The American Fibromyalgia Syndrome Association, Inc.

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AFSA is an all volunteer nonprofit organization dedicated to funding research that investigates the causes and treatments for fibromyalgia syndrome.

A 501(c)3 Nonprofit Charitable Organization.

Funding for 2008

Role of Myofascial Trigger Points in Fibromyalgia Syndrome - Part 1

Principal Investigator: Hong-You Ge, M.D., Ph.D.
Aalborg University, Denmark
Award Amount (September 2008): $30,000

Hong-You Ge, M.D., Ph.D., and his colleagues at Aalborg University in Denmark, plan to evaluate 30 fibromyalgia syndrome (FMS) patients and 30 healthy age-matched control subjects for the presence of active and latent MTPs. Initially the MTPs and their referred pain patterns will be identified by careful palpation of the muscles in the neck, shoulders, low back, and extremities. The pressure pain thresholds at all myofascial trigger points (MTPs) will also be measured. An anatomical map of the latent and active MTPs, as well as the areas of referred pain will be generated for each subject. Ge’s team also will confirm the presence of each MTP by measuring its electrical activity with electromyography (EMG).

In a second session one week later, subjects will be evaluated at the 18 diagnostic tender areas for FMS. Ge will look for the presence of latent or active MTPs at or near the 18 tender points. He will also determine if any of the tender points are located in an area of referred pain generated by an MTP. In addition, the MTPs will be confirmed by EMG. Since a tender point exam is done to identify areas of lowered pain threshold and MTPs have been documented to cause a lowering of pressure pain thresholds, it’s plausible that the 18 tender points might possibly be MTPs, but this has never been explored.

To fully assess the extent to which MTPs contribute to the generalized pain of FMS, Ge proposes to look at the impact of treating the MTPs in “Part 2” of his study. Upon successful completion of the evaluation phase, AFSA has already pre-approved the funding of Ge’s treatment phase. Obviously, if effective treatment of the MTPs does lead to significant pain and symptom relief, this would provide important evidence of the role of MTPs in FMS and will prompt increased education on the treatment of MTPs.

Myofascial Trigger Points and Central Sensitization in People with Fibromyalgia Syndrome

Principal Investigator: César Fernández de las Peñas, P.T., Ph.D.
Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
Award Amount (September 2008): $25,000

César Fernández de las Peñas, P.T., Ph.D., and his colleagues in Spain, propose to evaluate the role of myofascial trigger points (MTPs) in generating fibromyalgia syndrome (FMS) symptoms using a different approach from that of Ge’s team. Fifty FMS patients and 50 healthy age-matched controls will be carefully examined for the presence of active and latent MTPs. The referred pain patterns of each active MTP will also be charted. Muscles in the head, neck, shoulders, back, buttocks, legs, and forearms will be physically assessed for the presence of firm nodules and pain tenderness to identify the MTPs and their associated referral pain patterns. This will provide insight about each person’s peripheral pain generators in their muscles.

All subjects will undergo sensory pain testing to determine thresholds to pressure, cold, and heat pain. Muscles throughout the body will be used in these tests, which are designed to reflect impairments in the central nervous system’s ability to process pain. In addition, participants will fill out validated questionnaires to assess quality of life, physical functioning, and pain severity.

Statistical analyses will be performed to determine how the number of active and latent MTPs influence the sensory processing system, quality of life, functional ability, and overall pain severity.

The 18 diagnostic tender points will also be assessed to determine if any of the tender points are nearby active or latent MTPs, or in an area of referred pain that is produced by an active MTP. The goal of this part of the study is the same as that of Ge’s, because it will take more than one research team or medical journal report to draw attention to the possible overlap between the diagnostic tender points of FMS and the presence of MTPs.

Impact of Fibromyalgia on Brain Aging and Cognitive Function

Principal Investigator: M. Catherine Bushnell, Ph.D.
McGill University, Montreal, Canada
Award Amount (August 2008): $59,800

Several memory and mental processing tests show that fibromyalgia syndrome (FMS) patients have good reason to be complaining about their cognitive function, or what is called “fibro fog.” Putting your thought processes into perspective, one study showed that you are functioning at a level that is 20 years older than your actual age.1 Not surprisingly, last year M. Catherine Bushnell, Ph.D., of McGill University in Montreal, Canada, reported a premature loss of gray matter in several areas of the brain involved in pain and memory processing.2 The study was small and compared ten FMS patients to ten healthy pain-free control subjects (all women and age-matched to reduce variability).

As a person with FMS, you most likely want to know what the loss in gray matter means. Is it linked to your symptoms of pain? Does it correspond to your cognitive dysfunction? Or, perhaps loss of gray matter is tied to many symptoms. The initial study showed that gray matter loss increased with duration of symptoms, so a study involving a larger number of subjects is certainly warranted.

