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

This study has been completed.
Sponsor:
Collaborator:
University of Copenhagen
Information provided by (Responsible Party):
Uppsala University
ClinicalTrials.gov Identifier:
NCT00967707
First received: August 27, 2009
Last updated: October 11, 2011
Last verified: September 2011
  Purpose

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.


Condition Intervention Phase
Post-traumatic Neuropathic Pain
Drug: gabapentin and venlafaxine
Drug: gabapentin and donepezil
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Population Pharmacokinetic and Pharmacodynamic Modeling of Gabapentin in Neuropathic Pain - Effect of Adjuvant Pharmacotherapy

Resource links provided by NLM:


Further study details as provided by Uppsala University:

Primary Outcome Measures:
  • Pain intensity scorings on Numerical Rating Scale (NRS). Plasma concentrations of gabapentin. [ Time Frame: 0 - 8 hours follwing dose intake of gabapentin. during steady state ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Health-related quality of life assessed by SF-36. Pain according to McGill Pain Questionnaire. [ Time Frame: Minimum 6 weeks following initiation of gabapentin and combination therapy, respectively ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: August 2009
Study Completion Date: September 2011
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.


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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00967707

Locations
Sweden
Multidisciplinary Pain Centre, Uppsala University Hospital
Uppsala, Sweden, 75185
Sponsors and Collaborators
Uppsala University
University of Copenhagen
Investigators
Principal Investigator: Stephen H. Butler, MD Uppsala University
  More Information

No publications provided

Responsible Party: Uppsala University
ClinicalTrials.gov Identifier: NCT00967707     History of Changes
Other Study ID Numbers: GBPPKPD-09, EudraCT number 2009-010783-41
Study First Received: August 27, 2009
Last Updated: October 11, 2011
Health Authority: Sweden: Medical Products Agency
Sweden: Regional Ethical Review Board

Additional relevant MeSH terms:
Neuralgia
Pain
Neurologic Manifestations
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Signs and Symptoms
Gabapentin
Donepezil
Venlafaxine
Gamma-Aminobutyric Acid
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Anticonvulsants
Antiparkinson Agents
Anti-Dyskinesia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Excitatory Amino Acid Antagonists

ClinicalTrials.gov processed this record on September 18, 2014