The effect of amitriptyline, gabapentin, and carbamazepine on morphine-induced hypercarbia in rabbits.
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.
Kozer
Eran
E
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Levichek
Zina
Z
Hoshino
Noriko
N
Kapur
Bhushan
B
Leombruno
John
J
Taguchi
Nobuko
N
Garcia-Bournissen
Facundo
F
Koren
Gideon
G
Ito
Shinya
S
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*
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