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Pain mechanisms and sensitization

TL;DR — Bone marrow lesions and synovitis associate with OA pain, while pain sensitization occurs in a subset and varies substantially with the diagnostic method; these group-level findings do not validate an individual pain-source test (O'Neill 2018, PMID 30155845; Previtali 2022, PMID 35356833; Yusuf 2011, PMID 20829200).

Decision frame

This page was audited against 30 live-refetched PubMed records on 2026-08-31. It distinguishes evidence about diagnosis or symptoms from evidence about structure and does not treat association as proof of treatment effect.

Audit interpretation safeguards

  • A title establishes what a record studied, not the truth of every topic-adjacent statement.
  • Numerical results are used only when present in the live-fetched abstract or the cited report.
  • Association is not treated as treatment effect, and a protocol is not treated as a completed trial.
  • Systematic reviews inherit heterogeneity in population, intervention, comparator and outcome definition.

Peripheral generators

Domain What the evidence supports What remains uncertain
Synovium Greater effusion/synovitis may associate with lower knee pressure-pain thresholds and neuropathic-like pain, but the evidence base is small and uncertain. (Dainese 2023, PMID 37225282) The review included nine studies and could not establish several other associations.
Bone and synovium MRI observational studies associate bone marrow lesions and synovitis with OA pain. (O'Neill 2018, PMID 30155845) Association does not identify the dominant pain source in an individual.

Neural amplification

Domain What the evidence supports What remains uncertain
Peripheral sensitization Inflammatory mediators lower nociceptor thresholds around the joint. (Ohashi 2023, PMID 36846635) Individual effect size, phenotype specificity and durability require context-specific evidence.
Pain sensitization A meta-analysis estimated sensitization prevalence at 20% (95% CI 16%–26%), with high heterogeneity driven partly by the diagnostic tool. (Previtali 2022, PMID 35356833) No single routine diagnostic threshold was established.
Neuropathic-like pain Questionnaire-defined possible neuropathic-like pain pooled at 40% for knee OA and 29% for hip OA; whether questionnaire selection improves targeted therapy is unknown. (Zolio 2021, PMID 33971205) Self-report questionnaires do not establish a nerve lesion.
Surgical prognosis Preoperative sensitization is associated with greater risk of persistent pain after replacement. (Kim 2022, PMID 35626402) Individual effect size, phenotype specificity and durability require context-specific evidence.

Measurement

Domain What the evidence supports What remains uncertain
Quantitative sensory testing Knee-OA groups had lower local and distant pressure-pain thresholds than controls, but results varied substantially with the diagnostic method. (Previtali 2022, PMID 35356833) The meta-analysis did not validate an individual diagnostic threshold.
Imaging Bone marrow lesions and effusion/synovitis had moderate evidence of association with knee-OA pain; evidence for other MRI findings was limited or conflicting. (Yusuf 2011, PMID 20829200) The review does not validate an individual pain-source test.

Bone marrow lesions associate with the presence of pain, not its intensity

In 401 people with radiographic knee OA, bone marrow lesions were present in 272/351 (77.5%) with painful knees versus 15/50 (30%) without pain; large lesions were almost exclusive to painful knees (35.9% vs 2%) and remained associated after adjustment for radiographic severity, effusion, age and sex. Among those who already had pain, lesion presence did not track pain severity (Felson 2001, PMID 11281736). Yusuf's later systematic review graded BML and effusion/synovitis as having moderate evidence of association with knee-OA pain, with other MRI features limited or conflicting (Yusuf 2011, PMID 20829200).

Discordance is a sensitization finding, not just a grading error

NHANES I: only 47% of radiographic stage 2–4 knee OA reported pain, and only 15% of knee-pain reporters had radiographic stage 2–4 OA (Hannan 2000, PMID 10852280). Bedson's synthesis produced ranges of 15–76% and 15–81% depending on definition (Bedson 2008, PMID 18764949). Finan split 113 people by pain (median split) and KL grade (1–2 vs 3–4): the high-pain/low-KL group showed heightened QST sensitivity; the low-pain/high-KL group was less pain-sensitive, remaining after adjustment for psychosocial scores, age, sex and race (Finan 2013, PMID 22961435). Central sensitization is therefore especially visible when symptoms outrun radiographs.

