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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, MD, Wilhelm Erdmann, MD, PhD, and Burkhard Lachmann, MD, rhD Department of Anesthesiology, Erasmus University Rotterdam, The Netherlands The analgesic efficacy and safety of tramadol and morphine were compared in a double-blind, random- ized 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 satu- ration 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 trama- dol, \ye underline its safety for postoperative pain relief. (Anesth Analg 1992;74:51&4) espite respira D mains well-known disadvantages including tory depression, use of opiates re- a common method for treatment of postoperative pain (1). New analgesics have been developed over the last few decades including tram- adol, a synthetic opioid analgesic. On the basis of its potency, tramadol has comparatively few disadvan- tages associated with other opiates, such as cardio- vascular reactions and physical dependency (2-7). In opioid-sensitive experimental models, the antinoci- ceptive 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 respira- tory drive associated with increased airway resis- tance. A noninvasive method for measuring respira- Accepted 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 pro- cedures. Methods A comparative double-blind randomized study de- sign 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 stud- ied. All patients were considered reliable, coopera- tive, and mentally capable of adhering to the protocol and providing the relevant study information for the whole study period. All patients gave written in- formed 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 mono- amine oxidase inhibitors, or allergic to opioids. Pa- tients did not participate in other drug studies, were not previously admitted to this study, and had no 510 Ane5th Analg 1992,7-1 i104 r' 1992 by the International Anesthesia Research Society 0003-2999192155 00

Efficacy and Safety of Tramadol Versus Morphine for Moderate and Severe Postoperative Pain... Robert Jan

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Page 1: Efficacy and Safety of Tramadol Versus Morphine for Moderate and Severe Postoperative Pain... Robert Jan

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, MD, Wilhelm Erdmann, MD, PhD, and Burkhard Lachmann, MD, r h D

Department of Anesthesiology, Erasmus University Rotterdam, The Netherlands

The analgesic efficacy and safety of tramadol and morphine were compared in a double-blind, random- ized 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 satu- ration 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 trama- dol, \ye underline its safety for postoperative pain relief.

(Anesth Analg 1992;74:51&4)

espite respira D mains

well-known disadvantages including tory depression, use of opiates re- a common method for treatment of

postoperative pain (1). New analgesics have been developed over the last few decades including tram- adol, a synthetic opioid analgesic. On the basis of its potency, tramadol has comparatively few disadvan- tages associated with other opiates, such as cardio- vascular reactions and physical dependency (2-7). In opioid-sensitive experimental models, the antinoci- ceptive 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 respira- tory drive associated with increased airway resis- tance. A noninvasive method for measuring respira-

Accepted 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 pro- cedures.

Methods A comparative double-blind randomized study de- sign 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 stud- ied. All patients were considered reliable, coopera- tive, and mentally capable of adhering to the protocol and providing the relevant study information for the whole study period. All patients gave written in- formed 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 mono- amine oxidase inhibitors, or allergic to opioids. Pa- tients did not participate in other drug studies, were not previously admitted to this study, and had no

510 Ane5th Analg 1992,7-1 i 1 0 4 r' 1992 by the International Anesthesia Research Society

0003-2999192155 00

Page 2: Efficacy and Safety of Tramadol Versus Morphine for Moderate and Severe Postoperative Pain... Robert Jan

ANESTH ANALG 1992;74:510--1

HOUMES ET AL. 511 POSTOPERATIVE ANALGESIA AND t-Saoz

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 ) supple- mented 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, treat- ment failure was diagnosed, rescue medication (mor- phine 0.1 mg/kg IM) was given, and the last pain score recorded was used for the remaining observa- tion 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 eval- uated 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 con- tinuously (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 Morphine ( n = 100) ( P I = 50)

Age (yr) Mean Range

Height (cm) Mean Range

Weight (kg) Mean Range

35.6 2 7.5 36.4 2 7.8 23-58 2&57

165.7 2 6 166.8 2 6.2 145-186 15S180

63.4 2 8.4 56.6 2 8.4 48-89 44-83

Values are mean ? SD

If t-Sao, decreased S90%, patients would be in- structed 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 over- all 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 pos- sible interactions. When these were observed, a two- tailed t-test or a two-tailed Fisher's exact test was used. For the variables "treatment failure" and "in- cidence 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 dif- ferences 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 inad- equate 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

Page 3: Efficacy and Safety of Tramadol Versus Morphine for Moderate and Severe Postoperative Pain... Robert Jan

512 HOUMES ET AL. POSTOPERATIVE ANALGESIA AND t-Sao,

0.55

0 .70

0.85

1 . 0 0

1.15

I T -

- - -

-

ANESTH ANALG 1992;74:5104

A

80 85 90 95 100 TRANSCUTANEOUS SaO,(%)

n

2 0 2 - 15

z Y = 10 a 0 u.

5

0 80 85 90 95 100

TRANSCUTANEOUS SaO,(%)

25 ap

2 0 * 0 5 15 2

a

- -

s 10 u.

5

0 80 85 9 0 95 100

TRANSCUTANEOUS SaO,(%)

Figure 1. Relative frequency of 2-min interval t-Saoz measure- ments 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 treat- ment 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 mor- phine 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%

1.30 ' 0 1 2 3 4 5 6

HOURS AFTER lSTDOSE

0.40 I B

0.70

1 .oo d 4 1 . 3 0 0:

1.60

1.90

2 . 2 0 ' I

0 1 2 4 5 6

HOURS AFTER 1'' DOSE

0 .40 C

1.60 0 1 2 3 4 5 6

HOURS AFTER lST DOSE

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), mor- phine (/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 l ine , 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 oxy- gen saturation values from 92 min after administra- tion cannot be meaningfully interpreted a.; the num- ber 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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ANESTH ANALG 1992;74:5104

HOUMES ET AL. 513 POSTOPERATIVE ANALGESIA AND t-Sao,

Table 2. Percentage of Patients According to Time (baseline time is the time of the initial dose) of Remedica tion"

Combined Severe pain Moderate pain group

("/I pain (%) ("/.I T M T M T M

Initial dose only 0 0 18.4 25.0 9.0 12.0 Second dose within 3.9 30.8 18.4 20.8 11.0 26.0

Second dose within 15.7 7.7 8.2 4.2 12.0 6.0 20-40 min

2 M O min and third dose within 50-70 min

(requiring rescue medication)

the above)

Treatment failure 58.8 30.8 14.3 4.2 37.0 18.0

Remainder (none of 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

NESS T OTHERS M

T

DROWZI- M

0 10 2 0 3 0

% 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).

Table 2 shows relative percentage of patients ac- cording 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 be- tween the two study groups.

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

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 mor- phine are similar, tramadol has markedly less clini- cally significant respiratory depressive effects than morphine. Perhaps this is because the analgesic ef- fects of tramadol are mediated by non-opioid receptor mechanisms of action.

Despite the importance of postoperative pain treat- ment, fear of respiratory depression or hypotension may result in some withholding of opioid adminis- trations by medical and nursing staff, often aggravat- ing 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 sup- port 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 recom- mended. 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 anal- gesic (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.

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514 HOUMES ET AL ANESTH ANALC POSTOPERATIVE ANALGESIA AND t-Sao, 1992;74:5104

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the effects of different opioids, including tolerance and cross- tolerance to morphine. Eur J Pharmacol 1991;195:3745.

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11. Parkhouse J, Pleuvry BJ, Rees JMH. Controlled clinical trials of analgesic drugs. In: Analgesic drugs. London: Blackwell, 1979:

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8 a i i 4 .