Systemic and Inhalation Analgesia

Br.J. Anaesth. (1979), 51, IIS

SYSTEMIC AND INHALATION ANALGESIA M. ROSEN

pethidine 50-100 mg i.m. provides pain relief for only about 40% of patients (Moore, Carson and Hunter, 1970; Holdcroft and Morgan, 1974) whereas 50-60% of patients claim satisfactory pain relief with an i.m. dose of 150 mg (Grant, Holt and Noble, 1970). Biological variation gives rise to differences in drug requirements which cannot be met by any standard i.m. dose. Individual need can be met more satisfactorily by administering pethidine i.v. according to patient demand. This can be achieved safely, and without increasing medical participation, utilizing an apparatus programmed by the clinician (Evans et al., 1976; McCarthy et al., 1976). The total dose of analgesic prescribed by the clinician is delivered i.v. by a syringe pump which is set to deliver any increment between 1 fig and 999 mg. The speed of injection can be controlled to reduce side-effects from a peak blood concentration; 3-4 min has been used in labour. The minimum duration between two increments can be set at any interval from 0 to 99 min. This interval is Narcotics and tranquillizers I.m. pethidine is prescribed for about 70% of necessary to avoid overdose by allowing the mother mothers in labour (Chamberlain et al., 1975). Usually to appreciate the effects of the increment before a the timing of administration is left to the midwife's further demand. In labour an interval of 10 min has judgement, enabling a prompt response to the been used, which ensures that two or three conInitially an incremental mother's requests. The wide difference in the chosen tractions elapse for assessment. 1 dose (50-150 mg) arises mainly from concern over dose of 0.25 mg kg" was chosen empirically, but it the depressant effects of pethidine on the newborn. has since been shown by us that it is not necessary to However, in some women pethidine is associated with use such a precise dose, provided that the increments poor pain relief, resulting in drowsiness and an are not so small that, even cumulatively, they have unpleasant, almost dissociated, state (O'Driscoll and little effect, or are so large that undesirable side-effects Stronge, 1973). It is possible that smaller doses may result from each. It has been found that on offering1 be made more effective when reinforced by relaxation an incremental dose of 0.125, 0.25, or 0.375 mg kgtechniques, and when loneliness, fear and anxiety are to randomly selected mothers in labour, the times minimized (O'Driscoll and Stronge, 1973). Un- between demands were significantly longer with the fortunately, optimum conditions exist in only a few higher incremental doses (Hogg, 1977). This is obstetric units, most of which are imperfectly organ- presumably a result of "feedback" because the ized. Also, comparisons are lacking between the mother is balancing the maximum pain relief achievdose required under optimum and suboptimum con- able with pethidine (rarely perfect) against undesired ditions, so that the routine dose is usually dependent side-effects, such as drowsiness. This phenomenon is upon personal prejudice. Studies indicate that present also when inhalation analgesia is used (Latto, Molloy and Rosen, 1971). M. ROSEN, M.B., CH.B., F.F.A.R.C.S., Department of Anaes-

thetics, University Hospital of Wales, Heath Park, Cardiff, CF4 4XW. 0007-0912/79/130011-05 $01.00

The apparatus has been tested in an obstetric unit in which extradural analgesia was not available. Mothers who were willing to have pethidine had either © Macmillan Journals Ltd 1979

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Pain relief is not life saving for the mother or her baby, other than in exceptional circumstances. Therefore, comparisons of methods of pain relief should include consideration of safety, effectiveness and cost. In any case, dependence on a single technique for the management of labour pain is unsound, since it assumes falsely that there is uniformity of maternal requirements. Although safety is never absolute as far as the mother is concerned, inhalation analgesia and narcotics are very safe. There has been no death associated with these techniques and drugs in more than 15 million deliveries (Department of Health and Social Security 1975). No other method approaches this record. That is the main reason why pethidine and "gas" are so widely used in the United Kingdom under the supervision of midwives, although under strictly controlled conditions.

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Pethidine causes nausea and vomiting in about 15% of patients and some clinicians administer metoclopramide 10 mg or perphenazine 5 mg which reduces the frequency to 5% or less (McGarry, 1971). However, it is more logical to treat those who suffer nausea or vomiting than to administer anti-emetics routinely to every mother.

the mother can be detected in the neonate. PaCOi! is increased for at least 24 h (Koch and Wendel, 1968), there is a depression of feeding measures for days compared with children of mothers who received no drugs in labour (Kron, Stein and Goddard, 1966; Dubignon et al., 1969), and there is depression of other neurological functions (Richards and Bernal, 1972; Brackbill, Kane and Manniello, 1974; Weiner, Hogg and Rosen, 1977a, b). However, naloxone 40 pig i.v. when compared with placebo, administered at birth (Evans et al., 1976), resulted in a significant decrease in Pa C02 and an increase in alveolar ventilation for about 30 min after birth (Evans et al., 1976). After 4 h no difference could be found between the groups (Wiener, Hogg and Rosen, 1977a, b). When naloxone 200 ;xg or placebo was administered i.m. at birth, significant differences were present up to 48 h in ventilatory, feeding andneurobehavioural responses. Indeed the naloxone-treated babies seemed similar to babies whose mothers did not receive drugs during labour. It seems likely that naloxone can reverse the effects of pethidine in the newborn. It may now be more rational to relate pethidine dose to maternal requirements, with less concern about the fetus.

