Osteoarthritis-induced joint pain: Impact of Sex, Site and Exercise. Tamara King University of New England

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1 Osteoarthritis-induced joint pain: Impact of Sex, Site and Exercise Tamara King University of New England

2 Disclosures No financial conflicts of interest to disclose.

3 Learning Objectives 1. Understand the relationship between joint pathology and clinical characteristics of osteoarthritis pain 2. Gain an understanding of how exercise modulates osteoarthritis pain

4 Talk Overview Key features of osteoarthritis. What is known regarding mechanisms driving OA pain. What is the impact of exercise on OA pain. Clinical studies and reports Preclinical studies and proposed mechanisms Differences between different joints?

5 Joint Pain Arthritis is the most common joint pain pain (arthralgia) stiffness swelling limited function of joints

6 Joint Pain In the US, arthritis is a leading cause of disability; ~52.5 million (22.7%) adults in In 2014, approximately one fourth of adults with arthritis report severe joint pain (27.2%) Number of adults with severe joint pain was significantly higher in 2014 (14.6 million) than in 2002 (10.5 million) Prevalence of Severe Joint Pain Among Adults with Doctor-Diagnosed Arthritis United States, Barbour et al. CDC October 7, 2016

7 Projected Increase Obesity Population Growth Wang et al, Lancet 2011 Osteoarthritis is the most common form of arthritis

8 Arthritis Hand 8% 2.9 million Hip 4% Knee 16% 4.3 million 60+ yrs Feet 2% Data from CDC Osteoarthritis is the most common form of arthritis

9 Osteoarthritis Hand 8% 2.9 million Hip 4% Knee 16% 4.3 million Feet 2% Data from CDC Women are more likely to have OA Woman report more severe OA

10 Osteoarthritis Other risk factors include: Joint injury trans-articular fracture meniscal tear requiring meniscectomy anterior cruciate ligament injury Repetitive use of joints at work

11 Osteoarthritis Radiographic OA Focal and progressive loss of the hyaline cartilage Radiographic changes include joint space narrowing, osteophytes, and bony sclerosis Symptomatic OA Pain that worsens during activity and gets better during rest. Muscle spasms and contractions in the tendons. A grating sensation with joint use Degree of pathology observed on radiograph does not correspond to symptomatic OA

12 OA Pain: Potential mechanisms Osteoarthritis is marked by changes in cartilage and bone: Cartilage loss Subchondral bone shows sclerosis Development of bone marrow lesions and cysts In subsets of patients there are indices of bone resorption indicating loss of trabecular bone Radiograph MRI Lesion There are currently no treatments available to patients for modifying the underlying disease. Current treatments focus on pain relief.

13 Osteoarthritis Early OA (stage 1): Predictable sharp or other pain Usually brought on by a trigger (usually an activity) Eventually limits high impact activities Has relatively little other impact. Mid OA (stage 2): Predictable pain that becomes more constant Unpredictable locking (knees) or other joint symptoms Begins to affect daily activities Advanced OA (stage 3): Constant dull/aching pain Punctuated by short episodes of intense, often unpredictable pain Significant avoidance of activities Including social and recreational activities.

14 OA Pain: Potential mechanisms Potential Contributors to Pain: Inflammatory mediators Mechanical factors NSAIDs, steroids Joint splints or braces, Nerve damage Duloxetine Not all patients receive adequate pain relief. All have side effects. Dorsal Root Ganglia Facilitation Enhances pain Inhibition Diminishes pain Amplified Signal Peripheral Sensitization Hyperalgesia-enhanced pain response to noxious stimuli Allodynia pain response to non-noxious stimuli Central Sensitization

15 Difference Score (test-bl) Percent Shift in WB (ipsi/contra * 100) Rat Model of Advanced OA Pain-Males Okun et al, Pain, 2012 Intra-articular injections Shift in Weight Bearing Day 14 Post MIA ** ** ** Conditioned Place Preference Chamber 0 Saline 1 mg 3 mg 4.8 mg Dose intra-articular MIA Intra-articular Lidocaine Paired Chamber * Pairing Chamber 1 Unpaired (Neutral) Pairing Chamber 2 0 Saline 1 mg 3 mg 4.8 mg Dose intra-articular MIA CPP to intra-articular lidocaine was observed in 4.8 mg, but not 3.0 mg MIA treated rats.

