Effect of overuse of the antimigraine combination of indomethacin, prochlorperazine and caffeine (IPC) on the disposition of its components in chronic headache patients.
BACKGROUND
The combination of indomethacin, prochlorperazine and caffeine (IPC) is one of the most utilized formulations for the treatment of migraine attacks in Italy. Several patients suffering from chronic headache overuse this symptomatic medication in the attempt to control their headache.


OBJECTIVE
To verify whether overuse of IPC combination by chronic headache patients is associated with modified disposition of its components.


METHODS
We studied indomethacin, prochlorperazine, and caffeine disposition in 34 female subjects suffering from primary headaches, subdivided into four groups: eight migraine patients occasionally using IPC combination suppositories-group 1; nine patients with chronic headache and probable medication-overuse headache, daily taking one or more suppositories of the IPC combination-group 2; 11 migraine patients occasionally using "mild" suppositories of the IPC combination-group 3; six migraine patients occasionally taking tablets of the IPC combination-group 4. The IPC combination habitually used was administered to each patient. Blood samples were taken at baseline and at fixed intervals up to 6h after administration. Plasma levels of indomethacin and prochlorperazine were assayed by high-pressure liquid chromatographic (HPLC) method; caffeine levels were assayed by enzyme multiplied immunoassay test (EMIT). Pharmacokinetic parameters were calculated by means of a computer software (P K Solutions 2.0. Summit Research Services, Montrose, CO, USA).


RESULTS
Half-life of indomethacin was longer, and clearance lower, in group 2 than in the other groups; AUC of indomethacin in group 2 was twice that in group 1 (P<0.05, Newman-Keuls' test). Peak concentrations and AUC(0-->infinity) of caffeine were significantly higher in group 2 than in the other groups (P<0.05, Newman-Keuls' test). We could not define prochlorperazine disposition because it was not detectable in the majority of blood samples.


CONCLUSIONS
Overuse of IPC combination in chronic headache patients is associated with increased plasma levels of indomethacin and caffeine, and with delayed elimination of indomethacin; the high and sustained concentrations of these drugs may cause rebound headache, organ damages, and perpetuate medication-overuse headache.
Ferrari
Anna
A
Division of Toxicology and Clinical Pharmacology, Headache Centre, University Centre for Adaptive Disorders and Headache, University of Modena and Reggio Emilia, Largo del pozzo, 71, 41100 Modena, Italy. annaf@unimore.it
Savino
Gustavo
G
Gallesi
Daniela
D
Pinetti
Diego
D
Bertolini
Alfio
A
Sances
Grazia
G
Coccia
Ciro Pio Rosario
CP
Pasciullo
Gabriella
G
Leone
Sheila
S
Loi
Marianna
M
Sternieri
Emilio
E
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D002110:Caffeine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics / Q000627:therapeutic use; D002908:Chronic Disease; D004338:Drug Combinations; D005260:Female; D006207:Half-Life; D020773:Headache Disorders / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051271:Headache Disorders, Secondary / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007213:Indomethacin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D011346:Prochlorperazine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D004338:Drug Combinations; D002110:Caffeine; D007213:Indomethacin; D011346:Prochlorperazine