R-R Interval Variation and Sympathetic Skin Response in Fibromyalgia
This study proposed to assess the autonomic nervous system (ANS) functions in fibromyalgia (FM) by using two electrophysiological tests, sympathetic skin response (SSR) and the heart rate variability named R-R interval variation (RRIV). Sympathetic skin response and RRIV were studied in 29 female patients with FM and 22 healthy age-matched female controls. R-R interval variation at rest (R%), during deep breathing (D%), the difference between D% and R% (D-R) and the ratio of D-R% (D/R) were determined. Pain threshold was measured using a mechanical algometer. R-R interval variation at rest (R%) and D/R did not show significant difference between patients and controls, whereas D% and D-R were significantly lower in patients compared to controls. SSR latencies of patients' hands and feet had no significant difference compared to controls' hand and feet SSR latencies. SSR latencies of patients' hands correlated significantly with control point score, total myalgic score, Hamilton Anxiety Rating Scale (HARS) and Hamilton Depression Rating Scale. Sympathetic skin response latencies of patients' feet correlated only with HARS. Analysis of heart rate variability may be useful and complementary to clinical examination in patients with symptoms of dysfunction in cardiovascular reflex pathways.
R-R Interval Variation and Sympathetic Skin Response in Fibromyalgia
and Ozge Ardicoglu
Department of Physical Medicine and Rehabilitation,
Department of Neurology, Faculty of Medicine, Firat University, Elazig, Turkey
Received for publication July 1, 2005; accepted November 23, 2005 (ARCMED-D-05-00251).
Background. This study proposed to assess the autonomic nervous system (ANS) func-
tions in ﬁbromyalgia (FM) by using two electrophysiological tests, sympathetic skin re-
sponse (SSR) and the heart rate variability named R-R interval variation (RRIV).
Methods. Sympathetic skin response and RRIV were studied in 29 female patients with
FM and 22 healthy age-matched female controls. R-R interval variation at rest (R%), dur-
ing deep breathing (D%), the difference between D% and R% (D–R) and the ratio of D–
R% (D/R) were determined. Pain threshold was measured using a mechanical algome ter.
Results. R-R interval variation at rest (R%) and D/R did not show signiﬁcant difference
between patients and controls, whereas D% and D–R were signiﬁcantly lower in patients
compared to controls. SSR latencies of patients’ hands and feet had no signiﬁcant differ-
ence compared to controls’ hand and feet SSR latencies. SSR latencies of patients’ hands
correlated signiﬁcantly with control point score, total myalgic score, Hamilton Anxiety
Rating Scale (HARS) and Hamilton Depression Rating Scale. Sympathetic skin response
latencies of patients’ feet correlated only with HARS.
Conclusions. Analysis of heart rate variability may be useful and complementary to clin-
ical examination in patients with symptoms of dysfunction in cardiovascular reﬂex path-
ways. Ó 2006 IMSS. Published by Elsevier Inc.
Key Words: Sympathetic skin response, Heart rate variability, Autonomic dysfunction,
Fibromyalgia (FM) is a common, chronic, widespread pain
syndrome usually associated with other somatic and psy-
chological symptoms including fatigue, poor sleep, cogni-
tive difﬁculties, psychologic distress and features of
irritable bowel, Raynaud’s phenomena or bladder dysfunc-
tion (1). The diversity of symptoms and poorly understood
etiology make FM a frustrating condition.
Autonomic nervous system (ANS) is the portion of the
nervous system that controls the functions of the body or-
gans and systems, i.e., regulate body temperature, heart
beat rate, bowel and bladder tone, etc. Its control is auto-
nomic, in other words it works below the level of con-
sciousness and is activated by centers located in the
central nervous system. The ANS is an important compo-
nent of human stress response and works closely with hypo-
thalamic–pituitary–adrenal (HPA) axis (2–5).
Recent reports have shown that aberrant ANS function
may be responsible for some of the symptoms seen in
FM (2,3,5). While assessing ANS in FM, investigators have
used various techniques, some of which have assessed iso-
lated components of ANS whereas others have portrayed
how individuals respond to ‘‘stressors’’ that involve the
The aim of this study was to assess ANS functions in FM
by using two electrophysiological tests of autonomic func-
tion, sympat hetic skin response (SSR), and the heart rate
variability named R-R interval variation (RRIV).
Materials and Methods
Twenty nine female patients who met the 1990 American
College of Rheum atology (ACR) criteria for the classiﬁca-
tion of FM (1) and 22 healthy female controls matched
for age, height and weight were enrolled. The patients
and controls volunteered to participate in the study and gave
their informed consent. None of the patients was under
Address reprint requests to: Dr. Salih Ozgocmen, Firat Tip Merkezi,
Fiziksel Tip ve Rehabilitasyon AD, 23119, Elazig, Turkey; E-mail:
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc.
Archives of Medical Research 37 (2006) 630–634
anti-depressant treatment, muscle relaxants or analgesics and
were included only if they had stopped using them at lea st 3
weeks before the study. The inclusion criteria for the study
group comprised a negative history for heavy cigarette smok-
ing, neuropsychiatric diso rders (dementia, cerebrovascular
disease, alcohol abuse, severe depression), psychoactive or
cardiovascular drug (beta or calcium channel blockers)
treatment, and other neurological or endocrinological (i.e.,
diabetes mellitus, hypo- or hyperthyroidism) disorders. An
informative handout advising stopping caffeine and alcohol
intake and having restorative sleep 1 day before the study
was given to the patients and controls. To rule out peripheral
neuropathy, motor, sensory and F-wave response stud ies
were carried out using standardized electrophysiological
techniques in all patients and controls. In upper extremities
medial and ulnar nerve sensorial and motor conduction ve-
locity were examined. In lower extremities tibial and pero-
neal motor conduction velocity and sural nerve sensorial
conduction velocity were examined.
Assessing Myalgic Scores
The pressure pain threshold (PPT) measurements of pa-
tients were performed in the same room in the early after-
noon by using a mechanical algometer. The same doctor
carried out PPT measurements. Before the evaluations, pa-
tients were informed of the procedure. Pain threshold was
explained as the amount of pressure adequate to induce
a sensation of discom fort, and it was explained to patients
that the aim was to determine pain threshold but not pain
Eighteen tender points (TPs) and three control points
(CPs) were evaluated using the methods, which were previ-
ously deﬁned and used elsewhere (6–8). A positive TP was
deﬁned as a point at which the subject had mild or great
pain with !4 kg/cm
pressure. The sum of the PPTs of
21 points (18 TPs, 3 CPs) was calculated as the total myal-
gic score (TMS in kg).
The Hamilton Depression Rating Scale (HDRS) (9) and
Hamilton Anxiety Rating Scale (HARS) (10) were used to
evaluate the affective condition of patients with FM. Patients
were administered the Turkish version of the Fibromyalgia
Impact Questionnaire (FIQ) (11). All measurements were
performed on the same day as electrophysiological tests. Pa-
tients were also screened for distinctive features of FM like
fatigue, sleep disorders/non-restorative sleep, paresthesia,
headache, Raynaud’s phenomena, bladder dysfunction
(presence of voiding difﬁculties, frequency of voiding,
etc.), sicca symptoms, irritable bowel syndrome, orthostatic
intolerance (lightheadedness, concentration difﬁculties,
syncope or near syncope on standing).
R-R Interval Variation
All patients were studied in the supine position using equip-
ment from Dantec, Keypoint (Medtronic, Denmark) by the
same neurologist who was blinded to the patients’ and
controls’ identity and clinical data. Recordings were made
using two surface electrodes placed on the chest or alterna-
tively to the dorsum of each hand. A metal strap electrode
around one wrist was used as the ground electrode. Using
the triggering mode and delay line, the oscilloscope display
was adjusted by adjusting the trigger sensitivity and sweep
speed so that two QRS complexes were displayed on the
screen. As the ﬁrst displayed complex is the triggering po-
tential, the variation in timing of the second complex repre-
sents the variation in the R-R interval. Five groups of 20
sweeps were recorded at rest and two during forced deep
breathing at six breaths per minute. The bandpass was 5–
1000 Hz, the sensitivity 0.5 mV and the sweep duration
was 0.2–1 sec. The recordings and calculations were per-
formed by the computer software. The following algorithm
was used to analyze R-R variation (RRmax–RRmin) 3
100/RRmean (the difference between the shortest and the
longest RR intervals during 1 min given in percent of the
mean of all maximal and minimal peaks). Details of this
method have been published elsewhere (12,13).
The average of ﬁve recordings at rest was ter med as R%
and that of two recordings during deep breathing as D%.
The difference between D% and R% (D–R) and the ratio
of D–R% (D/R) were also calculated.
RRIV responses at rest and deep breathing were consid-
ered abnormal when beyond two standard deviations lower
than mean responses of age-matched normal controls
Sympathetic Skin Response
The SSR was studied using the standard method (16). The
skin temperature was maintained at 32
C (room tempera-
ture stabilized at 25–26
C). A standard electromyographic
active electrode was attached to the palm and sole and the
reference electrode to the dorsum of the hand and foot.
