.2 23.1 <4 70.2 58.5 59.1 58.2 57.0 50.6 47.0 43.8 37.8 36.4

140-160 4-8 65.7 53.4 54.1 53.1 51.9 45.5 41.9 36.8 33.2 31.8 >8 57.1 44.4 45.0 44.0 42.9 38.7 33.4 30.6 25.6 24.5

<4 72.7 61.5 62.2 61.2 60.1 53.8 50.1 46.9 40.9 39.4 >160 4-8 68.5 56.5 57.2 56.2 55.1 48.7 45.0 41.9 36.0 34.6

>8 60.2 47.5 48.2 47.2 46.0 39.7 36.3 33.4 28.1 26.9

M = metoprolol; P = placebo; SBP = systolic blood pressure.

phase of myocardial infarction after treatment with metoprolol.gJO

Although incidence and intensity of pain were not directly measured in the present trial, the amount of analgesics and the time span over which they were given undoubtedly reflect the intensity and duration of ischemic chest pain. The fact that a positive effect on chest pain could be detected even though more than half of the placebo patients were given nitrates is important because nitrates have been shown to be effective for pain control in AMI.i3 In fact there was a trend to less use of nitrates, as well as a significant reduction in the use of calcium-channel blockers, in the metoprolol group. This reflects a reduction in the incidence of a low degree of pain for which these drugs are used. The decreased usage of narcotic analgesics in the metoprolol group indicates that recurrent chest pain was prevented. The lower mean dose of narcotic analgesics among those patients receiving analgesics also indicates that pain intensity may have been re- duced by metoprolol.

In patients with acute heart failure a worsening of chest pain may have been anticipated after metopro- 101, as further dilatation of the ventricle may increase myocardial oxygen consumption. The effect of in- crease in wall tension on myocardial oxygen consump- tion may, however, have been counteracted by the pronounced reduction in rate-pressure product. Therefore, there is no support from the present trial for the proposal that AM1 patients with chest pain and mild heart failure should be treated with nitrates in preference to metoprolol. Patients with high heart rate and blood pressure at entry seemed to respond more favorably than those with low heart rate and blood pressure. However, a selection of patients with heart rate >65 beats/min for the trial may have obscured the true importance of heart rate. An interesting finding is that heart rate does not seem to be a strong determi- nant of the drug effect according to the multivariate analysis. The more pronounced benefit in patients with anterior infarction may be due to the fact that they seem to have more pain (higher usage of narcotic analgesics) (Table I) and to have higher heart rates compared with those with inferior infarction. The analysis does not exclude the possibility that metopro-

101 might be effective in patients with inferior infarc- tion and high heart rates.

Metoprolol was effective in patients admitted with short as well as long delay after onset of chest pain, even though the intensity of chest pain was more pro- nounced in patients arriving early (Table I). Metopro- 101 seems to be of special value for pain control in patients with severe and prolonged pain. It also seems that metoprolol has a pain-relieving effect additional to nitrates and calcium-channel blockers.

The additional effect of metoprolol in patients given nitrates may be because nitrates mainly affect blood pressure. An increase in heart rate may occur after treatment with nitrates in patients with left-sided heart failure.13J4 Similar effects are seen after calci- um-channel blockers.i5J6 Reduction of blood pressure is therefore common for all 3 drugs; a fall in heart rate is only seen after metoprolol.

Prevention and reduction of chest pain in patients with AM1 or impending infarction seem to be parallel

NIL Z-MAXIMAL

- - - placebo - metoprolol

FIGURE 4. Cumulative distribution curve of combined treatment with narcotic analgesics, nitrates and calcium-channel blockers in all patients during days 0 to 15.

346 MIAMI: Metoprolol In Acute Myocardial Infarction

to prevention of infarct developmentI and reduction of indexes of size of infarction.la Pain abolition may be mediated through common pathways.

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