ENDORPHINS AND ON-DEMAND PAIN RELIEF

769 tors. These

receptors

are

the

natural

substrates

for

endorphins which modulate pain.’ Measurement of endorphin activity or levels might give information as to the pre-disposi-

Time (min) patient demand for intravenous fentanyl Each demand was equivalent to 2 µg fentanyl. Epidural injections were: (A) 100 µg fentanyl, (B) normal saline, (C) diamorphine 5 mg.

Cumulative

study was confirmed by relief of the back pain by a final injection of 1.5 % lignocaine. This method produces many data points over a continuous period of several days, for each patient. Estimates of duration of pain relief may be obtained by differentiation of the cumulative dose curve. Regression analysis and visual determination gave simimlar values for duration of pain relief. For the data in the figure, this gives a duration of action for fentanyl of 1½ hours compared with zero for normal saline, and 9thours for diamorphine. Different patients show very similar durations of action, and our results for a 100 µg dose of fentanyl are in close agreement with those published.1 We believe that this method illustrates a longer duration of action of a dose of opiate administered into the epidural space than would be expected for the same dose given systemically. One problem, which may limit the use of some epidural opiates, has been severe pruritus which usually begins some 30 min after the onset of analgesia. It is usually generalised, but in one case occurred solely in the distribution of the epidural analgesia. The pruritus was only weakly relieved by either oral or systemic chlorpheniramine.

tion for analgesia demand. Endorphin levels in the cerebrospinal fluid (CSF) have been found to be significant for sensitivity to experimental pain’ and in the aetiology of chronic pain syndromes.6 Endorphin analysis has now been applied to CSF samples from a series of patients exposed to comparable trauma during abdominal surgery. Premedication and anaesthesia were standardised. CSF samples of 10 ml were obtained immediately after induction of anaesthesia and before surgery. A second CSF sample was obtained 24 h later (i.e., after surgery and during postoperative self-administration of pethidine). Plasma pethidine was assayed in central venous blood samples and in the second CSF sample.8 The mean plasma concentration of pethidine during self-administration and the ratio of CSF to plasma concentration of pethidine was used to calculate a mean CSF concentration of pethidine, assuming a constant CSF/plasma ratio at all times. The amount of drug demanded per hour varies between individuals more than the established minimum effective concentration levels, because of differences in drug distribution and elimination. The total amount of drug demanded is furthermore influenced by the magnitude of the doses. It is therefore more accurate to indicate plasma concentrations at steady state when comparing individual need for Endorphin fraction i levels were measured by receptor assay.7

analgesia.

’

Nuffield Department of Anæsthetics, Radcliffe Infirmary, Oxford 0X2 6HE

H. J. MCQUAY R. E. S. BULLINGHAM

P. J. D. EVANS J. W. LLOYD

30

Endorphin Relation between preoperative dine concentrations in CSF.

(r---080 p<0.01). I

Oxford Regional Pain Relief Unit, Abingdon

20

10

0

endorphin and calculated pethi-

Endorphin values

in pmol/ml, pethidine in

as

concentration of fraction

ng/ml.

Nuffield Department of Clinical,

Biochemistry,

Radcliffe Infiramry

R. A. MOORE

ENDORPHINS AND ON-DEMAND PAIN RELIEF

SIR Systems for patient controlled delivery of narcotic analgesics have lately been introduced into clinical practice.2 Patients will obtain subjectively satisfactory analgesia by selfadministering small intravenous doses through a programmable injection device. Computer simulation of plasma concentrations shows that additional doses are demanded as the concentration drops below an individual minimum effective concentration. This concentration shows considerable variation between patients, suggesting that there may be constitutional sensitivity differences at the level of the opioid recep1 Wolfe MJ, Nicholas ADG. Selective epidural analgesia. Lancet 2. Editorial. Patient-controlled analgesia. Lancet 1980;i: 289-90.

1979; ii: 150.

