Dorit Pud

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.

Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome.

Abstract Complex regional pain syndromes (CRPS, type I and type II) are devastating conditions that can occur following soft tissue (CRPS type I) or nerve (CRPS type II) injury. CRPS type I, also known as reflex sympathetic dystrophy, presents in patients lacking a well‐defined nerve lesion, and has been questioned as to whether or not it is a true neuropathic condition with an organic basis. As described here, glabrous and hairy skin samples from the amputated upper and lower extremity from two CRPS type I diagnosed patients were processed for double‐label immunofluorescence using a battery of antibodies directed against neural‐related proteins and mediators of nociceptive sensory function. In CRPS affected skin, several neuropathologic alterations were detected, including: (1) the presence of numerous abnormal thin caliber NF‐positive/MBP‐negative axons innervating hair follicles; (2) a decrease in epidermal, sweat gland, and vascular innervation; (3) a loss of CGRP expression on remaining innervation to vasculature and sweat glands; (4) an inappropriate expression of NPY on innervation to superficial arterioles and sweat glands; and (5) a loss of vascular endothelial integrity and extraordinary vascular hypertrophy. The results are evidence of widespread cutaneous neuropathologic changes. Importantly, in these CRPS type I patients, the myriad of clinical symptoms observed had detectable neuropathologic correlates.

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.

The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial

&NA; Neuropathic pain is often severe, persistent, and responds poorly to analgesic medications. Recent evidence suggests that N‐methyl‐d‐aspartate (NMDA) receptor antagonists may be effective in the treatment of neuropathic pain. The present trial was designed to test the efficacy of acute administration of the NMDA receptor antagonist amantadine in relieving surgical neuropathic pain in patients with cancer. The study sample consisted of 15 cancer patients with the diagnosis of surgical neuropathic pain. Two 500 ml infusions of either 200 mg amantadine or placebo were administered over a 3 h period, in a randomized order, 1 week apart from each other. Spontaneous and evoked pain were measured for 48 h before treatment, during treatment, and for 48 h following treatment. An average pain reduction of 85% was recorded at the end of amantadine infusion vs. 45% following placebo administration. The difference in pain relief between the two treatments was statistically significant (P=0.009). Mean pain intensity remained significantly lower during the 48 h following amantadine treatment as compared with the 48 h prior to treatment (31% reduction; P=0.006), whereas no such effect was found with the placebo (6% reduction; P=0.40). Amantadine, but not the placebo, also reduced ‘wind up’ like pain (caused by repeated pinpricking) in four patients. We conclude that amantadine infusion is a safe and effective acute treatment for surgical neuropathic pain in cancer patients. Further trials with long‐term oral or parenteral amantadine treatment should be conducted.

Prevalence and characteristics of post coronary artery bypass graft surgery pain (PCP)

&NA; Coronary artery bypass grafting (CABG) is one of the most common surgical procedures performed worldwide. However, its frequent complication, the post‐CABG pain (PCP) syndrome, remains poorly documented. This retrospective cohort study was aimed to investigate the prevalence and characteristics of this syndrome. Five hundred and four of 540 subjects, who underwent CABG surgery at our institution between January 1995 and December1996 and who could be identified, were mailed questionnaires regarding the presence and characteristics of chest wall pain. Eighty of 217 patients, who were defined as having PCP based on these questionnaires, were evaluated in detail. Main outcome measures included a preliminary pain questionnaire, pain localization on a body scheme, a five‐point verbal scale and the Visual Analogue Scale (VAS) for measuring pain intensity. Pain qualities, disability and depression were measured by the McGill Pain Questionnaire (MPQ), the Pain Disability Index (PDI), and the Beck Depression Inventory (BDI), respectively. Medical and neurological examinations were also conducted, as well as quantitative thermal testing (QTT) of the chest wall. The preliminary pain questionnaires indicated that 219 of the 387 respondents (56%) reported chest wall pain, which was categorized as PCP. One hundred and forty‐two (65%) of the patients with PCP reported pain of at least moderate severity, and 151 (72%) reported that the pain interfered with their daily activities. Eighty PCP patients were available for a detailed evaluation. Left‐sided chest wall pain was noted by 53 subjects, midline scar pain by 47, and right‐sided pain by nine subjects. Pain intensity (VAS) was 35±22 (mean±SD), MPQ score was 4.9±3.7, PDI score was 2.0±0.7, and BDI score was 9.3±7.3. The neurological examination and the QTT indicated three subcategories of PCP: (1) left‐sided chest wall pain often associated with hypoesthesia, mechanical allodynia, and elevated thermal thresholds; (2) midline scar pain accompanied primarily by mechanical allodynia; (3) right‐sided, relatively infrequent pain. While the first two subcategories seem to have a neurogenic etiology, this later subcategory of pain is of a mal‐defined etiology. This study indicates that PCP is a group of pain syndromes with a high prevalence, and with a negative effect on mood and performance of daily activities. The risk of developing PCP and its potential consequences should therefore be discussed with every patient prior to CABG surgery. These results will need to be confirmed in larger, multi‐center studies.

