Clinical trial NCT01601912: Unraveling the Nature of Impaired Pain Inhibition in Patients With Chronic Whiplash-associated Disorders
Official title: Unraveling the Nature of Impaired Pain Inhibition in Patients With Chronic Whiplash-associated Disorders: a Randomized Controlled Clinical Trial for the Treatment of Central Sensitization
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Whiplash Injuries
Keywords: Whiplash Injuries
Chronic Pain
Exercise
Cognition
Lead sponsor: Vrije Universiteit Brussel
Sponsor class: OTHER
First posted: 2012-05-18
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: WAD patients: primary care clinic \& community sample Healthy people: community sample

Brief summary: The primary study aim is to unravel the nature of impaired pain inhibition during exercise in patients with chronic Whiplash-Associated Disorders (WAD). This will be ascertained by examining whether activation of serotonergic and/or noradrenergic descending pathways improves pain inhibition during exercise in these patients. In addition, it is aimed at examining whether activation of serotonergic and/or noradrenergic descending pathways prevents post-exertional malaise following submaximal exercise in chronic WAD patients. A secondary study aim comprises of examining the effect of an acute submaximal exercise with and without activation of serotonergic or noradrenergic descending pathways on chronic WAD patients' cognitive performance. Furthermore, the isolated effect of activated serotonergic and noradrenergic descending pathways on chronic WAD patients' cognitive performance will be studied.

Detailed description: Chronic Whiplash-Associated Disorders (WAD) is a debilitating, costly condition, and remains a challenge for clinicians, including physicians, rehabilitation specialists and physiotherapists. There is now consistent evidence for central sensitization in people with chronic WAD. In a previous study in chronic WAD patients, our group showed that pain inhibition during exercise is impaired and that a submaximal exercise triggers a severe relapse named post-exertional malaise. On the other hand, imbalance of serotonin (5-HT) and norepinephrine (NE) is likely to be responsible for malfunctioning of pain inhibitory pathways. Indeed, NE is required for activation of descending noradrenergic pathways with established nociceptive inhibitory properties. Serotonin reuptake inhibitor drugs activate serotonergic descending pathways that recruit, in part, opioid peptide-containing interneurons in the dorsal horn. It becomes more and more clear that the lack of pain inhibition accounts in part for various symptoms at rest and following exercise in particular (post-exertional malaise). However, the mechanisms behind the lack of pain inhibition during exercise remain to be revealed. Besides the lack of endogenous pain inhibition during exercise in people with chronic WAD, there appears to be sufficient evidence to support the presence of impaired cognitive function in chronic pain patients in general and preliminary evidence in chronic WAD patients in particular.

The present study aimed at examining whether activation of serotonergic and/or noradrenergic descending pathways improves pain inhibition during exercise in chronic WAD patients. In addition, it is aimed at examining whether activation of serotonergic and/or noradrenergic descending pathways prevents post-exertional malaise following submaximal exercise in these patients. A secondary study aim comprises of examining the effect of an acute submaximal exercise with and without activation of serotonergic or noradrenergic descending pathways on chronic WAD patients' cognitive performance. Furthermore, the isolated effect of activated serotonergic and noradrenergic descending pathways on chronic WAD patients' cognitive performance will be studied.We will modulate endogenous serotonergic and adrenergic pain inhibitory mechanisms by using a selective NE reuptake inhibitor (NRI) and a selective 5-HT reuptake inhibitor (SSRI). Endogenous pain inhibition and cognitive function (sustained and selective attention, and executive function) will be studied at rest and in response to exercise (1) under baseline condition, (2) after the intake of a NRI (Atomoxetine), and (3) after the intake of a SSRI (Citalopram).

Eligibility criteria: Inclusion Criteria for patients:

* WAD grades I to III according to the Quebec Task Force criteria
* experienced a whiplash trauma at least three months ago
* with chronic pain as a result of a whiplash injury
* 18-65 years of age and with Dutch as their native language will be able to participate

Exclusion Criteria for patients:

* other comorbidities or health issues that could explain the pain complaints
* \< 18years \> 65 years
* pregnant or until 1 year postnatal (for women)
* use of anti-depressive, anti-epileptic and pain medication.

Inclusion Criteria for healthy volunteers:

* 18-65 years of age and with Dutch as their native language will be able to participate
* having a sedentary job and doing \< 3 h moderate physical activity/week
* being painfree without any chronic disease

Exclusion Criteria for healthy volunteers:

* \< 18years \> 65 years
* pregnant or until 1 year postnatal (for women)
* use of anti-depressive, anti-epileptic and pain medication.

Primary outcomes:
measure: Changes in pain inhibition
timeFrame: Baseline before and after the submaximal graded exercise= day 1 A & B, after first intervention before and after the submaximal graded exercise= day 8 A & B, after second intervention before and after the submaximal graded exercise = day 15 A & B
measure: Changes in psychomotor vigilance and alertness
timeFrame: Baseline before and after the submaximal graded exercise= day 1 A & B, after first intervention before and after the submaximal graded exercise= day 8 A & B, after second intervention before and after the submaximal graded exercise = day 15 A & B
measure: Changes in selective attention and executive function
timeFrame: Baseline before and after the submaximal graded exercise= day 1 A & B, after first intervention before and after the submaximal graded exercise= day 8 A & B, after second intervention before and after the submaximal graded exercise = day 15 A & B
Secondary outcomes:
measure: Change in scores on the Neck Disability Index questionnaire
timeFrame: Baseline = day 1, after the first intervention = day 8, after the second intervention = day 15
measure: Change in scores on the Brief Pain Inventory questionnaire
timeFrame: Baseline = day 1, after the first intervention = day 8, after the second intervention = day 15
measure: Changes in the scores on the Whiplash Associated Disorders Symptom list
timeFrame: Day 1 pre and post submaximal graded exercise and 24h after exercise = day 1 A,B&C, day 8 pre and post submaximal graded exercise & 24h after exercise = day 8 A,B&C, day 15 pre and post submaximal graded exercise & 24h after exercise = day 15 A,B&C
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
Study officials:
affiliation: Vrije Universiteit Brussel
name: Jo Nijs, PhD
role: STUDY_DIRECTOR
References:
citation: Van Oosterwijck J, Nijs J, Meeus M, Van Loo M, Paul L. Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: an experimental study. J Pain. 2012 Mar;13(3):242-54. doi: 10.1016/j.jpain.2011.11.006. Epub 2012 Jan 24.
citation: Ickmans K, Malfliet A, De Kooning M, Goudman L, Hubloue I, Schmitz T, Goubert D, Aguilar-Ferrandiz ME. Lack of Gender and Age Differences in Pain Measurements Following Exercise in People with Chronic Whiplash-Associated Disorders. Pain Physician. 2017 Sep;20(6):E829-E840.