Transitions from Acute to Chronic Pain

Chronic Post-surgical Pain An Important yet largely unrecognized clinical problem! 1,2

– Defined as pain and pain disability persisting more than 3 months after surgery

– May be associated with a definable nerve injury (Type-II complex regional pain syndrome) 2o to transection , retraction or inflammatory compression.

– May be associated with ongoing peripheral inflammation and sensitization

– May be associated with central sensitization and remodeling within spinal cord.

– Patients generally complain of increased noxious sensitivity

1.Leykin Y, et al. Expert Rev Neurother. 2007;7:533-45.2. Perkins FM, Kehlet H. Anesthesiology. 2000;93:1123-1133.

Acute ChronicDistinct onset1

Most severe within first 24 hours2 Persistent pain

Obvious cause1 Injury, disease, surgical procedure (post-operative pain)

Result of chronic disease2 Osteoarthritis, neuropathic pain, cancer related, chronic headache, chronic low back pain, fibromyalgia

Short duration2 < 1 month

Longer duration1 Persisting >3 months Beyond normal healing

Intensity indicates severity of injury or disease1

Prolonged functional impairment Physical and psychological1

May be easier to manage More difficult to manage1

Differences Between Acute and Chronic Pain

1. Ferrell BA. Acute and chronic pain. In: Cassell CK, et al. Geriatric Medicine: An Evidence Based Approach. 4th ed. New York, NY: Spring-Verlag New York, Inc.; 2003.

Chronic Postoperative Pain and Disability

ProcedureEstimated

incidence ofchronic pain

Estimated incidence of

chronic severe (disabling) painb

Number of surgeries in the United Statesa

Amputation 30-50% 5-10% 159,000Coronary artery bypass surgery 30-50% 5-10% 598,000

Thoracotomy 30-40% 10% UnknownBreast surgery(lumpectomy or mastectomy)

20-30% 5-10% 479,000

Cesarean section 10% 4% 220,000Inguinal hernia repair 10% 2-4% 609,000aNational Center for Health Statistics, United States of America, 1996.b>5 out of 10 pain scores.Kehlet H, et al. Lancet. 2006;367:1618-1625.

Temporal Differences in Postoperative Pain

Very Severe Pain

Severe Pain

Moderate Pain

Pain Intensity

No Pain

Mild Pain

Interventional

Potent IV Opioids

Oral Opioids

Non- Opioids

Progressive reductions in pain Intensity and analgesic requirement over a period of several weeks

None

Analgesic Requirements

Time

Transitions from Acute to Persistent Pain

Very Severe

Severe

Moderate

Mild

Decreasing Intensity

Postoperative Pain Increasing Intensity

None

Time

Peripheral and CentralPlasticity changes

Hyperalgesia,Central Sensitization

Patient Specific Risk Factors For Persistent

Diatchenko L, et al. Hum Mol Genet. 2005;14:135-143; Katz J, et al. Pain. 2005;119:16-25; Mogil JS, et al. Proc Natl Acad Sci USA. 2003;100:4867-4872; Poobalan AS, et al. Clin J Pain. 2003;19:48-54.

GeneticPredisposition

More intense inflammatory and neural regenerative responses (HLA, COMT), Variable responses to analgesics

GenderWomen generally

report higher levels of post operative pain

AgeOlder patients have reduced risk of chronic postherniorrhaphy and amputation pain

Hyperalgesia: Mechanisms that Increase Pain

Primary Hyperalgesia (Peripheral Sensitization): Inflammatory responses at the injury site increase pain sensitivity

Secondary Hyperalgesia (Central sensitization): Inflammatory responses and altered connectivity in the CNS increase pain sensitivity at sites adjacent to the injury

Normal ResponseHyperalgesia

Increasing Stimulus Intensity

Incr

easi

ng D

isco

mfo

rt

Allodynia

Hanley MA, et al. Disabil Rehabil. 2004;26:882-893; Katz J, et al. Clin J Pain. 1996;12:50-55;Katz J, et al. Pain. 2005;119:16-25; Perkins FM, Kehlet H. Anesthesiology. 2000;93:1123-1133;Reuben SS, Buvanendran A. J Bone Joint Surg Am. 2007;89:1343-1358.

