Opioid Induced Gait Variability

While the analgesic effects of opioids are well known, evidence suggest that there are differences in the adverse dizziness of the different opioid types, which may influence the gait function differently. However, this has not been investigated scientifically under controlled conditions. Normal gait function is characterized by cyclic movements with a high degree of predictability. As such, the amount of kinematic variability can provide important information about a condition or an intervention that may affect the gait function . Three-dimensional gait analysis is a recognized method to assess changes in stride-to-stride variability associated with a medical condition or caused by an intervention. Thus, opioid induced changes in gait variability, and possible differences between opioid types, can be assessed objectively from differences in the variability of movements obtained from a three-dimensional gait analysis.

The purpose of this study is to investigate differences in gait variability induced by two different single-dose opioid formulations and an inert placebo in healthy volunteers and knee osteoarthritis patients.

Study Overview

• Status: Completed
• Conditions: Opioid Induced Motor Disturbances
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Tramadol Hydrochloride 100 mg Extended Release Oral Tablet; Drug: Tapentadol 50 mg Oral Tablet

Detailed Description

The study is designed as an experimental single center, double-blind treatment, cross-over study with inert placebo, Tapentadol (Palexia Depot), and Tramadolhydrochlorid (Mandolgin Retard), with a minimum of 7days wash-out periods.

At day 1 (Visit 1), baseline measurements are carried out before tablet administration. Immediately after baseline measurements one tablet is administered, and hourly measurements are performed for 6 hours. Subsequently all participants enter a minimum 7 day washout period, after which they return to the facility to repeat the procedures at Visit 2 (day 8+) and Visit 3 (day 15+). The order of treatments will be randomized (1:1:1).

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2000
    • The Parker Institute, Frederiksberg Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Healthy subjects:

• In general good health, in the opinion of the Investigator, based on medical history and physical examination.
• Ability to comprehend and a willingness to provide written informed consent
• Age between 50 and 75 years
• No opioid usage 3 months prior to the study
• No musculoskeletal pain requiring medical attention during the previous 3 months
• Willing and able to complete study visits and procedures
• Willing to hold activity, exercise level, and concurrent treatments/therapies generally consistent during the study
• A body mass index (BMI) of ≤30

Patients with knee osteoarthritis (OA)

• Diagnosis of knee OA
• Ability to comprehend and a willingness to provide written informed consent
• Age between 50 and 75 years
• No opioid usage 3 months prior to the study
• Knee pain of at least 40 mm on a 0-100 mm visual analog scale (without analgesics) representing the average pain intensity during the previous week
• Willing to discontinue all pain medications 24 hours before and during examination visits
• Willing and able to complete study visits and procedures
• Willing to hold activity, exercise level, and concurrent treatments/therapies generally consistent during the study
• In general good health, in the opinion of the Investigator, based on medical history and physical examination.
• A body mass index (BMI) of ≤30

Exclusion Criteria:

The same exclusion criteria apply for both healthy subjects and patients with knee osteoarthritis:

• Clinical signs of gait ataxia assessed by clinical neurological examination
• Independent or unsteady walking (i.e. dependence on walking device or stumbling gait)

• Counter indications to either of the investigational products, including but not restricted to:

  • Allergy towards one or more of the investigational products or their excipient(s).
  • Significant respiratory depression
  • Current or serious asthma
  • Hypercapnia
  • Suspected or diagnosed paralytic ileus
  • Acute intoxication by alcohol, hypnotica, centrally acting analgesics, psychopharmaca or other pharmaceuticals.
  • Renal dysfunction
  • Hepatic dysfunction
  • Diseases of the biliary tract
  • Acute pancreatitis
  • Usage of monoamine oxidase inhibitors within the last 14 days
  • Galactose intolerance
  • Lactase deficiency
  • Glucose/galactose malabsorption
  • Epilepsy
• Previous usage of opioids without pain reliving effect.
• Patients who have a documented history of an allergic reaction or a clinically significant intolerance to opioids
• Malignant pain
• Excessive joint laxity in the lower extremities indicative of functional ligamentous deficiency.
• Dependency of walking aid (stick, cane, roller etc.).
• Positive Clock Drawing Test
• Abuse of alcohol, medicine and narcotics within past 5 years.
• History of symptoms of autoimmune disorders
• Diabetes
• Pregnancy or breast feeding
• History, diagnosis, or signs and symptoms of clinically significant neurological disease
• History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo oral tablet; One inert calcium tablet is administered after a set of baseline measurements are performed. Subsequently outcomes are assessed every hour for 6 hours, yielding a total of 7 hourly measurements.	Drug: Placebo Oral Tablet; calcium tablet; Other Names: Calcium tablet
EXPERIMENTAL: Tramadol Hydrochloride 100 mg Extended Release Oral Tablet; One tablet containing 100 milligrams (mg) Mandolgin Retard, Sandoz is administered after a set of baseline measurements are performed. Subsequently outcomes are assessed every hour for 6 hours, yielding a total of 7 hourly measurements.	Drug: Tramadol Hydrochloride 100 mg Extended Release Oral Tablet; 1 tablet administered; Other Names: Mandolgin Retard (100 mg)
EXPERIMENTAL: Tapentadol 50 mg Oral Tablet; One tablet containing 50 milligrams (mg) Palexia Depot, Grünenthal is administered after a set of baseline measurements are performed. Subsequently outcomes are assessed every hour for 6 hours, yielding a total of 7 hourly measurements.	Drug: Tapentadol 50 mg Oral Tablet; 1 tablet administered; Other Names: Palexia Depot (50 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Gait variability	Three dimensional gait analysis during 6 minutes of continuous treadmill walking.	every hour from pre-tablet administration (hour 0) to hour 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self reported dizziness	Current dizziness is assessed by means of a 100 mm visual analog scale	every hour from pre-tablet administration (hour 0) to hour 6
Self reported knee pain	Current knee pain is assessed by means of a 100 mm visual analog scale	every hour from pre-tablet administration (hour 0) to hour 6

Collaborators and Investigators

• Sponsor: Frederiksberg University Hospital

Publications and helpful links

General Publications

• Henriksen M, Alkjaer T, Raffalt PC, Jorgensen L, Bartholdy C, Hansen SH, Bliddal H. Opioid-Induced Reductions in Gait Variability in Healthy Volunteers and Individuals with Knee Osteoarthritis. Pain Med. 2019 Nov 1;20(11):2106-2114. doi: 10.1093/pm/pny286.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 19, 2015
• Primary Completion (ACTUAL): January 29, 2016
• Study Completion (ACTUAL): January 29, 2016

Study Registration Dates

• First Submitted: April 10, 2017
• First Submitted That Met QC Criteria: April 19, 2017
• First Posted (ACTUAL): April 20, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 6, 2017
• Last Update Submitted That Met QC Criteria: November 1, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Uptake Inhibitors; Tramadol; Tapentadol
• Other Study ID Numbers: 131 (Tumor Vaccine Group)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No