Post-Amputation Pain Dr R. Craig Davenport NSW Physiotherapists in Amputee Rehabilitation 14 June 2013 Dr R. Craig Davenport Rehabilitation Physician

Post-Amputation Pain Phantom Limb Pain Residual Limb Pain (Stump Pain) Phantom Sensations

Residual Limb (Stump) Pain More of an issue in immediate post-amputation period Descriptors: Sharp Burning Electrical-like Skin-sensitive Localised to a superficial incision, or deep pain, or generalised in the residual limb Residual limb pain incidence may be as high as 74% and can persist for many years

Phantom Sensations Defined as non-painful perceptions emanating from lost body part after de- afferentation or amputation Common ~1/3 in first 24 hours ¾ at 4 days 90% within 6 months Doesn’t require amputation  Can occur with Spinal Cord Injury and Brachial plexus avulsion Usually in hands and feet (large cortical representation) Not restricted to limbs, can occur in ear, teeth etc

Phantom Sensations Types of sensations: Kinetic – perceived movement of a body part Kinesthetic – size, shape, or position of body part Exteroceptive perceptions – touch, pressure, tingling, temperature, itch, vibration Associated with Phantom Pain  phantom pain rare in those without phantom sensations Often experience telescoping over time

Phantom Limb Pain Defined as an unpleasant sensation in distribution of the lost or de-afferentated body part

Phantom Limb Pain First described by 16th century French military surgeon Ambrose Pare The term “Phantom Limb Pain” coined by 19th century civil war surgeon Silas Weir Mitchell Incidence of PLP common – between 40% and 80% Similar between civilian and military, and between different aetiologies Not only in amputations, but also occurs in congenital limb deficiency

Risk Factors for Phantom Limb Pain Presence of pre-amputation pain severity Relationship to pre-amputation pain severity exists for first few months, but probably not for pain >6 months post-op

Fig 1 Pre‐amputation pain ≥20 increases the risk of phantom pain ≥20 after 1 week and 3 months (on a VAS, 0–100). Fig 1 Pre‐amputation pain ≥20 increases the risk of phantom pain ≥20 after 1 week and 3 months (on a VAS, 0–100). Data from the 1 week interview are shown. Each dot represents one patient, n=54. P=0.04, Fishers’ exact test. (From Nikolajsen and colleagues 1997, with permission). Nikolajsen L , and S. Jensen T Br. J. Anaesth. 2001;87:107-116 ©2001 by Oxford University Press

Risk Factors for Phantom Limb Pain Residual limb pain severity correlates to PLP severity Upper Limb Amputations > Lower Limb Amputations Females > Males Time after amputation Onset of PLP has two peaks: within 1st month & a year after amputation Typically occurs within first 6 months Prevalence decreases over time Like Phantom Sensations, up to 2/3 experience Telescoping over time

Phantom Limb Pain - Descriptors Pain description can change over time exteroceptive-like (knife-like, stabbing) in proximal limb or more generalised proprioceptive-like (burning, squeezing) localised to distal areas of amputated limb

PLP descriptors Most common: Others: Tingling Throbbing Piercing Pins and needles Others: Sharp Shooting Electrical-like Dull Squeezing Cramping

Factors influencing pain Stress/anxiety/depression/emotional triggers contribute to persistence or exacerbation of PLP Presence of depression associated with characterisation of more severe pain Possible genetic predisposition to development of neuropathic pain

Mechanisms of Phantom Pain Peripheral Central Spinal Supra-spinal (Brain & Brainstem)

Mechanisms of PLP Peripheral Tissue injury neural injury de-afferentation Proximal portion of nerve sprouts to form Neuroma  upregulation of voltage-gated sodium channels, down- regulation of K-channels. Development of ephapses (non- functional connections between neurons)  hyper-excitability and increased spontaneous discharge Chemosensitivity to circulating catecholamines (eg adrenalin)  pain increased with stress

Spinal Cord – Dorsal Horn changes Axonal sprouts form connections with neurons in receptive field Loss of afferent input causes reduced descending inhibitory input from reticular formation in brainstem Central sensitisation Expansion of neuronal receptive field, hyper-excitability Increased NMDA receptor activity – mediated by Substance P, tachykinins, neurokinins at dorsal horn “Wind-up” – up-regulation of receptors in the area Loss of target neurons for descending inhibitory pathways Spinal disinhibition due to loss of local inhibitory intersegmental spinal inter- neurons But spinal ablative treatments (cordotomy tractotomy etc) often fail to give long term relief

Brain Changes – The Homunculus

Brain changes Cortical re-organisation in primary somatosensory and motor cortex Extent of re-organisation related to degree of pain and size of de- afferented region Body-schema – Neuromatrix and Neurosignature – loss of input causes abnormal neurosignature to develop Incongruence of motor intention and sensory feedback – involves parietal and frontal lobes involved

fMRI in PLP and non-PLP subjects

Psychogenic mechanisms Not well supported by evidence previously thought to be associated with passive coping styles and catastrophising behaviour traits

Pain Limbic Connections

Phantom Pain often triggered by Residual Limb Pain What Causes might be identified and possibly treated?

