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INCIDENCE OF UNWANTED EFFECTS OF DIHYDROCODEINE BITARTRATE IN HEALTHY VOLUNTEERS
620
INCIDENCE OF UNWANTED EFFECTS OF DIHYDROCODEINE BITARTRATE IN HEALTHY VOLUNTEERS R. N. PALMER
O. E. BADE
INCIDENCE OF UNWANTED EFFECTS IN 95 VOLUNTEERS 41 FEMALE) ON DIHYDROCODEINE AND PLACEBO
(54 MAU;
P. J. O’SHEA
MEDICAL STUDENTS
M. F. CUTHBERT M.B. Lond. RESEARCH FELLOW
From the Department of Pharmacology and Medical Unit, London Hospital Medical College, London E.1
DIHYDROCODEINE bitartrate (’ DF 118 ’) is a moderately potent analgesic in wide clinical use. It is structurally related to both codeine and morphine and so may be expected to share some of the properties of either or both of these drugs. When given by subcutaneous injection, 30-70 mg. dihydrocodeine has approximately the same analgesic effect as 10 mg. morphine (Gravenstein et al. 1956, Beecher et al. 1957, Keats et al. 1957a and b, Wallenstein et al. 1957, Seed et al. 1958) and the incidence of unwanted effects is said not to differ significantly from that of injections of saline solution (Gravenstein et al. 1956, Keats et al. 1957a and b). By mouth dihydrocodeine and codeine are approximately equipotent (Cass and Frederick 1958) and so are 30 mg. dihydrocodeine and 100 mg. pethidine (Dundee 1960). Unwanted effects after oral administration have been considered negligible and in two trials did not differ significantly from those of a placebo (Cass and Frederick 1958, Keesling and Keats 1958). We had gained the impression that both nausea and constipation occasionally followed the use of dihydrocodeine tablets and we have investigated the incidence of unwanted effects in healthy volunteers.
* =Not statistically significant at the 0-05 level.
codeine 26 (48%) and placebo 18 (33%). The results arí shown in the table. The incidence of nausea and dizziness was significantly greater on dihydrocodeine than on
placebo (p < 0-05). Constipation was more frequent on dihydrocodeine than on placebo but this was not significant (P> 0.05). The incidence of other symptoms was about equal for each tablet. 2 females vomited after dihydro-
Methods We carried out a double-blind trial in 100 healthy volunteers aged between 16 and 70; many of the volunteers were hospital staff aged between 20 and 30 years. 95 subjects (41 female, 54 male) completed the trial. In two consecutive weeks, each volunteer was asked to take one tablet with water on Monday, Tuesday, and Wednesday mornings after breakfast. In one week they received three 30 mg. tablets of dihydrocodeine and in the other week three indistinguishable placebo tablets. The order of allocation of dihydrocodeine and placebo tablets to individual volunteers was randomised and known to only one of us who was not involved in the issue of tablets or questionaries. On Thursday of each week each volunteer was given a questionary listing eight " symptoms " (constipation, felt
sick, headache, dizziness, dry mouth, indigestion, diarrhoea,
symptoms) and was asked to indicate if " symptoms " occurred on any of the days the tablets were taken. The volunteers had no knowledge of the questionary until after the first course of tablets had been taken. The results were analysed by the sign test (Documenta Geigy 1962). Volunteers who had a symptom on an equal number of occasions on the drug and on placebo gave no information in the comparison of the two treatments. The other volunteers were classed + or - according to whether they reported the symptom more frequently on the drug (+) or on the placebo (-). The test gives the chance of obtaining the observed number of -+- and - signs if each has an equal chance of occurring. Results Of the 95 volunteers who completed the trial 52 (55%) had unwanted effects on dihydrocodeine and 31 (33%) had unwanted effects on placebo. The figures for the 41 women were: dihydrocodeine 26 (63%); placebo 13 (32%). For the 54 men the incidence was: dihydroany other
No. of Days
Symptom
on
Drug minus
no.
of
Days Symptom 01B
Placebo Incidence of constipation, nausea, and dizziness in 54 male Red 41 female volunteers on dihydrocodeine and placebo.
The scores on the abscissa were obtained by subtracting the number of times each volunteer had the symptom on placebo from the number of times the same subject had the symptom while on dihydrocodeine. Men were constipated more often on dihydrocodeine than on placebo (P=0-06) and there was a significant incidence of both nausea (p < 0-05) and dizziness (p < 0-01) in women on dihydrocodcinc-
621
codeine but there was no vomiting associated with the placebo tablets. The incidence of unwanted effects in volunteers who received dihydrocodeine in the first week did not differ from that in those who received dihydrocodeine in the second week. When men and women were considered separately (see figure), women showed a significant incidence of both nausea (p < 0.05) and dizziness (p < 0’01) but not of
constipation. In contrast,
men
infrequently complained
and dizziness but they were constipated more of often on dihydrocodeine than on placebo. The incidence of constipation in men approached but did not reach significance at the 0-05 level; the exact probability was 0.064. nausea
Discussion The unwanted effects of oral dihydrocodeine do not seem to have been investigated previously. Observations on unwanted effects have been made in two double-blind trials (Cass and Frederick 1958, Keesling and Keats 1958) designed to assess the analgesic potency of oral dihydrocodeine in comparison with other analgesics. In neither of these trials were inquiries made for specific symptoms but no significant difference was found in the incidence of unwanted effects on dihydrocodeine and placebo. In our investigation, the volunteers were told only that the object was to investigate the properties of dihydrocodeine and also that identical placebo tablets would be used. A double-blind randomised design was considered essential to assess the incidence of subjective unwanted effects. Secondly, some of the volunteers were probably aware of the possible unwanted effects of dihydrocodeine and, thirdly, when the questionary was issued after the first course of tablets, this knowledge might conceivably influence the results obtained after the second course of tablets. One objection might be that an assessment of an analgesic drug should have been done in patients receiving
dihydrocodeine therapeutically; however, dihydrocodeine is frequently administered to ambulant patients engaged in normal activities and we do not feel that the absence of pain in our subjects invalidates the results. The higher incidence of nausea in the female subjects after dihydrocodeine may be due to hormonal factors since post-operative nausea and vomiting are known to occur much more frequently in women than in men. (Knapp and Beecher 1956, Robbie 1959, Bellville et al. 1960). This has been attributed to levels of gonadotrophin as a higher incidence has been found in the third and fourth weeks of the menstrual cycle as compared with the first and second weeks; there is a correspondingly low incidence in women over 70, who also have low gonadotrophin levels (Bellville et al. 1960) and in children under 12 years of age (Tornetta 1962). We cannot explain the sex difference in the incidence of dizziness and constipation in our subjects.
Summary 95 normal active
54 male) took part in a trial designed to assess the incidence of unwanted effects of dihydrocodeine bitartrate (’ DF 118 ’) in a daily dosage of 30 mg. orally as compared with an indistinguishable placebo tablet. A significant incidence of nausea and dizziness was found in the women and the results also suggest that dihydrocodeine has a constipating effect in men. Previous reports that the incidence of unwanted effects of dihydrocodeine is no greater than those of a placebo appear to be misleading.
subjects (41 female,
We are indebted to Mrs. W. Fox for advice on the statistical tests and to Mr. J. Cooper, of Duncan Flockhart & Evans, Ltd., who
kindly supplied the dihydrocodeine bitartrate (’DF 118’) and identical placebo tablets. Our thanks are also due to Professor Miles Weatherall and Dr. A. Herxheimer for their helpful criticism of the manuscript. One of us (M. F. C.) was in receipt of a May & Baker Research Fellowship. Requests for reprints should be addressed to Dr. M. F. Cuthbert, Medical Unit, London Hospital Medical College, Turner Street, London E.1. REFERENCES
Beecher, H. K., Gravenstein, J. S., Pederson, D. P., Smith, G. M. (1957) Fedn Proc. Fedn Am. Socs exp. Biol. 16, 281. Bellville, J. W., Bross, I. D. J., Howland, W. S. (1960) Anesthesiology, 21, 186.
