“ NISENTIL ” IN OBSTETRICS

Clinical Trials with a New Analgesic BY

HILDA ROBERTS, M.R C.S., D.C.H., D.A. Lecturer in Anaesthetics, Postgraduate Medical School, London

FRED WRIGLEY, M.R.C.S., D.I.H., M.P.S.* Late Director of Clinical Research, Roche Products Limited,

Welwyn Garden City

AND

‘& Give yourself no unnecessary pain.” -SHELLEY: The Cenci “ 9 iv, 158.

As a preliminary one of us (H.R.) and her assistant received 20 mg. of the drug intra-

THE value of Pethidine, a piperidine derivative, muscularly. Approximately 5 minutes after the as an analgesic in obstetrics has been clearly injection both experienced a sense of warmth, demonstrated by Barnes (1947) and many other contentment, and a very mild degree of workers. Its special usefulness when supple- elation. A headache suffered by one of them merited with Scopolamine has also been was not abolished, but the pain seemed to be reported (Roberts, 1948). Consequently the Pushed into the background for a period of synthesis of another piperidine derivative, about 14 hours. NO ill effects were experienced. ‘+ Nisentil ” (Ziering and Lee, 1947), raised the After this initial personal trial the drug was question of its possible use in obstetrics. given to 200 patients in labour, 95 primi-

6‘ Nisentil 73 is d l-alpha- 1, 3-dimethyl-4- gravidae and 107 multiparae. The patients phenyl-4-propionoxy piperidine hydrochloride fell into 2 groups. (known also as Nu 1196). (A) Cases where the pregnancies had been

normal and where the labour was ex- pected to take a normal course.

(B) Patients who were sufficiently advanced in labour to require sedation at the time they were seen in the labour ward.

Dosage and the method of administration

I i‘i p \ I I \ 4 \, COOC, H, \/\/ OCOC,H,

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I I The same guiding principles were used as with CH, C*, Pethidine or Pethidine and Scopolamine.

Labour was well established and uterine con- Pethidine ‘‘ Nisentil ”

The pharmacology of ‘ 6 Nisentil*’ has been tractions were of good amplitude and occurring described by Randall and Lehmann (1948) and at regular intervals. The dilatation Of the 0 s Gmber et al. (1950) and clinical studies have uteri Was about 3 fingers in primigravidae and been reported by Smith and Nagyfy (1949) and 2 fingers in mdtiparae. All patients received LaForge (1951). the drug intramuscularly. Those in the early

The favourable results report& encouraged phase Of the trials were given an initial dose of US to undertake an investigation into its value in 40 which was r e P a t 4 in Some cases about hospital practice. 1 to 3 hours after the first injection. The number

______ of doses given depended on the needs of the * NOW Medical Director, Ciba co., Ltd., ~ ~ ~ t ~ ~ ~ l . patient. The initial dose was increased as our

experience of the drug widened, and the maxi-

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Canada. 538

‘‘ NISENTIL ” IN OBSTETRICS

mum single dose given was 80 mg. In the 200 observed cases the amount of “ Nisentil ” given had the distribution shown in Table I.

TABLE I __ No. of patients Initial dose

39 40 mg. 61 60 mg.

80 mg. 100

No. of patients Total amount of drug given

--

26 40 mg. 52 60 mg.

100 80 mg. 8 100 mg.

12 120 mg. 2 140 mg.

Five to 10 minutes after the administration of “ Nisentil ” the patients appeared to experi- ence the same feeling of warmth and relaxation already described and frequently fell asleep. The effects lasted approximately 2 to 3 hours.

Patients were disturbed by the uterine con- tractions, if they were asleep, and, if they were awake, maintained that they still felt the pain but invariably added that they were not unduly troubled by it. Most patients said that they felt rested, even if they had not slept, and appeared to be willing to co-operate and work in the 2nd stage. The response did not always corre- spond to the amount of “ Nisentil ” given as some of the patients were quite comfortable after 60 mg. (or even 40 mg.) yet others would receive only partial relief after the administra- tion of 80 mg. The pain and restlessness caused by uterine contractions of severe intensity were not relieved by “ Nisentil ”.

Some patients exhibited side-effects, i.e.. dizziness occurred in 10 patients, nausea in 1 and vomiting in 4 cases. The vomiting may not have been due to the drug as these 4 patients complained of nausea before the injection. These subjective symptoms were short-lived in the majority of cases. An urticaria1 rash appeared on 1 patient but it was localized to the site of the injection; it disap- peared the next day and there were no other symptoms associated with it.

Labour appeared to progress normally and there was no apparent alteration in the uterine contractions, providing the drug was not given

539 too early in labour. Figs. 1 and 2 show uterine contractions recorded on the kymograph using an abdominal tambour.

