title: Prolonged cutaneous analgesia with transdermal application of amitriptyline and capsaicin.
abstract: OBJECTIVE
  Capsaicin selectively binds to TRPV1, the vanilloid subtype 1 of the superfamily of transient receptor potential ion channels, which is highly expressed in pain-transmitting C fibers. Recent reports have demonstrated that the coadministration of capsaicin with a local anesthetic (LA) at the rat sciatic nerve elicits a prolonged nociceptive-selective nerve block, suggesting that activation of the TRPV1 receptor may allow LAs to enter the nerve through the TRPV1 pore. In previous studies, we demonstrated that transdermal amitriptyline achieves clinical analgesic effects and is more potent than lidocaine. Here we examine whether the combined application of amitriptyline and capsaicin as a transdermal patch will produce prolonged cutaneous analgesia compared with amitriptyline alone.
  
  
  METHODS
  Male Sprague-Dawley rats (weights 250-300 g) were assigned to five treatment groups (n = 6-8 per group). Transdermal patches containing amitriptyline with different concentrations of capsaicin were applied for 3 hrs to rats' shaved backs: 2.5% amitriptyline alone (control group) and in combination with 0.05%, 0.15%, 1%, and 8% capsaicin. Behavioral testing for cutaneous nociception was conducted before drug application and after patch removal using the cutaneous trunci muscle reflex. In addition, skin appearance was assessed to determine irritation by these formulations.
  
  
  RESULTS
  The cutaneous analgesic effect is significantly prolonged when amitriptyline is applied in combination with 8% capsaicin. Amitriptyline alone provided a complete block to pinprick for 4.5 hrs, and the time to full recovery was 96 hrs. Amitriptyline with 8% capsaicin produced a complete block to pinprick for 6 to 9 hrs, and the time to full recovery was 216 hrs (P = 0.002). Amitriptyline alone causes toxic effects in skin, whereas the higher the concentration of capsaicin, the less skin irritation was noted, and the combination of amitriptyline 2.5% with capsaicin 8% caused no adverse skin reactions.
  
  
  CONCLUSIONS
  This study demonstrates that the combined application of amitriptyline and capsaicin results in prolonged cutaneous analgesia compared with amitriptyline alone, suggesting that the activation of the TRPV1 channel by capsaicin facilitates the passage of amitriptyline into nociceptors. This transdermal patch achieves far longer cutaneous analgesia than currently available patch applications such as EMLA cream. The mechanism that underlies the lesser skin irritation noted when amitriptyline is combined with higher doses of capsaicin compared with amitriptyline alone is unclear and may be related to a counteraction of amitriptyline-induced vasoconstriction.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Anna Christin
authors.initials: AC
authors.lastname: Colvin
authors.forename: Chi-Fei
authors.initials: CF
authors.lastname: Wang
authors.forename: Mieke A
authors.initials: MA
authors.lastname: Soens
authors.forename: Aya A
authors.initials: AA
authors.lastname: Mitani
authors.forename: Gary
authors.initials: G
authors.lastname: Strichartz
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
mesh_terms: D000279:Administration, Cutaneous; D000639:Amitriptyline / Q000008:administration & dosage*; D000698:Analgesia / Q000379:methods*; D000779:Anesthetics, Local / Q000008:administration & dosage; D000818:Animals; D002211:Capsaicin / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D057968:Transdermal Patch
chemical_list: D000779:Anesthetics, Local; D000639:Amitriptyline; D002211:Capsaicin