title: Effect of overuse of the antimigraine combination of indomethacin, prochlorperazine and caffeine (IPC) on the disposition of its components in chronic headache patients.
abstract: 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.
authors.affiliation: 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
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrari
authors.forename: Gustavo
authors.initials: G
authors.lastname: Savino
authors.forename: Daniela
authors.initials: D
authors.lastname: Gallesi
authors.forename: Diego
authors.initials: D
authors.lastname: Pinetti
authors.forename: Alfio
authors.initials: A
authors.lastname: Bertolini
authors.forename: Grazia
authors.initials: G
authors.lastname: Sances
authors.forename: Ciro Pio Rosario
authors.initials: CP
authors.lastname: Coccia
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pasciullo
authors.forename: Sheila
authors.initials: S
authors.lastname: Leone
authors.forename: Marianna
authors.initials: M
authors.lastname: Loi
authors.forename: Emilio
authors.initials: E
authors.lastname: Sternieri
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D004338:Drug Combinations; D002110:Caffeine; D007213:Indomethacin; D011346:Prochlorperazine