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Controlled Clinical Studies of Orally Administered Antiemetic Drugs
Vol. 57, No.3 Printed in U.S.A.
GASTROF;NTEROLOGY
Copyright© 1969 by The Williams & Wilkin' C'o.
CONTROLLED CLINICAL STUDIES OF ORALLY ADMINISTERED ANTIEMETIC DRUGS CHARLES
G.
MOERTEL, M.D., AND RICHARD
J.
REITEMEIER, M.D.
Section of Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
In a controlled double blind study of marketed antiemetic drugs administered by the oral route, the phenothiazine agents, thiethylperazine (Torecan) and thiopropazate (Dartal), were found to have significant therapeutic activity when compared to placebo. Chlorprothixene (Taractan) showed antiemetic effectiveness but at a price of clinically intolerable sedative effect. A barbiturate (pentobarbital sodium) was not effective as an antiemetic. Of two investigational drugs studied, metoclopramide proved to be of no therapeutic value. Metopimazine showed an indication of antiemetic effect in the absence of any significant sedative effect. This agent should be evaluated over a higher dosage range. No consistent correlation was noted in comparing sedative effect and antiemetic effect of these agents. Nausea and vomiting are ubiquitous symptoms which complicate not only the disease states that we treat but also the treatment procedures themselves. Amelioration of these symptoms has provided the clinical pharmacologist with a formidable challenge which has been met at least in quantity, if not in quality. In the 1968 Physicians' Desk Reference, 125 drugs are advocated for treatment of nausea and 71 for vomiting. When one searches the credentials of these agents to find some factual basis for this claimed effectiveness, however, a distressing vacuum all too often is encountered. Nausea is largely subjective, and the occurrence of vomiting can be greatly influenced by the emotional status of the patient. Placebo treatment has been well established as effective in a substantial proportion of patients afflicted with these Received December 2, 1968. Accepted April 14, 1969. Address requests for reprints to: Dr. Charles G. Moertel, Mayo Clinic, Rochester, Minnesota 55901. The authors wish to thank Lila Elveback, Ph.D., for her assistance in the design and statistical analyses of this study.
symptoms. Before any drug can be claimed as an effective antiemetic agent, therefore, it must be demonstrated by controlled study to be more effective than placebo. Because the enthusiasm of the physician may have a striking influence on the patient's receptiveness of therapy as well as on the physician's own evaluation of therapeutic effectiveness, a double blind procedure is a sine qua non for the study of antiemetic agents. Controlled, double blind studies proving the effectiveness of orally administered antiemetic agents have been reported only infrequently, and controlled comparisons of the relative effectiveness of these agents, regardless of the route of administration, have been conspicuously rare in the literature. In 1963, we reported such a study of five antiemetic agents and placebo used for the prevention of nausea and vomiting in 300 patients with advanced malignant disease undergoing treatment with 5-fluorouracil (5-FU).' We found that the phenothiazines, thiopropazate (Dartal) and prochlorperazine (Compazine), showed a statistically significant therapeutic advantage over placebo. We
262
September 1969
263
CONTROLLED CLINICAL STUDIES
also found in this study that, for the agents employed, sedative effect seemed to parallel antiemetic effect. The two studies presented herein involve first an evaluation of other agents marketed for treatment of nausea and vomiting and second a study of new drugs under investigation for this purpose.
~S~
~N~CI
IHH 1\HH ~ HC- C - C - N N - C - C -0- C- CH3 HHH\__/HH
THIOPROPAZATE HYDROCHLORIDE
Study 1 For this study we chose to compare and to evaluate the antiemetic qualities of thiethylperazine, chlorprothixene, and sodium pentobarbital with an antiemetic of known effectiveness from our first study and placebo. Materials. Thiethylperazine (Torecan, fig. 1) is a phenothiazine which has a high degree of antiemetic activity in experimental animals and is marketed specifically for antiemetic purposes. A number of controlled clinical studies2 - 6 have demonstrated its significant antiemetic effectiveness when administered parenterally, but no report of its effectiveness by the oral route has been published. Chlorprothixene (Taractan) is not strictly a phenothiazine, but it has a similar molecular structure and pharmacological activity. Laboratory data have shown evidence of antiemetic activity. It has been employed clinically, primarily as a psychotherapeutic agent, but the manufacturer suggested its possible usefulness against nausea and vomiting attributable to various causes.' However, no controlled studies to prove its clinical antiemetic effectiveness have been made. The barbiturates had been employed in the past for palliation of nausea and vomiting, but more recently they have been supplanted largely by the phenothiazines. Since our initial study indicated some correlation between sedative effect and antiemetic effect, we considered it reasonable to include a barbiturate sedative in this evaluation. We chose sodium pentobarbital because its duration of action by the oral route approximates that of phenothiazines. As a standard of known antiemetic effectiveness, we chose thiopropazate (Dartal), the most effective agent in our first study. Lactose (U.S.P.) was employed as placebo. To avoid any possible distortion that this small amount of lactose might induce in the gastrointestinal symptoms of the patients, the active agents also were prepared with a lactose filler.
