Chronic Pain: an overview of mechanisms and management

Dr Helen Cohen Consultant Rheumatology & Chronic Pain Royal National Orthopaedic Hospital Overview

∗ How pain works ∗ Pain mechanisms ∗ Guidelines ∗ Pharmacologic treatment ∗ Interventional treatment ∗ Pain management & rehabilitation ∗ Multiple types of pain ∗ Evolutionary survival system Nociception ∗ Primary afferent small myelinated A-δ and unmyelinated C-fibre nociceptors ∗ Transmit impulses to the dorsal horn of the spinal cord. ∗ A- δ terminate primarily on neurones in laminas I, V and X ∗ C-fibres terminate in laminas I – V (mainly I and II). ∗ C-fibres transmit to spinal second order interneurones ∗ wide dynamic range (WDR) respond to pain & touch ∗ nociceptive specific neurones Ascending tracts Nociceptive impulses ascend by two main pathways:

∗ The more modern neospinothalamic anterolateral system ∗ A-delta fibres ∗ Pain & non-painful temperature ∗ connects to spinothalamic tracts; pass to the lateral thalamus ∗ connections to the sensory cortex allowing the localisation of pain ∗ Discriminative pain – quality, intensity, location; ‘fast pain’

∗ The primitive spino-reticulo-diencephalic tract in the posterolateral cord ∗ c-fibres ∗ connects to reticular system of the brainstem ∗ other connections to the thalamus and hypothalamus ∗ Affective/arousal/emotional aspects of pain; ‘slow pain’ ∗ Sympathetic outflow connections Descending control

∗ Periaqueductral gray-rostral ventromedial medulla (PAG-RVM) system ∗ Dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). ∗ Nucleus raphe magnus (NRM) and locus coeruleus in the pons

∗ These systems can be inhibitory or facilitatory ∗ Deficits of descending inhibition may be operating in some chronic pain syndromes eg. fibromyalgia ∗ Many different neurotransmitters ∗ Serotonin ∗ Noradrenaline Nociceptive neurotransmission ∗ Primary afferent neurones: ∗ Glutamate ∗ Other excitatory neuropeptides include calcitonin gene related peptide (cGRP) and substance P (SP), & many more ∗ Glutamate binds to NMDA and AMPA receptors ∗ GABA-ergic inhibitory neurones throughout spinal cord ∗ also activated by glycine ∗ receptors ∗ Nociceptive ion channels TRVP1, NaV1.7 – expressed in DRG and nociceptive cells ∗ Nerve – activation & sensitization of nociceptors ∗ receptors – CB1, CB2 ∗ Endocannabinoids – inc. anadamide; degraded by FAA(fatty acid amide hydrolase) Central Processing ∗ Chronic pain as a network dysfunction ∗ No single ‘pain centre’

∗ Many brain areas can be activated including: thalamus, reticular system, hypothalamus, periaqueductal grey, S1, S2 and cingulate cortex ∗ Thalamic connections to many cortical areas including limbic and anterior cingulate mediate the affective/emotional aspects of pain. ∗ Autonomic connections Peripheral sensitisation

Nociceptors ∗ reduction in threshold ∗ increase in responsiveness ∗ Previously ‘silent’ c-fibres become active

∗ Nociceptor & ion channel modulation; changes in gene expression Central sensitisation

∗ Central sensitization is an increase in the excitability of neurons within the central nervous system, so that normal inputs begin to produce abnormal responses.

∗ WDR spinal neurones: ∗ increased excitability, ∗ decreased thresholds, ∗ widened receptive field ∗ Neuronal synaptic plasticity ∗ Enhanced presynaptic neurotransmitter release, recruitment of post synaptic NMDA receptors; changes in microglia, astrocytes, gap junctions, membrane excitability and gene transcription ‘Centralised’ pain

Central Sensitization in Chronic Pain

Pain itself can change how pain works, resulting in more pain with less provocation

Neuroplasticity ∗ The process in which the brain's neural synapses and pathways are altered as an effect of environmental, behavioral, and neural changes ∗ Can be observed at multiple scales, from microscopic changes in individual neurons to larger-scale changes such as cortical remapping ∗ Maladaptive neuroplasticity in chronic pain conditions eg. phantom limb pain, CRPS

Kumbhare DA, Elzibak AH, Noseworthy MD. Evaluation of Chronic Pain Using Magnetic Resonance (MR) Neuroimaging Approaches: What the Clinician Needs to Know. Clin J Pain. 2017 Apr;33(4):281-290.

Kuner R, Flor H. Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci. 2016 Dec 15;18(1):20-30. Cortical Representation

Somatotopic maps S1,S2, & beyond Face or hand, not both: perceptual correlates of reafferentation in a former amputee

∗ Article in Current Biology 12(15):1342-6 · September 2002

Farnè A1, Roy AC, Giraux P, Dubernard JM, Sirigu A.

Cortical remapping following hand amputation and 5 months post transplantation. Changes in cortical reorganisation in PLP after training in sensory discrimination

Hand Mouth

Post training. Representation of the mouth moves to a more inferior lateral position

Pre-training. Representation of the mouth invades the hand area

Neuromagnetic source imaging

Flor H; The Lancet Neurology 2002 Pain & genetics Pain plus syndromes ∗ Gain of function: SCN9/Na1.7 channel ∗ Primary erythromelalgia ∗ Paroxsysmal extreme pain disorder ∗ Familial hemiplegic migraine – loss & gain mutations in different genes Congenital Insensitivity to Pain syndromes ∗ SCN9 mutation / Nav1.7 channelopathy ∗ FAA-OUT – mutation impairing FAA – increased endocannabinoids Other ∗ COMT (Catechol-O-methyltransferase) – catecholamines have a role in pain processing/perception; COMT degrades dopamine, nor-adrenaline and adrenaline – effect on pain & modulation of opioidergic activity ∗ OPRM1 (mu receptor) – impaired opioid response ∗ Pain is both a sensation And ∗ A perception

∗ This can dramatically change behavioural and emotional responses to pain Psychological factors

∗ Increased anxiety and depression ∗ Also attention deficit (and hyperactivity) disorder, autism spectrum disorders, obsessive-compulsive disorder, personality disorder, anorexia, self harm, PTSD, previous abuse ∗ Catastrophisation ∗ Psychological stress makes pain worse & vice-versa Guidelines for management of chronic pain

Scottish Intercollegiate Guidelines Network Evidence based recs

https://www.sign.ac.uk/assets/sign136_2019.pdf

Task force review Gaps & recs

U.S. Department of Health and Human Services (2019, May). Pain Management Best Practices Inter-Agency Task U.S. Department of Health and Human Services Force Report: Updates, Gaps, Inconsistencies, and Recommendations. Retrieved from U. S. Department of Health and Human Services website: https://www.hhs.gov/ash/advisory- committees/pain/reports/index.html Guidelines Neuropathic Pain

∗ International Association for the Study of Pain ∗ Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162–73. ∗ Haanpaa M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152:14–27. ∗ European Federation of Neurological Societies (EFNS) ∗ Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol.2010;17:1113. ∗ Cruccu G, Sommer C, Anand P, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010;17:1010–8. ∗ National Institute for Health and CareExcellence ∗ National Institute for Health and Care Excellence (NICE). Neuropathic pain: the pharmacological management of neuropathic pain in adults innon-specialist settings. 2013. ∗ Canadian Pain Society (CPS) ∗ Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19:328–35.

Fibromyalgia: European League Against Rheumatism (EULAR) 2008; revised 2016 American Pain Society (APS) 2005 German (Association of the Scientific Medical Societies, AWMF) 2012 Israeli Canadian Pain Society (CPS) 2013 Chronic pain

Interventional Rx

Controversies and challenges in fibromyalgia: a review and a proposal. Cohen H. Ther Adv Musculoskelet Dis. 2017 May;9(5):115-127. doi: 10.1177/1759720X17699199. Epub 2017 Mar 26. Review. Why don’t drugs seem to work?

Causes of chronic pain It is suggested that:

• Multiple mechanisms involving various regions of entire neuraxis

• Pathophysiology may vary from one patient to another Drug treatment ∗ NSAIDs – inflammatory pain ∗ Neuromodulatory medication ∗ Tricyclic antidepressants eg. – increase serotonin +/- noradrenaline, ∗ , – increase GABA ∗ SNRI eg. Duloxetine – increase S, NA ∗ , memantine – affect NMDA receptor ∗ ∗ – TRVP1 ∗ Anti- Ab biologic drugs (tanezumab) ∗ & derivatives? ∗ BIA 10-2474 - FAA inhibitor – French drug trial 2016 – 1 death, 5 hospitalised.

