1

When Acute Pain

Becomes Chronic – What

Do We Know and How

Can We Prevent It?

Sean Mackey, M.D.,Ph.D.

Chief – Pain Management Division Stanford University

Department of Anesthesia

Division of Pain Management http://paincenter.stanford.edu

http://anesthesia.stanford.edu

smackey@stanford.edu

Disclosures – funding sources National Institutes of Neurological Diseases and

Syndromes (NINDS)

R01 NS053961

National Institute of Diabetes and Digestive and Kidney

Diseases (NIDDK)

U01 DK082316

National Institutes of Drug Abuse (NIDA)

K24 DA029262

R21 DA026092

K23 DA25152 (Carroll)

Dodie and John Rosekrans Pain Research Endowment

Chris Redlich Pain Research Endowment

Overview

Impact of acute pain transitioning to chronic pain

Focus on low back pain and postsurgical pain

Mechanisms and factors that predict the transition from acute pain to chronic pain

Tools to prevent the transition

2

Impact of the Transition

from Acute to Chronic Pain

Low Back Pain and Perioperative Pain

as Models

Low Back Pain: Epidemiology 60%–90% lifetime prevalence

Second most common complaint

to prompt a medical evaluation

Leading cause of long-term work

disability

Estimated US direct and indirect costs: $30-50 billion/year

Disability and costs related to

pain, not to the disease process

Natural history non specific low

back pain (NSLBP)

80% of patients with first episode NSLBP will recover in 1 month

10% recover within 3 months

10% go on to CHRONIC PAIN

Recurrence rates high (5-80%) depending on study

Garcy P, Mayer T, Gatchel RJ, Spine 1996; 21(8):952-959

Rossignol M, Suissa S, Abenhaim L, Spine 1992;17(9):1043-1047

Von Korff M, Saunders K, Spine 1996;21:2833-2837

Nordin, et al. Proceedings of the 10th World Congress on Pain, Vol 24

3

Post Surgical Chronic Pain Thirty-four million Americans

undergo surgery each year.

Post operative chronic pain is

defined as pain that lasts longer

than 3 -6 months and is different in

quality and or location from pain

prior to surgery.

On average 10% of postsurgical

patients will develop chronic pain.

DeFrances, C.J. and M.N. Podgornik, 2004 National Hospital Discharge Survey. Advance Data from

Vital & Health Statistics of the National Center for Health Statistics, 2006(371): p. 1-19.

Persistent Postoperative Pain Thoracotomy: 30-60%*

Inguinal Hernia Repair: 6-11%1,2

Extremity Amputations: 30-80%

Cardiac Surgery

Caesarean section: 12% Additional 11% had discomfort or

abdominal skin sensitivity

Breast Surgery, especially with

dissection: 50%

Spinal Surgery

Orthopedic Surgery

Gallbladder surgery: 3-56%

Hysterectomy

Nephrectomy: 24%

Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. May 13 2006;367(9522):1618-

1625.*Maguire MF, Ravenscroft A, Beggs D, Duffy JP. A questionnaire study investigating the prevalence of the neuropathic

component of chronic pain after thoracic surgery. European Journal of Cardio-Thoracic Surgery. May 2006;29(5):800-805. 1.

Aasvang EK. Bay-Nielsen M. Kehlet H. Pain and functional impairment 6 years after inguinal herniorrhaphy.Hernia. 10(4):316-21,

2006 Aug 2. Nienhuijs S, et al. Chronic Pain after Mesh Repair: a systemic review. The American Journal of Surgery 194 (2007)

394–400

How many of your surgeons consent

their patients for the possibility of

chronic pain?

4

Factors and Biomarkers that

Predict the Transition from Acute

to Chronic Pain

Transition from Acute to Chronic Low

Back Pain In prospective longitudinal studies,

catastrophizing and fear were associated with

increased risk of chronic back pain one year after

acute low back injury.

Catastrophizing over seven times more powerful

than any other predictor in predicting transition

from acute to chronic pain.

Pain-related fear causes patients with pain to

over-predict the severity of pain they will

experience. This leads to over-production of

avoidance behavior Burton, A.K., et al., Psychosocial predictors of outcome in acute and subchronic low back trouble. Spine, 1995. 20(6): p. 722-8.

Swinkels-Meewisse, I.E., et al., Fear of movement/(re)injury predicting chronic disabling low back pain: a prospective inception

cohort study. Spine, 2006. 31(6): p. 658-64.

McCracken, L.M., et al., Prediction of pain in patients with chronic low back pain: effects of inaccurate prediction and pain-related

anxiety. Behav Res Ther, 1993. 31(7): p. 647-52.

Effects of Depression and Anxiety 30-65% of patients with chronic pain have co-morbid depression, often with

anxiety

Longitudinal epidemiologic studies determine that patients with depression

and anxiety are between 2-5 times more likely to have a new chronic pain

problem at follow-up from 1 to 8 years later.

Patients with depression appear to be less sensitive to pain in response to

experimental noxious stimuli compared to healthy controls.

Suggests that depression and possibly anxiety may elevate the risk of

chronic pain by altering pain persistence rather than by altering pain

thresholds or pain severity.

1. Croft, P.R., et al., Psychologic distress and low back pain. Evidence from a prospective study in the general population. Spine, 1995. 20(24): p. 2731-2737.

2. Hotopf, M., et al., Temporal relationships between physical symptoms and psychiatric disorder. Results from a national birth cohort . The British journal of

psychiatry, 1998. 173: p. 255-261.

3. Currie, S.R. and J. Wang, More data on major depression as an antecedent risk factor for first onset of chronic back pain. Psychol Med, 2005. 35(9): p. 1275-82.

4. Carroll, L.J., J.D. Cassidy, and P. Côté, Depression as a risk factor for onset of an episode of troublesome neck and low back pain. Pain, 2004. 107(1-2): p.

134-139.

5. Von Korff, M., L. Le Resche, and S.F. Dworkin, First onset of common pain symptoms: a prospective study of depression as a risk factor. Pain, 1993. 55(2): p.

251-258.

6. Magni, G., et al., Prospective study on the relationship between depressive symptoms and chronic musculoskeletal pain. Pain, 1994. 56(3): p. 289-297.

7. Dworkin, R.H., W.C. Clark, and J.D. Lipsitz, Pain responsivity in major depression and bipolar disorder. Psychiatry Res, 1995. 56(2): p. 173-81.

5

Factor Predicting Postsurgical

Chronic Pain

Few studies have explored multiple

psychological and physiological factors that

influence a patients’ post-operative pain

course.

Even fewer studies addressed how these

factors contribute to the patients post

operative pain resolution and opioid and

analgesic cessation.

Factors Predicting Chronic Pain

Acute pain experience predicts chronic pain:

True for herpes zoster and postherpectic neuralgia

True for thoracotomy, hernia repair, and most surgical procedures

Nerve damaging operations are at greater risk for chronic pain

Extent of surgically induced nerve damage doesn’t correlate well with chronic pain

Postsurgical Chronic Pain 625 patients, mixed surgical procedure.

Many variables collected

At 6 months, patients with high levels of pain on postop day #4 and surgery longer than 3 hours: More pain

More functional restrictions

Poor “global recovery”

Worse quality of life

Preoperative fear of surgery negatively associated with more pain, poor global recovery, and worse quality of life 6 months later.

Optimism was associated with better recovery and higher quality of life.

Peters ML, et al, Somatic and psychologic predictors of long-term unfavorable outcome

after surgical intervention. Annals of Surgery. 245(3):487-94, 2007

6

Longitudinal Study to Characterize Post-

Surgical Pain Persistence

Table C1: Patient Characteristics (n=77)

Characteristic Mean Range

Age 59 18 - 85

Beck Depression Inventory Score 9.6 0 - 54

Fear of Pain Score 70 14 - 134

Anxiety Sensitivity Index Score 35.4 3 - 98

SOAPP 13.6 4 - 41

Gender (percent male) 26%

Positive PTSD symptomatology 21%

Pre - operative Opiate Use 20%

History of Unprescribed Opioid Use 9%

Surgery Type Number

Thoracotomy 20

Total Hip Replacement 15

Total Knee Replacement 15

Radical Mastectomy 17

Lumpectomy 10

Table C3: Multivariate Analysis of Factors Promoting Delayed Pain Resolution

Characteristic Hazard Ratio P - Value Positive PTSD Symptoms 0.35 0.04

Pain Severity: Post Operative Day 1 0.85 0.04 Self - Perceived Risk of Addiction 0.41 0.05

Beck Depression Inventory Score 0.99 0.97

Carroll, Mackey in revision

The Transition from Acute to

Chronic Pain

Every Surgical Procedure

Cuts nerves

Cuts tissues

Induces the injury response

Alters peripheral and central nervous system pain

processing

Can cause chronic pain

Note: Similarly, most chronic low back pain starts with

an acute pain episode

7

Peripheral vs Central Mechanisms of

Neuropathic Pain: Experimental Effects

Peripheral Effects Central Effects

• Ectopic and spontaneous

discharge

• Nonsynaptic conduction

• Alterations in ion channel

expression

• Collateral sprouting of primary

afferent neurons

• Sprouting of sympathetic neurons

in dorsal root ganglion

• Nociceptor sensitization

• Neurogenic inflammation

• Central sensitization

• Spinal reorganization

• Cortical reorganization

• Changes in inhibitory

pathways

• Changes in glial cell

functioning

1. Reprinted with permission from M. Lotze, MD. Inst of Medical Psychology & Behavioral Neurobiology, Univ. of Tübingen, Germany. Lotze M, et al. Brain. 2001;124(pt 11):2268-2277.

Right arm amputation below elbow Lip pursing and phantom limb pain (PLP):

Face Hand

Upper Arm

patients without PLP

patients with PLP

healthy controls

1.

Individual Differences in Pain

8

Factors relevant to pain perception

Cognition: attention, distraction,

hypervigilance, catastrophizing,

re-appraisal, hypnotic suggestion Mood: depression, anxiety,

catastrophizing, emotional context

Genetics

Injury: peripheral and central

sensitization

Chemical and structural:

atrophy and

opioidergic / dopaminergic dysfunction?

Context: beliefs, expectations,

placebo

Nociception

Pain

Individual Differences –

Thermal Pain Sensitivity 500 healthy volunteers

49ºC stimulus

Gender, OPRD1 polymorphism, personality

temperment primary determinants of pain sensitivity

Kim H, et al, Pain 2004

Individual differences in the

subjective experience of pain Compared high vs low

sensitivity subjects

High sensitivity → more activation

Caudal and perigenual ACC

Primary somatosensory cortex

Prefrontal cortex

Reprinted with permission from the National Academy of Sciences, USA: Coghill RC, et al. Proc Natl Acad Sci USA. 2003;100(14):8538-8542.

9

Pain - Fear and Anxiety

Individual’s anxiety about, and fear of, painful sensations

predicts physical complaints and treatment outcomes in

patients with chronic pain (McCraken, 1998, 1999)

Patients high in anxiety more likely to develop post-

herpetic neuralgia (Dworkin, 1992)

Preop gababentin improves functional recovery after knee

surgery, AND decreases anxiety (Menigaux C, Anesth

and Analg, 2005)

Psychological construct? But why? What are the

neurophysiological underpinnings?

Individual difference in pain – Effects of fear of pain

Right Lateral Orbitofrontal Cortex Right Lateral orbital frontal activation may reflect attempts by fearful individuals to evaluate and/or regulate possible responses to painful stimuli

Ochsner KN, et al. Pain. 2006;120(1-2):69-77.

Lateral Orbitofrontal Cortex

-0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0

50 60 70 80 90 100 110

Fear of Pain Questionnaire Ratings

Para

mete

r E

stim

ate

s

r=0.912

Individual difference in pain – effects of somatic anxiety

Medial Prefrontal Gyrus: involved in self-focused elaboration of the negative personal implications of pain that may characterize individuals high in anxiety sensitivity

Ochsner KN, et al. Pain. 2006;120(1-2):69-77.

Anxiety State Inventory Ratings

Medial Prefrontal Cortex

r=.890

1.5

1

0.5

0

-0.5

-1

-1.5

10 20 30 40

Para

mete

r E

stim

ate

s

Medial Prefrontal Gyrus

10

Tools to Prevent the Transition

from Acute to Chronic Pain

Everything mentioned is off-label

Gabapentanoids – Should we add

this to the drinking water?

Gabapentanoids – Gabapentin and Pregabalin Meta-analyses and systemic review: Helpful for postop pain.

Hurley RW, et al Reg Anesth Pain Med 2006.

Ho K-Y. Gan TJ. Habib AS. Pain. 126(1-3):91-101, 2006.

600 – 1200 mg preop decreases pain and/or opioid requirements: breast, hysterectomy, chole, spine, thyroid, nephrectomy, knee, tonsillectomy Menigaux et al Anesthesia & Analgesia 2005;

Turan et al Anesthesia & Analgesia 2005;

Pandey et al Can J Anaesthesia 2004;

Dirks et al Anesthesiology 2002,

Al-Mujadi H et al. Can J Anaesth 2005

Makes epidural analgesia work better Turan A et al Br J Anaesth 2006

Works pre/post incision nephrectomy Pandey CK et al Can J Aneasth 2005

Combined with COX-2 Inhibitor works better than either separately Gilron I et al Pain 2005

Two weeks of perioperative pregabalin reduces neuropathic pain at 3 and 6 months (0%, 0%) compared to placebo (8.7%, 5.2%) after TKA Buvanendran et al Anesthesia and Analgesia 2010

11

Is gabapentin working entirely as a

pain med?

Gabapentin has also been shown to reduce

anxiety in a variety of circumstances including

pre-operative anxiety

Menigaux, C., et al., Preoperative Gabapentin Decreases Anxiety and Improves Early Functional

Recovery from Knee Surgery. 2005. p. 1394-1399.

de-Paris, F., et al., Effects of gabapentin on anxiety induced by simulated public speaking. J

Psychopharmacol, 2003. 17(2): p. 184-8.

