Jörn Schattschneider

Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: a case-control study

BACKGROUNDnComplex regional pain syndromes can be relieved by sympathetic blockage. The mechanisms of sympathetically maintained pain (SMP) are unclear. We aimed to establish the effect of physiological sympathetic cutaneous vasoconstrictor activity on pain and hyperalgesia in patients with complex regional pain syndromes.nnnMETHODSnHigh and low cutaneous vasoconstrictor activity was produced by whole-body cooling and warming (thermal suit) in 13 patients with type I disease and in ten controls. The degree of cutaneous vasoconstrictor discharge was monitored by measurement of skin blood flow and temperature at the arm and leg. Local skin temperature at the affected region was fixed at 35 degrees C. Pain was quantified during high and low cutaneous vasoconstrictor activity (intensity of spontaneous pain, area of mechanical hyperalgesias, heat-pain thresholds). Furthermore, pain was measured before and after diagnostic sympathetic blockage to identify patients with SMP and sympathetically independent pain.nnnFINDINGSnIn patients with SMP, intensity of spontaneous pain significantly increased, by 22%, and spatial distribution of mechanical dynamic and punctate hyperalgesia increased by 42% and 27%, respectively, during high sympathetic activity compared with low activity. Heat-pain thresholds did not differ during high and low cutaneous vasoconstrictor activity (cold and warm state, 43.6 degrees C vs 44.6 degrees C). Pain relief after sympathetic blockage correlated with augmentation of spontaneous pain after experimental stimulation of cutaneous vasoconstrictor activity (r=0.6, p=0.0244).nnnINTERPRETATIONnWe have shown that in complex regional pain syndromes with SMP, physiological activation of cutaneous vasoconstrictor neurons projecting to the painful arm or leg enhances spontaneous pain and hyperalgesia. We postulate that there is a pathological interaction between sympathetic and afferent neurons within the skin.

Postherpetic neuralgia: topical lidocaine is effective in nociceptor-deprived skin.

AbstractObjectivesTopical lidocainenis effective in postherpeticnneuralgia (PHN). The aim of thenpresent investigation was to classifynpatients according to their predominantnperipheral nociceptornfunction and to compare these datanwith the results of a controlled studynusing dermal lidocainenpatch.MethodsWithin the skinnarea of maximal pain QST (thermotest)nand QCART (histamineniontophoresis and laser Dopplernflowmetry) were performednprospectively in 18 PHN patients. Ancontrolled study using cutaneousnlidocaine (lidocaine 5% patch,nIBSA) followed.ResultsSix patientsn(group I, sensitised nociceptors)nhad no sensory loss. Heat painnthresholds were equal or lowernthan on the contralateral side. Histamine–induced flare and axon reflexnvasodilatation were not differentnon both sides. Histaminenevoked pain increased. In 12 patientsn(group II, nociceptor impairment)nheat pain thresholds werenhigher than contralateral. Histamine–induced flare was impairednor abolished. Histamine did not inducenany sensation. Lidocaine wasnefficacious in the entire group ofnpatients. Subgroup analysis revealednthat patients with impairmentnof nociceptor function hadnsignificantly greater pain reductionnunder lidocaine vs placebo. Patientsnwith preserved and sensitisednnociceptors demonstrated nonsignificant pain relief.ConclusionsPHN patients differ concerningntheir cutaneous nociceptor function:nIn the group I pain is causednby pathologically sensitised nociceptors.nIn subset II there is a lossnof function of cutaneous C–nociceptorsnwithin the allodynic skin.nPatients responded well to topicalnlidocaine even if the skin was completelyndeprived of nociceptors.nDifferent underlying mechanims ofnlidocaine action in nociceptor–deprivednskin are discussed.

Skin temperature side differences--a diagnostic tool for CRPS?

&NA; Complex regional pain syndrome type I (CRPS I) is a chronic painful disease of one extremity that may develop as a disproportionate consequence of a trauma affecting the limbs without overt nerve injury. It is clinically characterized by sensory, motor and autonomic symptoms including vascular abnormalities. Previously, we have reported that pathophysiological alterations of the ongoing sympathetic activity play a crucial role in vasomotor disturbances (Brain 124 (2001) 587). As a companion article, the aim of this study was to evaluate the diagnostic value of skin temperature side differences in consideration of the spontaneous sympathetic vasoconstrictor activity. Twenty‐five patients with CRPS I were studied. Fifteen patients with painful limbs of other origin and 20 healthy individuals served as controls. Controlled thermoregulation was performed to change cutaneous sympathetic vasoconstrictor activity by the use of a thermal suit: skin sympathetic vasoconstrictor neurones were activated by whole‐body cooling and nerve activity was abolished by whole‐body warming. Skin temperature at the affected and unaffected limbs (infra‐red thermometry) was measured under resting conditions and continuously monitored during controlled modulation of sympathetic activity. The results showed only minor skin temperature asymmetries between both limbs under resting conditions in most CRPS patients. However, during controlled thermoregulation temperature differences between both sides increased dynamically and were most prominent at a high to medium level of vasoconstrictor activity. In both control groups, there were only minor side differences in temperature both in rest and during thermoregulatory changes of sympathetic activity. When comparing the diagnostic value of skin temperature asymmetries in CRPS I, sensitivity was only 32% under resting conditions, but increased up to 76% during controlled alteration of sympathetic activity. Specificity was 100% at rest and 93% at controlled thermoregulation. We concluded that the degree of unilateral vascular disturbances in CRPS I depends critically on spontaneous sympathetic activity. Taking this into consideration, skin temperature differences in the distal limbs are capable of reliably distinguishing CRPS I from other extremity pain syndromes with high sensitivity and specificity.

