Walter Magerl

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values.

Abstract The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age‐ and gender‐matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response‐functions for pinprick and dynamic mechanical allodynia, and pain summation (wind‐up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z‐scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side‐to‐side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Quantitative sensory testing: a comprehensive protocol for clinical trials

We have compiled a comprehensive QST protocol as part of the German Research Network on Neuropathic Pain (DFNS) using well established tests for nearly all aspects of somatosensation. This protocol encompasses thermal as well as mechanical testing procedures. Our rationale was to test for patterns of sensory loss (small and large nerve fiber functions) or gain (hyperalgesia, allodynia, hyperpathia), and to assess both cutaneous and deep pain sensitivity. The practicality of the QST protocol was tested in 18 healthy subjects, 21–58 years, half of them female. All subjects were tested bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for the presence of paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64‐Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus‐response‐functions for pinprick and dynamic mechanical allodynia (pain to light touch), and pain summation (wind‐up ratio) using repetitive pinprick stimulation.

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

&NA; 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.

Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 × 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for >3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 μm diameter) in skin adjacent to the HFS–LFS conditioning skin site revealed a marked twofold to threefold increase in pain sensitivity (secondary hyperalgesia, undiminished for >3 hr) after HFS but also a moderate secondary hyperalgesia (30% above baseline) after strong LFS. Additionally, HFS but not LFS caused pain to light tactile stimuli in adjacent skin (allodynia). In summary, HFS and LFS stimulus protocols that induce LTP or LTD in spinal nociceptive pathways in animal experiments led to similar LTP- and LTD-like changes in human pain perception (long-term hyperalgesia or hypoalgesia) mediated by the conditioned pathway. Additionally, secondary hyperalgesia and allodynia in adjacent skin induced by the HFS protocol and, to a minor extent, also by the LFS protocol, suggested that these perceptual changes encompassed an LTP-like heterosynaptic facilitation of adjacent nociceptive pathways by a hitherto unknown mechanism.

Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data.

&NA; Clinical use of quantitative sensory testing (QST) requires standardization. The German research network on neuropathic pain (DFNS) solves this problem by defining reference data stratified for test site, gender and age for a standardized QST protocol. In this report we have targeted two further problems: how to adjust for age‐related sensory changes, and how to compare groups of patients with the reference database. We applied a moving average across ages to define reference values per decade. This analysis revealed that women were more sensitive to heat pain independent of age. In contrast, functions were converging at older age for blunt pressure pain, but diverging for punctate mechanical pain (pin prick). The probability that an individual patient dataset is within the range of normal variability is calculated by z‐transform using site‐, gender‐ and age‐specific reference data. To compare groups of patients with reference data, we evaluated two techniques: A: paired t‐test versus fixed mean; i.e. the reference mean value is considered as the known population mean, B: non‐paired t‐test versus the reference dataset and number of cases restrained to the same number of cases as the patient data set. Simulations for various sample sizes and variances showed that method B was more conservative than method A. We present a simple way of calculating method B for data that have been z‐normalized. This technique makes the DFNS reference data bank applicable for researchers beyond the DFNS community without a need for subsampling of subjects from the database.

Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans.

&NA; Wind‐up and secondary hyperalgesia both are related to central sensitization, but whereas the former is explained by homosynaptic facilitation, the latter is due to heterosynaptic facilitation. To investigate possible interactions between both types of facilitation, we tested for alterations of perceptual wind‐up in the secondary hyperalgesic skin zone adjacent to a capsaicin injection with light touch (by a cotton wisp) and punctate stimuli (calibrated von Frey hairs and pin pricks). Temporal summation of pain sensation (perceptual wind‐up) was only observed with a clearly noxious stimulus (pin prick) presented at a repetition frequency of 0.6 s−1, but not 0.2 s−1. Pain ratings to trains of pin pricks reached a plateau after 3–4 repetitions, which was 1.65 times the initial rating (‘wind‐up ratio’). Injection of capsaicin induced a tenderness to mechanical stimuli in adjacent uninjured skin (secondary hyperalgesia), including hyperalgesia to light touch (allodynia) and hyperalgesia to punctate stimuli. Hyperalgesia to punctate stimuli was characterized by a leftward shift of the stimulus response function, corresponding to a decrease in pain threshold and an increase of painfulness of suprathreshold stimuli by a factor of 3–4. After capsaicin, the difference between the ratings of the first and last stimuli of trains of pin pricks was increased, but the ratio was unchanged. This behavior is equivalent to an increase in effective stimulus intensity, and could be mimicked by increasing the pin prick force from 20 mN to 40 and 80 mN in normal skin. Thus, the leftward shift of the stimulus response function fully accounts for all alterations of pain sensitivity to punctate stimuli in the zone of secondary hyperalgesia. We conclude that when the gain of spinal transmission was changed in secondary hyperalgesia, the gain of wind‐up remained unchanged. These findings indicate that secondary hyperalgesia (heterotopic facilitation) and wind‐up of pain sensation (homotopic facilitation) are independent phenomena.

Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain.

&NA; Patients with sensory disturbances of painful and non‐painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in‐patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1 mm ∅). Thresholds and stimulus–response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2 mm ∅). Allodynia was tested by light stroking with a brush, Q‐tip, and cotton wisp. Perceptual wind‐up was tested by trains of punctate stimuli at 0.2 or 1 Hz. Intradermal injection of capsaicin (n=7) and A‐fiber conduction blockade (n=8) served as human surrogate models for neurogenic hyperalgesia and partial nociceptive deafferentation, respectively. Patients without pain (18/30) showed a continuous distribution of threshold shifts in the dysaesthetic skin area with a low to moderate increase in pain threshold (by 1.52±0.45 log2 units). Patients with painful dysaesthesia presented as two separate groups (six patients each): one showing lowered pain thresholds (by −1.94±0.46 log2 units, hyperalgesia) and the other elevated pain thresholds (by 3.02±0.48 log2 units, hypoalgesia). The human surrogate model of neurogenic hyperalgesia revealed nearly identical leftward shifts in stimulus–response function for pricking pain as patients with spontaneous pain and hyperalgesia (by a factor of about 5 each). The sensory changes in the human surrogate model of deafferentation were similar to patients with hypoalgesia and spontaneous pain (rightward shift of the stimulus–response function with a decrease in slope). Perceptual wind‐up did not differ between symptomatic and control areas. There was no exclusive association of any parameter obtained by quantitative sensory testing with a particular disease (of either peripheral or central origin). Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism‐based classification of neuropathic pain.

C- and Aδ-fiber components of heat-evoked cerebral potentials in healthy human subjects

Abstract Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40°C) was chosen, which is above C-fiber heat threshold, but clearly below Aδ-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of Aδ-fibers. Feedback-controlled stepped heat stimuli to 40°C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated from latency shifts between the hand and forearm sites of ultralate LEPs (2.4 m/s) and of reaction times (2.8 m/s) confirmed mediation of ultralate potentials by unmyelinated nerve fibers (nociceptors and/or warm fibers). The ultralate LEP could be differentiated from resolution of contingent negative variation (CNV), an endogenous potential related to expectation and response preparation, by its scalp topography. Strong heat stimuli of 48°C, which is suprathreshold for most Aδ- and C-fiber nociceptors, elicited the well-known late LEPs mediated by nociceptive Aδ-fibers confirming previous studies. The LEP waveform to strong heat stimuli also contained an ultralate component reminiscent of an ultralate LEP following the late LEP. Ultralate and late LEP had identical scalp topography. In conclusion, the method of temperature-controlled laser heat stimuli allows the selective and reliable examination of Aδ- and C-fiber-mediated afferent pathways and the related cortical processing without the complication of dissociating A-fiber nerve blocks.

Pain elicited by blunt pressure: neurobiological basis and clinical relevance

Polymodality is one of the distinguishing features of primary nociceptive afferents, meaning that these free nerve endings respond to mechanical, thermal and chemical stimuli (Raja et al., 1999). Tissue damage has originally been suggested to be the common denominator of these adequate stimuli. This concept is still important for terminology in terms like ‘noxious stimulus’ and ‘nociceptive system’, but outright damage is not necessary for the activation of most nociceptors. The molecular cloning of the capsaicin receptor VR1 (now called TRPV1) has unified two stimulus modalities as adequate activators of one specific signal transduction pathway (for noxious heat and for irritant substances of the vanilloid class). Noxious mechanical stimuli are encoded by mechanisms different from this signal transduction pathway, but these mechanisms have not been characterized yet. Mechanically evoked pain is important both for the enteroceptive and the exteroceptive aspects of pain perception. Tension or spasms in visceral organs, joint or muscle movements, and increased pressure within the tooth pulp or the bone marrow are important adequate stimuli to elicit visceral or deep somatic pain. These stimuli inform the nervous system about the inner state of the organism (enteroception). On the other hand, the exertion of pressure onto the skin from the outside gives information about impending injury (exteroception). Pressure that is exerted onto the skin may activate nociceptive afferents in several tissues, depending on the configuration of the object that exerts the pressure (Fig. 1). Contact with a punctate object such as a 0.2 mm diameter needle may exclusively activate intraepidermal nerve endings. Because deformation of the thin epidermis can be achieved with very small forces (Garnsworthy et al., 1988; Garell et al., 1996), these stimuli have little effect on afferents in deeper tissues. In contrast, a preferential activation of deep afferents is possible, if pressure is exerted on a large skin area (e.g. 1 cm) and the contact surface is rounded or padded. According to experiments using topical local anaesthesia, the contribution of cutaneous afferents to pain evoked by blunt pressure is minor (Kosek et al., 1995). The aim of this topical review is to outline where an altered sensitivity to blunt pressure that presumably activates nociceptors in deep tissues is clinically relevant. In addition, we will discuss the potential neural mechanisms of mechanically-induced pain.

Depression and changed pain perception: hints for a central disinhibition mechanism.

Abstract Although patients with a depressive disorder report often of pain, their sensitivity to experimental pain is controversial, probably due to differences in sensory testing methods and to the lack of normal values. Therefore, we used a standardized and validated comprehensive sensory testing paradigm to assess the peripheral and central nervous system performance in depressive patients compared to healthy controls and chronic pain patients with fibromyalgia syndrome (FMS), in which depression is a common comorbidity. Twenty‐five depressive psychiatric inpatients (pain‐free: n = 20), 35 FMS outpatients and 25 healthy controls underwent quantitative sensory testing (QST), including thermal and mechanical detection and pain thresholds, pain sensitivity and responsiveness to repetitive noxious mechanical stimuli (wind‐up). In depressive disorder (to a lesser extent also in FMS), significantly decreased cold pain thresholds and an increased wind‐up were found, although the mechanical pain thresholds and pain sensitivity were comparable to those of the healthy controls. All the detection thresholds were within the normal range in all the groups. In depressive disorder, there were no significant side differences in the detection and pain thresholds. The results contradict the former assumption of a general insensitivity to experimental pain in depressive disorder. In the mostly pain‐free patients signs of an enhanced central hyperexcitability are even more pronounced than usually found in chronic pain patients (e.g. FMS), indicating common mechanisms in depressive disorder and chronic pain in accordance with the assumption of non‐pain associated mechanisms in depressive disorder for central hyperexcitability, e.g. by inhibited serotonergic function. Furthermore, this trial demonstrates the feasibility of QST in depressive patients.