.4cta anaesth. scand. 1982, 26, 69-71

Epidural Met-Enkephalin (FK 33-824). A Dose-Effect Study H. B. ANDERSEN, B. C. JBRGENSEN and A. ENGQL'IST

Department of Anaesthesiology, Herlev Hospital, University of Copenhagen, Herlev, Denmark

The present study examines the analgesic effect on postoperative pain of 0.001-0.5 mgofepidural FK 33-824. a synthetic met-enkephalin analogue. The results showed that FK 33-824 diluted in 10 ml of isotonic aalinr induced analgesia in doses of0.02,0.05,0.1,0.2, and 0.5 mg. The analgesic effect, however, was inferior to that of epidural morphine (4 mg in lOml isotonic saline), since analgesia was unpredictable and clinically insuKcient in four out of eight patients receiving 0.02-0.5 rng. Additionally, the duration of action was shorter for FK 33-824 than for morphine.

Receiiad 13 April, accepted for publication 15 September 1981

The field of epidural and spinal opiates in clinical practice is promising and has been increasing ever since the first reports of BEHAR et al. and WANC et al. in 1979. In a few studies (BROMACE et al. 1980, JBRGENSEN et al. 1980a, b), both morphine and methadone have been shown to be superior alternatives to conventional pain treatment, when applied to the subarachnoid or epi- dural spaces.

The ideal opiate, however, with a minimum of side effects and a maximum of potency and duration of action has not been found. FK 33-824, a synthetic met- enkephalin analogue with higher affinity to the opiate receptors and longer duration of action (as shown in animals after intracerebroventricular, intravenous, or oral administration (ROEMER et al. 1977)) could possibly be a superior alternative to morphine or methadone. The purpose of the present study was to investigate in humans the effects and side effects ofepidural FK 33-824 with special reference to minimum effective dosage and duration of action.

MATERIAL AND METHODS Fifteen adults of both sexes, subjected to nephrectomy or pyelo- lithotomy, were included in the study after informed consent had been obtained. None of the patients suffered from cardiovarcular, pulmo- nary, cerebral or hepatic dysfunctions. Age, weight, type of operation and dosage given appear in Table 1.

Study deJign All patients were premedicated with diazepam 0.2 mg/kg orally 1 h before induction of anaesthesia. Preoperatively, a n epidural catheter (Portex 18 gauge) was placed in the lumbar region at the level of Lz-L3 or L3-L,. Anaesthesia was induced with thiopentone 4-5 mg/kg and suxamethonium 1 mg/kg was given to facilitate intubation. Anae- sthesia was maintained with halothane 1-2% inspiratory concentra-

tion and NzO/Oz 1:l. Pancuronium was given for muscular relasa- tion.

After termination of surgery the patients were transferred to the recovery room. When the patients awoke from anaesthesia, the intensity of pain was evaluated according to a visual analogue pain scale and a corresponding observer scale (Table 2). If pain scores exceeded 5, FK 33-824dissolved in 10 ml ofisotonic saline was injected via the epidural catheter in doses according to Table I . If pain reappeared or was not relieved within 15 min by FK 33-824, 5 mg of nicomorphine (VilanB) was given intravenously and 5 mg intra- muscularly.

Before the epidural application of FK 33-824and again 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, and 6 h after injection, the following variables were evaluated: (1) Pain intensity according to the pain analogue scales (Htrsttrsw~

1974) (Table 2). (2) Systolic and diastolic blood pressures. (3) Respiratory rate. (4) Size of pupils (unchanged, smaller. larger). (5) Auscultation of the abdomen (O=no bowel sounds, l = a fcw.

2=moderate, 3=vigorous bowel sounds). (6) Blood samples were taken from those patients receiving from

0.1 to 0.5 mg of FK 33-824 at 15 min, 30 min, and 1 h after the injection of the met-enkephalin analogue for measurements of plasma concentrations of FK 33-824 employing an immuno- assay technique (HAUSER & Cmsss 1981).

After termination of the 6-h study period, all patients received epidural morphine 4 mg in 10 cc ofsaline three times a day frx the next 3 days. The duration of analgesia after one dose of 4 mg of morphine was compared to that of FK 33-824.

Statistics

The Wilcoxoti test for paired differences was employed. P<0.05 was considered significant.

