PAIN EDUCATION Module 6: The chronification of pain

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1 The full version of this slide deck in MS PowerPoint format (containing presentation view and expanded notes) can be downloaded on please register! PAIN EDUCATION Module 6: The chronification of pain

2 2013 Excerpta Medica BV The material presented in this teaching slide deck is for educational purposes only. If you wish to reproduce, transmit in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, any part of the material presented, you will need to obtain all the necessary permissions by writing to the publisher, the original author, or any other current copyright owner. Please cite as: PAIN EDUCATION Teaching Slides, chapter: The chronification of pain, Available from No responsibility is assumed for any injury and/or damage to persons or property as a matter of products liability, through negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of rapid advances in the medical sciences, it is recommended that independent verification of diagnoses and drug dosages should be made. Produced by Excerpta Medica Radarweg NX Amsterdam Netherlands Supported by an unrestricted educational grant from Grünenthal. Produced in the Netherlands

Learning objectives Upon completion of this training module you should have gained an increased understanding of:

leading to the chronification of pain Signs and symptoms of chronic pain Comorbidities that can develop as a

patients with chronic pain For additional information and further educational content related to the

3 Learning objectives Upon completion of this training module you should have gained an increased understanding of: Pain pathways and the relative contributions of peripheral and central mechanisms to pain development The process leading to the chronification of pain Signs and symptoms of chronic pain Comorbidities that can develop as a consequence of pain The mechanisms by which treatments can modulate chronic pain Optimal treatment pathways for patients with chronic pain For additional information and further educational content related to the chronification of pain, please see Module 6 of the CME-accredited e-learning PAIN EDUCATION modules, available at

Overview of pain signalling Peripheral nerves Convey information from external stimuli to the spinal cord Spinal cord Integrates, amplifies and modifies incoming messages

mood, state of mind and sleep pattern Pain signalling Brain Limbic brain Descending controls Peripheral nerves Spinal cord Cortex Ascending pathways Yeung JC, et al.

4 Overview of pain signalling Peripheral nerves Convey information from external stimuli to the spinal cord Spinal cord Integrates, amplifies and modifies incoming messages Sends messages via ascending pathways to the brain Cortex Recognizes intensity and location of pain Limbic brain Conveys affective aspects of pain Can result in changes in mood, state of mind and sleep pattern Pain signalling Brain Limbic brain Descending controls Peripheral nerves Spinal cord Cortex Ascending pathways Yeung JC, et al. J Pharmacol Exp Ther. 1980;215: Marchand S. Rheum Dis Clin North Am. 2008;34: Heinricher MM, et al. Brain Res Rev. 2009;60: Heinricher MM, et al. Pain. 2001;92:

General principles of pain Nociceptors (sensory nerve fibres) Aδ fibres (large, myelinated, fast) C fibres (small, non-myelinated, slow) Located in every tissue, including skin, bone and viscera

5 General principles of pain Nociceptors (sensory nerve fibres) Aδ fibres (large, myelinated, fast) C fibres (small, non-myelinated, slow) Located in every tissue, including skin, bone and viscera Nociceptors transmit signals via chemical messengers via the spinal cord to the brain Excitatory neurotransmitters (e.g. glutamate) enhance pain Inhibitory neurotransmitters (e.g. GABA) modulate pain The spinal cord processes the signals from periphery and conveys them to the brain GABA = γ-aminobutyric acid. Peripheral sensory nerve fibres Spinal Nathan PW. J Neurol Neurosurg Psychiatry. 1976;39: cord Markenson JA. Am J Med. 1996; 101:6S 18S. Nociceptors Fundytus ME. CNS Drugs. 2001;15: Dorsal Jasmin L, et al. Curr Drug Targets CNS Neurol Disord. 2004;3: root Harvey VL, Dickenson AH. Curr Opin Support Palliat Care. 2008;2: Aβ A C

