Yelena Granovsky

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.

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.

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.

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.

Enhanced Presurgical Pain Temporal Summation Response Predicts Post-Thoracotomy Pain Intensity During the Acute Postoperative Phase

UNLABELLED Recent evidence points to an association between experimental pain measures obtained preoperatively and acute postoperative pain (POP). We hypothesized that pain temporal summation (TS) might be an additional predictor for POP insofar as it represents the neuroplastic changes that occur in the central nervous system following surgery. Therefore, a wide range of psychophysical tests (TS to heat and mechanical repetitive stimuli, pain threshold, and suprathreshold pain estimation) and personality tests (pain catastrophizing and anxiety levels) were administered prior to thoracotomy in 84 patients. POP ratings were evaluated on the 2nd and 5th days after surgery at rest (spontaneous pain) and in response to activity (provoked pain). Linear regression models revealed that among all assessed variables, enhanced TS and higher pain scores for mechanical stimulation were significantly associated with greater provoked POP intensity (overall r2 = 0.225, P = .008). Patients who did not demonstrate TS to both modalities reported lower scores of provoked POP as compared with patients who demonstrated TS in response to at least 1 modality (F = 4.59 P = .013). Despite the moderate association between pain catastrophizing and rest POP, none of the variables predicted the spontaneous POP intensity. These findings suggest that individual susceptibility toward a greater summation response may characterize patients who are potentially vulnerable to augmented POP. PERSPECTIVE This study proposed the role of pain temporal summation assessed preoperatively as a significant psychophysical predictor for acute postoperative pain intensity. The individual profile of enhanced pain summation is associated with the greater likelihood of higher postoperative pain scores.

Pain modulation profile and pain therapy: Between pro- and antinociception

0304-3959/

Pain perception in women with dysmenorrhea.

36.0

Simultaneous recording of late and ultra-late pain evoked potentials in fibromyalgia

OBJECTIVE To determine if systemic processing of pain differs in women with and without dysmenorrhea. METHODS Twenty‐two dysmenorrheic women and 31 nondysmenorrheic women were studied by pain threshold and supra‐threshold magnitude estimation to heat stimuli, pain‐evoked potentials by laser stimuli, and anxiety scores four times across their menstrual cycles. RESULTS Significant differences were found between dysmenorrheic and nondysmenorrheic women. In all four examinations across the menstrual cycle, dysmenorrheic women had longer latencies of pain‐evoked potentials (383.08 ± 6.8 msec versus 345.05 ± 7.0 msec, P < .001), higher magnitude estimations on visual analog scale of supra‐threshold pain (83.29 ± 2.87 versus 63.50 ± 3.82, P < .001), and higher state anxiety scores (37.69 ± 1.7 versus 29.20 ± 1.9, P = .002). CONCLUSION Women with dysmenorrhea show enhanced pain perception compared to nondysmenorrheic women. This augmentation of pain perception may be part of the development of dysmenorrhea.