MYALGIA

Abstract :
Fibromyalgia (FM) is a highly prevalent and disabling syndrome characterized
by chronic widespread musculoskeletal pain and a broad range of cognitive and
affective symptoms. Up to now, the pathogenesis of FM is unknown although a
peripheral and central sensitization involving an imbalance on immune
biomarkers appears to have a relevant role in its aetiology. The aim of this study
was to extend previous clinical findings of Mindfulness-Based Stress Reduction
(MBSR) to both its impact on clinical symptomatology and immune biomarkers
(IL-6, CXCL8, IL-10 and hs-CRP), and also to explore the role of biomarkers as
predictors of efficacy.
Methods:
A total of 70 female patients with FM were randomly assigned to two treatment
modalities, namely Treatment as Usual (TAU) plus MBSR (n = 35) or TAU
alone (n = 35). This study is embedded within a larger RCT (n = 225) that
includes three study arms (TAU; TAU plus MBSR; and TAU plus the
psychoeducative intervention FibroQoL), and a 12-month follow-up (clinical
trial registration: NCT02561416). Blood cytokine assays and clinical
assessment were conducted at baseline and post-treatment. Treatment effects
were analysed using linear mixed models with intention to treat and per protocol
analyses. In order to evaluate the balance between pro- and anti-inflammatory
pathways, ratios of pro-inflammatory IL-6, CXCL8 and hs-CRP with the anti-
inflammatory cytokine IL-10 were calculated (i.e., IL-6/IL-10, CXCL8/IL10
and hs-CRP/IL-10).
Results:
The results show that MBSR is an efficacious intervention to reduce clinical
severity of patients with FM. MBSR also prevents the tendency of IL-10 to
decrease as observed in the TAU group. Higher levels of baseline CXCL8 levels
attenuate the beneficial effect of MBSR practice on clinical symptomatology,
including pain, energy, stiffness, or quality of sleep. Furthermore, higher
baseline IL-6/IL-10 and CXCL8/IL-10 ratios were associated with less
improvement in psychological inflexibility following MBSR treatment. –1
Definition:
Myalgia means muscle pain something we have all felt at one time or
another. Sore muscles and body aches are common after exercise and when you
have the flu. Myalgia is usually temporary and not serious. But sometimes, it
can be a sign of a long-term condition that needs your attention. –2

Types of Myalgia:

There are two main forms of myalgia, including:

1. Localized myalgia: Pain that occurs in specific muscles or muscle groups.

This type often occurs due to muscle overuse, injury, tension, or infection.
As the muscle(s) heals, the pain typically goes away.
2. Diffuse myalgia: Pain that occurs and spreads throughout the body.
Systemic (body-wide) infections like the flu or COVID-19 can cause
temporary diffuse muscle pain. Chronic conditions like lupus, thyroid
disease, or liver disease can cause chronic pain. –3
3. Epidemic myalgia: This is the type of myalgia that is also known as
Bornholm disease. It is muscle pain caused by a viral infection and affects
the upper abdomen and the lower chest. The pain is characterized as
spasmodic and develops suddenly. The pain is also worsening with every
movement and deep breathing causing shortness of breath to the affected
individual.
4. Fibromyalgia: It is defined as myalgia that is widespread that usually
involves the joints, muscles and the ligaments. The pain can be perceived on
both sides of the body and is described as dull and constant ache. This form
of myalgia is often aggravated by pressure applied on the affected site while
 this form is commonly associated with insomnia, osteoarthritis, lupus,
irritable bowel movements and headaches.
5. Trapezius myalgia: Trapezius myalgia is myalgia that involves the muscle
of the neck and is triggered by a problem with the trapezius muscle. The pain
is described as long-lasting and is particularly reactive to stressful situations
and repetitive work tasks. This form of myalgia is more common in women
who are working for longer hours in front of the computer.
6. Polymyalgia rheumatica: Polymyalgia rheumatica is a type of myalgia that
involves several muscles. It is an anti-inflammatory disorder that usually
affects older people and rarely occurs in individual below the age of 50
years. The pain is often associated with stiffness and inflammation and
occurs in the muscle of the neck, shoulders, upper arms, hips and the
buttocks. –4

Pathophysiology:
 The pain arises from the activation of nociceptors (pain receptors) in muscle
tissue, which can be triggered by mechanical stress, chemical irritants, or
inflammation.

Research indicates that musculoskeletal pain can be driven by the

stimulation of Aδ and C-fibers through mechanical distortion, local acidosis
around nociceptors, and increased bone medullary pressure. –5

Signs and symptoms:

Depending on its causes, muscle pain can be mild or severe and, in some cases,
debilitating. Pain is the hallmark symptom of many chronic conditions. These
symptoms can vary depending on the underlying causes or illness.

Symptoms of myalgia include:

 Fever or chills if an infection causes your pain.
 Joint pain or weakness
 Fatigue or feelings of being overtired
 Depression
 Tenderness
 Swelling
 Redness
These signs are associated with most chronic pain conditions. Muscle pain may
be localized or widespread. It can be dull or sharp, mild, or even severe. With
myalgia, the pain can be different and may last a few minutes or continue for
hours. The intensity or duration of your pain will depend on the varying factors
causing it.
Performing your daily activities becomes a challenge with myalgia if you suffer
from these symptoms, as they limit your movement. Recurring or persistent
pain makes it tough for you to focus on the tasks and affects your life to a large
extent.
---6

Diagnosis:

Myalgia itself is a symptom, not a diagnosis. The diagnosis process is directed

toward finding an underlying condition that may have triggered the onset of
muscle pain.

Getting to a diagnosis may include several steps:

 Medical history: The process involves reviewing a complete history of

injuries and illnesses you have/had with your healthcare provider. All
medications you are currently taking are covered as well.
 Physical examination: Evaluates the area of pain, muscle tone, strength,
and stiffness. It also includes an observation of gait (manner of walking)
and posture.
 Blood tests: Might show changes consistent with muscle damage,
inflammation, or some underlying conditions.
 Imaging: Including X-rays and magnetic resonance image(MRI) scans,
can be used to diagnose and rule out some causes of myalgia.
Condition-Specific Testing:

Depending on the condition a healthcare provider may suspect, they can order
or perform additional diagnostic testing.

For example, specific blood work is done to identify autoimmune diseases,

including testing for certain antibodies and genes.

Nerve condition studies can determine whether the nerves supplying the
muscles are functioning normally. This could be used to diagnose myositis,
which causes inflammation and degeneration of muscle tissue.

Some muscle conditions, such as fibromyalgia, cannot easily be confirmed or

ruled out with blood work or imaging. In this instance, your healthcare provider
will rely on your symptoms and the ruling out of other conditions to reach a
diagnosis. –7

Treatment:

Treatment for myalgia depends on the cause and whether you have acute or
chronic pain.

