Autonomic nervous system profile in fibromyalgia patients and its modulation by exercise: a mini review

REVIEW ARTICLE

Autonomic nervous system profile in fibromyalgia patientsand its modulation by exercise: a mini reviewPoorvi Kulshreshtha1 and Kishore K. Deepak2

1Department of Physiology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India and 2Department of Physiology, All India

Institute of Medical Sciences, New Delhi, India

Summary

CorrespondenceKishore K. Deepak, Department of Physiology, All

India Institute of Medical Sciences, New Delhi

110608, India

E-mail: [email protected]

Accepted for publicationReceived 13 April 2012;

accepted 20 August 2012

Key words

adrenergic receptors; autonomic nervous system;

exercise; fibromyalgia; ischemia; pain

This review imparts an impressionistic tone to our current understanding of auto-nomic nervous system abnormalities in fibromyalgia. In the wake of symptomspresent in patients with fibromyalgia (FM), autonomic dysfunction seems plausi-ble in fibromyalgia. A popular notion is that of a relentless sympathetic hyperac-tivity and hyporeactivity based on heart rate variability (HRV) analyses andresponses to various physiological stimuli. However, some exactly opposite find-ings suggesting normal/hypersympathetic reactivity in patients with fibromyalgiado exist. This heterogeneous picture along with multiple comorbidities accountsfor the quantitative and qualitative differences in the degree of dysautonomiapresent in patients with FM. We contend that HRV changes in fibromyalgia maynot actually represent increased cardiac sympathetic tone. Normal muscle sympa-thetic nerve activity (MSNA) and normal autonomic reactivity tests in patientswith fibromyalgia suggest defective vascular end organ in fibromyalgia. Previ-ously, we proposed a model linking deconditioning with physical inactivityresulting from widespread pain in patients with fibromyalgia. Deconditioning alsomodulates the autonomic nervous system (high sympathetic tone and a low para-sympathetic tone). A high peripheral sympathetic tone causes regional ischaemia,which in turn results in widespread pain. Thus, vascular dysregulation and hypop-erfusion in patients with FM give rise to ischaemic pain leading to physical inac-tivity. Microvascular abnormalities are also found in patients with FM.Therapeutic interventions (e.g. exercise) that result in vasodilatation and favour-able autonomic alterations have proven to be effective. In this review, we focuson the vascular end organ in patients with fibromyalgia in particular and its mod-ulation by exercise in general.

Introduction

Fibromyalgia (FM) has gradually progressed from being a

vague debilitating illness to a discrete pain disorder. An Inter-

net survey of patients with FM reveals that some of their

symptoms like morning stiffness, fatigue, non-restorative

sleep, pain, loss of concentration and memory are aggravated

by emotional distress, weather changes, insomnia and strenu-

ous activity (Bennett et al., 2007). Catastrophic events (e.g.

war), physical trauma (car accident), psychological or

emotional distress, etc., act as potential triggers of fibromyal-

gia as well as of chronic fatigue syndrome (CFS), multiple

chemical sensitivity and Gulf War syndrome and organ-specific

diagnoses (irritable bowel syndrome, migraine and tension

headache) (Clauw, 2001; Ciccone & Natelson, 2003; Stein

et al., 2004). The enigmatic pathophysiology of fibromyalgia

eludes researchers because of multiple comorbidities.

Studies focusing on dysfunction of the descending

pain-inhibiting system, central sensitization which may be due

to a higher gain setting (analogous to high ‘volume control’

setting) of pain processing irrespective of peripheral nocicep-

tive input (indicating an abnormally low pain threshold and

greater amplification of pain signals at the neuronal level),

have gained momentum in the last few years (Mense, 2008;

Clin Physiol Funct Imaging (2013) 33, pp83–91 doi: 10.1111/cpf.12000

83© 2012 The AuthorsClinical Physiology and Functional Imaging © 2012 Scandinavian Society of Clinical Physiology and Nuclear Medicine 33, 2, 83–91

Ablin & Clauw, 2009; Clauw et al., 2011). Neurotransmitter

abnormalities may give rise to a heightened pain perception,

fatigue, sleep/mood dysfunction and memory problems

(Becker & Schweinhardt, 2012). However, few symptoms

such as stiffness and postexertional pain cannot be fully

explained on the basis of central pain processing abnormalities

and have been attributed to autonomic nervous system (ANS)

dysfunction (Martınez-Lavın & Hermosillo, 2000; Martinez-

Lavin, 2004). Both reductionist and holistic hypotheses have

been formulated in support of autonomic dysfunction in

fibromyalgia (Balasubramaniam et al., 2007; Felix & Fontenele,

2008; Martinez-Lavin et al., 2008). Patients with FM show an

abnormal stress response involving hypothalamo-pituitary axis

(HPA) and hyperactivity of the autonomic (sympathetic limb)

nervous system (Martinez-Lavin, 2007; Kadetoff & Kosek,

2010).

A reduced stress responsiveness underlines the female pre-

ponderance in fibromyalgia (Yunus, 2001; Stein et al., 2004;

Adler & Geenen, 2005; Riva et al., 2012). Reports of genomic

polymorphism (Vargas-Alarcon et al., 2007; Bradley, 2009)

corroborate fibromyalgia as a sympathetically maintained neu-

ropathic pain syndrome (Sarzi-Puttini et al., 2006; Martinez-

Lavin, 2012). We discussed a hypothesis linking autonomic

dysfunction with physical deconditioning in patients with fi-

bromyalgia (Kulshreshtha et al., 2011). In the light of these

reports, the present narrative review attempts to describe the

current state of autonomic nervous system in patients with

FM.

Autonomic nervous system and fibromyalgia

Sporadic reports of autonomic nervous system dysfunction for

the aetiopathogenesis of fibromyalgia surged up in the last

decade which can explain the symptomatology, physical and

psychological aspects in patients with FM (Buskila, 2009). The

patients with FM exhibit a higher pain rating after the injec-

tion of norepinephrine, supporting the concept of sympatheti-

cally maintained pain (Martinez-Lavin et al., 2002). Various

stressors (physical or emotional trauma including sexual

abuse; infections such as herpes zoster) lead to phenotypic

alterations (sympathetic sprouting and upregulation of

voltage-gated sodium channels in dorsal root ganglia; and

establish abnormal sympathetic-nociceptive short-circuit con-

nections through which catecholamines and sympathetic

impulses activate primary nociceptors) and cause widespread

pain in fibromyalgia (Bradley, 2009; Martinez-Lavin & Solano,

2009). The clinical comorbidities (other than pain) of the

fibromyalgia syndrome suggest a multifactorial involvement.

One of the most common autonomic abnormalities in

patients with FM is postural orthostatic tachycardia (present in

CFS also) (Staud, 2008a). But blood pressure (BP) changes;

discriminant score (quantifies BP and heart rate reactivity) and

QT interval during tilt test distinguish patients with FM from

patients with CFS despite similar autonomic symptoms

(Naschitz et al., 2001).

Questionnaire-based quest for autonomicdysfunction in fibromyalgia

The Composite Autonomic Symptom Scale (COMPASS)

presents a high score in orthostatic, digestive, sleep, sudomo-

tor and mucosal dysfunction domains in patients with FM

along with a highly significant correlation (r = 0�5, P �0�05) between the fibromyalgia impact questionnaire (FIQ)

(Solano et al., 2009). Similar correlation (r = 0�4, P � 0�01)is observed between COMPASS and a ‘fatigue impact scale’ in

patients with CFS (Newton et al., 2007). Various rating scales

like Hamilton Depression scale, Beck depression Inventory,

Arthritis Impact Measurement Scales, FIQ can be used to assess

depression and disability in patients with FM (Zachrisson et al.,

2002). Leeds assessment of neuropathic symptoms and signs

questionnaire demarcates fibromyalgia pain from the nocicep-

tive pain of rheumatoid arthritis (Martınez-Lavin et al., 2003).

A Glombok Rust Inventory of sexual dysfunction questionnaire

indicates sexual dysfunction (presence and severity) in fibrom-

yalgia (Unlu et al., 2006).

Autonomic reactivity in fibromyalgia asassessed by responses to various stimuli

Patients with FM show a blunted sympathetic response to dif-

ferent types of stressors like auditory stimulation and cold

pressor tests, orthostatic stress responses (Vaerøy et al., 1989;

Qiao et al., 1991; Bou-Holaigah et al., 1997; Raj et al., 2000;

Buskila, 2009). A mental stress (two-choice reaction time on

a monitor for 1 h) produces cardiovascular hyporeactivity (a

reduced rise in diastolic blood pressure and heart rate) in

patients with FM as compared to healthy controls (Nilsen

et al., 2007). Heart rate reactivity to this mental stress inver-

sely correlates with pain and shows that ANS influences pain

due to coupling between afferent nociceptive fibres and effer-

ent sympathetic fibres; pain worsening is due to reduced stress-

induced analgesia and reduced endogenous pain inhibition in patients

with FM (Nilsen et al., 2007; Martinez-Lavin & Solano, 2009).

A mental task also reveals functional deficit (baseline and

stress induced) in the baroreflex response and heart rate

variability (HRV), suggesting low parasympathetic tone and

reactivity. Mental stress does not affect the myocardial indices

like stroke volume and contractility index, which are already

low at rest (low sympathetic tone) (Reyes Del Paso et al.,

2010). A cold pressor test results in a lesser increase in stroke

volume (SV) and myocardial contractility as compared to

age-, sex- and BMI-matched healthy controls and reflects

decreased cardiac sympathetic reactivity (via b1-adrenergicinfluences) in patients with FM (Reyes del Paso et al., 2011).

A cardiovascular reactivity study (using a head-up tilt) does

not reveal a specific fibromyalgia-associated abnormality

(Naschitz et al., 2005). As compared to healthy pain-free

controls, patients with FM show higher overall BP and total

vascular resistance (TVR) [indicates sympathetic dominance;

a-activity > b-activity], and greater BP reactivity to postural

© 2012 The AuthorsClinical Physiology and Functional Imaging © 2012 Scandinavian Society of Clinical Physiology and Nuclear Medicine 33, 2, 83–91

Autonomic function in fibromyalgia, P. Kulshreshtha and K. K. Deepak84

and speech tasks (Light et al., 2009). Patients with fibromyal-

gia reveal a higher cold-induced increase in finger systolic

blood pressure (SBP) and an increase in the number of

a2-adrenoceptors on thrombocytes (Bennett et al., 1991).

Using capillary videomicroscopy of the nail fold, significant

vasospasm is observed in a cold provocation test in patients

with FM (Lapossy et al., 1994). Skin conductance levels

increase in response to stressors (social conflict and arithmetic

task) and represent sympathetic hyper-reactivity. Positive

covariation between stress and pain ratings suggests that stress

causes pain in patients with FM (Thieme et al., 2006). A

mental stress causes greater skin vasoconstriction and higher

noradrenaline levels but a decrease in cortisol and adrenaline

levels in patients with FM, suggesting an uncoupling of the

sympathoneural system (which regulates skin blood flow)

from the HPA/adrenomedullary system (Nilsen et al., 2007).

The attrition of baroreflex sensitivity (BRS) during a mental

task indicates malfunctioning of ANS in patients with FM. Baro-

reflex sensitivity correlates inversely with clinical pain in

patients with fibromyalgia (Reyes Del Paso et al., 2010).

Likewise, diastolic BP and HR also correlate inversely with pain

in patients with FM (Thieme et al., 2006). Antinociception

caused by high BP is mediated by a circuit involving barorecep-

tors, the nucleus tractus solitarius (NTS), the paraventricular

hypothalamus and the rostroventromedial medulla (RVM),

which sends projections to the spinal cord via dorsolateral

funiculus. Rise in BP stimulates the baroreflex, and baroreceptor

output via nucleus tractus solitarius affects descending

nociceptive inhibition which reduces pain transmission at the

dorsal horn. Reduced BRS in patients with FM reduces this baro-

reflex dampening of pain by facilitating descending pain arising

from the RVM. (Chung et al., 2008; Reyes del Paso et al., 2011).

Heart rate variability (HRV) as a tool to assessautonomic tone in patients with fibromyalgia

Heart rate variability, especially nocturnal HRV indices (indic-

ative of sympathetic predominance correlated with pain sever-

ity and depression), acts as a potential FM biomarker (Staud,

2008b; Lerma et al., 2011). Patients with FM have HRV

changes consistent with relentless sympathetic hyperactivity

and reduced parasympathetic activity as seen by a higher LF

and lower High-frequency (HF) components of power spec-

tral density (Martınez-Lavın et al., 1998; Raj et al., 2000; Co-

hen et al., 2001; Martınez-Lavın, 2002). Low values of all

time domain measures and a significantly lower high-fre-

quency percentage (HF%) in frequency domain support lesser

parasympathetic activity in patients with FM (Kulshreshtha

et al., 2011). The patients with FM exhibit a global increase in

central cardiovascular sympathetic activity while recumbent;

show blunted sympathetic vascular modulation and impaired

cardiac vagal withdrawal to gravitational stress [no increase in

muscle sympathetic nerve activity (MSNA), less decrease in

HF as compared to controls on tilt test]; and point to a

reduced orthostatic tolerance (high rate of syncope on tilt test)

(Furlan et al., 2005). Heart rate variability parameters are cor-

related with the quality of life, physical function, anxiety,

depression and perceived stress in patients with FM (Cohen

et al., 2000). Patients with fibromyalgia and the chronic

benign pain patients share similar HRV indices but show a

higher level of depression and physical function limitation

(Mostoufi et al., 2012). Daily home practice of the HRV

biofeedback technique in patients with FM at a resonant

frequency of about 5�5 breaths per minute strengthens barore-

flexes in addition to restoring the sympathovagal balance

(Hassett et al., 2007). Likewise, EEG and EMG biofeedbacks

have also a promising role in the relief of pain and other

symptoms of fibromyalgia (Hassett & Gevirtz, 2009).

All the above-mentioned studies are based on single/few

tests of autonomic function only. Using a standard battery of

autonomic tests, we concluded that the patients with FM have

a higher vascular sympathetic tone (higher resting both

systolic and diastolic) blood pressure and similar autonomic

reactivity to healthy controls (Kulshreshtha et al., 2012a). The

activity of the sympathetic reflex arc as measured by resting

MSNA between patients with fibromyalgia is similar to

controls and the MSNA responses to isometric muscle contrac-

tion, postcontraction ischaemia or mental stress are also not

exaggerated in patients with FM. Thus, the sympathetic reflex

arc is intact and the possibility of a neurally mediated muscle

vasomotor abnormalities cannot be ruled out in this condition

(Elam et al., 1992).

Comorbid illnesses, difference in the specificity of action of

catecholamines and their differential effects on different organs

are responsible for heterogeneity seen in patients with FM

(Naschitz et al., 2005; Thieme & Turk, 2006). Altered auto-

nomic/stress response and a low parasympathetic tone define

disturbed emotional regulation and impaired ability to cope

with stress (Naschitz et al., 2005; Reyes Del Paso et al., 2010).

Sympathetic blockade studies in patients withFM

Sympathetic blockade reduces the number of tender points

and direct pain-relieving effect observed in the patients with

fibromyalgia (Bengtsson & Bengtsson, 1988). A slower

baseline relaxation rate of muscles which increases after sym-

pathetic blockade links the activity of the muscle sympathetic

system to the muscular symptoms in patients with FM

(Backman et al., 1988). A low-grade mental stress–induced

pain and muscle activity remain unaffected by a unilateral

sympathoneural blockade and challenge the role of the periph-

eral sympathetic neural activity in stress-induced pain in

patients with FM (Nilsen et al., 2008).

Sympathetic skin response (SSR) studies inpatients with fibromyalgia

The SSR (reflective of sympathetic sudomotor activity) latency

is prolonged, and R–R interval variation (parasympathetic


Autonomic function in fibromyalgia, P. Kulshreshtha and K. K. Deepak 85

reflex activity) shows a decrease during deep breathing (Ulas

et al., 2006). The amplitude of SSR recorded from the palmar,

plantar and genital regions is reduced in the patients with FM,

indicating both autonomic and sexual dysfunction (Unlu et al.,

2006).

Exercise modulates autonomic function infibromyalgia

Exercise training in patients with fibromyalgia is well docu-

mented, and tailored aerobic or mixed-type training

programmes reduce pain and depression and improve physical

fitness (Jones et al., 2008; Staud et al., 2010; Busch et al.,

2011; Kayo et al., 2012). Both prescribed graded aerobic

and resistance exercise regimens evoke improvements in

FMS-specific symptoms (tender points and FIQ scores),

depression and global SF-36 (Short Form Health Survey 36)

scores (Richards & Scott, 2002; Sanudo et al., 2010). Exercise

in a warmwater (34°C) pool provides additional beneficial

effects on pain, depression and anxiety compared with land

exercise performed in a gymnasium (Jentoft et al., 2001).

Pool-aquatic exercise in warm water decreases high circulating

levels of the pro-inflammatory marker IL-8, which is specifi-

cally associated with increased nociception and activation of

sympathetic nervous system (Staud, 2007; Ortega et al.,

2009).

The patients with FM perceive repetitive isometric exercise

more painful and show attenuated adrenaline responses along

with higher muscle activity (Giske et al., 2008). Resistance

exercise training (RET) results in a greater parasympathetic

(total power, HF and root mean of squared successive RR

Intervals) modulation of HRV and improves pain perception

in patients with FM (Figueroa et al., 2008). Baroreflex sensitiv-

ity is not affected by RET because increased arterial stiffness

(evident by high pulse pressure) reduces the stimulation of

the baroreceptors in patients with FM (Figueroa et al., 2008).

FM patients with a normal autonomic profile at rest, after an

acute bout of resistance exercise, demonstrate a lower sympa-

thetic reactivity and greater parasympathetic (high HF;

impaired vagal withdrawal that persists during recovery in

postexercise phase) modulation. In the same study, a higher

BRS with a normal HR recovery postexercise suggests reduced

autonomic responses and a reduced sensitivity of sinus node

to autonomic modulation, respectively. These changes, how-

ever, pose a low cardiac risk after acute resistance exercise in

patients with FM (Kingsley et al., 2009). But no evidence of

HRV modulation after an acute bout of leg resistance exercise

is found in patients with FM who have undergone RET for

12 weeks and heart rate recovers in 20 min postexercise

(Kingsley et al., 2010). Patients with FM on a different exer-

cise protocol show a delayed heart rate recovery postexercise,

which may predispose patients to cardiovascular risk. Patients

with FM undergoing endurance exercise (modified Balke

treadmill maximal exercise test) show chronotropic incompe-

tence (the inability to increase heart rate with an increase in

exercise intensity), indicating sympathetic hyporeactivity and

cardiac autonomic impairment (da Cunha Ribeiro et al.,

2011). A blunted HR response during exercise is because of

desensitization of cardiac b1-receptors through a heightened

baseline sympathetic activity (Martinez-Lavin, 2004). A high

HR response in patients with FM during the static muscular

contraction leading to a higher HR at exhaustion is attributed

to deconditioning as evident with a low baroreflex control of

HR (Kadetoff & Kosek, 2007).

Muscle blood flow in Patients with FM

A Doppler ultrasound reveals a blunted increase in muscular

vascularity (duration and immediate flow response) following

dynamic and during static muscular contractions which can be

explained on the basis of deconditioning and derangement of

the sympathetic nervous system and/or pain-related muscle

ischaemia (Elvin et al., 2006). Propranolol increases the sensi-

tivity to pain induced by arm ischaemia in patients with FM,

suggesting that a greater a-adrenergic activation induces

higher vasoconstriction and BP and produces myalgic pain

through hypoperfusion. This reinforces existing knowledge

about disturbed microcirculation in patients with FM (Light

et al., 2009; Kulshreshtha et al., 2012a).

Vascular end organ in patients withfibromyalgia

Amitriptyline therapy (most common conventional pharmaco-

logical treatment for FM) improves blood flow at the affected

sites in patients with FM. This local action of amitriptyline

corroborates fibromyalgia as a case of vascular end organ

dysfunction (Kulshreshtha et al., 2012) Amitriptyline, through

the blockade of a1-adrenoceptors/extracellular calcium influx

through voltage-gated calcium channels, induces relaxation of

the isolated mesenteric vasculature and results in the dilatation

of resistance vessels in healthy subjects (Thorstrand &

Lindblad, 1976; Vila et al., 1999).

Vascular smooth muscle cells (VMC) express b-receptors forvasodilation and a1-/a2-adrenoceptors for vasoconstriction.

Activation of endothelial a2-adrenoceptor by the release of NE

from the sympathetic nerve terminals (which terminate in

medial VMC layer) releases NO causing endothelium-depen-

dent vasodilation (Guimaraes & Moura, 2001; Pinterova et al.,

2011). Endothelial-derived signals and physical factors, such

as hypoxia and stretching, stimulate vascular sensory afferents,

and resultant activity in the efferent vasomotor nerve causes

the release of catecholamines from the varicosities (Stohler,

2002). High sympathetic outflow and endothelial dysfunction

pose a higher detrimental cardiovascular risk than either of

them alone. Impaired endothelial function enhances the

contractile function of catecholamines (Joyner & Green,

2009). Exaggerated sympathetic activation impairs endothelial

function via a-/b-receptors whose blockade results in the

restoration of flow-mediated dilation (FMD) and lessens the



levels of von Willebrand factor vWF (an indirect marker of

endothelial function), respectively (Harris & Matthews, 2004).

A b-receptor desensitization/dysfunction causing intramuscu-

lar hypoperfusion is often discussed for fibromyalgia pain,

which results in a sympathetically mediated muscle ischaemia

even with unaltered/reduced exercise-induced MSNA (Maeka-

wa et al., 2002, 2003; Elvin et al., 2006). Local ischaemia also

explains the concurrence of Raynaud’s phenomenon seen in

some patients with FM (Staud, 2007). Functional disturbances

[time to peak blood flow after the release of occlusion] of

microcirculation and morphological abnormalities [capillary

dilatations and irregular formations] are present in the patients

with FM. The abnormal reactive hyperaemia pattern in

patients with FM is due to a higher sympathetic tone, which

in turn results in increased vasoconstriction (Morf et al.,

2005).

Stress and chronic pain enhance sympathetic activity by

altering cardiovascular responses and inducing arterial wall

stiffening and endothelial dysfunction. Patients with FM

exhibit an impaired endothelial-dependent FMD caused by

decreased endothelial NO activity, which directly regulates

large artery stiffness in vivo (Lee et al., 2011). Both decreased

endothelial-dependent and endothelial-independent (nitroglyc-

erine-induced) vasodilatation is present in patients with FM,

which correlates inversely with FIQ and pain parameters (Cho

et al., 2011). Patients with FM show a distinctive vascular cold

response caused by a relative ischaemia due to an increase in

endothelin-1 levels which further enhance vasospasm, thereby

creating a vicious circle (Pache et al., 2003).

Physical Deconditioning in fibromyalgiacaused by physical inactivity

Prolonged exercise training (RET and endurance) improves

endothelial function, whereas a sedentary lifestyle adversely

affects cardiovascular system, including endothelial functions.

Prolonged physical inactivity caused by microgravity or pro-

longed bed rest decreases BRS and impairs endothelial func-

tions by decreasing shear stress at the microcirculatory level

(Demiot et al., 2007; Coupe et al., 2009; Navasiolava et al.,

2010). Physical inactivity in humans induced by dry immer-

sion reveals an increase in endothelial microparticles and

decrease in ACh-mediated vasodilation. Endothelial dysfunc-

tion contributes to a decrease in exercise capacity, muscle

atrophy and decrease in VO2 max, one of the symptoms of

cardiovascular deconditioning (Coupe et al., 2009; Kingsley

et al., 2009). Functionally, patients with FM show a physio-

logical limitation of muscular exercise capacity because of

impairment in the capacity and utilization of oxygen (Okumus

et al., 2006).

Lower muscle strength, lower EMG and a high HR at rest

along with a low reactivity to stress (both HR and EMG

reactivity) observed are suggestive of deconditioning charac-

terizing autonomic dysfunction in patients with FM (Thieme

et al., 2006; Figueroa et al., 2008). Patients with fibromyalgia

are aerobically unfit because of prolonged inactivity due to

pain, and this reduction in physical activity leads to a progres-

sive detraining effect. This may subsequently aggravate both

pain and fatigue (Nampiaparampil & Shmerling, 2004;

Okumus et al., 2006).

Our model linking physical deconditioningwith pain-related physical inactivity inpatients with fibromyalgia

A model has been proposed on the basis of cardiovascular

autonomic changes (Kulshreshtha et al., 2012a) and its further

neural modulation by central sensitization (Fontenele & Felix,

2009) to elucidate the pathogenesis of pain in patients with

fibromyalgia. A hypothesis of impaired neuroeffector mecha-

nisms seems plausible in the light of a deconditioned status

and a normal sympathetic reflex arc in patients with fibrom-

yalgia (Elam et al., 1992; Kulshreshtha et al., 2012a,b).

