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American Journal of Pharmacological Sciences, 2013, Vol. 1, No. 5, 74-79 Available online at http://pubs.sciepub.com/ajps/1/5/1 Science and Education Publishing DOI:10.12691/ajps-1-5-1 Pharmacokinetics of Indomethacin in Chronic Migraine
Patients after Withdrawal from the Overused
Combination of Indomethacin, Prochlorperazine and
Caffeine
Anna Ferrari1,*, Diego Pinetti1, Daniela Gallesi1, Alfio Bertolini1, Grazia Sances2, Emilio Sternieri1
1Division of Toxicology and Clinical Pharmacology, Headache and Drug Abuse Inter-Department Research Centre, University of 2Headache Unit, IRCCS C. Mondino, University of Pavia, Pavia, Italy *Corresponding author: anna.ferrari@unimore.it Received January 13, 2013; Revised September 20, 2013; Accepted September 23, 2013 Abstract Indomethacin, in combination with prochlorperazine and caffeine (IPC), is often overused by migraine
patients who develop medication-overuse headache. Indomethacin clearance is slower in chronic migraine patients
overusing IPC combination than in migraine patients only occasionally taking it. The objective of this study was to
verify if indomethacin reduced clearance reverted to normal values after withdrawal of the overused IPC
combination. Therefore, we repeated the study of indomethacin pharmacokinetics in 9 female chronic migraine
patients after 3 months from inpatient withdrawal treatment from IPC combination overuse. The IPC combination
(indomethacin 50 mg, prochlorperazine 8 mg, caffeine 150 mg) habitually taken was administered by rectal route to
each patient. Blood samples were drawn before dosing and at the following post-dose times: 0.5, 1, 2, 3, 4, and 6 h.
Indomethacin concentrations were measured by HPLC method. We found that 4 of 9 patients (group A) who were
still overusing the combination and suffering from daily headache had still high indomethacin concentrations after 6
hours, therefore showing a slow elimination of the drug. Instead, in the 5 patients (group B) who had discontinued
overuse of IPC combination after withdrawal treatment, indomethacin concentrations after 6 hours were significantly
lower than those measured before withdrawal (P < 0.05, Student’s t-test for paired data), and also than those
observed in group A (P < 0.05, ANOVA and Newman-Keuls’test). Hence, by suspending IPC abuse indomethacin
clearance reverts to normal values and this is associated with an improvement of migraine. Instead, the higher
plasma levels of indomethacin in patients who continue IPC abuse do not solve migraine and might support
medication-overuse headache.
Keywords: indomethacin, pharmacokinetics, chronic migraine, medication-overuse headache, drug combinations
Cite This Article: Anna Ferrari, Diego Pinetti, Daniela Gallesi, Alfio Bertolini, Grazia Sances, and Emilio
Sternieri, “Pharmacokinetics of Indomethacin in Chronic Migraine Patients after Withdrawal from the Overused
Combination of Indomethacin, Prochlorperazine and Caffeine.” American Journal of Pharmacological Sciences 1,
no. 5 (2013): 74-79. doi: 10.12691/ajps-1-5-1.
treatment, according to the guidelines by the Italian Society for the Study of Headaches at the third level 1. Introduction
of recommendation, when triptans, which are first recommended, result ineffective against nausea and Indomethacin, an indole acetic acid derivative [1-(P- vomiting. It is instead not recommended if migraine chlorbenzoyl)-5-methoxy-2 methylindole-3-acetic acid], attacks have a medium/high frequency, because of the structurally related to serotonin, is a potent non-selective potential risk of overuse In spite of this, a large inhibitor of cyclooxygenases, with central analgesic number of chronic daily headache patients who overuse properties In Italy, it is one of the most used drugs for IPC combination are referred to the Headache Centre of acute headache treatment, in a fixed combination with the University of Modena, Italy These patients prochlorperazine and caffeine, which is available on the reported that this medication was initially an market in oral (tablets: indomethacin 25 mg, extraordinarily effective antimigraine drug, but then, year prochlorperazine 2 mg, caffeine 75 mg) and rectal by year, they had to increase daily dosages and intake (suppositories: indomethacin 50 mg, prochlorperazine 8 frequency gradually, sometimes up to true abuse, because mg, caffeine 150 mg; mild suppositories: indomethacin 25 of a gradual reduction in its effectiveness (both in the mg, prochlorperazine 4 mg, caffeine 75 mg) formulations. intensity and duration of the effect). At the same time, This combination (IPC) is indicated for acute headache American Journal of Pharmacological Sciences their headache turned into chronic daily headache. We 2. Patients and Methods
supposed that this gradual reduction in the effectiveness of IPC combination was related to an accelerated elimination 2.1. Subjects
of its components and, consequently, to plasma levels insufficient for therapeutic effects. We therefore studied We studied again the kinetics of indomethacin after the pharmacokinetics of each component of this giving IPC combination to 9 female subjects (all medication in migraine patients occasionally taking it and Caucasian) suffering from chronic migraine and in chronic migraine patients overusing it Contrary to medication-overuse headache according to ICDH-II our hypothesis, the elimination of the components of IPC classification criteria 3 months after withdrawal combination is not accelerated in overusing subjects: treatment from overuse (7-10 days of hospitalization with indomethacin clearance is instead reduced and its half-life standardized treatment; at discharge, a prophylactic longer in chronic migraine patients overusing this treatment with amitriptyline in the oral dosage of 30-60 combination than in episodic migraine patients only mg/day was prescribed to every patient). Before occasionally taking it. On the other hand, there are no withdrawal treatment, all these patients had only been significant differences in the kinetics of caffeine and overusing IPC combination for at least one year, taking prochlorperazine between subjects occasionally taking daily one or more suppositories of this medication, IPC combination and patients overusing These containing indomethacin 50 mg, prochlorperazine 8 mg, results suggest that in chronic migraine patients overusing and caffeine 150 mg. In these patients, the diagnosis of IPC combination, just indomethacin high concentrations headache at the onset was migraine without aura. In time, could have sustained and perpetuated medication-overuse their migraine became chronic. In each patient, the kinetics of indomethacin had already been studied before The objective of our study was therefore to verify if the withdrawal treatment the follow-up, 3 months later, reduced systemic indomethacin clearance found in 4 of these patients (group A) had relapsed into daily use of patients overusing IPC combination disappeared once one or more suppositories of IPC combination and still overuse was discontinued. Hence, we studied again the suffered from daily headache, while 5 patients (group B) kinetics of indomethacin in the same patients who had had a reduced headache frequency and were taking IPC been previously studied, 3 months after withdrawal combination only occasionally and with full effectiveness treatment from overuse, and we analysed if there were . The frequency of drug intake was recorded in differences in the kinetics of indomethacin, following IPC the diaries that patients kept until the follow-up. Informed combination administration, between patients who had consent was obtained from each subject, following the steadily discontinued overuse, with a clear improvement description of the study’s procedures and objectives. The in their headache, and those who had instead relapsed into study was approved by the ethical committees of Modena overuse and whose headache was still chronic. and Pavia and it was conducted in compliance with the declaration of Helsinki, latest version. Table 1. Patients’ characteristics (mean+S.D.; range in brackets)
a P < 0.05 vs. after withdrawal, group B before and after withdrawal (ANOVA and Newman-Keuls’test) b P < 0.05 vs. group B after withdrawal (ANOVA and Newman-Keuls’test) c P < 0.05 vs. group B after withdrawal (ANOVA and Newman-Keuls’test) No patient was a smoker, had kidney or liver 2.2. Procedures