6 Descending controls Signals transmitted to the brain are modulated by Brain stem Descending controls, via neurotransmitters Noradrenaline Key inhibitory transmitter Serotonin (5-HT) Inhibitory transmitter Stimulatory transmitter Noradrenaline Stop signal Pain signal Spinal cord Brain stem Serotonin (5-HT) Go signal Benarroch EE. Neurology. 2008;71: Woolf CJ. Ann Intern Med. 2004;140: Millan MJ. Prog. Neurobiol. 2002;66: Bannister K, et al. Neurotherapeutics. 2009;6:

Nociceptive or inflammatory pain Pain caused by inflammation or tissue damage

prostaglandin, substance P, histamine, bradykinin, CGRP, neurokinin A) are generated

Nociceptive pain may have multiple causes CGRP = calcitonin gene-related peptide.

7 Nociceptive or inflammatory pain Pain caused by inflammation or tissue damage Chemicals (e.g. prostaglandin, substance P, histamine, bradykinin, CGRP, neurokinin A) are generated in the damaged area and trigger nociceptors Chemicals Nociceptors Spinal cord Nociceptive pain may have multiple causes CGRP = calcitonin gene-related peptide. Botting RM et.al. Clin Drug Invest 2000;19 (Suppl 2):1 7. Schaible HG, et al. Exp Brain Res. 2009;196: Davis MP, et al. Am J Hosp Palliat Care. 2004;21:

8 Neuropathic pain Pain caused by a lesion or disease of the somatosensory system Nerve damage Surrounding tissues remain intact Neuropathic pain may have multiple causes Geber C. Am J Med. 2009;122:S3 12. Woolf CJ, et al. Lancet. 1999;353: Campbell JN. Neuron. 2006; 52:

Neuropathic pain and ion channels Sodium channels Act as accelerator: generate signals and allow them to pass on Calcium channels Act as a gear box: facilitate Potassium channels Act as a brake:

9 Neuropathic pain and ion channels Sodium channels Act as accelerator: generate signals and allow them to pass on Calcium channels Act as a gear box: facilitate Potassium channels Act as a brake: modulate signals transmission of pain signals These mechanisms may be disrupted in neuropathic pain and form targets for therapeutic intervention Todorovic SM, et al. CNS Neurol Disord Drug Targets. 2006;5: Hargus NJ. Expert Opin Investig Drugs. 2007;16: Munro G, et. al. J Med Chem. 2007;50:

10 Sodium channels and pain syndromes Pain Disorder Inherited erythromyalgia Channelopathy associated insensitivity to pain Paroxysmal extreme pain disorder Channel involved Na(v)1.7 Affect on channel Lower threshold, enhanced responses Symptoms Attacks of burning pain and redness in extremities Na(v)1.7 Loss of function Inability to sense pain Na(v)1.7 Impaired inactivation, enhanced response Episodic lower body, ocular and jaw pain Fischer TZ, et al. Ann N Y Acad Sci. 2010;1184: Catterall WA, et al. Neuron. 2006;52:

Nociceptive pain and neuropathic pain can become chronic Examples of chronic pain are Chronic

nociceptive and neuropathic pain: chronic back pain and cancer Chronic back pain Cancer pain

the chronification process Woolf CJ. J Pain. 2010;16:1241-7. Costigan M, et al.

11 Nociceptive pain and neuropathic pain can become chronic Examples of chronic pain are Chronic nociceptive pain: osteoarthritis Chronic neuropathic pain: diabetic neuropathy Chronic nociceptive and neuropathic pain: chronic back pain and cancer Chronic back pain Cancer pain To treat chronic pain effectively, it is important to understand the underlying mechanism of the chronification process Woolf CJ. J Pain. 2010;16: Costigan M, et al. Annu Rev Neurosci. 2009;32:1-32. Woolf CJ. Ann Intern Med. 2004;140: Woolf CJ, et al. Lancet. 1999;353:

threshold Receptive fields expand Neurons may become spontaneously active Consequence of central