16 W e ig h t A s y m m e try (% ip s i/c o n tra ) Advanced OA Joint Pain Male vs Female Rats Intra-articular injections Saline Duloxetine (30 mg/kg, i.p.) Pairing Chamber 1 Unpaired (Neutral) Pairing Chamber W e ig h t A s y m m e try F e m a le s M a le s * * * * * * * * * * * * * * * * Difference Scores (Test - Baseline) Duloxetine (30 mg/kg, i.p.) Induced CPP ** ** 0 B L M IA (m g /6 0 l) 1.0 Females A 5-fold lower concentration of MIA is sufficient to induce CPP in females. Consistent with clinical reports that females are more likely to develop OA and report more severe pain Males Concentration MIA (mg/ml) 4.8 Males

17 OA Pain: Modulation Enhanced and Chronic Pain Hypothesis: An important component underlying chronic pain is a change in descending pain modulation resulting in net pain facilitation. DRG + + Amplified Signal Inhibition Facilitation

18 OA Pain: Central Sensitization Inhibition Facilitation Clinical studies demonstrated signs of increased pain sensitization in OA patients reporting moderate to severe pain. Pain > 6 on VAS Pain < 6 on VAS Non-pain controls DRG + + Increased Temporal Summation Graphs from: Arendt-Nielsen, et al. PAIN: 2010,

19 OA Pain: Central Sensitization Inhibition Facilitation Clinical studies demonstrated signs of increased pain sensitization in OA patients reporting moderate to severe pain. DRG + + From: Expanded Distribution of Pain as a Sign of Central Sensitization in Individuals With Symptomatic Knee Osteoarthritis Phys Ther. 2016;96(8): doi: /ptj

20 Difference score (s) (test-baseline) Advanced Osteoarthritis Pain: Facilitation RVM Lidocaine ( AP from bregma; 8.5 DV from skull) facilitation RVM Lidocaine Induced CPP Off-site On-site ** 3.0 mg MIA 4.8 mg MIA Consistent with observations that patients with more severe pain ratings develop central sensitization.

21 OA Pain: Modulation Inhibition Facilitation Clinical studies indicate that there is impaired pain inhibition in chronic pain patients including OA patients. DRG + +

22 OA Pain: Modulation Inhibition Facilitation Clinical studies indicate that there is impaired pain inhibition in chronic pain patients including OA patients. Hyperalgesia CPM DRG + + Pain > 6 on VAS Pain < 6 on VAS Non-pain Controls From Arendt-Nielsen et al, PAIN, 2010

23 Diminished CPM as a predictive tool? Prediction of future pain Prediction of analgesic efficacy Less efficient CPM predicts improved duloxetine efficacy.

24 Treating OA Pain: Exercise Exercise is the #1 recommended non-pharmacological treatment for patients with OA pain. A meta-analysis of clinical studies examining exercise induced pain reduction of knee joint OA reported: Similar pain reduction for aerobic, resistance, and performance exercise. Single-type exercise programs were more effective than programs with multiple exercise types. The effect of aerobic exercise on pain relief was better with supervised sessions (3 times a week). For resistance exercise more pain reduction occurred with quadriceps specific exercise than with lower limb exercise. - (Juhl et al, 2014, Arthritis & Rheumatology)

25 Treating OA Pain: Exercise Exercise is the #1 recommended non-pharmacological treatment for patients with OA pain. A meta-analysis of clinical studies examining exercise induced pain reduction of knee joint OA concluded: For best results, the exercise program should be supervised and carried out 3 times a week. Such programs have a similar effect regardless of patient characteristics, including radiographic severity and baseline pain. - (Juhl et al, 2014, Arthritis & Rheumatology)

26 OA Pain: Potential mechanisms Potential Contributors to Pain: Inflammatory mediators Mechanical factors Nerve damage So how doe exercise reduce OA pain? Dorsal Root Ganglia Peripheral Sensitization Hyperalgesia-enhanced pain response to noxious stimuli Allodynia pain response to non-noxious stimuli Facilitation Enhances pain Inhibition Diminishes pain Amplified Signal Central Sensitization

27 Exercise diminishes pain in animals with MIA-induced knee OA Rats are placed onto treadmills starting 10 days post-mia Exercise consisted of 30 min sessions 4 days/wk. Behavioral analysis of weight was performed weekly in the absence of exercise. % Weight (ipsi/contra*100) Weight Asymmetry **** **** Sedentary Exercise **** **, # **, # **** **** **** ### ### *** Exercise begins D10 post-injection BL ** Time Post-MIA (Days) ### ** The same exercise treatment produced reversal of MIA-induced tactile hypersensitivity and weight asymmetry

28 Exercise diminishes pain in animals with MIA-induced knee OA MIA Sedentary Rat 12 Rat 11 MIA Exercise Rat 3 Rat 2 BL D14 D21 patella D28 femur Radiographs indicate that exercise treatment reverses of MIA-induced pain without altering cartilage loss or joint pathology tibia Allen et al, 2017

29 Allen et al, 2017 Exercise diminishes pain in animals with MIA-induced knee OA Subchondral Bone Epiphyseal Plate Saline MIA/Sedentary MIA/Exercise Lateral Medial Lateral Medial Lateral Medial Metaphysis Trabecular Number (N/mm) Metaphysis Trabecular Number Sedentary Exercise Saline *** * MIA * Trabecular Spacing (mm) Metaphysis Trabecular Spacing ** Sedentary * Exercise Saline MIA Connection Density Metaphysis Connection Density Sedentary Exercise Saline *** * MIA ** CT indicates that exercise treatment protects from MIA-induced joint pathology

30 Treating OA Pain: Targeting Pain Modulation Endogenous opioids DRG + + Inhibition Inhibition Facilitation Facilitation Perhaps exercise is a way to alter the balance away from pain facilitation towards increased pain inhibition.

31 Treating OA Pain: Targeting Pain Modulation Endogenous opioids Inhibition Inhibition Facilitation Facilitation % Weight (ipsi/contra*100) Naloxone, an opioid antagonist, blocks the pain alleviating effects of exercise Weight Asymmetry ** ** DRG BL Sedentary Exercise Exercise/ Naloxone D35 Post-MIA Exercise induces increased endogenous opioidergic signaling

32 Exercise diminishes pain in animals with MIA-induced OA Difference score (s) (test-baseline) Conditioning Day D35 Post-MIA 0 Intra-articular Pain Relief Lidocaine Paired Chamber Sedentary Exercise Saline * MIA Pain Relief Paired Chamber Allen et al, 2017 Unpublished Male rats show pain relief after 4 weeks of treadmill exercise in the knee joint OA model. Female rats with TMJOA did not show full blockade of ongoing pain until after 9 weeks of exercise.

33 Free will-voluntary Exercise Exercise is top RECOMMENDED non-pharmacological therapy for OA patients. Most patients are not forced to exercise. What about voluntary exercise? Will pain diminish exercise?

34 MIA diminishes voluntary wheel running Speed (m/min) Weekly Average Running Speed During Peak 30 Min Saline-Low Saline-High MIA-Low MIA-High ** n=6 n=5 *** *** *** *** *** *** Speed (m/min) Post MIA Weekly Average Running Speed During Peak 30 Min * *** *** *** *** *** * Time (Weeks) 0 Pre MIA Time (Weeks) The rate of 16 m/min was the rate used in the treadmill studies. MIA treated rats were capable and willing to achieve this rate. MIA treated rats maintained peak rates of m/min for remaining 4 weeks of the study.

35 Voluntary Exercise Pairing Chamber Unpaired (Neutral) Pairing Chamber Weight Asymmetry (%L/R) MIA-induced Weight Asymmetry Weight Asymmetry ** *** * * *** *** MIA-High MIA-Low ** ** Exercise begins D10 post-injection BL Time Course (weeks) * ** Difference Scores (Test - Baseline) Intra-articular Ongoing Lidocaine Pain Induced CPP ** Low High Running Group

36 Voluntary Exercise MIA Low Runner MIA High Runner Contralateral Sedentary Low Runners High Runners 0.15 Metaphysis Bone Volume Fraction ** Contralateral Sedentary Low Runners High Runners 4.8 mg/60 ml MIA Metaphysis ** Trabecular Number 4.8 mg/60 ml MIA Contralateral Sedentary Low Runners High Runners Metaphysis * Trabecular Number Metaphysis ** Connection Density Contralateral Sedentary Low Runners High Runners mg/60 ml MIA Contralateral Sedentary Low Runners High Runners Contralateral Sedentary Low Runners High Runners 4.8 mg/60 ml MIA * ** Metaphysis Trabecular Spacing Contralateral Spacing (mm) 0.10 Connection Density Connection Density 0.20 Metaphysis Connection Density ** mg/60 ml MIA Sedentary Low Runners High Runners Metaphysis Trabecular Spacing Spacing (mm) Bone Volume (BV/TV) Bone Volume (BV/TV) Metaphysis Bone Volume Fraction Number (N/mm) MIA-Sedentary Number (N/mm) Contralateral ** 4.8 mg/60 Contralateral Sedentary Low Runners Runners mlhigh MIA mg/60 ml MIA 4.8 mg/60 ml MIA

37 Conclusions LO 1. Understand the relationship between joint pathology and clinical characteristics of OA pain There is evidence that joint pathology does not predict pain. We need to gain a better understanding of what does generate pain, including understanding of pathology that we have missed using radiographs Understanding sex differences in pain perception and modulation Psychosocial factors and how these may impact descending modulation.

38 Conclusions LO 2. Gain an understanding of how exercise modulates OA pain 1. Exercise has been found to be successful in alleviating OA pain in patients (mostly knee joint studies) and in animal studies. 2. Exercise can alleviate pain in load bearing and non-load bearing joints. 3. Exercise can diminish joint pathology evidence in knee joint 4. Exercise induced pain relief is through recruitment of pain inhibitory circuits in the brain and separate from effects on joint pathology.

39 COBRE Award (P20GM103643) PI: Ian Meng UNE Histology and Imaging Core Peter Carodonna, Core Manager Glenn Stevenson Microcomputed Tomography Services Lucy Laiw, PhD Core Director Terry Henderson, Core Manager Laboratory Manager Victoria Eaton Sebastien Sannajust Peter Morgane Research Fellows Joseph Heath Elizabeth Kim Alex Chasse Undergraduate Students Jeremy Gervais Andrew Elkinson Owen Peterson Colby Williams Meredith Walker Caitlyn Daly Chelsea Nation Ian Imbert GSBSE Graduate Student Joshua Havelin

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