Transitions from Acute to Chronic Pain

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) 2 o 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.

Differences Between Acute and Chronic Pain Distinct onset 1 Acute Most severe within first 24 hours 2 Obvious cause 1 Injury, disease, surgical procedure (post-operative pain) Short duration 2 < 1 month Intensity indicates severity of injury or disease 1 Persistent pain Chronic Result of chronic disease 2 Osteoarthritis, neuropathic pain, cancer related, chronic headache, chronic low back pain, fibromyalgia Longer duration 1 Persisting >3 months Beyond normal healing Prolonged functional impairment Physical and psychological 1 May be easier to manage More difficult to manage 1 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 Procedure Estimated incidence of chronic pain Estimated incidence of chronic severe (disabling) pain b Number of surgeries in the United States a Amputation 30-50% 5-10% 159,000 Coronary artery bypass surgery 30-50% 5-10% 598,000 Thoracotomy 30-40% 10% Unknown Breast surgery (lumpectomy or mastectomy) 20-30% 5-10% 479,000 Cesarean section 10% 4% 220,000 Inguinal hernia repair 10% 2-4% 609,000 a National 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 Pain Intensity Analgesic Requirements Very Severe Pain Severe Pain Moderate Pain Mild Pain No Pain Time Interventional Potent IV Opioids Oral Opioids Non- Opioids None Progressive reductions in pain Intensity and analgesic requirement over a period of several weeks

Transitions from Acute to Persistent Pain Postoperative Pain Very Severe Severe Decreasing Intensity Increasing Intensity Moderate Mild None Hyperalgesia, Central Sensitization Time Peripheral and Central Plasticity changes

Patient Specific Risk Factors For Persistent Gender Women generally report higher levels of post operative pain Genetic Predisposition More intense inflammatory and neural regenerative responses (HLA, COMT), Variable responses to analgesics Age Older patients have reduced risk of chronic postherniorrhaphy and amputation pain 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.

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 Increasing Discomfort Hyperalgesia Allodynia Normal Response Increasing Stimulus Intensity

Operative Procedures Surgeries associated with risks of nerve damage Psychological Vulnerability Anxiety Depression Catastrophising Preceding Pain P1 month prior tp surgery Severe Pain Analgesic undermedication or poor acute pain management 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.

Severity of Post-Operative Acute Pain Was Associated With Development of Chronic Pain 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) *Chronic pain assessed 6 months to 3.5 years post-surgery Pluijms et al. Acta Anaesthesiol Scand. 2006;50:804-808.

Hyperalgesia: Mechanisms that Increase Acute Pain Intensity and Development of Persistent Pain Primary Hyperalgesia: Increased pain sensitivity at the site of injury. Related to peripheral inflammatory responses Secondary Hyperalgesia Increased pain sensitivity at sites adjacent to the site of injury Related to enhanced sensitivity and altered connectivity in the spinal cord and brainstem

Pain Sequencing Acute Tissue Injury Primary mediators (PGE) Milliseconds Nociceptor Activation Peripheral Sensitization Seconds Central Sensitization NMDA Activation and wind- up Minutes Neuronal Modification and Long Term Potentiation Altered gene regulation Altered connectivity Cell death Hours to Days Persistent Pathological Pain 3 Months to Years Adapted from Woolf and Salter, Science 2000; 288: 1765

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++ Acute Injury PGE, sp, CGRP, bradykinin, Serotonin, histamine Ca++ Macrophage TRPV-1 TRPV-1 Activated Nociceptor Kappa Receptors Damaged or Sensitized Nociceptor Persistent Injury Macrophage and Lymphocyte responses, Cytokines, Norepinephrine, NGF

Activated nociceptor Inhibitory Cell Secondary Hyperalgesia: Central Sensitization Hyperexcitable WDR dorsal horn neuron (EPSPs) Acute Pain Sensitized nociceptor High intensity stimulation Glial Activation Sensitized WDR Neuron (Windup) Convalescent Pain Sensitized nociceptor Persistent Glial Reactivity Altered WDR Neuron (Transcription dependent plasticity) Chronic Pain High threshold mechanoreceptor 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)

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). 10.0 Severe Phantom Limb Pain # Patients 7.5 5.0 2.5 Epidural IV Opioids 0 7 Days 6 Months 12 Months Bach S, Noreng MF, Tjellden NU: Phantom limb pain during the first 12 months following limb amputation, Pain 33:297-301, 1988

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 COX-2 Prostaglandin Synthesis Nociceptor Activation Peripheral Sensitization (Primary Hyperalgesia) Cytokines, IL-1B Intense and Prolonged Noxious Transmission Central Role (CNS) NMDA Activation, Ca ++ Flux, Central Sensitization (Secondary Hyperalgesia) Up-regulation COX & NOS Prostaglandin Synthesis Neural & Glial Remodeling Long-Term Potentiation Acute Pain Chronic Pain Copyright R. Sinatra MD 2002

Methods Advocated to Prevent Persistent Post-surgical Pain 1. Avoid surgery in patients or medical conditions associated with higher risk 2. Modify surgical technique (Laparoscopic or Robotic) 3. Aggressive preemptive and multimodal therapy (Reduce peripheral inflammation and 1 o 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 Aggressive Preventive (1913) 1 Analgesia (2001) 2,3 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 postsurgical period * * But for how long? 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.

Preventive Analgesia 1 Surgical & Postsurgical 2 Afferent Input Postsurgical Analgesia A Duration of Surgery Nociceptor Input Nociceptor Input Hypersensitivity Hypersensitivity 3 Preemptive Analgesia 4 Preventive Analgesia A A A A A Nociceptor Input Nociceptor Input Hypersensitivity Hypersensitivity Adapted from Gottschalk A & Smith D. Am Fam Physician. 2001;63(10):1979-85. Woolf CJ & Chong MS. Anesth Analg. 1993;77:362-79. A = Analgesia 24

Does Neuraxial Anesthesia/Analgesia Prevent Chronic Phantom Limb Pain? 1 year assessment of stump and phantom limb pain provides mixed results, as there are many variables. 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. 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 STUDY TYPE EPIDURAL CONTROL Epi Cont Sig Epi Cont Sig Meds Meds PLP PLP PLP PLP 6 Mo 6 Mo 12 Mo 12 Mo (%) (%) (%) (%) 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) 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

Conclusion 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 *M Lema, 2003