“It is well documented that cognitive functions, such as speed of information processing, working memory, and long-term memory, decline continuously across the adult life span beginning in the second decade of life,” says Bushnell. “So an obvious question arising from our preliminary findings is: ‘What is the relationship between accelerated brain aging in FMS patients and cognitive function?’ To answer this question, our study will examine the relationship between brain anatomy and different measures of cognitive functioning in 30 non-depressed, medication-free FMS patients. We will test the hypothesis that FMS patients have an increased age-related decline in cognitive functioning. We will determine the degree of dysfunction and the amount of gray matter loss relative to 30 age-matched control subjects.”

Other important goals of the study will be to determine if loss of gray matter correlates with:

  1. pain threshold and other experimental measures of pain
  2. level of physical functioning, and
  3. fatigue scores

It’s essential that fatigue or alertness be excluded as the cause of the cognitive difficulties in FMS patients. Given that widespread pain is present in all patients, how is this symptom related to the loss of gray matter and cognitive dysfunction? Could pain be distracting or interfering with a person’s ability to process information? Also, how does the gray matter loss relate to a patient’s functional ability (or disease severity) and duration of symptoms?

Answers to these questions are needed to better characterize the significance of the gray matter loss, as well as the interrelationships between pain, fatigue, physical function, and cognitive abilities. If accelerated gray matter loss is found to correlate with diminished cognitive function, then efforts must be placed on early identification of FMS as well as testing therapies that can reduce or reverse the structural changes in the brain.


1. Park DC, et al. Arthritis Rheum 44(9):2125-33, 2001.
2. Kuchinad A, et al. J Neurosci 27(15):4004-7, 2007.

Low-Dose Naltrexone for the Treatment of Fibromyalgia

Principal Investigators: Jarred Younger, Ph.D., and Sean Mackey, M.D., Ph.D.
Stanford University, Palo Alto, California
Award Amount: $50,000

Relief from chronic pain is difficult to achieve, and this may be partly explained by the fact that there are two targets: the neurons and the nearby glial cells. All drugs to date were designed to work on the neurons, but some of them have the ability to alter the function of the glial cells. Naltrexone is one of them.

The microglia are immune cells tasked with protecting your central nervous system (CNS) against any type of threat, such as viruses, that could harm the brain. When it comes to pain transmission, these cells usually sit quietly on the sidelines. However, many substances that can activate these immune cells are elevated in the spinal fluid of people with fibromyalgia (FM).

What happens when the microglia are in their activated state? They pour out cytokines and other chemicals that cause flu-like symptoms, such as widespread achiness, sleep disruption, profound fatigue, concentration difficulties and depressed mood. Anyone who has had a bad case of the flu knows what it feels like when their microglia are raising a ruckus. At this point, the person has mild inflammation that may not show up on routine lab tests. Ordinarily the microglia settle down after a few days and the symptoms disappear.

Younger and Mackey propose that the microglia are stuck in a chronically activated or inflammation-promoting state in FM and will test the ability of low-dose naltrexone (LDN) to relieve the symptoms of this condition. This represents the first treatment trial in FM that is designed to target the microglia instead of the neurons.

Naltrexone is available in 50 mg pills to treat opioid drug cravings in addicts. At this dose, the drug blocks pain-relieving chemicals such as endorphins (the body’s own opioids). But, even at low doses, the drug also blocks the activation of the microglia so they do not produce pain-promoting substances. The key is to use a small dose of naltrexone (3-4.5 mg), which may still “chill out” the microglia while not appreciably interfering with the body’s own opioid pain relievers. See Figure 1 below.

LDN Actions

The ability of naltrexone to shut down pain and other symptom-generating activities of the microglia appears to be safe with very few side effects. It has been tested in small trials for the treatment of Crohn’s disease and multiple sclerosis pain. Now it will be determined if the drug can benefit individuals with FM.

Thirty people with FM will participate in the trial. For part of the study (12 weeks), these individuals will receive low-dose naltrexone (LDN) every night before bedtime. For another part of the study, they will receive an inactive placebo. Neither the participants nor the researchers will know what the participants are receiving until the study is completed. Participants will start on either the drug or placebo and will then switch to the other substance. See study design in Figure 2 below.

LDN Study

Participants will fill out a short questionnaire every night to chart their pain levels, sleep quality, physical activity, mood, and fatigue. These symptom scores will be collected on hand-held computers to test the drug’s effectiveness.

Trial Results Promising

“Three out of ten people trying LDN will reap a significant improvement in pain, as well as fatigue or sleep,” says Jarred Younger, Ph.D. “This is twice as high as the current FDA-approved treatments for fibromyalgia, which typically provide a 15% response rate.” The study results are published in the February 2013 issue of Arthritis & Rheumatism.1

What does “significant improvement” really mean? Younger’s team required LDN responders to show at least a 30% reduction in pain PLUS a 30% improvement in either fatigue or sleep. Patients also showed benefits in general satisfaction with life and mood.

The overall impact of a drug on people with multi-symptom conditions (like FM) is often measured as Patient Global Impression of Change. At the end of the treatment trial, Younger states, “Half of the participants reported feeling ‘much improved’ or ‘very much improved’ from taking LDN.” See Figure 3 for a pie chart summarizing these findings.2

LDN Patient Impact

It would be impossible for any drug to provide the overall benefits shown in Figure 3 without reducing the energy-zapping fatigue associated with FM. “Even though over 30% of the participants had a strong improvement in fatigue,” says Younger, “the group average was not significant.” Rather than looking at group averages from the study, responder rates showed LDN relieved fatigue in three out of ten patients.