Cass, L. J., Frederick, W. S. (1958) Archs intern. Med. 102, 571. Documenta Geigy, Scientific Tables 1962; p. 160. Geigy Pharmaceutical Co. Ltd., Manchester. Dundee, J. W. (1960) Br. J. Anœsth. 32, 48. Gravenstein, J. S., Smith, G. M., Sphire, R. D., Isaacs, J. P., Beecher, H. K. (1956) New Engl. J. Med. 254, 877. Keats, A. S., Telford, J., Kurosu, Y. (1957a) J. Pharmac. exp. Ther. 119, 155. (1957b) ibid. 120, 354. Keesling, R., Keats, A. S. (1958) Oral Surg. Med. Path. 11, 736. Knapp, M. R., Beecher, H. K. (1956) J. Am. med. Ass. 160, 376. Robbie, D. S. (1959) Anœthesia, 14, 349. Seed, J. C., Wallenstein, S. L., Houde, R. W., Bellville, J. W. (1958) Archs intern. Pharmacodyn. 116, 293. Tornetta, F. (1962) Anesth. Analg. curr. Res. 41, 288. Wallenstein, S. L., Seed, J. C., Houde, R. W. (1957) J. Pharmac. exp. Ther. 119, 191. -
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Preliminary Communication A TEST FOR PYLORIC REGURGITATION REGURGITATION of duodenal juice and its effect on the stomach have interested clinicians for many years.l2 Such regurgitation has been cited as a cause of gastric disorders, often without adequate evidence-partly because there has been no reliable test to demonstrate regurgitation. The presence of bile in the aspirated gastric juices is not a reliable guide, since duodenal regurgitation may result simply from the presence of the indwelling gastric tube itself.3 Chronic superficial and atrophic gastritis has been clearly shown to follow duodenal regurgitation :4-11 it is therefore essential to find a reliable test for pyloric dysfunction. PYLORIC-REGURGITATION TEST
A
length of soft red rubber tubing, size 1/20 x 1/40, is prepared as for a Ryle’s tube, with marks at 45 cm. (cardia), 60 cm. (pylorus), and 75 cm. (mid-duodenum). The tube is weighted at the end by attaching a finger cot containing 0-5 ml. (6-8 g.) of mercury (fig. 1). Alternatively, the tube itself can be distended with this amount of mercury. A piece of wire inserted into the lumen at 7-5 cm. from the tip acts as a marker, and is just distal to the aperture. When the mercury bag is in mid-duodenum, the barium escapes into the duodenal cap. A rigid plastic tube is not suitable, since it may distort the pylorus and permit regurgitation. If the procedure is handled by an experienced and understanding nurse, sedation is seldom
required. The tube is passed by a slight modification of the method of Raskin et al. 12 The tube is swallowed until the bag is at the cardia. The patient lies on the left side in the head-up position at 60°. The tube is slowly passed along the greater curve to the antral mark at 60 cm. A drink of warm water or tea (1 oz.) may help 1. Spira, J. J. Gastroduodenal Ulcer. London, 1956. 2. Temeliescu, I., Oprisan, S. Presse méd. 1963, 71, 1853. 3. Beaumont, W. The Physiology of Digestion. Plattsburgh, 1833. 4. Capper, W. M. Hunterian Lecture, Royal College of Surgeons, England. 5. Howat, H. T. Personal communication. 6. Lawson, H. H. Br. J. Surg. 1953, 6, 493. 7. Lawson, H. H. Lancet, 1964, i, 469. 8. Lawson, H. H. Br. J. Surg. 1966, 6, 493. 9. du Plessis, D. J. S. Afr. med. J. 1960, 34, 101. 10. du Plessis, D. J. S. Afr. J. Surg. 1963, 1, 3. 11. du Plessis, D. J. Lancet, 1965, i, 974. 12. Raskin, H. F., Wenger, J., Sklar, M., Pleticka, B. S., Yarema, W. Gastroenterology, 1958, 34, 996.