RESULTS 1. Pain intensity (Table 3). Two patients were excluded from the study. Patient no. 10 did not have pain post-

0001-5172/82/010069-03 $ 02.50/0 @ 1982 The Scandinavian Society of Anaesthesiologists

70 H. B. ANDERSEN Er AL.

Table 1

Patient data.

Dose of FK 33-824 Age Weight Patient no. (mg) Sex (Years) (kg) Type of operation

1 0.00 1 9 60 69 Nephrectomy 2 0.002 9 61 82 Nephrectorny 3 0.005 9 46 45 Nephrectorny 4 0.010 8 57 87 Pyelolithotorny 5 0.010 8 67 61 Nephrectorny 6 0.020 9 55 60 Nephrolithotomy 7 0.020 9 59 57 Nephrolithotorny 8 0.050 8 30 69 Pyelolithotorny 9 0.050 8 33 79 Ureterolithotorny

10 0.100 8 35 68 Herniotomy 11 0.100 9 67 51 Ureterolithotomy 12 0.200 9 37 54 Pyelolithotorny 13 0.200 8 56 90 Nephrectorny 14 0.500 8 67 72 Nephrectomy 15 0.500 8 46 84 Nephrolithotomy

Table 2 Visual analogue and corresponding observer pain scales.

0 0 No pain 1-2

3-4

No pain at rest, slight pain on movement and

Slight pain at rest, moderate pain on movement

and 5-6 Moderate pain at rest, severe pain on movement

coughing

and coughing

and coughing

movement and coughing 7-8 Severe pain at rest, excruciating pain on

10 9-10 Excruciating pain

Table 3 The decrease in pain score, duration of analgesia after injection of FK 33-824 and total doses of nicomorphine during the study period of 6 h in eight patients after surgery.

Duration of Dose Patient Decrease in analgesia Nicornorphine (rng) no. pain score (hours) (mg)

0.02 6 8-2 7 0 7 8-3 3 5

0.05 8 7-2 >6 0 9 8-8 0 30

0.10 11 6- 1 2 20

0.20 12 8-2 7 0 13 8-2 1 30

0.50 14 7-2 7 0

operatively. In patient no. 15, the epidural catheter was displaced.

Before injection of FK 33-824, most patients showed pain scores of 6-9. After doses of 0.001-0.01 mg of FK 33-824 to five patients, pain scores decreased only 1-2 points. Additionally, these patients needed a mean total dose of 17k6.9mgofnicomorphine during the 6-hstudy period.

In two patients receiving 0.02 mg of FK 33-824 (patients no. 6 and 7, Table 3), analgesia was induced after 15 min, since pain scores decreased from 8 to 2 and 3, respectively. In these two patients pain relief was present for 7 and 3 h, respectively. Patient no. 8, who received 0.05 mg, showed a reduction in pain score from 7 to 2 after 30 min and a duration of pain relief exceeding 6 h. In patient no. 9, no analgesia was induced. Patient no. 11, who received 0.1 mg, showed a decrease in pain score from 6 to 1 after 16 min. The duration ofpain relief was 2 h. In the two patients receiving 0.2 mg (patients no. 12 and 13, Table 3), analgesia appeared after 30 and 15 min, respectively. There was a decrease in pain score from 8 to 2 in both patients, but duration of analgesia was 7 h in patient no. 12 and only 1 h in patient no. 13. In one patient, who received 0.5 mg (patient no. 14), analgesia commenced after 45 min. Pain score de- creased from 7 to 2 and duration of pain relief was 7 h.

Table 3 thus shows that FK 33-824 in patients receiving effective doses induced a dose-independent pain relief in only four out of eight patients. Analgesia was sufficient for more than 6 h in these four patients and they did not require injections of nicomorphine. The

EPIDURAL MET-ENKEPHALIN 71

effect in these patients was comparable to analgesia induced by 4 mg of epidural morphine given after the study period.

2. Systolic and diastolic blood pressures. Blood pressures varied insignificantly in all patients after the injection of

3. Respiratory rate. A slight but significant dose- independent decrease in respiratory rate (3-4 breath/ min) was found 4 h after the injections of FK 33-824 in four out of eight patients with sufficient analgesia. No episodes of delayed respiratory depression were observed after termination of the study.

