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Efficacy and tolerability of metoclopramide nasal spray in the symptomatic therapy of functional dyspepsia
CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 10, OCTOBER 1994
EFFICACY AND TOLERABILITY OF METOCLOPRAMIDE NASAL SPRAY IN THE SYMPTOMATIC THERAPY OF FUNCTIONAL DYSPEPSIA AURORA BORTOLI, 1 ALBERTO PRADA, 1 MAURIZIO CONFALONIERI, 2 BARBARA OMAZZI,~ CLAUDIO GOZZINI,1 AND GIAN BATTISTA PONTI1 1Medicina I a and Gastrointestinal Unit, Rho Hospital, Rho-Milan, and 2Medical Research Department Crinos S.p.A., Villa Guardia, Como, Italy
ABSTRACT A new p h a r m a c e u t i c a l form of metoclopramide (MTC) has recently been developed as a n a s a l spray. The a i m of the present study was to c o m p a r e the clinical efficacy and tolerability of two f o r m u l a t i o n s of M T C - - t h e new n a s a l spray versus the more well-established t a b l e t - - i n t h e t r e a t m e n t of o u t p a t i e n t s affected with f u n c t i o n a l dyspepsia. P a t i e n t s were r a n d o m l y allocated to receive, following clinical ultras o u n d and endoscopic evaluation, either MTC n a s a l spray 10 mg/0.1 m L (1 puff) twice daily (n = 15) or MTC tablets 10 m g twice daily (n = 15); one p a t i e n t i n the MTC n a s a l spray group did n o t attend the final visit a n d therefore was considered a dropout. The results obtained in 29 patients at the end of a 4-week t r e a t m e n t period c o n f i r m the clinical efficacy of MTC i n the t r e a t m e n t of dyspeptic symptoms of f u n c t i o n a l origin. No statistical difference was observed between the two pharm a c e u t i c a l f o r m u l a t i o n s of MTC. MTC n a s a l spray was well tolerated a n d no drug-related undesired effects were observed. In addition, nasal spray t r e a t m e n t was judged satisfactory by 100% of the p a t i e n t s who a c t u a l l y received it, and 78% of the patients treated with the oral f o r m u l a t i o n were favorable toward this new method of a d m i n i s t r a t i o n of MTC. T h u s the new f o r m u l a t i o n of MTC appears to be a valid p h a r m a c o l o g i c a l t e r n a t i v e to oral a d m i n i s t r a t i o n of MTC in t h e m a n a g e m e n t of o u t p a t i e n t s with f u n c t i o n a l dyspepsia. INTRODUCTION
The term dyspepsia is commonly used to define a series of symptoms affecting the upper digestive tract (eg, upper abdominal pain or discomfort, pyrosis, belching, a postprandial feeling of fullness, nausea, vomiting, regurgitation, or laborious digestion)J Thus, given the generic nature of the term, many diseases can be implicated in causing such symptoms. Dyspepsia may be secondary to organic diseases involving the upper gastroenteric tract, 2'3 the biliary ducts, and the pancreas, 4'5 or to systemic Address correspondenceto: Dr. M. Psilogenis,Piazza XX Settembre 2, Villa Guardia (Como),Italy. Received for publication on June 14, 1994. Printed in the U.S.A. Reproductionin whole or part is not permitted. 1192
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A, BORTOLI ET AL.
diseases. However, routine examinations do not always identify an organic cause in some dyspeptic patients that are considered to have functional dyspepsia. 6 Functional dyspepsia is a very common chronic syndrome whose etiology has still not been entirely defined, although in the majority of cases, its pathogenesis is linked to an alteration in motility, and, in particular, an alteration in gastric emptying. 3'7's Consequently, the most rational therapeutic approach for patients with dyspepsia is the use of so-called prokinetic drugs which, by means of their ability to act on the motility of the upper digestive tract, have been shown to be highly effective in controlling the symptoms of these patients in numerous clinical trials. 9'1° Metoclopramide (MTC) is primarily used in the treatment of gastric motility disorders because it has an antagonistic effect on the dopaminergic receptors of the gastrointestinal tract, activates intramural neurons by inducing the release of acetylcholine, and sensitizes the postsynaptic m u s carinic receptors of smooth muscle tissue. 11'12 Different oral and parenteral formulations of MTC are currently available and are given at doses of 10 mg before main meals. In addition to these formulations, a new form of MTC has recently been developed as a nasal spray. In both healthy volunteers and oncologic patients, the administration of MTC nasal spray as single 20-mg doses produces the following pharmacokinetics and bioavailability responses: the time to maximum concentration is 2 to 3 hours, the peak plasma concentration is 2.77 ng/mL, and the elimination half-life is 2.6 hours. The present nasal formulation, when compared with an intravenous MTC dose, provides an absolute bioavailability of 70%; in addition, the administration of MTC via the nasal route avoids the first-pass effect through the intestinal wall or liver usually observed after oral administration. 13'14 The pharmacotoxicologic characteristics of the active ingredient are well known, and studies of local tolerability have shown the absence of side effects involving the nasal mucosa in many animal species and in humans. 15'16 Thus the goal of the present study was to verify the therapeutic efficacy and tolerability of MTC nasal spray in patients with functional dyspepsia. PATIENTS AND METHODS
Thirty patients with dyspeptic symptoms were enrolled in the study. The diagnosis of functional dyspepsia was made on the basis of clinical and endoscopic evaluations. Men and women, between the ages of 18 and 70 years, who displayed dyspeptic-type clinical symptoms for at least 3 months (eg, day and nocturnal epigastralgia, pyrosis, feeling of postprandial fullness, regurgitation, nausea, and vomiting) were included in the study. 1193
METOCLOPRAMIDE NASAL SPRAY IN DYSPEPSIA
Other enrollment criteria consisted of echographic evidence (not more than 12 months old) of the absence of hepatic, biliary duct, and pancreas disease, as well as the absence of ulcerative lesions and gastroduodenal erosions on endoscopic evaluation. Endoscopic evaluation (rating) was conducted using the following scale: 0 = normal mucosa; 1 = edema or hyperemia of the mucosa; 2 = presence of erosions. Patients with endoscopic scores of 0 or 1 were enrolled in the study. Informed, written consent was given and patients had to be drug-free for at least 1 week before the study began. Exclusion criteria consisted of any of the following: peptic or neoplastic disease of the upper gastrointestinal tract; presence of clinical signs of cardiopathy or nephropathy which might impede correct drug evaluation; allergy to the study drug; anatomical abnormalities of the nasal mucosa; inflammatory diseases of the airways; concomitant therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, antacids, H 2 antagonists, or other prokinetic drugs. Eligible patients were randomly assigned to either of the following treatments for a period of 4 weeks: MTC nasal spray* 10 mg/0.1 L (1 puff) twice daily or MTC tabletst 10 mg twice daily. No other antisecretory, antacid, prokinetic, NSAIDs, or steroids were administered during the study period. Treatment effectiveness was assessed in terms of the following symptoms: epigastralgia (both daytime and nocturnal), regurgitation, feeling of postprandial fullness, pyrosis, nausea, and vomiting. Symptoms referring to the week prior to the study were registered at baseline, and at the end of the treatment according to a semi-quantitative scoring system: 0 = absent, 1 = mild (not affecting daily activities), 2 --- moderate (moderately affecting daily activities), and 3 = severe (significantly affecting daily activities). At baseline and at termination of the study, each patient received a battery of routine laboratory tests including: complete blood count, bilirubin assay, serum transaminases-alkaline phosphatase determination, gamma-glutamyl transferase, blood urea nitrogen assay, blood creatinine, glycemia, and complete urine assay. At the same time, the patients assigned to the nasal spray group also underwent an otorhinolaryngological examination to evaluate the anatomic status of the nasal mucosa. Information on possible adverse reactions was gained by asking patients whether the treatments had caused any discomfort.
Statistical Analysis Parametric variables (age) were analyzed by using Student's t test whereas the chi-square test was used for nonparametric variables (sex, personal habits, symptoms, endoscopic score). * Crinos S.p.A., Villa Guardia (Como), Italy. # Trademark: Plasil ® (Gruppo Lepetit S.p.A., Milan, Italy).
1194
A. BORTOLI ET AL.
RESULTS
Thirty patients were enrolled, 15 receiving MTC tablets 10 mg twice daily and 15 MTC nasal spray 10 mg/0.1 mL (1 puff) twice daily. One patient belonging to the MTC nasal spray group did not attend the final visit, and therefore was excluded from final evaluation. Thus this report deals with 29 patients who completed their assigned treatment and participated in all examinations required by the study protocol. Demographic data and personal habits of the patients are reported in Table I. The treatment groups were homogeneous in terms of age, sex, and smoking, alcohol, and coffee consumption. No differences were found concerning disease duration and previous therapies, as shown in Table II. Twenty-seven percent of the patients in the MTC nasal spray group and 47% in the MTC tablet group had previously been treated with prokinetic drugs. Table III compares the distribution of symptoms and endoscopic findings in the two treatment groups at baseline assessment: the two groups were homogeneous. Results of the endoscopic examination revealed mild hyperemia and edema of the gastric mucosa (endoscopic score = 1) in 20% and 33% of patients receiving the nasal spray and tablets, respectively. Table IV displays the progress of clinical symptoms with respect to the week before treatment and after 4 weeks of treatment. Given the limited size of the patient population, and to allow a more appropriate statistical evaluation, the "cured" and "improved" patients were grouped together to reduce the intensity of the individual symptoms by at least one scale point. Table I. Demographic data and personal habits of patients. No. of Patients Mean age (y) Range Men/women Smoking Nonsmokers Ex-smokers Smokers Wine None V~ L/d 1/2 L/d 1 L/d Spirits Never Rarely Often Coffee (cups/d) 0-4 5-10 >10
MTC Nasal Spray
MTC Tablets
Statistical Test
P
38.8 (18-65) 7/8
45.7 (23-65) 4/11
Student t = 1.238
0.333
x 2 yates = 0.889
0.537
8 5 2
8 4 3
x 2 = 0.338
0.844
7 5 3 --
6 8 1 --
X2
1.948
0.378
9 6 --
7 7 1
× 2 = 1.576
0.455
14 1 --
15 ---
x 2 yates = 0.000
1.000
MTC = metoclopramide.
