Dr. Mike Allan and Betsy Thomas

Taking the Pain Out of Osteoarthritis Pain Management

Methods

• Umbrella review of systematic reviews of RCTs

• Start with 1757 studies

• 235 studies included

• meta-analysis was infrequently reported so we ended up analyzing RCTs.

Can Fam Physician 2020;66(3)

Interventions

• Acetaminophen

• Oral NSAIDs

• Topical NSAIDs

• Serotonin and norepinephrine reuptake inhibitors (SNRI)

• Tricyclic antidepressants (TCAs)

• Cannabinoids

• Exercise

• Counselling

• Platelet-rich plasma (PRP)

• Viscosupplementation

• Glucosamine

• Chondroitin

• Intra-articular corticosteroids

• Rubefacients

• Opioids

Pain Outcomes: Change in Scale

• On a 0-10 point scale: Baseline ~6/10. - Placebo reduces Pain: ~1.4- Treatment: ~2.0

Placebo

Treatment

BMJ. 2013 May 3;346:f2690

How do these numbers work?

2.5 7.55 10

7.54.5 6

40%

60%

Placebo

Treatment

Clinically Meaningful Change

Who gets 30% better

4

Move 1.4

Move 2.0

0

Responder Outcomes

• Focus was RCTs that included responder outcomes for pain

• Pain prioritized over function because:• Function is rarely reported while pain is almost always reported

• Pain often the presenting issue in primary care offices

• Chose dichotomous outcomes versus Standard Mean Difference

• Created a hierarchy of responder outcomes which included (but not limited to):• OMERACT-OARSI response

• % improvement on a pain scale that is closest to 30% improvement

• Change of at least 1 on a 10- or 11- point VAS

BMJ open. 2019 Sep 24;9(9):e030060..

Meta-Analysis

• Completed for each intervention overall• i.e. Proportion of patients who achieved meaningful pain improvement

compared to placebo/control

• Subgroup analysis completed (where possible):• Size of trial (<150 patients vs > 150 patients)

• Funding (industry or clearly publicly funded)

• Duration (≤4 weeks, >4 to <12 weeks and ≥12 weeks)

RCTs we found and Limitations

Intervention RCTs Found

RCTs withResponder

Of Those with a Responder Analysis: Meet all Criteria>150 Patients >8 weeks Publicly Funded

Exercise 237 11 (5%) 5 10 11 5 (2%)

Steroid Injections 32 7 (22%) 1 7 3 0

Duloxetine 6 6 (100%) 6 6 0 0

Oral NSAIDs 115 43 (37%) 42 23 1 1 (1%)

Glucosamine 31 9 (29%) 4 7 3 3 (10%)

Topical NSAID 30 22 (73%) 15 8 0 0

Chondroitin 19 9 (47%) 4 9 1 1 (5%)

Viscosupplementation 166 31 (19%) 17 26 1 1 (1%)

Opioids (Oral) 32 15 (47%) 12 9 0 0

Acetaminophen 10 2 (20%) 2 1 0 0

Total 649 155 (24%) 108 106 20 11 (2%)

And now the results….

• In order of efficacy…..drum roll please….

Exercise

• 11 RCTs (1367 pts) followed 6-104 wks

• Results• Attained meaningful pain relief: 47% vs 21%, NNT=4• Most common type of exercise was physiotherapy-guided exercise programs

• Note: Benefit seen regardless of size or length of trial

Clinical Pearls:

Does not matter what type of exercise –just get moving!

Intra-articular Corticosteroids

• 7 RCTs (706 patients), 4 to 24 weeks

• Results:• Attained meaningful pain relief: 50% vs 31%, NNT=6

• Concerns:• Studies ≥12 weeks: no difference from placebo

• Industry funded trial was NSS

Clinical Pearls:

• Choice of steroid does not matter (eg.methylprednisolone, triamcinolone)

• Risk of joint infection rare – 1 in >14,0001

• Unclear if erodes cartilage

1. Tools for Practice #135 March 2015

SNRIs (Duloxetine)

• 6 RCTs (2060 patients), 10 to 18 weeks

• Results:• Attained meaningful pain relief: 64% vs 43%, NNT=5

• Most common dose was 60-120mg qd

• Concerns:• All industry funded trials

Clinical Pearls:

• Doses studied were mostly 60-120mg qd1

• Adverse events1: overall (NNH 6), withdrawal (NNH 17), GI (NNH 4)

• Cost: ~$110 for 90d supply (60mg) –covered on most plans

1. TFP Duloxetine and OA. In Press.

Oral NSAIDs• 43 RCTs (27,657 patients), 4 to 104 weeks

• Results• Attained meaningful pain relief 57% vs 39%, NNT=6

• Note: Both COX-2 inhibitors and traditional NSAIDs effective

• Concerns• One publicly funded trial showed smaller benefit

Clinical Pearls:

• COX-2 inhibitors and traditional NSAIDs, except naproxen, may increase the risk of major vascular events and death. 1

• naproxen or low- dose ibuprofen possibly preferred for patients at risk of CV disease1.

Tools for Practice #101 Jan 2018.

Glucosamine

• 9 RCTs (1643 patients), 4 to 156 weeks

• Results: • Attained meaningful pain relief: 47% vs 37%, NNT=11

• Concerns• Publicly funded trials found

no benefit vs placebo

Glucosamine (Allocation Concealment)

Osteoarthritis Cartilage. 2010; 18(4):476-99. Cochrane 2005; (2):CD002946.

Topical NSAIDs• 22 RCTs (7265 patients), 1 to 12 weeks

• Results• Attained meaningful pain relief: 61% vs 47%, NNT=8

• Concerns:• All industry funded trials

• Effect size smaller with larger (≥150 patients) and longer (≥12 weeks) trials, but still statistically significant

Clinical Pearls:

• Lack evidence to recommend one formulation over another (gels/creams)1

• Withdrawals for adverse effects similar toplacebo1

Tools for Practice #40 February 2015

Viscosupplementation(hyaluronic acid)

• 31 RCTs (6254 patients), 2 to 160 weeks

• Results: • Attained meaningful pain relief: 53% vs 44%, NNT=11

• Concerns:• One publicly funded RCT: no benefit

• Effect size lower in larger (≥150 patients) trials, but still statistically significant

Neurology® 2015;84:794–802. JAMA. 2008 Mar 5;299(9):1016-7.

Viscosupplementation(hyaluronic acid)

Other Research

Viscosupplementation(hyaluronic acid)

• So why do we see some difference in Practice?????

Bannuru RR, Schmid CH, Kent DM, et al. Ann Intern Med. 2015; 162:46-54.Neurology® 2015;84:794–802. JAMA. 2008 Mar 5;299(9):1016-7.

Expensive MattersParkinsons: Motor Symptom score change, All Stat diff,Levodopa 14, expensive placebo 8, cheap placebo 4Pain: High cost = better mean pain↓ ~12mm

85% high cost got better vs 61% discounted

Placebo Matters but Injections Matter More!Remember that Placebo effect is 1.4 out of 10 and ~40% will report meaningful improvementIntra-articular placebo vs oral placebo: Effect size 0.29 (0.04-0.54). Some better still.

Chondroitin

• 9 RCTs (2477 patients), 12 to 48 weeks

• Results:• Attained meaningful pain relief: 57% vs 45%, NNT=9

• Concerns• Publicly funded trials did not show a benefit vs placebo

Chondroitin

High Quality

Low Quality

Others also found that the certainty of benefit for Chondroitin was Low

Opioids

• 15 RCTs (6266 pts), 1.5 - 24 weeks

• Results• Attained meaningful pain relief: 47% vs 43%, NNT=32

• Concerns:• All industry funded trials

Do

Opioids

• Good to 4 weeks but not beyond

• Opioids do not work more than placebo for “Chronic Pain” in Osteoarthritis

Acetaminophen

• 2 RCTs (991 patients), 6-24 weeks

• Results: • No difference between acetaminophen and placebo

• Concerns• All industry funded trials

Clinical Pearls:

• No difference in overall AE or serious AE• Increases the risk of elevated liver

enzymes (>1.5x normal)1, NNH=21, 7% vs 2%

1. Tools for Practice #171 September 2016

Other Interventions

• Rubefacients: 1 RCT found (113 patients) • Capsaicin 0.025% no difference from placebo at 4, 8 or 12 weeks

• No responder analysis found for:

Tricyclic Antidepressants

Platelet-rich Plasma Injections

Cannabinoids Counselling

Summarizing the InterventionsTreatment Type RCTs Intervention Control NNT Time Frame

(Weeks)Evidence Certainty

Rate Ratio

Exercise 11 47% 21% 4 6 - 104 Low 2.4 (1.8-3.1)

Steroid Injections 8 50% 31% 6 4 - 24 Very Low 1.7 (1.2-2.6)

Duloxetine 6 64% 43% 5 10 - 18 Moderate 1.5 (1.3-1.9)

Oral NSAIDs 43 57% 39% 6 4 - 104 Moderate 1.44 (1.36-1.5)

Topical NSAIDs 22 61% 47% 8 1 - 12 Low 1.3 (1.2-1.4)

Glucosamine 9 47% 37% 11 4 to 156 Very Low 1.3 (1.0-1.7)

Chondroitin 9 57% 45% 9 12 - 48 Moderate 1.3 (1.1-1.4)

Viscosupplementation 31 53% 44% 11 2 - 160 Very Low 1.2 (1.1-1.3)

Opioids (Oral) 15 47% 43% 32 1.5 - 24 Very Low 1.2 (1.0-1.3)

Acetaminophen 2 47% 43% NSS 6 - 24 Low 1.2 (0.8-1.6)

Do Patients & Clinicians See the Same Things?

Are we speaking the same language?

Description EU Assigned

Meaning

Very Common >10%

Common 1-10%

Uncommon 0.1-1%

Rare 0.01 – 0.1%

Very Rare <0.01%

Lancet 2002; 359: 853–54

Are we speaking the same language?

Description EU Assigned

Meaning

Patients Perceived Chance

Very Common >10% 65%

Common 1-10% 45%

Uncommon 0.1-1% 18%

Rare 0.01 – 0.1% 8%

Very Rare <0.01% 2%

Lancet 2002; 359: 853–54

Shared Informed Decisions: Do Patients Want It?

• Results vary but 27-55% of population wants1

• Factors1

• presenting problem (more for procedures)

• age (more if younger)

• gender (more if female)

• social class/education (more if more)

• “some patients clearly gain reassurance from the medical profession adopting the politically incorrect paternalistic approach.”• Example: ~62% preferred doctors' opinion over any presentation (pictures or

numbers) for CVD interventions1b

1) BMJ 2000;321:867-71, Med Care 2000;38:335-41, Ann Fam Med 2011;9:121-127. Patient Education and Counseling 2011doi:10.1016/j.pec.2011.02.004 2) BMJ 2000;320:58

What do Decision-Aids Accomplish?Time: 8 minutes less to 23 minutes longer (median 2.5 minutes longer)

Usual care Decision Aid Studies (patients)

Knowledge score: from 0 (none) - 100 (perfect)

57% 70% 42 studies (10,842 patients)

Proportion who Understand Risk

30% 54% 19 studies (5868 patients)

Congruence between choice and values

32% 50% 13 studies (4670 patients)

Decisional conflict (<25 decisions made; >38 delayed decision)

13-49 7 lower 22 studies (4343 patients)

Decision made by Practitioner

17% 10% 14 studies (3234 patients)

Cochrane Database Syst Rev. 2014 Jan 28;1:CD001431.

Either of these methods are pretty good

RRR had worse understanding of risk vs ARR BUT more perceived risk with RRR

NNT not helpful: Hard to understand

Systematic Rev: 91 studiesAnn Intern Med. 2014;161:270-280.

Review of methods for promoting shared informed decision-making

• 91 studies

• Visual aids (icon arrays and bar graphs) improved understanding and satisfaction.

• Absolute risk > RRR for maximizing accuracy • But RRR more likely to get people to accept therapy.

• NNT reduces understanding.

Ann Intern Med. 2014;161:270-280.

PEER Decision Aid for Osteoarthritis

Can Fam Physician 2020;66(3):191-3.