Histamine-induced itch converts into pain in neuropathic hyperalgesia

Physiologically, itch and pain are transmitted in separate specific peripheral C-units and central afferent pathways. Some neuropathic pain patients with intact but sensitized (irritable) primary C-nociceptors have spontaneous pain, heat hyperalgesia, static and dynamic mechanical hyperalgesia. The question was whether cutaneous histamine application induces pain in these patients. For comparison histamine was applied into normal skin experimentally sensitized by capsaicin. Histamine application in the capsaicin-induced primary or secondary hyperalgesic skin did not change the intensity and quality of capsaicin pain. Itch was profoundly inhibited. Conversely, histamine application in neuropathic skin induced severe increase in spontaneous burning pain but no itch. In neuropathies irritable nociceptors may express histamine receptors or induce central sensitization to histaminergic stimuli so that itch converts into pain.

Idiopathic restless legs syndrome: abnormalities in central somatosensory processing.

Abstract.ObjectivesNeurophysiologicalnstudies have shown an impairmentnof temperature perceptionnin secondary and idiopathicnrestless legs syndrome (RLS). It isnunclear whether these deficits arencaused by peripheral nerve fibrendamage or by central impairmentnof somatosensory processing. Thenaim of the present study was (1) tondetermine the frequency of thermalnhypaesthesia in a large populationnof secondary and idiopathicnRLS patients; (2) to differentiatenbetween a peripheral and centralndisturbance of somatosensory processingnand (3) to correlate thesenfindings with the clinical manifestationnof the disease.MethodsFromnthe results of clinical examination,nnerve conduction studies andnblood samples the patients were dividedninto secondary and idiopathicnRLS groups. The severity ofnRLS symptoms was assessed bynstandardized questionnaires.nQuantitative sensory testing (QST)nassessing temperature perceptionnwas performed in all patients. Thenperipheral function of small nervenfibres was evaluated by the quantitativennociceptor axon reflex testn(QNART).Results22 secondarynand 20 idiopathic RLS patients participatednin the study. Impairmentnof temperature perception (QST)nwas found in 72% of the secondarynRLS patients and in 55% of idiopathicnRLS patients. The peripheralnC–fibre function (QNART) wasnnormal in idiopathic RLS patients.nIn contrast it was significantly impairednin secondary RLS patientsncompared with idiopathic RLS patientsnand age matched controls.nThere was no correlation betweennthe results obtained in QST andnclinical scores.ConclusionImpairmentnof temperature perception isnpresent in a high percentage of RLSnpatients. In secondary RLS the sensoryndeficits are at least in partncaused by small fibre neuropathy.nIn idiopathic RLS a functional impairmentnof central somatosensorynprocessing is present.

The Effect of Menthol on Cold Allodynia in Patients with Neuropathic Pain

OBJECTIVEnCutaneous application of menthol in healthy subjects induces cold allodynia via sensitization of cold-sensitive nociceptors. We investigated the effects of menthol on preexisting cold allodynia in patients to test whether the allodynia was exacerbated.nnnDESIGNnIn eight neuropathic pain patients (six of peripheral, two of central origin), 40% menthol was applied topically to an area of preexisting cold allodynia. Mirror-image skin areas and aged-matched healthy subjects served as controls in patients with unilateral and bilateral neuropathic pain, respectively. Prior to and after menthol, cold pain thresholds were measured using a thermotest device.nnnRESULTSnMenthol induced significant cold allodynia in control areas. However, in neuropathic areas, results were more heterogeneous. Overall, preexisting cold allodynia was not aggravated by topical menthol and was attenuated in 6/8 patients.nnnCONCLUSIONSnThese results suggest that, unlike in controls, menthol is not more hyperalgesic, but may be analgesic in some patients with peripheral and central neuropathic pain.

Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson’s disease

Dysfunctions of the autonomic nervous system (ANS) are common in Parkinson’s disease (PD). Regarding motor disability, deep brain stimulation of the subthalamic nucleus (STN) is an effective treatment option in long lasting PD. The aims of this study were to examine whether STN stimulation has an influence on functions of the ANS and to compare these effects to those induced by levodopa. Blood pressure (BP) and heart rate (HR) during rest and orthostatic conditions, HR variability (HRV) and breathing-induced cutaneous sympathetic vasoconstriction (CVC) were tested in 14 PD patients treated with STN stimulation during “ON” and “OFF” condition of the stimulator. The effects of a single dose of levodopa on ANS were tested in 15 PD patients without DBS. STN stimulation had no influence on cardiovascular ANS functions, whereas CVC was significantly increased. In contrast, levodopa significantly lowered BP and HR at rest and enhanced orthostatic hypotension. Further, HRV, skin perfusion and temperature increased after administration of levodopa. Our results suggest that in contrast to levodopa, STN stimulation has only minor effects on autonomic functions. Since less pharmacotherapy is needed after STN stimulation, reduced levodopa intake results in relative improvement of autonomic function in deep brain stimulated PD patients.

Harlequin syndrome - one face of many etiologies

Background A 55-year-old woman presented to hospital with a 3-month history of asymmetric facial flushing of the skin during exertion, and an 18-month history of left-sided ptosis and miosis. Detailed medical history analysis revealed that a palpable node measuring 0.8 × 1.2 × 1.2 cm (volume 1.1 ml) had been discovered 2 years previously, within the left lobe of an otherwise uncomplicated goiter that had been successfully managed for 20 years. Otherwise, the patient was healthy.Investigations Neurological examination, autonomic testing, duplex ultrasonography, scintigraphy and MRI.Diagnosis Harlequin syndrome following a lesion of the preganglionic sympathetic efferents, caused by neurovascular compression of the sympathetic chain between the stellate and superior cervical ganglion brought about by an elongated inferior thyroid artery.Management Explanation of pathophysiology and benign nature of the condition.

Docetaxel-induced nail changes--a neurogenic mechanism: a case report.

Docetaxel is a new taxoid widely used in chemotherapy for advanced breast cancer and other solid malignancies. Painful nail changes with onycholysis occur in about 40% of docetaxel-treated patients as a prominent adverse effect. We report a patient with a complete peripheral palsy of the right arm due to advanced breast cancer with diffuse tumor infiltration of the brachial plexus. Treatment with docetaxel led to onycholysis at all extremities except the paretic hand. Sensory and motoric innervation measured by nerve conduction studies showed a complete loss of large nerve fiber function of the right arm. Function of deep mechanosensitive Aβ-fibers (quantitative vibrametry) was severely decreased, but not absent. Sympathetic reflexes (induced by deep inspiration and measured with laser Doppler flowmetry) were absent on the right side and skin temperature was decreased consistent with a complete sympathetic denervation. Small afferent fibers investigated by quantitative thermotesting revealed a total loss of thermal and pain sensation. Furthermore, iontophoresis of histamine failed to induce any axon reflex-vasodilatation indicating a complete peripheral degeneration of small fiber afferents. In summary, a severe denervation of small and large fibers of the right upper limb was revealed. These results indicate that integrity of peripheral nerves seems to be a substantial factor for docetaxel-mediated nail changes. The role of an inflammatory process in onycholysis maintained by postganglionic sympathetic terminals and nociceptive C-fiber afferents is discussed. In accordance with this hypothesis, a cyclooxygenase-2 inhibitor improved nail alterations of the non-paretic limbs.

Interaction between histamine‐induced itch and experimental muscle pain

Itch sensation can be inhibited by simultaneously applied cutaneous pain at the same skin site via a central mechanism. Deep muscle pain is often associated with sensory changes in the corresponding dermatome. We investigated whether experimentally induced muscle pain has any influence on histamine‐induced itch and vice versa in a double blind placebo‐controlled study. Experiments were performed in 18 healthy subjects. In nine individuals control iontophoresis of histamine into the forearm produced a distinct itch sensation. Another nine individuals participated in an additional experiment in which histamine and saline were iontophoresed on the forearm in a randomized double‐blinded two‐way crossover design after intramuscular injection of capsaicin into the ipsilateral brachioradial muscle. Capsaicin‐induced muscle pain reduced itch sensation significantly. In contrast, capsaicin‐induced muscle pain increased significantly after cutaneous histamine application compared to muscle pain after iontophoresis of saline (placebo). These novel data indicate that muscle pain inhibits itch and histamine increases muscle pain. A bi‐directional interaction between cutaneous histamine‐sensitive afferents and nociceptive muscle afferents via central mechanisms is suggested.