Home A novel clinical applicable bed-side tool for assessing conditioning pain modulation: proof-of-concept
Article Publicly Available

A novel clinical applicable bed-side tool for assessing conditioning pain modulation: proof-of-concept

  • Lars Arendt-Nielsen EMAIL logo , Jesper Bie Larsen , Stine Rasmussen , Malene Krogh , Laura Borg and Pascal Madeleine
Published/Copyright: July 21, 2020
Download Article (PDF)
Become an author with De Gruyter Brill
Author Information Explore this Subject
Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 20 Issue 4

Abstract

Background and aims

In recent years, focus on assessing descending pain modulation or conditioning pain modulation (CPM) has emerged in patients with chronic pain. This requires reliable and simple to use bed-side tools to be applied in the clinic. The aim of the present pilot study was to develop and provide proof-of-concept of a simple clinically applicable bed-side tool for assessing CPM.

Methods

A group of 26 healthy volunteers participated in the experiment. Pressure pain thresholds (PPT) were assessed as test stimuli from the lower leg before, during and 5 min after delivering the conditioning tonic painful pressure stimulation. The tonic stimulus was delivered for 2 min by a custom-made spring-loaded finger pressure device applying a fixed pressure (2.2 kg) to the index finger nail. The pain intensity provoked by the tonic stimulus was continuously recorded on a 0–10 cm Visual Analog Scale (VAS).

Results

The median tonic pain stimulus intensity was 6.7 cm (interquartile range: 4.6–8.4 cm) on the 10 cm VAS. The mean PPT increased significantly (P = 0.034) by 55 ± 126 kPa from 518 ± 173 kPa before to 573 ± 228 kPa during conditioning stimulation. When analyzing the individual CPM responses (increases in PPT), a distribution of positive and negative CPM responders was observed with 69% of the individuals classified as positive CPM responders (increased PPTs = anti-nociceptive) and the rest as negative CPM responders (no or decreased PPTs = Pro-nociceptive). This particular responder distribution explains the large variation in the averaged CPM responses observed in many CPM studies. The strongest positive CPM response was an increase of 418 kPa and the strongest negative CPM response was a decrease of 140 kPa.

Conclusions

The present newly developed conditioning pain stimulator provides a simple, applicable tool for routine CPM assessment in clinical practice. Further, reporting averaged CPM effects should be replaced by categorizing volunteers/patients into anti-nociceptive and pro-nociceptive CPM groups.

Implications

The finger pressure device provided moderate-to-high pain intensities and was useful for inducing conditioning stimuli. Therefore, the finger pressure device could be a useful bed-side method for measuring CPM in clinical settings with limited time available. Future bed-side studies involving patient populations are warranted to determine the usefulness of the method.

Keywords: bed-side test; conditioning pain modulation; pain assessment; pressure pain stimulation; quantitative sensory testing

Introduction

Dysfunctional regulation of the endogenous descending pain control is considered a relevant contributor to the manifestation of sensitization and enhanced pain across many chronic pain conditions [1], [2], [3], [4].

It is well known from animal studies that deficiencies in descending nociceptive control may have an effect on the entire neuroaxis and provoke a situation of wide-spread hyperalgesia [5]. Likewise, it is known from animal studies that the status of the descending control is a balance between descending inhibition and descending facilitation [6] and important for maintaining neuropathic [7], [8] and inflammatory hyperexcitable stages [9], [10]. This balance between inhibition and facilitation could be a key phenomenon in the transition from acute to chronic pain [11].

In humans, we still lack methods available to probe separately the status of the descending facilitatory or inhibitory pathways, but can so far only assess the net balance. The conditioning pain modulation (CPM) methodology [12] has been developed as a human proxy for DNIC (descending noxious inhibitory control) as assessed in animals.

Several attempts have been made to establish normative data for CPM in large cohort studies [13], [14] and compare the different technological methods used for inducing and assessing CPM [15], [16], [17]. The general findings from those studies show that the CPM readouts are highly variable and a proportion of healthy volunteers have an anti-nociceptive CPM profile (i. e. increased pain response to the test stimulus during the conditioning stimulation) whereas others have a pro-nociceptive CPM profile (i. e. decreased pain response to the test stimulus during the conditioning stimulation). The substantial CPM variation has recently been addressed as a source of information and needs to be explored further [18].

Another general feature across CPM studies is the demand for advanced and expensive instrumentations requiring trained and skilled personnel. Only very recently the first attempt has been made to develop a simple CPM bed-side test kit which could be applicable in large-scale clinical settings [19]. The conditioning tonic painful pressure stimulus used in that recent study was an ear clip, but the pain intensity of the conditioning stimulus was relatively low and difficult to control. Therefore, refinements are needed. As it was previously suggested that pressure stimulating of the fingernail may be a useful painful tonic conditioning stimulus [20], a simple bed-side applicable method could be developed on this principle.

The aim of the present study was to elaborate on the development of a simple to use, clinically applicable bed-side tool for provoking conditioning pain stimulation by pressure stimulation of the fingernail.

Methods

Volunteers

In this cross-sectional study, a convenient sample of 26 healthy volunteers (13 women) participated (mean age: 24.0 ± 2.4 years). A total of 25 volunteers (96%) reported right as the dominant side. Inclusion criteria were age between 18 and 40 years and that all volunteers were healthy and pain free at the time of the study. The volunteers were asked to restrain from alcohol and medication 24 h prior to the test day. Furthermore, the volunteers were provided with written information and verbal explanation of the experiment and they signed informed consent before participating in the study. The study was approved by the local Ethics Committee (N-20170088) and was conducted according to the Declaration of Helsinki.

Experimental design

The volunteers were placed on an examination couch in a supine position. Measurement 1 was a test stimulus of pressure pain threshold (PPT) with a handheld electronic pressure algometer (Somedic, Hörby, Sweden), which was applied perpendicularly to the lower part of the iliotibial band on the dominant leg. A built-in display on the electronic algometer facilitated a constant rate of application of pressure (30 kPa/s) and a 1 cm2 rubber tip was attached to the probe. The subjects held a push button and were informed to press the button as soon as they felt the pressure turning into pain. When the subjects pushed the button, the recording of the algometer terminated and produced an audible sound to notice the test performer that the recording had ended. The average of three PPT assessments were calculated (measured in kPa).

Following measurement 1, a tonic conditioning pressure pain stimulus was applied. A custom-made spring-loaded finger presser device was developed to apply constant pressure to the index fingernail (Figure 1). In previous studies, this has been proven as an efficient tonic painful pressure stimulation [20]. A metal rod (lever) was attached to an eccentric wheel. The eccentric circular wheel was solidly fixed to a rotating axle with its center offset from that of the axle. When the lever was pushed downwards by the attached spring, the eccentric wheel applied a fixed pressure to the fingernail placed below it. The pressure was measured by a 1 cm2 and 1 cm high (mimicking the height of the fingernail from the base of the holder) custom-made strain gauge force transducer. The spring selected could be attached to different grooves marked on the metal rod to adjust the pressure to obtain 2.2 kg/cm2 (215 kPa). As the tension of standard springs differ, the different grooves marked made it possible to adjust the length of the lever (attachment of the spring to the lever) to ensure a known fixed pressure. In addition, this option to vary the pressure allows the device to be used for stimulus-response studies. However, the slight variation in people’s size of the index finger caused minor differences in the kPa applied, but pilot studies using the measured 215 kPa showed that consistent pain responses could be obtained across subjects. For the current experiment, the nail of the index finger contralateral to the dominant leg was used for the 2 min conditioning pressure stimulation. The subject rated the tonic pain intensity continuously throughout the 2 min on a 0–10 cm Visual Analog Scale (VAS “0 cm” represented “no pain” and “10 cm” represented “worst pain imaginable”). The VAS was displayed electronically on a tablet using the application VAS app (Aalborg University, Aalborg, Denmark), which sampled 0.07 Hz corresponding to a sampling every 15th second. Following the 2 min of tonic conditioning pain, the application of measurement 2 was conducted while the finger presser device was still applied. Subsequent to measurement 2, the tonic conditioning pain was removed from the index fingertip. The subject relaxed for 5 min and measurement 3 was conducted as a control (Figure 2).

Figure 1: Illustration of the custom-made finger pressure device.
Figure 1:

Illustration of the custom-made finger pressure device.

Figure 2: Timeline illustrating the timing of measurements and conditioned pain stimulus. Measurement 1, 2 and 3 represent the measurements of pain pressure threshold and conditioned pain stimulus represents the conditioned pain applied by a custom-made finger pressure device.
Figure 2:

Timeline illustrating the timing of measurements and conditioned pain stimulus. Measurement 1, 2 and 3 represent the measurements of pain pressure threshold and conditioned pain stimulus represents the conditioned pain applied by a custom-made finger pressure device.

Conditioned pain modulation effect was quantified as an increase in PPT from measurement 1 to measurement 2. Volunteers with a positive (> 0) CPM effect were defined as “CPM responders” while even or negative (≤ 0) CPM effect corresponded to “CPM non-responders” [19].

Statistical analysis

Data were checked for normality by calculating data frequency in histograms, QQ-plots, and Shapiro–Wilk tests and were deemed normally distributed. Paired samples t-tests were applied for all continuous outcomes. Data are presented as mean ± standard deviation (SD) unless otherwise stated. Furthermore, the CPM effect is presented in relative values as percentages. Paired samples t-test for the CPM effect was applied to evaluate the statistical significance.

Conditioned pain modulation was calculated as the absolute difference in PPT between measurement 1 (without conditioning stimulus) and measurement 2 (during conditioning stimulus). An increase in PPT indicates a CPM effect.

A significance level of 0.05 was used. All analyses were performed by means of the statistical software SPSS, Version 25.0 (SPSS Inc., Chicago, IL, USA).

Results

No adverse events, e. g. bruises or nail damage, were identified, and all volunteers completed all measurements.

PPT for measurements 1, 2, and 3 are summarized in Table 1. The CPM effect from measurement 1 to measurement 2 was 55 ± 126 kPa (mean ± SD) indicating a significant averaged CPM effect (p = 0.034). This equals a relative increase of PPT of 10%. The CPM responder rate showed a positive CPM effect in 18 volunteers (69%).

Table 1:

Pressure pain thresholds (PPT) and the calculated conditioned pain modulation (CPM) effect (mean ± SD). CPM effect: increase in pressure pain threshold (PPT in kPa) from measurement 1 to measurement 2 (during the tonic pain stimulation). * indicate significant differences between measurement 1 and 2 (P = 0.034).

PPT values and CPM effects
Measurement 1 Measurement 2 Measurement 3 CPM effect
PPT (kPa) 518 ± 173 573 ± 228 549 ± 230 55 ± 126*

When CPM data were analyzed and ranked according to individual absolute data (kPa), a distribution reflecting both positive (anti-nociceptive) and negative (pro-nociceptive) CPM responders (Figure 3A) was observed. Figure 3B illustrates the relative percentage increases (anti-nociceptive) or decreases (pro-nociceptive) in the CPM effect.

Figure 3: Frequency plot of the individual conditioned pain modulation effect for the 26 volunteers represented in absolute (A, kPa) and relative (B, %) values. Positive scores (CPM responder) indicate a conditioning pain modulation (CPM) effect as defined by an increased pressure pain threshold (PPT) during the tonic conditioning stimulation (PPT during conditioning stimulation minus PPT before conditioning stimulation).
Figure 3:

Frequency plot of the individual conditioned pain modulation effect for the 26 volunteers represented in absolute (A, kPa) and relative (B, %) values. Positive scores (CPM responder) indicate a conditioning pain modulation (CPM) effect as defined by an increased pressure pain threshold (PPT) during the tonic conditioning stimulation (PPT during conditioning stimulation minus PPT before conditioning stimulation).

Measurement 1 and measurement 3 (both without conditioning stimuli) were similar (p = 0.268).

The custom-made finger presser induced conditioning stimuli pain intensities, which increased steadily during the 2 min of stimulation. At 2 min, a median VAS pain intensity of 6.7 (interquartile range: 4.6–8.4) was observed (Table 2).

Table 2:

The conditioning (cond.) tonic painful pressure stimuli pain intensity (Visual Analog Scale in cm: VAS) during the continued 2 min finger pressure stimulation as assessed continuously on a 0–10 cm VAS (median ± interquartile range [IQR] cm).

Cond. stimuli after 15 s Cond. stimuli after 30 s Cond. stimuli after 45 s Cond. stimuli after 60 s Cond. stimuli after 75 s Cond. stimuli after 90 s Cond. stimuli after 105 s Cond. stimuli after 120 s
Median VAS (cm) 1.80 3.15 4.90 5.50 5.35 5.80 6.20 6.65
Percentiles VAS (cm) 25% 0.85 1.20 2.20 2.20 3.72 3.13 4.55 4.55
75% 5.08 5.78 6.80 6.93 7.85 7.95 8.48 8.40

Discussion

This pilot-study presented a newly developed simple-to-use pressure pain stimulator to induce CPM for bed-side testing in clinical settings.

A total of 69% of the volunteers tested were defined as positive CPM responders. The study supported the concept that individual (volunteers and patients) CPM data should be sub-group analyzed based on positive (CPM responder: pain inhibition) and no/negative (CPM non-responder = pain facilitation) CPM responders. The present study represents the first attempt to conduct a proof-of-concept for bed-side studies enabling investigation of CPM in a fast and simple way.

Methodological considerations

Many different paradigms have been suggested for CPM studies [15], [16], [17], [21] which make comparisons between studies difficult underlining the need of a golden standard [22]. Many attempts have been made to refine the methodology to reduce the intra-individual variation [23] without marked success. However, there is a possibility that the variation contains interesting and important information and the present study points towards a new way of analyzing CPM data.

Likewise, the reliability has been the focus of a recent CPM review [24] which clearly stated that the degree of reliability is heavily dependent on stimulation parameters and study methodology and this warrants consideration for investigators. Due to the fact that different methodologies elicit different CPM responses it has been recommended to use different methods [25] as the CPM responses may represent different processes when assessed by different paradigms.