2HCI
THIETHYLPERAZINE
~s~ ~CI
II H H ,....CH3 C-C-C-N H H H 'CH3
CHLORPROTHIXENE FIG.
1. Structure of antiemetic agents employed
in study 1.
Methods. Outpatients were studied during treatment with 5-FU for advanced gastrointestinal cancer. None had experienced prior vomiting or significant nausea. 5-FU was given by rapid intravenous injection (13.5 mg per kg per day) for 5 consecutive days or until specific toxicity was evident. One-hundred-fifty patients were observed during their first course of 5-FU therapy and 100 patients during their second course. They were given analgesics and nighttime sedation as needed, but none received any tranquilizer or daytime barbiturate. Patients were randomized into the following treatment groups: (1) placebo; (2) thiopropazate, 10 mg; (3) thiethylperazine, 10 mg; (4) chlorprothixene, 50 mg; and (5) sodium pentobarbital, 30 mg. Dosages of thiopropazate and thiethylperazine were those recommended as optimum for antiemetic effect by the manufacturers. The dosage of chlorprothixene was that stated by the manufacturer to produce a sedative effect comparable with that of the phenothiazine dosages that we employed. We estimated that the dosage of sodium pentobarbital would produce a sedative effect comparable with that of the phenothiazine dosages.
264
MOERTEL AND REITEMEIER
All study drugs were dispensed in identical opaque yellow capsules. One capsule was administered orally 20 min before each meal for 4 days. Patients were told that the capsules contained medication to help prevent nausea and vomiting. Each day patients were allowed first to volunteer the symptoms of nausea and vomiting by a general inquiry; they were then questioned specifically regarding the occurrence of nausea and vomiting during the preceding 24hr period. Excessive sedation was recorded only if the patient volunteered these as symptoms.
Results. The incidence of nausea and vomiting experienced with each antiemetic agent compared with that experienced with the placebo is shown in table 1. TABLE
1. Incidence of nausea and vomiting
according to antiemetic agent employed
I
Antiemetic agent
•
-
- - - -- - - -- - [ ·
Thiopropazate. Thiethylperazine . Chlorprothixene . Sodium pentobarbital. Placebo.
Percentage of patients with symptoms in 50 4-day study periods I
N au s~ ~
34
36 38 52 68
Vom iting
18 16 16 24 24
----------------~------~------
Vol. 57, No . 3
These figures pertain only to the incidence of the respective symptoms and do not reflect their severity. To permit an evaluation and comparison of the over-all antiemetic effect of each of the agents tested, responses of patients during each study period were graded as follows: 0. No nausea or vomiting 1. Mild nausea, admitted only on direct questioning 2. Severe nausea, volunteered as a significant symptom 3. Infrequent vomiting, not exceeding one time during any day of the study period 4. Frequent vomiting, two or more times during any day of the study period The graded occurrence of nausea and vomiting according to this method is shown in figure 2. The two phenothiazines, thiopropazate and thiethylperazine, as well as chlorprothixene show definite and essentially equal antiemetic activity. Their superiorities to placebo are statistically significant by the x" test (P < 0.01). Sodium pentobarbital was not effective in preventing the occurrence of vomiting and showed only a slight and insignificant advantage over placebo in preventing nausea. With the exception of 1 patient in whom a myoclonic reaction developed during
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.82
Placebo
Chlorprothixine
.84
.86
Thiopropazate
Thiethylperazine
Sodium pentobarbital
FIG. 2. Comparative effectiveness of antiemetic agents and placebo.
September 1969
CONTROLLED CLINICAL STUDIES
treatment with thiopropazate, the only significant side effect observed in this study was that of oversedation. The incidence of oversedation volunteered as a significant symptom is listed in table 2. This side effect occurred at a comparable rate with the phenothiazines and sodium pentobarbital but was much more frequent with chlorprothixene. The observations in this study demonstrate that the antiemetic effect of a pharmacological agent is not necessarily correlated with sedative effect, nor does an agent producing sedation necessarily also possess antiemetic activity.
