Population Pharmacokinetic-pharmacodynamic (PK-PD) Modeling of Co-administered Gabapentin in Neuropathic Pain
Information source: Uppsala University
Information obtained from ClinicalTrials.gov on October 19, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Post-traumatic Neuropathic Pain
Intervention: gabapentin and venlafaxine (Drug); gabapentin and donepezil (Drug)
Phase: Phase 2
Status: Recruiting
Sponsored by: Uppsala University Official(s) and/or principal investigator(s):
Stephen H. Butler, MD, Principal Investigator, Affiliation: Uppsala University
Overall contact:
Stephen H. Butler, MD, Phone: +46 18 6112945, Email: stephen.butler@akademiska.se
Summary
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.
Clinical Details
Official title: Population Pharmacokinetic and Pharmacodynamic Modeling of Gabapentin in Neuropathic Pain - Effect of Adjuvant Pharmacotherapy
Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Pharmacokinetics/Dynamics Study
Primary outcome: Pain intensity scorings on Numerical Rating Scale (NRS). Plasma concentrations of gabapentin.
Secondary outcome: Health-related quality of life assessed by SF-36.
Pain according to McGill Pain Questionnaire.
Detailed description:
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Diagnosis of post-traumatic neuropathic pain
- Spontaneous pain intensity ≥ 40 on VAS or ≥ 4 on NRS
- Man or woman ≥ 18 years old
- Informed consent to study participation
Exclusion Criteria:
- Presence of other type of pain as strong as or stronger than the neuropathic pain
- Impaired kidney function (GFR < 30 ml/min)
- Uncontrolled cardiovascular disease/hypertonia
- Uncontrolled narrow-angle glaucoma
- Uncontrolled pulmonary disease
- Epilepsia
- Pregnancy
- Nursing
- Woman of childbearing potential not using contraception or planning to become
pregnant during the study period
- Disability to understand and cooperate with study procedures
- Allergy to study medications
- Concomitant participation in other clinical study
Locations and Contacts
Stephen H. Butler, MD, Phone: +46 18 6112945, Email: stephen.butler@akademiska.se
Multidisciplinary Pain Centre, Uppsala University Hospital, Uppsala 75185, Sweden; Recruiting
Stepen H. Butler, MD, Phone: +46 18 6112945, Email: stephen.butler@akademiska.se
Torsten E.S. Gordh, MD, PhD, Phone: +46 18 6114876, Email: torsten.gordh@surgsci.uu.se
Stephen H. Butler, MD, Principal Investigator
Additional Information
Starting date: August 2009
Ending date: June 2011
Last updated: September 3, 2009
|
