SHORT COMMUNICATION
Recommendations on practice of conditioned pain modulation (CPM) testing D. Yarnitsky1, D. Bouhassira2, A.M. Drewes3, R.B. Fillingim4, M. Granot5, P. Hansson6,7, R. Landau8, S. Marchand9, D. Matre10, K.B. Nilsen10,11,12, A. Stubhaug6,13, R.D. Treede14, O.H.G. Wilder-Smith15,16 1 Department of Neurology, Technion Faculty of Medicine, Rambam Health Care Campus, Haifa, Israel 2 INSERM, Centre d’Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, Boulogne-Billancourt, France 3 Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark 4 College of Dentistry, University of Florida, Gainesville, USA 5 Department of Health and Welfare Studies, University of Haifa, Israel 6 Department of Pain Management and Research, Oslo University Hospital, Norway 7 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 8 Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, USA 9 Department of Surgery and Neurosurgery, Faculty of Medicine, Sherbrooke University, Canada 10 Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway 11 Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway 12 Department of Neurology, Section for Clinical Neurophysiology, Oslo University Hospital – Ullevål, Norway 13 Medical Faculty, University of Oslo, Norway 14 Department of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University, Germany 15 Department of Anesthesiology, Pain and Palliative Medicine, Radboudumc, Nijmegen, The Netherlands 16 Centre for Sensory-Motor Interaction, Aalborg University, Denmark
Correspondence David Yarnitsky E-mail: [email protected] Funding sources An educational stipend from Medoc supported the logistics of this meeting.
Abstract Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results.
Conflicts of interest None declared. Accepted for publication 7 August 2014 doi:10.1002/ejp.605
Researchers interested in conditioned pain modulation (CPM) met during the EFIC meeting in Florence (October 2013) to discuss current issues relevant to research on the topic. This was in continuation to the 2009 meeting, where we recommended the use of the terms ‘test stimulus’ for the painful stimulus upon which the conditioning effect is tested; ‘conditioning stimulus’ for the stimulus used to induce the change in pain perception; and ‘conditioned pain modulation (CPM)‘ for the phenomenon through which the conditioning stimulus affects perception of the test stimulus (Yarnitsky et al., 2010). © 2014 European Pain Federation - EFIC®
Participants agreed that the lack of uniform protocols for performing CPM is a major problem, hindering our ability to compare and combine data from various studies carried out in different laboratories and clinics, and reach firm conclusions on the clinical utilization of this test by meta-analyses and systematic reviews. The following summarizes the expert-opinion-based recommendations of the forum: (1) Testing paradigms Currently, we acknowledge that there are not enough data to identify a certain CPM protocol as preferable, generally or for any specific set-up, over the others, Eur J Pain •• (2014) ••–••
1
CPM consensus meeting recommendations 2014
requiring further research on CPM methodology. Nevertheless, we believe that a recommendation for a standardized CPM protocol for clinical studies is clearly needed. There is a pressing need to enable proper comparisons of CPM results in various research projects. It is therefore recommended that CPM protocols should be enriched, so that comparative data will be ‘built-in’ within the protocols of testing. Expert-opinion-based protocols are suggested by the forum, recommending use of one of following two options: (a) An additional test stimulus should be added to the one planned by the researcher. Since most centres use either thermal or mechanical stimuli, we recommend that each protocol should include the two types of test stimuli. The forum recommends use of one of two stimulation paradigms: (1) stimulus given at an ascending intensity, to be discontinued by the subject at pain40 (pain level of 40/100); or (2) a fixed intensity stimulus, given at predetermined level of pain40. Time permitting, mechanical and heat test-stimuli should preferably be performed twice, with at least 10-min inter-stimulus interval, at two different skin sites. The same conditioning stimulus should be used for both thermal and mechanical stimuli. The latter should be painful [typically >20/100 numerical pain score (NPS)]; mild to moderate pain levels should suffice to induce an effect (Willer et al., 1984; Granot et al., 2008; Nir et al., 2011) (b) A standard additional full CPM protocol should be added on top of the one planned by the researcher. The forum felt that a simple, relatively short and nonexpensive protocol is the following: Two successive mechanical pressure transients as test stimuli, given at either ascending or fixed protocol, destined at pain40 level, as described above; a 1-min cold water immersion of the hand to the wrist level as conditioning stimulus. The forum agreed that a sequential protocol, i.e., presentation of the ‘conditioned’ test stimulus immediately after, rather than in parallel, to the conditioning stimulus, provides a ‘cleaner’ representation of pain modulation, free of biases such as distraction. Since CPM effects are generally short-lived (Kakigi, 1994; Reinert et al., 2000; Sandrini et al., 2005), the interval between conditioning stimulus and second test stimulus must be short. Further, until additional data on