H H /C2H5 CONH-C -C- N H H 'C 2 H 5 OCH 3
Cl
0
NH 2
METOCLOPRAMIDE(MK 745)
Study2 In recent years, the pharmacological laboratories have been striving vigorously for more effective and specific antiemetic agents, both by studying variations on the proved phenothiazine theme as well as by exploring the potentialities of a number of new classes of compounds. Among the products of these investigations we chose two agents for clinical evaluation which seemed, from animal studies, to have outstanding potentiality: metoclopramide (MK 745) and metopimazine (EXP 999). Materials. Metoclopramide (fig. 3), a derivative of p-aminosalicylic acid, has been found in animal studies by Justin-Besancon and Laville"· " to have a manifold advantage over chlorpromazine and prochlorperazine in preventing vomiting induced by apomorphine, Hydergin, and copper sulfate. Klein and associates'" have shown this agent to be effective in preventing apomorphine-induced vomiting in man. In addition, metoclopramide has been found to have a unique action in stimulating TABLE
2. Incidence of oversedation according to
antiemetic agent employed Antiemetic agent
Percentage of p atients with oversedat10n in 50
study periods
Thiopropaza te. Thiethylper azine . Chlorprothixene. Sodium pentobarbital. Placebo . ._ .
16 14
54 12 4
265
I
D-
H- H HC - C C - N H H H
CON H 2
METOPIMAZINE (Exp 999) FIG . 3. Structure of antiemetic agents employed in study 2.
gastric motility." A number of reports by European authors have testified to the clinical antiemetic effectiveness of this agent in man; none of these studies, however, has been controlled. Two recent controlled studies"· '" have evaluated metoclopramide administered parenterally to patients after surgical treatment, but the results were conflicting. Metopimazine is a phenothiazine derivative which, in animal studies, has produced only minimal hypotension and sedation at an effective antiemetic dose range (personal communication, Pharmaceutical Division, E. I. du Pont de Nemours and Company, Wilmington, Del.). When studied against apomorphine-induced vomiting in the dog, it was vastly more potent than chlorpromazine when administered either subcutaneously or orally. Early clinical studies conducted in France and in Canada indicated effective activity against nausea and vomiting under a variety of circumstances but, again, none of the studies was controlled. The purpose of this study was to evaluate the antiemetic effectiveness of metoclopramide and metopimazine by a controlled double blind technique in comparison with placebo (lactose) and an antiemetic agent of known effectiveness (thiopropazate).
M OERTEL AND REJTEMEJER
266
M ethods . Patients with locally inoperable carcinoma of the stomach or pancreas received, on a randomized basis, either radiation therapy alone or radiation therapy plus 5-FU. Patients with all types of diffuse metastatic gastrointestinal carcinoma received only chemotherapy with either mitomycin C or 1 , 3-bis-(2-chloroethyl)-1~nitrosourea (BCNU) alone or in combination with each other or with 5-FU. Chemotherapy was administered on a 5-day schedule. Our earlier studies with these regimens showed that all induced nausea and vomiting in a significant proportion of patients treated. For 144 patients receiving chemotherapy only, the observation period of 4 days was broken into two 2-day intervals for comparison of the drugs and the placebo. The design was a balanced cross over with equal numbers of patients on each of the drug patterns. For 36 patients receiving radiation therapy alone, or with 5-FU, the observation period of 8 days was broken into four 2-day intervals so that each patient received each of the three drugs and the placebo in random drug order patterns. The mechanics of this investigation were otherwise the same as in study 1. The dosages of the antiemetic agents employed were those suggested by the manufacturer as optimal for antiemetic therapy: thiopropazate (10 mg, three times daily), metoclopramide (20 mg three times daily), and metopimazine (5 mg three times daily).
Results. Therapeutic effects. In this study each treatment day was considered as a single study unit. Results in table 3 are expressed in terms of the incidence of nausea and vomiting during these study periods. It can be seen that thiopropazate, our standard, again showed effective antiemetic activity as was true in our earlier 3. Incidence of nausea and vomiting according to antiemetic agent employed
TABLE
Antiemetic agent
Thiopropazate. Metopimazine .. Metoclopramide. Placebo ...
Percentage of patients with symptoms in 216 1-day study periods Nausea
Vomiting
23 27 36 30
13 15 16 19
Vol. 57, No.3
studies with this agent. Metopimazine and metoclopramide, however, showed little difference from placebo. To provide a more comprehensive picture of the nausea and vomiting expressed by the patients in this study and to put the data into a form in which each patient is represented only once so that statistical tests could be made, we scored these symptoms for each study unit in the manner described in study 1. (Since a shorter study period was used, the scores are proportionately lower.) In terms of these scores our standard, thiopropazate, again showed a statistically significant (P < 0.025 by / test) advantage over placebo (fig. 4). Metopimazine showed some superiority over placebo, but this did not achieve statistical significance. Metoclopramide showed no evidence of antiemetic activity. Side effects. As in our other studies, oversedation was the only significant side effect of treatment occurring with any frequency. In this study, patients were allowed to volunteer sedation and then were questioned specifically regarding this symptom. We graded sedation as follows: 0. No sedation 1. Sedation admitted only on questioning 2. Sedation volunteered as a significant symptom The mean grade of sedation for the agents used is listed in table 4. Thiopropazate, the only proved effective agent, showed the greatest incidence of sedation, but was closely followed by the ineffective agent, metoclopramide, again demonstrating that antiemetic activity cannot be equated with sedative activity. It is of interest that metopimazine showed no sedative activity of consequence in spite of suggestive evidence of antiemetic activity. This closely parallels the observations of. this agent in experimental animals, and it may well be that the dosage recommended for human beings is inappropriately low. Comment The phenothiazines have proved to be of significant value in the treatment of
September 1969
267
CONTROLLED CLINICAL STUDIES
1.0
.84
.82
0.8
.69 .55
0.6
Placebo
Thiopropazate
Metopimazine
Metoclopramide
FIG. 4. Comparative effectiveness of antiemetic agents and placebo.
