[Pain - a neglected neurological issue]. / Schmerz - ein vernachlässigtes neurologisches Thema.

Chronic pain represents a great challenge; according to epidemiological data increasing numbers of patients should be expected. Based on recent advances, a better understanding of the pathophysiology of chronic pain has been achieved and neurologists have made a major contribution to this understanding. Chronic pain is accompanied by substantial maladaptive plastic alterations in both the peripheral and central nervous systems; therefore, neurological knowledge is of paramount importance for pain therapists but this contrasts with the current treatment situation of pain patients in Germany. There are basically too few departments and practices undertaking treatment, and neurologists are an exception in most pain centers. Furthermore, due to economic reasons neurological hospitals are currently experiencing a dearth of inpatients suffering from chronic pain. Diagnostic and/or treatment procedures for neurological pain entities (e.g. headaches or neuropathic pain) are insufficiently represented in the German diagnosis-related groups (DRG) reimbursement system and the obstacles for an efficient pain therapy in neurological practices are too high. Finally, there are too few academic positions for pain medicine in neurological hospitals; therefore, career opportunities for motivated young neurologists with an interest in pain are lacking. In order to address the unmet therapeutic needs of patients with chronic pain there is a high demand for (i) establishment of departments for neurological pain medicine, (ii) modification of the German DRG system and (iii) education of young neurologists with expertise in pain. Pain medicine in particular should be especially appealing to neurologists .

Topical high-concentration menthol: reproducibility of a human surrogate pain model.

BACKGROUND: Human experimental pain models play an important role in studying neuropathic pain mechanisms. The objective of the present study was to test the reproducibility of the topical menthol model over a 1-week period. METHOD: We performed an open, two-period study in 10 healthy volunteers with 40 menthol applications. The side of menthol application was randomly assigned. Two trial periods were separated by 1 week. Before and after applying menthol, selected quantitative sensory testing (QST) was performed. The area of mechanical pin-prick hyperalgesia was quantified. Spontaneous pain was recorded. RESULTS: Application of menthol induced a statistically significant decrease in the cold pain threshold (CPT) (p < 0.001) and mechanical pain threshold and an increase in the mechanical pain sensitivity (MPS) (p < 0.001), indicating cold and mechanical (pin-prick) hyperalgesia. Test-retest reliability was best for CPT (r = 0.959) and MPS (r = 0.930). Intraclass correlation values showed excellent reliability for cold pain and MPS (ICC = 0.96, 0.89). The QST values post-menthol showed high inter-period correlation factors and no significant inter-period differences (paired t-test, t = 1.767-1.361; p = 0.111-0.988). The area size of mechanical hyperalgesia was not reliably reproducible. CONCLUSION: For an observation period of 1 week, the signs of cold and mechanical hyperalgesia were reproducible with a highly significant correlation of about r = 0.8 and good agreement except for the area size of mechanical pin-prick hyperalgesia. These results demonstrate that the topical menthol pain model is suitable for pharmacological interventions repeated within an observation period of 1 week.

Repetitive ipsilateral painful A-delta fibre stimuli induce bilateral LEP amplitude habituation.

BACKGROUND: In the scientific approach to central processing of pain, the habituation phenomenon has been frequently described. Recent studies mentioned electrophysiological habituation during the recording of laser-evoked potentials (LEP). In this study we intended to test whether habituation can be reproducibly induced by repetitive painful laser stimuli and simultaneously measured with LEP. Inspired by findings from previous imaging studies that showed bilateral activation of the operculo-insular cortices, we hypothesized that repetitive painful laser stimuli applied to one hand lead to bihemispheral LEP amplitude habituation. METHODS: One hundred painful stimuli were applied to the right hand of 13 healthy subjects to induce contralateral N2P2 amplitude habituation. The left hand was stimulated 25 times before and after the right-hand stimulation to measure ispilateral LEPs; the experiment was sham controlled. RESULTS: We achieved significant contralateral N2P2 amplitude and pain habituation in all subjects. After central habituation was established, there was also a significant ispilateral N2P2 amplitude decrement (derived from the left hand) compared with baseline; in the sham condition, the N2P2 amplitude was unchanged. The pain sensation showed no habituation in both the painful stimulation condition and the sham condition. CONCLUSIONS: Habituation (in the electrophysiological sense) is a physiological phenomenon that indicates normal central processing of pain in healthy controls. We showed bihemispheral N2P2 amplitude habituation after repetitive painful stimulation of the right hand. Our findings propose a bihemishperal contribution to central pain processing and pain modulation when electrophysiological habituation occurs.

Mechanism- and experience-based strategies to optimize treatment response to the capsaicin 8% cutaneous patch in patients with localized neuropathic pain.

The capsaicin 8% cutaneous patch is an emergent new treatment option for patients with peripheral neuropathic pain. In randomized controlled clinical studies relevant pain relief for 12 weeks was achieved in about one third of patients following a single application. The first part of this paper is a review of the pathophysiology, pharmacology, and published clinical trials with the capsaicin 8% cutaneous patch. The second part reports on outcomes of an interdisciplinary expert workshop, where new treatment results of three major German pain centers were presented and reviewed with the objectives of obtaining responder rates for different pain syndromes, assessing maintenance of effect under real-life conditions, and giving recommendations for practical care. The 12 week responder rates with pain relief of ≥ 30% were comparable in patients with mononeuropathies (37.9%) and postherpetic neuralgia (38.8%). Similar responder rates were seen in a subgroup of patients with cervical spine radiculopathy and back pain (46.7%). In HIV-associated neuropathy the responder rates were high (47.8%) but lower in patients with other polyneuropathies (17.6%). Response rates were nearly identical after 1 week (46.6%) and 4 weeks (43.3) and dropped only slightly at 12 weeks (37.4%). In a subgroup of 54 patients who underwent a second treatment, efficacy was maintained. Response rates in patients with or without lidocaine pretreatment were comparable. Treatment with the capsaicin 8% cutaneous patch was generally safe and well tolerated. The workshop panel recommended further investigation of opportunities to improve the application procedure and to perform studies on the skin penetration and distribution of capsaicin. A modified quantitative sensory testing (QST) should be developed for clinical practice in order to better understand the correlation of sensory profiles and response to capsaicin treatment.

Can widespread hypersensitivity in carpal tunnel syndrome be substantiated if neck and arm pain are absent?

Recent studies demonstrated that patients with carpal tunnel syndrome (CTS) have signs of thermal and mechanical hyperalgesia in extra-median territories suggesting an involvement of central pain mechanisms. As previous studies included patients with shoulder/arm symptoms or neck pain, a potential influence of these coexisting disorders cannot be excluded. This study therefore evaluated whether widespread sensory changes (hypoesthesia or hyperalgesia) are present in patients with unilateral CTS in the absence of coexisting disorders. Twenty-six patients with unilateral CTS with symptoms localised to their hand and 26 healthy controls participated in the study. A comprehensive quantitative sensory testing (QST) protocol including thermal and mechanical detection and pain thresholds was performed over the hands (median, ulnar and radial innervation area), lateral elbows, neck and tibialis anterior muscle. Patients with CTS demonstrated thermal and mechanical hypoesthesia in the hand but not at distant sites. Thermal or mechanical hyperalgesia was not identified at any location with traditional QST threshold testing. However, patients with CTS rated the pain during thermal pain testing significantly higher than healthy participants. This was especially apparent for heat pain ratings which were elevated not only in the affected hand but also in the neck and tibialis anterior muscle. In conclusion, CTS alone in the absence of coexisting neck and arm pain does not account for sensory changes outside the affected hand as determined by traditional QST threshold testing. Elevated pain ratings may however be an early indication of central pain mechanisms.

Dynamic cerebral autoregulation in stroke patients with a central sympathetic deficit.

OBJECTIVE: To investigate the functional role of the sympathetic innervation on cerebral autoregulation. MATERIALS AND METHODS: Seventeen patients with infarction of the dorsolateral medulla oblongata affecting central sympathetic pathways (Wallenberg's syndrome) and 21 healthy controls were included in the study. Cerebral blood flow velocity (CBFV) in the medial cerebral artery was investigated using transcranial Doppler ultrasound during decrease in cerebral perfusion pressure induced by leg-cuff test and tilt table. RESULTS: Upon leg-cuff test, changes of cerebral blood flow and mean arterial blood pressure as well as autoregulatory index did not differ between patients or controls. No differences were found in changes of CBFV, mean arterial blood pressure and heart rate between patients or controls during the tilt table test. CONCLUSIONS: We suggest that the sympathetic nervous system does not have an influence on cerebral autoregulation after decrease in perfusion pressure under normotonous conditions.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes.

