The Impact of Centralized Pain on Acute and Chronic Post-surgical Pain

The Impact of Centralized Pain on Acute and Chronic Post-surgical Pain Chad M. Brummett, M.D. Associate Professor Director, Clinical Anesthesia Research Director, Pain Research Department of Anesthesiology Division of Pain Medicine University of Michigan Medical School Email: cbrummet@med.umich.edu Twitter: @drchadb http://medicine.umich.edu/dept/pain-research www.michigan-open.org

Funding Funding and Disclosures NIAMS/NIH: R01 AR060392; P50 AR070600 NIDA/NIH: R01 DA038261; R01 DA042859 Michigan Department of Health and Human Services SAMHSA Michigan Genomics Initiative Department of Anesthesiology Neuros Medical, Inc Disclosures Patent for the use of peripheral perineural dexmedetomidine alone and in combination with local anesthetics. Application number 12/791,506; Issue Date 4/2/13; Patent Number 8410140 Consultant- Recro Pharma

Projected Rates of Primary Arthroplasty Kurtz S. et.al. J Bone Joint Surg 2007:89:780-785

There is substantial discordance between the degree of OA on radiograph and reported pain Grade 1 Grade 2 Grade 3 Grade 4 http://radforjieun.blogspot.com/2012/03/kellgren-lawrence-kl-score.html; Last accessed 10/30/13 Creamer P, Hochberg MC. Br J Rheumatol 1997;36

Grade 1 Grade 2 Grade 3 Grade 4 Only ~50% of people with Grade 3-4 OA reported pain http://radforjieun.blogspot.com/2012/03/kellgren-lawrence-kl-score.html; Last accessed 10/30/13 Creamer P, Hochberg MC. Br J Rheumatol 1997;36

Grade 1 Grade 2 Grade 3 Grade 4 ~10% of patients with no OA on radiographs report pain http://radforjieun.blogspot.com/2012/03/kellgren-lawrence-kl-score.html; Last accessed 10/30/13 Creamer P, Hochberg MC. Br J Rheumatol 1997;36

Persistent Pain After Knee and Hip Arthroplasty is Common 32% 17% Wylde V et al, Pain 2011, 152: 566-572

Predictors of poor TKA & THA outcomes Depression Pain Problems in 1-2 Locations Adjusted OR 1.3 Pain Problems in 3-4 Locations Adjusted OR 2.3-3.5 Pain Problems in 5 Locations 9 Adjusted OR 7-8.5 Adjusted OR 11.8-14.8 Wylde V, Pain 2011

Paradigm Shift in Fibromyalgia American College of Rheumatology (ACR) Criteria Discrete illness Focal areas of tenderness Psychologic and behavioral factors nearly always present and negative Anterior Posterior Final common Chronic pathway widespread pain Part of a larger Tenderness continuum in 11 of 18 tender Many somatic points symptoms, diffuse tenderness Psychologic and behavioral factors play roles in some individuals From Dr. Daniel Clauw- With permission

Differentiating pain that is more centralized could provide a mechanistic rationale for interventions Peripheral Pain Centralized Pain

Differentiating pain that is more centralized could provide a mechanistic rationale for interventions Peripheral Pain Centralized Pain Cohen SP, Raja SN. Anesthesiology 2007

Fibromyalgia-ness Symptom Severity Index (0-12) CNS derived symptoms that accompany centralized pain Total fibromyalgia survey score combines the two and ranges from 0-31 Widespread Pain Index (0-19) Measures the number of areas of chronic pain Clauw DJ. JAMA 2014;311(5) Wolfe F, Clauw DJ, et al. J Rheum 2011;38 Brummett CM et al. Pain 2016, 157(6)

Hypothesis #1: Higher fibromyalgia survey scores would independently predict increased opioid consumption in the acute postoperative period following TKA and THA.

Distribution of fibromyalgia survey scores in TKA/THA cohort

Fibromyalgia Survey Score Low Moderate High

Higher FM scores was associated with a worse preoperative pain phenotype LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA 1 5.4 4.0 4.2 0.3 ASA 2 61.7 63.1 52.8 ASA 3 32.3 32.8 43.0 ASA 4 0.6 0.0 0.0 Preop home opioid use (% on opioids) 10 23.1 38.1 <0.00001 Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) <0.00001 Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) <0.00001 Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) <0.00001 Duration of pain in surgical site (days) 1593 (1790) 1692 (2380) 1529 (1711) 0.76 Neuropathic Pain ([-1]-[+38]) 7.74 (5.05) 8.98 (5.66) 12.6 (6.74) <0.00001 Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) <0.00001 Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) <0.00001 Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) <0.00001 Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Higher FM scores was associated with a worse preoperative pain phenotype LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA 1 5.4 4.0 4.2 0.3 ASA 2 61.7 63.1 52.8 ASA 3 32.3 32.8 43.0 ASA 4 0.6 0.0 0.0 Preop home opioid use (% on opioids) 10 23.1 38.1 <0.00001 Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) <0.00001 Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) <0.00001 Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) <0.00001 Duration of pain in surgical site (days) 1593 (1790) 1692 (2380) 1529 (1711) 0.76 Neuropathic Pain ([-1]-[+38]) 7.74 (5.05) 8.98 (5.66) 12.6 (6.74) <0.00001 Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) <0.00001 Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) <0.00001 Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) <0.00001 Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Higher FM scores was associated with a worse preoperative pain phenotype LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA 1 5.4 4.0 4.2 0.3 ASA 2 61.7 63.1 52.8 ASA 3 32.3 32.8 43.0 ASA 4 0.6 0.0 0.0 Preop home opioid use (% on opioids) 10 23.1 38.1 <0.00001 Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) <0.00001 Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) <0.00001 Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) <0.00001 Duration of pain in surgical site (days) 1593 (1790) 1692 (2380) 1529 (1711) 0.76 Neuropathic Pain ([-1]-[+38]) 7.74 (5.05) 8.98 (5.66) 12.6 (6.74) <0.00001 Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) <0.00001 Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) <0.00001 Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) <0.00001 Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Higher FM scores was associated with a worse preoperative pain phenotype LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA 1 5.4 4.0 4.2 0.3 ASA 2 61.7 63.1 52.8 ASA 3 32.3 32.8 43.0 ASA 4 0.6 0.0 0.0 Preop home opioid use (% on opioids) 10 23.1 38.1 <0.00001 Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) <0.00001 Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) <0.00001 Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) <0.00001 Duration of pain in surgical site (days) 1593 (1790) 1692 (2380) 1529 (1711) 0.76 Neuropathic Pain ([-1]-[+38]) 7.74 (5.05) 8.98 (5.66) 12.6 (6.74) <0.00001 Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) <0.00001 Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) <0.00001 Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) <0.00001 Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Higher FM scores was associated with a worse preoperative pain phenotype LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA 1 5.4 4.0 4.2 0.3 ASA 2 61.7 63.1 52.8 ASA 3 32.3 32.8 43.0 ASA 4 0.6 0.0 0.0 Preop home opioid use (% on opioids) 10 23.1 38.1 <0.00001 Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) <0.00001 Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) <0.00001 Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) <0.00001 Duration of pain in surgical site (days) 1593 (1790) 1692 (2380) 1529 (1711) 0.76 Neuropathic Pain ([-1]-[+38]) 7.74 (5.05) 8.98 (5.66) 12.6 (6.74) <0.00001 Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) <0.00001 Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) <0.00001 Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) <0.00001 Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Opioid Consumption and Duration of Inpatient Admission by Tertile LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Duration of postoperative admission (days) 2.89 (0.95) 2.99 (0.89) 3.14 (0.983) 0.066 PACU Opioid Consumption (OMEs) 30.6 (22.4) 31.1 (25.3) 46.8 (63.4) 0.0034 Total Post-operative Opioid Consumption (OMEs) 175 (129) 221 (188) 381 (515) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Opioid Consumption and Duration of Inpatient Admission by Tertile LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Duration of postoperative admission (days) 2.89 (0.95) 2.99 (0.89) 3.14 (0.983) 0.066 PACU Opioid Consumption (OMEs) 30.6 (22.4) 31.1 (25.3) 46.8 (63.4) 0.0034 Total Post-operative Opioid Consumption (OMEs) 175 (129) 221 (188) 381 (515) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Opioid Consumption and Duration of Inpatient Admission by Tertile LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score 0-4 5-8 9-31 Duration of postoperative admission (days) 2.89 (0.95) 2.99 (0.89) 3.14 (0.983) 0.066 PACU Opioid Consumption (OMEs) 30.6 (22.4) 31.1 (25.3) 46.8 (63.4) 0.0034 Total Post-operative Opioid Consumption (OMEs) 175 (129) 221 (188) 381 (515) <0.00001 Brummett CM et al. Anesthesiology 2013;119(6)