The different CPM paradigms produce different degrees of CPM responses and the use of cold pressor pain (immersing the hand into ice water) as a conditioning stimulus and painful pressure as a test stimulus seems to be the combination eliciting the largest CPM response on average [17]. Furthermore, the response depends on the area exposed to the conditioning stimulus[26] and in some studies was found to depend on the pain intensity of the conditioning stimulus [27], [28], but this is not confirmed in other studies [29].

Despite the different CPM methodologies used and the variance experienced, attempts have been made to establish a meta-analysis for, e. g. irritable pain syndrome [30], orofacial pain [31], fibromyalgia [31], [32], psychological factors [33], aging [34] and therapeutic interventions [35].

The meta-analyses are based on averaged CPM responses, but as highlighted in previous [18], [36] and in the present studies, it is recommended to sub-group the analysis into CPM-responders and non-responders in future studies. This particular responder distribution has been shown but has not been further analyzed [13], [14]. A recent study suggesting the use of a bed-side CMP methodology [19] based on mechanical stimulation of the ear lope also showed a large intra-individual variation in the CPM effect with a CPM responder rate between 38 and 45% across repeated test sessions and thus further supports a distribution reflecting both positive and negative CPM responders. In a clinical, quantitative sensory testing profiling study on patients with painful knee osteoarthritis, a specific pain sensitization index has been developed, including the CPM response. A similar positive and negative CPM responder distribution has been found between those patients classified as sensitized and non-classified with approximately 27–38% of the OA patients being classified as sensitized and only 3% of the healthy controls [37].

Bed-side testing

The general concept is that CPM is impaired in chronic pain populations [2], [38] but with some exceptions, e. g. painful diabetic neuropathy [39] and low back pain [40], [41].

In order to apply the CPM methodology in routine screenings and in large clinical cohort studies, an easy-to-use set-up is needed. The present conditioning pain pressure stimulator is based on a simple spring-loaded actuator delivering a force of 2.2 kg to the nail of the index finger. Further, it is based on previous suggestions that this is sensitive area where tonic pain can be elicited in a reliable way [20]. For methodological studies, the conditioning pain intensity can easily be adjusted in steps by changing the position on the load shaft where the spring is attached (shorter or longer moment arm resulting in smaller or larger moment of force, see Figure 1). In the current study, the test stimulus used was the PPT as assessed by an electronic algometer. However, this device can also be replaced by a simple spring-loaded pressure actuator as previously developed [19], and pain intensity ratings can be assessed before, during, and after the conditioning stimulation using a numerical rating scale.

When comparing various CMP methodologies, it has previously been shown that the cold pressure as conditioning stimulus and the PPT as test stimulus provide the largest CPM responses in healthy volunteers [17], and the conditioning nail pressure stimulation has been shown to be at least as efficient for CPM induction as the cold pressor pain [20] which lead to the development presented in the present study. The finger pressure device induced a median pain rating of 6.7 (on a 0–10 cm VAS scale), which is considerably higher than our previous pressure-induced pain at the ear lobe (ranges from 2.2 to 4.4) [19]. This might explain the increase of CPM responders in the present study since higher conditioned pain intensities have been shown to evoke larger CPM effect [42].

It is known that within the same volunteer the CPM response can differ from session to session [17], and hence this variation is currently not fully understood but should be further explored [18].

Conclusion

The current pilot study showed that the newly developed simple-to-use finger pressure pain stimulator was efficient to induce CPM. This constitutes a proof-of-concept for a simple, clinical applicable set-up for bed-side CPM testing.

A total of 69% of the volunteers tested were defined as positive CPM responders supporting the concept that individual CPM data should be sub-grouped into positive (pain inhibition) and negative (pain facilitation) CPM responders. The bed-side method should be further investigated in clinical populations with chronic pain.

Corresponding author: Lars Arendt-Nielsen, Translational Pain Biomarkers, CNAP and Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, School of Medicine, Aalborg University, Fredrik Bajers Vej 7, Bld. D3, DK-9220 Aalborg East, Denmark, E-mail:

Funding source: Danish National Research Foundation

Award Identifier / Grant number: DNRF121

  1. Research funding: The study was partly funded by Innovationsfonden (Individualized Osteoarthritis Interventions), the Shionogi Science Program, and TaNeDS Europe Grant. Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Informed consent: Informed consent has been obtained from all individuals included in this study.

