Cyproheptadine and Chlorpromazine Effects on Spasticity

Phase 3 Study of Cyproheptadine and Chlorpromazine Effects on Spasticity After Spinal Cord Injury

The main goal of this research is to understand the neuronal mechanisms that mediate the development of spasticity and motor dysfunction after spinal cord injury. The investigators examine how neurons and neuronal circuits in an injured nervous system adapt to produce the uncontrolled and unwanted muscle contractions that affect the majority (80%) of patients with spinal cord injury. One of the neurons that the investigators study is the motoneuron that excites the muscles of the limbs to produce movement. Previously, the investigators have shown that after spinal cord injury, the excessive and uncontrolled activity of motoneurons during muscle spasms is mediated, in large part, by the activation of calcium currents in the human motoneuron. In human patients the investigators have used recordings from single muscle fibres to estimate the contribution of these calcium currents in activating the motoneuron during muscle spasms. In this proposal, the investigators study why motoneurons recover these calcium currents and self-sustained activity after chronic spinal cord injury. Because the calcium currents require the presence of the monoamine serotonin (5HT) to activate, and this monoamine is greatly reduced after injury, the investigators examine if the calcium currents recover because the 5HT receptors become spontaneously active without the need for 5HT to bind to the receptor, which the investigators hypothesize to be one of the causes of spasticity after spinal cord injury. This research will pave the way to develop new pharmacological and rehabilitative therapies to both control spasticity after spinal cord injury and augment residual motor movements.

Study Overview

• Status: Completed
• Conditions: Spinal Cord Injuries; Muscle Spasticity

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G2R3
      • University of Alberta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Spinal Cord Injury Patients

Description

Inclusion Criteria:

Patients must have suffered a trauma to the spinal cord at least 6 months ago or longer. In addition, subjects must exhibit some degree of spasticity as determined by having an Ashworth Spasticity Score, as assessed by a physical therapist, greater than 1.

Exclusion Criteria:

• If patients have damage to the nervous system other than to the spinal cord
• Pregnant women
• Elderly Patients and debilitated patients
• Alcoholic Patients

• Patients with:

  • Known or suspected allergy to the medication or its ingredients
  • Cardiovascular disease
  • Hypotension
  • Coronary artery disease
  • Reduced liver or kidney function
  • Comatose or depressed states due to CNS depressants
  • Blood dyscrasias
  • Bone marrow depression
  • History of seizures
  • Respiratory problems
  • Hypocalcemia
  • Monoamine oxidase inhibitor therapy
  • Angle-closure glaucoma
  • Stenosing peptic ulcer
  • Symptomatic prostatic hypertrophy
  • Bladder neck obstruction
  • Pyloroduodenal obstruction
  • History of bronchial asthma
  • Increased intraocular pressure
  • Hyperthyroidism
  • Cardiovascular disease
  • Hypertension

• Patients taking:

  • Amphetamines
  • Antihistamines-second generation
  • Anticonvulsants
  • Anticholinergics
  • CNS depressants
  • Antidepressants
  • Hypotensive agents
  • Levodopa
  • Lithium

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Complete Spinal Cord Injured Subjects; Patients with no motor scores in their legs and suffering a complete spinal cord injury.
Incomplete Spinal Cord Injured Subjects; Patient with some motor preservation below the injury and suffering an incomplete spinal cord injury.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cutaneomuscular Reflex Responses	Tibialis anterior reflex responses evoked by stimulation of the medial arch of the foot will be measured before and after drug administration.	Change after drug intake at baseline, 30minutes, 60minutes, 90minutes and 120minutes
Paired motor unit recordings	We obtain paired motor unit recordings to determine changes in neuronal excitability after drug intake in incomplete spinal-cord injured subjects only.	Change at baseline and 30, 60, 90 and 120min after drug intake

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure and Heart rate	We measure blood pressure and heart rate to determine the safety of the drug during the experiment and whether we can continue safely.	Change at baseline and 30, 60, 90, 120 minutes after drug intake

Collaborators and Investigators

• Sponsor: University of Alberta
• Investigators: Principal Investigator: Monica A Gorassini, PhD, University of Alberta

Publications and helpful links

General Publications

• Murray KC, Nakae A, Stephens MJ, Rank M, D'Amico J, Harvey PJ, Li X, Harris RL, Ballou EW, Anelli R, Heckman CJ, Mashimo T, Vavrek R, Sanelli L, Gorassini MA, Bennett DJ, Fouad K. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat Med. 2010 Jun;16(6):694-700. doi: 10.1038/nm.2160. Epub 2010 May 30.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: January 10, 2012
• First Submitted That Met QC Criteria: January 12, 2012
• First Posted (Estimate): January 13, 2012

Study Record Updates

• Last Update Posted (Estimate): November 20, 2012
• Last Update Submitted That Met QC Criteria: November 16, 2012
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Wounds and Injuries; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Trauma, Nervous System; Spinal Cord Diseases; Muscle Hypertonia; Spinal Cord Injuries; Muscle Spasticity
• Other Study ID Numbers: Pro00020682