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Efficacy and Safety of Tramadol Versus Morphine for Moderate and Severe Postoperative Pain With Special Regard

to Respiratory Depression
Robert-Jan M. Houmes, MD, Michael A. Voets, MD, Allan Verkaaik, Wilhelm Erdmann, MD,PhD, and Burkhard Lachmann, MD,r h D
Department of Anesthesiology, Erasmus University Rotterdam, The Netherlands

MD,

The analgesic efficacy and safety of tramadol and morphine were compared in a double-blind, randomized study of 150 female patients after gynecologic surgery. As required, patients could receive up to three intravenous doses of either 50 mg of tramadol or 5 mg of morphine within a period of 6 h. Pain intensity (verbal response score) was recorded before injection and at 0.5, 1, 2, 3, 5, and 6 h after the initial dose; at these times, pain relief was also assessed. Oxygen saturation was monitored continuously by pulse oximetry for at least 30 min after each injection.

In 13.3% of the morphine group (but in none of the tramadol group) transcutaneous pulse oxygen saturation decreased to less than 86%; in 50% of these patients the decrease occurred after only the first 5 mg of morphine. Both drugs produced acceptable analgesia, and there were no clinically significant adverse events. In demonstrating the absence of clinically relevant respiratory depression with tramadol, \ye underline its safety for postoperative pain relief.
(Anesth Analg 1992;74:51&4)

espite well-known disadvantages including respira tory depression, use of opiates remains a common method for treatment of postoperative pain (1). New analgesics have been developed over the last few decades including tramadol, a synthetic opioid analgesic. On the basis of its potency, tramadol has comparatively few disadvantages associated with other opiates, such as cardiovascular reactions and physical dependency (2-7). In opioid-sensitive experimental models, the antinociceptive effect of tramadol can be completely abolished by pretreatment with naloxone ( 3 ) . More recent work, however, suggests that non-opioid receptor mechanisms of action may contribute to the analgesic profile of tramadol in humais and result from the inhibition of noradrenaline uptake and stimulation of serotonin release (8,9). Respiratory depression with opiates is due in part to decreased brainstem response to CO, and the hypoxic drive, and to a blunted increase in respiratory drive associated with increased airway resistance. A noninvasive method for measuring respiraAccepted for publication December 10, 1991. Address correspondence to Prof. Dr. Lachmann, Department of Anesthesiology, Erasmus University, Post Box 1738, 3000 DR Rotterdam, The Netherlands.

tory depression is transcutaneous pulse oxygen saturation (t-Sao,). This study was designed to assess the analgesic efficacy, safety, and duration of action of intravenous tramadol versus morphine in patients with moderate or severe pain after gynecologic procedures.

Methods
A comparative double-blind randomized study design was used. One hundred fifty female patients (100 in the tramadol group and 50 in the morphine group; age range, 1%65 yr) experiencing moderate or severe pain requiring an intravenous centrally acting analgesic after gynecologic surgery (i.e., abdominal, vaginal, or combined abdominal-vaginal) were studied. All patients were considered reliable, cooperative, and mentally capable of adhering to the protocol and providing the relevant study information for the whole study period. All patients gave written informed consent, and the investigation was approved by the hospital Ethical Review Committee. None of the patients was pregnant or lactating, abusing centrally acting drugs, consuming monoamine oxidase inhibitors, or allergic to opioids. Patients did not participate in other drug studies, were not previously admitted to this study, and had no
r' 1992 by the International Anesthesia Research Society 0003-2999192155 00