1195
=
METOCLOPRAMIDE NASAL SPRAY IN DYSPEPSIA
Table II. Characteristics of the functional dyspepsia in patients.
Disease duration (mort) 3-6 >6--12 >12 Previous therapies None Cisapride Clehopride MTC Oomperidone Others
MTC Nasal Spray (n)
MTC Tablets (n)
2 3 10
1 1 13
11 1 1 -2 --
8 2 2
Statistical Test
P
;(2 = 1.725
0.422
x 2 yates = 0.574
0.449
2 1
MTC = metoclopramide.
Evaluation of therapeutic efficacy in terms of each clinical parameter showed that there was an improvement in both groups with no statistically significant difference found between the two treatments. In particular, symptoms either improved or disappeared in the following proportion of patients: daytime epigastralgia disappeared or improved in 78% of the MTC nasal spray group and 90% of the MTC tablet group; nocturnal epigastralgia was not evaluated because of the smallness of the sample (a total of only four patients in each group experienced the symptom); nevertheless, both treatments proved to be efficacious; regurgitation was alleviated in 100% of the patients in both treatment groups while the feeling of fullness disappeared or improved in 85% of the MTC nasal spray group and 80% in the MTC tablet group; pyrosis responded positively in 88% of patients treated with MTC nasal spray and in 100% of those treated with MTC tablet; and nausea disappeared or improved in 70% of the MTC nasal spray group and 100% in the MTC tablet group. Comparison of the initial (15 patients) and final (13 patients) evaluTable III. Baseline symptoms and endoscopic scores.
Symptom Daytime epigastralgia Nocturnal epigastralgia Regurgitation Feeling of fullness Pyrosis Nausea Endoscopic score 0 1
MTC Nasal Spray (n)
MTC Tablets (n)
9 4 8 13 8 10
10 4 8 15 8 7
x 2 = 0.691 ×2 4.00 ×2 2.667 ×2 1.400 ×2 0.000 x2 1.559
0.875 0.261 0.446 0.706 1.000 0.664
12 3
10 5
x 2 yates = 0.170
0.680
MTC = metoclopramide.
1196
Statistical Test
P
A. BORTOLI ET AL.
Table IV. Symptoms after 4 weeks of treatment.
Symptom
Daytime epigastralgia Nocturnal epigastralgia Regurgitation Feeling of fullness Pyrosis Nausea
MTC Treatment
Baseline (n)
Nasal spray Tablet Nasalspray Tablet Nasal spray Tablet Nasal spray Tablet Nasal spray Tablet Nasal spray Tablet
9 10 4 4 8 8 13 15 8 8 10 7
Cured/ Improved n (%)
Unchanged/ _ Worsened n (%)
Statistical Test
P
7 t '8/ 91 I0
~1~2/
X2 = 0.530
0.466
31 r 00 8 00
l l~I
X2= 0.000
1.000
--
X2 = 0.000
1.000
11 12 151 I0 7 18
23 ~'5) (20)
x2 = 0.100
0.750
1 (12)
x 2 = 1.070
0.302
3 (30)
x 2 = 2.550
0.110
ai / 8
00)
7
)
MTC = metoclopramide.
ations of the anatomical status of the nasal mucosa in the MTC nasal spray group of patients showed that, in spite of the complete absence of subjective symptoms in the patients, mild congestion of the nasal mucosa was observed in one patient before treatment and in three patients at the end of the study (Figure 1). 14
12
13
~ .......................
Normal Mucosa Congestion "
10 ~e-- 8
a.
6
o
d Z
4
2
0
Pretreatment
Posttreatment
Figure I. Anatomical status of n a s a l mueosa in patients treated with metoclopramide nasal spray. 1197
M E T O C L O P R A M I D E N A S A L S P R A Y IN D Y S P E P S I A
16 100% 14
12 ~10
......................... . . . . . . . . . . . . . . . . . . . . . .
~
Yes
~
No
.....
78% . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
._ a.
8
o Zd
6
0
:
:
Metoclopramide Nasal Spray Metoclopramide Tablets Study Group Figure 2. Acceptability of the new formulation of metocloprarnide.
The study also included a patient questionnaire concerning the acceptability of the new nasal spray formulation. Figure 2 shows that, after 4 weeks of treatment, 100% of the patients in the MTC nasal spray group expressed a favorable opinion of the new type of administration, particularly because of its ease of use. The same questionnaire was also given to the patients treated with MTC tablets. It is interesting to note that, although none had used the nasal spray, 11 of 14 (78%) patients said that they were in favor of the new form of administration. None of the patients experienced any adverse treatment reaction except for one patient in the MTC tablet group who complained of drowsiness 2 to 3 hours after drug administration; this disturbance did not require discontinuation of the therapy. Analysis of the most common laboratory indices, both before and after treatment, did not show any pathologic variations. DISCUSSION AND CONCLUSION
Prokinetic drug therapy represents a rational approach to the treatment of the symptoms of functional dyspepsia. In the majority of cases, the etiopathogenesis of this syndrome is associated with an alteration in gastroduodenal motility. MTC is a drug with proven prokinetic and antiemetic properties, but its primary route of administration (oral) has the 1198
