Pharmacokinetic-pharmacodynamic modelling of anti-allodynic effects of gabapentin and oxycodone in a rodent model of persistent neuropathic pain

Abstract

BackgroundGabapentin and oxycodone have established efficacy for the alleviation of neuropathic pain conditions such as post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN). As these drugs have modes of action, combined administration of these two agents has the potential to enhance symptomatic relief of neuropathic pain in the clinical setting. The global aim of this MPhil thesis was to use pharmacokinetic-pharmacodynamic ((PK)PD) modelling to describe the time course of effects following co-administration of gabapentin and oxycodone for attenuating tactile allodynia (a defining symptom of neuropathic pain) in a well-defined rodent model of neuropathic pain, viz rats with a chronic constriction injury (CCI) of the sciatic nerve. Published preclinical studies in rodents suggest that gabapentin may have neuroprotective properties. Thus this issue was also addressed herein.MethodsThere were a total of 6 groups of Sprague-Dawley (SD) rats in this study with four groups of CCI-rats (Groups 1^1) and two groups of control non-injured rats (Groups 5-6). Group 5 rats received active treatment(s) and Group 6 rats received no treatment for 6 weeks followed by vehicle treatment for 2 weeks.Group 1 CCI-rats were administered twice daily s.c. bolus doses of gabapentin (50mg/kg) for two weeks. This was followed by a further 2-week period of treatment involving co-administration of s.c. gabapentin (50 mg/kg) with s.c. oxycodone (2 mg/kg). Next, the gabapentin was withdrawn and these same animals continued to receive twice-daily s.c. injections of oxycodone (2 mg/kg) for a further 2 weeks. CCI-rats in Group 2 were administered s.c. gabapentin (50mg/kg) twice daily for 4 weeks, and Group 3 CCI-rats received the same daily dose of s.c. gabapentin (100 mg/kg) administered once daily for 4 weeks. Vehicle (NaCl 0.9% 200 uL) was administered by twice daily s.c. injection to CCI-rats in Group 4 for 4 weeks. Group 5 non-injured rats received the same treatment protocol as Group 1 CCI-rats. Group 6 non-injured rats received no treatment for the first 6 weeks, and this was followed by twice-daily injections of vehicle (NaCl 0.9% 200 uL) for 2 weeks.Drug effect was observed via attenuation of tactile allodynia quantified by minimum force required for the rat to withdraw its hindpaw (paw withdrawal threshold). The data generated from Groups 1-4 formed the input data set for the (PK)PD modeling experiment. The PD data collected were analyzed using NONMEM (Version 5, Level 1.1). The first order conditional (FOCE) with INTERACTION and the first order (FO) method was used in the analyses. Model selection was based on the likelihood ratio test.Results and DiscussionThe main finding from this study is that administration of gabapentin (100 mg/kg/day) for 4 weeks according to a twice daily (50 mg/kg) or a once (100 mg/kg) daily dosing regimen does not produce disease modifying effects since baseline pre- and post-treatment tactile allodynia scores in CCI-rats did not change significantly. This study also showed that s.c. oxycodone administered in a dose of 2 mg/kg produced a better intensity of anti-allodynic effect but was of a relatively short duration (≈2 hours) whereas s.c. bolus doses of gabapentin (50 mg/kg) produced lower levels of anti-allodynia but with a longer duration (≈6 hours). Co-administration of gabapentin plus oxycodone produced a marked enhancement of the extent and duration (> 12 hours) of the anti-allodynic effect compared with either agent administered alone. Additionally, there was no evidence of tolerance to oxycodone's anti-allodynic effects over the 2-week period that s.c. oxycodone was administered alone at 2 mg/kg twice daily and when co-administered with gabapentin (50 mg/kg) for two weeks or when gabapentin was administered alone. The lack of tolerance and lack of effect on disease progression were supported by both the model and an empirical treatment of the data. The final PKPD model included additive effects (based on a different receptor mechanism interaction model), with no evidence of synergism between the agents.ConclusionThe findings from this study suggest that combined administration of gabapentin and oxycodone may be beneficial in the clinical setting for the treatment of neuropathic pain,but further research is required.