Dextromethorphan Effect on Central Sensitization to Pain in Healthy Volunteers (Hydex)

The aim of this study is to assess the anti-hyperalgesic effect of dextromethorphan in healthy volunteers compared to placebo.

Study Overview

• Status: Completed
• Conditions: Hyperalgesia; Experimental Pain
• Intervention / Treatment: Drug: Pulmodexane® 30mg; Drug: lactose

Detailed Description

This is a cross-over group, double-blind, randomized clinical trial in healthy volunteers comparing dextromethorphan and inactive control on freeze-induced hyperalgesia, experimental pain, diffuse noxious inhibitory control (DNIC), pupillary reaction and reaction time.

The influence of CYP3A4 and MDR1 polymorphism on the dextromethorphan analgesic efficacy will be measured.

The study design is divided in two study sequences and each subject participates in the two study sequences and receive the two treatments (dextromethorphan and placebo).

Each study sequence consists of 3 assessment days (Day -1, Day 0 = first treatment administration and Day 1).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63003
    • CHU Clermont-Ferrand

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy male volunteers
• Aged between 18 and 45 years
• CYP2D6 Extensive and Intermediate metabolizers
• Body mass index (BMI) between 19 and 30 kg/m2
• Systolic blood pressure between 100 and 150 mmHg, diastolic blood pressure between 50 and 90 mmHg, heart rate between 45 and 90 beats per minute
• Without treatment during the 7 days before inclusion specially no use of analgesic and anti-inflammatory drugs
• Cooperation and understanding enough to conform to the study obligations
• Having given free informed written consent
• Affiliated to the French Social Security
• Inscription or acceptation of inscription in the national register of volunteers involved in trials.

Exclusion Criteria:

• Hypersensitivity to the active substance or to any of the excipients
• Lactose intolerance
• Hypertension
• History of stroke
• Severe heart failure
• Severe hepatic impairment
• Shortness of breath
• Congenital galactosemia, glucose-galactose malabsorption, lactase deficiency
• Association with linezolid
• Pre-existence or history of peripheral neuropathy due to a cause different from neurotoxic chemotherapy
• Diabetes (type I and II)
• CYP2D6 Poor and Ultra-rapid metabolizers
• AST, ALT, total bilirubin twice the average
• Dextromethorphan intake during the 7 days before inclusion
• Medical and surgical history incompatible with the study
• Disease progression during inclusion
• Excessive consumption of alcohol (> 50g/day), tobacco (≥ 10 cigarettes/day), coffee, tea or drinks with caffeine (equivalent to more than 4 cups a day) or any addiction to drugs
• Subject lacking concentration during tests training and low test results reproducibility
• Subject does not meet the selection criteria for its ability to discriminate sensations to noxious stimuli during psychometric tests
• Subject exclusion period, or the total allowable compensation exceeded
• Subject undergoing a measure of legal protection (guardianship, supervision

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dextromethorphan; The study design is divided in two study sequences and each subject participates in the two study sequences and receive the two treatments (dextromethorphan and placebo).	Drug: Pulmodexane® 30mg; The study design is divided in two study sequences and each subject participates in the two study sequences and receive the two treatments (dextromethorphan and placebo).
Placebo Comparator: Placebo; The study design is divided in two study sequences and each subject participates in the two study sequences and receive the two treatments (dextromethorphan and placebo).	Drug: lactose; The study design is divided in two study sequences and each subject participates in the two study sequences and receive the two treatments (dextromethorphan and placebo).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under the curve (AUC) of percentage changes in mechanical pain thresholds (MPT) using electronic von frey in secondary hyperalgesic zone (Z2)	at Day 0 after treatment administration: 1 hour post-dose (T0+1h), 2 hours post-dose (T0+2h) and 3 hours post-dose (T0+3h).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve (AUC) of percentage changes in mechanical pain thresholds (MPT) using electronic von frey in control skin zone (Z0) and primary hyperalgesic zone (Z1)		at D0 T0+1h, T0+2h and T0+3h after treatment administration
Percentage changes in mechanical pain thresholds (MPT) using electronic von frey in control skin zone (Z0)		at Day 0 after treatment administration: 1 hour post-dose (T0+1h), 2 hours post-dose (T0+2h) and 3 hours post-dose (T0+3h).
Percentage changes in mechanical pain thresholds (MPT) using electronic von frey in primary hyperalgesic zone (Z1)		at Day 0 30 min before treatment (T0-30min ) and at Day 0 after treatment administration: 1 hour post-dose (T0+1h), 2 hours post-dose (T0+2h) and 3 hours post-dose (T0+3h) and at Day 1 after treatment administration: 24,5 hours post-dose (T0+24h30).
Conditioned Pain Modulation (CPM) assessment		at Day -1 before treatment and Day 0 30 min before treatment (T0-30min)
Reaction time assessment using RTI CANTAB® test		at Day -1 before treatment and Day 0 30 min before treatment (T0-30min), after treatment administration: 1 hour post-dose (T0+1h) and 3 hours post-dose (T0+3h) and at Day 1 after treatment administration: 24,5 hours post-dose (T0+24h30).
Determination of potential central effects of dextromethorphan measuring pupillary reaction	Determination of potential central effects of dextromethorphan measuring pupillary reaction assessing the diameter of the pupil in real time in scotopic conditions (e.g. size variation [mm]; contraction speed [mm.s-1]; contraction latency [ms]) at Day 0 30 min before treatment (T0-30min ) and at Day 0 after treatment administration: 1 hour post-dose (T0+1h), 2 hours post-dose (T0+2h) and 3 hours post-dose (T0+3h) and at Day 1 after treatment administration: 24,5 hours post-dose (T0+24h30). - Study of genetic polymorphism of cytochrome P450 3A4 and MDR1 gene through study completion, up to 6 months.	at Day 0 30 min before treatment (T0-30min ) and at Day 0 after treatment administration: 1 hour post-dose (T0+1h), 2 hours post-dose (T0+2h) and 3 hours post-dose (T0+3h) and at Day 1 after treatment administration: 24,5 hours post-dose (T0+24h30).
Study of genetic polymorphism of cytochrome P450 3A4 and genetic polymorphism of MDR1 gene		up to 6 months.
Dosage of plasma concentration of dextromethorphan and dextromethorphan's metabolites from blood collections		at Day 0 30 min before treatment (T0-30min ) and at Day 0 after treatment administration: 2 hours post-dose (T0+2h) and at Day 1 after treatment administration: 24,5 hours post-dose (T0+24h30).

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: October 19, 2015
• First Submitted That Met QC Criteria: November 2, 2015
• First Posted (Estimate): November 4, 2015

Study Record Updates

• Last Update Posted (Estimate): April 1, 2016
• Last Update Submitted That Met QC Criteria: March 31, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Dextromethorphan; Pharmacogenetic; Antinociception; Freeze-induced hyperalgesia model; NMDA-receptors; CYP3A4 gene; MDR1 gene
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Sensation Disorders; Somatosensory Disorders; Hyperalgesia
• Other Study ID Numbers: CHU-0248; 2015-003271-30 (Registry Identifier: 2015-003271-30)