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:
- pain threshold and other experimental measures of
pain
- level of physical functioning, and
- 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.
References:
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.
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.
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
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
References
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.
References
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.