Abstract
Purpose
The formalin-induced rat model of nociception involves moderate continuous pain. Formalin-induced pain results in a typical repetitive flinching behaviour, which displays a biphasic pattern characterised by peaks of pain. Here we described the time course of pain response and the analgesic effect of gabapentin using a semi-mechanistic modelling approach.
Methods
Male Sprague-Dawley rats received gabapentin (10–100 mg/kg) or placebo 1 h prior to the formalin injection, as per standard protocol. A reduction in the frequency of the second peak of flinching was used as a behavioural measure of gabapentin-mediated anti-nociception. The flinching response was modelled using a mono-exponential function to characterise the first peak and an indirect response model with a time variant synthesis rate for the second. PKPD modelling was performed using a population approach in NONMEM v.7.1.2.
Results
The time course of the biphasic response was adequately described by the proposed model, which included separate expressions for each phase. Gabapentin was found to reversibly decrease, but not suppress the flinching frequency of the second response peak only. The mean IC50 estimate was 7,510 ng/ml, with relative standard error (RSE%) of 40%.
Conclusions
A compartmental, semi-mechanistic model provides the basis for further understanding of the formalin-induced flinching response and consequently to better characterisation of the properties of gabapentin, such as the potency in individual animals. Moreover, despite high exposure levels, model predictions show that gabapentin does not completely suppress behavioural response in the formalin-induced pain model.
Similar content being viewed by others
Abbreviations
- CI:
-
confidence interval
- COX-2:
-
cyclo-oxygenase 2
- CV:
-
coefficient of variation
- GABA:
-
γ-amino butyric acid
- IIV:
-
inter-individual variability
- MED:
-
median effective dose
- MOFV:
-
minimum objective function value
- NK1:
-
neuroenkephalin 1
- NMDA:
-
N-methyl d-aspartate
- PKPD:
-
pharmacokinetics and pharmacodynamics
- RSE:
-
relative standard error
- VPC:
-
visual predictive check
REFERENCES
Taneja A, Di Iorio VL, Danhof M, Della Pasqua O. Translation of drug effects from experimental models of neuropathic pain and analgesia to humans. Drug Discov Today. 2012;17:837–49.
Munro G, Erichsen HK, Mirza NR. Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety. Neuropharmacology. 2007;53:609–18.
Jarvisand MF, Boyce-Rustay JM. Neuropathic pain: models and mechanisms. Curr Pharm Des. 2009;15:1711–6.
Blackburn-Munro G. Pain-like behaviours in animals—how human are they? Trends Pharmacol Sci. 2004;25:299–305.
Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev. 2001;53:597–652.
Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain. 1992;51:5–17.
Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain. 1993;52:259–85.
Henry JL, Yashpal K, Pitcher GM, Coderre TJ. Physiological evidence that the ‘interphase’ in the formalin test is due to active inhibition. Pain. 1999;82:57–63.
Vissers KC, Geenen F, Biermans R, Meert TF. Pharmacological correlation between the formalin test and the neuropathic pain behavior in different species with chronic constriction injury. Pharmacol Biochem Behav. 2006;84:479–86.
Blackburn-Munro G, Ibsen N, Erichsen HK. A comparison of the anti-nociceptive effects of voltage-activated Na + channel blockers in the formalin test. Eur J Pharmacol. 2002;445:231–8.
Tanabe M, Ono K, Honda M, Ono H. Gabapentin and pregabalin ameliorate mechanical hypersensitivity after spinal cord injury in mice. Eur J Pharmacol. 2009;609:65–8.
Shannon HE, Eberle EL, Peters SC. Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats. Neuropharmacology. 2005;48:1012–20.
Vasquez-Bahena DA, Salazar-Morales UE, Ortiz MI, Castaneda-Hernandez G, Troconiz IF. Pharmacokinetic-pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats. Br J Pharmacol. 2010;159:176–87.
Giraudel JM, Diquelou A, Laroute V, Lees P, Toutain PL. Pharmacokinetic/pharmacodynamic modelling of NSAIDs in a model of reversible inflammation in the cat. Br J Pharmacol. 2005;146:642–53.
Martini C, Olofsen E, Yassen A, Aarts L, Dahan A. Pharmacokinetic-pharmacodynamic modeling in acute and chronic pain: an overview of the recent literature. Expert Rev Clin Pharmacol. 2011;4:719–28.
Taneja A, Nyberg J, de Lange EC, Danhof M, Della Pasqua O. Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain. J Pharmacokinet Pharmacodyn. 2012;39(6):673–81.
Cundy KC, Annamalai T, Bu L, De Vera J, Estrela J, Luo W, et al. XP13512 [(+/−)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol Exp Ther. 2004;311:324–33.
Kjellsson MC, Ouellet D, Corrigan B, Karlsson MO. Modeling sleep data for a new drug in development using markov mixed-effects models. Pharm Res. 2011;28:2610–27.
Maas HJ, Danhof M, Della Pasqua OE. Prediction of headache response in migraine treatment. Cephalalgia. 2006;26:416–22.
Dayneka NL, Garg V, Jusko WJ. Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm. 1993;21:457–78.
Lee DH, Chung K, Chung JM. Strain differences in adrenergic sensitivity of neuropathic pain behaviors in an experimental rat model. Neuroreport. 1997;8:3453–6.
Velez de Mendizabal N, Vasquez-Bahena D, Jimenez-Andrade JM, Ortiz MI, Castaneda-Hernandez G, Troconiz IF. Semi-mechanistic modeling of the interaction between the central and peripheral effects in the antinociceptive response to lumiracoxib in rats. AAPS J. 14:904–14.
Jonssonand EN, Karlsson MO. Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed. 1999;58:51–64.
Karlsson MO, Holford N. A tutorial on visual predictive checks, Population Approach Group of Europe Marseille France, 2008, p. 17 (2008 = abtract 1434).
Ette EI, Williams PJ, Kim YH, Lane JR, Liu MJ, Capparelli EV. Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol. 2003;43:610–23.
Beal SL, Sheiner L. NONMEM users guides. In: Boeckmann TLA (ed.), Globomax ICON Development Solutions, Ellicott City,MD, 1989–2006.
R Development Core Team. R:A language and environment for statistical computing. In: R Foundation for Statistical Computing (ed.), Vienna Austria, 2011.
Uchizono JA, Lane J. Empirical pharmacokinetic/pharmacodynamic models. In: Ette E, editor. Pharmacometrics:the science of quantitative pharmacology. New Jersey: Wiley; 2007. p. 529–45.
Wise ME. Negative power functions of time in pharmacokinetics and their implications. J Pharmacokinet Biopharm. 1985;13:309–46.
Levy G. Predicting effective drug concentrations for individual patients. Determinants of pharmacodynamic variability. Clin Pharmacokinet. 1998;34:323–33.
Rahim-Williams B, Riley 3rd JL, Williams AK, Fillingim RB. A quantitative review of ethnic group differences in experimental pain response: do biology, psychology, and culture matter? Pain Med. 2012;13:522–40.
Newton PK, Mason J, Bethel K, Bazhenova LA, Nieva J, Kuhn P. A stochastic Markov chain model to describe lung cancer growth and metastasis. PLoS One. 2012;7:e34637.
Anisimov VV, Maas HJ, Danhof M, Della Pasqua O. Analysis of responses in migraine modelling using hidden Markov models. Stat Med. 2007;26:4163–78.
Yoonand MH, Yaksh TL. The effect of intrathecal gabapentin on pain behavior and hemodynamics on the formalin test in the rat. Anesth Analg. 1999;89:434–9.
