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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