Clinical Neuropharmacology of Pain in Spinal Cord Injury- Dextromethorphan Dose Response Clinical Trial

This randomized, placebo-controlled, double-blind 4x4 crossover clinical trial was part of a larger NIH-funded study to evaluate the analgesic efficacy of three doses of chronic oral (PO) dextromethorphan compared to placebo in central neuropathic pain following spinal cord injury. Subjects' maximally tolerated doses (MTD) were first determined to establish individual dose-analgesic response relationships in a run-in period; following a washout period, subjects were then randomized to receive an order of four doses of dextromethorphan (including placebo) in a 4x4 Latin square cross-over design.

Study Overview

• Status: Completed
• Conditions: Spinal Cord Injury; Allodynia; Central Neuropathic Pain
• Intervention / Treatment: Drug: Dextromethorphan

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Translational Pain Research, Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy male or female adults, age 18 to 70 with central neuropathic pain for a minimum of 3 months following SCI as confirmed by neurologic evaluation, with an average pain intensity score of at least moderate over at least 50% of the day for the 7 days prior to the screening visit and over the 7 days prior to starting study medication.
2. Subjects used no medication or a stabilized medication regimen for chronic and well-controlled medical conditions

3. Serum laboratory examination obtained at study entry:

   • Liver function tests (albumin within 20% of normal, SGOT/SGPT within 50% of normal).
   • For women of childbearing age: negative serum beta HCG.
4. Postmenopausal women, or be physically incapable of childbearing, or be practicing an acceptable method of birth control.
5. Normal cognitive function.
6. Normal communicative ability (English).
7. Ability to demonstrate competence in recording five times daily in pain diary for 1 week (with 100% compliance), and in completing required questionnaires.
8. Signed informed consent.

Exclusion Criteria:

1. Pregnancy or breast-feeding.
2. Renal or hepatic dysfunction.
3. Significant cardiac disease (e.g. MI within 1 year).
4. Signs or symptoms of central neurological disorder, excluding SCI.
5. Severe psychological disorder requiring treatment.
6. Concurrent use of monoamine oxidase inhibitors within 2 weeks prior to study entry.
7. Use of known CYP2D6 (but not CYP3A4) inhibitors or inducers.
8. History of hypersensitivity or intolerance to dextromethorphan or lidocaine.
9. Chronic substance abuse, including alcohol.
10. Participation in a study of an investigational drug or device within 30 days prior to screening for this study.
11. Poor metabolizer of P450 2D6 substrates.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 0% MTD Dex; 0% MTD Dextromethorphan	Drug: Dextromethorphan; 0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
Experimental: 25% MTD Dex; 25% MTD Dextromethorphan	Drug: Dextromethorphan; 0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
Experimental: 50% MTD Dex; 50% MTD Dextromethorphan	Drug: Dextromethorphan; 0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
Experimental: 100% MTD Dex; 100% MTD Dextromethorphan	Drug: Dextromethorphan; 0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Pain Intensity (Percent Change From Baseline)	Primary outcome was percent change from baseline in mean pain intensity (transformed Gracely Scale; 0-35). Baseline was defined as the week prior to randomization. The greater the percent change, the bigger the reduction in pain intensity.	1st week of maintenance period (week prior to hospital admission for nested study; subjects traveled to Boston on days 6-7 of the maintenance period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Satisfaction	Satisfaction with study treatment assessed over the 7 days prior to admission (5-point categorical scale)	Last week prior to admission (end of 1-week maintenance period)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Christine N. Sang, MD, MPH, Translational Pain Research, Brigham and Women's Hospital (Disclosure: Patent)

Publications and helpful links

Helpful Links

• Translational Pain Research, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start: April 1, 2003
• Primary Completion (Actual): January 1, 2008
• Study Completion (Actual): January 1, 2008

Study Registration Dates

• First Submitted: September 15, 2011
• First Submitted That Met QC Criteria: September 16, 2011
• First Posted (Estimate): September 19, 2011

Study Record Updates

• Last Update Posted (Actual): April 4, 2017
• Last Update Submitted That Met QC Criteria: February 15, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: chronic pain; lidocaine; combination therapy; analgesia; spinal cord injury; dextromethorphan; central neuropathic pain
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Trauma, Nervous System; Spinal Cord Diseases; Sensation Disorders; Somatosensory Disorders; Neuralgia; Wounds and Injuries; Spinal Cord Injuries; Hyperalgesia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Respiratory System Agents; Antitussive Agents; Dextromethorphan
• Other Study ID Numbers: R01NS041503 (U.S. NIH Grant/Contract)