The same EMG equipment was used (Dantec, Keypoint,
Medtronic). The stimuli used were single electrical stimu-
lus at the wrist contralatera l to the recording side. Stimuli
were delivered unexpectedly and in irregular intervals of
more than 1 min to prevent habituation. The latency was
measured from the onset of the stimulus artifact to the on-
set of the ﬁrst negative deﬂection and expressed in sec-
onds. The amplitude was measured from the baseline to
the negative peak and expressed in mV. The response
was considered absent if no consistent voltage change oc-
curred using a sensitivity of 50 mV per division after three
trials at maximum stimuli intensity. In our study, the
amplitudes were not included in the analysis because the
amplitudes had extent variability even in the same subject
in repeated measurements due to possible habituation
phenomena. Response latencies were considered patholo-
gical when more than 2 SD above the mean latency of the
631Autonomic Nervous System in Fibromyalgia
Results are expressed as mean 6 SD, and differences
between the two groups were assessed using t test. Pearson
correlation coefﬁcients were used to assess relationship
between parameters. Two-tailed p value of !0.05 was con-
sidered statistically signiﬁcant. Statistics Package for Social
Sciences (SPSS Inc., Chicago, IL) was used for the analyses.
RRIV and SSR were successfully obtained in all patients
and healthy controls. Patients had a disease durat ion of
5.0 6 3.3 years, and mean age was 39.6 6 8.6 in patients
and 34.6 6 9.4 in controls. There was no signiﬁcant differ-
ence in age, height and weight between patients and con-
trols. Patients’ clinical variables and relationship with
sympathetic skin response latencies of hands and feet are
shown in Table 1. Mean values of RRIV for patients and
controls are shown in Table 2. R-R interval variation at rest
and the ratio of D–R% did not show signiﬁcant differences
between patients and controls whereas RRIV at deep breath
and the difference between D% and R% were signiﬁcantly
lower in patients compared to controls (Table 2).
SSR latencies of hands and feet were obtained in pa-
tients and control s. Mean latencies of SSR of hand and foot
for the patients and controls are shown in Table 3, and there
was no signiﬁcant difference between patients and controls.
R-R interval variation at rest and deep breathing nega-
tively correlated with age in control group but not in patient
group ( r 520.49, p 5 0.02 and r 520.43, p 5 0.05, re-
spectively). Patients SSR latencies for hands correlated sig-
niﬁcantly with CPS (r 5 0.56, p 5 0.002), TMS (r 5 0.46,
p 5 0.012), HARS (r 5 0.50, p 5 0.006) and HDRS (r 5
0.52, p 5 0.004). Sympathetic skin response latencies of
patients’ feet correlated only with HARS (r 5 0.42, p 5
R-R interval variation values during deep-breathing were
abnormal in seven patients (24%), of whom six had ortho-
static intolerance and sleep diso rders, six had sicca syp-
toms, three had irritable bowel syndrome, four had
bladder dysfunction, and one had Raynaud’s phenomena.
Despite a growing body of research, FM continues to be
a chronic pain syndrome without a clear etiology. Recent
studies have provided convincing evidence for central pain
processing abnormalities that share some features of neuro-
pathic pain syndromes in FM. Some of these abnormalities
are hyperalgesia, allodynia, abnormal activation of pain-
related brain regions, wind-up (temporal summation of sec-
ond pain) and neuroendocrine abnormalities (17). On the
other hand, some authors suggested that autonomic nervous
system dysfunction may play a role in the pathogenesis of
FM based on clinical and experimental research document-
ing autonomic nervous system involvement in FM patients
(2,3,5). Autonomic dysfunction has been suggested to be
associated with some of the FM symptoms as fatigue, morn-
ing stiffness, sleep disorders, anxiety, cold and clammy
hands, sicca symptoms and intestinal irritability (2,4,5,18).