Residual Limb Pain - Causes Post-surgical nocipceptive tissue trauma pain Neurogenic causes- clinically significant neuroma Prosthogenic causes Poor fitting socket Too tight/lack of distal contact, insufficient bony relief, Too loose, excessive end-bearing, pistoning Socket malalignment with torque forces in weight-bearing Incorrect donning of prosthesis Incorrect use of socks Adherent Scar tissue Heterotopic ossification – initially acute inflammatory pain and then pressure effects

Residual Limb Pain - Causes Arthrogenic – eg OA of knee Ischaemic – ongoing poor vascular supply Sympathetically-maintained – eg Complex Regional Pain Syndrome Referred from spine eg Radicular/Facet Joint/SI Joint pain generator Stump or wound Infection Pain from associated injuries Pain from co-morbidities Musculoskeletal Pain from Gait abnormalities

How to tell…… Referred from facet joint/ SI joint/ radiculopathy diagnostic blocks may help Ischaemia transcutaneous oxygen tension <20mmHg Neuroma Palpation point neuropathic pain, Ultrasound/MRI Prosthesis-related pain pain on weight bearing, or after prolonged wearing, skin or soft tissue changes may prompt socket adjustments which may relieve pain Stump infections – soft-tissue or bone blood tests/ultrasound/MRI/Nuclear imaging studies Bone spurs palpation and plain radiographs

Treatment

Treatment Approaches Few controlled trials to guide treatment Often extrapolation of treatments for neuropathic pain Multidisciplinary and Multi-modal Approach most successful Multimodal approach Injections Pharmacotherapies Physical therapies Psychological therapies Complimentary and alternative therapies Surgery Preventative Measures

Pharmacologic therapies Common oral medications: Simple Analgesics – Paracetamol & NSAIDs Opioids – some evidence for morphine and tramadol Effective for PLP, possibly reduces cortical re-organisation Better when combined with other agents Anti-depressants Tricyclic antidepressants/Serotonin Re-uptake inhibitors, Sodium channel blockade, NMDA antagonist effects - mixed results for PLP Mirtazepine Duloxetine Anti-convulsants Gabapentin – mixed results Carbamazepine Pregabalin (Lyrica)

Pharmacologic therapies - uncommon Calcitonin – mixed results, mechanism of effect unclear – not used NMDA receptor antagonists – blocks cascade leading to sensitisation of Wide Dynamic Range neurons in spinal cord Ketamine – short follow-up periods, psychogenic side effects Dextromethorphan – not used routinely Memantine – mixed results in RCTs – not used Others Sodium channel blockers – lignocaine/mexiletine – not effective B-blocker - Propranolol Ca-channel blocker - Nifedipine

Injection Therapies More useful for residual limb pain than phantom limb pain ? Due to greater contribution of peripheral mechanisms in RLP compared with PLP Regional nerve blocks (anaesthetics/corticosteroids) – often not long-lasting Botulinum toxin A perineural blocks – currently under study, not enough evidence yet Pulsed Radiofrequency – small study TNFα inhibitor (etanercept) perineural injection– small study Sympathetic nerve blocks – small study Ambulatory Continuous Peripheral nerve block for 6 days – small cross-over study – promising long term improvements in 2/3 subjects

Prosthetic Approaches Prosthetist review, adjustment of socket fit Alignment changes Replacement socket if stump volume change, weight change etc Utilise different prosthetic componentry eg. silicon/urethane liners, shock absorbers, torsion adaptors, multi-axial ankles Shift weight bearing away from stump: thigh-lacers, ischial bearing prostheses – much less common since Silicon available

Non-Pharm Treatments Psychological interventions – aim to facilitate adaptation to pain, body image, negative emotions EBM limited for these approaches Cognitive Behavioural Therapy – no RCTs; RCT combining CBT and mirror therapy in progress Hypnosis – small RCT showed benefit, 3 sessions Guided imagery – anecdotal Biofeedback – anecdotal Relaxation Techniques