  5. Ethical approval: The research related to human use complies with all the relevant national regulations, institutional policies and was performed in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

References

1. Arendt-Nielsen, L, Morlion, B, Perrot, S, Dahan, A, Dickenson, A, Kress, HG et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain 2018;22:216–41. https://doi.org/10.1002/ejp.1140.Search in Google Scholar PubMed

2. Lewis, GN, Rice, DA, McNair, PJ. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain 2012;13:936–44. https://doi.org/10.1016/j.jpain.2012.07.005.Search in Google Scholar PubMed

3. Staud, R. Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions. Expert Rev Neurother 2012;12:577–85. https://doi.org/10.1586/ern.12.41.Search in Google Scholar PubMed PubMed Central

4. Goubert, D, Danneels, L, Cagnie, B, Van, OJ, Kolba, K, Noyez, H, et al. Effect of pain induction or pain reduction on conditioned pain modulation in adults: a systematic review. Pain Pract 2015;15:765–77. https://doi.org/10.1111/papr.12241.Search in Google Scholar PubMed

5. Miranda, J, Lamana, SM, Dias, E V, Athie, M, Parada, CA, Tambeli, CH. Effect of pain chronification and chronic pain on an endogenous pain modulation circuit in rats. Neuroscience 2015;286:37–44. https://doi.org/10.1016/j.neuroscience.2014.10.049.Search in Google Scholar PubMed

6. Vanegas, H, Schaible, HG. Descending control of persistent pain: inhibitory or facilitatory? Brain Res Brain Res Rev 2004;46:295–309. https://doi.org/10.1016/j.brainresrev.2004.07.004.Search in Google Scholar PubMed

7. Wang, R, King, T, De, FM, Guo, W, Ossipov, MH, Porreca, F. Descending facilitation maintains long-term spontaneous neuropathic pain. J Pain 2013;14:845–53. https://doi.org/10.1016/j.jpain.2013.02.011.Search in Google Scholar PubMed PubMed Central

8. Ossipov, MH, Morimura, K, Porreca, F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care 2014;8:143–51. https://doi.org/10.1097/SPC.0000000000000055.Search in Google Scholar PubMed PubMed Central

9. Ambriz-Tututi, M, Cruz, SL, Urquiza-Marin, H, Granados-Soto, V. Formalin-induced long-term secondary allodynia and hyperalgesia are maintained by descending facilitation. Pharmacol Biochem Behav 2011;98:417–24. https://doi.org/10.1016/j.pbb.2011.02.012.Search in Google Scholar PubMed

10. Bannister, K, Dickenson, AH. What the brain tells the spinal cord. Pain 2016;157:2148–51. https://doi.org/10.1097/j.pain.0000000000000568.Search in Google Scholar PubMed

11. Voscopoulos, C, Lema, M. When does acute pain become chronic? Br J Anaesth 2010;105:i69–85. https://doi.org/10.1093/bja/aeq323.Search in Google Scholar PubMed

12. Yarnitsky, D, Arendt-Nielsen, L, Bouhassira, D, Edwards, RR, Fillingim, RB, Granot, M, et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 2010;14:339. https://doi.org/10.1016/j.ejpain.2010.02.004.Search in Google Scholar PubMed

13. Schliessbach, J, Siegenthaler, A, Streitberger, K, Eichenberger, U, Nuesch, E, Juni, P, et al. The prevalence of widespread central hypersensitivity in chronic pain patients. Eur J Pain 2013;17:1502–10. https://doi.org/10.1002/j.1532-2149.2013.00332.x.Search in Google Scholar PubMed

14. Skovbjerg, S, Jorgensen, T, Arendt-Nielsen, L, Ebstrup, JF, Carstensen, T, Graven-Nielsen, T. Conditioned pain modulation and pressure pain sensitivity in the adult danish general population: the DanFunD Study. J Pain 2017;18:274–84. https://doi.org/10.1016/j.jpain.2016.10.022.Search in Google Scholar PubMed

15. Vaegter, HB, Petersen, KK, Mørch, CD, Imai, Y, Arendt-Nielsen, L. Assessment of CPM reliability: quantification of the within-subject reliability of 10 different protocols. Scand J Pain 2018;18:729–37. https://doi.org/10.1515/sjpain-2018-0087.Search in Google Scholar PubMed

16. Petersen, KK, Vaegter, HB, Arendt-Nielsen, L. An updated view on the reliability of different protocols for the assessment of conditioned pain modulation. Pain 2017;158:988. https://doi.org/10.1097/j.pain.0000000000000833.Search in Google Scholar PubMed

17. Oono, Y, Nie, H, Matos, RL, Wang, K, Arendt-Nielsen, L. The inter- and intra-individual variance in descending pain modulation evoked by different conditioning stimuli in healthy men. Scand J Pain 2011;2:162–9. https://doi.org/10.1016/j.sjpain.2011.05.006.Search in Google Scholar PubMed

18. Potvin, S, Marchand, S. Pain facilitation and pain inhibition during conditioned pain modulation in fibromyalgia and in healthy controls. Pain 2016;157:1704–10. https://doi.org/10.1097/j.pain.0000000000000573.Search in Google Scholar PubMed

19. Larsen, JB, Madeleine, P, Arendt-Nielsen, L. Development of a new bed-side-test assessing conditioned pain modulation: a test–retest reliability study. Scand J Pain 2019;19:565–74. https://doi.org/10.1515/sjpain-2018-0353.Search in Google Scholar PubMed