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history of seizure disorders. Patients with pulmonary or cardiac diseases were excluded from the study. To avoid influence of other analgesics (e.g., fentanyl), patients underwent a standard anesthesic; anesthesia was induced with thiopental %7 mg/kg IV and a muscle relaxant (either pancuronium or vecuronium) followed by inhalation of N,O/O, ( 2 : l ) supplemented with a voIatiIe anesthetic for the duration of the procedure. Thus, before administration of study drugs, no analgesics and no perioperative medication that might influence analgesia were used. The two study drugs were identically packaged and coded in a manner suitable for randomized treatment allocation for moderate or severe pain groups. The packages were supplied with a quantity ratio of 2: 1 (i.e., tramadol/morphine). Drugs were administered by persons other than those responsible for data collection and clinical assessments; thus, the identity of the administered drugs was unknown to those performing the clinical evaluations (trained observers). Only after deliberation by the observer with the patient was any dose of study drug (including the initial dose) given. At the time of the first pain event (baseline) for which medication was required, pain intensity was evaluated and recorded as moderate or severe, a patient study number was allocated, and the first dose of either tramadol 50 mg or morphine 5 mg IV was given. The protocol allowed each patient to receive up to three doses of study medication (maximum of tramadol 150 mg IV, morphine 15 mg IV) with a minimum interval of 20 min between the first and second dose and 30 min between the second and third dose for a maximum of 6 h after the initial dose. If analgesia was still inadequate (i.e., patient requesting more analgesia) after three doses, treatment failure was diagnosed, rescue medication (morphine 0.1 mg/kg IM) was given, and the last pain score recorded was used for the remaining observation times (up to 6 h). Pain intensity was scored by the patient and the trained observer using a four-point verbal response scale (0 = no pain, 1 = slight pain, 2 = moderate pain, and 3 = severe pain) before injection and at 0.5, 1, 2, 3, 4, 5, and 6 h after the initial dose. At the time of assessing pain intensity, pain relief was also evaluated by the patient and the observer and recorded using a five-point verbal response scale (0 = no pain relief, 1 = little pain relief, 2 = some pain relief, 3 = a lot of pain relief, 4 = complete pain relief). Before administration of the first dose of study medication, supplemental oxygen (if any) was stopped. Heart rate and t-Sao, were monitored continuously (but recorded at 2-min intervals) with a pulse-oximeter (Minolta Pulsox-7) throughout the study period or at least for 30 min after each injection.

Table 1. Comparison of Age, Height, and Weight of the Two Study Groups
Tramadol ( n = 100) Age (yr) Mean Range Height (cm) Mean Range Weight (kg) Mean Range
Values are mean
? SD

Morphine
(PI =

50)

35.6 2 7.5 23-58


165.7 2 6 145-186 63.4 2 8.4 48-89

36.4 2 7.8 2&57


166.8 2 6.2

15S180 56.6 2 8.4 44-83

If t-Sao, decreased S90%, patients would be instructed to breathe deeply. If t-Sao, decreased ~ 8 0 7 0 , naloxone would be administered. All adverse events reported by the patient or elicited or observed by the observers were rated (slight, moderate, or severe) and recorded. Group differences in t-Sao, values were analyzed using the 2 test. Variables of race, maximum pain intensity difference score, patient and observer overall assessment of analgesia, incidence of adverse events, and of withdrawals from the study were investigated with maximum likelihood regression analyses carried out to obtain an impression of possible interactions. When these were observed, a twotailed t-test or a two-tailed Fisher's exact test was used. For the variables "treatment failure" and "incidence of adverse events," 95% confidence intervals according to Pearson and Clopper were calculated for the individual pain intensities and treatments. For each patient, pain intensity differences were computed as the difference between each pain score against the baseline pain score. At each time of pain assessment, means and maximum pain intensity differences were computed and recorded for analysis. As this approach does not take into account the frequency and time of remedication, numbers of patients requiring only one dose, two doses, or three doses, and those leaving the study because of inadequate analgesia after three doses, were listed.

Results
The two groups were comparable with regard to age, height, and weight (Table 1). Decreases in t-Sao, were observed in both treatment groups. However, in 13.3% ( n = 6) of the morphine group, but in none of the tramadol group, t-Sao, decreased to 86% and below: 50% ( n = 3) of these patients had received only 5 mg of morphine. Analysis of the t-Sao, data of all 131 assessable patients (13 of the tramadol versus

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0.55 0.70
0.85
1.00

1.15

1.30
80 85 90 95 TRANSCUTANEOUS SaO,(%)

'

1
2

100

HOURS AFTER lSTDOSE

0.40
0.70

2
Y

20

1 .oo

15

d
4

0:

1.30

= 0 a

10 5

1.60
1.90
2.20

u.

'

4 DOSE
C

80

85 90 95 TRANSCUTANEOUS SaO,(%)

100
0.40

HOURS AFTER 1''

ap
0

25
20

5
2

15 10
5
0

s a u .

1.60
0

80

85

90

95

100

HOURS AFTER lST DOSE

TRANSCUTANEOUS SaO,(%)

Figure 1. Relative frequency of 2-min interval t-Saoz measurements during a 30-min period (striped bar, tramadol; dark /Jar, morphine) after (A) first dose, (B) second dose, and (C) third dose of tramadol or morphine.

9 of the morphine patients were not assessable) in both groups for a period of 30 min after each treatment dose revealed a statistically significant ( P 5 lo-') larger group of 2-min interval t-Sao, recordings of 90% and below after every administration of morphine than after tramadol administration (Figure 1). No statistically significant difference was found in both treatment groups between the maxima t-Sao, values; whereas, statistically significant differences were found between the minima and also between the mean t-Sao, values. At 32-60 min after the initial dose, average minimum t-Sao, values of tramadol and morphine were 94% and 93%, respectively (P = 0.0101) and average mean t-Sao, values were 96%

Figure 2. Pain intensity difference scores (i.e., difference between each pain score against the baseline pain score) (error bars show standard error of the mean) during the 6-h study period. (A) Patients with moderate pain: tramadol (solid line, n = 49), morphine (/7r(ik~11 line, n = 24) (two-tailed t-test, P > 0.2); (B) patients with sesere pain: tramadol (solid line, n = 511, morphine (broken line, 11 = 26) (*two-tailed I-test, P < 0.05); and (C) combined pain group: tramadol (solid line, n = loo), morphine (broken line, n = 50) ('two-tailed t-test, P < 0.05).

and 95'3, respectively ( P = 0.0093). At 62-90 min after the initial dose, average minimum t-Sao, values were 95% for tramadol and 92% for morphine (P = 0.0001) with average mean values of 96% and 95% (P = 0.0008), respectively. Transcutaneous pulse oxygen saturation values from 92 min after administration cannot be meaningfully interpreted a.; the number of available t-Sao, values was reduced. Pain scores for moderate, severe, and combined pain groups show no statistically significant difference in analgesia in the moderate pain group (Figure 2).

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Table 2. Percentage of Patients According to Time (baseline time is the time of the initial dose) of Remedica tion"
Severe pain Moderate pain (%) T
18.4 18.4 8.2

Combined pain group

("/I
T Initial dose only Second dose within 20-40 min Second dose within 2 M O min and third dose within 50-70 min Treatment failure (requiring rescue medication) Remainder (none of the above) 0 3.9
15.7

("/.I
T
9.0 11.0 12.0

M 0
30.8 7.7

M
25.0 20.8 4.2

M
12.0 26.0 6.0

58.8

30.8

14.3

4.2

37.0

18.0

21.6

30.8

40.8

45.8

31.0

38.0

T, tramadol; M, morphine. "Tramadol and morphine both 100% in each pain group.

NAUSEA M T VOMITING M T DIZZINESS M T DROWZI- M NESS T OTHERS M T 0

10

20

30

% OF ALL ADVERSE EVENTS

Figure 3. Percentage of all reported and observed adverse events after receiving tramadol (T) or morphine (M) according to the level of severity. Adverse events: solid bar, mild; ope11 bar, moderate; striped bar, severe (*exact Fisher test, P = 0.005).