The figure shows that the calculated mean levels of pethidine and the preoperative fraction i levels in CSF are inversely related: a patient with low endorphin levels seems to require more analgesic. This fits in with our finding of a correlation 3. Tamsen E, Hartvig P, Dahlström B, Lindström B, Holmdahl M. H:son Patient controlled analgesia therapy in the early post-operative period. Acta Anœsth Scand 1979; 5: 462-70. 4. Terenius L. Endogenous peptides and analgesia. Ann Rev Pharmacol Toxi-

col 1978; 18: 189-204. Knorring L, Almay BGL, Johansson F, Terenius L. Pain perception and endorphin levels in cerebrospinal fluid. Pain 1978; 5: 359-65. 6. Almay BGL, Johansson F, von Knorring L, Terenius L, Wahlström A. 5.

von

Endorphins in chronic pain. Differences in CSF endorphin levels between organic and psychogenic pain syndromes. Pain 1978; 5: 153-62. 7. Terenius L, Wahlström A. Morphine-like ligand for opiate receptors in human CSF. Life Sci 1975, 16: 1759-64. 8. Hartvig P, Karlsson K-E, Johansson T, Lindberg C. Determination of therapeutic plasma concentrations of pethidine and norpethidine in man by electron capture gas chromatography. Eur J Clin Pharmacol 1977; 11: 65.

‘

770 between CSF endorphin levels and personality variables, a vulnerable personality being associated with low endorphins.9 This work is

supported by the Swedish Medical Research Council.

consumption of unleavened bread (as chapatty), high-extraction cereals, and pulses and, possibly, a low intake of animal protein in a situation of marginal vitamin D self-sufficiency.6-9 In our view, Asian rickets and osteomalacia are primarily nutritional in origin. Nevertheless, we agree with Dr Lawson that normal dietary vitamin D intakes play no significant role in maintaining vitamin D status and that the absence of vitamin D from the diet is not a risk factor for the development include the

Department of Anæsthesiology, University Hospital, Uppsala

ANDERS TAMSEN

Hospital Pharmacy, University Hospital, Uppsala

PER HARTVIG

ACO

BENGT DAHLSTRÖM

of rickets or osteomalacia.

AGNETA WAHLSTRÖM LARS TERENIUS

of Medicine, Stobhill General Hospital, Glasgow G21 3UW

M. G. DUNNIGAN

Department of Mathematics, Strathclyde University

IRIS ROBERTSON

Läkemedel, Solna

Department of Pharmacology, University of Uppsala, S-751 23 Uppsala, Sweden

RESIDENCE IN BRITAIN AS A RISK FACTOR FOR ASIAN RICKETS AND OSTEOMALACIA

SIR,--Dr Stamp’s letter (Feb. 9, p. 316) suggesting that residence in Britain is a risk factor for the development of rickets and osteomalacia in Asian immigrants should be qualified in two respects. His implied disagreement with Dr Lawson’s statement (Nov. 10, p. 1021) that Asian rickets is not due to lack of exposure to sunlight contains no evidence to refute detailed observations1,2 that the measured outdoor exposure of Asian adolescents in Britain with and without rickets does not differ from that of their White counterparts. We have found Asian rickets in schoolchildren who played out of doors for several hours a day in summer, accompanied their parents to nearby city parks at weekends, and took part in a full programme of outdoor recreation at school. These observations have been confirmed by Compston3 who found osteomalacia in Asian women in London who went out daily, wore Western dress, and sunbathed. The fact that many Asian women do not go out of doors for social or religious reasons does not invalidate these observations. We agree that moving from an area with equatorial levels of ultraviolet exposure such as East Africa to a country with limited ultraviolet exposure such as Britain can increase the risk of vitamin D deficiency in Asian immigrants. A study of Asian immigrants in Bradford4showed that in the first year after arrival serum 25-OHD levels were inversely related with time of residence in Britain. However, the detailed data on the incidence of Asian rickets and osteomalacia in England and Wales from 1962 to 1977 collected by Dr J. G. Ablett for the Committee on Medical Aspects of Food Policy (personal communication) show that the incidence of rickets has approximately halved in this time, while the incidence of osteomalacia has remained static. Thus, in the children of the Asian community residence in Britain is associated in the longer term with a declining risk of rickets while in first-generation adult immigrants the risk remains constant. We would interpret these important epidemiological observations as being due to a progressive though partial adaptation to a Western diet on the part of Asian children in Britain, while first-generation Asian immigrants usually remain on a traditional diet. Such an interpretation is supported by a current study of the dietary intakes of Asian children in Glasgow and lends support to previous studies suggesting that dietary factors other than vitamin D are important in the genesis of nutritional rickets and osteomalacia in man.2.5These factors Johansson F, Almay BGL, von Knorring L, Terenius L, Aström M. Personality traits in chronic pain patients related to endorphin levels in CSF. Psychiat Res 1979; 1: 231-39. 1. Dunnigan MG, Childs WC, Smith CM, McIntosh WB, Ford JA. The relative roles of ultra-violet deprivation and diet in the etiology of Asian rickets. 9.