dysfunction or was taking drugs able of causing drug-drug interactions with the components of IPC combination. In Experimental sessions were conducted at the in-patient particular, no patient was taking other drugs known as ward of the Headache Centres of Modena and Pavia inducers or inhibitors of cytochrome P450 2C9 (CYP2C9) University Hospitals. Under medical surveillance, the IPC All patients complained of gastrointestinal troubles, combination habitually taken (indomethacin 50 mg, two patients of group A were taking lansoprazole 30 prochlorperazine 8 mg, and caffeine 150 mg) was rectally mg/day, and three (one in group A and two in group B) administered to each patient, at 7 AM, after overnight were taking antihypertensive agents (lisinopril, fasting. Patients were maintained in supine position for the candesartan, amiloride/hydrochlorothiazide). At the time subsequent 30 minutes. Venous blood samples were of the experimental session, patients did not present acute drawn from an indwelling cannula into heparinized tubes, diseases, according to histories and physical and before dosing and at the following post-dose times: 0.5, laboratory evaluations (blood chemistry, blood count, 1.0, 1.5, 2.0, 3.0, 4.0, and 6.0 hours. Samples were immediately centrifuged, and kept at –20o C until the time American Journal of Pharmacological Sciences of assay. Indomethacin concentrations were measured on even when repeated after 3 months, in spite of the wide deproteinized serum, by means of a slightly modified inter-individuals variations observed above all in group A, reversed-phase high-pressure liquid chromatographic and in the first 2 hours. After withdrawal treatment from (HPLC) meth A detailed description of the method overuse of IPC combination, plasma indomethacin levels had decreased at all times of the curve, both in group A and B, but only patients in group B, who had steadily 2.3. Analysis of the Data and Statistical
discontinued overuse and whose headache had Evaluation
consequently improved, did not have measurable concentrations at baseline. Patients in group A, who were Pharmacokinetic parameters were calculated by means still overusing the combination (even if less than before) of the P K Solutions 2.0 program (Non compartmental and suffering from daily headache, had still high pharmacokinetics data analysis, Summit Research indomethacin concentrations (even if much lower than Services, Montrose, CO, USA). The following parameters before) after 6 hours, therefore showing a slow were determined for indomethacin: Cmax, peak plasma elimination of the drug. In patients of group B, who had concentration (maximum observed plasma concentration) discontinued overuse of IPC combination after withdrawal (µg/ml); Tmax, time to peak plasma concentration (hr); t1/2, treatment, indomethacin concentrations after 6 hours were half-life clearance, time for concentration to diminish by
significantly lower than those measured before withdrawal one-half (hr); MRT, mean residence time, time for 63.2% (P < 0.05, Student’s t-test for paired data) and also than of administered dose to be eliminated (hr); AUC0→t, those observed in group A (P < 0.05, ANOVA and cumulative area under the plasma concentration time curve, only using observed data points (µg-hr/ml); Before withdrawal treatment from overuse of IPC AUC0→∞, total AUC, computed using data points combination, pharmacokinetic parameters of extrapolated to infinity (µg-hr/ml); Vd, apparent volume of distribution, based on AUC∞ and clearance rate significant differences between groups A and B (Student’s normalized by weight (ml/Kg); Cl, systemic clearance, t-test for unpaired data). After withdrawal from overuse, the kinetics of indomethacin was still unchanged in All data were expressed as mean ± S.D. When patients of group A, who at the 3-months follow-up appropriate, Student’s t-test for paired and unpaired data, resulted to have relapsed into overuse of IPC combination and ANOVA, followed by Newman-Keuls post hoc (Student’s t-test for paired data). Instead, patients of group testing, were performed to assess statistical difference B, whose headache had improved after discontinuing between the groups. A level of P < 0.05 was considered overuse, had faster indomethacin elimination than before (P < 0.05, Student’s t-test for paired data) and also faster clearance than patients of group A, who were still overusing the combination (P < 0.05, ANOVA and 3. Results
Newman-Keuls’test), as it was shown by the statistically significant increase of clearance and by the reduction, The plasma time course of indomethacin levels, even if not statistically significant, in t1/2, AUC0-t, and following administration of one IPC suppository AUC0-∞, in the absence of Tmax and Vd. , had a similar pattern in the same group of patients, Table 2. Pharmacokinetic parameters (estimated by non-compartmental method) of indomethacin following rectal administration of IPC
combination (indomethacin 50 mg, prochlorperazine 8 mg, caffeine 150 mg) in 9 chronic migraine patients before and after 3 months from in-
patient withdrawal from the overused IPC combination (Group A: patients who relapsed into overuse; Group B: patients who steadily
discontinued overuse)

