Prolonged therapy with the anticonvulsant carbamazepine leads to increased plasma clearance of fentanyl

Ala Nozari, Oluwaseun Akeju, Hooman Mirzakhani, Emad N. Eskandar, Zhijun Ma, MD Amin Hossain, Qingping Wang, David J. Greenblatt, J. A.Jeevendra Martyn

Research output: Contribution to journalArticle

Abstract

Objectives: Fentanyl is a potent analgesic that accounts for an increasing number of overdose deaths in the United States. This study tested whether altered pharmacokinetics plays a pivotal role in the increased fentanyl dose requirements in patients receiving the enzyme-inducing anticonvulsant, carbamazepine. Methods: Neurosurgical patients receiving carbamazepine for >6 weeks (N = 11) or no carbamazepine (N = 6, controls) received a single bolus dose of fentanyl (200 μg) intravenously. Plasma was collected before and for up to 9 h after the bolus. Fentanyl concentrations were measured using liquid chromatography–mass spectrometry. Pharmacokinetic variables were derived from plasma concentration–time curves best fitted to a two-compartment model. Key findings: Fentanyl clearance was significantly higher in the carbamazepine group compared to controls (mean ± SD: 20.1 ± 6.8 vs 13.2 ± 4.8 ml/min per kg, P < 0.05), and area under the plasma concentration curve (AUC) was significantly lower (150 ± 65 vs 233 ± 70 ng/ml × min, P < 0.02). Volume of distribution was larger in the carbamazepine group, but the difference was not statistically significant (5.4 ± 3.1 vs 3.6 ± 1.2 l/kg, P > 0.15). The terminal elimination half-life did not differ between the two groups. Conclusions: Chronic carbamazepine therapy leads to increased fentanyl clearance and decreased AUC, which may result in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement. Assuming that carbamazepine does not change fentanyl pharmacodynamics, patients on chronic carbamazepine therapy may require more frequent or higher fentanyl doses to maintain therapeutic plasma concentrations.

Original languageEnglish (US)
Pages (from-to)982-987
Number of pages6
JournalJournal of Pharmacy and Pharmacology
Volume71
Issue number6
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

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Carbamazepine
Fentanyl
Anticonvulsants
Therapeutics
Pharmacokinetics
Area Under Curve
Half-Life
Analgesics
Spectrum Analysis
Enzymes

Keywords

  • carbamazepine
  • enzyme induction
  • fentanyl
  • pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Prolonged therapy with the anticonvulsant carbamazepine leads to increased plasma clearance of fentanyl. / Nozari, Ala; Akeju, Oluwaseun; Mirzakhani, Hooman; Eskandar, Emad N.; Ma, Zhijun; Hossain, MD Amin; Wang, Qingping; Greenblatt, David J.; Martyn, J. A.Jeevendra.

In: Journal of Pharmacy and Pharmacology, Vol. 71, No. 6, 01.06.2019, p. 982-987.

Research output: Contribution to journalArticle

Nozari, A, Akeju, O, Mirzakhani, H, Eskandar, EN, Ma, Z, Hossain, MDA, Wang, Q, Greenblatt, DJ & Martyn, JAJ 2019, 'Prolonged therapy with the anticonvulsant carbamazepine leads to increased plasma clearance of fentanyl', Journal of Pharmacy and Pharmacology, vol. 71, no. 6, pp. 982-987. https://doi.org/10.1111/jphp.13079
Nozari, Ala ; Akeju, Oluwaseun ; Mirzakhani, Hooman ; Eskandar, Emad N. ; Ma, Zhijun ; Hossain, MD Amin ; Wang, Qingping ; Greenblatt, David J. ; Martyn, J. A.Jeevendra. / Prolonged therapy with the anticonvulsant carbamazepine leads to increased plasma clearance of fentanyl. In: Journal of Pharmacy and Pharmacology. 2019 ; Vol. 71, No. 6. pp. 982-987.
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abstract = "Objectives: Fentanyl is a potent analgesic that accounts for an increasing number of overdose deaths in the United States. This study tested whether altered pharmacokinetics plays a pivotal role in the increased fentanyl dose requirements in patients receiving the enzyme-inducing anticonvulsant, carbamazepine. Methods: Neurosurgical patients receiving carbamazepine for >6 weeks (N = 11) or no carbamazepine (N = 6, controls) received a single bolus dose of fentanyl (200 μg) intravenously. Plasma was collected before and for up to 9 h after the bolus. Fentanyl concentrations were measured using liquid chromatography–mass spectrometry. Pharmacokinetic variables were derived from plasma concentration–time curves best fitted to a two-compartment model. Key findings: Fentanyl clearance was significantly higher in the carbamazepine group compared to controls (mean ± SD: 20.1 ± 6.8 vs 13.2 ± 4.8 ml/min per kg, P < 0.05), and area under the plasma concentration curve (AUC) was significantly lower (150 ± 65 vs 233 ± 70 ng/ml × min, P < 0.02). Volume of distribution was larger in the carbamazepine group, but the difference was not statistically significant (5.4 ± 3.1 vs 3.6 ± 1.2 l/kg, P > 0.15). The terminal elimination half-life did not differ between the two groups. Conclusions: Chronic carbamazepine therapy leads to increased fentanyl clearance and decreased AUC, which may result in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement. Assuming that carbamazepine does not change fentanyl pharmacodynamics, patients on chronic carbamazepine therapy may require more frequent or higher fentanyl doses to maintain therapeutic plasma concentrations.",
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T1 - Prolonged therapy with the anticonvulsant carbamazepine leads to increased plasma clearance of fentanyl

