The milestone effect of DNIC in our understanding of pain

2018 ◽  
Author(s):  
Serge Marchand
Keyword(s):  
Inhibitory Control ◽  
Pain Modulation ◽  
The Other ◽  
Major Influence ◽  
Conditioned Pain Modulation ◽  
Pain Mechanisms ◽  
Diffuse Noxious Inhibitory Control ◽  
Endogenous Pain Modulation

While thousands of articles are published each year on pain, only a few have such a major impact on the understanding of pain mechanisms as the landmark paper discussed in this chapter; published by Le Bars and colleagues in 1979, it introduced the concept of diffuse noxious inhibitory control (DNIC; also called diffuse noxious inhibition) mechanisms. Although this work is more than three decades old, it still has a major influence on both the understanding of pain mechanisms and the development of clinical approaches. It is known that apparently similar pain may be caused by different mechanisms: one may be caused by amplified excitatory mechanisms while the other may be related to a deficit of endogenous pain modulation, such as DNIC or conditioned pain modulation (or CPM); these will not respond to the same treatment. The work by Le Bars and colleagues provided a new understanding of mechanisms underlying pain.

Reliability of the conditioned pain modulation paradigm across three anatomical sites

2020 ◽  
Vol 20 (2) ◽  
pp. 283-296
Author(s):  
Rania Nuwailati ◽  
Michele Curatolo ◽  
Linda LeResche ◽  
Douglas S. Ramsay ◽  
Charles Spiekerman ◽  
...  
Keyword(s):  
Cold Pressor Test ◽  
Pressure Pain Threshold ◽  
Pain Modulation ◽  
Conditioned Pain Modulation ◽  
Dominant Hand ◽  
Pain Mechanisms ◽  
Relative Reliability ◽  
Contralateral Hand ◽  
The Face ◽  
Absolute Reliability

AbstractBackground and aimsConditioned Pain Modulation (CPM) is a measure of pain inhibition-facilitation in humans that may elucidate pain mechanisms and potentially serve as a diagnostic test. In laboratory settings, the difference between two pain measures [painful test stimulus (TS) without and with the conditioning stimulus (CS) application] reflects the CPM magnitude. Before the CPM test can be used as a diagnostic tool, its reliability on the same day (intra-session) and across multiple days (inter-session) needs to be known. Furthermore, it is important to determine the most reliable anatomical sites for both the TS and the CS. This study aimed to measure the intra-session and inter-session reliability of the CPM test paradigm in healthy subjects with the TS (pressure pain threshold-PPT) applied to three test sites: the face, hand, and dorsum of the foot, and the CS (cold pressor test-CPT) applied to the contralateral hand.MethodsSixty healthy participants aged 18–65 were tested by the same examiner on 3 separate days, with an interval of 2–7 days. On each day, testing was comprised of two identical experimental sessions in which the PPT test was performed on each of the three dominant anatomical sites in randomized order followed by the CPM test (repeating the PPT with CPT on the non-dominant hand). CPM magnitude was calculated as the percent change in PPT. The Intraclass Correlation Coefficient (ICC), Coefficient of Variation (CV), and Bland-Altman analyses were used to assess reliability.ResultsPPT relative reliability ranged from good to excellent at all three sites; the hand showed an intra-session ICC of 0.90 (0.84, 0.94) before CPT and ICC of 0.89 (0.83, 0.92) during CPT. The PPT absolute reliability was also high, showing a low bias and small variability when performed on all three sites; for example, CV of the hand intra-session was 8.0 before CPT and 8.1 during CPT. The relative reliability of the CPM test, although only fair, was most reliable when performed during the intra-session visits on the hand; ICC of 0.57 (0.37, 0.71) vs. 0.20 (0.03, 0.39) for the face, and 0.22 (0.01, 0.46) for the foot. The inter-session reliability was lower in all three anatomical sites, with the best reliability on the hand with an ICC of 0.40 (0.23, 0.55). The pattern of absolute reliability of CPM was similar to the relative reliability findings, with the reliability best on the hand, showing lower intra-session and inter-session variability (CV% = 43.5 and 51.5, vs. 70.1 and 73.1 for the face, and 75.9 and 78.9 for the foot). The CPM test was more reliable in women than in men, and in older vs. younger participants.DiscussionThe CPM test was most reliable when the TS was applied to the dominant hand and CS performed on the contralateral hand. These data indicate that using the CS and TS in the same but contralateral dermatome in CPM testing may create the most reliable results.

Defective Endogenous Pain Modulation in Fibromyalgia: A Meta-Analysis of Temporal Summation and Conditioned Pain Modulation Paradigms

2018 ◽  
Vol 19 (8) ◽  
pp. 819-836 ◽  
Author(s):  
Anthony Terrence O'Brien ◽  
Alicia Deitos ◽  
Yolanda Triñanes Pego ◽  
Felipe Fregni ◽  
Maria Teresa Carrillo-de-la-Peña
Keyword(s):  
Temporal Summation ◽  
Meta Analysis ◽  
Pain Modulation ◽  
Conditioned Pain Modulation ◽  
Endogenous Pain Modulation

Pain modulation as a function of hypnotizability: Diffuse noxious inhibitory control induced by cold pressor test vs explicit suggestions of analgesia

2017 ◽  
Vol 171 ◽  
pp. 135-141 ◽  
Author(s):  
Fabrizia Fidanza ◽  
Maurizio Varanini ◽  
Antonella Ciaramella ◽  
Giancarlo Carli ◽  
Enrica L. Santarcangelo
Keyword(s):  
Inhibitory Control ◽  
Cold Pressor Test ◽  
Cold Pressor ◽  
Pain Modulation ◽  
Diffuse Noxious Inhibitory Control ◽  
Pressor Test

REPRINTED WITH PERMISSION OF IASP – PAIN 160 (2019) 2679–2690: Conditioned pain modulation as a biomarker of chronic pain: a systematic review of its concurrent validity

Ból ◽  
2020 ◽  
Vol 21 (3) ◽  
pp. 1-15
Author(s):  
Carina Fernandes ◽  
Marina Pidal-Miranda ◽  
Noelia Samartin-Veiga ◽  
María T. Carrillo-de-la-Peña
Keyword(s):  
Systematic Review ◽  
Chronic Pain ◽  
Concurrent Validity ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Experimental Pain ◽  
Pain Modulation ◽  
Conditioned Pain Modulation ◽  
Pain Mechanisms ◽  
Chronic Pain Conditions

Conditioned pain modulation (CPM) is a promising psychophysical biomarker of central pain mechanisms because it significantly discriminates patients with chronic pain from healthy controls. Nevertheless, it is unclear in what extent CPM assessed experimentally is correlated with clinical manifestations of pain. To assess the concurrent validity of CPM, we performed a systematic review of the literature reporting correlations between CPM responses and pain intensity, disability, duration, and area in patients with different chronic pain conditions. We included 32 studies that altogether encompassed data from 1958 patients and provided 62 correlations. The majority of the results (69%) reported nonsignificant correlations between CPM efficiency and clinical manifestations of pain, whereas the remaining results showed a correlation between CPM reduction and worse clinical symptoms of pain. The modality of stimulation, the type of pain, and the stimulation site appear to be critical variables that influenced the pattern of results. Given that most of the studies were conducted with highly heterogeneous methodologies and unclear risk of bias, the findings highlight the need for future studies using standardized measures of clinical and experimental pain before considering CPM as a valid biomarker of pain. We discuss some guidelines to overcome the constraints in this promising line of research.

CGRP monoclonal antibody prevents the loss of diffuse noxious inhibitory controls (DNIC) in a mouse model of post-traumatic headache

Cephalalgia ◽  
2021 ◽  
pp. 033310242098168
Author(s):  
Caroline M Kopruszinski ◽  
Joelle M Turnes ◽  
Juliana Swiokla ◽  
Troy J Weinstein ◽  
Todd J Schwedt ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inhibitory Control ◽  
Mild Traumatic Brain Injury ◽  
Pain Modulation ◽  
Diffuse Noxious Inhibitory Controls ◽  
Diffuse Noxious Inhibitory Control ◽  
Cutaneous Allodynia ◽  
Calcitonin Gene ◽  
Post Traumatic

Aim Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice. Methods Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury. Results In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury. Interpretation Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.

scholarly journals Conditioned Pain Modulation Is Not Impaired in Individuals with Frozen Shoulder: A Case-Control Study

2021 ◽  
Vol 18 (23) ◽  
pp. 12330
Author(s):  
Marta Aguilar-Rodríguez ◽  
Lirios Dueñas ◽  
Mercè Balasch i Bernat ◽  
Mira Meeus ◽  
Filip Struyf ◽  
...  
Keyword(s):  
Frozen Shoulder ◽  
Pressure Pain Threshold ◽  
Conditioning Stimulus ◽  
Cross Sectional Study ◽  
Pain Modulation ◽  
Conditioned Pain Modulation ◽  
Central Pain ◽  
Cross Sectional ◽  
Pain Mechanisms ◽  
The Absolute

Frozen shoulder (FS) is a poorly understood condition resulting in substantial shoulder pain and mobility deficits. The mechanisms behind FS are not yet fully understood, but, similar to other persistent pain states, central pain mechanisms may contribute to ongoing symptoms in this population. The objective of this research was to investigate conditioned pain modulation (CPM) in people with FS compared with pain-free individuals. A total of 64 individuals with FS and 64 healthy volunteers participated in this cross-sectional study. CPM was assessed by using the pressure pain threshold (PPT) and an occlusion cuff (tourniquet test) as the test and conditioning stimulus, respectively. The absolute and percentage of change in PPT (CPM effect) as well as pain profiles (pro-nociceptive vs. anti-nociceptive) of individuals with FS and healthy controls were calculated. No significant differences in the absolute change in the PPT or CPM effect were found in people with FS compared to pain-free controls. Moreover, no between-group differences in the percentage of subjects with pro-nociceptive and anti-nociceptive pain profiles were observed. These results suggest that endogenous pain inhibition is normally functioning in people with FS. Altered central pain-processing mechanisms may thus not be a characteristic of this population.

Sustained exposure to acute migraine medications combined with repeated noxious stimulation dysregulates descending pain modulatory circuits: Relevance to medication overuse headache

Cephalalgia ◽  
2018 ◽  
Vol 39 (5) ◽  
pp. 617-625 ◽  
Author(s):  
Kelsey M Nation ◽  
David W Dodick ◽  
Edita Navratilova ◽  
Frank Porreca
Keyword(s):  
Inhibitory Control ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Conditioning Stimulus ◽  
Pain Modulation ◽  
Noxious Stimulation ◽  
High Dose ◽  
Acute Migraine ◽  
Diffuse Noxious Inhibitory Controls ◽  
Diffuse Noxious Inhibitory Control

Background Loss of conditioned pain modulation/diffuse noxious inhibitory controls has been demonstrated in patients with migraine and medication overuse headache. We hypothesized that exposure to acute migraine medications may lead to dysregulation of central pain modulatory circuits that could be revealed by evaluating diffuse noxious inhibitory controls and that prior noxious stimulus is required for a loss of the diffuse noxious inhibitory control response in rats exposed to these medications. Methods Rats were “primed” by continuous infusion of morphine or one of two doses of sumatriptan. Diffuse noxious inhibitory control was evaluated at the end of drug-priming (day 7) and again after sensory thresholds returned to baseline (day 21). The Randall-Selitto hindpaw pressure test was used as the test stimulus and forepaw capsaicin injection served as the conditioning stimulus. Results Morphine-primed rats showed opioid-induced hyperalgesia accompanied by a loss of diffuse noxious inhibitory controls on day 7. Sumatriptan-primed rats did not develop hyperalgesia or loss of diffuse noxious inhibitory controls on day 7. Morphine-primed and high-dose sumatriptan-primed rats only had a loss of diffuse noxious inhibitory control on day 21 if they received a capsaicin injection on day 7. Conclusions Prolonged exposure to migraine treatments followed by an acute nociceptive stimulation caused long-lasting alterations in descending pain modulation, shown by a loss of diffuse noxious inhibitory controls. Morphine was more detrimental than sumatriptan, consistent with clinical observations of higher medication overuse headache risk with opioids. These data suggest a mechanism of medication overuse headache by which migraine medications combined with repeated episodes of pain may amplify the consequences of nociceptor activation and increase the probability of future migraine attacks as well as risk of medication overuse headache.

scholarly journals Reference values of conditioned pain modulation

2019 ◽  
Vol 19 (2) ◽  
pp. 279-286
Author(s):  
Jürg Schliessbach ◽  
Christian Lütolf ◽  
Konrad Streitberger ◽  
Pasquale Scaramozzino ◽  
Lars Arendt-Nielsen ◽  
...  
Keyword(s):  
Reference Values ◽  
Cold Pressor Test ◽  
Conditioning Stimulus ◽  
Cold Pressor ◽  
Pain Modulation ◽  
Conditioned Pain Modulation ◽  
Abnormal Finding ◽  
Withdrawal Reflex ◽  
Endogenous Pain Modulation ◽  
Electrical Stimuli

Abstract Background and aims Endogenous pain modulation can be studied in humans by conditioned pain modulation (CPM): pain induced by a test stimulus is attenuated by a distantly applied noxious conditioning stimulus. The detection of impaired CPM in individual patients is of potential importance to understand the pathophysiology and predict outcomes. However, it requires the availability of reference values. Methods We determined reference values of CPM in 146 pain-free subjects. Pressure and electrical stimulation were the test stimuli. For electrical stimuli, we recorded both pain threshold and threshold for the nociceptive withdrawal reflex. Cold pressor test was the conditioning stimulus. The 5th, 10th and 25th percentiles for the three tests were computed by quantile regression analyses. Results The average thresholds increased after the conditioning stimulus for all three tests. However, a subset of subjects displayed a decrease in thresholds during the conditioning stimulus. This produced negative values for most of the computed percentiles. Conclusions This study determined percentile reference values of CPM that can be used to better phenotype patients for clinical and research purposes. The negative value of percentiles suggests that a slightly negative CPM effect can be observed in pain-free volunteers. Implications Pain facilitation rather than inhibition during the conditioning stimulus occurs in some pain-free volunteers and may not necessarily represent an abnormal finding.

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