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

• No financial conflicts of interest to disclose. 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 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? Joint Pain

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

In the US, arthritis is a leading cause of disability;

• ~52.5 million (22.7%) adults in 2010–2012

• 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, 2002–2014. Barbour et al. –CDC October 7, 2016 Projected Increase

Obesity Population Growth

Wang et al, Lancet 2011

Osteoarthritis is the most common form of arthritis Arthritis

Hip Hand 8% 4% 2.9 million

Knee 16% 4.3 million 60+ yrs

Feet 2% Osteoarthritis is the most Data from CDC common form of arthritis Osteoarthritis

Hip Hand 8% 4% 2.9 million

Knee 16% 4.3 million

Feet 2% • Women are more likely to have OA Data from CDC • Woman report more severe OA Osteoarthritis

• Other risk factors include: • Joint injury ⁻ trans-articular fracture ⁻ meniscal tear requiring meniscectomy ⁻ anterior cruciate ligament injury

• Repetitive use of joints at work Osteoarthritis

Radiographic OA Symptomatic OA • Focal and progressive loss of the • Pain that worsens during activity hyaline cartilage and gets better during rest. • Muscle spasms and contractions • Radiographic changes include joint in the tendons. space narrowing, osteophytes, and bony sclerosis • A grating sensation with joint use

Degree of pathology observed on radiograph does not correspond to symptomatic OA 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 • There are currently no treatments available to patients for modifying the underlying disease. Lesion • Current treatments focus on pain relief. 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. OA Pain: Potential mechanisms

Potential Contributors to Pain: NSAIDs, steroids • Inflammatory mediators Joint splints • Mechanical factors or braces, • Nerve damage Duloxetine

• Not all patients receive Descending adequate pain relief. Facilitation Enhances pain • All have side effects. Descending Amplified Inhibition Signal Dorsal Root Diminishes pain Ganglia

Peripheral Sensitization Central Hyperalgesia-enhanced pain Sensitization response to noxious stimuli Allodynia–pain response to non-noxious stimuli Rat Model of Advanced OA Pain-Males Okun et al, Pain, 2012

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Duloxetine Intra-articular Saline injections (30 mg/kg, i.p.)

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D W 0 -50 B L 1 .0 4 .8 1.0 1.0 4.8 Females Males Males M IA (m g /6 0  l) Concentration MIA (mg/ml) • 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. OA Pain: Descending Modulation

Hypothesis: An important component Enhanced and underlying chronic pain is a change in Chronic Pain descending pain modulation resulting in net pain facilitation.

Amplified Signal Descending Inhibition Descending Facilitation DRG ++ OA Pain: Central Sensitization

• Clinical studies demonstrated signs of increased pain sensitization in OA patients Descending reporting moderate to severe pain. Inhibition Descending Pain > 6 on VAS Pain < 6 on VAS Facilitation Non-pain controls

DRG ++

Graphs from: Arendt-Nielsen, et al. PAIN: 2010, 573–581 Increased Temporal Summation OA Pain: Central Sensitization

• Clinical studies demonstrated signs of increased pain sensitization in OA patients Descending reporting moderate to severe pain. Inhibition Descending Facilitation

DRG ++ From: Expanded Distribution of Pain as a Sign of Central Sensitization in Individuals With Symptomatic Knee Osteoarthritis Phys Ther. 2016;96(8):1196-1207. doi:10.2522/ptj.20150492 Advanced Osteoarthritis Pain: Descending Facilitation

RVM Lidocaine (-11.00 AP from bregma; 8.5 DV from skull)

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Consistent with observations that patients with more severe pain ratings develop central sensitization. OA Pain: Descending Modulation

• Clinical studies indicate that there is impaired pain inhibition in chronic pain Descending patients including OA patients. Inhibition Descending Facilitation

DRG ++ OA Pain: Descending Modulation

• Clinical studies indicate that there is impaired pain inhibition in chronic pain Descending patients including OA patients. Inhibition Descending Facilitation CPM Hyperalgesia

DRG ++

Pain > 6 Pain < 6 Non-pain on VAS on VAS Controls

From Arendt-Nielsen et al, PAIN, 2010 Diminished CPM as a predictive tool?

Prediction of future pain

Prediction of analgesic efficacy

Less efficient CPM predicts improved duloxetine efficacy. 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) 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) OA Pain: Potential mechanisms

Potential Contributors to Pain: • Inflammatory mediators • Mechanical factors • Nerve damage

So how doe exercise Descending reduce OA pain? Facilitation Enhances pain Descending Amplified Inhibition Signal Dorsal Root Diminishes pain Ganglia

Peripheral Sensitization Central Hyperalgesia-enhanced pain Sensitization response to noxious stimuli Allodynia–pain response to non-noxious stimuli Exercise diminishes pain in animals with MIA-induced knee OA

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Endogenous opioids

Descending Descending Inhibition Facilitation DRG ++ Descending Descending Inhibition Facilitation

Perhaps exercise is a way to alter the balance away from pain facilitation towards increased pain inhibition. Treating OA Pain: Targeting Pain Modulation

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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? MIA diminishes voluntary wheel running

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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. 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. 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 Fin