20. Schoen, CJ, Ablin, JN, Ichesco, E, Bhavsar, RJ, Kochlefl, L, Harris, RE, et al. A novel paradigm to evaluate conditioned pain modulation in fibromyalgia. J Pain Res 2016;9:711–9. https://doi.org/10.2147/JPR.S115193.Search in Google Scholar PubMed PubMed Central

21. Imai, Y, Petersen, KK, Morch, CD, Arendt-Nielsen, L. Comparing test–retest reliability and magnitude of conditioned pain modulation using different combinations of test and conditioning stimuli. Somatosens Mot Res 2016;33:169–77. https://doi.org/10.1080/08990220.2016.1229178.Search in Google Scholar PubMed

22. Yarnitsky, D, Bouhassira, D, Drewes, AM, Fillingim, RB, Granot, M, Hansson, P, et al. Recommendations on practice of conditioned pain modulation (CPM) testing. Eur J Pain 2015;19:805–6. https://doi.org/10.1002/ejp.605.Search in Google Scholar PubMed

23. Granovsky, Y, Miller-Barmak, A, Goldstein, O, Sprecher, E, Yarnitsky, D. CPM test–retest reliability: “standard” vs. “single test-stimulus” protocols. Pain Med 2016;17:521–9. https://doi.org/10.1111/pme.12868.Search in Google Scholar PubMed

24. Kennedy, DL, Kemp, HI, Ridout, D, Yarnitsky, D, Rice, AS. Reliability of conditioned pain modulation: a systematic review. Pain 2016;157:2410–9. https://doi.org/10.1097/j.pain.0000000000000689.Search in Google Scholar PubMed PubMed Central

25. Nahman-Averbuch, H, Yarnitsky, D, Granovsky, Y, Gerber, E, Dagul, P, Granot, M. The role of stimulation parameters on the conditioned pain modulation response. Scand J Pain 2013;4:10–4. https://doi.org/10.1016/j.sjpain.2012.08.001.Search in Google Scholar PubMed

26. Marchand, S, Arsenault, P. Spatial summation for pain perception: interaction of inhibitory and excitatory mechanisms. Pain 2002;95:201–6. https://doi.org/10.1016/S0304-3959(01)00399-2.Search in Google Scholar PubMed

27. Oono, Y, Wang, K, Svensson, P, Arendt-Nielsen, L. Conditioned pain modulation evoked by different intensities of mechanical stimuli applied to the craniofacial region in healthy men and women. J Orofac Pain 2011;25:364–75. 22247932.Search in Google Scholar PubMed

28. Razavi, M, Hansson, PT, Johansson, B, Leffler, AS. The influence of intensity and duration of a painful conditioning stimulation on conditioned pain modulation in volunteers. Eur J Pain 2014;18:853–61. https://doi.org/10.1002/j.1532-2149.2013.00435.x.Search in Google Scholar PubMed

29. Nir, RR, Granovsky, Y, Yarnitsky, D, Sprecher, E, Granot, M. A psychophysical study of endogenous analgesia: the role of the conditioning pain in the induction and magnitude of conditioned pain modulation. Eur J Pain 2011;15:491–7. https://doi.org/10.1016/j.ejpain.2010.10.001.Search in Google Scholar PubMed

30. Albusoda, A, Ruffle, JK, Friis, KA, Gysan, MR, Drewes, AM, Aziz, Q, et al. Systematic review with meta-analysis: conditioned pain modulation in patients with the irritable bowel syndrome. Aliment Pharmacol Ther 2018;48:797–806. https://doi.org/10.1111/apt.14965.Search in Google Scholar PubMed

31. Moana-Filho, EJ, Babiloni, AH, Theis-Mahon, NR. Endogenous pain modulation in chronic orofacial pain: a systematic review and meta-analysis. Pain 2018;159:1441–55. https://doi.org/10.1097/j.pain.0000000000001263.Search in Google Scholar PubMed

32. O’Brien, AT, Deitos, A, Triñanes Pego, Y, Fregni, F, Carrillo-de-la-Peña, MT. Defective endogenous pain modulation in fibromyalgia: a meta-analysis of temporal summation and conditioned pain modulation paradigms. J Pain 2018;19:819–36. https://doi.org/10.1016/j.jpain.2018.01.010.Search in Google Scholar PubMed

33. Nahman-Averbuch, H, Nir, RR, Sprecher, E, Yarnitsky, D. Psychological factors and conditioned pain modulation: a meta-analysis. Clin J Pain 2016;32:541–54. https://doi.org/10.1097/AJP.0000000000000296.Search in Google Scholar PubMed