Operative Procedures

Surgeries associated with

risks of nerve damage

Psychological Vulnerability

AnxietyDepression

Catastrophising

Severe Pain

Analgesic undermedication or

poor acute pain management

Preceding Pain

P1 month prior tp surgery

Severity of Post-Operative Acute Pain Was Associated With Development of Chronic Pain

*Chronic pain assessed 6 months to 3.5 years post-surgeryPluijms et al. Acta Anaesthesiol Scand. 2006;50:804-808.

Long term evaluation of thoracotomy patients (N=149) who developed chronic pain after surgery* vs those who did not reported:

More patients reported severe acute pain: 67% vs 40% (P = 0.0001)Duration of severe acute pain was more prolonged (P = 0.02)

Hyperalgesia: Mechanisms that Increase Acute Pain Intensity and Development of Persistent Pain

Increased pain sensitivity at the site of injury.

Increased pain sensitivity at sites adjacent to the site of injury

Related to peripheral inflammatory responses

Related to enhanced sensitivity and altered connectivity in the spinal cord and brainstem

Secondary Hyperalgesia

Primary Hyperalgesia:

Pain Sequencing

Adapted from Woolf and Salter, Science 2000; 288: 1765

Central Sensitization

Peripheral Sensitization

NMDA Activation and “wind- up”

Altered generegulation

Cell deathAlteredconnectivity

Persistent Pathological Pain

Neuronal Modification and Long Term Potentiation

Seconds

Minutes

Hours to Days

3 Months to Years

Nociceptor Activation

Acute Tissue Injury

Primary mediators (PGE) Milliseconds

Why do Some Patients Develop Chronic Pain Following Acute Injuries?

1. Neurons cannot replace themselves.

2. Injured neurons dedifferentiate into embyonic like cells, distal segments die off, and axonal sprouts attempt to regenerate

3. These vigorous plasticity changes can lead to neuroma formation, spontaneous firing and altered connections in the CNS.

In many post surgical settings- analgesic undermedication and severe pain can initiate similar plasticity responses, that can permanently facilitate noxious transmission!

Primary Hyperalgesia: Nociceptor Sensitization

Ca++

Ca++

Damaged or Sensitized Nociceptor

Acute InjuryPGE, sP, CGRP,bradykinin, Serotonin,histamine

TRPV-1

TRPV-1

Persistent InjuryMacrophage and Lymphocyte responses, Cytokines, Norepinephrine, NGF

Activated Nociceptor

Kappa Receptors

Macrophage

Secondary Hyperalgesia: Central Sensitization

Acute Pain

High intensity stimulation

Hyperexcitable WDRdorsal horn neuron (EPSPs)

Sensitized nociceptor

High thresholdmechanoreceptor

Modified from: Woolf C: Textbook of Pain 4th Edition 1999, Wall and Melzack;Churchill Livingstone, New York: 451, (WDR- Wide Dynamic Range Neuron, EPSPs- Excitatory Post-Synaptic Potentials)

Sensitized WDRNeuron (Windup)

Convalescent Pain

Chronic Pain Altered WDR Neuron (Transcription dependent plasticity)

Glial Activation

Inhibitory CellActivated nociceptor

Sensitized nociceptor

Persistent Glial Reactivity

Surgical Strategies That Reduce

• Utilize techniques that reduce risks of damage to major nerves– Laproscopic vs open herniorrhaphy– Preservation of the intercostal branchial nerve during

mastectomy– Minimally invasive or muscle-sparing thoracoscopic

techniques

Benedetti F, et al. J Thorac Cardiovasc Surg. 1998;115:841-847.Grant AM, et al. Br J Surg. 2004;91:1570-1574.Perkins FM, Kehlet H. Anesthesiology. 2000;93:1123-1133.

