David Yarnitsky

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.

Experimental and Clinical Applications of Quantitative Sensory Testing Applied to Skin, Muscles and Viscera

UNLABELLED Quantification of the human painful sensory experience is an essential step in the translation of knowledge from animal nociception to human pain. Translational models for assessment of pain are very important, as such models can be used in: 1) basic mechanistic studies in healthy volunteers; 2) clinical studies for diagnostic and monitoring purposes; 3) pharmacological studies to evaluate analgesic efficacy of new and existing compounds. Quantitative pain assessment, or quantitative sensory testing (QST), provides psychophysical methods that systematically document alterations and reorganization in nervous system function and, in particular, the nociceptive system. QST is defined as the determination of thresholds or stimulus response curves for sensory processing under normal and pathophysiological conditions. The modern concept of advanced QST for experimental pain assessment is a multimodality, multitissue approach where different pain modalities (thermal, mechanical, electrical, and chemical) are applied to different tissues (skin, muscles, and viscera) and the responses are assessed by psychophysical methods (thresholds and stimulus-response functions). Many new and advanced technologies have been developed to help relieve evoked, standardized, and painful reactions. Assessing pain has become a question of solving a multi-input, multi-output problem, with the solution providing the possibility of teasing out which pain pathways and mechanisms are involved, impaired, or affected. PERSPECTIVE Many methodologies have been developed for quantitative assessment of pain perception and involved mechanisms. This paper describes the background for the different methods, the use in basic pain experiments on healthy volunteers, how they can be applied in drug profiling, and the applications in clinical practice.

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.

The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans.

The exploration of endogenous analgesia (EA) via descending pain-modulatory systems started about three decades ago. The generation of analgesia in the rat by periaquaductal grey (PAG) stimulation was the first evidence for the existence of endogenous analgesic capabilities as a normal function of the central nervous system, exerting both inhibitory and facilatory effects (for review, see [5]). Consequent evidence demonstrated an important final common descending modulatory site in the brainstem, the rostral ventromedial medulla (RVM), which receives signals directly from the PAG, with both bearing opioid receptors. Subsequently, the RVM forwards signals downward to the spinal cord (for review, see [11]). This dorsolateral funiculus descending inhibitory pain pathway, consisting of serotonergic and noradrenergic neurons, is under ‘top-down’ cerebral control, mediating modulation of pain perception by emotional, motivational, and cognitive factors [5,11]. Further important evidence in this regard came in the late 1970s from Le Bars and his colleagues [21,22], who were the first to associate the effectiveness of the commonly known ‘pain-inhibits-pain’ counter-irritation phenomena with this EA mechanism. They reported that activity in the dorsal horn and trigeminal nuclei is inhibited by the application of noxious electrical stimuli to remote body areas in anaesthetized rats [21,22]. This phenomenon was termed ‘diffuse noxious inhibitory controls’ (DNICs). Both electrophysiological and anatomical data support the involvement of the subnucleus reticularis dorsalis (SRD) in the caudal medulla in spino-bulbo-spinal loops that are exclusively activated by neurons with a ‘whole-body receptive field’ [23]. Their descending projections pass through the dorsolateral funiculus and terminate in the dorsal horn at all levels of the spinal cord. Thus, DNIC is a ‘bottom-up’ activation of the pain-modulatory mechanism, as part of the descending endogenous analgesia (EA) system. In recent years, a DNIC-like effect, also commonly termed HNCS (heterotopic noxious conditioning stimulation), has been identified as an advanced psychophysical measure with high clinical relevancy in the characterization of one’s capacity to modulate pain and consequently one’s susceptibility to acquire pain disorders.

Recommendations on terminology and practice of psychophysical DNIC testing

a Department of Neurology, Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel b Department of Diagnostic Sciences, UMDNJ, Newark, NJ, USA c Laboratory of Experimental Pain Research, Aalborg University, Aalborg, Denmark d Hopital Ambroise Pare, Boulogne Billancourt, France e Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School Boston, MA, USA f College of Dentistry, University of Florida, Gainesville, FL, USA g Faculty of Health and Welfare Studies, University of Haifa, Haifa, Israel h Department of Molecular Medicine and Surgery, Karolinska Hospital/Institutet, Stockholm, Sweden i Department of Psychology, Bamberg University, Bamberg, Germany j Department of Surgery and Neurosurgery, Faculty of Medicine, Sherbrooke University, Sherbrooke, QC, Canada k Department of Anesthesiology, Radboud University, Nijmegen, Netherlands

Heat pain thresholds: normative data and repeatability.

&NA; Measurement of thresholds for heat‐induced pain was performed on 106 normal subjects, at thenar eminence and foot dorsum, using the reaction time‐inclusive method of limits. Tests were repeated 2 weeks following the first test for most of the subjects. After determination that there were no outlying data points and that there was no systematic relationship between magnitude and variability of test scores, data from between 72 and 76 subjects were used to define normal upper and lower ranges by age, as well as repeatability coefficients. This was done through ANOVA‐based procedures that extend standard repeatability assessment methods. Normative data tables are presented, with measures of repeatability for the various sites and modalities. For the conventional test range, reaching 55°C, measurement of heat pain thresholds can define both hyper‐ and hypoalgesia. Application of repeatability coefficients allows for intra‐individual inter‐session comparison in longitudinal studies.

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy

Summary Conditioned pain modulation (CPM) predicts efficacy of duloxetine in painful diabetic neuropathy; patients with less efficient CPM are more likely to benefit from the drug. ABSTRACT This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug’s mechanism of action with the patient’s pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study’s primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r = 0.628, P < .001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R2 = 0.673; P = .012) showed that drug efficacy was predicted only by CPM (P = .001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment‐induced improvement in CPM was correlated with drug efficacy (r = −0.411, P = .033). However, this improvement occurred only in patients with less efficient CPM (16.8 ± 16.0 to −1.1 ± 15.5, P < .050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision‐making process. This evaluative approach promotes personalized pain therapy.

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.

Postcesarean section pain prediction by preoperative experimental pain assessment.

Background Postcesarean section pain is a common cause of acute pain in obstetrics, yet pain relief and patient satisfaction are still inadequate in many cases. The present study was conducted to determine whether preoperative assessment of experimental pain perception by quantitative sensory tests could predict the level of postcesarean section pain. Methods Fifty-eight women who were scheduled for elective cesarean section were enrolled in the study. Heat pain threshold and magnitude estimation of suprathreshold pain stimuli at 44°–48°C were assessed for both algosity (the sensory dimension of pain intensity) and unpleasantness 1 or 2 days before surgery. The day after the operation, the women reported the level of pain at the surgical wound on a visual analog scale at rest and during activity. Regression analysis was performed to evaluate the usefulness of preoperative scores in predicting postcesarean section pain. Results Postoperative visual analog scale scores at rest and during activity significantly correlated with preoperative suprathreshold pain scores at 44°–48°C (r = 0.31–0.58 for algosity and r = 0.33–0.74 for unpleasantness). The stimulus of 48°C was found to be the best predictor of postoperative pain for both conditions (r = 0.434–0.527;P < 0.01). In contrast to suprathreshold pain stimuli, pain threshold was not correlated with postoperative pain. Conclusions The results show that a simple and quick preoperative test is useful in identifying those women who will experience greater pain after a cesarean section. This test may be suggested for caregivers to tailor the postoperative treatment to specific patient needs and to improve postoperative outcome and patient satisfaction.

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.