Scott Med J 1975; 20: 217-18. Dunnigan MG. Asian rickets and osteomalacia in Britain. In: Child nutrition and its relation to mental and physical development. London: Kellogg Company of Great Britain, 43-70. 3. Compston J. Rickets in Asian immigrants, Br Med J 1979; ii: 612. 4. Preece MA, Tomlinson S, Ribot CA, Pietrek J, Korn HT, Davies DM, Ford JA, Dunnigan MG, O’Riordan JLH. Studies of vitamin D deficiency in man. Quart J Med 1975; 44: 575-89. 5. Boyle IT. Vitamin D and ultra-violet radiation. Scott Med J 1980; 25: 1-3. 2.

Department

SULPHINPYRAZONE, ASPIRIN, AND URIC ACID SIR,—Ibelieve I may have answered your editorial question - Anturane Works but How? (Feb. 9, p. 295)-in an earlier letter. I do not think that the anti-platelet activity of ’Anturane’ (sulphinpyrazone) is as important in arterial disease patients as is its effect on the blood uric acid. The point is well illustrated by comparing the results of the anturane trial2 with a recent aspirin Aspirin and anturane have very similar antiplatelet activity. However, in the two studies, these drugs

study.’

had very different effects on the blood uric acid and the incidence of sudden death. In the anturane group there was a marked decrease in blood uric acid and a significant reduction in sudden death compared with controls. In the aspirin group there was a significant increase in blood uric acid and an increase in sudden death compared with controls. Although the increase in sudden deaths in the aspirin study did not attain significant levels, it is perhaps of more importance than allowed, since significantly more of the controls had documented arrhythmia. I have previously discussed the epidemiological and experimental data regarding uric acid as a factor in arterial disease and have suggested that reduction of blood uric acid will benefit arterial disease patients.5 I think that anturane works as it always has, by reducing the blood level of uric acid. Aspirin can be as effective as anturane, if given in doses large enough to lower uric acid levels. Athens General

Hospital,

HILLARY R. NEWLAND

Athens, Georgia, U.S.A.

PERSISTENT HYPERFIBRINOGENÆMIA IN NECROTISING ENTEROCOLITIS

SIR,-Necrotising enterocolitis (NEC) is generally assumed be preceded by intestinal injury or infection which subsequently leads to tissue necrosis. A high percentage of infants with NEC have been reported to have, at necropsy, evidence of inadequate tissue perfusion by the intestinal blood supply. to

6. Ford JA, Colhoun EM, McIntosh WB, Dunnigan MG. Biochemical response of late rickets and osteomalacia to a chapatty-free diet. Br Med J 1972; iii: 446-47. 7. Robertson I, Kelman A, Dunnigan MG. Chapatty intake, vitamin D status and Asian rickets. Br Med J 1977; i: 229. 8. Dunnigan MG, McIntosh WB, Ford JA. Rickets in Asian immigrants. Lancet 1976, i: 1346. 9. Hunt SP, Nash AH, Watson R, Truswell S. Vitamin D status in different subgroups of British Asians. Br Med J 1977;i: 641. 1. Newland H. Antithrombotic effect of sulphinpyrazne. Lancet 1979, i:1157. 2. Anturane Reinfarction Trial Research Group. Sulphinpyrazone in the prevention of sudden death after myocardial infarction. N Engl J Med 1980, 302: 250-56. 3. Aspirin Myocardial Infarction Study Research Group. A randomized, controlled trial of aspirin in persons recovered from myocardial infarction JAMA 1980; 243: 661-69. 4. Weiss HJ. Antiplatelet therapy. N Engl J Med 1977; 298: 1344-47 5. Newland H. Hyperuricemia in coronary, cerebral and peripheral arterialdisease: an

explanation.

Med Hypoth

1975; 1: 152-55.