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ANESTHETIC PHARMACOLOGY

The Effect of Amitriptyline, Gabapentin, and Carbamazepine on Morphine-Induced Hypercarbia in Rabbits

Eran Kozer, MD^*, Zina Levichek, MD^*, Noriko Hoshino, MD^*, Bhushan Kapur, PhD^*, John Leombruno, BScPharm, Nobuko Taguchi, MD^*, Facundo Garcia-Bournissen, MD^*, Gideon Koren, MD^*, and Shinya Ito, MD^*

From the *Division of Clinical Pharmacology and Toxicology, the Hospital for Sick Children; Department of Clinical Pathology, Sunnybrook Health Sciences Centre; and Department of Pharmacy, the Hospital for Sick Children, Toronto, Ontario, Canada.

Address correspondence and reprint requests to Shinya Ito, MD, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Address e-mail to shinya.ito{at}sickkids.ca.

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.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999