title: The effect of amitriptyline, gabapentin, and carbamazepine on morphine-induced hypercarbia in rabbits.
abstract: BACKGROUND
  Severe exacerbation of chronic neuropathic pain often requires morphine in patients already treated with drugs such as tricyclic antidepressants, carbamazepine and gabapentin. However, it is unclear if a combination of these drugs intensifies the effects of morphine on the respiratory system and, if so, whether these effects are due to pharmacokinetic or pharmacodynamic interaction.
  
  
  METHODS
  We gave rabbits (n=6 per group) the following drugs daily for 4 days: subcutaneous normal saline 1 mL (control); amitriptyline subcutaneously 7 mg/kg; carbamazepine orally 100 mg/kg; gabapentin subcutaneously 25 mg/kg; and all three drugs concurrently (combination). On the fifth day, morphine 5 mg/kg was given IV, and Paco2, Pao2 and pH were measured. Morphine, morphine 3-glucoronide and morphine 6-glucoronide concentrations were measured in the plasma over the 4 h period after morphine injection.
  
  
  RESULTS
  Compared with controls, premorphine baseline Paco2 was significantly higher (P<0.05) in the amitriptyline group. Postmorphine Paco2 was significantly higher in the amitriptyline and combination groups at all time points over the 240 min, and in the gabapentin group at 10 and 30 min after morphine injection (P<0.05). Peak Paco2 was significantly higher in the amitriptyline group (58.4+/-1.6 mm Hg; mean SD, P<0.005) and in the combination group (57.4+/-1.0 mm Hg, P<0.02) than in the control group (50.2+/-5.2 mm Hg). Similarly, the area under the curve of Paco2 from zero to 240 min was significantly higher in the amitriptyline and combination groups than in the control (P<0.001). There were no significant differences among the groups in plasma concentrations of morphine and its metabolites.
  
  
  CONCLUSIONS
  We conclude that pretreatment with amitriptyline increases morphine- induced hypercarbia through pharmacodynamic processes. The effects of carbamazepine or gabapentin were not obvious in this model.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Eran
authors.initials: E
authors.lastname: Kozer
authors.forename: Zina
authors.initials: Z
authors.lastname: Levichek
authors.forename: Noriko
authors.initials: N
authors.lastname: Hoshino
authors.forename: Bhushan
authors.initials: B
authors.lastname: Kapur
authors.forename: John
authors.initials: J
authors.lastname: Leombruno
authors.forename: Nobuko
authors.initials: N
authors.lastname: Taguchi
authors.forename: Facundo
authors.initials: F
authors.lastname: Garcia-Bournissen
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.forename: Shinya
authors.initials: S
authors.lastname: Ito
mesh_terms: D000588:Amines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000639:Amitriptyline / Q000493:pharmacokinetics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D000077206:Gabapentin; D006935:Hypercapnia / Q000139:chemically induced*; D008297:Male; D009020:Morphine / Q000493:pharmacokinetics / Q000633:toxicity*; D011817:Rabbits; D012131:Respiratory Insufficiency / Q000139:chemically induced; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000588:Amines; D000701:Analgesics, Opioid; D000927:Anticonvulsants; D000929:Antidepressive Agents, Tricyclic; D003509:Cyclohexanecarboxylic Acids; D000639:Amitriptyline; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine