Elliot Sprecher

Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk.

&NA; Surgical and medical procedures, mainly those associated with nerve injuries, may lead to chronic persistent pain. Currently, one cannot predict which patients undergoing such procedures are ‘at risk’ to develop chronic pain. We hypothesized that the endogenous analgesia system is key to determining the pattern of handling noxious events, and therefore testing diffuse noxious inhibitory control (DNIC) will predict susceptibility to develop chronic post‐thoracotomy pain (CPTP). Pre‐operative psychophysical tests, including DNIC assessment (pain reduction during exposure to another noxious stimulus at remote body area), were conducted in 62 patients, who were followed 29.0 ± 16.9 weeks after thoracotomy. Logistic regression revealed that pre‐operatively assessed DNIC efficiency and acute post‐operative pain intensity were two independent predictors for CPTP. Efficient DNIC predicted lower risk of CPTP, with OR 0.52 (0.33–0.77 95% CI, p = 0.0024), i.e., a 10‐point numerical pain scale (NPS) reduction halves the chance to develop chronic pain. Higher acute pain intensity indicated OR of 1.80 (1.28–2.77, p = 0.0024) predicting nearly a double chance to develop chronic pain for each 10‐point increase. The other psychophysical measures, pain thresholds and supra‐threshold pain magnitudes, did not predict CPTP. For prediction of acute post‐operative pain intensity, DNIC efficiency was not found significant. Effectiveness of the endogenous analgesia system obtained at a pain‐free state, therefore, seems to reflect the individual’s ability to tackle noxious events, identifying patients ‘at risk’ to develop post‐intervention chronic pain. Applying this diagnostic approach before procedures that might generate pain may allow individually tailored pain prevention and management, which may substantially reduce suffering.

Thermal testing: normative data and repeatability for various test algorithms

Measurement of thresholds for warm and cold sensation was performed on 106 normal subjects, at thenar eminence and foot dorsum. Three test algorithms were used, the reaction-time-inclusive method of limits, and reaction-time-exclusive methods of levels and staircase. Tests were repeated 2 weeks following the first for most of the subjects, and after elimination of 5 outlying subject data points, and determination of no systematic relationship between magnitude and variability of test scores, data from between 72 and 76 subjects were used to derive repeatability coefficients, by ANOVA-based procedures which extend standard repeatability assessment methods. Normative data tables are presented, with measures of repeatability for the various algorithms and modalities. Method of limits tests exhibited inter-session bias, and large repeatability coefficients, compared with methods of levels and staircase, which exhibited no bias and had better (lower) repeatability coefficients. All three methods had similar test durations. We conclude that on the basis of these data, the reaction-time-exclusive methods of levels and staircase have a definite advantage over the method of limits.

Quantitative measurement of pain sensation in patients with Parkinson disease

Background: Pain is common in patients with Parkinson disease (PD) and can precede the diagnosis of the disease. Experimental studies and clinical evidence indicate involvement of basal ganglia and dopaminergic pathways in central pain processing. Objective: To quantitatively assess and compare pain perception in patients with unilateral PD with and without pain and in patients with response fluctuations. Methods: Thirty-six patients with PD (mean age, 61.8 ± 11.2 years) with predominantly unilateral disease, 15 patients with response fluctuations (mean age, 65.3 ± 10.4 years), and 28 age-matched healthy control subjects participated in the study. Subjective pain was assessed using the visual analog scale with von Frey filaments for tactile thresholds and contact thermode for warm sensation (WS) and heat pain thresholds (HPTs). Results: Tactile and WS thresholds did not differ between patients in both patient groups and control subjects nor between sides. HPT was lower in patients with PD who experienced pain (n = 21) compared with those who did not (42.6 ± 3.0 °C vs 45.6 ± 2.8 °C; p < 0.01) and those who experienced pain in the more affected side (41.4 ± 2.6 °C vs 43.7 ± 3.3 °C; p < 0.0001). In patients with fluctuations there were no side differences in WS and HPT or between “on” and “off” periods. Conclusion: Endogenous pain in patients with Parkinson disease is accompanied by increased sensitivity to some painful stimuli, suggesting that basal ganglia abnormality also involves pain encoding.

Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: Do conditioning stimulus painfulness, gender and personality variables matter?

&NA; Descending modulation of pain can be demonstrated psychophysically by dual pain stimulation. This study evaluates in 31 healthy subjects the association between parameters of the conditioning stimulus, gender and personality, and the endogenous analgesia (EA) extent assessed by diffuse noxious inhibitory control (DNIC) paradigm. Contact heat pain was applied as the test stimulus to the non‐dominant forearm, with stimulation temperature at a psychophysical intensity score of 60 on a 0–100 numerical pain scale. The conditioning stimulus was a 60 s immersion of the dominant hand in cold (12, 15, 18 °C), hot (44 and 46.5 °C), or skin temperature (33 °C) water. The test stimulus was repeated on the non‐dominant hand during the last 30 s of the conditioning immersion. EA extent was calculated as the difference between pain scores of the two test stimuli. State and trait anxiety and pain catastrophizing scores were assessed prior to stimulation. EA was induced only for the pain‐generating conditioning stimuli at 46.5 °C (p = 0.011) and 12 °C (p = 0.003). EA was independent of conditioning pain modality, or personality, but a significant gender effect was found, with greater EA response in males. Importantly, pain scores of the conditioning stimuli were not correlated with EA extent. The latter is based on both our study population, and on additional 82 patients, who participated in another study, in which EA was induced by immersion at 46.5 °C. DNIC testing, thus, seems to be relatively independent of the stimulation conditions, making it an easy to apply tool, suitable for wide range applications in pain psychophysics.

Contact heat-evoked temporal summation: Tonic versus repetitive-phasic stimulation

Abstract Temporal summation (TS) is usually evoked by repetitive mechanical or electrical stimuli, and less commonly by tonic heat pain. The present study aimed to examine the TS induction by repetitive‐phasic versus tonic heat pain stimuli. Using 27 normal volunteers, we compared the extent of summation by three calculation methods: start‐to‐end pain rating difference, percent change, and double‐logarithmic regression of successive ratings along the stimulation. Subjects were tested twice, and the reliability of each of the paradigms was obtained. In addition, personality factors related to pain catastrophizing and anxiety level were also correlated with the psychophysical results. Both paradigms induced significant TS, with similar increases for the repetitive‐phasic and the tonic paradigms, as measured on 0–100 numerical pain scale (from 52.9 ± 11.7 to 80.2 ± 15.5, p < 0.001; and from 38.5 ± 13.3 to 75.8 ± 18.3, p < 0.001, respectively). The extent of summation was significantly correlated between the two paradigms, when calculated by absolute change (r = 0.543, p = 0.004) and by regression (r = 0.438, p = 0.025). Session‐to‐session variability was similar for both paradigms, relatively large, yet not biased. As with other psychophysical parameters, this poses some limitations on TS assessment in individual patients over time. The extent of TS induced by both paradigms was found to be associated with anxiety level and pain catastrophizing. Despite some dissimilarity between the repetitive‐phasic and the tonic paradigms, the many similarities suggest that the two represent a similar physiological process, even if not precisely the same. Future clinical applications of these tests will determine the clinical relevance of the TS paradigms presented in this study.

Repeated noxious stimulation of the skin enhances cutaneous pain perception of migraine patients in-between attacks: clinical evidence for continuous sub-threshold increase in membrane excitability of central trigeminovascular neurons

Recent clinical studies showed that acute migraine attacks are accompanied by increased periorbital and bodily skin sensitivity to touch, heat and cold. Parallel pre‐clinical studies showed that the underlying mechanism is sensitization of primary nociceptors and central trigeminovascular neurons. The present study investigates the sensory state of neuronal pathways that mediate skin pain sensation in migraine patients in between attacks. The assessments of sensory perception included (a) mechanical and thermal pain thresholds of the periorbital area, electrical pain threshold of forearm skin, (b) pain scores to phasic supra‐threshold stimuli in the same modalities and areas as above, and (c) temporal summation of pain induced by applying noxious tonic heat pain and brief trains of noxious mechanical and electrical pulses to the above skin areas. Thirty‐four pain‐free migraine patients and 28 age‐ and gender‐matched controls were studied. Patients did not differ from controls in their pain thresholds for heat (44±2.6 vs. 44.6±1.9°C), and electrical (4.8±1.6 vs. 4.3±1.6 mA) stimulation, and in their pain scores for supra‐threshold phasic stimuli for all modalities. They did, however, differ in their pain threshold for mechanical stimulation, just by one von Frey filament (P=0.01) and in their pain scores of the temporal summation tests. Increased summation of pain was found in migraineurs for repeated mechanical stimuli (delta visual analog scale (VAS) +2.32±0.73 in patients vs. +0.16±0.83 in controls, P=0.05) and repeated electrical stimuli (delta VAS +3.83±1.91 vs −3.79±2.31, P=0.01). Increased summation corresponded with more severe clinical parameters of migraine and tended to depend on interval since last migraine attack. The absence of clinically or overt laboratory expressed allodynia suggests that pain pathways are not sensitized in the pain‐free migraine patients. Nevertheless, the increased temporal summation, and the slight decrease in mechanical pain thresholds, suggest that central nociceptive neurons do express activation‐dependent plasticity. These findings may point to an important pathophysiological change in membrane properties of nociceptive neurons of migraine patients; a change that may hold a key to more effective prophylactic treatment.