A. BORTOLI ET AL.
drawback of a wide range of interindividual variability in terms of the bioavailability of the active ingredient. This variability may lead to a highly differentiated clinical and toxicologic response. 17 To avoid this problem, and bearing in mind the fact that symptoms such as nausea and vomiting may make oral therapy impracticable, is the present study was done to compare the clinical efficacy and tolerability of two formulations of MTC, a new nasal spray versus the more well-established tablet. The results obtained confirm the clinical efficacy of the nasal spray active ingredient in the treatment of dyspeptic symptoms of functional origin. Given the considerable overlapping of the efficacy values in the two groups, expressed in terms of the number of cured or improved patients, it can be said that even the relatively small patient population was sufficient to demonstrate the bioequivalence of the two pharmaceutical formulations of MTC. The therapeutic effect was obtained despite a high proportion of patients (27% in the MTC nasal spray group and 47% in the MTC tablet group) having had their dyspeptic symptoms previously treated with prokinetic drugs. Metoclopramide therapy is well tolerated, with no drug-related undesired effects being observed. The local tolerability of the nasal spray was clearly evident: none of the treated patients complained of nasal disturbances or discomfort. Nasal spray treatment was judged satisfactory by 100% of the patients who actually received it, and 78% of the patients receiving oral treatment of the drug expressed a favorable attitude toward this new method of administration. Therefore, the results of the present trial show that the MTC nasal spray, given its equal clinical efficacy, offers a valid pharmacologic alternative to oral administration of MTC in patients affected with functional dyspepsia. References: 1. Colin-Jones DG. Management of dyspepsia: Report of a working party. Lancet. 1988;1: 576-579. 2. Barbara L, Camilleri M, Corinaldesi R, et al. Definition and investigation of dyspepsia: Consensus of an international ad hoc working party. Dig Dis Sci. 1989;34:1272-1276. 3. Talley NJ, Phillips SF. Non-ulcer dyspepsia: Potential cause and pathophysiology. Ann Intern Med. 1988;108:865-879. 4. Saunders JHB, Oliver RJ, Higson DL. Dyspepsia incidence of non-ulcer disease in a controlled trial of ranitidine in general practice. BMJ. 1986;292:665-668. 5. Capurso L, Koch MM, Dezi A, et al. Towards a quantitative diagnosis of dyspepsia: The value of clinical symptoms. The dyspepsia project report. Ital J Gastroenterol. 1988;20: 191-202. 6. Gear MWL, Barnes RJ. Endoscopic studies of dyspepsia in general practice. BMJ. 1980; 280:1136-1137. 1199
METOCLOPRAMIDENASALSPRAYIN DYSPEPSIA
7. Rees WDW, Miller l.J, Malagelada JR. Dyspepsia, antral motor dysfunction and gastric stasis of solids. Gastroenterology. 1980;78:360-365. 8. Galmiche JP, Bruley Des Varannes S, Le Bodic L. Les medicaments prokivhetiques en Gastroenterologie. Gastroenterol Clin Biol. 1991;15:T7-T10. 9. Corinaldesi R, Stanghellini V, Raiti C, et al. Effects of chronic oral administration of clebopride and metoclopramide on gastric emptying of solids and symptoms in patients with functional dyspepsia. Curr Ther Res. 1985;38:790-796. 10. Corinaldesi R, Raiti C, Stanghellini V, et al. Comparative effects of oral cisapride and metoclopramide on gastric emptying of solids and symptoms in patients with functional dyspepsia. Curr Ther Res. 1987;42:428-435. 11. Guslandi M. Drugs for upper digestive motility disorders. Drugs Today. 1989;25:101110. 12. Indovina I, Cataldo MG, Scaffidi A. Action of metoclopramide on gastric motility: Study with a 99m Tc Alb-labeled standard meal. Boll Soc Ital Biol Sper. 1978;154:795-798. 13. Seaglione F, Scanni A, Tomirotti M, et al. Pharmacokinetics and bioavailability of metoelopramide nasal spray versus metoclopramide intravenous in healthy volunteers and cancer patients. Arzneim-Forsch Drug Res. 1993;43(9):986-989. 14. Bateman DN, Kahn C, Davies DS. The pharmaeokineties of metoclopramide in man with observations in the dog. Br J Clin Pharmacol. 1980;9:371-377. 15. Data on file. Reynolds JA. Study no. T85 M00466. Nasal mucosal irritation study of metoclopramide nasal in rabbits. Rugby, Inc., August 8, 1986. 16. Data on file. Reynolds JA. Study no. T85 M01676.30-Day nasal mucosal irritation study of metoclopramide nasal in rabbits. Rugby, Inc., May 11, 1986. 17. Ross-Lee LM, Eadie MJ, Hooper WD, et al. Single-dose pharmacokinetics of metoclopramide. Eur J Clin Pharmacol. 1981;20:465-471. 18. Block W, Pingoud A, Khan M, et al. The pharmacokinetics, bioequivalence and bioavailability of different formulations of metoclopramide in man. Arzneim-Forsch Drug Res. 1981;31(6):1041-1045.