severe postoperative pain with special regard to type and frequency of adverse events and respiratory depression. The results of this study show that whereas the analgesic potency of tramadol and morphine are similar, tramadol has markedly less clinically significant respiratory depressive effects than morphine. Perhaps this is because the analgesic effects of tramadol are mediated by non-opioid receptor mechanisms of action. Despite the importance of postoperative pain treatment, fear of respiratory depression or hypotension may result in some withholding of opioid administrations by medical and nursing staff, often aggravating the patient's pain. Thus, equianalgesic drugs free of these adverse events would be preferred. Because upper abdominal surgery itself affects lung function (5), a group of lower abdominal (i.e., gynecologic) procedures was selected to study changes in t-Sao,, analgesic potency of the drugs, and adverse events. To best compare the analgesic effect of opioids, Bromage recommended a clinical setup (lo), whereas to assess the effect and to produce objective and reproducible data Parkhouse et al. suggested the use of independent observers (11). Published data support a 1 O : l efficacy ratio for tramadol to morphine (12,13). Our results generally confirm this, although the pain intensity differences observed in the severe pain group may be attributed to the relatively low initial dose of tramadol. Our results indicate that the 50-mg treatment dose of tramadol fulfills the requirements of an analgesic for treatment of moderate postoperative pain, whereas for severe pain a higher dose is recommended. In demonstrating the absence of clinically relevant respiratory depression with tramadol, we underline one of the potential dangers of morphine and therefore suggest first-line use of another analgesic (e.g., tramadol) for postoperative pain.
We thank our surgical and nursing colleagues for their cooperation during this study and Laraine Visser-Isles for English language editing. Tramadol was kindly supplied by Grunenthal GmbH, Stolberg, Germany.

Table 2 shows relative percentage of patients according to time of remedication. Figure 3 summarizes all adverse events (the "other" group includes dry mouth, anxiety, fatigue, dysphoria, oculariacoustic complaints, headache). No adverse event in any patient gave reason to abort the study (i.e., not clinically significant). Adverse events were reported after tramadol by 32 of 100 patients (23.0% 5 44.0% 5 42.1%) and by 22 of 50 patients (27.0% 5 44.0% 5 54.1%) after morphine. Drowziness was the only event with a statistically significant difference between the two study groups.

References
Dodson ME. A review of methods for relief of postoperative pain. Ann R Coll Surg Engl 1982;64:324-7. Barth H, Giertz H, Schrnal A, Lorenz W. Anaphylactoid reactions and histamine release d o not occur after application of the opioid tramadol. Agent Actions 1987;20:310-3. Friderichs E, Felgenhauer F, Jongschaap P, Osterloh G. Pharmakologische Untersuchungen zur Analgesie, Abhingigkeitsund Toleranzentwicklung von Tramadol, einem stark wirkenden Analgetikum. Arzneimittelforschung 1978;26:122-34. Murano 7, Yamamoto Y, Endo N, et al. Studies of dependence on tramadol in rats. Arzneimittelforschung 1978;28:152-8.

Discussion
This study was designed to investigate the efficacy of intravenous tramadol and morphine for moderate or

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5. Paravivini D, Zander J, Hansen J. Wirkung van Tramadol auf Hamodynamik und Blutgase in der fruhen postoperativen Phase. Anaesthesist 1982;31:6114. 6. Vogel W, Burchardi H, Sihler K, Valic L. Uber die Wirkung von Tramadol auf Atmung und Kreislauf. Arzneimittelforschung 1978;28:183-6. 7. Yanagita T. Drug dependence potential of I-(in-methoxyphenyl)-2-(dimethylaminomethyl)-cycIohexan-1-01hydrochloride (tramadol) tested in monkeys. Arzneimittelforschung 1978;28: 15863. 8. Dhasmana KM, Banerjee AK, Rating W, Erdmann W. Analgesic effect of tramadol in the rat. Acta Pharmacol Sinica 1989;lO: 567-73. 9. Kayser V, Besson JM, Guilbaud G. Effects of the analgesic agent tramadol in normal and arthritic rats: comparison with

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the effects of different opioids, including tolerance and crosstolerance to morphine. Eur J Pharmacol 1991;195:3745. Bromage PR. Spirometry in assessment of analgesia after abdominal surgery. A method of comparing analgesic drugs. Br Med J 1955;3:589. Parkhouse J, Pleuvry BJ, Rees JMH. Controlled clinical trials of analgesic drugs. In: Analgesic drugs. London: Blackwell, 1979: 8aii4. Lehmann KA. 'On-demand'-analgesie. Dtsch Med Wochenschr 1983;108:647-50. Lehmann KA, Kratzenberg U, Schroeder-Bark B, HorrichsHaermeyer G. Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations. Clin J Pain 1990;6:212-20.