Impact of suggestion on the human experimental model of cold hyperalgesia after topical application of high-concentration menthol [40%].

BACKGROUND: Human experimental pain models in healthy subjects offer unique possibilities to study mechanisms of pain within a defined setting of expected pain symptoms, signs and mechanisms. Previous trials in healthy subjects demonstrated that topical application of 40% menthol is suitable to induce cold hyperalgesia. The objective of this study was to evaluate the impact of suggestion on this experimental human pain model. METHODS: The study was performed within a single-centre, randomized, placebo-controlled, double-blind, two-period crossover trial in a cohort of 16 healthy subjects. Subjects were tested twice after topical menthol application (40% dissolved in ethanol) and twice after ethanol (as placebo) application. In the style of a balanced placebo trial design, the subjects received during half of the testing the correct information about the applied substance (topical menthol or ethanol) and during half of the testing the incorrect information, leading to four tested conditions (treatment conditions: menthol-told-menthol and menthol-told-ethanol; placebo conditions: ethanol-told-menthol and ethanol-told-ethanol). RESULTS: Cold but not mechanical hyperalgesia was reliably induced by the model. The cold pain threshold decreased in both treatment conditions regardless whether true or false information was given. Minor suggestion effects were found in subjects with prior ethanol application. CONCLUSIONS: The menthol model is a reliable, nonsuggestible model to induce cold hyperalgesia. Mechanical hyperalgesia is not as reliable to induce. SIGNIFICANCE: Cold hyperalgesia may be investigated under unbiased and suggestion-free conditions using the menthol model of pain.

Laser-evoked potentials in painful radiculopathy.

OBJECTIVE: The aims of this exploratory study were (1) to develop a standardized objective electrophysiological technique with laser-evoked potentials to assess dorsal root damage quantitatively and (2) to correlate these LEP measures with clinical parameters and sensory abnormalities (QST) in the affected dermatome. METHODS: Thirty-eight patients with painful radiculopathy and 20 healthy subjects were investigated with LEP recorded from the affected dermatome and control areas as well as with quantitative sensory testing. Questionnaires evaluating severity and functionality were applied. RESULTS: On average, LEP amplitudes and latencies from the affected dermatomes did not differ from the contralateral control side. In patients with left L5 radiculopathy (more severely affected) the N2 latency was longer and the amplitudes reduced. CONCLUSIONS: The N2P2 amplitude correlated with pinprick evoked sensations in QST. The N2 latency from the affected dermatome correlates with pain intensity, chronicity, clinical severity and with a decrease of physical function. SIGNIFICANCE: An increase in N2-latency indicates a more pronounced nerve root damage, which is associated with a decrease of function and an increase of severity and pain. LEP amplitudes are associated with the functional status of the nociceptive system and may distinguish between degeneration of neuronal systems and central sensitization processes.

Reduced laser-evoked potential habituation detects abnormal central pain processing in painful radiculopathy patients.

BACKGROUND: Repetitive painful laser stimuli lead to physiological laser-evoked potential (LEP) habituation, measurable by a decrement of the N2/P2 amplitude. The time course of LEP-habituation is reduced in the capsaicin model for peripheral and central sensitization and in patients with migraine and fibromyalgia. In the present investigation, we aimed to assess the time course of LEP-habituation in a neuropathic pain syndrome, i.e. painful radiculopathy. METHODS: At the side of radiating pain, four blocks of 25 painful laser stimuli each were applied to the ventral thigh at the L3 dermatome in 27 patients with painful radiculopathy. Inclusion criteria were (1) at least one neurological finding of radiculopathy, (2) low back pain with radiation into the foot and (3) a positive one-sided compression of the L5 and/or S1 root in the MRI. The time course of LEP-habituation was compared to 20 healthy height and age matched controls. Signs of peripheral (heat hyperalgesia) and central sensitization (dynamic mechanical allodynia and hyperalgesia) at the affected L5 or S1 dermatome were assessed with quantitative sensory testing. RESULTS: Painful radiculopathy patients showed decreased LEP-habituation compared to controls. Patients with signs of central sensitization showed a more prominent LEP-habituation decrease within the radiculopathy patient group. CONCLUSIONS: Laser-evoked potential habituation is reduced in painful radiculopathy patients, which indicates an abnormal central pain processing. Central sensitization seems to be a major contributor to abnormal LEP habituation. The LEP habituation paradigm might be useful as a clinical tool to assess central pain processing alterations in nociceptive and neuropathic pain conditions. SIGNIFICANCE: Abnormal central pain processing in neuropathic pain conditions may be revealed with the laser-evoked potential habituation paradigm. In painful radiculopathy patients, LEP-habituation is reduced compared to healthy controls.