Multivariate Model of Opioid Consumption Estimate Std. Error t value Pr(> t ) (Intercept) 393.17 71.29 5.51 <0.00001 Age (Years) -6.86 0.99-6.90 <0.00001 Preoperative opioid use (OMEs) 3.30 0.26 12.51 <0.00001 Anesthesia- GA+Block -78.61 52.53-1.50 0.14 Anesthesia- GA+Neuraxial -55.51 32.34-1.72 0.087 Anesthesia- Neuraxial -71.72 24.18-2.97 0.0032 TKA (vs. THA) 78.94 22.58 3.50 0.00051 Length of postoperative stay (Days) 64.85 11.88 5.46 <0.00001 Fibromyalgia survey score 9.09 2.57 3.54 0.00044 Brummett CM, et al. Anesthesiology 2013;119(6)

Multivariate Model of Opioid Consumption Estimate Std. Error t value Pr(> t ) (Intercept) 312.82 54.23 5.77 <0.00001 Age (Years) -4.53 0.77-5.91 <0.00001 Anesthesia- GA+Block -32.03 40.04-0.80 0.42 Anesthesia- GA+Neuraxial 3.37 23.69 0.14 0.89 Anesthesia- Neuraxial -50.32 17.63-2.85 0.0046 TKA (vs. THA) 76.94 16.60 4.64 <0.00001 Length of postoperative stay (Days) 37.17 8.64 4.30 0.00002 Fibromyalgia survey score 7.49 2.06 3.63 0.00033 Patients using opioids preoperatively excluded from the model Brummett CM, et al. Anesthesiology 2013;119(6)

Multivariate Model of Opioid Consumption Estimate Std. Error t value Pr(> t ) (Intercept) 312.82 54.23 5.77 <0.00001 Age (Years) -4.53 0.77-5.91 <0.00001 Anesthesia- GA+Block -32.03 40.04-0.80 0.42 Anesthesia- GA+Neuraxial 3.37 23.69 0.14 0.89 Anesthesia- Neuraxial -50.32 17.63-2.85 0.0046 TKA (vs. THA) 76.94 16.60 4.64 <0.00001 Length of postoperative stay (Days) 37.17 8.64 4.30 0.00002 Fibromyalgia survey score 7.49 2.06 3.63 0.00033 Possible explanations: Increased pain Decreased responsiveness to opioids Combination of both Brummett CM, et al. Anesthesiology 2013;119(6)

The fibromyalgia survey score was also independently associated with increased opioid consumption after hysterectomy Janda et al. Anesthesiology 2015; 122(5)

Many neurotransmitters influence CNS pain processing and other co-morbid symptoms Facilitation Substance P Glutamate and EAA Serotonin (5HT 2a, 3a ) Nerve growth factor + Inhibition Descending antinociceptive pathways Norepinephrineserotonin (5HT 1a,b ), dopamine Opioids GABA Cannabanoids From Dr. Daniel Clauw- With permission