ml/hr/Kg a P < 0.05 vs before (Student’s t-test for paired data) b P < 0.05 vs group A before (ANOVA and Newman-Keuls’test) c P < 0.05 vs group B before, group A before and after (ANOVA and Newman-Keuls’ test) American Journal of Pharmacological Sciences Figure 1. Plasma levels (mean ± S. D.) of indomethacin in patients of group A (upper panel) and of group B (bottom panel) before (●) and after (■)
withdrawal from the overused IPC combination (statistical differences between mean levels: * P < 0.05, Student’s t-test for paired data)
hours, t1/2 2-11 hours, Cl 0.44 to 109 ml/min/kg, Vd 411-450 ml/kg)and comparable to those calculated in 4. Discussion
migraine patients only occasionally taking IPC combination (Tmax 1.62 ± 0.7 hours, t1/2 1.27 ± 0.4 hours, Delayed indomethacin elimination, that we observed in Cl 130.90 ± 30.2 ml/min/kg, Vd 235.31 ± 69.3 ml/Kg) patients with chronic migraine overusing IPC combination Notably, the normalization of the kinetics of indomethacin (containing indomethacin 50 mg, prochlorperazine 8 mg, in patients of group B, who had definitively suspended and caffeine 150 mg), was reversible once overuse was discontinued. Indomethacin clearan increased improvement in migraine, which turned from daily into significantly in these patients (group B), passing from occasional, reducing its mean frequency to 6 ± 1.58 days 64.05 ± 30.16 ml/hr/Kg during overuse to 123.98 ± 39.91 per month. The high and sustained levels of indomethacin ml/hr/Kg after steadily discontinuing overuse of IPC , observed in patients of group A, both at combination. All pharmacokinetic parameters of baseline (as likely residual of previous assumptions) and 6 indomethacin, calculated in subjects in group B after hours after IPC administration, were instead associated withdrawal from overuse of IPC combination, were with overuse and chronic migraine. This pattern of plasma consistent with published data obtained following indomethacin concentrations was certainly the administration of therapeutic dosages of indomethacin to consequence of several and repeated daily intakes of IPC healthy volunteers and rheumatic patients (Tmax 1 to 4 American Journal of Pharmacological Sciences combination, since repeated doses of indomethacin tend to of headache, and overused medication. We did not study accumulate Moreover, indomethacin undergoes the kinetics of all three components of IPC combination, enterohepatic circulation In patients overusing IPC because the disposition of caffeine and prochlorperazine is combination, a higher and continual enterohepatic unchanged in migraine patients overusing IPC circulation could have caused reduced indomethacin clearance. This modified disposition of indomethacin did The present is one of the few studies on the kinetics of not depend on metabolic characteristics of the patients an acute migraine medication during overuse, apart from studied. No patient, neither in group A nor B, suffered from hepatic or kidney failure, or was taking medications unrestricted use of ergotamine is often associated with capable of inducing or inhibiting CYP2C9-mediated ergotamine medication-overuse headach frequent use of IPC combination can lead to reduced effect and dosage Since a relationship between indomethacin plasma escalation in trying to control headache. Hence, plasma levels and degree of pharmacological effect has been indomethacin levels which stayed higher than those in the reported chronic migraine patients overusing IPC therapeutic range for a long time [proposed therapeutic combinations should steadily be free from headache. concentration is 1 µg/mldid not resolve the headache Instead, these patients said to have had to take more and but, on the contrary, might have sustained medication- more IPC combinations over time, because this overuse headache. On the other hand, in patients who only medication had become less and less effective against occasionally took IPC combination after withdrawal their migraine. Some patients of group A took up to 8 treatment, headache improved, the effectiveness of this doses a day of IPC combination, that is, 400 mg/day of medication was restored, indomethacin levels were lower indomethacin, the double of the maximal therapeutic daily dosage of 200 mg. This apparently paradoxical effect of IPC combination is a widely used drug for acute the overuse of IPC combination in migraine treatment treatment of migraine attacks In our opinion, it is (higher concentrations of indomethacin associated with important to warn patients using this medication, and reduced effectiveness) can be explained considering the physicians prescribing it, that, even if IPC combination is unique features of indomethacin, different from those of composed of low dosages of three active principles, the other NSAIDs. Indomethacin causes cerebral overuse of this medication might induce rebound vasoconstriction, which is rapid in onset and resolution, headache and sustain medication-overuse headache. closely related to plasma concentrations The mechanism of vasoconstriction induced by indomethacin is not fully understood. The other NSAIDs have been Declaration of Interest
shown to have no effects on cerebral blood flowMoreover, the most common dose-dependent CNS adverse reaction to indomethacin is headache. It has been attributed to compensatory vasodilatation that follows vasoconstriction In some cases, especially in the References
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