Post-traumatic Neuropathic Pain Clinical Trial
Official title:
Population Pharmacokinetic and Pharmacodynamic Modeling of Gabapentin in Neuropathic Pain - Effect of Adjuvant Pharmacotherapy
The primary objective of this study is to develop a pharmacokinetic (PK) and a
pharmacokinetic-pharmacodynamic (PK-PD) model for gabapentin in patients with neuropathic
pain.
The secondary objectives are to investigate whether adjuvant therapy of venlafaxine or
donepezil contributes to 1) improved analgesic efficacy and 2) improved health-related
quality of life (assessed by the SF-36 questionnaire) in neuropathic pain patients treated
with gabapentin.
Neuropathic pain is estimated to affect 2-3 % of the population and the condition is
difficult to treat with conventional analgesics. The drug of first choice is typically a
tricyclic antidepressant drug (TCA) or the antiepileptic drug gabapentin. TCAs have
well-documented effects, but the use is commonly interrupted due to intolerable adverse
effects. Gabapentin, on the other hand, is generally well tolerated in patients. Clinical
trials have proven that gabapentin is efficacious for neuropathic pain of various origins.
Nevertheless, monotherapy is seldom sufficient for the management of severe neuropathic
pain. Combination therapy, e.g. of gabapentin and an analgesic with complementary mechanism
of action, may be a rational strategy to obtain improved results at lower doses and with
fewer side effects. Although many neuropathic pain patients receive a combination of drugs,
there is an absence of clinical evidence for optimal drug combinations.
Gabapentin binds to the alpha-2-delta subunit on presynaptic voltage-gated calcium channels,
which results in modulation of the release of neurotransmitters from presynaptic nerve
terminals. Recent studies in animal models of neuropathic pain have shown that gabapentin is
effective on supraspinal structures, to activate the descending pain inhibitory
noradrenergic-cholinergic cascade. Thus, it might be possible to potentiate the analgesic
effect of gabapentin by concomitant administration of a drug able to prolong the action of
noradrenaline or acetylcholine in the synapse cleft. In this study, the adjuvant effect of
the noradrenaline and serotonin reuptake inhibitor venlafaxine and the cholinesterase
inhibitor donepezil will be investigated in neuropathic pain patients treated with
gabapentin.
The study consists of two periods. All patients are treated with gabapentin in the first
period, and receive randomised adjuvant therapy of venlafaxine or donepezil in the second
period. Repeated pain intensity ratings and blood samples for analysis of gabapentin plasma
concentrations will be collected over one dosing interval of gabapentin at the end of each
period.
Data will be analysed by means of nonlinear mixed effect modeling. The NONMEM programme will
be used to develop models describing the PK and the PK-PD relationship of gabapentin in
patients with neuropathic pain. The potential effect of concomitant treatment with
venlafaxine or donepezil will be evaluated by covariate analysis in the developed PK and
PK-PD models of gabapentin.
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Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment