The Impact of Centralized Pain on Acute and Chronic Post-surgical Pain
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1 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
2 Funding Funding and Disclosures NIAMS/NIH: R01 AR060392; P50 AR NIDA/NIH: R01 DA038261; R01 DA 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 Consultant- Recro Pharma
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4 Projected Rates of Primary Arthroplasty Kurtz S. et.al. J Bone Joint Surg 2007:89:
5 There is substantial discordance between the degree of OA on radiograph and reported pain Grade 1 Grade 2 Grade 3 Grade 4 Last accessed 10/30/13 Creamer P, Hochberg MC. Br J Rheumatol 1997;36
6 Grade 1 Grade 2 Grade 3 Grade 4 Only ~50% of people with Grade 3-4 OA reported pain Last accessed 10/30/13 Creamer P, Hochberg MC. Br J Rheumatol 1997;36
7 Grade 1 Grade 2 Grade 3 Grade 4 ~10% of patients with no OA on radiographs report pain Last accessed 10/30/13 Creamer P, Hochberg MC. Br J Rheumatol 1997;36
8 Persistent Pain After Knee and Hip Arthroplasty is Common 32% 17% Wylde V et al, Pain 2011, 152:
9 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 Pain Problems in 5 Locations 9 Adjusted OR Adjusted OR Wylde V, Pain 2011
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13 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
14 Differentiating pain that is more centralized could provide a mechanistic rationale for interventions Peripheral Pain Centralized Pain
15 Differentiating pain that is more centralized could provide a mechanistic rationale for interventions Peripheral Pain Centralized Pain Cohen SP, Raja SN. Anesthesiology 2007
16 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)
17 Hypothesis #1: Higher fibromyalgia survey scores would independently predict increased opioid consumption in the acute postoperative period following TKA and THA.
18 Distribution of fibromyalgia survey scores in TKA/THA cohort
19 Fibromyalgia Survey Score Low Moderate High
20 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 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA ASA ASA ASA Preop home opioid use (% on opioids) < Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) < Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) < Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) < 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) < Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) < Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) < Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) < Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) < Brummett CM et al. Anesthesiology 2013;119(6)
21 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 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA ASA ASA ASA Preop home opioid use (% on opioids) < Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) < Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) < Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) < 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) < Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) < Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) < Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) < Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) < Brummett CM et al. Anesthesiology 2013;119(6)
22 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 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA ASA ASA ASA Preop home opioid use (% on opioids) < Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) < Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) < Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) < 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) < Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) < Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) < Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) < Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) < Brummett CM et al. Anesthesiology 2013;119(6)
23 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 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA ASA ASA ASA Preop home opioid use (% on opioids) < Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) < Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) < Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) < 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) < Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) < Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) < Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) < Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) < Brummett CM et al. Anesthesiology 2013;119(6)
24 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 Medical Phenotype BMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3 ASA Status ASA ASA ASA ASA Preop home opioid use (% on opioids) < Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) < Preoperative Pain Phenotype Surgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) < Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) < 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) < Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) < Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) < Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) < Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) < Brummett CM et al. Anesthesiology 2013;119(6)
25 Opioid Consumption and Duration of Inpatient Admission by Tertile LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score Duration of postoperative admission (days) 2.89 (0.95) 2.99 (0.89) 3.14 (0.983) PACU Opioid Consumption (OMEs) 30.6 (22.4) 31.1 (25.3) 46.8 (63.4) Total Post-operative Opioid Consumption (OMEs) 175 (129) 221 (188) 381 (515) < Brummett CM et al. Anesthesiology 2013;119(6)
26 Opioid Consumption and Duration of Inpatient Admission by Tertile LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score Duration of postoperative admission (days) 2.89 (0.95) 2.99 (0.89) 3.14 (0.983) PACU Opioid Consumption (OMEs) 30.6 (22.4) 31.1 (25.3) 46.8 (63.4) Total Post-operative Opioid Consumption (OMEs) 175 (129) 221 (188) 381 (515) < Brummett CM et al. Anesthesiology 2013;119(6)
27 Opioid Consumption and Duration of Inpatient Admission by Tertile LOW MODERATE HIGH p-value n = 170 n = 199 n = 147 Fibromyaglia Survey Score Duration of postoperative admission (days) 2.89 (0.95) 2.99 (0.89) 3.14 (0.983) PACU Opioid Consumption (OMEs) 30.6 (22.4) 31.1 (25.3) 46.8 (63.4) Total Post-operative Opioid Consumption (OMEs) 175 (129) 221 (188) 381 (515) < Brummett CM et al. Anesthesiology 2013;119(6)
28 Multivariate Model of Opioid Consumption Estimate Std. Error t value Pr(> t ) (Intercept) < Age (Years) < Preoperative opioid use (OMEs) < Anesthesia- GA+Block Anesthesia- GA+Neuraxial Anesthesia- Neuraxial TKA (vs. THA) Length of postoperative stay (Days) < Fibromyalgia survey score Brummett CM, et al. Anesthesiology 2013;119(6)
29 Multivariate Model of Opioid Consumption Estimate Std. Error t value Pr(> t ) (Intercept) < Age (Years) < Anesthesia- GA+Block Anesthesia- GA+Neuraxial Anesthesia- Neuraxial TKA (vs. THA) < Length of postoperative stay (Days) Fibromyalgia survey score Patients using opioids preoperatively excluded from the model Brummett CM, et al. Anesthesiology 2013;119(6)
30 Multivariate Model of Opioid Consumption Estimate Std. Error t value Pr(> t ) (Intercept) < Age (Years) < Anesthesia- GA+Block Anesthesia- GA+Neuraxial Anesthesia- Neuraxial TKA (vs. THA) < Length of postoperative stay (Days) Fibromyalgia survey score Possible explanations: Increased pain Decreased responsiveness to opioids Combination of both Brummett CM, et al. Anesthesiology 2013;119(6)
31 The fibromyalgia survey score was also independently associated with increased opioid consumption after hysterectomy Janda et al. Anesthesiology 2015; 122(5)
32 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
33 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
34 Fibromyalgia Patients Have Reduced MOR BP *corrected Harris et al. JNeurosci 2007
35 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
36 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
37 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.
38 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
39 The fibromyalgia survey score independently predicted poorer long term knee/hip pain outcomes (WOMAC) Variable Estimate SE P (Intercept) Fibromyalgia survey score Baseline WOMAC pain < < THA (vs. TKA) < Brummett et al. Arthritis & Rheumatology, 67:
40 FM also predictive of less change in overall body pain Brummett et al. Arthritis & Rheumatology 2015, 67
41 Patient A Patient B Patient C
42 80mg more OME during first 48 be an adjusted 5 times less likely to
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44 Can we differentiate different forms of centralized pain? Top Down Functional Somatic Syndromes Bottom Up Central Sensitization
45 Validation of a body map to assess widespread pain Brummett CM et al. Pain 2016, 157(6)
46 Electronic Assessing Version pain severity of the Michigan together with Body widespread Map (MBM) pain
47 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,
48 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 <= to to to to to Brummett CM et al., unpublished data Data from the Michigan Genomics Initiative,
49 Need to broaden our phenotyping and sensory testing 49 Childhood trauma Non-Noxious Stimuli
50 High fibromyalgia score Possible candidate for TKA Obtain additional information or consider other therapies Low fibromyalgia score Proceed with intervention
51 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
52 80mg more OME during first 48 be an adjusted 5 times less likely to
53 Phenotype -Medical history -Medications -Questionnaires
54 54 Thanks to Team Pain!
55 55 Thank You and Go Blue
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