Pharmacological Strategies That Reduce Persistent Postsurgical Pain

1. Significant reductions noted with pre-emptive initiation, and aggressive maintenance of multimodal analgesia

2. Effectiveness reported with: Neural blockade Neuraxial analgesia NSAID/Coxibs Ketamine Pregabalin No benefits with oral/IV opioids!

Brennan TJ, Kehlet H. Anesthesiology. 2005;103:681-683., Kehlet H, et al. Lancet. 2006;367:1618-1625., Perkins FM, Kehlet H. Anesthesiology. 2000;93:1123-1133.

Reduction in Chronic Pain Following Amputation

25 Patients undergoing below knee amputation were randomized to 2 groups:1. General anesthesia with IV opioids for postop pain (n=11).2. Epidural neural blockade (Bupiv & Morphine) initiated 72 hrs prior to surgery and maintained for postop pain (n=14).

Bach S, Noreng MF, Tjellden NU: Phantom limb pain during the first 12 months following limb amputation, Pain 33:297-301, 1988

0

2.5

5.0

7.5

10.0

7 Days 6 Months 12 Months

EpiduralIV Opioids

Severe Phantom Limb Pain

# Patients

Preop Neural Blockade Reduced Acute Pain Intensity and Development of Chronic Pain

• 60 patients undergoing breast surgery were randomized to receive a preincisional paravertebral block (n=30) or sham block (n=30)

• Patients receiving PVB reported significantly less acute pain vs sham block in the first 2 weeks postsurgery (P<0.05)

• Effective control of acute pain resulted in lower prevalence of chronic neuropathic pain at six and 12 months following surgery

Kairaluoma et al. Anesth Analg. 2006;103:703-708.

The Role of Prostaglandins in Pain Perception: An Overview

Peripheral Role

Tissue Injury

Release of Arachadonic Acid

Prostaglandin Synthesis

Nociceptor Activation

“Peripheral Sensitization”(Primary Hyperalgesia)

Central Role(CNS)

Intense and ProlongedNoxious

Transmission

NMDA Activation, Ca++ Flux,“Central Sensitization”

(Secondary Hyperalgesia)

Up-regulation COX & NOS

Prostaglandin Synthesis

“Long-Term Potentiation”Neural & Glial Remodeling

Cytokines, IL-1B

Acute Pain

COX-2

ChronicPain Copyright

R. Sinatra MD2002

Methods Advocated to Prevent Persistent Post-surgical Pain

1. Avoid surgery in patients or medical conditionsassociated with higher risk

2. Modify surgical technique (Laparoscopic or Robotic)

3. Aggressive preemptive and multimodal therapy(Reduce peripheral inflammation and 1o Hyperalgesia)

4. Administer anti-neuropathic analgesics and NMDA Antagonists (Reduce central sensitization and plasticity Changes)

Surgical techniques with reduced risk of

– Laparoscopic herniorrhaphy– Preservation of the intercostal brachial nerve

during mastectomy– Minimally invasive or muscle-sparing

thoracoscopic techniques

Benedetti F, et al. J Thorac Cardiovasc Surg. 1998;115:841-847.Grant AM, et al. Br J Surg. 2004;91:1570-1574.Perkins FM, Kehlet H. Anesthesiology. 2000;93:1123-1133.

Anoci-Association (1913)1

Aggressive Preventive Analgesia (2001)2,3

1. Crile GW. The kinetic theory of shock and its prevention through anoci-association (shockless operation). Lancet. 1913;185:7-16 2. Gottschalk A & Smith D. Am Fam Physician. 2001;63(10):1979-85, 3.Woolf CJ & Chong MS. Anesth Analg. 1993;77:362-79.

Reduce or prevent central sensitization and wound hypersensitivity

“Need to block inflammation, pain transmission and spinal sensitization prior to surgery, during surgical dissection, and throughout the post-surgical period” *

* But for how long?

