Learning Objectives: After participating in this continuing professional development activity, the provider should be better able to:

1. Describe how conditioned pain modulation (CPM) is measured and interpreted.

2. Explain the underlying mechanisms involved in the CPM response.

3. Examine the evidence on CPM as a prognostic indicator and predictor of pain outcomes and response to treatment.

Conditioned pain modulation (CPM) is an experimental paradigm for assessing the endogenous pain inhibitory pathway, or the pain-inhibits-pain phenomenon, and represents the net effect of the facilitatory and inhibitory functions of the descending pain pathways. The measurement of CPM magnitude quantifies the efficacy of the brain in activating endogenous analgesia, which is thought to be impaired in the context of chronic pain. The following narrative review explores the scientific evidence for and against using CPM to predict common pain outcomes and the potential for this psychophysical measure to inform mechanism-based treatment.

Background

CPM provides a measure of the net effect of facilitatory and inhibitory descending pain pathways in humans.1,2 CPM evolved from the diffuse noxious inhibitory control (DNIC) model, which was first described by Le Bars and colleagues in 1979.3 Le Bars used anesthetized rats to demonstrate that wide dynamic range neurons located in the dorsal horn of the spinal cord are inhibited when a second noxious stimulus is applied to a different location on the body-the pain-inhibits- pain phenomenon. However, the measurement of dorsal horn neuron activity in humans is challenging and it is unclear whether neural activity at the spinal cord correlates with clinical pain, thus the term DNIC is used only to describe the neurophysiological phenomenon with objective outcomes, whereas CPM is recommended to describe the psychophysical paradigm for subjective testing.2

As a subjective surrogate measure of the DNIC response and the efficacy of the descending endogenous analgesic system, CPM may provide a clinically relevant value of the brain's ability to activate endogenous analgesia.1,2 The assessment of CPM consists of the application of a noxious test stimulus (TS) followed by the application of a painful conditioning stimulus (CS) at a second location.2 Depending on the CPM protocol used, the physical unit (eg, temperature at pain 40 or when the pain rating is 40/100) or rating data (eg, numerical pain score for a fixed temperature stimulus) is obtained.4 When using physical units, the calculation of CPM is obtained by subtracting the first value minus the second value, whereas rating data are calculated by subtracting the last value from the first value. This method is recommended along with the guidance of denoting pain inhibition with a negative value (antinociceptive profile) and pain facilitation by a positive value (pronociceptive profile).

In individuals with an antinociceptive profile, the application of the CS will result in reduced pain at the site of the TS, reflecting the effect of the endogenous pathways on reducing afferent noxious stimuli. A positive value, or pronociceptive profile, suggests that CPM is inefficient and this may be a pathogenetic risk factor of idiopathic pain syndromes and a predictor of neuropathic pain levels and postoperative pain.5

However, defining a normal range of CPM effect has been difficult due to variations in the CPM protocol across studies. Although there is evidence of individual differences in the CPM magnitude related to age and sex,6-8 a review of the various CPM protocols used among pain-free controls reported that the median CPM effect was 29% although this value should be used cautiously as it has not been validated.9 Considering that the CPM effect has been reported to be absent in some pain-free populations,10 it has been suggested that the CPM effect range may be better understood as a spectrum that is dependent on the CPM paradigm used and individual variability.11

Mechanisms of the CPM Effect

CPM is a cerebral/supraspinal and cerebrospinal process12,13 that involves an activation of brainstem regions including the periaqueductal gray (PAG), nucleus raphe magnus (NRM), a part of the rostral ventromedial medulla (RVM), and dorsal reticular nucleus (DRt).14 Neurons within these regions project to the spinal or medullary dorsal horns to enhance or diminish nociceptive input, thereby modulating the experience of pain. The PAG and NRM serotonergic and noradrenergic descending pathways recruit enkephalinergic interneurons in the spinal cord to produce an analgesic response.15 In addition, activation of opioid receptors in the medullary reticularis nucleus dorsalis induces analgesia.16

Further studies have demonstrated the importance of the DRt in pain modulation. The DRt receives nociceptive inputs from spinal projections and sends pain modulatory projections to the spinal cord and cortical sites, communicates with the PAG, NRM, thalamus, and amygdala. On top of those functions of the DRt, even a single DRt neuron can project to different cortical sites.17-19 Thus, the DRt, PAG, and RVM make up the spinal-supraspinal-spinal feedback loop of pain modulation.

CPM is mediated by limbic and higher brain regions including the amygdala, infralimbic cortex, and prefrontal cortex.20 This may explain why psychological factors, such as pain catastrophizing and negative pain expectations, are associated with reduced CPM.21 A systematic review of 36 studies identified other characteristics associated with larger CPM responses that included younger adult age, male sex, ovulatory phase of the menstrual cycle, carrier of the serotonin transporter-linked polymorphic region (5-HTTLPR) long allele, and attention to the conditioning stimulus and positive expectations.22

CPM Paradigms

A pre-CS (or first) test stimuli procedure is used to determine the average value required to reach the fixed physical unit or the individual's pain threshold (rating unit). The most commonly used test stimuli are pressure pain or heat pain threshold,22 although other thermal and mechanical, electrical, or chemical stimuli are also common.4

It is recommended to use 2 types of TS in the protocol, such as thermal and mechanical stimuli, and that they be performed twice for pre-CS and post-CS (or second) testing with at least a 10-minute interstimulus interval at 2 different skin sites.4 The most common and reliable CS is cold pressor pain in which the participant immerses a limb into cold water to elicit pain.4,22 Ischemic pain using cuff inflation or a tourniquet, capsaicin injection, or noxious heat stimulation, using contact heat thermode or water bath, has also been used.