∗ IF IT DOES NOT WORK OR CAUSES SIDE EFFECTS, STOP IT Medication

∗ WHO pain ladder not appropriate – opiate rung ∗ Where are are used – caution, monitoring, pain clinic involvement

http://www.sign.ac.uk/guidelines/fulltext/136/section5.html Guidelines summary ∗ Not much difference between Chronic pain, FMS and NeuPain guidelines ∗ Non-NeuPain – more use of NSAIDs, , weak opioids, topical NSAIDs

∗ (Cruccu) “There is a broad agreement among the guidelines on pharmacological treatment of neuropathic pain” ∗ Three drug classes have received strong recommendations for first-line therapy in all guidelines: ∗ tricyclic antidepressants, particularly amitriptyline ∗ serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine ∗ Gabapentinoids ∗ “recommended by most guidelines for second-line treatment of neuropathic pain…...... NICE recommend tramadol only for use in rescue therapy” ∗ “Drugs recommended for third- and fourth-line treatment commonly include” ∗ strong opioids, ∗ anti-epileptic agents other than gabapentinoids, and ∗ . ∗ Topical preparations of capsaicin and are recommended for localized neuropathic pain.

COMBINATION THERAPY: AN UNDER-RESEARCHED SOLUTION BEYOND NNT AND NNH: QOL IMPROVEMENT IS A REAL NEED, NOT A BONUS www.hhs.gov/ash/advisory-committees/pain/reports/index.html Interventional approaches U.S. Department of Health and Human Services (2019, May). Pain Management Best Practices Inter-Agency Task Force Report: Updates, Gaps, Inconsistencies, and Recommendations. Retrieved from U. S. Department of Health and Human Services website: https://www.hhs.gov/ash/advisory- committees/pain/reports/index.html

Pain Clinic

CPS. Mailis A, Taenzer P. Evidence-based guideline for neuropathic pain interventional treatments: spinal cord stimulation, intravenous infusions, epidural injections and nerve blocks. Pain Res Manag. 2012;17:150–8. IASP. Dworkin RH, O’Connor AB, Kent J, et al. Interventional management of neuropathic pain: NeuPSIG recommendations. Pain. 2013;154:2249–61. Cruccu G, Aziz TZ, Garcia-Larrea L, et al. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol. 2007;14:952– 70. Pain Ther (2017) 6 (Suppl 1):S35–S42 S41 Interventional approaches

∗ A comprehensive assessment by a skilled pain specialist is necessary to identify which procedure is indicated for a given patient’s pain syndrome. ∗ Unfortunately, pain specialists are typically not involved in the multidisciplinary approaches of diagnosing and treating a pain patient early enough in his or her treatment, which can lead to suboptimal patient outcomes.

∗ The interventions are not curative; pt still needs non- pharmacologic coping skills

U.S. Department of Health and Human Services (2019, May). Pain Management Best Practices Inter-Agency Task Force Report: Updates, Gaps, Inconsistencies, and Recommendations. Retrieved from U. S. Department of Health and Human Services website: https://www.hhs.gov/ash/advisory-committees/pain/reports/index.html Pain Management Programmes

https://www.britishpainsociety.org/static/uploads/resources/files/pmp2013_main_FINAL_v6.pdf Medical Rehabilitation Principles

∗ Education ∗ Rehabilitation ∗ Pain control ∗ Physical and vocational rehabilitation ∗ Psychological support ∗ Self-management ∗ Goal focussed

∗ Rooted in a biopsychosocial model Royal National Orthopaedic Hospital Pain management programme Sessions include: ∗ Making changes & maintaining change ∗ Pacing ∗ ‘Your move’ stretch programme ∗ Pain education ∗ Coping skills ∗ Sport & recreation ∗ Postural management ∗ Anatomy & healing ∗ Goal setting ∗ Foiling a flare up ∗ Relaxation ∗ Nutrition ∗ Work support ∗ Medicines & future medical management ∗ Friends & family group Challenging chronic pain: neurology, rheumatology,psychiatry interface

∗ Functional Neurological Disorders ∗ Focal dystonia ∗ Non-epileptic seizures ∗ Ehlers-Danlos Syndrome/hypermobility ∗ Chiari I ∗ Postural Orthostatic Tachycardia Syndrome ∗ CRPS ∗ Hereditary erythromelalgia Approach to chronic pain

∗ Biopsychosocial model ∗ Acute vs chronic Can co-exist ∗ Individualised ∗ Sources of pain ∗ Musculoskeletal factors ∗ Psychological factors ∗ Judicious and careful use of medication ∗ Medication as an adjunct not the focus https://www.hhs.gov/ash/advisory-committees/pain/reports/index.html Thank you for listening!