Adapted from Gottschalk A & Smith D. Am Fam Physician. 2001;63(10):1979-85.Woolf CJ & Chong MS. Anesth Analg. 1993;77:362-79.

Preventive Analgesia

Postsurgical Analgesia

Nociceptor Input

Hypersensitivity

A

“Preemptive” Analgesia

Nociceptor Input

Hypersensitivity

A

“Preventive Analgesia”

Nociceptor Input

Hypersensitivity

A A A A

Surgical & Postsurgical Afferent Input

Nociceptor Input

Hypersensitivity

Duration of Surgery

A = Analgesia

1 2

3 4

24

Does Neuraxial Anesthesia/Analgesia Prevent Chronic Phantom Limb Pain?

1. Should we evaluate both vasculopathic/neuropathic Patients or only traumatic amputations?2. When should we initiate neuraxial blockade? 3. Should we study LA’s?, opioids?, both? 4. How dense a block?5. For how long?6. Since not all afferents may be blocked should we co-administer Analgesic adjuvants 7. What adjuvants should be used?

1 year assessment of stump and phantom limb pain provides mixed results, as there are many variables.

1. Bach S, Noreng MF, Tjellden NU.. Pain. 1988;33:297-301. 2. Jahangiri M, Jayatunga AP, Bradley JW,et al. Ann R Coll Surg Engl. 1994;76:324-6. 3. Nikolajsen L, Ilkjaer S, Christensen JH, et al. Lancet. 1997;350:1353-7.

Phantom Limb Pain (PLP): Continuous Neuraxial Analgesia vs IV Opioids

1. Bach PCT Bup/Mor IV Opioids 0 28 <0.05 0 28 <0.05 et al (1988) (n= 11) (n= 14)

2. Jonargiri PCT Bup/Diam/ IV Opioids 8 73 <0.02 8 73 <0.02 et al (1994) Clon (n= 13) (n= 11)

STUDY TYPE EPIDURAL CONTROL Epi Cont Sig Epi Cont Sig Meds Meds PLP PLP PLP PLP 6 Mo 6 Mo 12 Mo 12 Mo (%) (%) (%) (%)

3. Nicolajsen RCT Bup/Mor IV Opioids 81 55 NS 75 69 NS et al 1997 (n= 29) (n= 30)

1. Bach S, Noreng MF, Tjellden NU. Phantom limb pain in amputees during the first 12 months following limb amputation after preoperative lumbar epidural blockade. Pain. 1988;33:297-301; 2. Jahangiri M, Jayatunga AP, Bradley JW, Dark CH. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll Surg Engl. 1994;76:324-6; 3. Nikolajsen L, Ilkjaer S, Christensen JH, Kroner K, Jensen TS. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet. 1997;350:1353-7.

ACTION: Partnerships to Develop Analgesics That Prevent the Development of Chronic Pain

• WHY is the Food and Drug Administration (FDA) holding up the development and approval of products developed to prevent chronic pain following surgery?”

• The reality is that the agency has not received a single marketing application for such a drug product.

• The Analgesic Clinical Trial Innovations, Opportunities, and Networks (ACTION) initiative is a public–private partnership that brings together experts from academic, government, and private organizations with the goal of sharing data, best practices, and innovative thinking.

• These entities can leverage resources (data, infrastructure, funds) and develop specific analgesics in an expedited and efficient manner.

Rappaport, Bob A. M.D.†; Cerny, Igor Pharm.D.†; Sanhai, Wendy R. Ph.D., M.B.A.‡, Anesthesiology 2010 - Volume 112 pp 509-510

1. “All Chronic Pain Begins as Acute Pain” *

2. Post-surgical chronic pain generally has persistent inflammatory and neuropathic components,

3. Post-surgical chronic pain results in suffering, reduced functionality, reduced quality of life, and can be very difficult to palliate

4. Syndrome prevention is far more effective than palliation of symptoms

5. By understanding the causative mechanisms and providing effective multimodal and preventative analgesia, Anesthesiologists

Conclusion

*M Lema, 2003