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible.

Cytokine expression in serum and cerebrospinal fluid in non-inflammatory polyneuropathies.

BACKGROUND: Pain is a common symptom in polyneuropathies (PNPs), although it is still not known why some PNPs are painful and others are painless. Increased pro-inflammatory cytokines have been found in conditions resulting in exaggerated pain states in animal studies. Recently, elevated pro-inflammatory cytokine levels have also been found in the cerebrospinal fluid (CSF) of patients suffering from complex regional pain syndrome. Pro-inflammatory cytokines have been shown to induce or increase inflammatory or neuropathic pain. METHODS: Using chemiluminescent enzyme immunometric assays, cytokine levels in 36 patients with painful and painless non-inflammatory PNPs in serum and CSF were investigated. The severity of PNPs was measured with electroneurography (ENG). In subjects with normal results using conventional ENG, quantitative thermo-testing was performed to investigate small-nerve-fibre function. RESULTS: Interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha in serum or CSF did not differ between patients with (n = 18) or without (n = 18) painful PNPs, whereas patients with mechanical allodynia (n = 5) had elevated serum TNF-alpha levels compared to those without allodynia. TNF-alpha and IL-6 serum levels were higher in patients with severe (n = 21) compared to those with mild neuropathy (n = 15), and showed a positive correlation with severity of neuropathy. CONCLUSIONS: Results suggest that nerve fibre degeneration and presence of mechanical allodynia in peripheral non-inflammatory neuropathy determine cytokine expression in serum.

Endothelial dysfunction in cold type complex regional pain syndrome.

The authors examined endothelial function in cold type chronic complex regional pain syndrome (CRPS) I using acetylcholine- and sodium nitroprusside-induced vasodilation combined with laser Doppler flowmetry in 14 patients and 10 controls. On the affected side, acetylcholine-induced vasodilation was significantly reduced in comparison to controls and the unaffected extremity. No significant differences were found after application of sodium nitroprusside. The results demonstrate impaired endothelial function in chronic CRPS I.

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.

[Recent trends in understanding and therapy of complex regional pain syndromes]. / Das komplexe regionale Schmerzsyndrom. Neue Erkenntnisse.

Since the term "complex regional pain syndromes" (CRPS) was introduced based on a revised taxonomy for disorders previously called reflex sympathetic dystrophy and causalgia in 1995, much knowledge grew up on the understanding and therapy of the disease. This review gives an overview on the clinical characteristics, pathophysiology, diagnostic tools and therapeutic options in CRPS. It will especially focus on recent findings on the role of the sympathetic nervous system, the central nervous system and peripheral inflammatory processes as underlying mechanisms. Although there is no diagnostic gold standard, careful clinical evaluation and additional apparative test procedures are very helpful for the diagnosis. An early and interdisciplinary approach is the basis for an optimal and successful treatment.

[The symptom sympathetic maintained pain]. / Das Symptom sympathisch unterhaltener Schmerz.

Sympathetically maintained pain is a symptom which occurs in neuropathic pain syndromes of different etiologies. From animal experiments it is known that nociceptive afferents after partial nerve lesions develop adrenergic sensitivity at the site of the injury. In addition, a sympathetic-afferent coupling takes place in the dorsal root ganglia. It is still controversial if these pathophysiological mechanisms are responsible for the developing of SMP in humans. Clinical studies support the idea that also in humans the application of adrenergic substances in pharmacological doses is capable to influence nociception, but a direct interaction between the sympathetic system and the nociceptive system had not been demonstrated so far. By using a thermal suit for whole body cooling and warming, which produces low and high activity of sympathetic vasoconstrictor neurons, it was possible for the first time to demonstrate an interaction between physiological changes in sympathetic activity and nociception.