Prediction of response to tapentadol in chronic low back pain.

BACKGROUND: Many chronic low back pain (cLBP) patients do not satisfactorily respond to treatment. The knowledge of responders and non-responders before initiating treatment would improve decision making and reduce health care costs. The aims of this exploratory prediction study in cLBP patients treated with tapentadol were to identify predictors of treatment outcome based on baseline characteristics, to evaluate quality-of-life and functionality as alternative outcome parameters and to develop nomograms to calculate the individual probability of response. METHODS: In a retrospective analysis of an open-label phase 3b trial, 46 baseline characteristics were included into statistical prediction modelling. One hundred and twenty-one patients were followed up during the titration and treatment period and 67 patients were analysed who discontinued the trial. RESULTS: Demographic data were not relevant for response prediction. Nine baseline co-variables were robust: painDETECT score, intensity of burning and painful attacks, SF36 Health Survey score (MCS, PCS), EuroQol-5, Hospital Anxiety/Depression Scale. Gender had a minor influence. Alternative outcomes (quality-of-life, functionality) were more important for response prediction than conventional pain intensity measures. Neuropathic symptoms (high painDETECT score) had a positive predictive validity. Painful attacks and classical yellow flags (depression, anxiety) negatively influenced the treatment response. High depression scores, female gender and low burning predicted discontinuation during titration. CONCLUSION: In this exploratory study, predictive baseline characteristics have been identified that can be used to calculate the individual probability of tapentadol response in cLBP. The small sample size in relation to the number of initial variables is a limitation of this approach. SIGNIFICANCE: Predictors for treatment response of tapentadol were identified in patients with chronic low back pain based on clinical pre-treatment characteristics that can guide personalized treatment. Quality-of-life and functionality were the most relevant outcomes for response prediction.

Evaluation of the antihyperalgesic effect of tapentadol in two human evoked pain models - the TapCapMentho pilot trial.

OBJECTIVE: Tapentadol is effective in the treatment of neuropathic and nociceptive pain and in acute and chronic pain conditions; two mechanisms combining opioid µ-receptor agonism and noradrenergic reuptake inhibition underlie its analgesic effect. RESEARCH DESIGN AND METHODS: With this single-center, placebo-controlled, double-blind, cross-over pilot-study, we investigated the antihyperalgesic effect of a single oral dose of 100 mg immediate-release tapentadol on thermal and mechanical hyperalgesia in two human models (i.e. 0.6 % topical capsaicin and 40% topical menthol) of evoked neuropathic pain signs in healthy volunteers. RESULTS: No significant differences regarding experimentally induced heat or cold and mechanical (pinprick) hyperalgesia, as assessed by quantitative sensory testing, could be observed between a single dose of drug and placebo (thermal pain thresholds p>0.4, mechanical pain sensitivity p>0.1). Only few mild side effects of tapentadol were reported. CONCLUSIONS: The discrepancy between pain models using healthy volunteers and drug trials under real acute and chronic pain conditions in patients as well as methodological aspects may have contributed to this result. The impact of these findings questions the general use of pain models as predictors for early decision making during drug development. The study was registered in ClinicalTrials.gov (NCT01615510).

Cold-evoked potentials - Ready for clinical use?

BACKGROUND: Cold-evoked potentials (CEPs) are known to assess the integrity of A-delta fibres and the spinothalamic tract. Nevertheless, the clinical value was not investigated previously. The aim of this study was to measure CEPs in 16 healthy subjects from the face, hand and foot sole and to investigate whether CEPs reliably detect A-delta fibre abnormalities. METHODS: Swift cold stimuli were applied to the skin with a commercially available thermode, which cooled down from 30 to 25 °C in approximately 0.5 s. CEP latencies (N1, N2 and P2) and amplitudes (N1, N2/P2) were recorded with EEG. Reversible A-fibre function loss was induced by applying a selective A-fibre block at the superficial radial nerve. RESULTS: In all 16 subjects CEPs could be recorded from all locations; N2, P2 mean latencies were 276.4 ± 38.9 and 389.8 ± 52.5 (face), 318.6 ± 31.6 ms and 477.7 ± 43.6 (hand), and 627.6 ± 84.4 and 774.2 ± 94.0 (foot sole). N2/P2 amplitudes were 10.7 ± 4.1, 11.3 ± 4.1 and 7.5 ± 4.1 µV. During A-fibre block no CEPs were detectable in the grand average, which restored 10 min after block removal. CONCLUSIONS: CEPs were reliably recorded in healthy subjects at the hand, face and foot. Experimentally induced reversible A-delta fibre function loss was detected by CEPs. Functional recovery was assessed as well. This study is basis for further CEP evaluation studies and might be the first step for implementing CEPs in clinical routine for the early diagnosis of small-fibre disease. WHAT DOES THIS STUDY ADD?: Cold-evoked potentials are capable of reliably measuring A-delta fibre integrity, loss of function and functional recovery in healthy subjects, which is an essential prerequisite for diagnostic use in patients with small-fibre disease.