Diazepam Diazepam reduced the total dose of pethidine required in one trial which was not double-blind (Friedman, Niswander and Sachtlebern, 1969). Since it is difficult to conceal the effects of diazepam, this effect may have been artefactual. Diazepam 0.3 mg kg" 1 i.m. improved the maternal opinion of pain Effects on the baby relief, but the required dose of pethidine was unPethidine administered to the mother during labour changed (Davies and Rosen, 1977). During labour depresses the respiration of the newborn at birth diazepam is now mainly reserved for the management (Rosen et al., 1969) and for at least 48 h afterwards of severe pre-eclampsia or eclampsia. (Wiener, Hogg and Rosen, 1977a, b). It has been Diazepam can cause severe hypotonia in the suggested, from information derived in a retronewborn at birth and subsequent hypothermia and spective study of Apgar scores, that pethidine these effects may be evident for several days. It is administered more than 4 h or less than 1 h before recommended therefore that no more than 30 mg of delivery has less effect on respiration at birth (Shnider diazepam be administered to the mother during and Moya, 1964). However, urinary excretion of labour (Cree, Meyer and Hailey, 1973). pethidine is greater and significantly so, up to a doseto-delivery interval of 5 h (Hogg et al., 1977). Although pethidine depresses respiratory adaptation Inhalation analgesia at birth, reducing the Apgar score by 1-2 points In the United Kingdom inhalation agents are self(Rosen et al., 1969), this is rarely substantial as a sole administered intermittently by the mother in labour, factor. However, the effects of pethidine may be more under the supervision and encouragement of a midserious for the premature infant (Maternal and Child wife. A fixed concentration of 50% nitrous oxide in Health Service, 1967), although no definite evidence oxygen (Entonox) or 0.35% methoxyflurane in air are exists to determine if this is so. used commonly, although trichloroethylene 0.5% is After birth the effects of pethidine administered to still available. The effectiveness of self-administered

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100 mg i.m. (the routine dose in that unit) or i.v. by self-administration usually with 350 mg available. The total dose of pethidine was prescribed by the doctor, who inserted the i.v. cannula. The apparatus was prepared and supervised entirely by midwives according to prepared instructions. An incremental dose of pethidine 20 mg was administered to all mothers of 60-80 kg weight, and 15 mg for lighter or 25 mg for heavier mothers. In 103 primagravidae, the mean dose of pethidine demanded i.v. was 217 mg (range 60-600 mg) compared with 171 mg (range 100-300 mg) administered by the i.m. route. Seventythree per cent of the mothers who had selfadministered pethidine reported complete or considerable pain relief, compared with 40% of those who had pethidine i.m. (P< 0.005). The apparatus was used for approximately 25% of deliveries and about three apparatus were required to cover simultaneous demands in the unit (2500 deliveries per annum). The apparatus was found to be most valuable in early labour, since there was more time to balance the need for analgesia. Other analgesics are being tested since pethidine is not ideal in some respects.

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inhalation depends upon how closely peak brain concentration can be made to coincide with the peak of the contraction, that is with the greatest pain. In the periods between contractions the mothers' blood concentration is reduced and she is therefore less likely to fall asleep or become semi-conscious. In that way maximum suppression of painful stimuli can be attained with reasonable safety. It is most important as an element of safe practice that the mask should only be held on the mother's face by herself; then if she falls asleep the mask can fall away and she will breathe air. When inhalation analgesia is used effectively about 70% of mothers report considerable or complete pain relief (Rosen et al., 1969; Holdcroft and Morgan, 1974), but accurate timing of inhalation is essential to successful administration. With a soluble agent such as methoxyflurane this is achieved more easily since the mother regulates her breathing to attain optimum blood concentration (Latto, Molloy and Rosen, 1971), and in any case the fluctuations in blood concentrations of methoxyflurane during and between contractions are about half the peak concentration. Under optimal conditions about 90% of mothers having methoxyflurane consider pain relief as complete or considerable (Major, Rosen and Mushin, 1967; Rosen, 1975). However, it is a drawback that about one-third of mothers and midwives dislike the smell of methoxyflurane. Therefore Entonox, which has no smell, is the more popular agent. The relative insolubility of nitrous oxide renders it much more difficult for the mother and midwife to judge the timing of inhalation and the rapid uptake and excretion are reflected in less satisfactory results.

Effects on the baby Inhalation agents have little effect on fetalneonatal respiratory adaptation and are excreted rapidly when respiration is established. After continuous inhalation, end-tidal nitrous oxide decreased to less than 2% 8 min after birth (Arthurs and Rosen, 1979). Methoxyflurane is metabolized by the neonate and low concentrations of fluoride can be found in neonatal urine up to 48 h after birth (Weiss and deCarlini, 1975). However, there has been no evidence of renal abnormality.

A method has been evolved which attempts to reduce- fluctuation in blood concentrations by ensuring a steady blood concentration between contractions so that the time needed to reach peak concentration can be reduced during intermittent administration. A flow (5 litre min"1) of Entonox is inhaled continuously through a nasal catheter while Entonox is breathed through a mouthpiece during uterine contractions (Dolan and Rosen, 1976). It was found in controlled trials that more than 70% of mothers were willing to accept the method during labour. The mean concentration of end-tidal nitrous oxide between contractions was 14.8% with nitrous oxide administered nasally compared with only 2% with intermittent nitrous oxide only. There is a substantial improvement in the mothers' opinions of the pain relief, and the method is undergoing wider field trials (Arthurs and Rosen, 1979).

REFERENCES

Arthurs, G., and Rosen, M. (1979). Self administered intermittent nitrous oxide analgesic for labour. Anaesthesia (in press). Brackbill, Y., Kane, J., and Manniello, R. L. (1974). Obstetric meperidine usage and assessment of neonatal status. Anesthesiology, 40, 116. Chamberlain, R., Chamberlain, G., Howlett, B., and Claireaux, A. (1975). British Births 1970, Volume 1: The First Week of Life. London: Heinemann. Cree, J. E., Meyer, J., and Hailey, D. M. (1973). Diazepam in labour: its metabolism and effect on the clinical condition and thermogenesis of the newborn. Br.J. Med., 4, 251. Davies, J. M., and Rosen, M. (1977). Intramuscular diazepam in labour. A double-blind trial in multiparae. Br. J. Anaesth., 49, 601. Department of Health and Social Security (1975). Report on Confidential Enquiries into Maternal Deaths in England and Wales 1970-1972. Reports on Health and Social Subjects No. 11. London: H.M.S.O. Dolan, P., and Rosen, M. (1976). Inhalational analgesia in labour: facemask or mouthpiece? Lancet, 2, 1030. Dubignon, T., Campbell, D., Curtis, M., and Partington, M. W. (1969). The relation between laboratory measures of sucking, food intake and perinatal factors during the newborn period. Child Dev., 40, 1107. Evans, J. M., and Rosen, M. (1976). Reversal of narcotic depression in the neonate by naloxone. Br. Med. J., 2, 1098. McCarthy, J. P., and Hogg, M. I. J. (1976). Apparatus for patient-controlled administration of intravenous narcotics during labour. Lancet, 1, 17. Friedman, E. A., Niswander, K. R., and Sachtlebern, M. R. (1969). Effect of diazepam during labour. Obstet. Gynecol., 34, 82. Grant, A. M., Holt, E. M., and Noble, A. D. (1970). A comparison between pethidine and phenazocine (Narphen) for relief of pain in labour. J. Obstet. Gynaecol. Br. Commonw., 77, 824. Hogg, M. I. J. (1977). The pharmacokinetics of drugs administered systemically during labour. M.Sc. Thesis, Welsh National School of Medicine, University of Wales. Wiener, P. C , Rosen, M., and Mapleson, W. W. (1977). Urinary excretion and metabolism of pethidine and norpethidine in the newborn. Br.J. Anaesth., 49,891.