12 Chronification of pain: central sensitization Spinal cord is key in chronification of pain Persistent peripheral stimuli lead to central sensitization Spinal cord Central sensitization Decrease in neuronal threshold Receptive fields expand Neurons may become spontaneously active Consequence of central sensitization Allodynia Hyperalgesia Spontaneous pain Woolf CJ. Pain. 2010;16: Woolf CJ. Ann Intern Med. 2004;140:

Mechanism of central sensitization NMDA receptors In dorsal horn spinal cord Normally unavailable for

prolonged activation of NMDA receptors Activated NMDA receptor Enhances pain and central sensitization Leads to

Br J Anaesth. 2008; 101:8-16. Woolf J. Pain. 2010;16:1241-7. Mannion R, Woolf J. Clin J Pain 2000;16:S144-S156.

13 Mechanism of central sensitization NMDA receptors In dorsal horn spinal cord Normally unavailable for stimulation by its excitatory neurotransmitter glutamate Repeated stimulation of pain pathways results in prolonged activation of NMDA receptors Activated NMDA receptor Enhances pain and central sensitization Leads to wind-up and temporal summation Petrenko AB, et al. Anesth Analg. 2003;97: Mello RD, Dickenson AH. Br J Anaesth. 2008; 101:8-16. Woolf J. Pain. 2010;16: Mannion R, Woolf J. Clin J Pain 2000;16:S144-S156. AMPA = ɑ-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid; mglur = metabotropic glutamate receptors; NMDA = N-methyl D-aspartate. 9

Consequences of central sensitization Central sensitization leads to Enhanced release of

anxiety Sleep disturbance Depression Rapidly enhanced and ongoing pain Greater area of pain

Ann Intern Med. 2004;140:441-51. Woolf J. Pain. 2010;16:1241-7. Turk. Mayo Clin Proc.

14 Consequences of central sensitization Central sensitization leads to Enhanced release of neurotransmitters Amplified output to the brain Disruption of limbic brain function Fear, anxiety Sleep disturbance Depression Rapidly enhanced and ongoing pain Greater area of pain Hyperalgesia Allodynia Marchand S. Rheum Dis Clin North Am. 2008;34: Woolf CJ. Ann Intern Med. 2004;140: Woolf J. Pain. 2010;16: Turk. Mayo Clin Proc. 2010;85:S Benarroch EE. Neurology. 2008;71: Millan MJ. Prog Neurobiol. 2002;66:

Change of BOLD signal (vmax) withing PAG mask (%) Preview for Consequences of central sensitization in patients Osteoarthritis Continuous nociceptive input from

Both peripheral and central aspects of pain should be considered for patients who display signs of central 2 1,5 1 0,5 sensitization 0 0 5 10 15 20 25 Arendt L, et

15 Change of BOLD signal (vmax) withing PAG mask (%) Preview for Consequences of central sensitization in patients Osteoarthritis Continuous nociceptive input from damaged knee Central sensitization in brain stem periaqueductal grey matter (PAG) Correlation between blood oxygen level dependent (BOLD) response and pain score Both peripheral and central aspects of pain should be considered for patients who display signs of central 2 1,5 1 0,5 sensitization Arendt L, et al. Pain. 2010;149: Gwilym S, et al. Arthritis and Rheumatism. 2009;61: Pain DETECT score Source: Gwilym SE, et al. Arthritis Rheum. 2009;61:

Descending excitatory and inhibitory controls Descending pathways Activate facilitatory neurons increase dorsal horn activity in spinal cord Activate inhibitory neurons decrease dorsal horn activity

16 Descending excitatory and inhibitory controls Descending pathways Activate facilitatory neurons increase dorsal horn activity in spinal cord Activate inhibitory neurons decrease dorsal horn activity in spinal cord Central sensitization Less effective descending inhibitory pathways Hyperexcitable state in spinal cord Failure of descending inhibition plays a role in chronic pain conditions Heinricher MM, et al. Brain Res Rev. 2009;60: Benarroch EE. Neurology. 2008;71: Bannister K. Neurotherapeutics ;6:

