A Study to Evaluate the Effects of Milnacipran on Pain Processing and Functional MRI in Patients With Fibromyalgia

A Randomized, Double-blind,Placebo-controlled, Two-way Crossover Study to Evaluate the Effect of Milnacipran on Pain Processing and Functional Magnetic Resonance Imaging Activation Patterns in Patients With Fibromyalgia

Fibromyalgia is a condition that includes pain, tenderness, stiff muscle, and fatigue. Researchers want to find out if "a drug" called milnacipran can help people with fibromyalgia. milnacipran (Savella) is approved by the FDA for the management of fibromyalgia. In this study, milnacipran will be given to find out more about how it affects pain and thinking in people with fibromyalgia.

Study Overview

• Status: Completed
• Conditions: Fibromyalgia
• Intervention / Treatment: Drug: milnacipran; Drug: Placebo

Detailed Description

The objective of this study is to evaluate the effect of milnacipran on pain processing in patients with fibromyalgia and to assess the correlation between this effect and neural activation patterns during functional Magnetic Resonance Imaging (fMRI).

NOTE regarding Changes in Outcome Measures

In this Crossover Study, participants were involved for approximately 16 weeks in this sequence: a week of preparing for the initial assessments, baseline measurements (Week 0), 6 weeks on placebo or study drug followed by measurements for effect of drug or placebo (Week 6); a week of titration off of drug, if appropriate (or continued placebo, if on placebo), two weeks of washout, a new baseline assessment (Week 9), six weeks of study drug (or placebo), another set of measurements for effect of drug or placebo (Week 15), and a final titration period to maintain masking of assignment to drug or placebo. Of 17 participants who completed both sequences, data was analyzed for the 15 whose values for all measurement variables were usable.

When Outcome measure data was originally and accurately posted for baseline and change after treatment, the time frames listed were 0 and 15 weeks, because the last assessment was gathered at approximately week 15 for each person whose data is in the data set. However, given the crossover design, it seems more accurate and understandable, to show the time frame for the outcome measure as 6 because the participants were each administered drug or placebo for six weeks total. (Of course for the Placebo then Study Drug arm, the placebo data was collected at week 6, and for the Study Drug then Placebo arm, the drug data was collected at week 6, and similarly for the first group the drug data was collected at week 15 (first assignment, plus 1 week titration, 2 weeks washout, new baseline at week 9, and final collection at week 15), and for the second group the placebo data was collected at week 15.

Thus, outcome measures originally listed for 6 and 9 weeks, which were previously shown as "Data Not Reported" were effectively already included within the data presented for change from baseline shown in Week 15 in this fashion: 9 week data for the second assignment is part of the "week 0 data" for the first assignment, to get pre-treatment baseline for each treatment shown. Week 6 data is the post-treatment data which was shown as week 15, but is now recategorized as 6 week data. There is no, and never was, any data that could represent assignment to drug or placebo for 9 or 15 weeks.

Additionally, several outcome measures based on fMRI values were always listed in the protocol as other outcomes (not secondary outcomes), but had been incorrectly posted in the earlier listings on ClinicalTrials.gov. They have been accurately reclassified in the 2017 resubmission.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • University of Michigan, Chronic Pain and Fatigue Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• You may be eligible to take part in this study if the following are true:

  • You are between the age of 18 and 70 years
  • If you are female
  • If you are right handed
  • You have a diagnosis of fibromyalgia for at least 3 months, as defined by the American College of Rheumatology 1990 Criteria
  • You are willing to stop taking certain medicines that you may be taking on a regular basis. The researchers will discuss these medications with you in detail

Exclusion Criteria:

• You may not be eligible take part in this study if any of the following are true for you:

  • You have problems with your heart or cardiovascular system
  • You have problems with your liver or kidneys
  • You have an autoimmune disease, or a whole-body infection like HIV or hepatitis
  • You have cancer
  • You are pregnant or breastfeeding
  • You abuse drugs or alcohol
  • You have suicidal thoughts or wishes
  • You have taken milnacipran or another study drug within the last 30 days
  • You have a medical problem not listed here that would make it unsafe for you to take part in the study
  • The research team feels that you will be unable to complete all phases of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Milnacipran; Milnacipran will be given orally twice daily in tablet form at different times during the course of the study. The highest dose of milnacipran to be used in the study is 200mg/day.	Drug: milnacipran; Milnacipran will be given orally twice daily in tablet form at different times during the course of the study. The highest dose of milnacipran to be used in the study is 200mg/day.; Other Names: Savella
Experimental: Placebo; Placebo will be given orally twice daily in tablet form at different times during the course of the study.	Drug: Placebo; Placebo will be given orally twice daily in tablet form at different times during the course of the study.; Other Names: placebo/sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Threshold at Baseline	The primary outcome parameter is the medium pressure pain threshold at pre-treatment baseline (pressure that evokes a perceived pain intensity of 40-50 out of 100 on a numerical rating scale). Measured in kg/cm^2.	Baselines measured at week 0 and week 9 after washout from first assignment to treatment
Change in Pain Threshold From Baseline to End of Treatment.	The primary outcome parameter is the change in medium pressure pain threshold (pressure that evokes a perceived pain intensity of 40-50 out of 100 on a numerical rating scale) from baseline to end of treatment. Measured in kg/cm^2. Lower values represent a worse outcome.	baseline compared with 6 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diffuse Noxious Inhibitory Control (DNIC) Effect at Baseline.	0-100 numerical rating scale. 0 on the numerical scale represents a better outcome. 100 represents a worse outcome.	Baselines measured at week 0 and week 9 after washout from first assignment to treatment
Change in Diffuse Noxious Inhibitory Control (DNIC) Effect From Baseline to End of Treatment.	0-100 numerical rating scale. 0 on the numerical scale represents a better outcome. 100 represents a worse outcome.	baseline compared with 6 weeks of treatment
Pain Tolerance at Baseline	The primary outcome parameter is the pressure pain tolerance (maximum tolerated pressure) at pre-treatment baseline.	Baselines measured at week 0 and week 9 after washout from first assignment to treatment
Change in Pain Tolerance From Baseline to End of Treatment	The primary outcome parameter is the change in pressure pain tolerance (maximum tolerated pressure) from baseline to end of treatment. Measured in kg/cm^2. Lower values represent a worse outcome.	baseline compared wtih 6 weeks of treatment

Other Outcome Measures

Outcome Measure	Time Frame
Change in fMRI Brain Activation Patterns During Pressure Stimulation From Baseline to End of Treatment	Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later
Change in Descending Pain Modulation From Baseline to End of Treatment (as Assessed by Changes in fMRI Brainstem Activation Patterns)	Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later
Change in fMRI Activation Patterns During N-back Procedure From Baseline to End of Treatment.	Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: Forest Laboratories
• Investigators: Principal Investigator: Daniel Clauw, MD, University of Michigan

Publications and helpful links

General Publications

• Ichesco E, Peltier SJ, Mawla I, Harper DE, Pauer L, Harte SE, Clauw DJ, Harris RE. Prediction of Differential Pharmacologic Response in Chronic Pain Using Functional Neuroimaging Biomarkers and a Support Vector Machine Algorithm: An Exploratory Study. Arthritis Rheumatol. 2021 Nov;73(11):2127-2137. doi: 10.1002/art.41781. Epub 2021 Sep 22.

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: July 29, 2010
• First Submitted That Met QC Criteria: July 29, 2010
• First Posted (Estimate): July 30, 2010

Study Record Updates

• Last Update Posted (Actual): November 8, 2017
• Last Update Submitted That Met QC Criteria: October 4, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Muscular Diseases; Neuromuscular Diseases; Fibromyalgia; Myofascial Pain Syndromes; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Milnacipran; Levomilnacipran
• Other Study ID Numbers: MD-SAV-09