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doi:10.1093/brain/awh441 Brain (2005), 128, 906–917
The role of opioids in restless legs syndrome:an [11C]diprenorphine PET study
Sarah von Spiczak,1,4 Alan L. Whone,1 Alexander Hammers,1,3 Marie-Claude Asselin,2
Federico Turkheimer,1 Tobias Tings,4 Svenja Happe,4 Walter Paulus,4
Claudia Trenkwalder4 and David J. Brooks1
Correspondence to: Sarah von Spiczak, Department of
Clinical Neurophysiology, Georg-August University
Goettingen, Robert-Koch-Strasse 40, D-37099 Goettingen,
Germany.
E-mail: [email protected]
1Division of Neuroscience and MRC Clinical Sciences
Centre, Faculty of Medicine, Imperial College and2Hammersmith Imanet, Hammersmith Hospital, London,3Department of Clinical and Experimental Epilepsy,
Institute of Neurology, UCL, London, UK, 4Department
of Clinical Neurophysiology and Georg-August University,
Goettingen, Germany
SummaryOpioids have been shown to provide symptomatic relief
from dysaesthesias and motor symptoms in restless legs
syndrome (RLS). However, the mechanisms by which
endogenous opioids contribute to the pathophysiology of
RLS remain unknown. We have studied opioid receptor
availability in 15 patients with primary RLS and 12 age-
matched healthy volunteers using PET and [11C]dipren-
orphine, a non-selective opioid receptor radioligand.Ligand binding was quantified by generating parametric
images of volume of distribution (Vd) using a plasma-
derived input function. Statistical parametric mapping
(SPM) was used to localize mean group differences
between patients and controls and to correlate ligand
binding with clinical scores of disease severity.
There were no mean group differences in opioid receptor
binding between patients and controls. However, we found
regional negative correlations between ligand binding and
RLSseverity (international restless legs scale, IRLS) inareas
serving the medial pain system (medial thalamus, amy-
gdala, caudate nucleus, anterior cingulate gyrus, insular
cortex and orbitofrontal cortex). Pain scores (affective
component of the McGill Pain Questionnaire) correlatedinversely with opioid receptor binding in orbitofrontal cor-
tex and anterior cingulate gyrus. Our findings suggest that,
the more severe the RLS, the greater the release of endo-
genous opioids within the medial pain system.We therefore
discuss a possible role for opioids in the pathophysiology of
RLS with respect to sensory and motor symptoms.
Keywords: PET; opiates; [11C]diprenorphine; pain; RLS
Abbreviations: IRLS = international restless legs scale; PLM = periodic limb movement; PLMS = periodic limb
movement in sleep; RLS = restless legs syndrome; SPECT = single photon emission computed tomography;
SPM = statistical parametric mapping; Vd = volume of distribution
Received March 17, 2004. Revised July 11, 2004. Accepted January 18, 2005. Advance Access publication
February 23, 2005
IntroductionRestless legs syndrome (RLS) is a common neurological dis-
order affecting up to 10% of the Caucasian population
(Rothdach et al., 2000) and may lead to significant levels of
morbidity. RLS exists in both primary (often hereditary) and
secondary forms, and is clinically characterized by an urge to
move associated with sensory, sometimes even painful sensa-
tions deep within the legs and feet. Symptoms occur in situ-
ations of rest and relaxation and are worse in the evening and at
night. Voluntary movements provide temporary relief. RLS is
a clinical diagnosis and criteria have been defined by the Inter-
national RLS Study Group (Allen et al., 2003; Walters, 1995).
In addition, involuntary leg movements, termed ‘periodic
limb movements’ (PLM), may occur during sleep and lead
to frequent arousal or awakening. The most severe problem
for RLS patients is sleepdisturbance and restlessness during the
evening, which may impact on all other aspects of life.
The aetiology and pathophysiology of primary RLS remain
unknown.Levodopaanddopamineagonistsaresymptomatically
# The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
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effective in the majority of RLS patients (Hening et al.,
1999). However, imaging studies have failed to reveal any
consistent functional changes in the nigrostriatal dopaminer-
gic system, with several position emission tomography (PET)
and single photon emission computed tomography (SPECT)
studies showing either no (Trenkwalder et al., 1999;
Eisensehr et al., 2001; Linke et al., 2004; Tribl et al., 2004)
or only mild reductions in dopamine terminal [18F]dopa
uptake, transporter binding, or postsynaptic dopamine D2
receptor binding (Turjanski et al., 1999; Ruottinen et al.,
2000; Michaud et al., 2002; Mrowka et al., 2004). The res-
olution of PET and SPECT used in these studies was of the
order of 5–8 mm and only examined striatal function and so
substriatal or brainstem/spinal changes in dopaminergic func-
tion would not have been detected.
Major components of RLS are dysaesthesias and pain,
which appear to promote the urge to move. Consistent
with this viewpoint, opioid receptor agonists, which are
known to act predominantly on the pain system, have been
found to significantly improve RLS symptoms (Hening et al.,
1986; Ondo, 2004; Trzepacz et al., 1984; Walters et al., 1993;
Walters et al., 2001; review in: Walters, 2002).
Changes in opioid receptor availability in chronic pain syn-
dromes such as rheumatoid arthritis and trigeminal neuralgia
(Jones et al., 1999; Jones et al., 1991a) have previously been
demonstrated using [11C]diprenorphine, a non-specific opioid
receptor antagonist with similar affinities for mu, kappa and
delta receptor subtypes, and PET. In these studies, ligand bind-
ing was reported to be decreased in areas involved in pain
perception, including ‘prefrontal’, insular and cingulate corti-
ces, thalamus and the basal ganglia, compatible with either
heightened endogenous opioid release and/or receptor intern-
alization. More recently, Willoch et al. (2004) investigated
[11C]diprenorphine binding in central post-stroke pain in a
limited number of patients and showed reduced binding in
thalamus, parietal, secondary somatosensory, insular and lat-
eral prefrontal cortices contralateral to the lesion as well as in
anterior and posterior cingulate cortices along the midline and
in midbrain grey matter. These findings were supported by
Jones et al. who again measured [11C]diprenorphine binding
in central neuropathic pain, mainly post-stroke pain, and found
reductions in similar areas with exception of the secondary
somatosensory cortex and prefrontal areas (Jones et al., 2004).
In addition to alterations in chronic pain, [11C]dipren-
orphine binding has been reported to be decreased in striatal
regions in a number of hyperkinetic movement disorders
including dyskinetic Parkinson’s disease (Piccini et al.,
1997) and Huntington’s disease (Weeks et al., 1997). In
the afore mentioned neurodegenerative diseases preclinical
investigations have suggested that altered opioid transmission
within the basal ganglia may, in part, be responsible for the
genesis of involuntary movements (Augood et al., 1996;
Henry et al., 1999; Henry et al., 2001).
We have investigated opioid receptor availability in
patients with idiopathic RLS using [11C]diprenorphine PET
and discuss a possible role for opioidergic dysfunction in the
pathophysiology of this condition with respect to motor and
pain symptoms. Statistical parametric mapping (SPM) was
used to compare group means and to correlate opioid receptor
binding with clinical ratings of RLS severity.
MethodsSubjectsFifteen Caucasian patients with idiopathic RLS (five men; 10
women; mean age = 45.2, SD = 15.8 years) and 12 age-matched
healthy volunteers (five men; seven women, mean age = 45.6, SD =
12.1; P = 0.95) were recruited from a specialized outpatient clinic at
the Department of Clinical Neurophysiology, Goettingen, Germany,
and by advertisements in London, UK, respectively.
All pre-examinations were performed at the Department of Clin-
ical Neurophysiology in Goettingen, Germany, during a 2 day stay in
hospital. A thorough medical and neurological examination was
performed in all patients (TT and CT) and patients with severe
medical or neurological disorders such as cardiovascular problems
were excluded from participation in this study. All patients fulfilled
the minimum clinical diagnostic criteria for RLS (Allen et al., 2003;
Walters, 1995) and underwent two nights of polysomnography to
confirm the diagnosis. Polysomnography provides an objective
measure of PLM and their effect on sleep stages. The sleep profile
of RLS patients characteristically consists of a reduced sleep
efficiency caused by frequent awakenings mostly attributable to
periodic limb movements in sleep (PLMS) and a low or absent
percentage of deep sleep (stage 3 and 4). Using polysomnography
the clinical diagnosis of RLS was confirmed and differential
diagnoses such as respiratory disorders or parasomnias were ruled
out. Polysomnographic recordings were analysed according to
Rechtschaffen and Kales (1968) by an experienced sleep specialist
(SH). Patients were included only if they had a PLMS-index of
greater than five movements per hour or a severe sleep disorder
consistent with the diagnosis of RLS. Patient 15 had no polysomno-
graphic recordings owing to technical reasons and data from three
patients (Patients 2, 11 and 13) were not valid enough to be correl-
ated with clinical scores and PET data because of severe sleep
disturbances (one of these had to be excluded from the SPM analysis
anyway because of problems with blood collection during the PET
scan, see further down). However, as these patients fulfilled the
clinical diagnostic criteria and all had a positive family history of
RLS, they were included in the study.
Periodic limb movements in sleep were counted visually and
PLMS-indices per hour of total sleep time as well as the sleep
efficiency were calculated (mean = 74.55%, SD = 14.42%, range =
52–94% for sleep efficiency; mean = 391.91 min, SD = 83.02 min,
range = 281–569 min for total sleep time and mean = 36.31, SD =
33.62, range = 0–91.63 for PLMS/h).
Nerve conduction studies (electrophysiological tests) of the right
peroneal and sural nerves were performed to exclude a peripheral
neuropathy. Subjects also had blood tests (blood count, iron, ferritin,
folic acid, vitamin B12, renal and thyroid function) to exclude iron
deficiency, haematological or thyroid dysfunction. The above invest-
igations were undertaken to rule out secondary forms of RLS.
RLS symptom severity was assessed using scores obtained on
the International Restless Legs Scale (IRLS). This scale was
developed and validated by the International Restless Legs
Syndrome Study Group (IRLSSG, 2003) and contains questions
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that relate to the frequency and overall severity of (motor) symptoms
(e.g. restlessness and urge to move), severity of sleep disturbances
and the impact on the patient’s daily living. Using this scale, patients
are asked to rate the above-mentioned features for the previous two
weeks.
To assess pain severity, a German version of the McGill Pain
Questionnaire (Stein and Mendl, 1988) was used. This questionnaire
offers a list of 78 adjectives used to describe different qualities
(sensory, affective and evaluative) and different degrees of pain
severity. The words are divided into subclasses and rated from
least to worst pain within each subclass (Melzack, 1975; Stein
and Mendl, 1988). In contrast to the original version, where patients
are asked to rate their current pain, we asked patients to select words
that characterize their usual RLS symptoms, therefore these ratings
do not refer to a limited time period.
Both scales were completed whilst patients were in hospital for
pre-examinations.
Correlations of polysomnographic parameters (PLMS/h and
sleep efficiency) with the individual scores of the IRLS and total-
and sub-scores of the McGill Pain Questionnaire were calculated in
SPSS1 using a Pearson linear correlation.
Patients were either untreated or taking low doses of levodopa or
dopamine agonists (Table 1). RLS medication was stopped at least
48 h prior to PET scanning. Neither patients nor controls had pre-
viously been treated with opioid agonists.
In London, UK, T1-weighted MRI scans were performed on the
same day of PET scanning in all but one patient (Patient 15) in order
to screen out any morphological abnormalities.
The study was approved by the Ethics Committees of the Georg-
August University Goettingen, Germany, and the Hammersmith Hos-
pitals Trust, London, UK. Written informed consent was requested
separately by both review boards and was signed in Goettingen and in
London. Permission to administer radioactivity was obtained from the
Administration of Radioactive Substances Advisory Committee
(ARSAC) of the Department of Health, UK. This study was performed
according to the requirements of the Declaration of Helsinki.
Scanning procedurePositron emission tomography scans in 3D acquisition mode
were performed at the Cyclotron Building, MRC Clinical
Sciences Centre, Hammersmith Hospital, London, UK.
Prior to administration of the radioactive tracer, a 5 min
transmission scan was performed using a rotating point
source of 150 MBq of [137Cs] to correct acquired emission
data for tissue attenuation. 185 MBq (5 mCi) of [11C]dipren-
orphine in 5 ml of normal saline were injected intravenously
as a bolus over 30 s and dynamic emission data were collected
in list mode over the following 95 min using an ECAT
EXACT3D PET scanner (model 966, CTI, Knoxville, TN,
USA) (Spinks et al., 2000). Emission data were re-binned into
32 time frames, corrected for attenuation and scatter [using
the model-based method of Watson et al. (1996)] and recon-
structed using a reprojection algorithm (Kinahan and Rogers,
1989), with Colsher and ramp filters set at Nyquist frequency,
into images with a spatial resolution of 5.1 mm 3 5.1 mm 3
5.9 mm (full width half maximum, FWHM). Arterial blood
activity was sampled continuously over the whole time of the
scan using a BGO (bismuth germanate) detector system
(Ranicar et al., 1991) at pump rates of 300 ml/h (5 ml/min)
for the first 10 min and of 150 ml/h (2.5 ml/min) thereafter.
Discrete samples were taken at 5, 10, 20, 30, 40, 60, 75 and
90 min and processed for the determination of the ratio of
radioactivity concentration in plasma and whole blood and
the peripheral metabolism of [11C]diprenorphine in order to
create a metabolite corrected plasma input function.
Quantification of [11C]diprenorphine binding[11C]Diprenorphine uptake was quantified using spectral
analysis with individual metabolite corrected plasma input
Table 1 Demographic data of RLS patients
Patient Sex Age(years)
Age of onset(years)
Duration ofdisease (years)
Familyhistory*
Medication**(per day)
1 F 24 14 10 + �2 M 64 7 57 + Pergolide 2 mg3 M 62 47 15 + Cabergoline 3 mg4 F 47 42 5 � �5 F 23 16 7 � L-Dopa on demand6 F 34 24 10 + �7 F 63 40 23 + Pergolide 0.5 mg8 M 62 26 36 + �9 F 49 35 14 + �
10 M 43 23 20 + �11 F 53 23 30 + L-Dopa 100 mg +
L-dopa retard 100 mg12 F 30 28 2 + �13 F 49 45 4 + �14 M 25 5 20 + �15 F 67 45 22 + L-Dopa 100 mg +
L-dopa retard 100 mgMean 6 SD 45.2 6 15.8 29 6 13.9 18.3 6 14.5
* + , positive family history; �, negative family history; **all medication was stopped at least 48 h prior to PET scanning.
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functions to create parametric images of ligand volume of
distribution (Vd) (Cunningham and Jones, 1993). The Vd is
the ratio of tissue to free plasma ligand concentration at
equilibrium and provides an estimate of receptor binding
(Jones et al., 1994). Parametric images of Vd were created
using RPM (receptor parametric mapping, spectral analysis:
MRCCU, Vin Cunningham and Roger Gunn) as implemented
in Matlab5 (The MathWorks, Inc., Natick, MA, USA) and
thus provided the Vd for each and every voxel (voxel size
2.096 mm 3 2.096 mm 3 2.43 mm). In one subject (Patient
11) the initial part of the on line blood collection was inter-
rupted, rendering the plasma input function unreliable. This
subject was, therefore, excluded from assessments of Vd.
In order to include this subject in an analysis of study out-
comes, parametric ratio images of specific to non-specific
[11C]diprenorphine binding were created in addition to para-
metric images of Vd, using the occipital cortex as a reference
region. By using a reference region approach, radioligand
measurements in blood are no longer required to provide
an input function. This dual approach of quantifying
[11C]diprenorphine uptake using both spectral analysis and
tissue specific:non-specific ratios has previously been
employed by our laboratory (Piccini et al., 1997; Weeks
et al., 1997). Ratio images were generated from 60 to 90 min
following radioligand injection using software developed in
house created in IDL (interactive data language, Research
Systems International, Boulder, CO, USA).
Prior to statistical analysis, [11C]diprenorphine Vd and
ratio images were normalized to the space defined by the
Montreal Neurological Institute (MNI)/International Consor-
tium for Brain Mapping (ICBM) T1-weighted 152 brain aver-
age as supplied with SPM99, using an [11C]diprenorphine
template created in house from the PET scans of seven
healthy volunteers. Smoothing was applied with a Gaussian
kernel of 8 mm3 8 mm3 8 mm.
Image analysis: statistical parametricmappingStatistical parametric mapping (SPM99) was applied to both
parametric Vd and ratio images to localize mean group differ-
ences in [11C]diprenorphine uptake between RLS patients and
controls on a voxel-by-voxel basis (Friston, 1995) (SPM99,
Wellcome Department of Cognitive Neurology, London, UK).
Within SPM, significant differences were assessed using
parametric statistics. The resulting statistics had Student’s t
distribution under the null hypothesis. Using SPM, values of
the t statistic are corrected for multiple comparisons using a
theory of random fields approach. They are converted into Z
scores and assembled into an image (statistical parametric
map).Tovisualize thestatisticalparametricmaps, the threshold
was set toP< 0.01 uncorrected excluding clusters with a spatial
extent of <50 voxels. Using the same significance threshold and
cluster extent, comparisons to localize differences between
patients and controls were performed using normalized ratio
images.Forbothanalyses, the thresholdwas reduced toP<0.05
uncorrected with a cluster extent of 50 voxels when the first
analysis did not reveal any significant results.
SPM was also used to localize clusters where ligand bind-
ing (using both Vd and ratio images) correlated significantly
with individual scores of the IRLS and total- and sub scores
(sensory, affective, evaluative, miscellaneous) of the McGill
Pain Questionnaire. As described above, the threshold was
initially set to P < 0.01 uncorrected with a cluster extent of 50
voxels and reduced to P < 0.05 uncorrected with a cluster
extent of 50 voxels if no changes where localized at the P <
0.01 level. Therefore, by using the method described, we
initially evaluated the entire brain volume (>200 000 voxels).
However, clusters localized at the above stated thresholds
were investigated further using regional volume correction.
This was applied to the SPM map by using a single template
object image which defined all of the regions for which we
had an a priori hypothesis for change in opioid receptor
availability in RLS. These hypotheses were based on pre-
viously reported activation (Firestone et al., 1996; Adler
et al., 1997; Peyron et al., 2000; Casey, 2000a) and
[11C]diprenorphine PET studies (Jones et al., 1991a; Jones
et al., 1991b; Jones et al., 1999) in different conditions of
clinical and experimental pain and an fMRI study investig-
ating activated brain areas in RLS (Bucher et al., 1997). The
regions included: caudate nucleus, putamen, thalamus,
insular cortex, anterior cingulate gyrus, orbitofrontal cortex,
amygdala, midbrain and pons. The primary sensory cortex
was not included as the lateral (discriminating) pain system is
relatively devoid of opioid receptors (see discussion). Using
regional volume correction, voxels outside the above men-
tioned regions were not compared, therefore reducing the
number of comparisons made and consequently the level
of statistical correction required.
In a similar manner correlations between polysomno-
graphic parameters (PLMS/h and sleep efficiency) and tracer
binding were calculated.
Finally, we analysed the subgroup of untreated de novo
patients (n = 9) in the same way as described above to test
whether medication had a major influence on the results.
ResultsPatientsDemographic details for the RLS patients are shown in
Table 1. Clinical status, as assessed by IRLS scores and
scores and sub scores of the McGill Pain Questionnaire,
are shown in Table 2. The MRI scans performed in all
patients (with the exception of Patient 15) were normal in
every case.
Significant correlations of polysomnographic parameters
(n = 11) were found between the IRLS and the sleep effici-
ency (r = �0.690; P = 0.019) and between the IRLS and the
PLMS-index (r = 0.656; P = 0.028). Following a Bonferroni–
Holm correction for multiple comparisons, none of these
correlations remained significant.
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Analysis of group meansNeither at a threshold of P < 0.01 uncorrected nor at the
reduced threshold of P < 0.05 uncorrected (both times
with a cluster extent of 50 voxels), did SPM localize any
significant clusters of group mean decreased or increased
opioid receptor binding between RLS patients and controls
throughout the brain when assessing both [11C]diprenorphine
Vd and uptake ratio images. Furthermore, there were no cor-
relations between [11C]diprenorphine Vd or ratio images and
age or disease duration. No gender differences in ligand
binding were seen.
Correlation analysis: Vd imagesWhen applied to Vd images, at a P < 0.01 uncorrected thresh-
old and a cluster extent of 50 voxels, SPM localized negative
correlations between [11C]diprenorphine binding and RLS
symptom severity (IRLS score) (n = 14 patients) in bilateral
insular, orbitofrontal and anterior cingulate cortices, and
bilateral medial thalamus, amygdala and caudate nucleus
(Fig. 1). High severity scores correlated with low opioid
receptor availability. The voxel with the highest t value
was in the left amygdala (t = 5.48, Z = 3.81, SPM coordinates
�18, 8, �24) and part of a large cluster of 2806 voxels (P =
0.002, corrected for the entire brain volume), which included
the amygdala, insula and caudate nucleus in the left hemi-
sphere and caudate nucleus and medial thalamus in the right
hemisphere.
The results of the investigation examining clusters local-
ized in the above analysis following regional volume correc-
tion are shown in Table 3. Regional cluster corrected P values
are quoted following regional volume correction, which was
applied as outlined in the methods section.
In order to further examine the effect sizes of these regional
negative correlations between [11C]diprenorphine Vd and
RLS severity (IRLS), individual regional Vd data were
extracted from 6 mm diameter spheres centred on the
peak voxel of significant correlation within the amygdala,
thalamus, anterior cingulate gyrus and orbitofrontal cortex.
These correlations are shown in Fig. 2.
At the reduced threshold of P < 0.05 uncorrected with a
cluster extent of 50 voxels, SPM also localized negative
correlations between [11C]diprenorphine binding (Vd, n =
14) and the affective component of the McGill Pain
Questionnaire bilaterally in orbitofrontal cortex, anterior
cingulate gyrus and caudate nucleus (Fig. 3). The voxel
with the highest t value was in a large 2447 voxel cluster,
which included the orbitofrontal cortex and right insula [t =
4.19; Z = 3.23; SPM coordinates: �16, 32, �16; P = 0.362
(corrected for the entire brain)]. After regional volume
correction, applied as outlined above, none of the regional
correlations remained significant.
Correlation analysis: ratio imagesInterrogating images of specific:non-specific radioligand
uptake ratios with SPM revealed no significant correlations
when the significance threshold was set to P < 0.01 uncor-
rected with a cluster extent of 50 voxels. However, following
reduction of the threshold to P < 0.05, the same regional
pattern of negative correlations (amygdala, thalamus, caudate
nucleus, anterior cingulate gyrus, insular and orbitofrontal
cortex) was seen between [11C]diprenorphine specific:non-
specific uptake ratios and the IRLS score when all RLS
patients were included (Fig. 4). Regional volume correction
yielded a significant cluster of 683 voxels centered on the
right medial thalamus (t = 2.93; Z = 2.52; SPM coordinates: 6,
�8, 12; P = 0.008) and encompassing the medial thalamus
and caudate nuclei bilaterally. For completeness, a ratio
SPM analysis was also performed with subject 11 excluded
Table 2 Clinical status of RLS patients assessed by IRLS and McGill Pain Questionnaire
Patient IRLS McGill Pain Questionnaire
Sensory Affective Evaluative Miscellaneous Total
1 17 3 0 1 4 82 35 18 5 1 7 313 37 8 1 5 3 174 25 17 4 1 11 335 23 6 3 4 4 176 17 10 6 1 3 207 30 19 1 1 1 228 23 7 1 1 5 149 27 15 7 5 7 34
10 25 12 5 4 8 2911 36 21 8 5 6 4012 15 10 2 0 4 1613 25 8 0 1 1 1014 19 17 2 3 3 2515 27 23 1 3 5 32Mean 6 SD 25.4 6 6.9 12.9 6 6.1 3.1 6 2.6 2.4 6 1.8 4.8 6 2.7 23.3 6 9.6
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(i.e. n = 14: the same population as for the Vd analysis) and
the same results as for the above mentioned n = 15 ratio
analysis were obtained.
Negative correlations were also found between
[11C]diprenorphine ratio images (n = 15) and the affective
component of the McGill Pain Questionnaire in the orbito-
frontal cortex, left anterior cingulate gyrus and left caudate
nucleus at P < 0.05 uncorrected threshold and a cluster extent
of 50 voxels.
No clusters of positive correlation between [11C]dipren-
orphine Vd or ratio images and either the IRLS scores or
the affective component of the McGill Pain Questionnaire
were localized. Neither the total score nor other components
of the McGill Pain Questionnaire correlated with ligand
binding.
The correlation analysis of sleep laboratory measurements
and [11C]diprenorphine binding (n = 11) showed a significant
positive correlation in two clusters (P < 0.01), one included
Fig. 1 Localized clusters of negative correlations between [11C]diprenorphine Vd (n = 14) and RLS severity (IRLS) at P < 0.01 uncorrectedthreshold, cluster extent of 50 voxels. All clusters throughout the whole brain are demonstrated (top left) in the maximum intensityprojection ‘glass brain’ from SPM99. The top right and bottom two panels show significant clusters overlain on the Montreal NeurologicalInstitute single subject representative brain from SPM99. The colour bar represents Z values of statistical significance.
Table 3 Localized regional negative correlations between [11C]diprenorphine Vd (n = 14) and RLS severity (IRLS)following regional volume correction
Region SPM coordinates (mm) Cluster size(voxels)
t Score Z Score Regionalvolume-correctedP value
x y z
Right caudate 8 18 2 193 4.53 3.39 0.034Left caudate �6 12 2 270 3.90 3.08 0.013Medial thalamus* 4 �4 4 269 3.90 3.07 0.013Anterior cingulate gyrus* 0 4 28 241 3.59 2.90 0.018Right insula 46 �2 0 243 3.24 2.70 0.018Left insula �46 �4 6 376 4.29 3.28 0.004Orbitofrontal cortex 2 64 �18 63 3.52 2.86 N.S. (0.233)Right amygdala 18 2 �20 119 3.47 2.83 N.S. (0.096)Left amygdala �18 8 �24 138 5.48 3.81 N.S. (0.073)
N.S. = not significant; *Cluster extends over both left and right sides.
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parts of pre- and postcentral gyrus (representing neck,
arm, shoulder, very close to the edge of the image); the
other was within the inferior posterior temporal lobe.
There was no negative correlation between tracer binding and
PLMS/h at significance thresholds up to P < 0.05. Further-
more, there were no significant correlations with the sleep
efficiency.
Correlation analyses using only the subgroup of untreated
de novo patients (n = 9) showed the same regional patterns of
negative correlation between [11C]diprenorphine and IRLS
score as described above, although these correlations failed to
reach significance.
DiscussionThis is the first study to measure opioid receptor binding in
RLS patients using PET. We have found significant negative
correlations between opioid receptor availability and severity
of RLS symptoms in brain regions involved in the medial
affective pain system. Using both an [11C]diprenorphine Vd
and specific:non-specific uptake ratio approach to ligand
quantification, negative correlations were seen in orbito-
frontal, insular and cingulate cortices, medial thalamus, caud-
ate nucleus and amygdala bilaterally.
This decrease in [11C]diprenorphine binding may indicate
increased occupancy of opioid receptors by endogenous
opioids and, therefore, reflect their heightened release.
Thus, one possible interpretation is that the more severe
the symptoms of RLS the greater the endogenous release
of opioids in the medial affective pain system. Furthermore,
scores of the affective component of the McGill Pain Ques-
tionnaire were inversely correlated with ligand binding in
orbitofrontal areas and anterior cingulate gyrus. Again, this
may indicate increased opioid release caused by pain/dysaes-
thesia leading to decreased opioid receptor availability. Other
possible explanations for reduced [11C]diprenorphine bind-
ing, such as receptor internalization and/or receptor down
Fig. 2 Effect sizes for correlations between [11C]diprenorphine uptake (Vd) and RLS severity (IRLS scores). Open rhombus: rightamygdala; closed circle, left amygdala; in the anterior cingulate gyrus and orbitofrontal cortex the clusters extend over both hemispheres.
Fig. 3 Localized clusters of negative correlations between[11C]diprenorphine Vd (n = 14) and the McGill Pain Questionnaireaffective subscores at P < 0.05 uncorrected threshold with acluster extent of 50 voxels. The localized clusters are shownoverlain on the Montreal Neurological Institute single subjectrepresentative brain from SPM99. Z values of statisticalsignificance are represented by the colour bar on the right.
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regulation cannot be distinguished from the above-mentioned
hypothesis with the technique of PET, but seem to be less
likely. Atrophy of specific brain regions as a possible
explanation for reduced ligand binding is ruled out by normal
MRI scans.
[11C]Diprenorphine PET did not reveal any regional dif-
ferences in opioid receptor availability when categorically
comparing the patient and control group means.
We have investigated opioid receptor availability using
[11C]diprenorphine PET in a homogeneous group of RLS
patients as pre-examinations excluded all patients with sec-
ondary forms of RLS and 13 out of 15 patients reported a
positive family history suggesting mostly hereditary forms.
All patients fulfilled the criteria for a chronic syndrome with a
moderate to severe manifestation of symptoms over more
than six months. Scores of the IRLS were evenly distributed
and the lowest score was 15, which is the minimum value now
required for inclusion in many treatment trials. Not all of our
RLS patients were untreated de novo patients: three were
taking low doses of L-dopa formulations and three were
receiving dopamine agonists (medication was stopped 48 h
prior to PET). This medication could have affected our PET
results; however, this seems to be unlikely given the fact that
we found similar patterns of reduced [11C]diprenorphine
binding as for the whole patient group when correlating tracer
binding and RLS/pain severity in the subgroup of nine
untreated de novo patients. These correlations did not
reach significance due to reduced statistical power in this
smaller subset.
The sleep efficiency as well as the PLMS-index was cor-
related with RLS severity as measured with the IRLS. This
supports findings by Garcia-Borreguero and colleagues, who
recently reported significant correlations between IRLS
scores and various sleep laboratory measurements (Garcia-
Borreguero et al., 2004). However, there is some doubt about
the correlation with PLMS/h as the individual values were not
evenly distributed.
As the correlation of PET data with the PLMS-index is
positive in contrast to negative correlations with the severity
scale and occurs in anatomical regions that have not been
shown to be activated in RLS/during periodic leg movements
(Bucher et al., 1997) we do not believe that they represent
true biological findings but occurred by chance and/or due to
edge effects.
Although opioids are known to reduce sensory and motor
symptoms in RLS patients, the involvement of pain systems
in the pathophysiology of RLS has previously only been
demonstrated using H2[15O] PET, as evidenced by changes
in regional cerebral blood flow (rCBF) in two RLS patients
(San Pedro et al., 1998). In these patients (father and daugh-
ter), rCBF was significantly decreased in caudate nucleus and
significantly increased in the thalamus bilaterally with
Fig. 4 Localized clusters of significant negative correlations between [11C]diprenorphine uptake ratios (n = 15) and RLS severity (IRLS)at P < 0.05 uncorrected threshold, cluster extent of 50 voxels. All of the significant localized clusters throughout the whole brain aredemonstrated (top left) in the maximum intensity projection ‘glass brain’ from SPM99. The top right and bottom two panels showsignificant clusters overlain on the Montreal Neurological Institute single subject representative brain from SPM99. The colour barrepresents Z values of statistical significance.
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increasing pain. Levodopa reduced pain and normalized
blood flow in these two cases. Using functional magnetic
resonance imaging (fMRI), Bucher et al. (1997) showed
activation in the cerebellum bilaterally and in the thalamus
contralaterally to the affected leg during the condition of
sensory leg discomfort. More recently, increased ratings of
pin-prick pain were reported in untreated RLS patients indic-
ating static hyperalgesia that was more pronounced in the
lower limb and reversed by long-term dopaminergic treat-
ment (Stiasny-Kolster et al., 2004). In addition to these find-
ings we report alterations in opioid receptor availability in
structures that constitute the medial pain system in a large
group of idiopathic RLS patients.
Pain perception can be divided into sensory-discriminative
and affective-motivational components. Post-mortem studies
(Pfeiffer et al., 1982; Atweh and Kuhar, 1983; Peckys and
Landwehrmeyer, 1999) as well as functional imaging studies
using [11C]diprenorphine PET (Jones et al., 1991b) have
shown high levels of opioid receptor binding in structures
known as the medial pain system. This system projects
through medial and intralaminar nuclei of the thalamus to
several cortical and limbic regions: frontal and insular cor-
tices and anterior cingulate gyrus. It is thought to mediate
affective-motivational aspects of pain such as emotional reac-
tions, arousal and attention to the stimulus, as well as the
drive to escape from the noxious stimuli (Treede et al., 1999).
In contrast to the medial (affective) pain system, the lateral
(sensory-discriminative) pain system (projecting to the prim-
ary sensory cortex) is relatively devoid of opioid receptors
(Jones et al., 1991b).
Following experimentally induced pain in the masseter
muscles, significant negative correlations between mu-
opioid receptor binding measured with [11C]carfentanil
PET and affective subscores of the McGill Pain Question-
naire have previously been shown bilaterally in the dorsal
anterior cingulate cortex and thalamus and ipsilaterally in the
nucleus accumbens. Additional correlations with McGill Pain
Questionnaire sensory scores were found in thalamus, nuc-
leus accumbens and amygdala ipsilateral to the painful stimu-
lus (Zubieta et al., 2001).
In contrast to these findings, we found no correlations in
the nucleus accumbens, possibly due to the fact that we used a
non-specific opioid receptor antagonist as a PET-radioligand,
which binds similarly to all three subtypes of opioid recept-
ors. However, even more important may be the fact that our
RLS patients were not experiencing frank pain during the
scan. In contrast to the study of Zubieta et al. (2001) who
studied acute, experimentally induced pain, the dysaesthesia
in RLS is a chronic condition and static mechanical hyper-
algesia has been shown to occur in RLS patients indicating
permanent changes in pain modulation mechanisms (Stiasny-
Kolster et al., 2004); therefore, opioid binding changes may
differ from those changes that occur during acute pain. Fur-
thermore, we found negative correlations of [11C]dipren-
orphine binding in the medial pain system not only with
the McGill Pain Questionnaire but also with IRLS scores,
a clinical score assessing RLS severity, which is biased
towards motor (restlessness) symptoms rather than sensory
(pain) phenomena. There were no correlations with the
sensory part of the McGill Pain Questionnaire, which is
explicable if one considers the paucity of opioid receptors
in the lateral pain system, which is responsible for mediating
sensory-discriminative aspects of pain perception (Jones
et al., 1991b).
The cluster localized in the cerebellum (Fig. 3) in the
correlations between [11C]diprenorphine Vd and the affective
component of the McGill Pain Questionnaire was not seen
when correlating this clinical score with ratio images and
given the predominantly white matter and mid line location
of this cluster we cannot rule out this being an artefact.
However, the above mentioned fMRI study by Bucher
et al. (1997) has shown activation in the cerebellum during
sensory RLS symptoms and the presence of opioid receptors
in this brain region was proven by [11C]diprenorphine PET,
mRNA expression and autoradiography studies (Schadrack
et al., 1999). Furthermore, changes in rCBF during experi-
mentally induced pain and following the administration of
opioid receptor agonists have also been shown in the cere-
bellum (Firestone et al., 1996; Peyron et al., 2000; Casey
et al., 2000b).
Although our negative correlations occurred in regions
serving the medial pain system, only a minority of our
RLS patients described pain as a major symptom. In personal
interviews several patients reported their symptoms to be
‘painful in some way, but not like a typical pain such as
toothache’ and finally judged these feelings as being ‘non-
painful’. The McGill Pain Questionnaire offers a list of
descriptions and patients were asked to choose those words
that described their symptoms best. Therefore, we obtained
an impression of the quality and quantity of the patients’
usual RLS symptoms and found that by a standardized
questionnaire symptoms were rated as being painful although
the quality of this pain seemed to be somewhat different
from ‘typical pain’ as indicated by the discrepancy between
subjective statements and standardized scores. Mean values
of McGill Pain Questionnaire total- and subscores in
RLS (Table 2: mean = 23.3, SD = 9.6 for the total score)
were within the middle range compared to other chronic
pain syndromes [e.g. arthritis: McGill Pain Questionnaire
total score of 18.8, back pain: total score of 26.3,
(Melzack, 1975)].