INCIDENCE OF UNWANTED EFFECTS OF DIHYDROCODEINE BITARTRATE IN HEALTHY VOLUNTEERS R. N. PALMER
O. E. BADE
INCIDENCE OF UNWANTED EFFECTS IN 95 VOLUNTEERS 41 FEMALE) ON DIHYDROCODEINE AND PLACEBO
(54 MAU;
P. J. O’SHEA
MEDICAL STUDENTS
M. F. CUTHBERT M.B. Lond. RESEARCH FELLOW
From the Department of Pharmacology and Medical Unit, London Hospital Medical College, London E.1
DIHYDROCODEINE bitartrate (’ DF 118 ’) is a moderately potent analgesic in wide clinical use. It is structurally related to both codeine and morphine and so may be expected to share some of the properties of either or both of these drugs. When given by subcutaneous injection, 30-70 mg. dihydrocodeine has approximately the same analgesic effect as 10 mg. morphine (Gravenstein et al. 1956, Beecher et al. 1957, Keats et al. 1957a and b, Wallenstein et al. 1957, Seed et al. 1958) and the incidence of unwanted effects is said not to differ significantly from that of injections of saline solution (Gravenstein et al. 1956, Keats et al. 1957a and b). By mouth dihydrocodeine and codeine are approximately equipotent (Cass and Frederick 1958) and so are 30 mg. dihydrocodeine and 100 mg. pethidine (Dundee 1960). Unwanted effects after oral administration have been considered negligible and in two trials did not differ significantly from those of a placebo (Cass and Frederick 1958, Keesling and Keats 1958). We had gained the impression that both nausea and constipation occasionally followed the use of dihydrocodeine tablets and we have investigated the incidence of unwanted effects in healthy volunteers.
* =Not statistically significant at the 0-05 level.
codeine 26 (48%) and placebo 18 (33%). The results arí shown in the table. The incidence of nausea and dizziness was significantly greater on dihydrocodeine than on
placebo (p < 0-05). Constipation was more frequent on dihydrocodeine than on placebo but this was not significant (P> 0.05). The incidence of other symptoms was about equal for each tablet. 2 females vomited after dihydro-
Methods We carried out a double-blind trial in 100 healthy volunteers aged between 16 and 70; many of the volunteers were hospital staff aged between 20 and 30 years. 95 subjects (41 female, 54 male) completed the trial. In two consecutive weeks, each volunteer was asked to take one tablet with water on Monday, Tuesday, and Wednesday mornings after breakfast. In one week they received three 30 mg. tablets of dihydrocodeine and in the other week three indistinguishable placebo tablets. The order of allocation of dihydrocodeine and placebo tablets to individual volunteers was randomised and known to only one of us who was not involved in the issue of tablets or questionaries. On Thursday of each week each volunteer was given a questionary listing eight " symptoms " (constipation, felt
sick, headache, dizziness, dry mouth, indigestion, diarrhoea,
symptoms) and was asked to indicate if " symptoms " occurred on any of the days the tablets were taken. The volunteers had no knowledge of the questionary until after the first course of tablets had been taken. The results were analysed by the sign test (Documenta Geigy 1962). Volunteers who had a symptom on an equal number of occasions on the drug and on placebo gave no information in the comparison of the two treatments. The other volunteers were classed + or - according to whether they reported the symptom more frequently on the drug (+) or on the placebo (-). The test gives the chance of obtaining the observed number of -+- and - signs if each has an equal chance of occurring. Results Of the 95 volunteers who completed the trial 52 (55%) had unwanted effects on dihydrocodeine and 31 (33%) had unwanted effects on placebo. The figures for the 41 women were: dihydrocodeine 26 (63%); placebo 13 (32%). For the 54 men the incidence was: dihydroany other
No. of Days
Symptom
on
Drug minus
no.
of
Days Symptom 01B
Placebo Incidence of constipation, nausea, and dizziness in 54 male Red 41 female volunteers on dihydrocodeine and placebo.
