Background & Aims
Although sensitization of the peripheral nervous system influences joint pain, changes in central pain processing are also likely to contribute[1, 2]. In patients, central pain processing is often measured using a quantitative sensory test (QST) called conditioned pain modulation (CPM) which measures spatial aspects of pain processing. However, the clinical relevance of CPM to joint pain remains unclear[3, 4]. A less frequently used QST measure, offset analgesia, reflects time-dependent modulatory effects and, specifically, refers to the phenomenon in which pain intensity is dramatically reduced with a small drop, or offset, in noxious stimulus intensity[5]. Although neuropathic and nociplastic pain conditions show deficits in offset analgesia[6], whether offset analgesia is altered in knee osteoarthritis was unknown. Therefore, the primary goal of the current study was to determine whether knee osteoarthritis pain is associated with changes in offset analgesia.
Methods
In an observational study, we enrolled knee osteoarthritis patients with equivalent joint degeneration but moderate-to-severe pain (n=37) or mild pain intensity (n=36). We also enrolled pain-free controls (n=30), matching for age, gender, and body mass index. Standardized questionnaires, a QST battery, 6-minute walk test, and stair climb test were performed. The QST battery included heat pain threshold (Medoc Qsense 9 cm2 thermode), pressure pain threshold (Wagner algometer), pinprick sensitivity (Neuropen), temporal summation to pinprick, CPM (concurrent pressure pain threshold with distracting cold water bath), and offset analgesia[7]. QST was performed at both the painful knee and nonpainful sites. An offset analgesia index was calculated reflecting the percent change in pain intensity at stimulus offset[6]. This primary outcome was compared across groups with a 1-way ANOVA. Linear regression with post-estimation tests and Pearson correlation coefficients were calculated.
Results
Offset analgesia at the nonpainful forearm was significantly reduced in knee osteoarthritis groups (control: -81.7% SD 21.0%, mild: -68.5% SD 23.2%, mod-sev: -64.1% SD 27.5%, 1-way ANOVA F(2,99) = 4.57, p=0.013). In secondary analysis, we found that men (n=41) had less offset analgesia than women (n=62). Controlling for age, gender, and radiographic knee joint degeneration, a statistically significant difference in offset analgesia remained across groups. Measuring offset analgesia at the knee yielded similar results. Consistent with prior studies, knee pinprick hyperalgesia and temporal summation was associated with greater knee pain. CPM was not significantly different between groups at either the knee or remote test sites. Finally, in the knee pain groups, less forearm offset analgesia was associated with greater pain and worse objective performance on the 6-minute walk and stair climb tests. Temporal summation and CPM were not associated with mobility evoked pain or performance.
Conclusions
These results demonstrate that deficits in offset analgesia are observed in patients with greater pain and functional impairment from knee osteoarthritis, suggesting that temporal pain inhibition contributes to clinically relevant outcomes in knee osteoarthritis. In the same cohort, CPM was no different between knee pain groups and pain-free controls. This suggests that CPM and offset analgesia represent different aspects of pain inhibitory systems. Additionally, greater deficits in offset analgesia were associated with worse objective performance while walking and stair climbing, while CPM and temporal summation were not. In knee osteoarthritis and particularly weight-bearing pain, temporal pain inhibition measured with offset analgesia may be more clinically relevant than spatial pain inhibition or temporal summation. In conclusion, offset analgesia is reduced in knee osteoarthritis, implicating temporal pain inhibition as a mechanism and potential therapeutic target in joint pain.
References
1.Arant, K.R., J.N. Katz, and T. Neogi, Quantitative sensory testing: identifying pain characteristics in patients with osteoarthritis. Osteoarthritis Cartilage, 2022. 30(1): p. 17-31.
2.Lockwood, S.M., K. Bannister, and A.H. Dickenson, An investigation into the noradrenergic and serotonergic contributions of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis. J Neurophysiol, 2019. 121(1): p. 96-104.
3.Fernandes, C., et al., Conditioned pain modulation as a biomarker of chronic pain: a systematic review of its concurrent validity. Pain, 2019. 160(12): p. 2679-2690.
4.Petersen, K.K., et al., The predictive value of quantitative sensory testing: a systematic review on chronic postoperative pain and the analgesic effect of pharmacological therapies in patients with chronic pain. Pain, 2021. 162(1): p. 31-44.
5.Grill, J.D. and R.C. Coghill, Transient analgesia evoked by noxious stimulus offset. Journal of neurophysiology, 2002. 87: p. 2205-8.
6.Szikszay, T.M., W.M. Adamczyk, and K. Luedtke, The Magnitude of Offset Analgesia as a Measure of Endogenous Pain Modulation in Healthy Subjects and Patients with Chronic Pain – A Systematic Review and Meta-analysis. Clin J Pain, 2018.
7.Alter, B.J., et al., Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity. PLoS One, 2020. 15(12): p. e0231124.
Presenting Author
Benedict Alter
Poster Authors
Benedict Alter
MD, PhD
University of Pittsburgh
Lead Author
Maya Maurer
University of Pittsburgh
Lead Author
Ajay Wasan
University of Pittsburgh
Lead Author
Brian O'Connell
MS
Univ. of Pittsburgh
Lead Author
Andrea Gomez Sanchez
MD
University of Pittsburgh
Lead Author
A. Murat Kaynar
MD
University of Pittsburgh
Lead Author
Anthony DiGioia
MD
University of Pittsburgh Medical Center
Lead Author
Theodore Huppert
PhD
University of Pittsburgh
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Rheumatology, Arthritis, and Other