We found correlations between opioid receptor binding
and severity scores not only in areas of the medial pain system
but also in the caudate nucleus and amygdala bilaterally. The
medial pain system as well as the amygdala is known to
interact with the basal ganglia which Chudler and Dong
(1995) speculated might play a role in the integration of
incoming sensory information, so aiding planning of a
coordinated motor response to pain perception. As the
basal ganglia receive information from areas involved in
sensory-discriminative as well as affective-motivational
processing of painful stimuli this may include both direction
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and speed of escape behaviour and the motivational drive to
terminate the noxious stimulus.
It is possible that such basal ganglia motor activity
following noxious stimulation might be regulated via
dopamine–opiate interactions. For example, Chudler and
Dong (1995) stated that reductions in central levels of dopam-
ine are able to reverse the analgesia caused by opioids. Apo-
morphine has been shown to have a biphasic effect on
morphine induced analgesia with lower doses attenuating
analgesia (probably via presynaptic autoreceptor stimulation)
and higher doses potentiating the antinociceptive effect of
morphine (via postsynaptic dopamine receptor stimulation)
(Gupta et al., 1989; Paalzow and Paalzow, 1983). Further-
more, dopamine–opiate interactions seem to depend on the
type of the stimulus as well as on the response/response
selection mechanisms evoked by this stimulus (Dennis and
Melzack, 1983) and on the brain area integrating the response
(Gupta et al., 1989; Paalzow and Paalzow, 1983). With
respect to striatal and extrastriatal regions, opioid receptor
agonists increase D2 and D3 receptor binding of PET radi-
oligands [[11C]raclopride for striatal (Hagelberg et al., 2002)
and [11C]FLB 457 for extrastriatal dopamine receptor binding
(Hagelberg et al., 2004)] and decrease binding of the SPECT
tracer [123I]beta-CIT to presynaptic dopamine transporters
(Bergstrom et al., 1998). This may reflect reduced dopamine
release and increased dopamine reuptake, but is dependent
on the kind of the opioid receptor agonist (Lubetzki et al.,
1982). Whether and how these different mechanisms contrib-
ute to the pathophysiology of RLS remains unclear at this
time; dopamine–opiate interactions are very complex, and
may occur also on a spinal level [for review see Trenkwalder
and Paulus (2004)].
We speculate that motor symptoms and especially the rest-
lessness in RLS result from a disturbed balance of dopamine–
opiate inputs to brain regions involved in motor actions and/
or pain perception and may represent an aberrant behavioural
response to sensory input. This might also explain why both
dopaminergic agents and opioids are almost equally effective
in RLS treatment. Furthermore, an altered balance between
dopamine and opioid action rather than an absolute deficit of
one neurotransmitter might be a reason for our failing to
demonstrate mean group differences between patients and
controls in opioid receptor availability as well as for the
inconsistent findings of other imaging studies investigating
dopaminergic function in the basal ganglia. Discussing their
findings, authors of these studies raised the possibility of
changes in dopaminergic systems other than the nigrostriatal
projection, for example spinal and the diencephalic dopam-
inergic system thought to be involved in pain regulation
(Lindvall et al., 1983).
In contrast to other hyperkinetic movement disorders
where changes in opioid receptor availability have been
shown in the basal ganglia, for example reduced ligand bind-
ing in striatal regions in dyskinetic Parkinson’s disease
(Piccini et al., 1997) and decreased [11C]diprenorphine
uptake in caudate nucleus and putamen in patients with
Huntington’s disease (Weeks et al., 1997), in patients with
idiopathic RLS opioid receptor function seems to be affected
primarily in sensory and association but not in motor areas.
This might suggest hyperkinetic motor symptoms in RLS are
secondary to sensory symptoms. Consistent with this view is
that sensory discomfort and the urge to move are the first
symptoms in RLS followed by a voluntary or involuntary
(PLM) motor response (Pelletier et al., 1992; Trenkwalder
et al., 1996).
Our finding that mean [11C]diprenorphine binding was not
different between the patient and control group may indicate
that there is not an overall change of endogenous opioid
transmission in RLS. Increased and possibly abnormal sens-
ory input might cause a secondary deficit of endogenous
opioids that results in insufficient levels of endogenous
opioids. The source of these abnormal sensations in RLS
still remains unknown. The primary cause of RLS may lie
distal to supraspinal structures. In support of this view, sev-
eral groups have reported signs of subclinical polyneuropath-
ies in idiopathic RLS patients (Iannaccone et al., 1995;
Rutkove et al., 1996; Polydefkis et al., 2000), abnormal cuta-
neous thermal thresholds indicating small fibre neuropathy
(Happe and Zeitlhofer, 2003; Schattschneider et al., 2004)
and the occurrence of RLS following spinal cord injury
(Hartmann et al., 1999; Lee et al., 1996). This hypothesis
could not be addressed further in this study.
Summarizing our findings, we have been able, for the first
time, to demonstrate a central nervous system involvement of
opioids in the pathophysiology of RLS. Furthermore, we have
shown that pain is an underlying problem in RLS patients and
suggested that motor symptoms in RLS are secondary to
sensory symptoms. Derangement of opioid binding in RLS
provides a rationale for using opioids in RLS treatment.
AcknowledgementsThis study was sponsored by the Medical Research Council
(MRC) and the German Research Foundation (DFG), grant
632 (European Graduate College). Alan Whone is a Wellcome
Research Training Fellow. Alexander Hammers is supported
by the MRC (G9901497). We would like to thank
Drs Matthias Koepp and Gary Hotton for the provision of
additional control datasets and our colleagues at the MRC
Cyclotron Building for their help in the acquisition and
analysis of PET data.
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