TABLE 4 .
Grade of sedation according to antiemetic agent employed Antiemetic agent
Thioprop azate . Metopimazine ... . Metoclopramide. Placebo.... .. . .. . . ... . .
Mean grade of sedation
0 .64
0.29 0.44
0.25
nausea and vomiting, and indeed are the only antiemetic agents of established value except under the special circumstance of motion sickness. They have been shown in a number of controlled studies to be superior to placebo when administered parentally, and we have demonstrated three phenothiazines (thiopropazate, prochlorperazine, and thiethylperazine) to be effective when administered orally in standard capsule form. There would seem to be no criteria for choice among these effective agents since they are essentially equal in incidence of side effects and cost to the patient. Chlorprothixene showed a significant antiemetic effect in our study but at a dosage level at which the incidence and severity of sedation were sufficiently troublesome to outweigh the clinical usefulness of the antiemetic effect. The antihistamines, which we pre-
viously studied, cinnarizine as a representative, 1 seem to be effective specifically for motion sickness 14 but not for nausea and vomiting from other causes. Trimethobenzamide (Tigan), although it did not produce oversedation, was the least effective of the five agents tested in our earlier investigation. 1 There are now eight double blind studies 1 ' ti. tu. u. 15 - 1" in which this highly advertized and widely used drug has been found to have no advantage over placebo in the treatment of nausea and vomiting. Indeed, when used in higher doses it has been associated with a significantly greater incidence of nausea and vomiting than placebo." This agent would not seem to have any role in clinical practice. Of the two investigational antiemetic agents we have studied, metoclopramide would seem to have no clinical value. Metopimazine showed some promise of being an ideal antiemetic agent, that is, one with significant antiemetic activity in the absence of significant sedative activity. This promise, however, still Jacks the fulfillment that has to be provided by controlled study at a higher dosage level. It must be emphasized that these conclusions can be strictly applied only to the type of patient that we have observed, to our methodology, and to the emetic stimuli that we have employed.
268
MOERTEL AND REITEMEIER REFERENCES
1. Moertel, C . G., R. J. Reitemeier, and R. P. Gage. 1963. A controlled clinical evaluation of antiemetic drugs. J. A.M. A. 186: 116- 118. 2. Brizzee, K. R., and K. B. Gibson. 1963. Antiemetic action of thiethylperazine : experimental findings . Arch. Int . Pharmacodyn. 146: 4046. 3. Browne, D. C., and R. Sparks. 1961. Vomiting mechanisms: a clinical study of thiethylperazine. Southern Med. J. 54: 953-961. 4. Sparks, R. D ., D. C. Browne, and V. J . Ferrans. 1962. Thiethylperazine: effect on postoperative vomiting and localization in the central nervous system by fluorescence technics. Amer. J. Gastroent. 37: 404-413. 5. North, W. C., T. H . Collawn, A. B. Hudnell, Jr., and C. R. Stephen. 1963. Postoperative vomiting: influence of thiethylperazine. Anesth. Ana/g. (Cleveland) 42: 559-565. 6. Purkis, I. E. 1965. The action of thiethylperazine (Torecan ® ), a new anti-emetic, compared with perphenazine (Trilafon ® ), trimethobenzamide (Tigan ® ), and a placebo in the suppression of postanaesthetic nausea and vomiting. Canad. Anaesth. Soc. J. 12: 595-607. 7. Council of Drugs. 1963. Evaluation of chlorprothixene (Taractan) . J. A. M . A. 186: 144-145. 8. Justin-Besancon, L. , and C. Laville. 1964. Action antiemetique du metoclopramide vis-a-vis de !'apomorphine et de l'hydergine. C. R. Soc. Bioi. (Paris) 158: 723-727. 9. Laville, C. 1964. Protection exercee par le metoclopramide contre les effets vomitifs du sulfate de cuivre. Path. Biol. (Paris) 12: 577-578. 10. Klein, R. L., T. E. M ilitello, and C. M. Ballinger.
11.
12.
13.
14.
15.
16.
17.
18.
Vol. 57, No. 3
1968. Antiemetic effect of metoclopramide. Evaluation in humans. Anesth. Ana/g. (Clevelnnd) 47: 259-264. Jacoby, H. 1., and D. A. Brodie. 1967. Gastrointestinal actions of metoclopramide: an experimental study. Gastroenterology 52: 676- 684. Dobkin, A. B. , W. Evers, and J. S. Israel. 1968. Double-blind evaluation of metoclopramide (MK 745, Sinemet ® ), trimethobenzamide (Tigan ® ), and a placebo as postanaesthetic anti-emetics following methoxyflurane anaesthesia. Canad . Anaesth. Soc. J. 15: 80-91. Handley, A. J. 1967. Metoclopramide in prevention of post-operative nausea and vomiting. Brit. J. Clin. Pract. 21: 460- 462. Trumbull, R., H . I. Chinn, C. H. Maag, L. J. Milch, S. W. Handford, R. Seibert, P . Sperling, and P. K. Smith. 1960. Effect of certain drugs on the incidence of seasickness. Clin. Pharmacal. Ther. 1: 280- 283. Blatchford, E . 1961. Studies of anti-emetic drugs: a comparative study of cyclizine (Marzine ®), pipamazine (Momidine ® ), trimethobenzamide (Tigan ® ), and hyoscine. Canad. Anaesth. Soc . J. 8: 159-165. Bellville, J. W. , I. D. J. Bross, and W. S. Howland. 1960. Postoperative nausea and vomiting. IV. Antiemetic efficacy of trimethobenzamide and perphenazine. Clin. Pharmacal. Ther. 1: 590-596. Bradford, N. W. 1965. Preliminary report of trials of anti-motion sickness drugs. Med. Serv. J. Canada 21: 310-315. Bardfeld, P. A. 1966. A controlled double-blind study of trimethobenzamide, prochlorperazine, and placebo. J . A . M. A. 196: 796- 798.
GASTROF;NTEROLOGY
Copyright© 1969 by The Williams & Wilkin' C'o.
CONTROLLED CLINICAL STUDIES OF ORALLY ADMINISTERED ANTIEMETIC DRUGS CHARLES
G.
MOERTEL, M.D., AND RICHARD
J.
REITEMEIER, M.D.
Section of Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
In a controlled double blind study of marketed antiemetic drugs administered by the oral route, the phenothiazine agents, thiethylperazine (Torecan) and thiopropazate (Dartal), were found to have significant therapeutic activity when compared to placebo. Chlorprothixene (Taractan) showed antiemetic effectiveness but at a price of clinically intolerable sedative effect. A barbiturate (pentobarbital sodium) was not effective as an antiemetic. Of two investigational drugs studied, metoclopramide proved to be of no therapeutic value. Metopimazine showed an indication of antiemetic effect in the absence of any significant sedative effect. This agent should be evaluated over a higher dosage range. No consistent correlation was noted in comparing sedative effect and antiemetic effect of these agents. Nausea and vomiting are ubiquitous symptoms which complicate not only the disease states that we treat but also the treatment procedures themselves. Amelioration of these symptoms has provided the clinical pharmacologist with a formidable challenge which has been met at least in quantity, if not in quality. In the 1968 Physicians' Desk Reference, 125 drugs are advocated for treatment of nausea and 71 for vomiting. When one searches the credentials of these agents to find some factual basis for this claimed effectiveness, however, a distressing vacuum all too often is encountered. Nausea is largely subjective, and the occurrence of vomiting can be greatly influenced by the emotional status of the patient. Placebo treatment has been well established as effective in a substantial proportion of patients afflicted with these Received December 2, 1968. Accepted April 14, 1969. Address requests for reprints to: Dr. Charles G. Moertel, Mayo Clinic, Rochester, Minnesota 55901. The authors wish to thank Lila Elveback, Ph.D., for her assistance in the design and statistical analyses of this study.
symptoms. Before any drug can be claimed as an effective antiemetic agent, therefore, it must be demonstrated by controlled study to be more effective than placebo. Because the enthusiasm of the physician may have a striking influence on the patient's receptiveness of therapy as well as on the physician's own evaluation of therapeutic effectiveness, a double blind procedure is a sine qua non for the study of antiemetic agents. Controlled, double blind studies proving the effectiveness of orally administered antiemetic agents have been reported only infrequently, and controlled comparisons of the relative effectiveness of these agents, regardless of the route of administration, have been conspicuously rare in the literature. In 1963, we reported such a study of five antiemetic agents and placebo used for the prevention of nausea and vomiting in 300 patients with advanced malignant disease undergoing treatment with 5-fluorouracil (5-FU).' We found that the phenothiazines, thiopropazate (Dartal) and prochlorperazine (Compazine), showed a statistically significant therapeutic advantage over placebo. We
262
September 1969
263
CONTROLLED CLINICAL STUDIES
also found in this study that, for the agents employed, sedative effect seemed to parallel antiemetic effect. The two studies presented herein involve first an evaluation of other agents marketed for treatment of nausea and vomiting and second a study of new drugs under investigation for this purpose.
