Effect of Milnacipran on Pain in Fibromyalgia (Forest)

• ClinicalTrials.gov Identifier: NCT01288807
• Recruitment Status: Completed
• First Posted: February 2, 2011
• Results First Posted: September 24, 2019
• Last Update Posted: September 24, 2019
• Sponsor: University of California, San Diego
• Collaborators: Forest Laboratories; US Department of Veterans Affairs
• Information provided by (Responsible Party): Tobias Moeller-Bertram, University of California, San Diego

Study Description

Brief Summary:

The investigators want to study the effects of milnacipran treatment on neurotransmitter release in fibromyalgia.

Condition or disease	Intervention/treatment	Phase
Fibromyalgia	Drug: Milnacipram	Phase 4

Detailed Description:

Fibromyalgia (FM) is a chronic pain condition with significant morbidity. Current research suggests a primarily central mediation of the widespread pain including central sensitization at the spinal level and abnormal pain processing at the cerebral level. Findings in FM patients include abnormal neurotransmitter levels in cerebrospinal fluid (CSF), abnormal activation of cerebral pain processing areas and abnormal peripheral pain and sensory thresholds. Continuous low level spinal cord activation by primary nociceptive afferents (C and A delta fibers) is believed to significantly drive the central sensitization. One major spinal neurotransmitter released by these pain fibers is substance P (SP). Several studies have shown that FM patients have up to three times higher baseline SP levels in the CSF compared to controls. Since spinal neurotransmitter release and therefore nociceptive afferent activity is also regulated via a descending inhibitory pathway releasing norepinephrine (NE) and serotonin (5HT), decreased activity of this pain modulating system could also be involved in abnormal pain processing in FM. Indeed, there is support in the literature for decreased CSF levels of both NE and 5HT or their metabolites. Milnacipran, a NE and 5HT reuptake inhibitor, has been shown to potentially effectively reduce FM pain and symptoms of FM by affecting the above pathologies.

The investigators propose an open label clinical trial with milnacipran 200 mg over 12-weeks in order to investigate the pain pathway in FM patients at peripheral and spinal levels before and after treatment. In addition, the investigators will assess pain intensity and symptoms of FM before, during and after treatment. To determine if there are peripheral effects, the investigators will characterize the systemic neurotransmitter release and their metabolites in plasma. The investigators will also measure the heart rate variability using an electrocardiogram to look for effects on the sympathetic nervous system.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effects of a 12 Week Milnacipran 200 mg Treatment on Pain Perception and Pain Processing in Fibromyalgia - An Open Label Study
• Study Start Date: February 2011
• Actual Primary Completion Date: January 2015
• Actual Study Completion Date: January 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment; Titrated Milnacipram doses	Drug: Milnacipram; Titration to 200mg PO daily; Other Name: Savella

Outcome Measures

Primary Outcome Measures :

1. Concentration of Substance P in Cerebrospinal Fluid in Response to Experiemental Pain Before and After Milnacipran Treatment. [ Time Frame: 12 weeks ]

   Measure levels of Substance P present in serial samples of CSF and plasma collected over the course of 4 hours in response to application of a painful thermal stimulus at baseline ("before") and the end of 12 weeks of treatment with milnacipran 200mg daily ("after").

   Substance P levels are presented. Presented data show the 10 minute and 40 minute timepoint for Substance P after pain challenge. Additional time points were not analyzed.

Secondary Outcome Measures :

1. Measure Sensory Threshold for Temperature Pain [ Time Frame: 12 weeks ]
   Investigators will utilize quantitative sensory testing to assess changes in sensory thresholds among patients with fibromyalgia before and after a twelve (12) week course of milnacipran.
2. Measure Sensory Thresholds for Pressure Pain [ Time Frame: 12 weeks ]
   Investigator will utilize sensory testing to assess changes in sensory thresholds among patients with fibromyalgia before and after a twelve (12) week course of milnacipran.
3. Measure Pain Ratings and Fibromyalgia Symptoms [ Time Frame: 12 weeks ]

   Fibromyalgia patients will be asked to keep a pain diary which assess spontaneous pain ratings daily, a subjective weekly assessment, as well as degree of improvement weekly during treatment period on a numeric rating scale.

   The Numeric Pain Rating Scale (NPRS) is assessing the patients pain on a 11-point rating scale from 0 - 10 with 0 corresponding to 'No Pain' and 10 corresponding to 'Worst Pain imaginable'.

4. Measure Concentrations of Serotonin and Norepinephrine Cerebrospinal Fluid and Plasma [ Time Frame: 12 weeks ]

   The investigators will measure cerebrospinal fluid and plasma concentrations of serotonin and norepinephrine in CSF and plasma before and after twelve (12) weeks of treatment with milnacipran.

   Assays for these outcomes were not performed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Female age 18 or older
• Written informed consent and written release of health and research study information
• Diagnosis of Fibromyalgia
• Participant has pain greater than 4 on the NRS of 0 to 10 on average over the last week prior to initial evaluation that interferes with function most days per week
• Pain duration greater than 6 months
• Negative urine pregnancy test on experimental day 1 and 2 and on first day of treatment prior to administration of study medication and fluoroscopy
• Ability to speak and understand English, to follow instructions, and fill out study questionnaires
• Likely to complete all required visits
• Must be ambulatory and able to lay prone for 30 minutes

Exclusion Criteria:

• Any condition or situation that in the investigator's opinion may put the participant at significant risk, confound the study results, or interfere significantly with the participant's participation in the study
• Serious, unstable medical illness that could lead to hospitalization over the next three months; and/or a DSM-IV diagnosis(es) with active problems within the last six months, such as: schizophrenia, bipolar disorder, antisocial personality disorder, or substance use disorder
• Known, uncontrolled, serious systemic disease, including: hypertension and/or tachyarrythmia
• Females who are pregnant, breast feeding, or who plan to become pregnant, or who may potentially become pregnant
• Allergy or sensitivity to any component of the study medication or to contrast dye
• Patients on coumadin, heparin, or any other known increase risk of bleeding
• Signs of increased intracranial pressure
• Patients who are unable to continue current pain medication
• Allergy or contraindication to acetaminophen
• Use of monoamine oxidase inhibitors
• Uncontrolled narrow-angle glaucoma

Contacts and Locations

Locations

United States, California

UCSD Medical Center, La Jolla

San Diego, California, United States, 92037

Sponsors and Collaborators

University of California, San Diego

Forest Laboratories

US Department of Veterans Affairs

Investigators

• Principal Investigator: Tobias Moeller-Bertram, MD, PhD, MAS; University of California, San Diego

More Information

• Responsible Party: Tobias Moeller-Bertram, MD, PhD, MAS Associate Clinical Professor, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT01288807
• Other Study ID Numbers: 100686
• First Posted: February 2, 2011
• Results First Posted: September 24, 2019
• Last Update Posted: September 24, 2019
• Last Verified: September 2019

Keywords provided by Tobias Moeller-Bertram, University of California, San Diego:

Fibromyalgia; pain

Additional relevant MeSH terms:

Fibromyalgia; Myofascial Pain Syndromes; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases; Milnacipran; Serotonin and Noradrenaline Reuptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents