In this issue of the Scandinavian Journal of Pain Nahman-Averbuch and co-workers  publish a study in which the aim was to characterize and explore the associations between conditioned pain modulation (CPM) responses assessed by different paradigms in the same cohort of subjects.
1 Endogenous modulation of nociceptive pathways is central in pain physiology
Through a relatively well-characterized network, our body is able to regulate nociceptive processing to produce either facilitation or inhibition of the pain experience . Put simply, facilitation of nociceptive activity will produce more intense pain, and inhibition will produce less pain. Increased pain inhibitory activity may be necessary during stress or the need to escape from threat. Increased pain facilitatory activity may be useful during recuperation from injury by producing hyperalgesia or allodynia around the injured tissue, reducing movement and promoting healing. Clearly, a physiological system with pain modulating capabilities is of outmost importance.
2 Dysfunctional endogenous pain regulation and chronic pain conditions
It has been proposed that a dysfunctional endogenous pain modulatory system may contribute to chronic pain states . In combination with other factors such as genetic predisposition and psychosocial factors such as context, mood, and cognitive set, dysfunctional pain modulation may lead to an increased vulnerability for long-lasting pain . The possible role of the pain modulatory network in long-lasting pain makes it valuable to compare the efficacy of this network across populations and conditions. A widely used test of pain modulatory networks is to quantify the change in a perceived painful ‘test stimulus’ (TS) induced by another painful ‘conditioning stimulus’ (CS). This paradigm is termed conditioned pain modulation (CPM). The term conditioned pain modulation is relatively new. It was coined by Yarnitsky and co-workers in 2010  as a term describing psychophysical human studies on modulation of pain. CPM was suggested to replace the term ‘diffuse noxious inhibitory controls’ (DNIC), which originally was used to describe descending inhibitory mechanisms of nociception in animals .
3 Varying ways of assessing conditioned pain modulation
The CPM paradigm is relatively easy to perform in an experimental setting and numerous studies have tested endogenous pain modulation in a CPM paradigm during the recent years. Two pain stimuli are induced experimentally in the CPM protocol (TS and CS). With the large number of experimental stimulus modalities available the number of TS/CS combinations becomes high. Hence, it is challenging to draw conclusions based on CPM studies since different TS/CS combinations may trigger different afferent and modulating pathways. Furthermore, little consistency in the use of terms and standard modes of calculating and reporting the magnitude of the CPM effects make comparisons across studies even more difficult .
The challenge with methodological diversity has also been pointed out in two recent reviews. In a systematic review of sex differences in CPM the authors point out that it was not possible with standardized meta-analysis because of the heterogeneity across study methods . Another systematic review studied the relationship between CPM and chronic pain . The authors conclude that conditioned pain modulation is impaired in populations with chronic pain. However, the authors point out that the causality in this relationship can only be given by longitudinal studies in which CPM is measured several times. Meta-analyses as well as longitudinal studies both require a certain level of validity and reproducibility of the experimental method under study.
In summary, in order to test whether endogenous pain modulation varies with different factors such as sex, age, or clinical condition, more knowledge is clearly needed on the variability and repeatability of the CPM paradigm itself. It is in this context the present paper by Nahman-Averbuch and co-workers should be seen .
4 Large intra-individual differences with different test stimuli
The most important finding in Nahman-Averbuch et al.’s study is that the psychophysical CPM response varies greatly in the same subjects when different test stimuli are investigated. This represents the major methodological strength of the study. The variability in CPM responses is indicated in Figure 1 of their paper . The most significant inhibitory CPM effect was found on the pressure pain thresholds (PPT). By assigning colour codes to the most and least efficient CPM responses, the figure indicates the spread in CPM responses following the five other TS modalities relative to PPT. The correlations presented in Table 3 in their paper indicate a weak correlation between the CPM responses from the PPT, heat pain (HP) and pressure pain (PP) test stimulus modalities . This correlation does not survive a correction for multiple comparisons.
Another study attempting to resolve the methodological challenges with the CPM paradigm is Oono et al. . TS modalities as well as CS modalities were varied in that study. Direct comparison with the present study is difficult since the study population was young healthy men in , whereas middle aged men and women were studied by Nahman-Averbuch et al. . Nahman-Averbuch et al. did not find differences between the two genders, confirming similar findings by Gullander et al. .
5 Continuous spectrum of CPM responses and when to choose what CPM-paradigm
Another message in the paper by Nahman-Averbuch et al. is to utilize the continuous spectrum of CPM responses in the statistical tests. This has been done successfully in at least two CPM studies. Both studies indicate that the CPM response may identify people at risk for developing post-operative pain by utilizing the continuous variation in the pain inhibitory response when assessing the association between pain inhibition and developmentofpost-operative or chronic pain [12,13]. Conditioning stimuli in these studies were immersion of a hand in hot  or cold  water. With the large variability in CPM responses between test modalities, the choice of test modality is central when the CPM response is used as a predictor of future outcome. The authors argue that “. . .it is the clinical application that will eventually direct researchers to prefer the use of a certain paradigm”. On what basis the researcher should decide which paradigm to use is the difficult part of this argument. Combining the large number of paradigms with a large number clinical applications seems like a long way to go in order to reveal which paradigm that better predicts which treatment. It is possible that first of all amore systematic investigation is necessary of the physiological mechanismsin the various methods. A first approach could be to repeat this experiment with another conditioning stimulus, namely the cold pressor pain, that was shown to give the smallest variability in a test–retest paradigm . It also gave the strongest inhibitory CPM response.
However, using tourniquet-induced pain as the conditioning stimulus, Nilsen et al.  were able to document that stress reduced significantly the CPM effect on the TS heat pain threshold (HPT), supra-threshold heat pain level (SHPL), and pressure pain threshold (PPT).
A strength that increases the external validity of the findings of Nahman-Averbuch and co-workers  is the relatively high age of participants (>40 years old).
Two limitations that deserve to be mentioned are that the experiments were performed by three different experimenters and across different days. This is also mentioned as limitations by the authors. Testing across different days introduces an additional unknown factor in which the CPM paradigm is lacking knowledge, namely reproducibility. Therefore, future methodological CPM studies on the reproducibility across days within the same group of subjects are surely needed. This work has already been started by Oono and co-workers, who tested inter- and intra-individual variability of several CS/TS combinations .
6 More methodological studies are needed to resolve the many conundrums of CPM
Taken together, the present methodological study by Nahman-Averbuch underlines two challenges with the CPM paradigm; the large variation in CPM responses between individuals and the large variation in CPM responses between test stimulus modalities within the same individuals. The former probably represents the normal variation in response magnitude seen in any experimental study. It is in line with the large variation in response magnitude to any experimental pain manipulation and can probably, at least partly, be explained by genetic or other trait factors. The continuous response spectrum may have predictive value (e.g. in response to treatment) given that the “right” CPM paradigm is chosen. The latter type of variation represents the new information in this paper. It shows that conditioned pain modulation is not one single phenomenon. What remains to be untangled is the relative importance of the various independent factors. There are several: the type of peripheral nerve fibres activated by the conditioning stimulus as well as by the test stimulus, the intensity and temporal characteristics of these stimuli, psychological factors, as well as genetic factors.
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Published Online: 2013-01-01
Published in Print: 2013-01-01