Relief of pain based on the mothers’ opinions

Relief ... ... ... Good Fair Poor No. of Patients ... ... 148 48 4

Incidence of foetal asphyxia Out of 200 cases 29 showed asphyxia of

varying degree. Excluding the mild cases that responded immediately to the aspiration of the mouth and pharynx the percentage is reduced to 6.5. Flagg’s classification is used in analyzing the incidence of asphyxia neona- torum. Degree of asphyxia Mild Moderate Severe Stillbirths No. of babies 16 11 2 1

In the case of the stillbirth there was delay in the second stage of labour due to a contracted pelvic outlet. The foetal heart became irregular approximately 10 minutes before the infant was delivered by forceps. A general anaesthetic, nitrous oxide oxygen and Neothyl, was given for the instrumental delivery and the infant was extracted with some difficulty. The mother had received “ Nisentil ” 80 mg. 4 hours 45 minutes before delivery and a second injection of 60 mg. 13 hours before the baby was born. The second stage lasted 1 hour 10 minutes. Many abnormal factors have to be taken into account and how much the drug contributed to the stillbirth can- not be ascertained. The 2 babies severely asphyxiated were :

both during and after labour :

In a patient 36 weeks pregnant in whom 80 mg. “ Nisentil ” was given 40 minutes before delivery. Labour proceeded much more rapidly than was expected. The infant responded to endotracheal intuba- tion and oxygenation and the condition was satisfactory after 15 minutes. The infant was born with the cord wound tightly around its neck. The mother had 60 mg. of “ Nisentil ” 3 hours 20 minutes before delivery. The condition of the baby was satisfactory within 15 minutes of delivery, responding quickly to intu- bation and oxygenation.

540 JOURNAL OF OBSTETRICS AND GYNAECOLOGY

The moderately asphyxiated infants res- ponded to aspiration of the upper respiratory passages, administration of oxygen, and rocking. In every case except 3 there were obstetric causes to account for the asphyxia and in these it is again difficult to say what part, if any, the drug played in producing asphyxia.

The maternal blood-pressure showed little variation during the administration of the drug, and any recorded rise usually coincided with a uterine contraction.

Incidence of complications occurring in the third stage of labour: Retained placenta and postpartum haemorrhage 1 Retained placenta . . . . . . . . . . . . . . . 1 Postpartum haemorrhage . . . , , . , .. ... 6

DISCUSSION It is appreciated that 200 cases cannot bring

to light the merits and deficiencies of any drug, and it has proved rather difficult to compare the value of “ Nisentil ” with that of Pethidine, or Pethidine and Scopolamine in combination, and the barbiturates. However, it is felt that this drug will relieve the stress and pain of labour. Perhaps its effectiveness lies in its apparent ability to relieve anxiety and produce a calmer and more relaxed patient. Where the uterine contractions were very strong and painful the drug did not appear to have a marked analgesic effect, but even the most powerful pain-relieving drugs may fail in these cases, and only actual anaesthesia will obliterate the pain. After our long experience of Pethidine and Scopolamine it was a little disturbing to see patients reacting restlessly to each contraction. Nevertheless, a

very large proportion of the mothers were favourably impressed and their comments pointed to the effectiveness of the drug. The full co-operation of the patient was maintained and amnesia was not evident in any of the cases observed, hence the memory of their labour was not blurred by any amnesic effect of the “ Nisentil ”. This makes their personal obser- vations all the more valuable.

SUMMARY .‘ Nisentil ”, a piperidine derivative, has been

used as an analgesic in 200 obstewic cases. The anxious patient was calmed. Cases of asphyxia were few and complications rare in the series treated.

Our thanks are due to Professor J. C. McClure Browne for allowing us access to patients and for permission to publish our results. We should also like to express our thanks to Sister Kanz, Instructress in Obstetric Analgesia, and Sister Summers, late Assistant Instructress in Obstetric Analgesia, for their patient and conscientious help in conducting this investigation, and to Roche Products Limited for the “ Nisentil ”.

REFERENCES Barnes, J. (1947): Brit. med. J . , 1, 437. Gruber, C. M., jr., Lee, K. S., and Gruber, C. M.

(1950): J . Pharmacol., 99, 312. LaForge, H. G. (1951): N.Y. Sz. J . Med., 51, 1835. Randall, L. O., and Lehmann, G. (1948): 1. Pharma-

Roberts, H. (1948): Brit. med. J . , 2, 590. Smith, E. J., and Nagyfy. S. F. (1949): Arner. J.

Ziering, A., and Lee., J. (1947): J. org. Chem., 12, 91 I .

cot., 93, 314.

Obstet. Gynec., 58, 695.

FIG. 1

H.R. 8L F.W.