34. Hackett, J, Naugle, KE, Naugle, KM. The decline of endogenous pain modulation with aging: a meta-analysis of temporal summation and conditioned pain modulation. J Pain 2019. https://doi.org/10.1016/j.jpain.2019.09.005. S1526-5900(19)30813-2.Search in Google Scholar PubMed

35. O’Brien, AT, El-Hagrassy, MM, Rafferty, H, Sanchez, P, Huerta, R, Chaudhari, S, et al. Impact of therapeutic interventions on pain intensity and endogenous pain modulation in knee osteoarthritis: a systematic review and meta-analysis. Pain Med 2019;20:1000–11. https://doi.org/10.1093/pm/pny261.Search in Google Scholar PubMed PubMed Central

36. Rabey, M, Poon, C, Wray, J, Thamajaree, C, East, R, Slater, H. Pro-nociceptive and anti-nociceptive effects of a conditioned pain modulation protocol in participants with chronic low back pain and healthy control subjects. Man Ther 2015;20:763–8. https://doi.org/10.1016/j.math.2015.02.011.Search in Google Scholar PubMed

37. Arendt-Nielsen, L, Egsgaard, LL, Petersen, KK, Eskehave, TN, Graven-Nielsen, T, Hoeck, HC, et al. A mechanism-based pain sensitivity index to characterize knee osteoarthritis patients with different disease stages and pain levels. Eur J Pain 2015;19:1406–17. https://doi.org/10.1002/ejp.651.Search in Google Scholar PubMed

38. Fernandes, C, Pidal-Miranda, M, Samartin-Veiga, N, Carrillo-de-la-Peña, MT. Conditioned pain modulation as a biomarker of chronic pain: a systematic review of its concurrent validity. Pain 2019;160:2679–90. https://doi.org/10.1097/j.pain.0000000000001664.Search in Google Scholar PubMed

39. Granovsky, Y, Nahman-Averbuch, H, Khamaisi, M, Granot, M. Efficient conditioned pain modulation despite pain persistence in painful diabetic neuropathy. Pain Rep 2017;2:e592. https://doi.org/10.1097/PR9.0000000000000592.Search in Google Scholar PubMed PubMed Central

40. Goudman, L, Huysmans, E, Coppieters, I, Ickmans, K, Nijs, J, Buyl, R, et al. Electrical (pain) thresholds and conditioned pain modulation in patients with low back-related leg pain and patients with failed back surgery syndrome: a cross-sectional pilot study. Pain Med 2019;21:538–47. https://doi.org/10.1093/pm/pnz118.Search in Google Scholar PubMed

41. den Bandt, HL, Paulis, WD, Beckwée, D, Ickmans, K, Nijs, J, Voogt, L. Pain mechanisms in low back pain: a systematic review with meta-analysis of mechanical quantitative sensory testing outcomes in people with nonspecific low back pain. J Orthop Sport Phys Ther 2019;49:698–715. https://doi.org/10.2519/jospt.2019.8876.Search in Google Scholar PubMed

42. Graven-Nielsen, T, Izumi, M, Petersen, KK, Arendt-Nielsen, L. User-independent assessment of conditioning pain modulation by cuff pressure algometry. Eur J Pain 2017;21:552–61. https://doi.org/10.1002/ejp.958.Search in Google Scholar PubMed

Received: 2020-03-05
Accepted: 2020-05-20
Published Online: 2020-07-21
Published in Print: 2020-10-25