Pain is the hallmark of fibromyalgia and gets aggravated fol-

lowing extreme exertion/concentric exercise, suggesting that

the pain is induced by vasomotor dysregulation and hypoper-

fusion in muscles (Jeschonneck et al., 2000; Bengtsson, 2002;

Katz et al., 2007). A high dose (intensity, frequency and dura-

tion) of aerobic/mixed exercise worsens pain, whereas a

lower exercise dose results in clinical improvements (Jones

et al., 2008). Short bouts of strenuous exercise are painful,

and brief rest reduces overall clinical pain, fatigue and hyper-

algesia, indicating that a muscle source causes pain in patients

with FM (Staud et al., 2010). The outcome of chronic pain is

massive inactivity (McBeth et al., 2010). Even a slight activity

produces microtrauma and amplifies local and generalized

pain, so the patients with FM decrease their activity levels

(Kop et al., 2005). Physical inactivity results in endothelial

dysfunction, promotes vascular stiffness and results in a high

sympathetic tone with little or no parasympathetic tone

(Maekawa et al., 2002). An altered sympathetic/parasympa-

thetic balance can, as in case of hypertension and diabetes

mellitus, decrease the release of endothelial progenitor cells

from the bone marrow, thus disrupting the vascular homoeo-

stasis (Zubcevic et al., 2011).

Effective therapeutic interventions in patients with FM aim

at disrupting the cycle of inactivity/deconditioning. Vasodila-

tory influences, including physical activity, relieve the pain of

FMS by increasing muscle perfusion (Katz et al., 2007). Exer-

cise evokes an inhibitory effect on pain by the production of

endorphins and activation of the descending inhibitory path-

ways that are impaired in FM (Jones & Liptan, 2009; Williams

& Clauw, 2009). Resistance exercise training ensures fast

return of parasympathetic modulation of HR supporting the

use of RET in rehabilitation programmes for FM (Kingsley

et al., 2010).

In healthy humans, 4–10 weeks of endurance exercise

training improves the endothelial function by recurrent

changes in haemodynamics and arterial shear stress (Green

et al., 2004, 2011). Exercise training induces flow-mediated



dilation as well as metabolic dilation in the vascular endothe-

lium resultant of increased NO bioactivity related to increased

shear stress and various metabolites. Through various molec-

ular mediators, exercise induces the transcription of vascular

endothelial growth factor in the skeletal muscles, which

promotes endothelial cell proliferation and angiogenesis (Gie-

len et al., 2010). Exercise induces the gene expression of

endothelial NO synthase and extracellular superoxide dismutase,

which increase NO activity whose bioavailability regulates

central sympathetic flow (Vierck, 2012). Self-reported time

spent on physical activity assessed in hours per week is

inversely related to MSNA [sympathetic outflow] and

positively related to Reactive Hyperemic index (the rate between

resting flow and the maximum flow) [endothelial function],

thus categorizing mechanisms linking sympathetic outflow to

pathologies associated with endothelial dysfunction (Sver-

risdottir et al., 2010). This finding also underlines the impor-

tance of daily exercise in the maintenance of cardiovascular

health. Mechanistic modulation of the autonomic nervous

system in fibromyalgia makes aerobic exercise overall most

effective treatment for fibromyalgia (Wigers et al., 1996).

Therefore, exercise/physical activity by modulating ANS and

vascular end organ substantiates our previous claim that

fibromyalgia may be a vascular end organ malfunction

primarily (Kulshreshtha et al., 2012a,b).

Conclusions

This review attempts to substantiate our previous research

findings that a high vascular sympathetic tone (significantly

higher baseline blood pressure in the patients with fibromyal-

gia than controls) does not necessarily reflect the cardiac sym-

pathetic tone and the autonomic reflex arc is normal in

fibromyalgia. It is also prudent to understand that downstream

precipitant of pain is vasoconstriction due to vascular end

organ dysfunction. The primary or secondary role of enhanced

vascular sympathetic activity factors that initiate and further

perpetuate autonomic changes and the risk of cardiovascular

disorder in patients with fibromyalgia can be determined by

longitudinal studies. Future pharmacological/non-pharmaco-

logical/mechanistic interventions should target specific anom-

alies and should be directed at increasing the physical activity

in patients with fibromyalgia. Longitudinal studies need to be

designed to study the upshots of different types of exercise

training (low/high intensity; resistance/endurance/combined

exercise programmes) on autonomic nervous system and

symptom relief in patients with fibromyalgia.

Conflict of interest

Nothing to disclose and no conflict of interest.

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Autonomic nervous system profile in fibromyalgia patients and its modulation by exercise: a mini review