4. Size of pupils. No changes were observed after injection of FK 33-824.

5. Auscultation of the abdomen. No changes were ob- served after injection of FK 33-824.

6. Plasma concentrations. The results are shown in Table 4. Fifteen min after the epidural application of 0.1-0.5 mg of FK 33-824, there was a vascular uptake. During the next 60 min the plasma concentration increased significantly. A dose-dependent increase in plasma concentrations was found. However, there was no corre- lation between plasma concentrations and pain relief.

FK 33-824.

Table 4 Plasma levels of FK 33-824 (ng/ml) 15, 30, and 60 min after epidural injection. Measurements are made in triplicate. (Mean fs .d . ) .

Patients Dose (mg) 15 rnin 30 min 60 min

1 0.1 1.31f0.07 1.84f0.17 2.03f0.11 1 0.2 3.24f0.21 4.5 f0 .20 5.02f0.34 1 0.5 11.28f0.25 13.11f0.31 10.21k0.22

DISCUSSION Met-enkephalin, a naturally occurring opiate peptide, is subject to rapid metabolic breakdown in the blood and brain by proteolytic enzymes when injected parenterally or even directly into the cerebral ventricles. FK 33-824, a synthetic analogue ofmet-enkephalin is less susceptible to enzymatic degradation. It has been shown that FK 33-824 exerts long-lasting and potent analgesic effects in the mouse and in the rat after intracerebroventricular, intravenous and even after oral administration (ROEMER et al. 1977). In humans there have been subjective side effects (feeling of heaviness in the legs, feeling of pressure on the chest, chemosis, increased bowel sounds and diarrhoea) (GRAFFENRIED personal communication 1978).

The results of the present study showed that epidural FK 33-824 induced postoperative analgesia (after neph-

rectomy or pyelolithotomy) in doses ranging from 0.02 to 0.5 mg after 15-45 min. The analgesic effect persisted for from 2 to 7 hours, independent of the doses given. The analgesic effect, however, was found unpredictable since acceptable analgesia was found in only four out of eight patients as measured by the doses ofnicomorphine given. When compared to epidural morphine, FK 33- 824 had a slower onset and a shorter duration of action (BEHAR et al. 1979, JBRGENSEN et a]. 1980a). A rapid vascular uptake of FK 33-824 took place after epidural application, as seen in Table 4. This has also been shown after epidural morphine (JBRGENSEN et a]. 1981).

Conclusion Only four out of eight patients receiving FK 33-824 in doses ranging from 0.02 to 0.5 mg showed sufficient analgesia after nephrectomy or pyelolithotomy. The analgesic effect was thus unpredictable and dose-inde- pendent. Although no side effects were observed, FK 33- 824 showed no advantages compared to epidural mor- phine.

ACKNOWLEDGEMENTS FK 33-824 was kindly supplied by Dr. Beat von Graffenried, Sandoz, Basle.

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BROMAGE, P. K., CAMPORESI, E. & CHESTNI!T, D. (1980) Epidural

HAUSER, D. & CLOSSE, A. (1981) Plasma levels of FK 33-824 hy

HUSKISSON, E. C. (1974) Measurement of pain. Lancet ii, 1127.

Epidural morphine in the treatment of pain. Lancet i, 527.

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JBRGENSEN, B. c . , ANDERSEN, H. B. & ENGQUIST, A. (1980a) Epidural morphine in the treatment of acute and chronic pain. lipesskr. Lag. 142, 2266.

JBRGENSEN, B. C., ANDERSEN, H. B. & ENGQUIST, A. (1980b) Epidural morphine and postoperative pain. Abstracts of 7th World Congress of Anaesthesiologists, Hamburg, Excerpta Medica, p. 456.

and plasma concentrations of morphine after epidural application. Anesthesiolou. In press.

ROEMER, D., BUESCHER, H. H. & HILL, R. C. (1977) A synthetic enkephaline analogue with prolonged parenteral and oral analgesic activity. Nature 268, 547.

WANG, J. K., NAUSS, L. A. & THOMAS, J. E. (1979) Pain relief by intrathecally applied morphine in man. Anesthesiofogy 50, 149.

J0RGENSEN, B. C., ANDERSEN, H. B. & ENGQUIST, A. (1981) Spinal-

Address: Hans B. Andersen, M.D. Department of Anaesthesiology Herlev Hospital University of Copenhagen DK-2730 Herlev Denmark