Mirror Therapy Mirror neurons in the brain – fire when perform movement or when observe movement Activation may modulate somatosensory inputs and block protopathic pain perception in phantom limb i.e. lessens effect of de- afferentation RCTs one +ve, one –ve Recent study added illusory touch stimulation for cases where movement caused increased pain (Schmalzl et al 2013)

Mirror therapy – influencing cortical re-organisation Reduction of PLP with fMRI evidence of reduction in re-organisation

Non-Pharm Treatments Acupuncture – No RCTs, only descriptive studies TENS – shown to be helpful ?Contralateral limb Low-Freq, hi intensity Laser Ultrasound/Heat – musculoskeletal pain

Non-Pharm Treatments Successful rehabilitation may reduce the amount of pain Stump massage and familiarisation/desensitisation Early prosthetic use In upper extremity amputees, phantom pain was decreased by the use of a prosthesis which allowed extensive use of the affected limb but not with cosmetic prosthesis use Oedema control/Use of stump shrinker/RRD

Early weight-bearing?? No consensus on the impact of weight bearing on early wound healing Possible benefits for reducing oedema and stimulation of circulation, reducing cortical re- organistaion Possible detrimental effects of excessive loading damaging fragile new tissue and harming the healing response Still no standard protocols for the amount, time, and advancement of weight bearing Published studies use many different weight-bearing protocols Main concern will be for poorly vascularised limbs or friable skin My approach… anytime after 1 week if the tissues look good, but logistics mean that rarely less than 2-3 weeks post-op, otherwise after clips out and suture line healed in questionable stumps

Surgical Intervention Stump Revision occasionally useful for difficult to fit stumps Clinically significant neuromas may require resection if prosthetic changes not sufficient - mixed results with excision Excision of Heterotopic bone and bone spurs – may recur Neurosurgical procedures: DREZ lesioning Spinal Cord Stimulation – evidence for PAP less robust than for other neuropathic pain states Peripheral Nerve Stimulation – might work if one or two nerve territories affected, may not work if spinal or cortical re-organisation Deep Brain Stimulation – PVG, thalamic nuclei, motor cortex – case series evidence – mixed results for PAP Electroconvulsive therapy A case report

Spinal Cord Stimulator

Surgical Intervention Stump Revision occasionally useful for difficult to fit stumps Clinically significant neuromas may require resection if prosthetic changes not sufficient - mixed results with excision Excision of Heterotopic bone and bone spurs – may recur Neurosurgical procedures: DREZ lesioning Spinal Cord Stimulation – evidence for PAP less robust than for other neuropathic pain states Peripheral Nerve Stimulation – might work if one or two nerve territories affected, may not work if spinal or cortical re-organisation Deep Brain Stimulation – PVG, thalamic nuclei, motor cortex – case series evidence – mixed results for PAP Electroconvulsive therapy A case report

Deep Brain Stimulation

Surgical Intervention Stump Revision occasionally useful for difficult to fit stumps Clinically significant neuromas may require resection if prosthetic changes not sufficient - mixed results with excision Excision of Heterotopic bone and bone spurs – may recur Neurosurgical procedures: DREZ lesioning Spinal Cord Stimulation – evidence for PAP less robust than for other neuropathic pain states Peripheral Nerve Stimulation – might work if one or two nerve territories affected, may not work if spinal or cortical re-organisation Deep Brain Stimulation – PVG, thalamic nuclei, motor cortex – case series evidence – mixed results for PAP Electroconvulsive therapy A case report

Preventative Treatments Pre-emptive analgesia/anaesthesia Pre-op, intra-op, early post-op period (<2 weeks) – goal to avoid long term spinal sensitisation Still no definitive evidence Prevention of Acute PLP Epidural treatments – 3 trials – mixed results, best quality study no benefit Regional nerve blocks – 3 studies – no effect IV calcitonin – 1 study – no benefit TENS – 1 study, no benefit Prevention of chronic PLP Pre-op epidural anaesthesia – studies mixed but may suggest need to be started at least 24 hours pre-op May not need epidural Rx, other forms of good pre-op pain control may be equivalent Perineural anaesthesia – mixed results Prophylactic gabapentin from D1-30 not shown to prevent PLP TENS – RCT showed lower incidence at 4 months but no benefit at 4 weeks and 1 year, but improved wound healing time and lower re-amputation rate Mirror therapy prophylactically – small case series showed promise

Cochrane Review 2012 – Pharmacologic Interventions for PLP Morphine - Short-term effect for pain relief Ketamine – analgesic effects Gabapentin – trend towards pain relief Amitriptyline – not effective for PLP Memantine – not effective Calcitonin – variable findings i.e. NOT MUCH HELP

Thankyou