Binding Potential (BP) Occupancy and number of µ-opioid receptors influences BP Increased Release of Endogenous Opioids µ-opioid receptor endogenous opioids carfentanil BP BP From Richard Harris, PhD- With permission Zubieta et al. Science 2001

Fibromyalgia Patients Have Reduced MOR BP *corrected Harris et al. JNeurosci 2007

Possible Explanations µ-opioid receptor endogenous opioids carfentanil I. Increased Pain II. Fewer Receptors Increased Release of Endogenous Opioids BP BP From Richard Harris, PhD- With permission Increased Pain Baraniuk et al. BMC Musc Dis 2004

Our new study will assess preop functional connectivity (fmri), mu-opioid binding availability (PET) and CSF endogenous opioids prior to TKA to assess centralized pain mechanisms fmri PET CSF NIDA/NIH: R01 DA038261

Hypothesis #2: Higher fibromyalgia survey scores would independently predict less change in pain and lower patient global impression of change 6 months after TKA and THA.

Covariates Included in Modeling 6-Month Outcomes Demographics Age Sex Ethnicity Race Pain Phenotype Fibromyalgia score Overall body pain Surgical site pain Neuropathic pain score Depression Anxiety Catastrophizing WOMAC pain, stiffness, function PMH Preop opioids BMI ASA status Clinical Care Surgery (Knee vs Hip) Primary anesthetic Brummett CM et al. Unpublished data

The fibromyalgia survey score independently predicted poorer long term knee/hip pain outcomes (WOMAC) Variable Estimate SE P (Intercept) 1.46 0.46 0.0015 Fibromyalgia survey score Baseline WOMAC pain 0.25 0.044 <0.00001 0.92 0.042 <0.00001 THA (vs. TKA) 1.96 0.27 <0.00001 Brummett et al. Arthritis & Rheumatology, 67: 1386 1394. 2015

FM also predictive of less change in overall body pain Brummett et al. Arthritis & Rheumatology 2015, 67

Patient A Patient B Patient C

80mg more OME during first 48 be an adjusted 5 times less likely to

Can we differentiate different forms of centralized pain? Top Down Functional Somatic Syndromes Bottom Up Central Sensitization

Validation of a body map to assess widespread pain Brummett CM et al. Pain 2016, 157(6)

Electronic Assessing Version pain severity of the Michigan together with Body widespread Map (MBM) pain

GWAS of 2011 Fibromyalgia Survey Score does not reveal any significant associations n = 26,749 Brummett CM et al., unpublished data Data from the Michigan Genomics Initiative, www.michigangenomics.org

Heritability of the fibromyalgia survey score much higher in younger patients (<50) Age Category FM- Heritability( %) SE(% ) Sample Size FM- Heritability(%) SE(%) Sample Size FM-Heritability (%) SE (%) Sample Size <=30 24.1 22.4 2773 30 to 40 19.8 20.1 2920 22.9 13.3 5693 23.5 7.9 10201 40 to 50 13.4 15.1 4508 50 to 60 9.1 11.3 6486 60 to 70 7.5 11.5 6247 70 to 80 4.5 18.1 3071 13.0 8.0 10091 7.3 8.1 9318 8.6 5.3 15804 Brummett CM et al., unpublished data Data from the Michigan Genomics Initiative, www.michigangenomics.org

Need to broaden our phenotyping and sensory testing 49 Childhood trauma Non-Noxious Stimuli

High fibromyalgia score Possible candidate for TKA Obtain additional information or consider other therapies Low fibromyalgia score Proceed with intervention

Symptoms of Pain, Fatigue, etc. Nociceptive processes (damage or inflammation of tissues) Disordered sensory processing Dually Focused Treatment Functional Consequences of Symptoms Increased Distress Decreased activity Isolation Poor sleep Maladaptive illness behaviors Pharmacological therapies to improve symptoms Nonpharmacological therapies to address dysfunction Clauw and Crofford. Best Pract Res Clin Rheumatol. 2003;17

80mg more OME during first 48 be an adjusted 5 times less likely to

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