A retrospective analysis of the long-term test-retest stability of pain descriptors of the painDETECT questionnaire.

OBJECTIVE: PainDETECT (PD-Q) is a patient reported screening questionnaire to identify patients with neuropathic pain based on questions regarding typically sensory symptoms of neuropathic pain. The aim of the present investigation was to assess the test-retest stability of pain descriptors of the PD-Q within a time window of 1-3 weeks. METHODS: Data sets of 74 chronic pain patients sampled in an open pain register at two visits were analyzed and compared. Patients with change of pain localization between visits were excluded from analysis. Beside conventional measures (Pearson correlation coefficient r, intraclass correlation coefficient ICC, kappa), also calculated measures known from method comparison were used. RESULTS: The mean duration between visits was 15 days. The measures were in the range of r = 0.72-0.86, ICC = 0.71-0.86, and kappa = 0.62-0.72 for PD-Q pain descriptors (burning, prickling, mechanical allodynia, pain attacks, thermal hyperalgesia, numbness, pressure induced pain). CONCLUSION: The individual PD-Q pain descriptors showed accurate test-retest stability as a prerequisite for use in repeated measurements (e. g. post baseline or follow up data) in clinical trials.

Central habituation and distraction alter C-fibre-mediated laser-evoked potential amplitudes.

BACKGROUND: Recent studies applied laser-evoked potentials (LEP) for the analysis of small nerve fibre function and focused on the detection of stable C-fibre-mediated potentials (C-LEPs); high technical requirements were needed. The diagnostic significance is still controversially discussed. So far, only few studies focused on the susceptibility of C-LEPs to distraction and other influences. We hypothesized that C-LEPs are altered by habituation processes and distraction. METHODS: Twelve subjects were tested with a C-fibre laser set-up (neodymium:yttrium-aluminium-perovskite laser with a 10-mm beam diameter and 10-ms stimulus time) at the left perioral area. In condition I, the subjects received repetitive painful laser stimuli at the right hand to induce habituation. In condition II, the subjects had to fulfil an auditory discrimination task (where the subjects had to estimate the pitch of different tones on a scale for 20 min). C-LEPs were retrieved before and after the habituation or distraction paradigm. C-LEPs were also measured in a control group who was not influenced by laser stimuli or other disturbances during a 23-min break between the two test sessions. RESULTS: In both test conditions, there was significant C-LEP amplitude reduction. The LEP amplitudes of the control group remained unchanged. CONCLUSIONS: In the approach of detecting C-fibre-mediated potentials with LEP, future studies should take the high susceptibility to distraction and habituation into account.

Peripheral sensitization reduces laser-evoked potential habituation.

OBJECTIVE: Laser-evoked potential (LEP) habituation was investigated under the influence of capsaicin-induced peripheral and central sensitization. MATERIAL AND METHODS: Fifteen subjects received 100 repetitive painful laser stimuli at the right hand dorsum at primary (application area; condition I) and secondary areas (beyond application area; condition II) in two different sessions after applying capsaicin topically. Conditions I and II were compared to a control condition without capsaicin application. N1, N2, and P2 latencies and N1 and N2/P2 amplitudes were recorded by EEG. Quantitative sensory testing (QST) and the Liewald Diary reaction time experiment were used as control tests. RESULTS: QST documented heat hyperalgesia as a sign of peripheral sensitization in the primary area and pinprick hyperalgesia in the primary and secondary area as a sign of central sensitization, after applying capsaicin. The N2/P2 amplitude habituation was significantly reduced in the primary area compared to controls (the primary area represents peripheral sensitization). The LEPs of the secondary area (the secondary area represents central sensitization) showed no significant N2/P2 amplitude habituation compared to controls. The comparison between conditions I vs. II showed no significant difference regarding N2/P2 amplitude and laser pain rating. CONCLUSION: Capsaicin-induced central sensitization does not alter LEP habituation. The physiological habituation of LEP amplitudes is reduced due to peripheral mechanisms after applying capsaicin topically. These findings form a basis for future studies, which use the habituation paradigm to investigate pain conditions promoted by sensitization phenomena.

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.