Mula, M., S. Pini, and G.B. Cassano, The role of anticonvulsant drugs in anxiety disorders: a critical

review of the evidence. J Clin Psychopharmacol, 2007. 27(3): p. 263-72

Perioperative Ketamine

Ketamine: dose before incision, low dose infusion during the surgical procedure Subanesthetic dosing

Infrequent adverse effects

Review: “Ketamine in subanesthetic dose (that is a dose which is below that required to produce anesthesia) is effective in reducing morphine requirements in the first 24 hours after surgery. Ketamine also reduces postoperative nausea and vomiting. Adverse effects are mild or absent.” Bell RF, et al.

Acta Anaesthesiologica Scandinavica Volume 49 Issue 10 Page 1405-1428, November 2005

Post-surgical residual pain:

Effect of subanesthetic IV ketamine

0

5

10

15

20

25

30

35

40

45

Placebo Ketamine (0.5mg/kg

load+0.25mg/kg/hr infusion)

% o

f pa

tien

ts

with

res

idu

al p

ain

2 weeks postop

1 month postop

6 months postop

De Kock M, Lavand'homme P, Waterloos H, Pain 92 (2001) 373-380

100 patients for rectal

adenocarcinoma resection

5 groups compared:

placebo, 2 doses IV

ketamine, 2 doses

epidural ketamine

Presurgical thoracic

epidural continued

through perioperative

period

12

Perioperative ketamine does not prevent

chronic pain after thoracotomy 86 patients randomized to perioperative

IV ketamine (1mg/kg at the induction, 1mg/kg h1 during surgery, then 1mg/kg

during 24 h)

IV saline

Battery of tests to assess pain at 1-2wks, 1m and 4m after surgery

No differences between ketamine and saline groups

C. Dualé et al. / European Journal of Pain 13 (2009) 497–505

1 month 4 months

A Comparison of Gabapentin and Ketamine in

Acute and Chronic Pain After Hysterectomy

60 patients randomized to:

Ketamine – 0.3mg/kg IV bolus and 0.05mg/kg/hr infusion until

end of surgery, PO placebo

Gabapentin – PO1200mg, IV saline

Oral placebo, IV saline

Assessed 1, 3 and 6m after surgery

Postop pain decreased in gabapentin group

compared with ketamine and saline

Reduced opioids in gabapentin and ketamine

Incidence of incisional pain reduced at 1, 3, and

6m in gabapentin group Sen, H., et al., Anesth Analg, 2009. 109(5): p. 1645-50

Perioperative Multimodal Analgesia Minimally invasive surgery along with:

Neural Blockade or other local anesthetic

NSAID/COX-2 Inhibitor/Acetaminophen/Steroid

Gabapentin/Pregabalin

NMDA antagonist

Mexiletine

Clonidine

Recovery/rehabilitation plan

Together, these interventions can reduce immediate post-op pain,

facilitate recovery, and possibly reduce chronic pain

Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. May 13 2006;367(9522):1618-1625. Straube S, et al.

Effect of preoperative Cox-II-selective NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized studies. Acta

Anaesthesiologica Scandinavica. May 2005;49(5):601-613. Tiippana EM, et al. Do surgical patients benefit from perioperative gabapentin/pregabalin?

A systematic review of efficacy and safety. Anesthesia & Analgesia. of contents, 2007 Jun 2007;104(6):1545-1556

13

Summary Most chronic pain started with an acute pain event

We are creating an epidemic of chronic pain with our surgeries

Factors have been identified to predict the transition of acute to

chronic pain in postsurgical patients and LBP

Preoperative and immediate postop pain

Fear, anxiety, depression, catastrophizing, PTSD

Exaggerated response to experimental pain stimuli

Tantalizing data that some anti-neuropathics, Coxibs, and

regional anesthesia may reduce this transition

We may learn much about the transition from acute to chronic

postsurgical pain by applying research from other chronic pain

conditions

Much more research needed.

Stanford Systems Neuroscience and Pain Lab (SNAPL) • Faculty

• Sean Mackey, MD, PhD

• Ian Carroll, MD, MS

• Jarred Younger, PhD

• Research Fellows

• Paul Nash, PhD

• Heather Chapin, PhD

• Kevin Johnson, PhD

• Jiang-Ti Kong, MD

• Elizabeth Stringer, PhD

• Lab Manager

• Rebecca McCue

• Research Assistants

• Epifanio Bagarinao, PhD

• Noorulain Noor

• Rachel Moericke

• Debra Clay, RN

• Laura Jastrzab, MS

• Hoameng Ung

• Graduate Students

• Justin Brown

• Administration

• Andrew Morrow

• Matthew Chen

• Undergraduate Student Research Assistants

• Juan-Carlos Foust

• J.C. Lopez

• Stephen Matzat

• Laura Pulido

• Gabriella Ruchelli

• Daniel Schwarz