~S~
~N~CI
IHH 1\HH ~ HC- C - C - N N - C - C -0- C- CH3 HHH\__/HH
THIOPROPAZATE HYDROCHLORIDE
Study 1 For this study we chose to compare and to evaluate the antiemetic qualities of thiethylperazine, chlorprothixene, and sodium pentobarbital with an antiemetic of known effectiveness from our first study and placebo. Materials. Thiethylperazine (Torecan, fig. 1) is a phenothiazine which has a high degree of antiemetic activity in experimental animals and is marketed specifically for antiemetic purposes. A number of controlled clinical studies2 - 6 have demonstrated its significant antiemetic effectiveness when administered parenterally, but no report of its effectiveness by the oral route has been published. Chlorprothixene (Taractan) is not strictly a phenothiazine, but it has a similar molecular structure and pharmacological activity. Laboratory data have shown evidence of antiemetic activity. It has been employed clinically, primarily as a psychotherapeutic agent, but the manufacturer suggested its possible usefulness against nausea and vomiting attributable to various causes.' However, no controlled studies to prove its clinical antiemetic effectiveness have been made. The barbiturates had been employed in the past for palliation of nausea and vomiting, but more recently they have been supplanted largely by the phenothiazines. Since our initial study indicated some correlation between sedative effect and antiemetic effect, we considered it reasonable to include a barbiturate sedative in this evaluation. We chose sodium pentobarbital because its duration of action by the oral route approximates that of phenothiazines. As a standard of known antiemetic effectiveness, we chose thiopropazate (Dartal), the most effective agent in our first study. Lactose (U.S.P.) was employed as placebo. To avoid any possible distortion that this small amount of lactose might induce in the gastrointestinal symptoms of the patients, the active agents also were prepared with a lactose filler.
2HCI
THIETHYLPERAZINE
~s~ ~CI
II H H ,....CH3 C-C-C-N H H H 'CH3
CHLORPROTHIXENE FIG.
1. Structure of antiemetic agents employed
in study 1.
Methods. Outpatients were studied during treatment with 5-FU for advanced gastrointestinal cancer. None had experienced prior vomiting or significant nausea. 5-FU was given by rapid intravenous injection (13.5 mg per kg per day) for 5 consecutive days or until specific toxicity was evident. One-hundred-fifty patients were observed during their first course of 5-FU therapy and 100 patients during their second course. They were given analgesics and nighttime sedation as needed, but none received any tranquilizer or daytime barbiturate. Patients were randomized into the following treatment groups: (1) placebo; (2) thiopropazate, 10 mg; (3) thiethylperazine, 10 mg; (4) chlorprothixene, 50 mg; and (5) sodium pentobarbital, 30 mg. Dosages of thiopropazate and thiethylperazine were those recommended as optimum for antiemetic effect by the manufacturers. The dosage of chlorprothixene was that stated by the manufacturer to produce a sedative effect comparable with that of the phenothiazine dosages that we employed. We estimated that the dosage of sodium pentobarbital would produce a sedative effect comparable with that of the phenothiazine dosages.
264
MOERTEL AND REITEMEIER
All study drugs were dispensed in identical opaque yellow capsules. One capsule was administered orally 20 min before each meal for 4 days. Patients were told that the capsules contained medication to help prevent nausea and vomiting. Each day patients were allowed first to volunteer the symptoms of nausea and vomiting by a general inquiry; they were then questioned specifically regarding the occurrence of nausea and vomiting during the preceding 24hr period. Excessive sedation was recorded only if the patient volunteered these as symptoms.
Results. The incidence of nausea and vomiting experienced with each antiemetic agent compared with that experienced with the placebo is shown in table 1. TABLE
1. Incidence of nausea and vomiting
according to antiemetic agent employed
I
Antiemetic agent
•
-
- - - -- - - -- - [ ·
Thiopropazate. Thiethylperazine . Chlorprothixene . Sodium pentobarbital. Placebo.