The scores on the abscissa were obtained by subtracting the number of times each volunteer had the symptom on placebo from the number of times the same subject had the symptom while on dihydrocodeine. Men were constipated more often on dihydrocodeine than on placebo (P=0-06) and there was a significant incidence of both nausea (p < 0-05) and dizziness (p < 0-01) in women on dihydrocodcinc-
621
codeine but there was no vomiting associated with the placebo tablets. The incidence of unwanted effects in volunteers who received dihydrocodeine in the first week did not differ from that in those who received dihydrocodeine in the second week. When men and women were considered separately (see figure), women showed a significant incidence of both nausea (p < 0.05) and dizziness (p < 0’01) but not of
constipation. In contrast,
men
infrequently complained
and dizziness but they were constipated more of often on dihydrocodeine than on placebo. The incidence of constipation in men approached but did not reach significance at the 0-05 level; the exact probability was 0.064. nausea
Discussion The unwanted effects of oral dihydrocodeine do not seem to have been investigated previously. Observations on unwanted effects have been made in two double-blind trials (Cass and Frederick 1958, Keesling and Keats 1958) designed to assess the analgesic potency of oral dihydrocodeine in comparison with other analgesics. In neither of these trials were inquiries made for specific symptoms but no significant difference was found in the incidence of unwanted effects on dihydrocodeine and placebo. In our investigation, the volunteers were told only that the object was to investigate the properties of dihydrocodeine and also that identical placebo tablets would be used. A double-blind randomised design was considered essential to assess the incidence of subjective unwanted effects. Secondly, some of the volunteers were probably aware of the possible unwanted effects of dihydrocodeine and, thirdly, when the questionary was issued after the first course of tablets, this knowledge might conceivably influence the results obtained after the second course of tablets. One objection might be that an assessment of an analgesic drug should have been done in patients receiving
dihydrocodeine therapeutically; however, dihydrocodeine is frequently administered to ambulant patients engaged in normal activities and we do not feel that the absence of pain in our subjects invalidates the results. The higher incidence of nausea in the female subjects after dihydrocodeine may be due to hormonal factors since post-operative nausea and vomiting are known to occur much more frequently in women than in men. (Knapp and Beecher 1956, Robbie 1959, Bellville et al. 1960). This has been attributed to levels of gonadotrophin as a higher incidence has been found in the third and fourth weeks of the menstrual cycle as compared with the first and second weeks; there is a correspondingly low incidence in women over 70, who also have low gonadotrophin levels (Bellville et al. 1960) and in children under 12 years of age (Tornetta 1962). We cannot explain the sex difference in the incidence of dizziness and constipation in our subjects.
Summary 95 normal active
54 male) took part in a trial designed to assess the incidence of unwanted effects of dihydrocodeine bitartrate (’ DF 118 ’) in a daily dosage of 30 mg. orally as compared with an indistinguishable placebo tablet. A significant incidence of nausea and dizziness was found in the women and the results also suggest that dihydrocodeine has a constipating effect in men. Previous reports that the incidence of unwanted effects of dihydrocodeine is no greater than those of a placebo appear to be misleading.
subjects (41 female,
We are indebted to Mrs. W. Fox for advice on the statistical tests and to Mr. J. Cooper, of Duncan Flockhart & Evans, Ltd., who
kindly supplied the dihydrocodeine bitartrate (’DF 118’) and identical placebo tablets. Our thanks are also due to Professor Miles Weatherall and Dr. A. Herxheimer for their helpful criticism of the manuscript. One of us (M. F. C.) was in receipt of a May & Baker Research Fellowship. Requests for reprints should be addressed to Dr. M. F. Cuthbert, Medical Unit, London Hospital Medical College, Turner Street, London E.1. REFERENCES
Beecher, H. K., Gravenstein, J. S., Pederson, D. P., Smith, G. M. (1957) Fedn Proc. Fedn Am. Socs exp. Biol. 16, 281. Bellville, J. W., Bross, I. D. J., Howland, W. S. (1960) Anesthesiology, 21, 186.