Applying a prognostic risk approach to chronic pain in clinical practice Defining chronic pain by

conditions that are not continuous Multidimensional approach includes other factors Duration of

aim of this approach is to reduce the risk of pain chronification Comorbidities associated with

17 Applying a prognostic risk approach to chronic pain in clinical practice Defining chronic pain by duration: Is unidimensional May not be clinically significant Is difficult in recurrent pain conditions that are not continuous Multidimensional approach includes other factors Duration of pain Concern about pain condition Concern about disability Depressive symptoms Chronic pain The aim of this approach is to reduce the risk of pain chronification Comorbidities associated with chronic pain are key to multidimensional management Comorbidities Von Korff M, Dunn K. Pain. 2008;138:

Chemicals and channels involved in nociceptive processes Different formulations can block chemical messages in nociceptive pain Triptans can

prostaglandins COX = cyclooxygenase; NSAIDs = nonsteroidal anti-inflammatory drugs. Phillips WJ. J Am Acad Orthop Surg. 2004;12:213-20.

18 Chemicals and channels involved in nociceptive processes Different formulations can block chemical messages in nociceptive pain Triptans can block serotonin Local anaesthetics like lidocaine can non-selectively block ion channels NSAIDs and COX inhibitors can block the production of prostaglandins COX = cyclooxygenase; NSAIDs = nonsteroidal anti-inflammatory drugs. Phillips WJ. J Am Acad Orthop Surg. 2004;12: Botting RM, et.al. Clin Drug Invest. 2000;19 Suppl. 2:1-7 Tepper ST, et.al. Arch Neurol. 2002;59: Caracas HC, et. al. J Dent. 2009;37:

pregabalin target calcium channels These compounds reduce incoming activity to the spinal cord Mantegazza M, et al.

19 Chemicals and channels involved in neuropathic processes Treatment for neuropathic pain relate to abnormalities in the function of ion channels due to damaged nerves Carbamazepine and lidocaine target sodium channels Gabapentin and pregabalin target calcium channels These compounds reduce incoming activity to the spinal cord Mantegazza M, et al. Lancet. Neurol. 2010;9: Kalso E, et al. Curr Pharm Des. 2005;11: Tzellos TG, et al. Hippokratia. 2010;14:

(abnormal) electrical activity produced by pain Opioid receptors are located in both the presynaptic and

20 Opioid analgesia The opioid system is the major inhibitory system related to pain, via dampening of excitatory events Activated opioid receptors open potassium channels, thereby acting as a highly effective brake on (abnormal) electrical activity produced by pain Opioid receptors are located in both the presynaptic and post-synaptic cleft Przewłocki R, Przewłocka B. Eur J Pharmacol. 2001;429: McFadzean I. Neuropeptides. 1988;11:

Opioid receptors Type of receptor Endogenous opiod peptides Function μ Endomorphins Opens K + δ Enkephalins Opens K + κ Dynorphin Closes Ca 2+ ORL-1 Nociceptin Opens K + Endogeneous ligand Drugs

21 Opioid receptors Type of receptor Endogenous opiod peptides Function μ Endomorphins Opens K + δ Enkephalins Opens K + κ Dynorphin Closes Ca 2+ ORL-1 Nociceptin Opens K + Endogeneous ligand Drugs Morphine Codeine Fentanyl Pethidine Heroin Oxycodon μ-opioid receptor Minimal pain inhibition Significant pain inhibition Przewłocki R, et. al. Eur J Pharmacol. 2001;429: Przewlocki R, et. al. Curr Pharm Des. 2005;11: Vaccarino AL, et. al. Peptides. 2000;21:

Opioid analgesia Opioids Spinal cord C- and

1986;162:389-404. Kohno T, et al. J Physiol.