2 Eur J Pain •• (2014) ••–••
D. Yarnitsky et al.
interrelations between segmental and generalized pain modulation are obtained, the forum felt that an upper and a lower limb should be the default two sites used for the CPM protocol. (2) Results presentation The forum recommends that pain inhibition along the test protocol should be denoted by a negative value, whereas pain facilitation will be denoted by a positive value. Thus, when using physical units, such as reporting temperature at ‘pain40’ level, a first minus last calculation should be used, whereas when using rating data, such as reporting NPS for a fixed temperature stimulus, the calculation should be last minus first. This way, results denoting pain inhibition will always be reported by a negative value, and those denoting pain facilitation will be reported by a positive value. The difference between the parameters obtained along the pain modulation protocol can be presented as absolute values, percent change or, preferably, both.
Author contributions All authors participated in the meeting, reviewed and commented on the text.
References Granot, M., Weissman-Fogel, I., Crispel, Y., Pud, D., Granovsky, Y., Sprecher, E., Yarnitsky, D. (2008). Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: Do conditioning stimulus painfulness, gender and personality variables matter? Pain 136, 142–149. Kakigi, R. (1994). Diffuse noxious inhibitory control. Reappraisal by painrelated somatosensory evoked potentials following CO2 laser stimulation. J Neurol Sci 125, 198–205. Nir, R.R., Granovsky, Y., Yarnitsky, D., Sprecher, E., Granot, M. (2011). A psychophysical study of endogenous analgesia: The role of the conditioning pain in the induction and magnitude of conditioned pain modulation. Eur J Pain 15, 491–497. Reinert, A., Treede, R., Bromm, B. (2000). The pain inhibiting pain effect: An electrophysiological study in humans. Brain Res 862, 103–110. Sandrini, G., Serrao, M., Rossi, P., Romaniello, A., Cruccu, G., Willer, J.C. (2005). The lower limb flexion reflex in humans. Prog Neurobiol 77, 353–395. Willer, J.C., Roby, A., Le Bars, D. (1984). Psychophysical and electrophysiological approaches to the pain-relieving effects of heterotopic nociceptive stimuli. Brain 107 (Pt 4), 1095–1112. Yarnitsky, D., Arendt-Nielsen, L., Bouhassira, D., Edwards, R.R., Fillingim, R.B., Granot, M., Hansson, P., Lautenbacher, S., Marchand, S., Wilder-Smith, O. (2010). Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14, 339.
© 2014 European Pain Federation - EFIC®
Recommendations on practice of conditioned pain modulation (CPM) testing D. Yarnitsky1, D. Bouhassira2, A.M. Drewes3, R.B. Fillingim4, M. Granot5, P. Hansson6,7, R. Landau8, S. Marchand9, D. Matre10, K.B. Nilsen10,11,12, A. Stubhaug6,13, R.D. Treede14, O.H.G. Wilder-Smith15,16 1 Department of Neurology, Technion Faculty of Medicine, Rambam Health Care Campus, Haifa, Israel 2 INSERM, Centre d’Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, Boulogne-Billancourt, France 3 Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark 4 College of Dentistry, University of Florida, Gainesville, USA 5 Department of Health and Welfare Studies, University of Haifa, Israel 6 Department of Pain Management and Research, Oslo University Hospital, Norway 7 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 8 Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, USA 9 Department of Surgery and Neurosurgery, Faculty of Medicine, Sherbrooke University, Canada 10 Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway 11 Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway 12 Department of Neurology, Section for Clinical Neurophysiology, Oslo University Hospital – Ullevål, Norway 13 Medical Faculty, University of Oslo, Norway 14 Department of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University, Germany 15 Department of Anesthesiology, Pain and Palliative Medicine, Radboudumc, Nijmegen, The Netherlands 16 Centre for Sensory-Motor Interaction, Aalborg University, Denmark
Correspondence David Yarnitsky E-mail: [email protected] Funding sources An educational stipend from Medoc supported the logistics of this meeting.
Abstract Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results.
Conflicts of interest None declared. Accepted for publication 7 August 2014 doi:10.1002/ejp.605
Researchers interested in conditioned pain modulation (CPM) met during the EFIC meeting in Florence (October 2013) to discuss current issues relevant to research on the topic. This was in continuation to the 2009 meeting, where we recommended the use of the terms ‘test stimulus’ for the painful stimulus upon which the conditioning effect is tested; ‘conditioning stimulus’ for the stimulus used to induce the change in pain perception; and ‘conditioned pain modulation (CPM)‘ for the phenomenon through which the conditioning stimulus affects perception of the test stimulus (Yarnitsky et al., 2010). © 2014 European Pain Federation - EFIC®
Participants agreed that the lack of uniform protocols for performing CPM is a major problem, hindering our ability to compare and combine data from various studies carried out in different laboratories and clinics, and reach firm conclusions on the clinical utilization of this test by meta-analyses and systematic reviews. The following summarizes the expert-opinion-based recommendations of the forum: (1) Testing paradigms Currently, we acknowledge that there are not enough data to identify a certain CPM protocol as preferable, generally or for any specific set-up, over the others, Eur J Pain •• (2014) ••–••
1
CPM consensus meeting recommendations 2014
requiring further research on CPM methodology. Nevertheless, we believe that a recommendation for a standardized CPM protocol for clinical studies is clearly needed. There is a pressing need to enable proper comparisons of CPM results in various research projects. It is therefore recommended that CPM protocols should be enriched, so that comparative data will be ‘built-in’ within the protocols of testing. Expert-opinion-based protocols are suggested by the forum, recommending use of one of following two options: (a) An additional test stimulus should be added to the one planned by the researcher. Since most centres use either thermal or mechanical stimuli, we recommend that each protocol should include the two types of test stimuli. The forum recommends use of one of two stimulation paradigms: (1) stimulus given at an ascending intensity, to be discontinued by the subject at pain40 (pain level of 40/100); or (2) a fixed intensity stimulus, given at predetermined level of pain40. Time permitting, mechanical and heat test-stimuli should preferably be performed twice, with at least 10-min inter-stimulus interval, at two different skin sites. The same conditioning stimulus should be used for both thermal and mechanical stimuli. The latter should be painful [typically >20/100 numerical pain score (NPS)]; mild to moderate pain levels should suffice to induce an effect (Willer et al., 1984; Granot et al., 2008; Nir et al., 2011) (b) A standard additional full CPM protocol should be added on top of the one planned by the researcher. The forum felt that a simple, relatively short and nonexpensive protocol is the following: Two successive mechanical pressure transients as test stimuli, given at either ascending or fixed protocol, destined at pain40 level, as described above; a 1-min cold water immersion of the hand to the wrist level as conditioning stimulus. The forum agreed that a sequential protocol, i.e., presentation of the ‘conditioned’ test stimulus immediately after, rather than in parallel, to the conditioning stimulus, provides a ‘cleaner’ representation of pain modulation, free of biases such as distraction. Since CPM effects are generally short-lived (Kakigi, 1994; Reinert et al., 2000; Sandrini et al., 2005), the interval between conditioning stimulus and second test stimulus must be short. Further, until additional data on
2 Eur J Pain •• (2014) ••–••
D. Yarnitsky et al.
interrelations between segmental and generalized pain modulation are obtained, the forum felt that an upper and a lower limb should be the default two sites used for the CPM protocol. (2) Results presentation The forum recommends that pain inhibition along the test protocol should be denoted by a negative value, whereas pain facilitation will be denoted by a positive value. Thus, when using physical units, such as reporting temperature at ‘pain40’ level, a first minus last calculation should be used, whereas when using rating data, such as reporting NPS for a fixed temperature stimulus, the calculation should be last minus first. This way, results denoting pain inhibition will always be reported by a negative value, and those denoting pain facilitation will be reported by a positive value. The difference between the parameters obtained along the pain modulation protocol can be presented as absolute values, percent change or, preferably, both.
Author contributions All authors participated in the meeting, reviewed and commented on the text.
References Granot, M., Weissman-Fogel, I., Crispel, Y., Pud, D., Granovsky, Y., Sprecher, E., Yarnitsky, D. (2008). Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: Do conditioning stimulus painfulness, gender and personality variables matter? Pain 136, 142–149. Kakigi, R. (1994). Diffuse noxious inhibitory control. Reappraisal by painrelated somatosensory evoked potentials following CO2 laser stimulation. J Neurol Sci 125, 198–205. Nir, R.R., Granovsky, Y., Yarnitsky, D., Sprecher, E., Granot, M. (2011). A psychophysical study of endogenous analgesia: The role of the conditioning pain in the induction and magnitude of conditioned pain modulation. Eur J Pain 15, 491–497. Reinert, A., Treede, R., Bromm, B. (2000). The pain inhibiting pain effect: An electrophysiological study in humans. Brain Res 862, 103–110. Sandrini, G., Serrao, M., Rossi, P., Romaniello, A., Cruccu, G., Willer, J.C. (2005). The lower limb flexion reflex in humans. Prog Neurobiol 77, 353–395. Willer, J.C., Roby, A., Le Bars, D. (1984). Psychophysical and electrophysiological approaches to the pain-relieving effects of heterotopic nociceptive stimuli. Brain 107 (Pt 4), 1095–1112. Yarnitsky, D., Arendt-Nielsen, L., Bouhassira, D., Edwards, R.R., Fillingim, R.B., Granot, M., Hansson, P., Lautenbacher, S., Marchand, S., Wilder-Smith, O. (2010). Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14, 339.
© 2014 European Pain Federation - EFIC®
