Population Pharmacokinetic-pharmacodynamic (PK-PD) Modeling of Co-administered Gabapentin in Neuropathic Pain

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.

Study Overview

• Status: Completed
• Conditions: Post-traumatic Neuropathic Pain
• Intervention / Treatment: Drug: gabapentin and venlafaxine; Drug: gabapentin and donepezil

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, 75185
    • Multidisciplinary Pain Centre, Uppsala University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gabapentin + venlafaxine	Drug: gabapentin and venlafaxine; Week 1-6: Gabapentin monotherapy (titration to individual maximum tolerated dose or maximum 800 mg 3 times daily). Week 7-12: Venlafaxine 75 mg once daily is added.
Active Comparator: Gabapentin + donepezil	Drug: gabapentin and donepezil; Week 1-6: Gabapentin monotherapy (titration to individual maximum tolerated dose or maximum 800 mg 3 times daily). Week 7-12: Donepezil 5 mg once daily is added.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pain intensity scorings on Numerical Rating Scale (NRS). Plasma concentrations of gabapentin.	0 - 8 hours follwing dose intake of gabapentin. during steady state

Secondary Outcome Measures

Outcome Measure	Time Frame
Health-related quality of life assessed by SF-36. Pain according to McGill Pain Questionnaire.	Minimum 6 weeks following initiation of gabapentin and combination therapy, respectively

Collaborators and Investigators

• Sponsor: Uppsala University
• Collaborators: University of Copenhagen
• Investigators: Principal Investigator: Stephen H. Butler, MD, Uppsala University

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: August 27, 2009
• First Submitted That Met QC Criteria: August 27, 2009
• First Posted (Estimate): August 28, 2009

Study Record Updates

• Last Update Posted (Estimate): October 12, 2011
• Last Update Submitted That Met QC Criteria: October 11, 2011
• Last Verified: September 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Antimanic Agents; Nootropic Agents; Cholinesterase Inhibitors; Gabapentin; Donepezil; Venlafaxine Hydrochloride
• Other Study ID Numbers: GBPPKPD-09; EudraCT number 2009-010783-41