Complex regional pain syndrome--diagnostic, mechanisms, CNS involvement and therapy.

Complex regional pain syndromes (CRPS, formerly reflex sympathetic dystrophy and causalgia) are neuropathic pain conditions of one extremity developing inadequately after a trauma. The initiating trauma affects primarily the extremity, but can also be a central lesion (e.g., spinal cord injury, stroke). CRPS is clinically characterized by sensory, autonomic and motor disturbances. Pathophysiologically there is evidence for functional changes within the central nervous system and for involvement of peripheral inflammatory processes. The sympathetic nervous system plays a key role in maintaining pain and autonomic dysfunction in the affected extremity. After a primary central lesion, secondary peripheral changes in the paretic extremity are suggested to be important in initiating a CRPS. Though there is no diagnostic gold standard, careful clinical evaluation and additional test procedures should lead to an adequate diagnosis. An early diagnosis and an interdisciplinary approach are important for optimal and successful treatment.

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

BACKGROUND: Complex 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. METHODS: High 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. FINDINGS: In 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). INTERPRETATION: We 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.

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.

Complex regional pain syndromes.

Complex regional pain syndromes (CRPS) (formerly reflex sympathetic dystrophy and causalgia) are neuropathic pain conditions that are initiated by an extremity trauma or peripheral nerve lesion. Clinical definition and scientific understanding of CRPS are still evolving; however, both the clinical picture and therapeutic options are significantly influenced by a dysfunction of the sympathetic nervous system. Recent investigations suggest functional central abnormalities and a peripheral inflammatory component in the pathophysiology of CRPS. Interdisciplinary treatment includes physical, pharmacologic, and invasive interventional therapy, as well as stimulation techniques.

Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value.

Complex regional pain syndrome type I (CRPS I, formerly known as reflex sympathetic dystrophy) is a painful neuropathic disorder that develops after trauma affecting the limbs without overt nerve injury. Clinical features are spontaneous pain, hyperalgesia, impairment of motor function, swelling, changes in sweating, and vascular abnormalities. In this study, the pathophysiological mechanisms of vascular abnormalities were investigated. Furthermore, the incidence, sensitivity and specificity of side differences in skin temperature were defined in order to distinguish patients with definite CRPS I from patients with extremity pain of other origin. In 25 CRPS I patients and two control groups (20 healthy subjects and 15 patients with other types of extremity pain), cutaneous sympathetic vasoconstrictor activity was altered tonically by the use of controlled thermoregulation. Whole-body temperature changes were induced with a thermal suit in which cold or hot water circulated. The vascular reflex response (skin blood flow, laser Doppler flowmetry, skin temperature, infrared thermometry) was analysed to quantify sympathetic outflow. Measurements were performed during a complete thermoregulatory cycle, i.e. during the entire spectrum of sympathetic vasoconstrictor activity from high (whole-body cooling) to low sympathetic activity (whole-body warming). Venous noradrenalin levels were determined bilaterally in five CRPS patients. (i) Three distinct vascular regulation patterns were identified related to the duration of the disorder. In the "warm" (acute) type of regulation, the affected limb was warmer and perfusion values were higher than in the contralateral limb during the entire spectrum of sympathetic activity. In the "intermediate" type of regulation the limb was either warmer or colder. In the "cold" (chronic) type of regulation, skin temperature and perfusion values were lower on the affected side during the entire spectrum of sympathetic vasoconstrictor activity. (ii) Noradrenalin levels were lower on the affected side, even in chronic patients with considerable cutaneous vasoconstriction. (iii) Temperature and blood flow differences between the two sides were dynamic and most prominent at a high to medium level of vasoconstrictor activity. (iv) In both control groups, there were only minor side differences in flow and temperature. In conclusion, it is suggested that, in CRPS I, unilateral inhibition of sympathetic vasoconstrictor neurones leads to a warmer affected limb in the acute stage. Secondary changes in neurovascular transmission may lead to vasoconstriction and cold skin in chronic CRPS I, whereas sympathetic activity is still depressed. Vascular abnormalities are dynamic. The maximal skin temperature difference that occurs during the thermoregulatory cycle distinguishes CRPS I from other extremity pain syndromes with high sensitivity and specificity.