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Moore, J., Carson, R. M., and Hunter, R. J. (1970). A comparison of the effects of pentazocine and pethidine administered during labour. J. Obstet. Gynaecol. Br. Commonw., 11, 830. O'Driscoll, K., and Stronge, M. (1973). Active management of labour. Br. Med.J., 3, 590. Richards, M. P. M., and Bernal, J. F. (1972). An observational study of mother-infant interaction; in Ethological Studies of Child Behaviour (ed. N. B. Jones). Cambridge: Cambridge University Press. (1975). A survey of current methods of pain relief in labour; in The Management of Labour. Proceedings of the Third Study Group of the Royal College of Obstetricians and Gynaecologists (eds.R. Beard, M. Brudenell, P. Dunn, and D. Fairweather), p. 140. London: R.C.O.G. Mushin, W. W., Jones, P. L., and Jones, E. V. (1969). Field trial of methoxyflurane, nitrous oxide and trichloroethylene as obstetric analgesics. Br. Med.J., 3, 263. Shnider, S. M., and Moya, F. (1964). Effects of meperidine on the newborn infant. Am.J. Obstet. Gynecol., 84, 1969. Wiener, P. C , Hogg, M. I. J., and Rosen, M. (1977a). Effects of naloxone on pethidine-induced neonatal depression. I: Intravenous naloxone. Br. Med. J., 2, 228. (1977b). Effects of naloxone on pethidineinduced neonatal depression. II: Intramuscular naloxone. Br. Med. J., 2, 229. Weiss, V., and de Carlini, C. (1975). Placental transfer of fluoride during methoxyflurane anaesthesia for Caesarean section. Experientia, 31, 339.

DISCUSSION DR M. FINSTER (NEW YORK) : I was very interested in your remarks regarding the variability in the dosage of pethidine between patients. However, your slide did not show the important factor of time. It is not the total dose of pethidine given during labour that is so important, rather the dose per hour. Do you have any data on this ? In addition, am I right in saying that although your babies in the naloxone study received only one dose of naloxone their arterial carbon dioxide tensions were lower than in the control group for as long as 48 h ? DR ROSEN : Of course time is very important and, when this is allowed for, the variability between patients is narrowed. However, it is still very considerable, some patients requiring as much as six times more than others. We were also very surprised to find that a single i.m. dose of naloxone had such a long-lasting effect. Because of this we repeated the study and found exactly the same results. From measurements of drug concentrations we are now of the opinion that naloxone is pharmacologically active for at least 12 h. However, it may well be that naloxone triggers other mechanisms which are responsible for the much longer-lasting respiratory effects. For instance naloxone-treated babies all fed better than the control group, thus giving the baby an increased acid fluid load. This and other factors, therefore, may well lead to a much more rapid excretion of pethidine in the treated neonate.

DR BONICA: I think that the use of maternal mortality rates in assessing obstetric analgesia is far too crude. There should be no mortality in properly conducted analgesia by whatever method. It is much more important to look at morbidity in both mother and neonate and when this is done for abnormal deliveries you will see a clear advantage to local anaesthetic methods. DR ROSEN : Yes, I quite agree with that and there is some evidence that extradural block may be important for the delivery of premature infants (Maternal and Child Health Service, 1967). However, I did just want to point out that all hospitals do not have the same high standards and it is towards improving standards that we must direct most of our effort. DR H. H. BRAUTIGAM (HAMBURG): I cannot agree that the use of pethidine is free from dangers to the fetus and neonate. If the fetal heart rate is carefully monitored, you will see that the administration of pethidine often has a deleterious effect on the fetus. Neonatal morbidity and mortality are much higher when narcotic analgesics are given. D R ROSEN : We carry out careful monitoring of the fetal heart rate during labour and do not see abnormalities in the heart rate patterns following the administration of pethidine.

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Holdcroft, A., and Morgan, M. (1974). An assessment of the analgesic effect in labour of pethidine and 50 per cent nitrous oxide in oxygen (Entonox). J. Obstet. Gynaecol. Br. Commonw., 81, 603. Koch, G., and Wendel, H. (1968). The effect of pethidine on the postnatal adjustment of respiration and acid-base balance. Acta Obstet. Gynecol. Scand., 47, 27. Kron, R. E. Stein, M. S., and Goddard, K. E. (1966). Newborn sucking responses affected by obstetric sedation. Pediatrics, 37, 1012. Latto, I. P., Molloy, M. J., and Rosen, M. (1971). Changes in arterial blood levels of methoxyflurane (0.35 per cent inspired vapour concentration) during intermittent patient-controlled inhalation in labour. Br. J. Anaesth., 43, 201. McCarthy, J. P., Evans, J. M., Hogg, M. I. J., and Rosen, M. (1976). Patient-controlled administration of intravenous analgesics; in Application of Electronics in Medicine. I. E. R. E. Conference Proceedings, Southampton, 1976. McGarry, J. M. (1971). A double-blind comparison of the anti-emetic effect during labour of metoclopramide and perphenazine. Br.J. Anaesth., 43, 631. Major, V., Rosen, M., and Mushin, W. W. (1967). Concentration of methoxyflurane for obstetric analgesia by self-administered intermittent inhalation. Br. Med. J., 4, 767. Maternal and Child Health Service (1967). Second Report of the Perinatal Mortality Study in Ten University Teaching Hospitals, Ontario, Canada. Toronto: Special Health Services Branch, Ontario Department of Health.