Stability of conditioned pain modulation in patients with chronic pain: Implications for pain assessment & treatment

Over the past few decades, considerable evidence has accumulated indicating that pain may be modulated by a variety of endogenous pain-inhibitory processes. These operate at various levels of the central nervous system (CNS), and play a role in shaping the subjective experience of pain. Importantly, several lines of research suggest that abnormalities in endogenous pain inhibition may contribute to the development and persistence of pain conditions.

In the lab, a common method for investigating individual differences in pain inhibition is the use of conditioned pain modulation (CPM) paradigms. Formerly termed “diffuse noxious inhibitory control (DNIC)”, CPM refers to the psychophysical procedure during which one noxious stimulus (i.e., conditioning stimulus) inhibits or reduces the perception of a second noxious stimulus (i.e., test stimulus) applied to a remote area of the body. During a research meeting  taking place in Europe a couple of years ago, David Yarnitsky and a group of experts decided to clarify and standardize the terminology associated with DNIC in order to reduce confusion and enhance consistency across DNIC studies. In the paper that emerged from their consensus meeting (Yarnitsky et al. Euro J Pain 2010;14:339), they recommended using the term CPM (instead of DNIC) when referring to the phenomenon by which the conditioning stimulus affects the test stimulus. In their opinion, the term DNIC should only be used when referring to the neurophysiologic activity at the brainstem level that is assumed to underlie the CPM phenomenon. In the next couple of sections, I’ll try to adhere as best as I can to their recommendation.

In recent years, there has been a growing interest in using the CPM paradigm as a clinical tool for the assessment of patients with pain conditions. This interest stems, in part, from the growing emphasis that has been placed on mechanism-based pain diagnosis, and mechanism-based approaches to treatment selection for patients with pain. Given that treatments (e.g., medications) are likely to exert their clinical benefits by impacting the mechanisms underlying patients’ pain conditions, many authors have advocated for the bedside use of quantitative sensory testing (QST) and CPM paradigms in order to improve pain assessment and clinical decision making. The potential clinical utility of CPM paradigms is supported by the preliminary findings of Yarnitsky et al. (Pain 2012;153:1193), who found that inter-individual differences in CPM predicted the efficacy of duloxetine in patients with diabetic neuropathy. Based on results of this study, it was concluded that patients with deficits in endogenous pain inhibition (i.e., DNIC) might particularly benefit from drugs that are assumed to increase pain-inhibitory activity, such as SNRI antidepressants.

While the potential clinical utility of CPM is appealing, the potential value of the CPM paradigm as a clinical tool implies that CPM is, at least to some extent, reproducible and stable over time. If the CPM paradigm (and its underlying endogenous pain-inhibition construct) is not stable over time, there are reasons to believe that flawed and/or erroneous treatment decisions could emerge from its use as a clinical assessment tool. Surprisingly, to date, there is a paucity of research that has addressed the temporal stability of CPM. In previous research, the stability of CPM has been examined among healthy/pain-free individuals, but not among patients with chronic pain. In a recent study (Martel et al. 2013), we examined the stability of CPM over a 10-day period among patients with chronic musculoskeletal pain conditions, using the cold pressor task as the “conditioning stimulus” and pressure pain as the “test stimulus”.  In this study, our results provided support for the stability of CPM. Results, however, revealed considerable sex differences in the stability of CPM, with significantly greater degrees of CPM stability observed for women than men. The difference between men and women in the stability of CPM could not be accounted for by any demographic (e.g., age), medication use, and/or psychological variables (e.g., negative affect, catastrophizing).

Although preliminary, our findings suggest that CPM paradigms might possess sufficient reliability to be incorporated into bedside clinical evaluation of patients with chronic pain, but only among women. The lack of CPM reliability/stability observed among men places potential limits on the use of CPM paradigms in clinical settings for the assessment of men’s endogenous pain-inhibitory function. However, additional research using different procedures and CPM paradigms will be needed before drawing more definite conclusions regarding sex differences in the stability of CPM, and regarding the potential use of CPM as a bedside clinical tool for the assessment of endogenous pain-inhibitory function. Interestingly, our findings on the stability of CPM were recently replicated by the Florida group (Valencia et al. 2013) in a study conducted among a sample of patients with shoulder pain. While this is reassuring, more research will be needed in this area, particularly on the factors that may contribute to the stability/instability of CPM over time. More research will also be needed on the value of CPM for predicting responses to analgesic treatment in patients with chronic pain.

About  Marc O (Olivier) Martel

Marc O Martel Stability of conditioned pain modulation in patients with chronic pain: Implications for pain assessment & treatmentMarco is currently completing a postdoctoral fellowship in the Department of Anesthesiology at Harvard Medical School/Brigham & Women’s Hospital under the supervision of Dr. Robert Edwards. He holds a PhD in Clinical Psychology from McGill University, where he worked with Mick Sullivan. His primary research interests lie in exploring the biopsychosocial aspects of pain and disability.  As a parallel line of research, he is interested in exploring the biological and psychological factors that are associated with prescription opioid misuse among patients with chronic pain prescribed long-term opioid therapy.


Martel MO, Wasan AD, & Edwards RR (2013). Sex differences in the stability of conditioned pain modulation (CPM) among patients with chronic pain. Pain Med, 14 (11), 1757-68 PMID: 23924369

Valencia C, Kindler LL, Fillingim RB, & George SZ (2013). Stability of conditioned pain modulation in two musculoskeletal pain models: investigating the influence of shoulder pain intensity and gender. BMC Muscul Diso, 14 (1) PMID: 23758907


  1. Daniel Harvie says:

    Thanks Marc, are people using the cold pressure + pressure pain procedure at a test of the integrity of inhibitory mechanisms clinically?


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