Percentage of patients with symptoms in 50 4-day study periods I
N au s~ ~
34
36 38 52 68
Vom iting
18 16 16 24 24
----------------~------~------
Vol. 57, No . 3
These figures pertain only to the incidence of the respective symptoms and do not reflect their severity. To permit an evaluation and comparison of the over-all antiemetic effect of each of the agents tested, responses of patients during each study period were graded as follows: 0. No nausea or vomiting 1. Mild nausea, admitted only on direct questioning 2. Severe nausea, volunteered as a significant symptom 3. Infrequent vomiting, not exceeding one time during any day of the study period 4. Frequent vomiting, two or more times during any day of the study period The graded occurrence of nausea and vomiting according to this method is shown in figure 2. The two phenothiazines, thiopropazate and thiethylperazine, as well as chlorprothixene show definite and essentially equal antiemetic activity. Their superiorities to placebo are statistically significant by the x" test (P < 0.01). Sodium pentobarbital was not effective in preventing the occurrence of vomiting and showed only a slight and insignificant advantage over placebo in preventing nausea. With the exception of 1 patient in whom a myoclonic reaction developed during
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.82
Placebo
Chlorprothixine
.84
.86
Thiopropazate
Thiethylperazine
Sodium pentobarbital
FIG. 2. Comparative effectiveness of antiemetic agents and placebo.
September 1969
CONTROLLED CLINICAL STUDIES
treatment with thiopropazate, the only significant side effect observed in this study was that of oversedation. The incidence of oversedation volunteered as a significant symptom is listed in table 2. This side effect occurred at a comparable rate with the phenothiazines and sodium pentobarbital but was much more frequent with chlorprothixene. The observations in this study demonstrate that the antiemetic effect of a pharmacological agent is not necessarily correlated with sedative effect, nor does an agent producing sedation necessarily also possess antiemetic activity.
H H /C2H5 CONH-C -C- N H H 'C 2 H 5 OCH 3
Cl
0
NH 2
METOCLOPRAMIDE(MK 745)
Study2 In recent years, the pharmacological laboratories have been striving vigorously for more effective and specific antiemetic agents, both by studying variations on the proved phenothiazine theme as well as by exploring the potentialities of a number of new classes of compounds. Among the products of these investigations we chose two agents for clinical evaluation which seemed, from animal studies, to have outstanding potentiality: metoclopramide (MK 745) and metopimazine (EXP 999). Materials. Metoclopramide (fig. 3), a derivative of p-aminosalicylic acid, has been found in animal studies by Justin-Besancon and Laville"· " to have a manifold advantage over chlorpromazine and prochlorperazine in preventing vomiting induced by apomorphine, Hydergin, and copper sulfate. Klein and associates'" have shown this agent to be effective in preventing apomorphine-induced vomiting in man. In addition, metoclopramide has been found to have a unique action in stimulating TABLE
2. Incidence of oversedation according to
antiemetic agent employed Antiemetic agent
Percentage of p atients with oversedat10n in 50
study periods
Thiopropaza te. Thiethylper azine . Chlorprothixene. Sodium pentobarbital. Placebo . ._ .
16 14
54 12 4
265
I
D-
H- H HC - C C - N H H H
CON H 2
METOPIMAZINE (Exp 999) FIG . 3. Structure of antiemetic agents employed in study 2.
gastric motility." A number of reports by European authors have testified to the clinical antiemetic effectiveness of this agent in man; none of these studies, however, has been controlled. Two recent controlled studies"· '" have evaluated metoclopramide administered parenterally to patients after surgical treatment, but the results were conflicting. Metopimazine is a phenothiazine derivative which, in animal studies, has produced only minimal hypotension and sedation at an effective antiemetic dose range (personal communication, Pharmaceutical Division, E. I. du Pont de Nemours and Company, Wilmington, Del.). When studied against apomorphine-induced vomiting in the dog, it was vastly more potent than chlorpromazine when administered either subcutaneously or orally. Early clinical studies conducted in France and in Canada indicated effective activity against nausea and vomiting under a variety of circumstances but, again, none of the studies was controlled. The purpose of this study was to evaluate the antiemetic effectiveness of metoclopramide and metopimazine by a controlled double blind technique in comparison with placebo (lactose) and an antiemetic agent of known effectiveness (thiopropazate).
M OERTEL AND REJTEMEJER
266
M ethods . Patients with locally inoperable carcinoma of the stomach or pancreas received, on a randomized basis, either radiation therapy alone or radiation therapy plus 5-FU. Patients with all types of diffuse metastatic gastrointestinal carcinoma received only chemotherapy with either mitomycin C or 1 , 3-bis-(2-chloroethyl)-1~nitrosourea (BCNU) alone or in combination with each other or with 5-FU. Chemotherapy was administered on a 5-day schedule. Our earlier studies with these regimens showed that all induced nausea and vomiting in a significant proportion of patients treated. For 144 patients receiving chemotherapy only, the observation period of 4 days was broken into two 2-day intervals for comparison of the drugs and the placebo. The design was a balanced cross over with equal numbers of patients on each of the drug patterns. For 36 patients receiving radiation therapy alone, or with 5-FU, the observation period of 8 days was broken into four 2-day intervals so that each patient received each of the three drugs and the placebo in random drug order patterns. The mechanics of this investigation were otherwise the same as in study 1. The dosages of the antiemetic agents employed were those suggested by the manufacturer as optimal for antiemetic therapy: thiopropazate (10 mg, three times daily), metoclopramide (20 mg three times daily), and metopimazine (5 mg three times daily).