Pain severity or duration of symptoms didn’t predict who benefited from the drug in this study. The same findings were found by the same research team in a prior trial of ten FM patients (also partially funded by AFSA).3

LDN doesn’t work overnight. Symptom improvements from this medication took at least a month to show up. This is because it takes time for the shape and function of microglia to change throughout the brain.

Probably the greatest advantage LDN has over most drugs prescribed for FM is its very low incidence of side effects. Patients didn’t know if they were taking LDN or the placebo, yet they rated them equally tolerable. The only two side effects that occurred more frequently when taking LDN were vivid dreams and headaches.

Vivid dreams were described as being more colorful and rememberable. Any person experiencing an unpleasant side effect was put on a lower dose of 3 mg before bedtime (as opposed to 4.5 mg). This did the trick because no one dropped out of the study.

Although LDN is relatively cheap ($30/month or less), this medication has one major drawback: the low-dose version must be prepared at a compounding pharmacy (as an immediate-release formula), which means insurance companies will not pick up the tab. In addition, naltrexone (even at low doses) may interfere with the pain-relieving action of opioid medications. Patients taking opioids may require a lower starting dose.

AFSA's LDN Trial Snapshot

  • 3 out of 10 patients significantly improved
  • takes at least one month to reap the benefits
  • low side effects - vivid dreams and headaches
  • must be compounded for low dose; insurance doesn’t cover
  • targets microglia function rather than the neurons, so it may augment other treatments designed to improve neuron function

1. Younger J, Mackey S, et al. Low-Dose Naltrexone for the Treatment of Fibromyalgia. Arthritis Rheum 2013; 65(2):529-538. The report is free to read but not print.
2. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol 2014; 33:451-459. It’s free to print.
3. Younger J, Mackey S. Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study. Pain Med 2009; 10(4)633-72. It’s free to print.

A Decade of LDN Experience

After the AFSA-funded trial on LDN was published in 2013, additional studies involving this drug have appeared in the medical journals. Key findings are highlighted below. In addition, if you are interested in trying LDN, several physicians offer practical advice in a separate article: Giving LDN Your Best Shot.

Brain Microglia Activation Found - Three brain imaging studies, including one funded by AFSA, have shown that the microglia in FM patients are activated compared to healthy controls.1,2,3 These reports help support the rationale for using LDN because this drug is known to reduce the activation of these cells. For details about the project funded by AFSA, click here.

Pro-Inflammatory Cytokines Reduced by LDN - Upon activation, microglia can signal the peripheral tissues to secrete more cytokines, which end up in the bloodstream. Blood assays before and after an eight-week trial of LDN in people with FM found that the drug significantly reduced the level of 17 cytokines.4 So, not only are the microglia activated in FM, but they may also be causing a low level type of inflammation in the tissues that is not responsive to aspirin or NSAIDs.

No Serious Side Effects - A literature review involving over 11,000 people taking naltrexone (daily dose ranging from 3 to 320 mg) revealed no harmful adverse events over that of placebo.5 However, LDN can still produce mild side effects that occur infrequently. Aside from vivid dreams and headaches reported in the AFSA trial, patients may experience nausea, diarrhea, anxiety, and transient insomnia.6

LDN Might Reduce Opioid Use - Analysis of 15,000 patients who began using LDN after a documentary on the treatment aired in Norway showed that opioid consumption went down 46%.7 If this drop in opioid use had been due to concerns that LDN might interfere with the action of opioids, then an increase in other classes of medications would have been expected. However, the use of alternative pain-relievers did not go up.

1. Albretch DS, et al. Brain glial activation in fibromyalgia - a multi-site positron emission tomography investigation. Brain Behav Immun 2019; 75:72-83.
2. Seo S, at al. Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET. PLoS One 2021; 16(2):e0245152.
3. Mueller C, Younger JW, et al. Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 position emission tomography study. PAIN 2023 Oct; 164(10)2285-2295. Click here for the full report.
4. Parkitny L, Younger J. Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Natrexone for Fibromyalgia. Biomedicines 2017; 5(2):16.
5. Bolton M, et al. Serious adverse events reported in placebo randomized controlled trials of oral naltrexone: a systemic review and meta-analysis. BMC Med 2019; 17(1):10.
6. Noelle Driver C, D’Souza RS. Efficacy of Low-Dose Naltrexone and Predictors of Treatment Success or Discontinuation in Fibromyalgia and Other Chronic Pain Conditions: A Fourteen-Year Enterprise-Wide Retrospective Analysis. Biomedicines 2023; 11(4):1087.
7. Raknes G, Smabrekke L. Low-dose naltrexone and opioid consumption: a drug utilization cohort study based on data from the Norwegian prescription database. Pharmacoepidremiol Drug Saf 2017; 26(6):685-693.

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