Heterotopic nociceptive conditioning stimulation is recommended to trigger the CPM response using application of the TS and CS on 2 remote and separate anatomic regions of the body (an upper and a lower limb) to reflect ascending-descending long tract activity.15 Activation of endogenous inhibition has been shown to occur using spatial summation ipsilaterally,23 whereas the use of ipsilateral homotopic sites can reduce CPM effects.24

Recommendations for standard measurement of CPM include that mechanical and heat TS should be delivered at a fixed pain intensity of 40 on a 0- to 100-point pain rating scale or at an ascending intensity and discontinued when pain intensity of 40/100 is reached.4 The CS should be mild to moderately painful (>20/100 pain intensity) and administered as rapidly as possible after (as opposed to in parallel with) the first TS, because it may minimize biases such as distraction and because the duration of CPM effects is short. It is also recommended to present the results using a positive (pain facilitation) or negative (pain inhibition) value and percent change.

A systematic review of the reliability of CPM using various protocols demonstrated that the intersession reliability of the effect was good to excellent. The authors concluded that it is a reliable measure, but that reliability is heavily dependent on population parameters and study methodology.11 Further recommendations for comprehensive reporting on sample demographics, recruitment strategies, and study attrition were made and attention given to blinding, control for confounding factors, and standardization of statistical analyses.

CPM as a Predictor of Chronic Pain or Treatment Response

An impaired CPM response has been associated with numerous chronic pain conditions, including fibromyalgia,25 whiplash-associated disorders, osteoarthritis and low back pain,26 migraine and tension-type headaches,27 temporomandibular disorders and atypical trigeminal neuralgia,28 HIV-related pain,29 and irritable bowel syndrome.30,31 However, it is important to note that many of these studies were cross-sectional with only associations identified, which do not imply causality.

In a prospective longitudinal study of 35 patients with spinal cord injury, a decrease in the efficacy of CPM was observed over time only in patients already suffering with neuropathic pain at admission.32 The results suggest that neuropathic pain leads to inefficiency of the CPM response, rather than CPM inefficiency as a risk factor for the development of neuropathic pain.

Similarly, associations between increased incidence of postoperative pain and hyperalgesia after cesarean section or abdominal surgery and preoperative inefficient CPM have been reported.33,34 On the other hand, studies of chronic postoperative pain after total knee replacement have shown that inefficient CPM preoperatively is not a risk factor.35,36

A systematic review of 32 studies, involving 1958 participants that reported correlations between CPM responses and pain intensity, disability, duration, and area, concluded that further research is necessary before considering CPM as a valid biomarker of pain.37 The authors recommended standardized measures of clinical pain, including pain type, and experimental pain, including the modality of stimulation and stimulation site, in future research.

Likewise, CPM has not consistently shown an association with treatment response after an intervention.1 In a placebo-controlled study, it was found that a weaker CPM magnitude was associated with a better response to duloxetine treatment for painful diabetic neuropathy.38 In addition, a positive correlation was reported between the efficacy of duloxetine and improvement in CPM; however, this was only found among participants with less efficient CPM.

Another study reported an association between a pronociceptive pain modulation profile, defined as reduced CPM, and enhanced temporal summation (TS), and lower pain severity at 3 months after spinal cord stimulation.39 However, an open-label trial that examined the effect of topical diclofenac for knee osteoarthritis reported that a more efficient pretreatment CPM was predictive of a better analgesic response.40

Although there is a growing evidence base on the value of including CPM as a phenotypic measure in pain research, it is recommended to interpret the CPM effect along the spectrum of pain facilitation and inhibition with other indices, such as temporal summation, to produce a pain modulation profile.41 The current evidence for considering CPM as a reliable prognostic indicator, predictor of pain outcomes, and response to treatment is inadequate for routine use in clinical settings; however, there is justification for continuing to build on the evidence through increased rigor and reproducibility in future studies and by integrating the interpretation of results within the context of the pain modulation profile. Constraints in summarizing the evidence on CPM are due to lack of standardization in methodology, poor intersession reliability, limited study reproducibility, and a lack of normative values.1,15 These aspects are important to consider in future studies using CPM to advance its application in clinical settings.

Conclusion

CPM has a strong theoretical basis and reflects the net effects of facilitatory and inhibitory functions of the descending pain pathways. CPM is a psychophysical measure that can be used along with temporal summation to produce a pain modulation profile. Although the current evidence base regarding the research and clinical utility of using CPM as a phenotypic aspect of pain conditions is growing, the inconsistencies in study methodologies and reporting have hampered the ability to summarize results across studies. Future studies are needed that integrate the recommendations for standardization to advance knowledge of this potentially useful measure in pain research and clinical practice.

References