1200
EFFICACY AND TOLERABILITY OF METOCLOPRAMIDE NASAL SPRAY IN THE SYMPTOMATIC THERAPY OF FUNCTIONAL DYSPEPSIA AURORA BORTOLI, 1 ALBERTO PRADA, 1 MAURIZIO CONFALONIERI, 2 BARBARA OMAZZI,~ CLAUDIO GOZZINI,1 AND GIAN BATTISTA PONTI1 1Medicina I a and Gastrointestinal Unit, Rho Hospital, Rho-Milan, and 2Medical Research Department Crinos S.p.A., Villa Guardia, Como, Italy
ABSTRACT A new p h a r m a c e u t i c a l form of metoclopramide (MTC) has recently been developed as a n a s a l spray. The a i m of the present study was to c o m p a r e the clinical efficacy and tolerability of two f o r m u l a t i o n s of M T C - - t h e new n a s a l spray versus the more well-established t a b l e t - - i n t h e t r e a t m e n t of o u t p a t i e n t s affected with f u n c t i o n a l dyspepsia. P a t i e n t s were r a n d o m l y allocated to receive, following clinical ultras o u n d and endoscopic evaluation, either MTC n a s a l spray 10 mg/0.1 m L (1 puff) twice daily (n = 15) or MTC tablets 10 m g twice daily (n = 15); one p a t i e n t i n the MTC n a s a l spray group did n o t attend the final visit a n d therefore was considered a dropout. The results obtained in 29 patients at the end of a 4-week t r e a t m e n t period c o n f i r m the clinical efficacy of MTC i n the t r e a t m e n t of dyspeptic symptoms of f u n c t i o n a l origin. No statistical difference was observed between the two pharm a c e u t i c a l f o r m u l a t i o n s of MTC. MTC n a s a l spray was well tolerated a n d no drug-related undesired effects were observed. In addition, nasal spray t r e a t m e n t was judged satisfactory by 100% of the p a t i e n t s who a c t u a l l y received it, and 78% of the patients treated with the oral f o r m u l a t i o n were favorable toward this new method of a d m i n i s t r a t i o n of MTC. T h u s the new f o r m u l a t i o n of MTC appears to be a valid p h a r m a c o l o g i c a l t e r n a t i v e to oral a d m i n i s t r a t i o n of MTC in t h e m a n a g e m e n t of o u t p a t i e n t s with f u n c t i o n a l dyspepsia. INTRODUCTION
The term dyspepsia is commonly used to define a series of symptoms affecting the upper digestive tract (eg, upper abdominal pain or discomfort, pyrosis, belching, a postprandial feeling of fullness, nausea, vomiting, regurgitation, or laborious digestion)J Thus, given the generic nature of the term, many diseases can be implicated in causing such symptoms. Dyspepsia may be secondary to organic diseases involving the upper gastroenteric tract, 2'3 the biliary ducts, and the pancreas, 4'5 or to systemic Address correspondenceto: Dr. M. Psilogenis,Piazza XX Settembre 2, Villa Guardia (Como),Italy. Received for publication on June 14, 1994. Printed in the U.S.A. Reproductionin whole or part is not permitted. 1192
0011-393x/94/$3.50
A, BORTOLI ET AL.
diseases. However, routine examinations do not always identify an organic cause in some dyspeptic patients that are considered to have functional dyspepsia. 6 Functional dyspepsia is a very common chronic syndrome whose etiology has still not been entirely defined, although in the majority of cases, its pathogenesis is linked to an alteration in motility, and, in particular, an alteration in gastric emptying. 3'7's Consequently, the most rational therapeutic approach for patients with dyspepsia is the use of so-called prokinetic drugs which, by means of their ability to act on the motility of the upper digestive tract, have been shown to be highly effective in controlling the symptoms of these patients in numerous clinical trials. 9'1° Metoclopramide (MTC) is primarily used in the treatment of gastric motility disorders because it has an antagonistic effect on the dopaminergic receptors of the gastrointestinal tract, activates intramural neurons by inducing the release of acetylcholine, and sensitizes the postsynaptic m u s carinic receptors of smooth muscle tissue. 11'12 Different oral and parenteral formulations of MTC are currently available and are given at doses of 10 mg before main meals. In addition to these formulations, a new form of MTC has recently been developed as a nasal spray. In both healthy volunteers and oncologic patients, the administration of MTC nasal spray as single 20-mg doses produces the following pharmacokinetics and bioavailability responses: the time to maximum concentration is 2 to 3 hours, the peak plasma concentration is 2.77 ng/mL, and the elimination half-life is 2.6 hours. The present nasal formulation, when compared with an intravenous MTC dose, provides an absolute bioavailability of 70%; in addition, the administration of MTC via the nasal route avoids the first-pass effect through the intestinal wall or liver usually observed after oral administration. 13'14 The pharmacotoxicologic characteristics of the active ingredient are well known, and studies of local tolerability have shown the absence of side effects involving the nasal mucosa in many animal species and in humans. 15'16 Thus the goal of the present study was to verify the therapeutic efficacy and tolerability of MTC nasal spray in patients with functional dyspepsia. PATIENTS AND METHODS
Thirty patients with dyspeptic symptoms were enrolled in the study. The diagnosis of functional dyspepsia was made on the basis of clinical and endoscopic evaluations. Men and women, between the ages of 18 and 70 years, who displayed dyspeptic-type clinical symptoms for at least 3 months (eg, day and nocturnal epigastralgia, pyrosis, feeling of postprandial fullness, regurgitation, nausea, and vomiting) were included in the study. 1193
METOCLOPRAMIDE NASAL SPRAY IN DYSPEPSIA
Other enrollment criteria consisted of echographic evidence (not more than 12 months old) of the absence of hepatic, biliary duct, and pancreas disease, as well as the absence of ulcerative lesions and gastroduodenal erosions on endoscopic evaluation. Endoscopic evaluation (rating) was conducted using the following scale: 0 = normal mucosa; 1 = edema or hyperemia of the mucosa; 2 = presence of erosions. Patients with endoscopic scores of 0 or 1 were enrolled in the study. Informed, written consent was given and patients had to be drug-free for at least 1 week before the study began. Exclusion criteria consisted of any of the following: peptic or neoplastic disease of the upper gastrointestinal tract; presence of clinical signs of cardiopathy or nephropathy which might impede correct drug evaluation; allergy to the study drug; anatomical abnormalities of the nasal mucosa; inflammatory diseases of the airways; concomitant therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, antacids, H 2 antagonists, or other prokinetic drugs. Eligible patients were randomly assigned to either of the following treatments for a period of 4 weeks: MTC nasal spray* 10 mg/0.1 L (1 puff) twice daily or MTC tabletst 10 mg twice daily. No other antisecretory, antacid, prokinetic, NSAIDs, or steroids were administered during the study period. Treatment effectiveness was assessed in terms of the following symptoms: epigastralgia (both daytime and nocturnal), regurgitation, feeling of postprandial fullness, pyrosis, nausea, and vomiting. Symptoms referring to the week prior to the study were registered at baseline, and at the end of the treatment according to a semi-quantitative scoring system: 0 = absent, 1 = mild (not affecting daily activities), 2 --- moderate (moderately affecting daily activities), and 3 = severe (significantly affecting daily activities). At baseline and at termination of the study, each patient received a battery of routine laboratory tests including: complete blood count, bilirubin assay, serum transaminases-alkaline phosphatase determination, gamma-glutamyl transferase, blood urea nitrogen assay, blood creatinine, glycemia, and complete urine assay. At the same time, the patients assigned to the nasal spray group also underwent an otorhinolaryngological examination to evaluate the anatomic status of the nasal mucosa. Information on possible adverse reactions was gained by asking patients whether the treatments had caused any discomfort.
Statistical Analysis Parametric variables (age) were analyzed by using Student's t test whereas the chi-square test was used for nonparametric variables (sex, personal habits, symptoms, endoscopic score). * Crinos S.p.A., Villa Guardia (Como), Italy. # Trademark: Plasil ® (Gruppo Lepetit S.p.A., Milan, Italy).
1194
A. BORTOLI ET AL.
RESULTS
Thirty patients were enrolled, 15 receiving MTC tablets 10 mg twice daily and 15 MTC nasal spray 10 mg/0.1 mL (1 puff) twice daily. One patient belonging to the MTC nasal spray group did not attend the final visit, and therefore was excluded from final evaluation. Thus this report deals with 29 patients who completed their assigned treatment and participated in all examinations required by the study protocol. Demographic data and personal habits of the patients are reported in Table I. The treatment groups were homogeneous in terms of age, sex, and smoking, alcohol, and coffee consumption. No differences were found concerning disease duration and previous therapies, as shown in Table II. Twenty-seven percent of the patients in the MTC nasal spray group and 47% in the MTC tablet group had previously been treated with prokinetic drugs. Table III compares the distribution of symptoms and endoscopic findings in the two treatment groups at baseline assessment: the two groups were homogeneous. Results of the endoscopic examination revealed mild hyperemia and edema of the gastric mucosa (endoscopic score = 1) in 20% and 33% of patients receiving the nasal spray and tablets, respectively. Table IV displays the progress of clinical symptoms with respect to the week before treatment and after 4 weeks of treatment. Given the limited size of the patient population, and to allow a more appropriate statistical evaluation, the "cured" and "improved" patients were grouped together to reduce the intensity of the individual symptoms by at least one scale point. Table I. Demographic data and personal habits of patients. No. of Patients Mean age (y) Range Men/women Smoking Nonsmokers Ex-smokers Smokers Wine None V~ L/d 1/2 L/d 1 L/d Spirits Never Rarely Often Coffee (cups/d) 0-4 5-10 >10
MTC Nasal Spray
MTC Tablets
Statistical Test
P
38.8 (18-65) 7/8
45.7 (23-65) 4/11
Student t = 1.238
0.333
x 2 yates = 0.889
0.537
8 5 2
8 4 3
x 2 = 0.338
0.844
7 5 3 --
6 8 1 --
X2
1.948
0.378
9 6 --
7 7 1
× 2 = 1.576
0.455
14 1 --
15 ---
x 2 yates = 0.000
1.000
MTC = metoclopramide.