Results. Therapeutic effects. In this study each treatment day was considered as a single study unit. Results in table 3 are expressed in terms of the incidence of nausea and vomiting during these study periods. It can be seen that thiopropazate, our standard, again showed effective antiemetic activity as was true in our earlier 3. Incidence of nausea and vomiting according to antiemetic agent employed
TABLE
Antiemetic agent
Thiopropazate. Metopimazine .. Metoclopramide. Placebo ...
Percentage of patients with symptoms in 216 1-day study periods Nausea
Vomiting
23 27 36 30
13 15 16 19
Vol. 57, No.3
studies with this agent. Metopimazine and metoclopramide, however, showed little difference from placebo. To provide a more comprehensive picture of the nausea and vomiting expressed by the patients in this study and to put the data into a form in which each patient is represented only once so that statistical tests could be made, we scored these symptoms for each study unit in the manner described in study 1. (Since a shorter study period was used, the scores are proportionately lower.) In terms of these scores our standard, thiopropazate, again showed a statistically significant (P < 0.025 by / test) advantage over placebo (fig. 4). Metopimazine showed some superiority over placebo, but this did not achieve statistical significance. Metoclopramide showed no evidence of antiemetic activity. Side effects. As in our other studies, oversedation was the only significant side effect of treatment occurring with any frequency. In this study, patients were allowed to volunteer sedation and then were questioned specifically regarding this symptom. We graded sedation as follows: 0. No sedation 1. Sedation admitted only on questioning 2. Sedation volunteered as a significant symptom The mean grade of sedation for the agents used is listed in table 4. Thiopropazate, the only proved effective agent, showed the greatest incidence of sedation, but was closely followed by the ineffective agent, metoclopramide, again demonstrating that antiemetic activity cannot be equated with sedative activity. It is of interest that metopimazine showed no sedative activity of consequence in spite of suggestive evidence of antiemetic activity. This closely parallels the observations of. this agent in experimental animals, and it may well be that the dosage recommended for human beings is inappropriately low. Comment The phenothiazines have proved to be of significant value in the treatment of
September 1969
267
CONTROLLED CLINICAL STUDIES
1.0
.84
.82
0.8
.69 .55
0.6
Placebo
Thiopropazate
Metopimazine
Metoclopramide
FIG. 4. Comparative effectiveness of antiemetic agents and placebo.
TABLE 4 .
Grade of sedation according to antiemetic agent employed Antiemetic agent
Thioprop azate . Metopimazine ... . Metoclopramide. Placebo.... .. . .. . . ... . .
Mean grade of sedation
0 .64
0.29 0.44
0.25
nausea and vomiting, and indeed are the only antiemetic agents of established value except under the special circumstance of motion sickness. They have been shown in a number of controlled studies to be superior to placebo when administered parentally, and we have demonstrated three phenothiazines (thiopropazate, prochlorperazine, and thiethylperazine) to be effective when administered orally in standard capsule form. There would seem to be no criteria for choice among these effective agents since they are essentially equal in incidence of side effects and cost to the patient. Chlorprothixene showed a significant antiemetic effect in our study but at a dosage level at which the incidence and severity of sedation were sufficiently troublesome to outweigh the clinical usefulness of the antiemetic effect. The antihistamines, which we pre-
viously studied, cinnarizine as a representative, 1 seem to be effective specifically for motion sickness 14 but not for nausea and vomiting from other causes. Trimethobenzamide (Tigan), although it did not produce oversedation, was the least effective of the five agents tested in our earlier investigation. 1 There are now eight double blind studies 1 ' ti. tu. u. 15 - 1" in which this highly advertized and widely used drug has been found to have no advantage over placebo in the treatment of nausea and vomiting. Indeed, when used in higher doses it has been associated with a significantly greater incidence of nausea and vomiting than placebo." This agent would not seem to have any role in clinical practice. Of the two investigational antiemetic agents we have studied, metoclopramide would seem to have no clinical value. Metopimazine showed some promise of being an ideal antiemetic agent, that is, one with significant antiemetic activity in the absence of significant sedative activity. This promise, however, still Jacks the fulfillment that has to be provided by controlled study at a higher dosage level. It must be emphasized that these conclusions can be strictly applied only to the type of patient that we have observed, to our methodology, and to the emetic stimuli that we have employed.
268
MOERTEL AND REITEMEIER REFERENCES
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