The Impact of Centralized Pain on Acute and Chronic Post ......American College of Rheumatology (ACR) Criteria Final common pathway Part of a larger continuum Many somatic symptoms,

The Impact of Centralized Pain on Acute and Chronic

Post-surgical Pain Chad M. Brummett, M.D.Associate ProfessorDirector, Clinical Anesthesia ResearchDirector, Pain ResearchDepartment of AnesthesiologyDivision of Pain MedicineUniversity of Michigan Medical SchoolEmail: [email protected]: @drchadbhttp://medicine.umich.edu/dept/pain-researchwww.michigan-OPEN.org

mailto:[email protected]

http://medicine.umich.edu/dept/pain-research

http://www.michigan-open.org/

Funding and Disclosures• Funding

– 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

http://radforjieun.blogspot.com/2012/03/kellgren-lawrence-kl-score.html; Last accessed 10/30/13

Grade 1 Grade 2 Grade 3 Grade 4

Creamer P, Hochberg MC. Br J Rheumatol 1997;36

http://radforjieun.blogspot.com/2012/03/kellgren-lawrence-kl-score.html




Only ~50% of people with

Grade 3-4 OA reported pain





~10% of patients with no OA on radiographs report

pain


Persistent Pain After Knee and Hip Arthroplasty is Common

Wylde V et al, Pain 2011, 152: 566-572

32% 17%

Predictors of poor TKA & THA outcomes

9

Adjusted OR 1.3Adjusted OR 2.3-3.5

Adjusted OR 7-8.5 Adjusted OR 11.8-14.8

Depression Pain Problems in 1-2 Locations

Pain Problems in 3-4 Locations Pain Problems in ≥ 5 Locations

Wylde V, Pain 2011

Paradigm Shift in Fibromyalgia

Anterior Posterior

■ Discrete illness■ Focal areas of

tenderness■ Psychologic

and behavioralfactors nearlyalways present and negative

■ Chronic widespread pain

■ Tenderness in ≥11 of 18 tender points

American College of Rheumatology (ACR) Criteria

■ Final common pathway

■ Part of a larger continuum

■ Many somatic 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

CentralizedPain

PeripheralPain

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

CentralizedPain

Cohen SP, Raja SN. Anesthesiology 2007

PeripheralPain

“Fibromyalgia-ness”

Clauw DJ. JAMA 2014;311(5)Wolfe F, Clauw DJ, et al. J Rheum 2011;38

Brummett CM et al. Pain 2016, 157(6)

Symptom Severity Index(0-12)

CNS derived symptoms that accompany centralized pain

Widespread Pain Index(0-19)

Measures the numberof areas of chronic pain

Total fibromyalgia survey score combines the two and ranges from 0-31

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

Brummett CM et al. Anesthesiology 2013;119(6)

LOW MODERATE HIGH p-valuen = 170 n = 199 n = 147

Fibromyaglia Survey Score 0-4 5-8 9-31

Preoperative Pain PhenotypeSurgical Site Pain Severity (0-10) 4.28 (2.21) 4.72 (1.94) 5.61 (2.05) <0.00001Overall Body Pain Severity (0-10) 4.12 (2.06) 4.74 (1.83) 5.73 (1.96) <0.00001Duration of pain in surgical site (days) 1593 (1790) 1692 (2380) 1529 (1711) 0.76Neuropathic Pain ([-1]-[+38]) 7.74 (5.05) 8.98 (5.66) 12.6 (6.74) <0.00001Depressive Symptoms (0-21) 3.06 (2.22) 4.43 (2.62) 7.2 (3.89) <0.00001Anxiety Symptoms (0-21) 3.89 (2.81) 5.44 (3.1) 7.71 (4.19) <0.00001Catastrophizing (0-36) 2.52 (3.49) 4.15 (4.55) 9.11 (7.59) <0.00001Positive Affect (0-18) 1.96 (1.93) 3.17 (2.49) 5.62 (3.62) <0.00001

Medical PhenotypeBMI (kg/m2) 30.1 (10.8) 31.3 (5.72) 30.6 (6.2) 0.3ASA Status

ASA 1 5.4 4.0 4.2 0.3ASA 2 61.7 63.1 52.8ASA 3 32.3 32.8 43.0ASA 4 0.6 0.0 0.0

Preop home opioid use (% on opioids) 10 23.1 38.1 <0.00001Home opioid dose (24-hr OME) 1.19 (5.01) 6.69 (19.7) 27.2 (74.6) <0.00001







ASA 1 5.4 4.0 4.2 0.3ASA 2 61.7 63.1 52.8ASA 3 32.3 32.8 43.0ASA 4 0.6 0.0 0.0








ASA 1 5.4 4.0 4.2 0.3ASA 2 61.7 63.1 52.8ASA 3 32.3 32.8 43.0ASA 4 0.6 0.0 0.0








ASA 1 5.4 4.0 4.2 0.3ASA 2 61.7 63.1 52.8ASA 3 32.3 32.8 43.0ASA 4 0.6 0.0 0.0








ASA 1 5.4 4.0 4.2 0.3ASA 2 61.7 63.1 52.8ASA 3 32.3 32.8 43.0ASA 4 0.6 0.0 0.0





Duration of postoperative admission (days) 2.89 (0.95) 2.99 (0.89) 3.14 (0.983) 0.066PACU Opioid Consumption (OMEs) 30.6 (22.4) 31.1 (25.3) 46.8 (63.4) 0.0034Total Post-operative Opioid Consumption (OMEs) 175 (129) 221 (188) 381 (515) <0.00001