22 Opioid analgesia Opioids Spinal cord C- and Aδfibres Pre-synaptic inhibition Transmission of pain to spinal cord is blocked Post-synaptic inhibition Pain signal output of the spinal cord is modulated Staren ED, et al. Surg Gynecol Obstet. 1986;162: Kohno T, et al. J Physiol. 1999;518: Zieglgänsberger W, et al. Brain Res. 1976;115:

Ketamine: NMDA receptors and wind-up Wind-up Repetitive

receptors Ketamine Neuronal response amplified and prolonged

surgery Beneficial effect on central sensitization in the spinal

of chronic pain Dickenson AH, Sullivan AF.

23 Ketamine: NMDA receptors and wind-up Wind-up Repetitive stimulation of C- fibres by noxious stimuli Ketamine NMDA receptors Ketamine Neuronal response amplified and prolonged Ketamine Usable for its analgesic and sedative effects during surgery Beneficial effect on central sensitization in the spinal cord Unwanted side effects not suitable for every day management of chronic pain Dickenson AH, Sullivan AF. Neuropharmacology 1987;26: Mello RD, Dickenson AH. Br J Anaesth. 2008;101:8-16. NMDA = N-methyl D-aspartate. 19

Descending control and supraspinal analgesia Supraspinal sites Area above the spinal cord in the brain Involved in processing of pain Opioids Placebo Descending controls Originate in the higher

24 Descending control and supraspinal analgesia Supraspinal sites Area above the spinal cord in the brain Involved in processing of pain Opioids Placebo Descending controls Originate in the higher centres Modulate pain Can inhibit or enhance pain sensation Activation of the opioidergic descending control system by placebo analgesia indicates that opioid receptors at the supraspinal level should be considered in the management of chronic pain patients Heinricher MM, et al. Brain Res Rev. 2009;60: Eippert F, et al. Science 2009;326:

Supraspinal opioid analgesia Opioids work at the pre- and post-synaptic receptors in the spinal cord Opioids at the supraspinal level change descending controls Switch to inhibitory mode to decrease

25 Supraspinal opioid analgesia Opioids work at the pre- and post-synaptic receptors in the spinal cord Opioids at the supraspinal level change descending controls Switch to inhibitory mode to decrease enhancement and excitation Can alter emotional assessment of pain by affecting the thalamus and limbic system Opioid actions in the mid-brain and the brain stem allow descending controls to further reinforce the spinal inhibition by switching descending pathways into inhibitory mode as well Jensen TS, et al. Acta Anaesthesiol Scand. 1997;41: Dickenson AH. In: Gebhart GF, et al., editors. Proceedings of the 7th World Congress on Pain, Progress in Pain Research and Management pp Ananthan S. AAPS J. 2006;8:E

26 Descending controls and analgesia Opioids (e.g. morphine) Switch descending pathways to inhibitory mode Antidepressants (SSRIs, SNRIs) Block reuptake noradrenaline (NA) and serotonin (5-HT) Modulate descending controls Tramadol Weak opioid action Blocks reuptake NA and 5-HT Noradrenaline Opioids Brain stem Serotonin (5-HT) SSRI/SNRI Opioids Spinal cord Dworkin RH. Mayo Clin Proc. 2010;85:S3-14. Mattia C, et. al. Minerva Anestesiol. 2002; 68: SNRI = serotonin-norepinephrine reuptake inhibitor; Benarroch EE. Neurology. 2008;71: Nossaman VE, et al. Anesthesiol Clin. 2010;28: SSRI = selective serotonin reuptake inhibitor. 22

supraspinal and spinal opioid mode of action, as well as noradrenaline reuptake

27 Descending controls and analgesia: tapentadol MOR-NRI: Tapentadol μ-opioid receptor antagonist (MOR) Noradrenalin reuptake inhibitor (NRI) Tapentadol is a MOR-NRI, having supraspinal and spinal opioid mode of action, as well as noradrenaline reuptake inhibition Nossaman VE, et al. Anesthesiol Clin. 2010;28: Kress H. Eur J Pain. 2010; 14:

Typical treatment pathway of chronic pain patient WHO step-up analgesic approach is based on increasing strength of medication, depending on increase in

Not applicable for patients with chronic pain The pharmalogical treatment of chronic pain should focus mainly on the underlying mechanism and not on the

28 Typical treatment pathway of chronic pain patient WHO step-up analgesic approach is based on increasing strength of medication, depending on increase in severity of pain Underlying mechanisms in patients with chronic pain are not taken into account Does not include multidimensional aspects of chronic pain Not applicable for patients with chronic pain The pharmalogical treatment of chronic pain should focus mainly on the underlying mechanism and not on the intensity of pain Vargas-Schaffer G. Can Fam Physician. 2010;56: Dworkin RH, et al. Mayo Clin Proc. 2010;85:S3-14. Woolf CJ. Ann Intern Med. 2004;140:

29 Multiple mechanisms of pain: corresponding medications Stepped approach: 1. Links drugs to mechanism of pain 2. Has a drug that addresses chemical modulation of one or more pain mechanisms at each step If a single drug is insufficient, it is logical to use more than one agent at a time Drugs with more than one analgesic mechanism of action, such as tapentadol, target multiple pain pathways and may have a synergy of effect CNS = central nervous system; NSAID = non-steroidal anti-inflammatory drug; TCAs = tricyclic antidepressants. Lidocaine and carbamazepine work on the Na channels NSAID + coxib (associated with tissue-related systems) Gabapentin and pregabalin work on the Ca 2+ channels Peripheral level Altered ion channel function (neuropathy) TCAs and duloxetine work on the descending control mechanisms Calcium channel function increases Tapentadol acts at both the descending control mechanisms and opioid receptors Wind-up and central sensitization are induced Brain facilitations up inhibitions down CNS level Dworkin RH, et al. Mayo Clin Proc. 2010;85:S3-14. Altered chemical mediation Opioids (work on multiple Woolf CJ. Ann Intern Med. 2004;140: (nociceptive inflammation pain mechanisms as brakes) 24

Treatment pathway in chronic pain patients GP NSAIDs weak opioids Pain specialist

suffered chronic pain in previous 5 years 63% were aware of option to see pain

patient with chronic pain as he/she maintains a key relationship with the patient

= non-steroidal anti-inflammatory drugs.

30 Treatment pathway in chronic pain patients GP NSAIDs weak opioids Pain specialist Strong opioids antidepressants or -convulsants UK survey 2010 with 4438 people: 210 suffered chronic pain in previous 5 years 63% were aware of option to see pain specialist 23% was referred to pain specialist The GP is central in managing a patient with chronic pain as he/she maintains a key relationship with the patient Late referral from GPs to specialists is a key issue in chronic pain patients NSAIDs = non-steroidal anti-inflammatory drugs. Information source: Public attitudes to pain UK pain study available at: 25

31 Summary Spinal cord is key in the development of chronic pain via central sensitization Repeated stimulation results in prolonged activation of NMDA receptors Enhanced release of neurotransmitters and amplified input to the brain Consequences are allodynia, hyperalgesia and spontaneous pain Analgesia may act on supraspinal sites and descending controls Opioids switch descending controls in inhibitory mode Antidepressants modulate descending controls by blocking transmitter reuptake Tramadol has weak opioid action and blocks transmitter reuptake Tapentadol is a µ-opioid receptor antagonist and noradrenalin reuptake inhibitor Effective management of chronic pain requires a multidimensional and mechanism-based approach Risk factors for development of chronic pain, such as depression, emotional distress, activity limitation Treatment based on (chemical) modulation of pain mechanism(s) 26

Pharmacology of Pain Transmission and Modulation

Pharmacology of Pain Transmission and Modulation 2 Jürg Schliessbach and Konrad Maurer Nociceptive Nerve Fibers Pain is transmitted to the central nervous system via thinly myelinated Aδ and unmyelinated