Cass, L. J., Frederick, W. S. (1958) Archs intern. Med. 102, 571. Documenta Geigy, Scientific Tables 1962; p. 160. Geigy Pharmaceutical Co. Ltd., Manchester. Dundee, J. W. (1960) Br. J. Anœsth. 32, 48. Gravenstein, J. S., Smith, G. M., Sphire, R. D., Isaacs, J. P., Beecher, H. K. (1956) New Engl. J. Med. 254, 877. Keats, A. S., Telford, J., Kurosu, Y. (1957a) J. Pharmac. exp. Ther. 119, 155. (1957b) ibid. 120, 354. Keesling, R., Keats, A. S. (1958) Oral Surg. Med. Path. 11, 736. Knapp, M. R., Beecher, H. K. (1956) J. Am. med. Ass. 160, 376. Robbie, D. S. (1959) Anœthesia, 14, 349. Seed, J. C., Wallenstein, S. L., Houde, R. W., Bellville, J. W. (1958) Archs intern. Pharmacodyn. 116, 293. Tornetta, F. (1962) Anesth. Analg. curr. Res. 41, 288. Wallenstein, S. L., Seed, J. C., Houde, R. W. (1957) J. Pharmac. exp. Ther. 119, 191. -
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Preliminary Communication A TEST FOR PYLORIC REGURGITATION REGURGITATION of duodenal juice and its effect on the stomach have interested clinicians for many years.l2 Such regurgitation has been cited as a cause of gastric disorders, often without adequate evidence-partly because there has been no reliable test to demonstrate regurgitation. The presence of bile in the aspirated gastric juices is not a reliable guide, since duodenal regurgitation may result simply from the presence of the indwelling gastric tube itself.3 Chronic superficial and atrophic gastritis has been clearly shown to follow duodenal regurgitation :4-11 it is therefore essential to find a reliable test for pyloric dysfunction. PYLORIC-REGURGITATION TEST
A
length of soft red rubber tubing, size 1/20 x 1/40, is prepared as for a Ryle’s tube, with marks at 45 cm. (cardia), 60 cm. (pylorus), and 75 cm. (mid-duodenum). The tube is weighted at the end by attaching a finger cot containing 0-5 ml. (6-8 g.) of mercury (fig. 1). Alternatively, the tube itself can be distended with this amount of mercury. A piece of wire inserted into the lumen at 7-5 cm. from the tip acts as a marker, and is just distal to the aperture. When the mercury bag is in mid-duodenum, the barium escapes into the duodenal cap. A rigid plastic tube is not suitable, since it may distort the pylorus and permit regurgitation. If the procedure is handled by an experienced and understanding nurse, sedation is seldom
required. The tube is passed by a slight modification of the method of Raskin et al. 12 The tube is swallowed until the bag is at the cardia. The patient lies on the left side in the head-up position at 60°. The tube is slowly passed along the greater curve to the antral mark at 60 cm. A drink of warm water or tea (1 oz.) may help 1. Spira, J. J. Gastroduodenal Ulcer. London, 1956. 2. Temeliescu, I., Oprisan, S. Presse méd. 1963, 71, 1853. 3. Beaumont, W. The Physiology of Digestion. Plattsburgh, 1833. 4. Capper, W. M. Hunterian Lecture, Royal College of Surgeons, England. 5. Howat, H. T. Personal communication. 6. Lawson, H. H. Br. J. Surg. 1953, 6, 493. 7. Lawson, H. H. Lancet, 1964, i, 469. 8. Lawson, H. H. Br. J. Surg. 1966, 6, 493. 9. du Plessis, D. J. S. Afr. med. J. 1960, 34, 101. 10. du Plessis, D. J. S. Afr. J. Surg. 1963, 1, 3. 11. du Plessis, D. J. Lancet, 1965, i, 974. 12. Raskin, H. F., Wenger, J., Sklar, M., Pleticka, B. S., Yarema, W. Gastroenterology, 1958, 34, 996.