Uncovering Neural and Immune Mechanisms of Chronic Pain in Post Treatment Lyme Syndrome

Chronic Pain Clinical Trial

— CP-PTLS  

Official title:

Uncovering Neural and Immune Mechanisms Underlying Chronic Pain and Central Sensitization in Post-treatment Lyme Syndrome

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05055622
• Other study ID #: 7003
• Status: Terminated
• Phase: Phase 2
• Start date: December 2015
• Est. completion date: January 27, 2018

Study information

• Verified date: September 2021
• Source: Research Foundation for Mental Hygiene, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study that has the following goals:

a) To systematically characterize symptomatology of patients with PTLS by conducting multimodal sensory and neurocognitive assessments and comparing patients with PTLS to healthy controls and to identify biomarkers associated with chronic pain and sensory hypersensitivity among patients with PTLS, c) To investigate whether pharmacologic treatment with milnacipran is associated with clinical improvement chronic pain and physical functioning and with specific changes both in the cerebral and ventricular neurochemistry and in the neural activation patterns d) To investigate whether augmentation with a glutamatergic agent (D-cycloserine) can increase the pain -alleviating effect of an SNRI agent (milnacipran) among patients with PTLS

First, patients with chronic PTLS pain and healthy controls will carefully assessed and compared on the brain imaging measures, sensory battery, neuropsychologic tests, and immune markers. After this extensive clinical and neural markers assessment, patients with PTLS and chronic pain will be randomized to (i) 12 weeks of milnacipran +d-cycloserine augmentation, or (ii) 12 weeks of milnacipran + placebo augmentation. Milnacipran (an SNRI) reduces both pain and depression and was shown in previos studies to reduce pain in fibromyalgia. D-Cycloserine (as a glutamate modulator) as a SNRI adjunct was shown to further reduce depression and in animal models to reduce pain. Primary outcome measure will be improvement in pain on visual analog scale, physical functioning and quality of life. All patients will undergo sensory, immune, glycine, self-reports, neuropsychologic testing, and neural markers assessments pre- and post-treatment.

Description:

At least 5-15% of patients with Lyme disease (7,500-45,000 new cases a year) develop Post-treatment Lyme Syndrome (PTLS) - debilitating residual symptoms that last months to years despite antibiotic treatment. Many patients with PTLS experience chronic widespread pain which may be mediated by the process of central sensitization. To date, central neural mechanisms underlying this debilitating syndrome are still unknown, and, to our knowledge, there have been no studies exploring the aberrantly working neural pain circuits, neurochemistry, and possible associated immune system dysregulation in PTLS. Understanding the central neural and immune markers of PTLS can lead to the development of new targeted treatments, which are urgently needed.

There are also no known treatments for patients with persistent widespread pain after antibiotic-treatment for Lyme disease. Because SNRIs have been shown to be helpful in reducing pain among patients with central sensitization syndromes (e.g., fibromyalgia), treatment with a SNRI would be expected to help patients with PTLS. However the magnitude of this effect is modest, ranging from mild to moderate in different studies. Agents that augment the improvement in pain are needed. We propose to conduct a study that has the following goals:a) To systematically characterize symptomatology of patients with PTLS by conducting multimodal sensory and neurocognitive assessments and comparing patients with PTLS to healthy controls b) To identify biomarkers associated with chronic pain and sensory hypersensitivity among patients with PTLS, including: immune markers, neural circuits involved in pain processing, and neurochemistry of pain processing brain regions (glutamate and GABA in the insula)c) To investigate whether pharmacologic treatment with milnacipran with/without DCS is associated with clinical improvement and with specific changes both in the cerebral and ventricular neurochemistry and in the neural activation patterns d) To investigate whether augmentation with a glutamatergic agent (D-cycloserine) can increase the pain -alleviating effect of an SNRI agent (milnacipran) among patients with PTLS.

To accomplish this, first, 40 patients with PTLS and chronic pain and 20 healthy controls will carefully assessed and compared on the following measures: Multimodal Sensory Battery (thermal, pressure, vibration, sound, & light sensitivity); neurocognitive testing; self-report measures of pain, fatigue, mood, functioning, quality of life, lifetime stressors, peripheral neuropathy; physical exam and detailed medical history; lab testing for Lyme and co-infections; serum glycine; autonomic nervous system measures; neural circuits in the brain using fMRI during rest and reactivity to pain stimuli; neurochemistry of the brain using MRS, including Glutamate & GABA in pain regions (anterior and posterior insula) as well as ventricular lactate; immune markers (cytokines and chemokines using stimulated macrophage methodology -lipopolysaccharide (LPS) challenge). After this extensive clinical and neural markers assessment, 40 patients with PTLS and chronic pain will be randomized to (i) 12 weeks of milnacipran +d-cycloserine augmentation or (ii) 12 weeks of milnacipran + placebo augmentation. Primary outcome measure will be improvement in pain on visual analog scale, physical functioning and quality of life. Milnacipran (an SNRI) reduces both pain and depression and was shown in previos studies to reduce pain in fibromyalgia. D-Cycloserine (as a glutamate modulator) as a SNRI adjunct was shown to further reduce depression and in animal models to reduce pain.All patients will undergo sensory, immune, glycine, self-reports, neuropsychologic testing, and neural markers assessments pre- and post-treatment.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: January 27, 2018
• Est. primary completion date: January 27, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

