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Multiplicative interactions to enhance gabapentin to treat neuropathic pain.
Eur J Pharmacol. 2008 Nov 19; 598(1-3):21-6.EJ

Abstract

We previously reported that gabapentin activates the bulbospinal-spinal noradrenergic-cholinergic pathway to produce analgesia in rats after nerve injury. Also, gabapentin interacts synergistically with a cholinesterase inhibitor donepezil to produce analgesia. Duloxetine, a serotonin/noradrenaline re-uptake inhibitor, has been used for the treatment of neuropathic pain and should amplify the noradrenergic mechanisms recruited by gabapentin. In the present study, we determined the interaction between duloxetine and gabapentin with and without donepezil when administered by the clinically preferred oral route in rats after spinal nerve ligation. The ED(50) value of gabapentin, donepezil, and duloxetine to reduce mechanical hypersensitivity after nerve injury was 45, 3.7, and 32 mg/kg, respectively. In the examination of two drug combinations, oral duloxetine with either gabapentin or donepezil were additive to reduce hypersensitivity. The combination of all three drugs yielded a synergistic interaction with an observed ED(50) at 1/4th the predicted dose of additivity, likely due to the gabapentin-donepezil interaction. This three drug combination did not affect motor coordination or show signs of sedation in the rotarod test. Analgesia by the combination of these three drugs was reversed by intrathecal injection either of the alpha(2)-adrenoceptor antagonist idazoxan or by the muscarinic receptor antagonist atropine. These results suggest that the combination of these drugs, which stimulate and augment the bulbospinal-spinal noradrenergic-cholinergic pathway, lowers the dose requirement for each drug to reduce hypersensitivity after nerve injury without sedative effects. The current study provides the rationale for clinical study of the combination of gabapentin, donepezil and duloxetine to treat neuropathic pain.

Authors+Show Affiliations

Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA. khayashi@wfubmc.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18822281

Citation

Hayashida, Ken-Ichiro, and James C. Eisenach. "Multiplicative Interactions to Enhance Gabapentin to Treat Neuropathic Pain." European Journal of Pharmacology, vol. 598, no. 1-3, 2008, pp. 21-6.
Hayashida K, Eisenach JC. Multiplicative interactions to enhance gabapentin to treat neuropathic pain. Eur J Pharmacol. 2008;598(1-3):21-6.
Hayashida, K., & Eisenach, J. C. (2008). Multiplicative interactions to enhance gabapentin to treat neuropathic pain. European Journal of Pharmacology, 598(1-3), 21-6. https://doi.org/10.1016/j.ejphar.2008.09.004
Hayashida K, Eisenach JC. Multiplicative Interactions to Enhance Gabapentin to Treat Neuropathic Pain. Eur J Pharmacol. 2008 Nov 19;598(1-3):21-6. PubMed PMID: 18822281.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Multiplicative interactions to enhance gabapentin to treat neuropathic pain. AU - Hayashida,Ken-Ichiro, AU - Eisenach,James C, Y1 - 2008/09/17/ PY - 2008/04/04/received PY - 2008/08/26/revised PY - 2008/09/04/accepted PY - 2008/9/30/pubmed PY - 2009/1/10/medline PY - 2008/9/30/entrez SP - 21 EP - 6 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 598 IS - 1-3 N2 - We previously reported that gabapentin activates the bulbospinal-spinal noradrenergic-cholinergic pathway to produce analgesia in rats after nerve injury. Also, gabapentin interacts synergistically with a cholinesterase inhibitor donepezil to produce analgesia. Duloxetine, a serotonin/noradrenaline re-uptake inhibitor, has been used for the treatment of neuropathic pain and should amplify the noradrenergic mechanisms recruited by gabapentin. In the present study, we determined the interaction between duloxetine and gabapentin with and without donepezil when administered by the clinically preferred oral route in rats after spinal nerve ligation. The ED(50) value of gabapentin, donepezil, and duloxetine to reduce mechanical hypersensitivity after nerve injury was 45, 3.7, and 32 mg/kg, respectively. In the examination of two drug combinations, oral duloxetine with either gabapentin or donepezil were additive to reduce hypersensitivity. The combination of all three drugs yielded a synergistic interaction with an observed ED(50) at 1/4th the predicted dose of additivity, likely due to the gabapentin-donepezil interaction. This three drug combination did not affect motor coordination or show signs of sedation in the rotarod test. Analgesia by the combination of these three drugs was reversed by intrathecal injection either of the alpha(2)-adrenoceptor antagonist idazoxan or by the muscarinic receptor antagonist atropine. These results suggest that the combination of these drugs, which stimulate and augment the bulbospinal-spinal noradrenergic-cholinergic pathway, lowers the dose requirement for each drug to reduce hypersensitivity after nerve injury without sedative effects. The current study provides the rationale for clinical study of the combination of gabapentin, donepezil and duloxetine to treat neuropathic pain. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18822281/Multiplicative_interactions_to_enhance_gabapentin_to_treat_neuropathic_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00941-2 DB - PRIME DP - Unbound Medicine ER -