At-home treatment can often provide some relief for muscle pain. For pain that's
chronic or accompanied by other symptoms, physical therapy or medications
may be recommended.
Acute Myalgia Treatments

Cases of short-term myalgia often respond well to home remedies. Some things
you can do to relieve acute muscle pain include:

 Resting the achy area

 Taking over the counter (OTC) pain relievers such as Advil
(ibuprofen) or Tylenol (acetaminophen)
 Alternating between ice and heat to reduce swelling and relieve pain.
 Gently stretching muscles
 Avoiding high-impact activity until the pain goes away.
 Doing stress relief exercises, such as yoga and meditation, to relieve
muscle tension

Chronic Myalgia Treatments:

Physical therapy is the most common treatment for chronic myalgia. It can
increase flexibility in sore muscles and help strengthen the surrounding tissues.
A therapist can also help you find ways to manage stress and focus
on ergonomics on the job and at home. Ergonomics can improve your
workspace and environment to minimize the risk of injury or harm.
In addition to physical therapy, your healthcare provider might suggest OTC
pain relievers or prescribe drugs to help manage your pain. Pain medications
and anti-inflammatory drugs are sometimes directly injected into a sore area to
decrease pain.
Fibromyalgia sometimes improves with prescription medicines. These can
include anti-seizure drugs Lyrica(pregabalin) and anti-depressants like
Cymbalta(duloxetine), which modify the body’s chemical responses to pain.
Autoimmune disease cause excessive systemic (whole-body) inflammation.
Treatment depends on the condition but may include medications such as
corticosteroids, which can reduce inflammation. –8
 1. https://doi.org/10.1016/j.berh.2019.101433
2. https://my.clevelandclinic.org
3. https://www.health.com/myalgia-8636228#toc-types-of-myalgia
4. https://pmc.ncbi.nlm.nih.gov/articles/PMC7934019/
#:~:text=Discussion,and%20increased%20bone%20medullary
%20pressure.
5. Myalgia - Types, Symptoms, Causes, Treatment and Diagnosis
6. https://redefinehealthcare.com/what-is-myalgia-causes-symptoms-and-
treatments/
7. https://www.verywellhealth.com/myalgia-overview-
4584594
8. https://www.verywellhealth.com/myalgia-overview-
4584594

TREATMENT MODELS:

MODEL-1:
Animals:
Forty male Wistar rats, weighing 200–220 g, were acquired from the Modern
Veterinary Office for Laboratory Animals, Giza, Egypt. Male rats were utilized
in this study to examine the effects of MOD without being influenced by the
female rats' hormones or estrous cycle, especially that male and female rats
exhibit FMS following RES administration in a comparable manner (Nagakura
et al. 2009). Rats were kept under controlled room temperature, humidity, and a
light/dark cycle of 12/12 h. They were allowed free access to food and water.
The investigation complies with the Guide for Care and Use of Laboratory
Animals issued by the US National Institutes of Health (NIH Publication No.
85–23, revised 2011), following the ARRIVE guidelines. All the experiment
steps were approved by the Ethics Committee for Animal Experimentation at
the Faculty of Pharmacy, Cairo University, Egypt (PT: 2823).
Drugs and Chemicals:
Reserpine, MOD, and HAL were purchased from Sigma-Aldrich (St. Louis,
MO, USA). Reserpine was dissolved in glacial acetic acid and diluted to a final
concentration of 1 mg/mL of 0.5% acetic acid with distilled water. Modafinil
and HAL were dissolved in saline. Other chemicals used in this study were of
high analytical grade.
Reserpine Administration:
To induce FMS, each rat was injected subcutaneously with RES (1 mg/kg) daily
for three consecutive days to deplet the biogenic amines (Nagakura et al. 2009).
Experimental Design:
As shown in Fig. 1, rats were arbitrarily allocated to four groups (n = 10). Group
I (Normal): rats received 0.5% glacial acetic acid subcutaneously and
represented the control group. Group II (RES): rats received RES (1 mg/kg, s.c)
once daily for three consecutive days and represented the FMS group.
Following three days of RES injection, rats of group III (RES + MOD) received
MOD (100 mg/kg, p.o.) (Moreira et al. 2010), while those of group IV (RES +
MOD + HAL) received HAL (1 mg/kg, i.p.) (Vasconcelos et al. 2003) before the
administration of MOD, starting on day four and continued for 21 days. Rats
were trained daily in the last three days of the experiment on an automated five-
lane rotarod. At the termination point of the experiment, motor coordination was
assessed using the rotarod test, while thermal allodynia/hyperalgesia and
mechanical hyperalgesia were monitored through cold immersion, hot plate, and
Randall-Sellito tests, respectively. Furthermore, the influence of FMS on mood
quality was tested by a forced swimming test (FST). The order of the behavior
tests commenced with the least stressful test and concluded with the most
stressful one. Moreover, equipment were sanitized using 70% ethanol after each
rat to remove any animal cues. After behavioral testing, the animals were
sacrificed under light anesthesia using thiopental sodium (50 mg/kg, i.p.)
(Gazdhar et al. 2013), and their brains were quickly excised, washed with ice-
cold saline, and divided into two sets. The first set (n = 3) was subjected to
immediate fixation in 10% formalin for 72 h to perform histopathological
staining with hematoxylin/eosin (H&E) and toluidine blue along with
immunohistochemical analysis of activated microglia using ionized calcium-
binding adaptor molecule 1 (Iba-1) stain. The second set was weighed, and the
thalami were collected. Parts of three different thalami were used for western
blotting. The rest of the second set was homogenized at 3000 × g (4 °C for five
minutes) in ice-cold saline to prepare 10% homogenates, then centrifuged at
10,000 × g for twenty minutes to obtain the supernatants, which were stored at
−80 °C for biochemical assessment. Carcasses were frozen at −80 ºC till
incineration. Throughout the experimental work, all samples were kept
anonymous, and an independent investigator coded and decoded them.
Illustration of the experimental design timeline. RES: reserpine, MOD:
modafinil, HAL: haloperidol

Behavioural Tests:
Rotarod Performance Assessment
In this procedure, rats were placed on the automated five-lane rotarod apparatus
(Model 47750, Ugo Basile, Italy) with a fixed speed of 14 rpm for five minutes.
Training sessions were conducted three days before testing (one session per
day). The duration of the rat’s descent off the rotating rod throughout the five-
minute interval was recorded (Murai et al. 2017).
Cold Immersion Test:
The distal portion of the tail (5 cm) was submerged in a container of cold water
at 4 ± 1 °C. The duration of time each rat took to withdraw its tail from cold
water was recorded. A cut-off time of 15 s was selected to avoid tissue injury
(Jung et al. 2017).
Hot Plate Test:
Rats were positioned separately on a hot plate (Model 7280, Ugo Basile, Italy),
where its temperature was adjusted at 55 ± 1 °C. The response latency was
recorded as the time the rat takes to shake, jump off the surface, or lick the hind
paw. A cut-off time of 20 s was selected to prevent tissue injury (Kamel et
al. 2022).

Randall-Selitto Test:
Randall-Selitto assay measures withdrawal reactions caused by applying a
mechanical force that gradually increases to the mid-gastrocnemius muscle of
the rat’s hind paw. (Model 7200, Ugo Basile, Italy). A pointed cylindrical
mechanical probe was used to apply progressively growing pressure to the rat’s
hind paw’s dorsum. Rats were gently restrained, and mechanical pressure was
raised till vocalization or a withdrawal response manifested. The thresholds
were measured in grams. An arbitrary cut-off value of 250 g was applied
(Abdelkader et al. 2022).
Forced Swimming Test:
As previously described, mood disturbance was assessed using FST (Atta et
al. 2023a). In this procedure, rats were placed in a cylindrical plastic tank filled
with water that was kept at a height of 17 cm and a temperature of 23 ± 2 °C.
The immobility time during the five-minute period was recorded. Immobility
time is the absence of all movements except those needed to keep the head
above the water surface.
Histopathological Examination:
The whole brains of three animals per group were excised and fixed in 10%
neutral-buffered formalin. After 72 h, brain samples were processed using serial
grades of ethanol and then cleared in xylene. Samples were infiltrated and
embedded using Paraplast embedding media. Later, samples were sectioned to a
thickness of five μm and stained with H&E to investigate structural
abnormalities and with toluidine blue as an indicator of mast cell activation. An
independent investigator performed the histopathological and
immunohistochemical analysis blindly to obliterate any possible bias and ensure
the results' transparency.
Immunohistochemical Analysis
Microglial activation was measured immunohistochemically using Iba-1
staining. Brain Sects. (4–5 μm) were sliced on adhesive slides, deparaffinized,
and retrieved. The brain samples were incubated overnight at 4 ℃ with anti-
Iba-1 primary antibody (Cat. No. MA5-27726, ThermoFisher Scientific,
Waltham, USA) at a dilution factor of 1:1000. Then, a two-hour incubation with
HRP-labeled secondary antibody (Abcam, Cambridge, UK) was done, followed
by the addition of DAB-substrate for detection. The positive reaction was
measured as the area percentage of expression in five randomly selected, non-
overlapping fields from each sample, analyzed by CellSens dimensions
(Olympus software).

Statistical Analysis:
Data was expressed as mean ± SD. Statistical analysis was performed using a
one-way ANOVA test followed by Tukey’s as a post hoc test for multiple
comparisons using GraphPad Prism statistical software (version 9.00 for
Windows, San Diego, CA, USA). For all statistical testing, the significance
level was set at p < 0.05.
Modafinil Ameliorated Fibromyalgia Syndrome in Rats by Modulating Mast
Cells and Microglia Activation Through Dopamine/Substance
P/MRGPRX/Histamine and PI3K/p-Akt/NF-κB Signaling Pathways - PMC
MODEL -2:
Materials and Methods
Animal Treatment
90 Sprague Dawley male rats (4–5 weeks old) were housed in standard cages
located in a temperature-controlled animal facility (+20 °C) with a 12-h/12-h
light-dark cycle for a period up to 3 months. Before the beginning of the
treatment with reserpine or melatonin, rats were left housed in the animal
facility for at least 1 week. The RIM animal model is based on the hypothesis
that dysfunction of biogenic amine-mediated control in the central nervous
system (CNS) leads to a disease condition mimicking FM [34,63,64]. In fact,
reserpine is an indole alkaloid that depletes catecholamine and so blocks
irreversibly the vesicular monoamine transport, causing a marked reduction in
the amount of dopamine, norepinephrine and serotonin in various brain regions
inducing, in turn, muscle hyperalgesia and tactile allodynia which persist for
one week or longer and increases immobility time, an indicator of pain and
depression [65]. In the present study, reserpine was injected subcutaneously into
the back of rats once a day for 3 consecutive days at a final dose of 1 mg/kg
body weight; it was dissolved in 0.5% glacial acetic acid [63,64,66]. Since
reserpine treatment may cause a significant decrease in food consumption,
during the treatment food pellets was placed directly in the cages, so the RIM
experimental animals could feed with less difficulty.
The treatment with melatonin (Melapure™ kindly provided by Flamma S.p.A.,
Chignolo d’Isola, Italy), in combination or not with reserpine, was administered
in two different dosages and three different duration of treatments: melatonin
was administrated orally for three days (simultaneously to the treatment of
reserpine), or for one month or for two months at a final dose of 2.5 mg/kg body
weight for day [67] or at a final dose of 5 mg/kg body weight for day [68].
Powdered pure melatonin was given after being dissolved in 1% of ethanol and
then in drinking tap water. In addition to the groups identified above, in the
current study were also assessed rats without any treatment (control), rats
treated with reserpine and then with only tap water for one month or two
months, rats treated for three days with subcutaneous injection of 0.5% glacial
acetic acid (vehicle of treatment with reserpine) and rats treated orally with 1%
ethanol dissolved in drinking water for one month or two months (vehicles of
treatment with melatonin).
The animals of all experimental groups were monitored for weight gain, food
consumption and spontaneous motor activity. At the end of treatments period,
the animals were killed by decapitation and both gastrocnemius muscles were
carefully removed, weight (normalized to body weight) and processed for
morphometric, ultrastructural, sulfydryl group (SH) level and
immunofluorescence analyses.
Assessment of Voluntary Locomotor Activity:
The present study used a non-reflexive measures of locomotor activity that
require voluntary decision and integrations of multiple CNS centers. The
running wheel is of particular interest as a motor test in experimental animals
because the locomotion is not forced and potentially reflects whether the
activity is painful [69,70]. Voluntary locomotor activity was assessed in
polycarbonate cages with free access to stainless steel activity wheels (Bioseb,
In Vivo Research Instruments, Vitrolles, France). The wheel (diameter 23 cm;
width 5 cm) could be turned in both direction and it is connected to an analyzer
that automatically recorded the running activity. The animals had food and
water available ad libitum. In this study we evaluated the distance travelled
(expressed in meters) and the number of spontaneous accesses to the wheel
during 1 h of evaluation session for each animal. No experimenters were present
in the room during the recording period. Rats were habituated in an individual
activity cage for three sessions over at least three days [33]. A baseline
measurement was recorded one day after the last habituation. The rats that
refused to run in the wheel during the baseline measurement were discarded
from further evaluation (representing 2–4% of the animals tested).
All the protocols were approved by the Animal Care and Use Committee
(OPBA) of the University of Brescia (Brescia, Italy) and by the Italian Ministry
of Health (558/2015-PR-22/06/2015) and comply the commonly-accepted
“2Rs” indication.

Total Thiol Evaluation

The total thiol (TSH) levels of gastrocnemius samples were evaluated as
previously described by Oliveira and colleagues [71,72]. Briefly, 200 µL of
proteic supernatant fraction were precipitated with 200 µL of 4% trichloroacetic
acid (v/v) by centrifugation (1050× g for 10 min). Then, the colorimetric
analyses were carried out in 1 M phosphate-buffered, pH 7.4. A curve using
glutathione as standard was constructed to calculate the total TSH of each
sample.
Morphometrical Analysis
Gastrocnemius samples were fixed in 4% buffered paraformaldehyde for 24 h,
dehydrated in progressive ethanol solutions, xylene and embedded in paraffin
wax, following the standard procedures. Subsequently, 7 mm-thick paraffin
sections were cut with a microtome and so the serial paraffin sections were
dewaxed in xylene, rehydrated through decreasing scale of ethanol and stained
with haematoxylin-eosin, following standard protocol. Then the sections were
observed with an optical light microscope (Olympus, Deutschland, Germany) at
the final magnification of 200×. Digital images of gastrocnemius were captured
and the Feret’s diameter (expressed in µm) of 50 myotubes for each animal
muscle was determined using an image analyser (Image Pro Premier 9.1, Media
Cybernetics, Rockville, MD, USA) by two observers blinded to the treatment,
whose evaluation was assumed to be correct if the values were not significantly
different. In case of dispute concerning interpretation, the case was reconsidered
to reach an agreement [73,74].
Ultrastructural Transmission Electron Microscopy Evaluation
A piece of gastrocnemius muscle of each rat was treated for ultrastructural
analysis [74]. Briefly skeletal muscle tissue was fixed by immersion in 2.5%
glutaraldehyde in cacodilate buffer 0.1 M (pH 7.4) for 3 h at +4 °C and
postfixed in 2% osmium tetroxide in cacodilate buffer for 1 h at +4 °C.
Dehydration process was performed in increasing ethanol concentrations and
propylene oxide, then the samples were embedded in Araldite-Epon resin.
Semithin sections (1 µm-thick) were collected at an UltraCut E ultramicrotome
stained by toluidine blue and observed at a light microscope (Olympus,
Deutschland, Germany) to assess the morphological structure of the skeletal
muscle. Subsequently, from representative blocks, 70–80 nm-thick ultrathin
sections were obtained using a diamond knife, collected on formvar coated
copper grids, double stained with uranyl acetate and lead citrate and observed
under a transmission electron microscopy (Tecnai G2 Spirit) at 80 kV.

Immunofluorescence Evaluations
Serial paraffin sections were dewaxed in xylene, rehydrated through decreasing
scale of ethanol and then washed with phosphate buffer solution 1× (PBS 1×).
The blocking step was performed by incubating gastrocnemius sections with
specific serum (diluted 1:50 in PBS 1×) for 1 h in a humid chamber.
Subsequently, the sections were incubated 1 h at room temperature and then
overnight at 4 °C in a humid chamber with the following primary antibodies:
rabbit polyclonal antibody against superoxide dismutase 1 (SOD1, diluted
1:300, Santa Cruz Biotechnology Inc., Dallas, TX, USA), goat polyclonal
antibody against catalase (CAT, diluted 1:200, Santa Cruz Biotechnology Inc.,
Dallas, TX, USA), rabbit polyclonal antibody against sirtuin3 (SIRT3, diluted
1:200, Santa Cruz Biotechnology Inc., Dallas, TX, USA), mouse monoclonal
antibody against cyclooxygenase 1 (COX-1, diluted 1:100; Cayman Chemical,
Ann Arbor, MI, USA) and rabbit polyclonal antibody against Nod-like receptor
protein 3 antibody against (NLRP3, diluted 1:650, Novus Biologicals, Milano,
Italy). Sections were then washed in PBS 1× and labelled using specific
conjugated secondary antibodies (diluted 1:200 in PBS 1×; Invitrogen, Paisley,
UK): goat anti-rabbit Alexa Fluor-488, goat anti-rabbit Alexa Fluor 546, rabbit
anti-goat Alexa Fluor 546 and goat anti-mouse Alexa Fluor 546. Finally, the
samples were counterstained with 4′,6-diamidino-2-phenylindole (DAPI) for 8
min [75,76]. The samples were mounted with fluorescent medium and observed
with a fluorescent microscope (i50 Eclipse, Nikon, Düsseldorf, Germany) at
final magnification of 400× [71]. Sections without primary antibody and in the
presence of isotype-matched IgG served as negative immunofluorescent
controls.
Twenty random fields, each with an area of 0.04 mm 2, from a total of five
sections for each rat’s gastrocnemius were analyzed and the immunostaining for
each primary antibody were calculated using an image analyzer (Image Pro
Premier 9.1, MediaCybernetics, Rockville, MD, USA). Two blinded
investigators, whose evaluation was assumed to be correct if the values were not
significantly different, made the evaluation of positive immunostaining. In the
case of dispute concerning interpretation, the case was reconsidered to reach an
agreement [73,74].
Statistical Analysis
The data obtained in the current study were presented as means ± SD. Statistical
analyses were performed using a two-way analysis of variance test corrected by
Bonferroni, evaluating both dose and duration of treatments as different
variable. Differences among groups were considered statistically significant
at p ≤ 0.05.
Oral Supplementation of Melatonin Protects against Fibromyalgia-Related
Skeletal Muscle Alterations in Reserpine-Induced Myalgia Rats

MODEL -3:
Objectives:
The main study objective was to examine the role of pregabalin in depressive
symptomatology comorbid to chronic widespread pain using a reserpine-
induced myalgia model.
Study Design:
 A randomized, controlled, animal study. Setting: Research and data analyses
were performed at the GESADA laboratory, Department of Human Anatomy
and Embryology, University of Valencia, Spain.
Methods:
Forty-six Sprague-Dawley male rats were used. Acute chronic pregabalin
administration was tested for depressive-like behaviours (Forced Swimming and
Novelty Suppressed Feeding Tests) and for alteration of pain thresholds (tactile
allodynia, Electronic Von Frey test; and mechanical hyperalgesia, Randall and
Selitto test). The same procedures were followed with duloxetine as a positive
control.
Forty-six male Sprague-Dawley rats (Janvier Labs, Saint Berthevin, France) of
consistent weight (300–400 g) were used. Water and food were given ad libitum
(not to the animals used for the Novelty Suppressed-Feeding Test). After
experimental procedures, animals were euthanized by a sodium pentobarbital
overdose (120 mg/kg). All the experiments were approved by the ethics
committee of the University of Valencia (Procedure numbers:
A1359998202530; A1385127985666) and in accordance with International
Association for the Study of Pain (IASP) ethical guidelines.
Reserpinization:
Reserpine was administered after a 15-minute habituation process by a single
daily subcutaneous injection of 1 mg/kg on 3 consecutive days. Reserpine
(Sigma-Aldrich, crystallized, ≥ 99.0%; high performance liquid
chromatography [HPLC]) (Sigma-Aldrich AG, Industriestrasse, Buchs,
Switzerland) was diluted in glacial acetic acid to a final concentration of 0.5%
ace tic acid in distilled water (vehicle) (17). All the animals received reserpine.

Drug Regime
Animals were randomly allocated to the experimental groups. On the one hand,
a group of 16 animals orally received PGB (Lyrica; Pfizer, Madrid, Spain) at a
single daily dose of 30 mg/kg. A group of 16 animals were orally given
duloxetine (DLX, Cymbalta; Eli Lilly and Company, Fresno, CA) at a single
daily dose of 30 mg/kg as an antidepressant control. A group of 14 animals were
orally given tap water as a vehicle at a single daily dose. These treatments were
maintained for 15 days. It has been established that acute treatment is a single
30 mg/kg oral dose, whereas chronic treatment is a 15-day treatment of the drug
at a single daily dose of 30 mg/kg.
Depressive-Like Behaviours Measurement:
Forced Swimming Test:
The modified Forced Swimming Test (FST) was per formed as previously
described by Slattery and Cryan (19). On days 4 and 5 after the last reserpine
dose, animals were exposed to the FST in 2 stages, a pretest and test,
respectively. In the first stage (pretest), rats were individually placed inside a
40-cm depth x 20 cm-diameter methacrylate cylinder filled with water (25ºC) at
a height of 30 cm for 15 minutes. Then rats were administered a single dose of
drug or vehicle. After 24 hours (test), rats were administered a second single
dose of drug or vehicle and were exposed to the same test conditions for 5
minutes. This test involves scoring active (swimming and climbing) and passive
(immobility) behaviours while forcing rodents to swim in a cylinder from which
there is no escape. Immobility behaviour reflects failure to persist with directed
escape at tempts (learned helplessness). Therefore, this behaviour is related to
clinical depression. It has been proposed that swimming behaviour is mediated
by serotonergic action, whereas climbing behaviour is norepinephrine mediated,
and an increase in these behaviours spells a direct decrease in immobility (19).
FST has become the most widely used model to evaluate the antidepressant
effect of new-generation drugs in animals, and it has also been shown to be
sensitive to both the acute effect of antidepressant treatments and depressive
states induced by various factors. The sample size (N) for this procedure was 24
male rats: 8 treated with PGB, 9 with DLX, and 7 with the vehicle.
Novelty-Suppressed Feeding Test:
The whole procedure was performed as previously described by Blasco-Serra et
al (20) in 2017. The open field was 100 x 100 x 40 cm, and the center of the test
was well-lit (1,000 lumens) with 800 lumens intensity in the periphery, whereas
the surrounding environment remained in the dark. A Petri dish containing a
small amount of high palatability food was placed in the center of the field on a
white platform. The whole procedure was video-recorded. Food deprivation was
carried out by a 3-phase food deprivation method (20). The Novelty-Suppressed
Feeding Test (NSFT) is based on the phenomenon of hyponeophagy, which is
inhibition of intake produced by exposure to a novelty, for example, an
unknown environment or new food. In this paradigm, rodents face a conflict
between avoiding an unknown and highly lit environment (due to their innate
fear of new open spaces) and their need to eat. Thus latency to eat is measured
as depressive-like behavior. The use of NSFT as a validated depressive-like
behavior test has increased in the last decade (20). The sample size (N) for this
procedure was 22 male rats: 8 treated with PGB, 7 with DLX, and 7 with the
vehicle.
Pain Thresholds Measurements:
Pain thresholds were measured by an Electronic Von Frey test (EVF) for tactile
allodynia and the Randall and Selitto test (R&S) for mechanical hyperalgesia.
The whole procedure was performed as previously described (21). Briefly, the
EVF animals were placed on an elevated grid floor inside a 20-cm diameter and
30 cm high clear methacrylate cylinder. An electronic Von Frey Tester (IITC
Inc., Woodland Hills, CA) was used with an attached 0.8-mm diameter rigid tip.
Pain thresholds were acquired by applying increasing pressure to the right hind
paw sole until the animal withdrew its limb. To perform the R&S, the center
section of the animal’s body was held with an elevated fabric support, and hind
paws were slipped through holes in the fabric. Increasing pressure was applied
to the midsection of the gastrocnemius muscle of the right hind paw using an
adapted R&S Tester (IITC Inc., Woodland Hills, CA, USA) until the animal
withdrew its paw. Three measurements were taken by applying a 30-second
inter stimulus range. Data were obtained on treatment days 1, 3, 5, 7, 9, 11, 13,
and 15. Pain threshold measures were taken in all the study animals.
Statistics:
Data were analysed and represented on graphs using SPSS Version 22 (IBM
Corporation, Armonk, NY). They were expressed as the mean ± standard error
mean and were analysed for normality (Kolmogorov–Smirnov test) and
variance homogeneity (Levene test). A value of P < 0.05 was considered
statistically significant for all the comparisons. The most adequate statistical test
was used for each experimental procedure.
https://www.painphysicianjournal.com/current/pdf?article=NzE1NA%3D
%3D&journal=131

TREATMENT REGIMEN:
NONPHARMACOLOGIC TREATMENT
Patient education is important for patients with fibromyalgia and improves
outcomes.27,28 Educating patients about the diagnosis, pathophysiology, and
clinical manifestations can reassure patients, improve patient satisfaction,
decrease symptoms, and reduce health care utilization. 6,12,27 Clinicians can refer
patients to websites such as the University of Michigan's Pain Guide and the
National Fibromyalgia Association. Combining self-management strategies with
exercise is beneficial.
Nonpharmacologic Treatments for Fibromyalgia

There is moderate-quality evidence that exercise (i.e., aerobic, resistance,

stretching, or a combination) produces small improvements in quality of life,
pain, and physical function in patients with fibromyalgia. 33,39 The strongest
evidence exists for aerobic exercise of moderate intensity. In addition to
improvements in pain and function, exercise can decrease fatigue and improve
sleep quality.32 Exercise prescriptions should start at a low intensity and low
frequency and gradually increase in intensity and frequency.
CBT teaches patients how to change negative thoughts and behaviors, and helps
promote skills to improve chronic pain, fatigue, and poor sleep. Options include
traditional CBT, acceptance-based cognitive therapies, and operant
therapy. Three systematic reviews demonstrated moderate-quality evidence that
patients with fibromyalgia treated with CBT experience modest improvements
in pain and disability in the short and medium term.32,34,35
As part of a multidisciplinary treatment approach, patients with fibromyalgia
may pursue complementary and alternative medicine options such as
acupuncture, massage, meditation, nutritional supplements, and herbs. 27,28 Most
complementary and alternative medicine options have not been extensively
studied, and there is no consistently high-quality evidence to support them. 40 A
systematic review found that yoga, Pilates, and tai chi improved function and
reduced pain.36 One randomized trial found that performing tai chi for one hour
twice per week for 12 to 24 weeks led to moderate symptomatic improvement
in pain and function.37 Meditation and mindfulness techniques are also
promising options.40 A Cochrane review concluded that acupuncture could
improve short-term pain and stiffness compared with usual care, but it is not
consistently better than sham acupuncture. 41 Manual therapy, specifically
myofascial release, may decrease symptoms and improve the quality of life in
patients with fibromyalgia.38 Manual therapy acts on the ascending nociceptive
pathways involved in the process of central sensitization. 38 A small trial
suggested that patient self-myofascial release improves pain and quality of
life.42
There are limited studies showing uncertain benefits of cannabinoids for the
treatment of fibromyalgia, although use is becoming more common. 40 Other
possible treatments that have not been well studied in patients with fibromyalgia
include transcutaneous electrical nerve stimulation units, thermal therapies,
hyperbaric oxygen, laser and phototherapy, transdermal magnesium, and
vibroacoustic and rhythmic sensory stimulation.13,40
PHARMACOLOGIC TREATMENT
Because nonpharmacologic measures often do not provide adequate symptom
relief, medications are also used to treat the most problematic symptoms.
Potentially useful medication classes include tricyclic antidepressants,
serotonin-norepinephrine reuptake inhibitors, and gabapentinoids. 28 A single
medication should be started at a low dosage, slowly increased to the
recommended dosage, and then continued for at least three months to ensure an
adequate trial, unless adverse effects are intolerable. If a satisfactory clinical
response is achieved, treatment should be continued for at least 12 months. In
patients who do not respond to an adequate trial of medication, clinicians should
assess medication adherence, confirm that nonpharmacologic management has
been maximized, and exclude other conditions that may need additional
intervention.43 Few studies compare monotherapy with combination
pharmacotherapy for fibromyalgia; however, combinations are sometimes
needed.44,45 Duloxetine (Cymbalta), milnacipran (Savella), and pregabalin
(Lyrica) are approved by the U.S. Food and Drug Administration for the
treatment of fibromyalgia in the United States; however, several other
medications are beneficial
Medications for Fibromyalgia

Tricyclic antidepressant medications improve several symptoms of

fibromyalgia. A systematic review of amitriptyline demonstrated reduced pain,
improved sleep, and improved patient satisfaction after six to eight
weeks.47 Other tricyclic agents such as nortriptyline have fewer adverse effects
and may be better tolerated; however, there are few studies evaluating their use
in fibromyalgia.53 For patients unable to tolerate amitriptyline, cyclobenzaprine,
a muscle relaxant that is a tricyclic derivative, can be a reasonable option. A
meta-analysis of five randomized trials found that cyclobenzaprine produced
modest pain reduction without affecting fatigue or sleep. 48 There is insufficient
evidence for other muscle relaxants in the treatment of fibromyalgia.
A Cochrane review found low-quality evidence that duloxetine and milnacipran
improved pain relief.50 A systematic review showed that duloxetine produced
greater pain relief compared with placebo and other antidepressants such as
sertraline, paroxetine, fluoxetine, and bupropion.49 Milnacipran improves pain,
fatigue, and cognition compared with placebo over three months. 28,51,54 Other
serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, have not
been examined as extensively. A Cochrane review did not find evidence that
selective serotonin reuptake inhibitors helped treat pain, fatigue, or sleep
problems in fibromyalgia, although they can effectively treat depression. 55
Gabapentinoids may be helpful in fibromyalgia with severe sleep disturbances.
Pregabalin reduces pain by up to 50% with a number needed to treat of 10, and
improves sleep, fatigue, and quality of life. 52,56 The evidence is insufficient to
determine if gabapentin is effective for fibromyalgia.57
There is also insufficient evidence to recommend the routine use of opioids in
fibromyalgia. Opioids are not recommended for fibromyalgia because they do
not target the processes involved in centralized sensitization, and their use may
cause additional harm because of the risk of dependence, misuse, worsening of
hyperalgesia, and other significant adverse effects. 28,58 A Cochrane review
concluded that nonsteroidal anti-inflammatory medications are not superior to
placebo for pain in fibromyalgia and can have significant adverse effects. 59 The
data are insufficient to determine the benefit of acetaminophen for pain in
fibromyalgia.28
Fibromyalgia: Diagnosis and Management | AAFP

Treatment
In general, treatments for fibromyalgia include both medicine and other
techniques. The goal is to lessen your symptoms and improve your overall
health. No one treatment works for all symptoms, so it can help to try a few.

Medicines
Medicines can help ease the pain of fibromyalgia and improve sleep. Common
choices include:
  Pain relievers. Nonprescription pain relievers such as acetaminophen
(Tylenol, others), ibuprofen (Advil, Motrin IB, others) or naproxen
sodium (Aleve, others) may be helpful. Your doctor may recommend you
take them along with other medicines. Opioid medicines are not
recommended. They can lead to side effects, dependence and pain that
gets worse over time.
 Antidepressants. These medicines may help even if you don't have
depression with fibromyalgia. Duloxetine (Cymbalta) and milnacipran
(Savella) may help ease fibromyalgia pain and fatigue. Your doctor may
prescribe amitriptyline or the muscle relaxant cyclobenzaprine to help
with pain or sleep.
 Anti-seizure medicines. Epilepsy medicines often help ease some types
of pain. Pregabalin (Lyrica) is used as a fibromyalgia treatment. And
gabapentin (Gralise, Neurontin) sometimes helps ease fibromyalgia
symptoms.
Other therapies
Other treatments can help reduce the effect that fibromyalgia has on your body
and your life. Examples include:
 Physical therapy. A physical therapist can teach you exercises to boost
your strength, flexibility and stamina. Water-based exercises might be
especially helpful.
 Occupational therapy. An occupational therapist can help you make
changes to your work area or the way you do certain tasks. The changes
cause less stress on your body.
 Counseling. Talking with a counselor can help strengthen your belief in
your abilities. It also can teach you ways to deal with stressful situations.
It can be especially helpful to see a counselor who is trained in cognitive
behavioral therapy.
Fibromyalgia - Diagnosis & treatment - Mayo Clinic

The purpose of the present review is to provide an updated perspective of the

pharmacological alternatives available for the treatment of FMS. Table
1 summarizes the current clinical evidence regarding effective treatments for
FMS.
Drug Mechanism Effects on disease Quality of evidence
symptoms

Amitriptyline Tricyclic Improvement in pain, Several randomized

antidepressant fatigue, and sleep controlled trials,
abnormalities. guideline recommended
[8–10]

Duloxetine Serotonin- Improvement in pain and Several randomized

noradrenaline depression. controlled trials, meta-
reuptake inhibitor analysis [11, 12]

Milnacipran Serotonin- Improvement in pain and Several randomized

noradrenaline fatigue. controlled trials, meta-
reuptake inhibitor analysis [11, 12]

Reboxetine Selective Improvement in pain. Mostly case reports [13]

noradrenaline
reuptake inhibitor

Esreboxetine Selective Improvement in pain and Randomized controlled

noradrenaline fatigue. trial [14]
reuptake inhibitor

Citalopram, Selective serotonin Improvement in pain and Randomized controlled

escitalopram, reuptake inhibitors depression. trials, meta-analysis,
fluoxetine, guideline recommended
paroxetine [8–10, 12, 15, 16]

Cyclobenzaprine 5-HT2 receptor Moderately improves Randomized controlled

blocker sleep, mild improvement trial [17–19]
in pain. Development
stopped due to low
efficacy.

Pregabalin, Gabapentinoid Improvement in pain, Randomized controlled

gabapentin fatigue, and sleep trials, guideline
abnormalities. recommended [8–
10, 15, 20–22]

Lacosamide Gabapentinoid Effective in animal Randomized controlled

Drug Mechanism Effects on disease Quality of evidence
symptoms

models. No clear evidence trial [23]

in FMS.

Naltrexone Opioid receptor Improvement in pain in Randomized controlled

antagonist, TLR-4 depression. trial [24, 25]
antagonist

Tramadol Opioid with SNRI Improvement in pain. Guideline recommended

activity Mostly for severe [6]
symptoms and short
duration, see text.

Nabilone Cannabinoid Improvement in pain and Randomized controlled

anxiety. Conflicting trials, meta-analysis [26–
results, see text. 28]

Dronabinol Cannabinoid Improvement in pain and Randomized controlled

depression. Conflicting trials, meta-analysis [29]
results, see text.

Ketamine NMDA antagonist Improvement in referred Clinical trial, animal

pain. models [30]

Memantine NMDA antagonist Improvement in pain, Randomized controlled

conflicting evidence, see trials, meta-analysis [31–
text. 34]

NYX-2925 NMDA receptor Improvement in pain. Animal models, pending

modulator clinical trials in humans
[35, 36]

Overview of effective pharmacological treatments for FM discussed in this

review.
2. FMS Pathophysiology
Assumed to be of neurogenic origin, both hyperalgesia and allodynia are usually
found [37]. However, the exact pathogenesis of FMS is still unknown. With
CNS involvement being a key element, neural oversensitization (or “central
sensitization”) is suggested to be the main pathophysiological change [37–39],
meaning the CNS interprets benign stimulations as unpleasant. This principal
was demonstrated by an increased CNS response to stimulation and decreased
conditioned pain modulation (CPM). CPM is a neural process of sensitization
modulation, which involves activation of specific neurotransmitters including
serotonin and noradrenaline. Thus, medications that modulate levels of these
neurotransmitters in the CNS have the potential to improve CPM and reduce
central sensitization [40, 41].
Other neurotransmitters, including GABA, cannabinoid receptors, substance P,
NGF, and opioid receptors participate in this complex modulation of pain
transmission [42], therefore functioning as optional therapeutic targets. There is
also evidence that glial cells may play a role in maintaining central sensitization
and contribute to chronic pain production by producing IL-6, IL-8, and other
cytokines, which are found to be at high levels in FMS patients' sera [43].
Comorbid conditions, including mood disorders, anxiety, headaches, irritable
bowel syndrome, sleep disturbances, and chronic fatigue syndrome, are found in
a large percentage of FMS patients [2, 44, 45]. Accordingly, medications which
improve sleep disorders, as well as those that improve daytime alertness, could
be useful for the management of FMS. From a neurobiological perspective,
sensory, affective, and cognitive centers within the brain interact in producing
the final pain experience. Indeed, increased connectivity between different brain
areas is a known phenomenon in FMS [46]. Increased connectivity has also
been demonstrated between various other areas participating in pain processing,
alertness, and cognition [46]. By perceiving brain function in general, and
specifically the pathophysiology of FMS, new targets for medication
development for the syndrome can be found [47].
Pharmacotherapeutic Agents Used for FMS
Only three drugs, pregabalin (a gabapentinoid that acts by blocking calcium
channels), duloxetine, and milnacipran (both are serotonin-noradrenaline
reuptake inhibitors), have been approved for use in the treatment of FMS by the
FDA. However, other types of antidepressants are used for the treatment of
various chronic pain syndromes, including FMS, with varying levels of
evidence regarding their efficacy.
Tricyclic Antidepressants (TCAs)
Although different TCAs have been used in the treatment of chronic pain, the
largest body of evidence on therapeutic utility in FMS exists regarding
amitriptyline. It is recommended by all various clinical practice guidelines [8–
10, 15].
Amitriptyline was found to reduce the FIQ questionnaire results from baseline
to endpoint by over 30% [48–50]. It was found to improve pain, fatigue, sleep,
and quality of life [11].
Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)
Various clinical trials published evaluating duloxetine showed a significant
improvement in FMS-associated pain and depressive symptoms [11]. The vast
majority of clinical trials evaluating milnacipran have shown a significant
improvement in pain levels, in addition to fatigue. Results regarding
improvement in psychological effects of FMS (namely, depression) are more
controversial [11].
A meta-analysis reviewing five different studies regarding duloxetine and five
different studies regarding and milnacipran showed that these drugs had positive
effects on pain and patient-perceived clinical improvement [12].
Selective noradrenaline reuptake inhibitors (NRIs), such as reboxetine and its
enantiomer esreboxetine, were also suggested as possible treatments for FMS,
while the body of evidence regarding the efficacy of reboxetine is rather
sporadic and is based mostly on case reports [13], esreboxetine was shown to
reduce pain, fatigue, and improve overall quality of life in a randomized,
double-blind, placebo-controlled trial [14]. No other trials regarding it were
published.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Among the SSRIs investigated for the treatment of FMS were citalopram,
escitalopram, fluoxetine, paroxetine, and sertraline. Despite the theoretical
assumption, that the combined inhibition of serotonin and noradrenaline is more
efficacious than selective serotonin augmentation vis-à-vis the inhibition of pain
[51], the use of this class of drugs is recommended in practice guidelines [8–
10, 15]. According to the results of a meta-analysis performed by Häuser et al.,
SSRIs improve pain, depression, and overall quality of life, but to a small
extent. The effect size for improvement in sleep disorders was found to be
nonsubstantial [16].
Cyclobenzaprine
Cyclobenzaprine is a 5-HT2 receptor blocker, which acts on a subfamily of
serotonin receptors, and causes muscle relaxation. It resembles amitriptyline in
structure and is commonly used in FMS patients. A systematic review of the
literature reported that it has a moderate benefit in improving sleep disturbances
and only a mild improvement in pain [17]. Moldofsky et al. have previously
shown that bedtime very low doses of cyclobenzaprine were shown to
significantly improve pain and sleep in patients with a specific sleep
architecture [18]. A sublingual formulation of low-dose cyclobenzaprine (TNX-
102SL, 2.8 mg) has been reported to improve nonrestorative sleep in FMS
patients [19]; however, this formulation has subsequently failed to reach
primary pain-related endpoints, and its development has been stopped.
Mirtazapine
Mirtazapine is an atypical antidepressant with noradrenergic and specific
serotonergic activity. It is not licensed for use in FMS. A meta-analysis held by
Welsch et al. did not find the drug effective for pain relief in FMS nor for any
other associated mental or functional symptoms related to it (depression, sleep
problems, fatigue, etc.) [52].
Gabapentin
The two main members of this family of drugs, pregabalin and gabapentin, act
by binding to the alpha2delta subunit of voltage-gated calcium channels in the
CNS. Originally used as anticonvulsants, they are currently mainly used for the
treatment of chronic pain [11]. Pregabalin has FDA approval for the treatment
of FMS, and its use is recommended in guidelines [8–10, 15]. A series of
placebo-controlled clinical trials showed pregabalin to improve pain and sleep
disturbances. However, compared to placebo, it was not found to significantly
improve complaints of fatigue in some trials, and none of the trials indicated
any improvement in depressive symptoms [20, 21, 53]. A meta-analysis of
randomized controlled trials regarding both pregabalin and gabapentin further
emphasized their effect in improving pain, fatigue, sleep, and overall quality of
life, in addition to their lack of effect on depressive symptoms and relatively
nonsubstantial effect on anxiety [22].
Lacosamide is another anticonvulsant that has been evaluated as a therapeutic
modality for neuropathic pain. In animal models, it effectively reduced
muscular hyperalgesia and was more effective than gabapentin and pregabalin
[54]. It was also found effective in a placebo-controlled, double-blind trial for
treating neuropathic pain [55]. Lacosamide has been tested for the treatment of
FMS in a randomized double-blind trial including 160 patients randomized for
either the drug or placebo. No significant effect was demonstrated on major
endpoints (pain, sleep, and cognitive function), and therefore, there is currently
no clear evidence regarding the efficacy of this medication in FMS [23]. A
newer gabapentinoid, mirogabalin (DS-5565) was shown to have analgesic
qualities in animal models of both central and peripheral neuropathies [56],
while approved for the treatment of peripheral neuropathy in Japan, its
development as a treatment modality for FMS in the USA and Europe was
stopped after it failed in meeting primary endpoints in phase 3 trials [57]; three
13-week randomized, double-blind studies comparing both placebo and
pregabalin to two different daily doses of mirogabalin, failed to show a
reduction in the average daily worse pain score (ADPS) in the mirogabalin arm
[58].
Kim et al. demonstrated that low-to-moderate alcohol consumption was
associated with an improvement in FMS symptoms, namely, pain level, physical
and social function, general health perception, and general quality of life. The
same association was not observed in heavy drinkers [59]. It was assumed that
the effect might be centrally mediated through ethanol enhancement of GABA
release in the CNS [60, 61].
Opioids
Endogenous descending antinociceptive activity is postulated to be reduced in
FMS. In humans, such two descending pain inhibitory pathways exist: the
noradrenaline/serotonin-mediated pathway and the opioid-mediated one [62].
Baraniuk et al. suggested an excess of endogenous opioids in FMS [63].
Following these data, Harris et al. used positron emission tomography (PET)
technology to show that the availability of µ-opioid receptors in FMS patients is
reduced in certain areas of the brain, possibly as a result of receptor
downregulation secondary to their increased levels. Reduced availability was
inversely correlated with clinical pain ratings [64]. Following these findings,
naltrexone, a competitive opioid receptor antagonist, was proposed as potential
new means of treating chronic pain. The beneficial effect of naltrexone on
fibromyalgia symptoms was shown by Youner and Mackey in a pilot study in
2009 [24], with a randomized controlled trial published in 2013, finding it to be
superior to placebo in reducing pain and associated depressive symptoms [25].
Apart from its opioid receptor antagonist activities, naltrexone also has
antagonist activity to other nonopioid receptors (toll-like receptor 4) expressed
on activated microglia cells, which are specialized population of macrophages
involved in neuroinflammatory processes. Overactivation of microglia cells in
the cerebral cortex of FMS patients was recently demonstrated by Albrecht et al.
using PET [65]. Inhibition of microglial activation by naltrexone or naloxone
therefore has an anti-inflammatory effect through the decrease in production of
neurotoxic chemicals [66, 67], which is suggested to contribute to its analgesic
effect [25]. The ability to quantitatively assess microglial activation using
nuclear methods may provide researchers and clinicians with the opportunity to
use it as a biomarker for FMS activity and for measuring the effect of
naltrexone.
There is no evidence from clinical trials that opioids are effective in treating
FMS, and the EULAR guidelines discourage the use of opioid analgesics. Only
tramadol (a weak opioid with mild SNRI activity), administered alone or
together, with paracetamol is currently supported by the EULAR
recommendations and was found to reduce pain by 30%. Generally, it is
believed that only short-term use of opioids may be appropriate in carefully
selected patients, particularly those with severe FMS [6].
Dopamine Receptor Agonists
Evidence indicating involvement of dopaminergic pathways in the
pathophysiology of FMS has led to attempts to develop medications intervening
in dopaminergic metabolism [68]. With most evidence about the benefit of
dopaminergic agonists being sporadic, it is worth mentioning tergulide, which
in a randomized, double-blind placebo-controlled trial, was found to improve
FMS symptoms in a subgroup of patients with spinal stenosis (as opposed to the
comparing all tergulide-assigned patients to the placebo group, where no
significant improvement was found) [69]. Despite the EULAR
recommendations for management of FMS from 2008, recommending the
consideration of dopamine agonists [8], a meta-analysis conducted by Sommer
et al. did not find them of proven benefit [70], and hence, they are not included
in the revised 2016 EULAR recommendations [6].

Cannabinoids
There are two major active components in cannabinoids: tetrahydrocannabinol
(THC) and cannabidiol (CBD). The former is the psychoactive component,
which affects pain (as well as emotions) and works through CB1 and CB2
receptors. The latter has anti-inflammatory and analgesic traits. The THC:CBD
therefore determines the product's overall effect [71]. CB1 cannabinoid
receptors are found predominantly in the CNS and peripheral nervous system.
Their agonists act along sensory pathways as modulators of pain [72]. With
regard to the complex function of the endocannabinoid system in pain
modulation, FMS is hypothesized to be induced, among other factors, by a lack
of endocannabinoid activity [73].
The main cannabinoids studied were nabilone and dronabinol, with conflicting
results. Three randomized controlled studies have been published regarding
cannabinoid treatment for FMS to date: Fiz et al. reported a significant relief in
pain two hours after consumption [74]. Skrabek et al. reported a reduction in
pain, as well as level of anxiety, and an improved quality of life when using
nabilone in comparison with placebo [26]. Ware et al. found a moderate effect
on insomnia when using nabilone versus amitriptyline but no proven effect on
pain or general quality of life [27].
A systematic review by Walitt et al. concluded that no convincing evidence
suggests that nabilone is useful in treating people with FMS [28]. A work by
Weber et al. showed dronabinol significantly reduce pain and depressive
symptoms in FMS patients with neuropathic pain [29].
van de Donk et al. conducted a randomized, placebo-controlled trial exploring
the analgesic effect of different cannabis varieties (with different THC:CBD
contents) on fibromyalgia patients. They found that THC-containing products
increased the pain threshold, whereas CBD-containing products increased
plasma-THC levels but diminished THC analgesic effect [75]. This study
demonstrated the complex effect of cannabinoids and the endocannabinoid
system on chronic pain.
A prospective observational study recently published by Sagy et al. followed a
relatively large cohort of FMS patients (n = 367) for a period of six months. The
researchers showed a significant reduction in average pain intensity, sleep
disturbance, and depression-related symptoms [76].
Cannabinoids have been offered by the Canadian guidelines for the
management of FMS as a therapeutic option for FMS patients with prominent
sleep abnormalities [10]. However, more controlled studies are needed to clarify
the role of cannabinoids in this syndrome. Furthermore, research is called for
focusing on the effects of various cannabinoids (as well as their combinations)
on the basic neurophysiological aspects of FMS such as altered CNS
connectivity patterns.
Manipulating the endocannabinoid system is gradually emerging as another
fascinating strategy for treating pain [77]. Endocannabinoids such as
anandamide are metabolized by specific enzymes including fatty acid amide
hydrolase (FAAH) and monacylglycerol lipase (MAGL), and agents capable of
inhibiting these enzymes are being tested as novel analgesic targets [78]. Future
research into the clinical utility of endocannabinoid metabolism manipulation in
FMS is expected.
NMDA Antagonists
Glutamate is the most abundant excitatory neurotransmitter in the nervous
system. Central sensitization of pain transmission pathways is associated with
hyperexcitability of the glutamatergic system, which leads symptoms observed
in persons suffering from chronic pain [79].
The N-methyl-D-aspartate (NMDA) receptors are one of three subgroups of
glutamate receptors. Activated by a variety of agonists, including substance P
and neurokinin, it is known to be involved in the pathogenesis of central
sensitization [80], a trait for which efforts were made to develop NMDA
antagonists as therapeutic options for FMS, as well as other disorders resulting
from central sensitization.
Ketamine, an NMDA antagonist, was found to reduce muscular and referred
pain in FMS patients [30]. Memantine, another receptor antagonist, was
suggested to be useful because of its ability to reduce neurotoxicity caused by
high levels of glutamate found in different brain areas of FMS patients [31, 32].
These high glutamate levels were found to be related to the severity of FMS
symptoms [81]. A double-blind, randomized-controlled trial published in 2014
found memantine to achieve a significant reduction in pain [33], with another
hypothesis suggesting the combined use of pregabalin and memantine to
concomitantly affect voltage-gated calcium channels and NMDA receptors, as a
possible therapeutic approach [82]. A recent meta-analysis of 15 studies
regarding the benefit of memantine in treating chronic pain (either neuropathic
or FMS) concluded that the current evidence regarding memantine for chronic
pain is limited and reported an increase in dizziness as a side effect of the
medication [34].

Novel Therapeutic Approaches

NYX-2925((2S,3R)-3-hydroxy-2-((R)-5isobutyryl1oxo2,5diazaspiro[3,4]octan-
2-yl)butanamide) is a new NMDA receptor modulator which was shown by
Khan et al. to affect NMDA receptor synaptic plasticity. This finding led to the
hypothesis that it would be effective in NMDA receptor-associated CNS
disorders [83]. As demonstrated by Ghoreishi-Haack et al. NYX-2925 was
shown to induce efficient analgesia in rat models of neuropathic pain [35]. The
first in human phase I trial recently published checked the safety, tolerability,
and pharmacokinetics of the molecule in 84 healthy volunteers. NYX-2925 was
shown to be safe, well tolerated, and to cross the blood-brain barrier. These
promising findings support further clinical development of the drug as an agent
for treating chronic pain conditions, such as diabetic neuropathy and FMS [36].
Conclusions and Expert Opinion
Chronic pain in general and FMS in particular continue to be an unmet
challenge, while great progress has been made over recent years in the field of
rheumatology in controlling the broad spectrum of inflammatory and
autoimmune disorders, those clinical entities such as FMS which are centered
on pain amplification within the CNS continue to baffle both clinicians and
researchers alike due to their complexity. Thus, future breakthrough in the field
of FMS will clearly necessitate a truly eclectic and multidisciplinary approach.
Notably, while we may yet see in the future some incremental progress in the
development of novel agents from the families currently in use, e.g., novel
SNRIs or gabapentinoids, it does not seem likely that major breakthroughs will
be found in these pathways.
Current and Emerging Pharmacotherapy for Fibromyalgia - PMC