Complementary and alternative medicine use in breast cancer patients in Europe

Complementary and alternative medicine (CAM) has gained popularity among cancer patients in the past years. For this study, CAM includes any group of health care systems, practices or products that are not considered to be part of conventional medicine at present (National Center for Complementary and Alternative Medicine). The present study assessed patterns of CAM use in breast cancer patients in Europe. The study used a descriptive cross-sectional design, and data were collected through a 27-item questionnaire. The sample, which was part of a larger study, consisted of 282 breast cancer patients from 11 countries in Europe. Among participants, 44.7% used CAM since their diagnosis of cancer. The most common therapies used included herbal medicine (46.4%) and medicinal teas, relaxation techniques, spiritual therapies, homeopathy and vitamins/minerals. Younger patients with higher education and who had received combination treatments for their cancer in the past were more likely to use CAM. High levels of satisfaction were reported, with only 6.5% of the women reporting no benefits from the CAM used. Main sources of information about CAM were mostly friends/family and the media. Findings suggested that a high proportion of breast cancer patients used CAM, which may have implications for the clinical management of these patients.

Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid-induced hyperalgesia.

Abstract Opioids can elicit unexpected changes in pain sensitivity, known as opioid‐induced hyperalgesia (OIH). The aim of this study was to explore whether OIH exists in patients with chronic pain treated with oral opioids (OP) versus non‐opioid (NOP) analgesics. The sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) were evaluated in 73 OP and 37 NOP treated patients. Pain threshold, intensity and tolerance in response to the cold pressor (1 °C) were measured. DNIC was tested by co‐administrating conditioned heat stimulation (47 °C) to the left forearm and a conditioning stimulation of 12 °C for 30 s to the right hand. The results showed no differences between the two groups in any of the cold pain measures. In contrast, the magnitude of DNIC was significantly larger in the NOP than in the OP treated patients (p = 0.003). A gender based analysis showed a significant difference in DNIC between OP and NOP treated men only. However, a mixed model ANOVA demonstrated a significant effect of treatment (OP versus NOP) (F = 5.928, p = 0.017) rather than gender on DNIC. A regression analysis showed that opioid dosage and treatment duration had a significant negative effect on the magnitude of DNIC in OP treated men (β = −2.175, p = 0.036 and β = −2.061, p = 0.047, respectively). In conclusion, oral opioids usage for the treatment of chronic pain does not result in abnormal sensitivity to cold pain, but seems to alter pain modulation. The use of ‘advanced’ psychophysics tests such as evaluation of DNIC can help understanding the phenomenon of OIH.

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.

'Pain inhibits pain' mechanisms: Is pain modulation simply due to distraction?

&NA; ‘Diffuse noxious inhibitory controls’ (DNIC), a form of supraspinal descending endogenous analgesia, requires a noxious conditioning stimulus for pain attenuation. This may be partly dependent on a distraction effect. The term “conditioned pain modulation” (CPM) has recently been introduced to describe the psychophysical paradigm to test DNIC. The present study aimed to determine whether distraction and tonic heat stimulation inhibit pain through the same or different mechanisms by looking at whether there is a similar or even an additive effect on pain attenuation. Test pain was brief heat stimulation applied to the left volar of 34 healthy volunteers. For conditioning, the right hand was immersed in 46.5 °C water. Distraction was provided by three different difficulty levels of continuous cognitive visual tasks. Experimental blocks consisted of test pain: (1) alone; ‘baseline’, (2) with conditioning pain; ‘CPM’, (3) with distraction; ‘distraction’ and (4) with conditioning pain and distraction; ‘combined’. They were randomized and repeated three times and pain intensity and unpleasantness rated. Results showed an overall effect of experimental block on test pain intensity (P = 0.0125). Post‐hoc tests revealed a significant reduction in pain intensity ratings under Combined (21.2 ± 2.3; mean ± SEM) compared to CPM alone (16.0 ± 2.3) (P < 0.05). Furthermore, at all levels of distraction there were always a few subjects who were not distracted despite expressing CPM. Based on the additive effect of CPM and distraction on pain inhibition, and the cases of no distraction despite CPM, we suggest that CPM acts independently from distraction.

Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study.

&NA; For most healthy subjects, both subjective pain ratings and pain‐evoked potentials are attenuated under conditioned pain modulation (CPM; formerly termed diffuse noxious inhibitory controls, or DNIC). Although essentially spinal‐bulbar, this inhibition is under cortical control. This is the first study to observe temporal as well as spatial changes in cortical activations under CPM. Specifically, we aimed to investigate the interplay of areas involved in the perception and processing of pain and those involved in controlling descending inhibition. We examined brief consecutive poststimulus time windows of 50 ms using a method of source‐localization from pain evoked potentials, sLORETA. This enabled determination of dynamic changes in localized cortical generators evoked by phasic noxious heat stimuli to the left volar forearm in healthy young males, with and without conditioning hot‐water pain to the right hand. We found a CPM effect characterized by an initial increased activation in the orbitofrontal cortex (OFC) and amygdala at 250–300 ms poststimulus, which was correlated with the extent of psychophysical pain reduction. This was followed by reduced activations in the primary and secondary somatosensory cortices, supplementary motor area, posterior insula, and anterior cingulate cortex from 400 ms poststimulus. Our findings show that the prefrontal pain‐controlling areas of OFC and amygdala increase their activity in parallel with subjective pain reduction under CPM, and that this increased activity occurs prior to reductions in activations of the pain sensory areas. In conclusion, achieving pain inhibition by the CPM process seems to be under control of the OFC and the amygdala. The orbitofrontal cortex and the amygdala seem to play a pivotal early role in pain inhibition under conditioned pain modulation.