Spallone V, Lacerenza M, Rossi A, Sicuteri R, Marchettini P. Painful diabetic polyneuropathy: approach to diagnosis and management. Clin J Pain.
Vorobeychik Y, Gordin V, Mao J, Chen L. Combination therapy for neuropathic pain: a review of current evidence. CNS Drugs. 25:1023–34.
Johnson M, Kozielska M, Pilla Reddy V, Vermeulen A, Li C, Grimwood S, et al. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D2 receptor occupancy of olanzapine in rats. Pharm Res. 2011;28:2490–504.
Taneja A, Nyberg J, Danhof M, Della Pasqua O. Optimised protocol design for the screening of analgesic compounds in neuropathic pain. J Pharmacokinet Pharmacodyn. 2012;39:661–71.
Milligan PA, Brown MJ, Marchant B, Martin SW, van der Graaf PH, Benson N, et al. Model-based drug development: a rational approach to efficiently accelerate drug development. Clin Pharmacol Ther. 2013;93:502–14.
Aryal B, Tae-Hyun K, Yoon-Gyoon K, Hyung-Gun K. A comparative study of the pharmacokinetics of traditional and automated dosing/blood sampling systems using gabapentin. Indian J Pharmacol. 2011;43:262–9.
Todorovic SM, Rastogi AJ, Jevtovic-Todorovic V. Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats. Br J Pharmacol. 2003;140:255–60.
Lockwood PA, Cook JA, Ewy WE, Mandema JW. The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain. Pharm Res. 2003;20:1752–9.
Hamaand A, Sagen J. Behavioral characterization and effect of clinical drugs in a rat model of pain following spinal cord compression. Brain Res. 2007;1185:117–28.
Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther. 2004;311:576–84.
Hurley RW, Chatterjea D, Rose Feng M, Taylor CP, Hammond DL. Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia. Anesthesiology. 2002;97:1263–73.
Yoonand MH, Yaksh TL. Evaluation of interaction between gabapentin and ibuprofen on the formalin test in rats. Anesthesiology. 1999;91:1006–13.
Yaksh TL. Spinal systems and pain processing: development of novel analgesic drugs with mechanistically defined models. Trends Pharmacol Sci. 1999;20:329–37.
Whiteside GT, Adedoyin A, Leventhal L. Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology. 2008;54:767–75.
Whiteside GT, Harrison J, Boulet J, Mark L, Pearson M, Gottshall S, et al. Pharmacological characterisation of a rat model of incisional pain. Br J Pharmacol. 2004;141:85–91.
Huntjens DR, Danhof M, Della Pasqua OE. Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. Rheumatology (Oxford). 2005;44:846–59.
Huntjens DR, Spalding DJ, Danhof M, Della Pasqua OE. Differences in the sensitivity of behavioural measures of pain to the selectivity of cyclo-oxygenase inhibitors. Eur J Pain. 2009;13:448–57.
ACKNOWLEDGMENTS AND DISCLOSURES
The authors acknowledge the contribution of Scott Marshall (Modelling & Simulation, Pfizer, Sandwich, UK), Ian Machin (Pain Research Unit, Sandwich, UK), and Dinesh DeAlwis (Global PK/PD/TS Europe, Eli Lilly, Erl Wood, UK), who have shared their experience with TIPharma and provided valuable insight into the issues faced by R&D during early drug development. Top Institute Pharma, a tripartite consortium involving industry, academia and the Netherlands government, has sponsored the PhD research programme of A. Taneja.
Author information
Authors and Affiliations
Consortia
Corresponding author
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
ESM 1
(DOCX 140 kb)
Rights and permissions
About this article
Cite this article
Taneja, A., Troconiz, I.F., Danhof, M. et al. Semi-mechanistic Modelling of the Analgesic Effect of Gabapentin in the Formalin-Induced Rat Model of Experimental Pain. Pharm Res 31, 593–606 (2014). https://doi.org/10.1007/s11095-013-1183-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-013-1183-4