Opioid Consumption and Duration of Inpatient Admission by Tertile











Multivariate Model of Opioid Consumption

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

Brummett CM, et al. Anesthesiology 2013;119(6)


Estimate Std. Error t value Pr(>|t|)(Intercept) 312.82 54.23 5.77 <0.00001Age (Years) -4.53 0.77 -5.91 <0.00001Anesthesia- GA+Block -32.03 40.04 -0.80 0.42Anesthesia- GA+Neuraxial 3.37 23.69 0.14 0.89Anesthesia- Neuraxial -50.32 17.63 -2.85 0.0046TKA (vs. THA) 76.94 16.60 4.64 <0.00001Length of postoperative stay (Days) 37.17 8.64 4.30 0.00002Fibromyalgia survey score 7.49 2.06 3.63 0.00033

Patients using opioids preoperatively excluded from the model



Estimate Std. Error t value Pr(>|t|)(Intercept) 312.82 54.23 5.77 <0.00001Age (Years) -4.53 0.77 -5.91 <0.00001Anesthesia- GA+Block -32.03 40.04 -0.80 0.42Anesthesia- GA+Neuraxial 3.37 23.69 0.14 0.89Anesthesia- Neuraxial -50.32 17.63 -2.85 0.0046TKA (vs. THA) 76.94 16.60 4.64 <0.00001Length of postoperative stay (Days) 37.17 8.64 4.30 0.00002Fibromyalgia survey score 7.49 2.06 3.63 0.00033

Possible explanations:• Increased pain• Decreased responsiveness to opioids• Combination of both


The fibromyalgia survey score was also independently associated with increased opioid consumption after hysterectomy

Janda et al. Anesthesiology 2015; 122(5)

+

■ Substance P

■ Glutamate and EAA

■ Serotonin (5HT2a, 3a)

■ Nerve growth factor

■ Descending anti-nociceptive pathways

■ Norepinephrine-serotonin (5HT1a,b), dopamine

■ Opioids

■ GABA

■ Cannabanoids

Facilitation Inhibition

Many neurotransmitters influence CNS pain processing

and other co-morbid symptoms

From Dr. Daniel Clauw- With permission

Binding Potential (BP)

Occupancy and number of µ-opioid receptors influences BP

endogenous opioidscarfentanil

µ-opioid receptor

BP

Increased Release of Endogenous Opioids

Zubieta et al. Science 2001

BP

From Richard Harris, PhD- With permission

Fibromyalgia Patients Have Reduced MOR BP

*corrected Harris et al. JNeurosci 2007

Possible Explanations

endogenous opioidscarfentanil

µ-opioid receptor

Increased Release of Endogenous Opioids

Increased Pain

Increased PainI. Fewer ReceptorsII.

BP

BP

Baraniuk et al. BMC Musc Dis 2004From Richard Harris, PhD- With permission

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 PETCSF

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, functionBrummett CM et al. Unpublished data

PMH• Preop opioids• BMI• ASA status

Clinical Care• Surgery (Knee

vs Hip)• Primary

anesthetic

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 −0.25 0.044 <0.00001

Baseline WOMAC pain 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

Brummett CM et al. Pain 2016, 157(6)

Validation of a body map to assess widespread pain

Electronic Version of the Michigan Body Map (MBM)

Assessing pain severity together with widespread pain

GWAS of 2011 Fibromyalgia Survey Score does not reveal any significant associations

Brummett CM et al., unpublished dataData from the Michigan Genomics Initiative, www.michigangenomics.org

n = 26,749

http://www.michigangenomics.org

Heritability of the fibromyalgia survey score much higher in younger patients (<50)

Age Category

FM-Heritability(

%)

SE(%)

SampleSize

FM-Heritability(%)

SE(%) Sample Size

FM-Heritability (%)

SE (%) Sample Size

<=30 24.1 22.4 277322.9 13.3 5693

23.5 7.9 1020130 to 40 19.8 20.1 2920

40 to 50 13.4 15.1 450813.0 8.0 10091

50 to 60 9.1 11.3 6486

8.6 5.3 1580460 to 70 7.5 11.5 62477.3 8.1 9318

70 to 80 4.5 18.1 3071

Brummett CM et al., unpublished dataData from the Michigan Genomics Initiative, www.michigangenomics.org

http://www.michigangenomics.org

Need to broaden our phenotyping and sensory testing

49

Childhood traumaNon-Noxious Stimuli

Possible candidate for TKA

Proceed with intervention

Obtain additional information or consider other therapies

High fibromyalgiascore

Low fibromyalgiascore

■ Pharmacological therapies to improve

symptoms

■ Increased Distress■ Decreased activity■ Isolation■ Poor sleep■ Maladaptive illness behaviors

■ Nociceptive processes (damage or inflammation of tissues)

■ Disordered sensory processing

Clauw and Crofford. Best Pract Res Clin Rheumatol. 2003;17

Symptoms of Pain, Fatigue, etc.

Functional Consequences of Symptoms

Dually FocusedTreatment

■ Nonpharmacological therapies to address dysfunction

80mg more OME during first 48

be an adjusted 5 times less likely to

Phenotype-Medical history-Medications-Questionnaires

Thanks to Team Pain!

54

Thank You and “Go Blue”

55

Documents

The Impact of Centralized Pain on Acute and Chronic Post ......American College of Rheumatology (ACR) Criteria Final common pathway Part of a larger continuum Many somatic symptoms,