The role of opioids in restless legs syndrome: an [ C - Brain

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

Opioid receptors in RLS 907

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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.

908 S. von Spiczak et al.

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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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