1195
=
METOCLOPRAMIDE NASAL SPRAY IN DYSPEPSIA
Table II. Characteristics of the functional dyspepsia in patients.
Disease duration (mort) 3-6 >6--12 >12 Previous therapies None Cisapride Clehopride MTC Oomperidone Others
MTC Nasal Spray (n)
MTC Tablets (n)
2 3 10
1 1 13
11 1 1 -2 --
8 2 2
Statistical Test
P
;(2 = 1.725
0.422
x 2 yates = 0.574
0.449
2 1
MTC = metoclopramide.
Evaluation of therapeutic efficacy in terms of each clinical parameter showed that there was an improvement in both groups with no statistically significant difference found between the two treatments. In particular, symptoms either improved or disappeared in the following proportion of patients: daytime epigastralgia disappeared or improved in 78% of the MTC nasal spray group and 90% of the MTC tablet group; nocturnal epigastralgia was not evaluated because of the smallness of the sample (a total of only four patients in each group experienced the symptom); nevertheless, both treatments proved to be efficacious; regurgitation was alleviated in 100% of the patients in both treatment groups while the feeling of fullness disappeared or improved in 85% of the MTC nasal spray group and 80% in the MTC tablet group; pyrosis responded positively in 88% of patients treated with MTC nasal spray and in 100% of those treated with MTC tablet; and nausea disappeared or improved in 70% of the MTC nasal spray group and 100% in the MTC tablet group. Comparison of the initial (15 patients) and final (13 patients) evaluTable III. Baseline symptoms and endoscopic scores.
Symptom Daytime epigastralgia Nocturnal epigastralgia Regurgitation Feeling of fullness Pyrosis Nausea Endoscopic score 0 1
MTC Nasal Spray (n)
MTC Tablets (n)
9 4 8 13 8 10
10 4 8 15 8 7
x 2 = 0.691 ×2 4.00 ×2 2.667 ×2 1.400 ×2 0.000 x2 1.559
0.875 0.261 0.446 0.706 1.000 0.664
12 3
10 5
x 2 yates = 0.170
0.680
MTC = metoclopramide.
1196
Statistical Test
P
A. BORTOLI ET AL.
Table IV. Symptoms after 4 weeks of treatment.
Symptom
Daytime epigastralgia Nocturnal epigastralgia Regurgitation Feeling of fullness Pyrosis Nausea
MTC Treatment
Baseline (n)
Nasal spray Tablet Nasalspray Tablet Nasal spray Tablet Nasal spray Tablet Nasal spray Tablet Nasal spray Tablet
9 10 4 4 8 8 13 15 8 8 10 7
Cured/ Improved n (%)
Unchanged/ _ Worsened n (%)
Statistical Test
P
7 t '8/ 91 I0
~1~2/
X2 = 0.530
0.466
31 r 00 8 00
l l~I
X2= 0.000
1.000
--
X2 = 0.000
1.000
11 12 151 I0 7 18
23 ~'5) (20)
x2 = 0.100
0.750
1 (12)
x 2 = 1.070
0.302
3 (30)
x 2 = 2.550
0.110
ai / 8
00)
7
)
MTC = metoclopramide.
ations of the anatomical status of the nasal mucosa in the MTC nasal spray group of patients showed that, in spite of the complete absence of subjective symptoms in the patients, mild congestion of the nasal mucosa was observed in one patient before treatment and in three patients at the end of the study (Figure 1). 14
12
13
~ .......................
Normal Mucosa Congestion "
10 ~e-- 8
a.
6
o
d Z
4
2
0
Pretreatment
Posttreatment
Figure I. Anatomical status of n a s a l mueosa in patients treated with metoclopramide nasal spray. 1197
M E T O C L O P R A M I D E N A S A L S P R A Y IN D Y S P E P S I A
16 100% 14
12 ~10
......................... . . . . . . . . . . . . . . . . . . . . . .
~
Yes
~
No
.....
78% . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
._ a.
8
o Zd
6
0
:
:
Metoclopramide Nasal Spray Metoclopramide Tablets Study Group Figure 2. Acceptability of the new formulation of metocloprarnide.
The study also included a patient questionnaire concerning the acceptability of the new nasal spray formulation. Figure 2 shows that, after 4 weeks of treatment, 100% of the patients in the MTC nasal spray group expressed a favorable opinion of the new type of administration, particularly because of its ease of use. The same questionnaire was also given to the patients treated with MTC tablets. It is interesting to note that, although none had used the nasal spray, 11 of 14 (78%) patients said that they were in favor of the new form of administration. None of the patients experienced any adverse treatment reaction except for one patient in the MTC tablet group who complained of drowsiness 2 to 3 hours after drug administration; this disturbance did not require discontinuation of the therapy. Analysis of the most common laboratory indices, both before and after treatment, did not show any pathologic variations. DISCUSSION AND CONCLUSION
Prokinetic drug therapy represents a rational approach to the treatment of the symptoms of functional dyspepsia. In the majority of cases, the etiopathogenesis of this syndrome is associated with an alteration in gastroduodenal motility. MTC is a drug with proven prokinetic and antiemetic properties, but its primary route of administration (oral) has the 1198
