Participants demonstrated a significant increase in PPT measured at wrist and elbow sites during and immediately after the CPM and MIA stimuli (P<0.001). There was also a significant improvement in the secondary outcome measures of PFG and ULNDT-RN immediately after the CLG mobilization (Table 2).
The CPT stimulus rated highly on the pain VAS (mean: 8.10, SD: 1.3), while conversely the CLG stimulus rated highly on a pleasantness VAS (mean: 8.16, SD: 1.4), indicating that they induced markedly different sensations. There were significant differences between the CPM and MIA responses measured at both sites during the cold pressor and cervical lateral glide stimuli (P<0.001), with larger increases in PPT measured during CPM. The average increase from baseline in PPT during CPM was 195.84 kPa at the elbow and 201.87 kPa at the wrist. During MIA the average increase at the elbow was 123.01 kPa and at the wrist it was 126.06. However, no differences were detected between the stimuli at either test site immediately after the cold pressor and mobilization stimuli (Wrist: P=0.569, elbow: P=0.839, mean increase after CPM: 126.06 kPa for elbow, 114.24 kPa for wrist and after MIA 123.50 kPa for elbow, 122.16 kPa for wrist) (Fig. 3).
The partial correlation values (controlling for baseline PPT values) for the association between PPT measures for MIA and CPM at each assessment time point are presented in the Table 3. The Pearson partial correlation coefficient (r) values showed statistically significant, moderate (r>0.3) positive partial correlations (r: 0.40 to 0.54, P<0.001) between CPM and MIA PPT values. The regression analysis showed that CPM PPT values are a significant predictor of MIA PPT values (P<0.001) measured at both sites over different time points. The adjusted R2 values ranged between 0.73 and 0.85, indicating that between 73% and 85% of the variance in MIA PPT values was explained by CPM PPT values (Table 3).
This is the first study to investigate the association between CPM and MIA. There was a significant increase in PPT at both test sites (wrist and elbow) during and immediately after the CPT and the cervical lateral glide mobilization, indicating an analgesic response to both stimuli. There were significant differences between the CPM and MIA PPT values during the cold water immersion and CLG mobilization, with the CPT stimulus producing a more pronounced analgesic effect during the intervention. However, no difference was seen between CPM and MIA responses in the period following the interventions. PPT did not increase as much during the CLG mobilization but the increase was maintained during the later mobilization period, whereas it decreased substantially following the CPT stimulus. This suggests that the analgesic effect experienced by individuals after the intervention is similar for the cervical mobilization and the cold water immersion. There was also a significant association between the CPM and MIA responses (controlling for baseline variability) and the level of CPM response explained >73% of the variance in MIA response.
This study, therefore, showed an intact CPM response in people with LE, in accordance with recent research findings of preserved CPM response reported for other chronic musculoskeletal conditions such as chronic back pain,34 patellofemoral pain,35 and long-term trapezius myalgia.36 The CPM response found in this LE sample was similar to that observed in pain-free healthy populations,21,37 suggesting unaltered endogenous inhibitory mechanisms in LE. However, a study by Lim et al38 reported an impaired CPM response in people with LE when compared with healthy controls. The difference in the CPM responses reported in both studies may be explained by variations in the testing parameters used. Although Lim et al38 used contact thermal heat to elicit CPM the current study protocol used the CPT as a conditioning stimulus, which has been found to induce a more pronounced analgesic effect.39 In pain-free healthy controls Lim et al38 reported a 19.02 (±27.49) to 24.75 (±26.21) percentage increase in PPT during thermal pain compared with a 35.80 (±26.26) percentage increase reported by Locke et al21 during CPT. There may be a weaker CPM effect in response to contact thermal heat relative to CPT and this may provide a reason for the less efficient CPM effect.38 These data suggest that there was an efficient CPM response in the current cohort.
The increase in PPT during the CPT was significantly greater than during the CLG, suggesting a stronger initial analgesic response associated with the noxious cold conditioning stimulus compared with the nonpainful mobilization stimulus. Participants rated the CPT stimulus as inducing a relatively high level of pain but they conversely rated the CLG mobilization as a highly pleasant sensation. Despite these differences in the nature of the stimuli and the fact that the CPT stimulus elicited a very marked increase in PPT during the 2 minute immersion period, both interventions showed very similar increases (~120 kPa) in PPT in the period after intervention.
There are few studies investigating the association between different forms of EA, although an association between CPM and exercise-induced analgesia has been demonstrated.16,17 A previous study43 reported an enhanced CPM response with the addition of a mobilization stimulus in patients with knee osteoarthritis but the authors did not examine the association between CPM and MIA. The current study appears to be the first to investigate this association between CPM and MIA in people with musculoskeletal pain, demonstrating a significant, positive association between PPT measures at the wrist and elbow sites both during and following the CPT and CLG stimuli. This suggests that those individuals who show a significant analgesic response to the cold pressor stimulus also show a positive analgesic response to the mobilization treatment. Regression analysis showed that a significant proportion of the variance in MIA response could be explained by the CPM response. These findings suggest that while the nature of the 2 stimuli is quite distinct there are clear associations between the analgesic responses induced by both stimuli. This suggests that they may activate similar neurophysiological mechanisms.
One potential implication of this in the clinical setting is that measuring CPM response could be a useful predictor of the likelihood that an individual would respond positively to a course of joint mobilization treatments. CPM testing should be further evaluated as a possible predictor of response to manual therapy treatment over a longer treatment period and in different musculoskeletal conditions, reflective of normal clinical practice. An improved understanding of manual therapy analgesia may also lead to more appropriate and more effective treatment.
Recent imaging studies in humans suggest similarities in the cortical activity accompanying CPM and MIA. La Cesa et al44 utilized functional magnetic resonance imaging and reported activity in several cortical structures in response to cold water hand immersion. These regions included medial areas of the postcentralgyrus bilaterally, the secondary somatosensory cortex (S2), posterior areas of the insular cortex, regions of the cingulate cortex and the cerebellum. Cortical activity has also been shown in other areas during CPM such as thalamus, medulla, amygdala,45 supplementary motor area, and prefrontal cortex.46 Previous research has also47 found that MIA is associated with immediate changes in functional cortical connectivity of S1, posterior insular cortex, posterior cingulate cortex, and the periaqueductal gray region in experimentally induced low back pain. Other brain areas such as S2, premotor, and supplementary areas, amygdala, insula, anterior cingulate cortex, thalamus,48 anterior cerebellum, and frontal cortex were also active during manual therapy.49 These data suggest that both CPM and MIA are mediated by similar cortical structures, which supports the hypothesis of overlapping cortical and descending neuronal networks being responsible for both forms of analgesia.
There is also evidence suggesting that CPM and MIA are mediated by serotonergic and noradrenergic neuronal networks. In a group with diabetic neuropathy CPM effect was improved in patients with less efficient CPM by the selective serotonin (5-hydroxytryptamine: 5-HT) and noradrenaline (NA) reuptake inhibitor, duloxetine.50 In a recent animal study blockade of α2-AR through α2-AR antagonists, spinal atipamezole, or subcutaneous yohimbine, abolished the CPM response in intact animals, but it was augmented in spinally injured animals after intrathecal administration of a norepinephrine-reuptake inhibitor, reboxetine, or systemic injection of the norepinephrine-reuptake inhibitor and μ-opioid receptor agonist, tapentadol.51 Some studies in humans have shown that CPM-induced analgesia is not affected by naloxone (an opioid antagonist)52–54 suggesting a nonopioid form of analgesia. However, other studies have demonstrated that naloxone partially45 or completely reverses CPM analgesia.55,56 Therefore, the current evidence on the involvement of opioid pathways in CPM analgesia is inconclusive.
In summary, the present study showed that the CPT and CLG stimuli both induced an analgesic response. CPM and MIA responses were of similar magnitude (postintervention) and were significantly correlated in a population with LE. This suggests that there is a considerable overlap between both forms of EA and that they may share similar neurophysiological mechanisms, potentially involving descending serotonergic and noradrenergic neurons. Assessment of CPM may have some value as potential predictor of clinical response to manual therapy treatment. Further research is required to understand the detailed similarities and differences between the neurophysiological mechanisms responsible for both forms of analgesia.
The authors thank all of the participants who contributed their time to the study.
1. Yarnitsky D, Arendt-Nielsen L, Bouhassira D, et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain. 2010;14:339.
2. Le Bars HD, Dickenson HA, Besson HJ-M. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain. 1979;6:283–304.
3. Reinert A, Treede R-D, Bromm B. The pain inhibiting pain effect: an electrophysiological study in humans. Brain Res. 2000;862:103–110.
4. Kennedy LD, Kemp IH, Ridout SCD, et al. Reliability of conditioned pain modulation
: a systematic review. Pain. 2016;157:2410–2419.
5. Yarnitsky D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain. 2015;156(suppl 1):S24–S31.
6. Wright A. Hypoalgesia post-manipulative therapy: a review of a potential neurophysiological mechanism. Man Ther. 1995;1:11–16.
7. Wright A, Vicenzino BShacklock M. Cervical mobilisation techniques, sympathetic nervous system effects and their relationship to analgesia. Moving in on Pain. Melbourne: Butterworth-Heinemann; 1995:164–173.
8. Voogt L, de Vries J, Meeus M, et al. Analgesic effects of manual therapy
in patients with musculoskeletal pain: a systematic review. Man Ther. 2015;20:250–256.
9. Vicenzino B, Collins D, Benson HAE, et al. An investigation of the interrelationship between manipulative therapy-induced hypoalgesia and sympathoexcitation. J Manipulative Physiol Therap. 1998;21:448–453.
10. Chalaye P, Devoize L, Lafrenaye S, et al. Cardiovascular influences on conditioned pain modulation
. Pain. 2013;154:1377–1382.
11. Chalaye P, Lafrenaye S, Goffaux P, et al. The role of cardiovascular activity in fibromyalgia and conditioned pain modulation
. Pain. 2014;155:1064–1069.
12. Sanada T, Kohase H, Makino K, et al. Effects of alpha-adrenergic agonists on pain modulation in diffuse noxious inhibitory control. JMed Dental Sci. 2009;56:17–24.
13. Makino K, Kohase H, Sanada T, et al. Phenylephrine suppresses the pain modulation of diffuse noxious inhibitory control in rats. Anesth Analg. 2010;110:1215–1221.
14. Bannister K, Lockwood S, Goncalves L, et al. An investigation into the inhibitory function of serotonin in diffuse noxious inhibitory controls in the neuropathic rat. Eur J Pain. 2017;21:750–760.
15. Skyba DA, Radhakrishnan R, Rohlwing JJ, et al. Joint manipulation reduces hyperalgesia by activation of monoamine receptors but not opioid or GABA receptors in the spinal cord. Pain. 2003;106:159–168.
16. Lemley JK, Hunter KS, Bement HMK. Conditioned pain modulation
predicts exercise-induced hypoalgesia in healthy adults. Med Sci Sports Exerc. 2015;47:176–184.
17. Vaegter HB, Handberg G, Jørgensen MN, et al. Aerobic exercise and cold pressor test induce hypoalgesia in active and inactive men and women. Pain Med. 2015;16:923–933.
18. Haker E, Lundeberg T. Acupuncture treatment in epicondylalgia: a comparative study of two acupuncture techniques. Clin J Pain. 1990;6:221–226.
19. Waller R, Straker L, O’Sullivan P, et al. Reliability of pressure pain threshold testing in healthy pain free young adults. Scand J Pain. 2015;9:38–41.
20. Fernández-Carnero J, Fernández-De-Las-Peñas C, De La Llave-Rincón A, et al. Widespread mechanical pain hypersensitivity as sign of central sensitization in unilateral epicondylalgia: a blinded, controlled study. Clin J Pain. 2009;25:555–561.
21. Locke D, Gibson W, Moss P, et al. Analysis of meaningful conditioned pain modulation
effect in a pain-free adult population. J Pain. 2014;15:1190–1198.
22. Vicenzino B, Collins D, Wright A. The initial effects of a cervical spine manipulative physiotherapy treatment on the pain and dysfunction of lateral epicondylalgia
. Pain. 1996;68:69–74.
23. Paungmali A, O’Leary S, Souvlis T, et al. Hypoalgesic and sympathoexcitatory effects of mobilization with movement for lateral epicondylalgia
. Phys Ther. 2003;83:374–383.
24. Smidt N, van Der Windt DA, Assendelft WJ, et al. Interobserver reproducibility of the assessment of severity of complaints, grip strength, and pressure pain threshold in patients with lateral epicondylitis. Arch Phys Med Rehabil. 2002;83:1145–1150.
25. Butler DS. The Sensitive Nervous System. Adelaide: Noigroup Publications; 2000.
26. Yaxley GA, Jull GA. Adverse tension in the neural system. A preliminary study of tennis elbow
. Aust J Physiother. 1993;39:15–22.
27. Hoffken O, Ozgul O, Enax-Krumova E, et al. Evoked potentials after painful cutaneous electrical stimulation depict pain relief during a conditioned pain modulation
. BMC Neurol. 2017;17:167.
28. Vicenzino B, Neal R, Collins D, et al. The displacement, velocity and frequency profile of the frontal plane motion produced by the cervical lateral glide treatment technique. Clin Biomech (Bristol, Avon). 1999;14:515–521.
29. Vicenzino B, Cartwright T, Collins D, et al. An investigation of stress and pain perception during manual therapy
in asymptomatic subjects. Eur J Pain. 1999;3:13–18.
30. Macdermid J. Update: the Patient-Rated Forearm Evaluation Questionnaire is now the Patient-Rated Tennis Elbow
. Evaluation. 2005;18:407–410.
31. Overend TJ, Wuori-Fearn JL, Kramer JF, et al. Reliability of a Patient-rated Forearm Evaluation Questionnaire for patients with lateral epicondylitis. J Hand Ther. 1999;12:31–37.
32. Rompe JD, Overend TJ, Macdermid JC. Validation of the Patient-rated Tennis Elbow
Evaluation Questionnaire. J Hand Ther. 2007;20:3–11.
33. Vincent JI, Macdermid JC, King GJ, et al. Validity and sensitivity to change of patient-reported pain and disability measures for elbow pathologies. J Orthop Sports Phys Ther. 2013;43:263–274.
34. Gerhardt A, Eich W, Treede R-D, et al. Conditioned pain modulation
in patients with nonspecific chronic back pain with chronic local pain, chronic widespread pain, and fibromyalgia. Pain. 2017;158:430–439.
35. Rathleff M, Stephenson A, Mellor R, et al. Adults with patellofemoral pain do not exhibit manifestations of peripheral and central sensitization when compared to healthy pain-free age and sex matched controls—An assessor blinded cross-sectional study. PLoS One. 2017;12:e0188930.
36. Leffler A-S, Hansson P, Kosek E. Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia. Eur J Pain. 2002;6:149–159.
37. Pud D, Sprecher E, Yarnitsky D. Homotopic and heterotopic effects of endogenous analgesia in healthy volunteers. Neurosci Lett. 2005;380:209–213.
38. Lim WEC, Sterling M, Vicenzino B. Chronic lateral epicondylalgia
does not exhibit mechanical pain modulation in response to noxious conditioning heat stimulus. Clin J Pain. 2017;33:932–938.
39. Oono Y, Nie H, Matos RL, et al. The inter- and intra-individual variance in descending pain modulation evoked by different conditioning stimuli in healthy men. Scand J Pain. 2011;2:162–169.
40. Fernández-Carnero J, Fernández-de-Las-Peñas C, Cleland JA. Immediate hypoalgesic and motor effects after a single cervical spine manipulation in subjects with lateral epicondylalgia
. J Manipulative Physiol Ther. 2008;31:675–681.
41. Maduro de Camargo V, Alburquerque-Sendín F, Bérzin F, et al. Immediate effects on electromyographic activity and pressure pain thresholds after a cervical manipulation in mechanical neck pain: a randomized controlled trial. J Manipulative Physiol Ther. 2011;34:211–220.
42. Moss P, Sluka K, Wright A. The initial effects of knee joint mobilization on osteoarthritic hyperalgesia. Man Ther. 2007;12:109–118.
43. Courtney CA, Steffen AD, Fernández-De-Las-Peñas C, et al. Joint mobilization enhances mechanisms of conditioned pain modulation
in individuals with osteoarthritis of the knee. J Orthop Sports Phys Ther. 2016;46:168–176.
44. La Cesa S, Tinelli E, Toschi N, et al. fMRI pain activation in the periaqueductal gray in healthy volunteers during the cold pressor test. Magn Reson Imaging. 2014;32:236–240.
45. Sprenger C, Bingel U, Büchel C. Treating pain with pain: supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation. Pain. 2011;152:428–439.
46. Piché M, Arsenault M, Rainville P. Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci. 2009;29:14236–14246.
47. Gay CW, Robinson ME, George SZ, et al. Immediate changes following manual therapy
in resting state functional connectivity as measured by magnetic resonance imaging (fMRI) In subjects with induced low back pain. J Manipulative Physiol Ther. 2014;37:614–627.
48. Sparks C, Cleland JA, Elliott JM, et al. Using functional magnetic resonance imaging to determine if cerebral hemodynamic responses to pain change following thoracic spine thrust manipulation in healthy individuals. J Orthop Sports Phys Therapy. 2013;43:340–348.
49. Boendermaker B, Meier ML, Luechinger R, et al. The cortical and cerebellar representation of the lumbar spine. Hum Brain Mapp. 2014;35:3962–3971.
50. Yarnitsky D, Granot M, Nahman-Averbuch H, et al. Conditioned pain modulation
predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012;153:1193–1198.
51. Bannister K, Patel R, Goncalves L, et al. Diffuse noxious inhibitory controls and nerve injury: restoring an imbalance between descending monoamine inhibitions and facilitations. Pain. 2015;156:1803–1811.
52. Edwards RR, Ness TJ, Fillingim RB. Endogenous opioids, blood pressure, and diffuse noxious inhibitory controls: a preliminary study. Percept Mot Skills. 2004;99:679–687.
53. Hermans L, Nijs J, Calders P, et al. Influence of morphine and naloxone on pain modulation in rheumatoid arthritis, chronic fatigue syndrome/fibromyalgia, and controls: a double‐blind, randomized, placebo‐controlled, cross‐over study. Pain Pract. 2018;18:418–430.
54. Peters LM, Schmidt JMA, Van Den Hout AM, et al. Chronic back pain, acute postoperative pain and the activation of diffuse noxious inhibitory controls (DNIC). Pain. 1992;50:177–187.
55. Pertovaara A, Kemppainen P, Johansson G, et al. Ischemic pain nonsegmentally produces a predominant reduction of pain and thermal sensitivity in man: a selective role for endogenous opioids. Brain Res. 1982;251:83–92.
56. Willer JC, Le Bars D, De Broucker T. Diffuse noxious inhibitory controls in man: involvement of an opioidergic link. Eur J Pharmacol. 1990;182:347–355.
57. Vicenzino B, O’Callaghan J, Kermode F, et al. No influence of naloxone on the initial hypoalgesic effect of spinal manual therapy
. Proceedings of the 9th World Congress on Pain. Prog Pain Res Manag. 2000;16:1039–1044.
58. Zusman M, Edwards BC, Donaghy A. Investigation of a proposed mechanism for the relief of spinal pain with passive joint movement. J Man Med. 1989;4:58–61.
59. Paungmali A, O’Leary S, Souvlis T, et al. Naloxone fails to antagonize initial hypoalgesic effect of a manual therapy
treatment for lateral epicondylalgia
. J Manipulative Physiol Ther. 2004;27:180–185.
60. Sluka KA, Wright A. Knee joint mobilization reduces secondary mechanical hyperalgesia induced by capsaicin injection into the ankle joint. Eur J Pain. 2001;5:81–87.