1. History of Lyme Disease and treatment:

• History of prior diagnosis of Lyme disease that met the Centers for Disease Control (CDC) surveillance criteria case definition

• For erythema migrans (EM) rash, this has to be physician diagnosed;

• For later stages of Lyme disease, this has to be physician diagnosed and laboratory testing has to confirm the serum was positive historically

• Documentation of prior treatment for Lyme Disease that meets Infectious Diseases Society of America (IDSA) recommended standards for the stage of illness;

2. Current chronic pain in the musculoskeletal system of at least moderate intensity (pain severity recall rating over the prior week of at least 5 on a 0-10 point Visual Analog Scale), that has been present for at least 3 months, developed within 6 months after the onset of Lyme disease, and is not better attributed to another independent medical condition

3. Self-report of clinically troubling sensory hypersensitivity (e.g., light or touch) that developed after the onset of Lyme disease and is not better attributed to another independent medical condition

4. Able to speak and read English

Exclusion Criteria:

1. Diagnosis of another (not LYME) general medical condition that has a major role in the onset, severity, exacerbation or maintenance of pain, or sensory hypersensitivity.

2. DSM-IV Axis I lifetime diagnosis of Pervasive Developmental Disorder, Autism, Psychotic disorder, Bipolar Disorder, Substance dependence.

3. DSM-IV Axis I current diagnosis of Major Depressive Disorder or substance abuse

4. History of head injury with loss of consciousness (>5min), neurologic disease, seizures (excluding febrile seizures) or serious unstable medical condition (e.g. cancer, diabetes)

5. Current or recent (last month) opiate use

6. For 2 weeks prior to MRI and diagnostic visit, unable to be free of centrally active medications or treatment methods. These include medications commonly used to treat pain (eg, antidepressants, muscle relaxants, centrally-acting analgesics), as well as transcutaneous electrical nerve stimulation, biofeedback, tender and trigger point injections, acupuncture, and anesthetic or narcotic patches. PRN doses of short acting medications, e.g. acetaminophen, aspirin, and nonsteroidal anti-inflammatory agents will be allowed for pain with usage carefully monitored, but patients must be willing to be off of these medications for 24 hours prior to the major evaluations at intake and MRI study visit.

Stable doses of non-benzodiazepines will be allowed for sleep (but not tricyclics)

7. Ferromagnetic implants (e.g. pacemaker, etc.)

8. Metal Braces or Retainers

9. Transdermal medicinal patches that cannot be removed

10. Birth at < 37 weeks gestational age (prior studies have shown dramatic effects on brain structure and function in prematurely born children)

11. Claustrophobia

12. Women will be excluded if they are pregnant, lactating, or not either surgically-sterile or using appropriate methods of birth control. Women must agree to continue using applicable birth control throughout the trial. All women of child-bearing potential must have a negative pregnancy test at the intake visit.

13. Inability to reliably rate intensity of pain in response to a fixed thermal stimulus

14. Ongoing legal or disability claims

15. Individuals with physical disability that might make study participation difficult

16. Inability to tolerate sound intensity of fMRI

17. Individuals currently successfully treated by medications for their pain.

18. History of inability to tolerate treatment with SSRI or SNRI medications or d-cycloserine; or medication induced mania

19. Renal insufficiency or congestive heart failure

20. Suicide attempts within the last 6 months or current suicidal thoughts

Related Conditions & MeSH terms

• Central Sensitization
• Chronic Pain
• Syndrome

Intervention

Drug:
• Milnacipran with D-cycloserine augmentation

• Milnacipran with placebo augmentation

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Research Foundation for Mental Hygiene, Inc.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pain Visual Analog Scale (VAS)	Assesses pain severity	7 days
Secondary	SF-36 Physical Composite Scale.	Assesses Physical Functioning	30 days
Secondary	Quality of Life (Q-LES-Q)	Assesses quality of life experiences and satisfaction	7 days