A. BORTOLI ET AL.
drawback of a wide range of interindividual variability in terms of the bioavailability of the active ingredient. This variability may lead to a highly differentiated clinical and toxicologic response. 17 To avoid this problem, and bearing in mind the fact that symptoms such as nausea and vomiting may make oral therapy impracticable, is the present study was done to compare the clinical efficacy and tolerability of two formulations of MTC, a new nasal spray versus the more well-established tablet. The results obtained confirm the clinical efficacy of the nasal spray active ingredient in the treatment of dyspeptic symptoms of functional origin. Given the considerable overlapping of the efficacy values in the two groups, expressed in terms of the number of cured or improved patients, it can be said that even the relatively small patient population was sufficient to demonstrate the bioequivalence of the two pharmaceutical formulations of MTC. The therapeutic effect was obtained despite a high proportion of patients (27% in the MTC nasal spray group and 47% in the MTC tablet group) having had their dyspeptic symptoms previously treated with prokinetic drugs. Metoclopramide therapy is well tolerated, with no drug-related undesired effects being observed. The local tolerability of the nasal spray was clearly evident: none of the treated patients complained of nasal disturbances or discomfort. Nasal spray treatment was judged satisfactory by 100% of the patients who actually received it, and 78% of the patients receiving oral treatment of the drug expressed a favorable attitude toward this new method of administration. Therefore, the results of the present trial show that the MTC nasal spray, given its equal clinical efficacy, offers a valid pharmacologic alternative to oral administration of MTC in patients affected with functional dyspepsia. References: 1. Colin-Jones DG. Management of dyspepsia: Report of a working party. Lancet. 1988;1: 576-579. 2. Barbara L, Camilleri M, Corinaldesi R, et al. Definition and investigation of dyspepsia: Consensus of an international ad hoc working party. Dig Dis Sci. 1989;34:1272-1276. 3. Talley NJ, Phillips SF. Non-ulcer dyspepsia: Potential cause and pathophysiology. Ann Intern Med. 1988;108:865-879. 4. Saunders JHB, Oliver RJ, Higson DL. Dyspepsia incidence of non-ulcer disease in a controlled trial of ranitidine in general practice. BMJ. 1986;292:665-668. 5. Capurso L, Koch MM, Dezi A, et al. Towards a quantitative diagnosis of dyspepsia: The value of clinical symptoms. The dyspepsia project report. Ital J Gastroenterol. 1988;20: 191-202. 6. Gear MWL, Barnes RJ. Endoscopic studies of dyspepsia in general practice. BMJ. 1980; 280:1136-1137. 1199
METOCLOPRAMIDENASALSPRAYIN DYSPEPSIA
7. Rees WDW, Miller l.J, Malagelada JR. Dyspepsia, antral motor dysfunction and gastric stasis of solids. Gastroenterology. 1980;78:360-365. 8. Galmiche JP, Bruley Des Varannes S, Le Bodic L. Les medicaments prokivhetiques en Gastroenterologie. Gastroenterol Clin Biol. 1991;15:T7-T10. 9. Corinaldesi R, Stanghellini V, Raiti C, et al. Effects of chronic oral administration of clebopride and metoclopramide on gastric emptying of solids and symptoms in patients with functional dyspepsia. Curr Ther Res. 1985;38:790-796. 10. Corinaldesi R, Raiti C, Stanghellini V, et al. Comparative effects of oral cisapride and metoclopramide on gastric emptying of solids and symptoms in patients with functional dyspepsia. Curr Ther Res. 1987;42:428-435. 11. Guslandi M. Drugs for upper digestive motility disorders. Drugs Today. 1989;25:101110. 12. Indovina I, Cataldo MG, Scaffidi A. Action of metoclopramide on gastric motility: Study with a 99m Tc Alb-labeled standard meal. Boll Soc Ital Biol Sper. 1978;154:795-798. 13. Seaglione F, Scanni A, Tomirotti M, et al. Pharmacokinetics and bioavailability of metoelopramide nasal spray versus metoclopramide intravenous in healthy volunteers and cancer patients. Arzneim-Forsch Drug Res. 1993;43(9):986-989. 14. Bateman DN, Kahn C, Davies DS. The pharmaeokineties of metoclopramide in man with observations in the dog. Br J Clin Pharmacol. 1980;9:371-377. 15. Data on file. Reynolds JA. Study no. T85 M00466. Nasal mucosal irritation study of metoclopramide nasal in rabbits. Rugby, Inc., August 8, 1986. 16. Data on file. Reynolds JA. Study no. T85 M01676.30-Day nasal mucosal irritation study of metoclopramide nasal in rabbits. Rugby, Inc., May 11, 1986. 17. Ross-Lee LM, Eadie MJ, Hooper WD, et al. Single-dose pharmacokinetics of metoclopramide. Eur J Clin Pharmacol. 1981;20:465-471. 18. Block W, Pingoud A, Khan M, et al. The pharmacokinetics, bioequivalence and bioavailability of different formulations of metoclopramide in man. Arzneim-Forsch Drug Res. 1981;31(6):1041-1045.
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