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. The history of the idea of widespread pain and its relation to fibromyalgia
  4. Clinical Pain Research
  5. Pain perception in chronic knee osteoarthritis with varying levels of pain inhibitory control: an exploratory study
  6. Fibromyalgia 2016 criteria and assessments: comprehensive validation in a Norwegian population
  7. Development and preliminary validation of the Chronic Pain Acceptance Questionnaire for Clinicians
  8. Static mechanical allodynia in post-surgical neuropathic pain after breast cancer treatments
  9. Preoperative quantitative sensory testing and robot-assisted laparoscopic hysterectomy for endometrial cancer: can chronic postoperative pain be predicted?
  10. Exploring the impact of pain management programme attendance on complex regional pain syndrome (CRPS) patients’ decision making regarding immunosuppressant treatment to manage their chronic pain condition
  11. Preliminary validity and test–retest reliability of two depression questionnaires compared with a diagnostic interview in 99 patients with chronic pain seeking specialist pain treatment
  12. Pain acceptance and its impact on function and symptoms in fibromyalgia
  13. Observational studies
  14. Cooled radiofrequency for the treatment of sacroiliac joint pain – impact on pain and psychometrics: a retrospective cohort study
  15. Pain perception during colonoscopy in relation to gender and equipment: a clinical study
  16. The association between initial opioid type and long-term opioid use after hip fracture surgery in elderly opioid-naïve patients
  17. Pain in adolescent chronic fatigue following Epstein-Barr virus infection
  18. Patients with shoulder pain referred to specialist care; treatment, predictors of pain and disability, emotional distress, main symptoms and sick-leave: a cohort study with a six-months follow-up
  19. Original Experimental
  20. The effect of periaqueductal gray’s metabotropic glutamate receptor subtype 8 activation on locomotor function following spinal cord injury
  21. Baseline pain characteristics predict pain reduction after physical therapy in women with chronic pelvic pain. Secondary analysis of data from a randomized controlled trial
  22. A novel clinical applicable bed-side tool for assessing conditioning pain modulation: proof-of-concept
  23. The acquisition and generalization of fear of touch
  24. Associations of neck and shoulder pain with objectively measured physical activity and sedentary time among school-aged children
  25. Health-related quality of life in burning mouth syndrome – a case-control study
  26. Stretch-induced hypoalgesia: a pilot study
  27. Educational Case Report
  28. Erector spinae plane and intra thecal opioid (ESPITO) analgesia in radical nephrectomy utilising a rooftop incision: novel alternative to thoracic epidural analgesia and systemic morphine: a case series
  29. Short Communication
  30. Above and beyond emotional suffering: the unique contribution of compassionate and uncompassionate self-responding in chronic pain
  31. Letter to the Editor
  32. Labor pain, birth experience and postpartum depression
  33. Reply: Response to Letter to the Editor “Labor pain, birth experience and postpartum depression”
  34. Corrigendum
  35. Corrigendum to: Are labor pain and birth experience associated with persistent pain and postpartum depression? A prospective cohort study
https://doi.org/10.1515/sjpain-2020-0033
Keywords for this article
bed-side test; conditioning pain modulation; pain assessment; pressure pain stimulation; quantitative sensory testing

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. The history of the idea of widespread pain and its relation to fibromyalgia
  4. Clinical Pain Research
  5. Pain perception in chronic knee osteoarthritis with varying levels of pain inhibitory control: an exploratory study
  6. Fibromyalgia 2016 criteria and assessments: comprehensive validation in a Norwegian population
  7. Development and preliminary validation of the Chronic Pain Acceptance Questionnaire for Clinicians
  8. Static mechanical allodynia in post-surgical neuropathic pain after breast cancer treatments
  9. Preoperative quantitative sensory testing and robot-assisted laparoscopic hysterectomy for endometrial cancer: can chronic postoperative pain be predicted?
  10. Exploring the impact of pain management programme attendance on complex regional pain syndrome (CRPS) patients’ decision making regarding immunosuppressant treatment to manage their chronic pain condition
  11. Preliminary validity and test–retest reliability of two depression questionnaires compared with a diagnostic interview in 99 patients with chronic pain seeking specialist pain treatment
  12. Pain acceptance and its impact on function and symptoms in fibromyalgia
  13. Observational studies
  14. Cooled radiofrequency for the treatment of sacroiliac joint pain – impact on pain and psychometrics: a retrospective cohort study
  15. Pain perception during colonoscopy in relation to gender and equipment: a clinical study
  16. The association between initial opioid type and long-term opioid use after hip fracture surgery in elderly opioid-naïve patients
  17. Pain in adolescent chronic fatigue following Epstein-Barr virus infection
  18. Patients with shoulder pain referred to specialist care; treatment, predictors of pain and disability, emotional distress, main symptoms and sick-leave: a cohort study with a six-months follow-up
  19. Original Experimental
  20. The effect of periaqueductal gray’s metabotropic glutamate receptor subtype 8 activation on locomotor function following spinal cord injury
  21. Baseline pain characteristics predict pain reduction after physical therapy in women with chronic pelvic pain. Secondary analysis of data from a randomized controlled trial
  22. A novel clinical applicable bed-side tool for assessing conditioning pain modulation: proof-of-concept
  23. The acquisition and generalization of fear of touch
  24. Associations of neck and shoulder pain with objectively measured physical activity and sedentary time among school-aged children
  25. Health-related quality of life in burning mouth syndrome – a case-control study
  26. Stretch-induced hypoalgesia: a pilot study
  27. Educational Case Report
  28. Erector spinae plane and intra thecal opioid (ESPITO) analgesia in radical nephrectomy utilising a rooftop incision: novel alternative to thoracic epidural analgesia and systemic morphine: a case series
  29. Short Communication
  30. Above and beyond emotional suffering: the unique contribution of compassionate and uncompassionate self-responding in chronic pain
  31. Letter to the Editor
  32. Labor pain, birth experience and postpartum depression
  33. Reply: Response to Letter to the Editor “Labor pain, birth experience and postpartum depression”
  34. Corrigendum
  35. Corrigendum to: Are labor pain and birth experience associated with persistent pain and postpartum depression? A prospective cohort study
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 3.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/sjpain-2020-0033/html?lang=en
Scroll to top button