Multiple session experimental pain measurement

&NA; Experimental heat pain transients were administered to 30 normal volunteers over four weekly sessions, measuring both heat pain (HP) threshold and suprathreshold magnitude estimation through VAS. Repeatability and bias for these two factors were evaluated. Heat pain thresholds measured through the method of limits were previously shown to have inter‐session bias, presumably due to a practice effect. Existence of such a bias between first and second measurement sessions casts doubt on the usefulness of this parameter for pain assessment of individuals over time. In the present study, measurements of normal HP thresholds over four sessions showed that bias exists between the first and successve sessions, but not among sessions other than the first. It is concluded that (i) HP thresholds obtained from a single session are of limited value, and should be carefully interpreted. (ii) Long‐term studies that use the HP threshold should take results from the second (or later) session as their baseline. The Visual Analog Scale (VAS) is considered the ‘gold standard’ for assessment of clinical and suprathreshold experimental pain, and changes in VAS score are regarded as significant evidence of individual response to treatment, placebo, or experimental manipulation. Although its overall group accuracy and precision have been examined for both clinical and experimental pain, and found adequate (Price 1988), the VAS has not been rigorously assessed for repeatability. Stimuli at three pain levels, 1.5, 3 and 4.5°C above each individuals heat pain threshold as determined at each session, were given. Several models of analysis of the VAS were tested and repeatabilities (r) obtained from these analyses demonstrate poor precision for each of the tested analysis models. For example, inter‐session repeatabilities for the three individual pain levels ranged from r = 2.8–4.7, effectively providing a confidence interval of 7.6–9.4 for any VAS reading on a 0‐ to 10‐point scale. An examination of intra‐session VAS provided somewhat better results. Thus, use of the VAS in similar experimental settings is called into question. The use of the VAS in clinical settings, where individual assessments are necessary, is also called into question, but remains to be specifically tested.

The P300 in pain evoked potentials

&NA; Pain evoked potentials (EPs) have been used in the last two decades as means of obtaining objective measures of pain, in clinical and experimental setups. The possibility that the pain EP wave contains elements of the endogenous P300 potential rather than being a neurophysiological correlate of pain has been raised by a number of authors, but the issue has not been resolved. In this study, two experiments were performed to study the effect of non‐modality‐specific factors on the laser EP: (1) a stimulus attend as opposed to a stimulus‐ignore condition and (2) counterbalanced oddball and task P300 stimulus presentations. The latter was to permit full examination of the separate and combined influences of each condition on the EP. Stimuli were given to the radial hand of 10 healthy volunteers using a CO2 laser. The positive component of the laser EP was affected by both manipulations relating to (1) attention (P = 0.0146) and (2) the frequency condition (P = 0.003) in the P300 paradigm. The task condition in the second paradigm did not affect the positive wave on its own, although its effect was visible in interaction with frequency (P = 0.033). In conclusion, although the presence of a somatic component in the laser EP cannot be ruled out, we suggest that the laser EP contains a definite non‐modality‐specific P300 component, and is not a pure neurophysiological correlate of pain intensity.

Normative values for female genital sensation.

OBJECTIVES Neurologic disorders might be responsible for many cases of female sexual dysfunction. Yet, they are currently undiagnosed because of the lack of measurement tools to assess genital neural function. Therefore, our objective is to provide norms for sensory thresholds in the vagina and clitoris, for a wide range of patient ages. METHODS Vaginal and clitoral warm, cold, and vibratory sensory thresholds were measured in 89 healthy paid volunteers by the method of limits. Normograms were derived from this group of healthy volunteers. An additional 61 patients were also tested, for a total of 150 individuals. Sixty-two individuals (42 healthy volunteers and 20 patients) from the total group were tested twice to provide test-to-test repeatability data across the range of clinical (normal and abnormal) responses. RESULTS Normograms are presented, providing age-corrected upper and lower normal values, expressed as 95% confidence limits for warm, cold, and vibratory thresholds. Intertest repeatability is also reported. CONCLUSIONS Thermal and vibratory thresholds of both the vaginal and clitoral region are clinically feasible, valid, and repeatable. These can be applied as a valuable diagnostic tool to assess neural dysfunction through sensory assessment of the female genitalia.

Homotopic and heterotopic effects of endogenous analgesia in healthy volunteers.

Although research on DNIC has revealed the inhibitory effect occurring between two remote pain stimuli, the interrelation between two adjacent painful stimuli has not yet been characterized. In the present study, we used a sample of 40 healthy volunteers to examine the effect of 30-s immersion of the fingers in water of 1 degree C, as a conditioning stimulus, on pain intensities produced by conditioned mechanical punctuate stimuli, applied both adjacent and contralateral to the cooled area. There was a significant decrease in mechanical pain intensities from 17.23+/-2.39 at baseline to 12.45+/-2.39 when stimulating immediately after the cold immersion at an adjacent site, and from 20.00+/-2.39 to 15.08+/-2.39 at remote sites (F=20.02, p<0.0001). A significant positive correlation between the extent of pain reduction in the cooled and in the uncooled hand was found (r(s)=0.59, p=0.0001). The extent of pain reduction following cooling in the cooled and in the uncooled hand was also found to be similar for males and for females (p=0.63). It is concluded that under the conditions of this experiment, EA affects heterotopic and homotopic regions similarly and without gender differences.