AU - Nozari, Ala

AU - Akeju, Oluwaseun

AU - Mirzakhani, Hooman

AU - Eskandar, Emad N.

AU - Ma, Zhijun

AU - Hossain, MD Amin

AU - Wang, Qingping

AU - Greenblatt, David J.

AU - Martyn, J. A.Jeevendra

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Objectives: Fentanyl is a potent analgesic that accounts for an increasing number of overdose deaths in the United States. This study tested whether altered pharmacokinetics plays a pivotal role in the increased fentanyl dose requirements in patients receiving the enzyme-inducing anticonvulsant, carbamazepine. Methods: Neurosurgical patients receiving carbamazepine for >6 weeks (N = 11) or no carbamazepine (N = 6, controls) received a single bolus dose of fentanyl (200 μg) intravenously. Plasma was collected before and for up to 9 h after the bolus. Fentanyl concentrations were measured using liquid chromatography–mass spectrometry. Pharmacokinetic variables were derived from plasma concentration–time curves best fitted to a two-compartment model. Key findings: Fentanyl clearance was significantly higher in the carbamazepine group compared to controls (mean ± SD: 20.1 ± 6.8 vs 13.2 ± 4.8 ml/min per kg, P < 0.05), and area under the plasma concentration curve (AUC) was significantly lower (150 ± 65 vs 233 ± 70 ng/ml × min, P < 0.02). Volume of distribution was larger in the carbamazepine group, but the difference was not statistically significant (5.4 ± 3.1 vs 3.6 ± 1.2 l/kg, P > 0.15). The terminal elimination half-life did not differ between the two groups. Conclusions: Chronic carbamazepine therapy leads to increased fentanyl clearance and decreased AUC, which may result in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement. Assuming that carbamazepine does not change fentanyl pharmacodynamics, patients on chronic carbamazepine therapy may require more frequent or higher fentanyl doses to maintain therapeutic plasma concentrations.

AB - Objectives: Fentanyl is a potent analgesic that accounts for an increasing number of overdose deaths in the United States. This study tested whether altered pharmacokinetics plays a pivotal role in the increased fentanyl dose requirements in patients receiving the enzyme-inducing anticonvulsant, carbamazepine. Methods: Neurosurgical patients receiving carbamazepine for >6 weeks (N = 11) or no carbamazepine (N = 6, controls) received a single bolus dose of fentanyl (200 μg) intravenously. Plasma was collected before and for up to 9 h after the bolus. Fentanyl concentrations were measured using liquid chromatography–mass spectrometry. Pharmacokinetic variables were derived from plasma concentration–time curves best fitted to a two-compartment model. Key findings: Fentanyl clearance was significantly higher in the carbamazepine group compared to controls (mean ± SD: 20.1 ± 6.8 vs 13.2 ± 4.8 ml/min per kg, P < 0.05), and area under the plasma concentration curve (AUC) was significantly lower (150 ± 65 vs 233 ± 70 ng/ml × min, P < 0.02). Volume of distribution was larger in the carbamazepine group, but the difference was not statistically significant (5.4 ± 3.1 vs 3.6 ± 1.2 l/kg, P > 0.15). The terminal elimination half-life did not differ between the two groups. Conclusions: Chronic carbamazepine therapy leads to increased fentanyl clearance and decreased AUC, which may result in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement. Assuming that carbamazepine does not change fentanyl pharmacodynamics, patients on chronic carbamazepine therapy may require more frequent or higher fentanyl doses to maintain therapeutic plasma concentrations.

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KW - enzyme induction

KW - fentanyl

KW - pharmacokinetics

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