The ANS, particularly sympathetic nervous system, is also
an important component of human stress response and acts
closely with the HPA axis (3)
ANS involvement in FM was ﬁrst described by Bengts-
son and Bengtsson who reported improvement in pain and
number of tend er points in response to stellate ganglion
blockade in a controlled trial (19). Based on their ﬁndings,
the researchers suggested that aberrant muscle sympathetic
nerve activity might be a possible mechanism in FM path-
ogenesis (19). Although Elam et al. reported similar resting
sympathetic nerve activity between patients and controls in
response to brief isometric muscle contraction, muscle is-
chemia and mental stress (20), Wachter showed muscle
dampening in pendulum test possibly due to sympathetic
stimulation of intrafusal muscle ﬁbers (21). Martinez-Lavin
suggested that sympathetic nervous system dysfunction
may explain complex symptomatology of FM, i.e., sympa-
thetic hyperactivity may explain endocrine abnormalities
like HPA axis dysfunction, sleep disorders, sicca symp-
toms, and pseudo-Raynaud’s phenomena (5,18). In our
patients, we found similar SSR latencies compared to
matched controls. On the other hand, close correlation be-
tween SSR latencies in hands and clinical measurements
renders an interesting clinical scenario that the sympathetic
nervous system may play an important role in FM
Table 1. Clinical variables of patients and relationship with sympathetic skin response latencies
Mean (SD) Min-max Palm latency r ( p) Sole latency r ( p)
CPS 12.9 (2.1) 8.8–17.5 0.56 (0.002) 0.20 (NS)
TMS 79.4 (10.4) 57.7–101.4 0.46 (0.012) 20.10 (NS)
HDRS 18.2 (5.7) 6–28 0.52 (0.004) 0.33 (NS)
HARS 20.9 (8.7) 8–38 0.50 (0.006) 0.42 (0.024)
FIQ-ﬁrst item 0.9 (0.4) 0–1.75 20.07 (NS) 20.05 (NS)
FIQ-ﬁfth item 6.8 (1.4) 4.3–9.5 20.15 (NS) 20.06 (NS)
CPS, control point score; TMS, total myalgic score; HDRS, Hamilton Depression Rating Scale; HARS, Hamilton Anxiety Rating Scale; FIQ-ﬁrst item,
Fibromyalgia Impact Questionnaire ﬁrst item score (patient’s physical functioning), FIQ-ﬁfth item, Fibromyalgia Impact Questionnaire ﬁrst item (visual
analog scale of pain); NS, not signiﬁcant; r, correlation coefﬁcient.
632 Ozgocmen et al./ Archives of Medical Research 37 (2006) 630–634
symptomatology. The fact that intra-individual variation of
amplitudes is considerably high, we reasonably preferred
to use latencie s. The intra-individual variation for latency
has been reported in a range of 2–22% and for amplitudes
2–48% in different studies (21–24).
Regarding microcirculation abnormalities, which are in
close relation with autonomic nervous system, contradic-
tory results have been reported in different studies. Some
of these studies suggested diminished vasoconstrictor re-
sponse to cold and/or noise stimuli (25,26), whereas others
reported contradictory ﬁndings in vasoconstrictor response
R-R interval variation is based on the variability of heart
rate in a relaxed state and following hyperventilation (2,29).
Indeed, heart rate variability is the result of the instanta-
neous relationship between excitatory, i.e., sympathetic,
and inhibitory, i.e., parasympathetic, neural inﬂuences on
the sino-atrial node automatism.
Martinez-Lavin et al. studied tilt table test in 19 female
patients with FM and 19 age-matched controls. These re-
searchers found that FM patients failed to increase their
low frequency band power after adopting the upright pos-
ture and they interpreted this result as an orthostatic sympa-
thetic derangement (30). These results were conﬁrmed by
other researchers using different types of maneuvers
(31–34). A further study by Martinez-Lavin and colleagues
demonstrated that FM patients had less heart rate variability
and altered circadian variation of sympathetic/parasympa-
thetic balance (35).
The major limitation of this study and also the method is
that R-R interval variation is computer drawn from a very
short period of recording of heart beat (nearly 1 min). A
longer period (i.e., 200–500 beats) would be more valuable
and help draw more ﬁrm conclusions.
Our study revealed lower values of heart rate variability
during deep breathing and difference between D% and R%.
Seven patients (24%) had abnormal RRIV, most of whom had
orthostatic intolerance, sleep disorders and sicca symptoms.
Together these ﬁndings may be interpreted that autonomic
nervous system dysfunction exists in FM and may be respon-
sible for some of the symptoms of this disorder. Additionally,
this study included patients who were not under medication,
in other words, drug-free patients who made the results of
this study more valuable.
In summary, these two practical methods, RRIV and
SSR, may help clinicians to evaluate involvement in spe-
ciﬁc subsystems of ANS like dysfunction of cardiovascular
reﬂex pathways and sudomotor system. Analysis of heart
rate variability may be useful and complementary to clini-
cal evaluation in patients with symptoms of dysfunction in
cardiovascular reﬂex pathways.
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SD, standard deviation; NS, not signiﬁcant.
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