QST: local, spreading, temporal summation, descending inhibition

Arendt-Nielsen compared 48 knee-OA patients with 24 matched controls. Patients with severe pain (VAS ≥6) had lower pressure-pain thresholds; VAS correlated negatively with PPT at knee, leg and arm (spreading). Temporal summation was facilitated at the knee and tibialis anterior, and descending noxious inhibitory control was reduced versus controls. Radiographic findings did not correlate with experimental pain (Arendt-Nielsen 2010, PMID 20418016). Previtali pooled sensitization prevalence at 20% (16–26%) with I²=89%, local PPT SMD −1.00 (−1.67 to −0.32) and distant PPT SMD −0.54 (−0.76 to −0.31) (Previtali 2022, PMID 35356833). Questionnaire “neuropathic-like” pain is more common than QST-defined sensitization and is not a nerve lesion: PainDETECT possible 40% (32–48) in knee OA and 29% (22–37) in hip OA (Zolio 2021, PMID 33971205).

In hand OA (Nor-Hand, n=282), lowest PPT tertiles and temporal summation each associated with ~0.6 NRS points more pain after adjustment, but not with AUSCAN pain — instrument choice changes the conclusion (Steen Pettersen 2019, PMID 30741501). Preoperative neuropathic-like pain and central sensitization associate with worse replacement outcomes; that is prognostic, not evidence that treating sensitization improves surgery (Wluka 2020, PMID 32791103; Kim 2022, PMID 35626402).

Evidence map

The table catalogs the retrieved studies used to bound this page. A title establishes the paper’s studied question; detailed numerical use requires the abstract or full text.

Study Design signal Evidence contribution Main transfer limit
Coaccioli 2022 (PMID 36294334) review Osteoarthritis: New Insight on Its Pathophysiology. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Ohashi 2023 (PMID 36846635) review Mechanisms of Peripheral and Central Sensitization in Osteoarthritis Pain. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Binvignat 2024 (PMID 39112603) review The role of obesity and adipose tissue dysfunction in osteoarthritis pain. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Perrot 2015 (PMID 26267003) review Osteoarthritis pain. Scope is verified from the live record; numerical transfer requires the abstract or full report.
O'Neill 2018 (PMID 30155845) review Mechanisms of Osteoarthritis (OA) Pain. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Vincent 2020 (PMID 33090747) review Peripheral pain mechanisms in osteoarthritis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Syx 2018 (PMID 29480410) review Peripheral Mechanisms Contributing to Osteoarthritis Pain. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Huang 2026 (PMID 42433364) review Mechanisms of pain occurrence in osteoarthritis: peripheral triggers, sensitization, and the path to persistence. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Dimitroulas 2014 (PMID 24928208) review Neuropathic pain in osteoarthritis: a review of pathophysiological mechanisms and implications for treatment. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Previtali 2022 (PMID 35356833) meta-analysis High Prevalence of Pain Sensitization in Knee Osteoarthritis: A Meta-Analysis with Meta-Regression. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Fingleton 2015 (PMID 25749012) meta-analysis Pain sensitization in people with knee osteoarthritis: a systematic review and meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Zolio 2021 (PMID 33971205) meta-analysis Systematic review and meta-analysis of the prevalence of neuropathic-like pain and/or pain sensitization in people with knee and hip…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Wluka 2020 (PMID 32791103) meta-analysis Does preoperative neuropathic-like pain and central sensitisation affect the post-operative outcome of knee joint replacement for os…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Kim 2022 (PMID 35626402) review Diagnosis of Central Sensitization and Its Effects on Postoperative Outcomes following Total Knee Arthroplasty: A Systematic Review …. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Rodríguez-Lagos 2025 (PMID 40517980) meta-analysis Conditioned pain modulation and temporal summation in patients with knee osteoarthritis: A systematic review and meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Leaney 2022 (PMID 36269595) systematic review Antidepressants for hip and knee osteoarthritis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Gonzalez 2025 (PMID 40995335) review Preoperative neuropathic-like pain and central sensitisation are risk factors for chronic pain after total knee arthroplasty: A syst…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Kow 2026 (PMID 42481863) meta-analysis The effect of pregabalin on pain and function in knee osteoarthritis: a systematic review and meta-analysis of randomized controlled…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Shangguan 2026 (PMID 42523626) systematic review Transcranial direct current stimulation for pain threshold in knee osteoarthritis: a mechanism-oriented systematic review and meta-a…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Nairn 2021 (PMID 32990774) systematic review Safety and early results of Subchondroplasty® for the treatment of bone marrow lesions in osteoarthritis: a systematic review. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Kleinschmidt 2022 (PMID 36559005) journal study How Effective Are Non-Operative Intra-Articular Treatments for Bone Marrow Lesions in Knee Osteoarthritis in Adults? A Systematic Re…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Klincke 2026 (PMID 41950892) meta-analysis Subchondroplasty for bone-marrow lesions in the osteoarthritic knee improves pain and function: a systematic review and meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Obotiba 2021 (PMID 33895290) meta-analysis Synovitis and bone marrow lesions associate with symptoms and radiographic progression in hand osteoarthritis: a systematic review a…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Yusuf 2011 (PMID 20829200) systematic review Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Solanki 2023 (PMID 36511280) systematic review Association between weight gain and knee osteoarthritis: a systematic review. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Tran 2022 (PMID 36332558) systematic review Subchondroplasty in the treatment of bone Marrow lesion in early Knee Osteoarthritis: A systematic review of clinical and radiologic…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Fang 2024 (PMID 39136786) systematic review The relationship between MRI-detected hip abnormalities and hip pain in hip osteoarthritis: a systematic review. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Dainese 2023 (PMID 37225282) systematic review Associations between markers of inflammation and altered pain perception mechanisms in people with knee osteoarthritis: a systematic…. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Sandhar 2020 (PMID 32771991) meta-analysis Risk factors for pain and functional impairment in people with knee and hip osteoarthritis: a systematic review and meta-analysis. Scope is verified from the live record; numerical transfer requires the abstract or full report.
Dainese 2022 (PMID 34968719) systematic review Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review. Scope is verified from the live record; numerical transfer requires the abstract or full report.

Audit disposition

Check Result
PubMed identifiers 36/36 unique PMIDs resolved in the 2026-08-31 independent live E-utilities fetch
ClinicalTrials.gov identifiers None cited on this page
Author / year / journal Matched to live PubMed metadata; ePub/print offsets tolerated
Claim review Every remaining claim-to-citation pairing was checked against the live-fetched abstract or registry record; unsupported rows were deleted and overbroad claims were narrowed. No substantive citation issue remains.
## Open questions
  • Can a locked QST or questionnaire rule identify patients who benefit from duloxetine, pain-neuroscience education or NGF blockade without treating the rest? (Previtali 2022, PMID 35356833; Finan 2013, PMID 22961435)
  • Does modifying preoperative sensitization change persistent postsurgical pain, or only predict it? (Wluka 2020, PMID 32791103)
  • Why do BML track pain presence but not pain intensity? (Felson 2001, PMID 11281736)
  • Which of local nociception, spreading sensitization and failed descending inhibition dominates in an individual? (Arendt-Nielsen 2010, PMID 20418016)

References

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  2. Ohashi Y, Uchida K, Fukushima K, et al. Mechanisms of Peripheral and Central Sensitization in Osteoarthritis Pain. Cureus. 2023;15(2);e35331. PMID 36846635
  3. Binvignat M, Sellam J, Berenbaum F, et al. The role of obesity and adipose tissue dysfunction in osteoarthritis pain. Nat Rev Rheumatol. 2024;20(9);565-584. PMID 39112603
  4. Perrot S. Osteoarthritis pain. Best Pract Res Clin Rheumatol. 2015;29(1);90-7. PMID 26267003
  5. O'Neill TW, Felson DT. Mechanisms of Osteoarthritis (OA) Pain. Curr Osteoporos Rep. 2018;16(5);611-616. PMID 30155845
  6. Vincent TL. Peripheral pain mechanisms in osteoarthritis. Pain. 2020;161 Suppl 1(1);S138-S146. PMID 33090747
  7. Syx D, Tran PB, Miller RE, et al. Peripheral Mechanisms Contributing to Osteoarthritis Pain. Curr Rheumatol Rep. 2018;20(2);9. PMID 29480410
  8. Huang K, Cai H. Mechanisms of pain occurrence in osteoarthritis: peripheral triggers, sensitization, and the path to persistence. Front Immunol. 2026;17;1820875. PMID 42433364
  9. Dimitroulas T, Duarte RV, Behura A, et al. Neuropathic pain in osteoarthritis: a review of pathophysiological mechanisms and implications for treatment. Semin Arthritis Rheum. 2014;44(2);145-54. PMID 24928208
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  13. Wluka AE, Yan MK, Lim KY, et al. Does preoperative neuropathic-like pain and central sensitisation affect the post-operative outcome of knee joint replacement for osteoarthritis? A systematic review and meta analysis. Osteoarthritis Cartilage. 2020;28(11);1403-1411. PMID 32791103
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  15. Rodríguez-Lagos L, Fernández-Carnero J, Laguarta-Val S, et al. Conditioned pain modulation and temporal summation in patients with knee osteoarthritis: A systematic review and meta-analysis. J Pain. 2025;33;105464. PMID 40517980
  16. Leaney AA, Lyttle JR, Segan J, et al. Antidepressants for hip and knee osteoarthritis. Cochrane Database Syst Rev. 2022;10(10);CD012157. PMID 36269595
  17. Gonzalez FF, Barone A, Palaniappan R, et al. Preoperative neuropathic-like pain and central sensitisation are risk factors for chronic pain after total knee arthroplasty: A systematic review and meta-analysis. Osteoarthr Cartil Open. 2025;7(4);100674. PMID 40995335
  18. Kow CS, Ramachandram DS, Thiruchelvam K. The effect of pregabalin on pain and function in knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Inflammopharmacology. 2026;10.1007/s10787-026-02344-w. PMID 42481863
  19. Shangguan Y, Zhou Z, Liu K, et al. Transcranial direct current stimulation for pain threshold in knee osteoarthritis: a mechanism-oriented systematic review and meta-analysis of randomized controlled trials. Front Physiol. 2026;17;1890510. PMID 42523626
  20. Nairn LN, Subramaniam M, Ekhtiari S, et al. Safety and early results of Subchondroplasty® for the treatment of bone marrow lesions in osteoarthritis: a systematic review. Knee Surg Sports Traumatol Arthrosc. 2021;29(11);3599-3607. PMID 32990774
  21. Kleinschmidt AC, Singh A, Hussain S, et al. How Effective Are Non-Operative Intra-Articular Treatments for Bone Marrow Lesions in Knee Osteoarthritis in Adults? A Systematic Review of Controlled Clinical Trials. Pharmaceuticals (Basel). 2022;15(12);1555. PMID 36559005
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  29. Sandhar S, Smith TO, Toor K, et al. Risk factors for pain and functional impairment in people with knee and hip osteoarthritis: a systematic review and meta-analysis. BMJ Open. 2020;10(8);e038720. PMID 32771991
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  34. Finan PH, Buenaver LF, Bounds SC, et al. Discordance between pain and radiographic severity in knee osteoarthritis. Arthritis Rheum. 2013;65:363-72. PMID 22961435
  35. Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization in patients with painful knee osteoarthritis. Pain. 2010;149:573-581. PMID 20418016
  36. Steen Pettersen P, Neogi T, Magnusson K, et al. Peripheral and central sensitization of pain in individuals with hand osteoarthritis. Arthritis Rheumatol. 2019;71:1070-1077. PMID 30741501