Phantom Limb Pain Current Theories and Evidence Based

Phantom Limb Pain: Current Theories and Evidence Based Treatments Christopher V Boudakian, DO PGY-4 Rusk Rehabilitation NYU Langone Medical Center

Objectives • Identify the definition and characteristics of phantom pain • Understand the current theories in the etiology and pathophysiology of phantom pain • Identify current evidence-based treatments for phantom pain

What is phantom limb pain? • The concept, first introduced by French military surgeon Ambrose Pare in the mid 16 th century, is pain that is perceived in a region of the body that is no longer present. • Later expanded by Silas Weir Mitchell in the mid 19 th century who coined the term “phantom pain” • Traditionally described as two separate phenomena • Perhaps a spectrum disorder? • In 1998, Weinstein proposed phantom sensations can be divided into 3 categories: kinetic sensations, kinesthetic components, and exteroceptive perceptions

3 categories of sensation • Kinetic sensations are the perception of movement, both spontaneous and willed • Kinesthetic components refer to the size, shape, and position of the missing body part • Exteroceptive perceptions include touch, pressure, temperature, itch, and vibration • Pain described in this category, however, distinguished by greater intensity

Characteristics of phantom pain • Seen in both patients with congenital and acquired limb deficiency. *** • Symptoms not limited to the limbs • Reports of phantom sensations and pain emanating from less common regions of the body including breast, nose, teeth and also visceral organs including rectum, uterus, and bladder. • Recent studies report 50 to 85% of patients with limb loss experience phantom pain. • This is in contrast to earlier studies which report rates under 10% • Incidence rates have been shown to be independent of gender, age, and location/level of amputation. • Not likely affected by mechanism, elective vs traumatic 1

Characteristics of phantom pain • Correlations with residual limb pains remain unclear • Kooijman et al. (2000) and Nikolajsen et al. (1997) reported positive correlation between phantom pain and residual limb pain. • Estimates show 50% of people with acquired amputations experience phantom pain in the first 24 hours and an additional 25% in the first week following limb loss 1 • Uustal and Meier report most people with amputations do not experience significant pain beyond 3 months.

Characteristics of phantom pain • Often described as burning, cramping, electrical shocks, severe itching, or stabbing • Episodes may last seconds to hours.

Theories of phantom pain • Despite numerous attempts to classify and define phantom pain, the pathophysiology and etiology of the condition remain unclear. • Both central and peripheral theories have been proposed. • Likely multifactorial

Central Nervous System Theories • Revolves around the concept of neuroplasticity and cortical reorganization. • Areas representing the amputated body part are taken over by neighboring representational zones in both the somatosensory and motor cortex • Extent of remapping proportional to intensity of pain

Central Nervous System Theories • Body schema theory postulated by Head and Holmes in 1912, later expanded by Melzack and termed neuromatrix theory • Involves the internal representation of spatial and biomechanical processes reflecting in bodily experience • Damage within any of the systems involved result in perceptual distortion • Neuromatrix theory adds to this by including cognitive and emotional factors. • Neurosignature refers to the patterns of activity generated within the brain that are continuously being updated based upon one’s conscious awareness and perception of the body and self. • Deprivation of various inputs from the limbs to the neuromatrix cause an abnormal neurosignature to be produced

Peripheral Nervous System Theories • Reinforced by correlation between residual limb pain and phantom pain • Mechanism remains unclear, however, it is postulated phantom pain may stem from neuromas formed at the site of amputation • Neuromas may exhibit abnormal activity following mechanical or chemical stimulation generating ectopic impulse discharge • Ectopia may drive neuroplasticity and sensitization leading to increased sympathetic tone that serves as a feedback loop to maintain phantom pain • Pain is not consistently abated with neuroma or nerve/plexus blocks • Vaso et al. (2014) propose the dorsal root ganglia, which remain intact after amputation may also be implicated in pain due to ectopia

Multifactorial Theory • Ramachandran and Hirstein (1998) propose that there at least 5 different sources that contribute to phantom pain: 1. 2. 3. 4. 5. Residual limb neuromas Cortical remapping Corrollary discharge Body image Somatic memories All 5 components may work together and reinforce each other

Treatment options • Limited options without clear consensus on an optimal regimen • Common pharmacological treatment includes opioids, anticonvulsants, lidocaine/mexiletine, clonidine, ketamine, amitryptaline, NSAIDs, and calcitonin. • Opioids bind to central and peripheral receptors providing analgesia without loss of touch, proprioception, or consciousness.

Pharmacological treatment • Studies demonstrate opioids may diminish cortical reorganization • Huse et al. (2001) small, double-blind crossover trial (n=12) showing evidence of reduced cortical reorganization with morphine leading to reduced pain. • Mc. Cormick et al. (2014) reports the best evidence in the literature for use of IV ketamine and IV morphine perioperatively and PO morphine for long term treatment, 8 weeks to 1 year • Level 2 evidence for gabapentin, both oral (PO) and intravenous (IV) morphine, tramadol, intramuscular (IM) botulinum toxin, IV and epidural Ketamine • Level 3 evidence for amitriptyline, dextromethorphan, topiramate, IV calcitonin, PO memantine, continuous perineural catheter analgesia with ropivacaine • Level 4 evidence for methadone, intrathecal (IT) buprenorphine, IT and epidural fentanyl, duloxetine, fluoxetine, mirtazapine, clonazepam, milnacipran, capsaicin, and pregabalin. • Sympathetic targets and NSAIDS have not been well studied

TENS • Katz and Melzack demonstrated significant pain relief in patients with the use of transcutaneous electrical stimulation • RCT (1991) demonstrated significant decrease in pain with auricular TENS • Carabelli and Kellerman (1985) showed pain relief with application of TENS to unaffected side in 3 patients, no return of symptoms at 6 month follow up • Finsen et al. (1988) performed a single–blinded trial (n=51) and found no significant difference in post operative or chronic limb pain with the use of TENS. • Phantom pain after TENS was significantly lower between four months and one year follow up • Mulvey et al. (2012) performed a pilot study demonstrating reduction of pain on movement and at rest in 10 subjects.

Implantable Stimulators • Temporary and immediate relief found by deep brain stimulation of the ventral caudal thalamic nucleus and posterior columns. • Bittar et al. (2005) showed mean reduction of pain by 62% at one year follow up for 3 patients • Perreira and Boccard (2013) demonstrated efficacy in 5 amputee subjects at one year. • Spinal cord stimulation does not appear to help reliably decrease the intensity or frequency of phantom pain. • Largest study performed by Broggi et al in 1996 (n=26), with 58% success rate at 2 year follow up. • With advances in spinal cord stimulators, recent literature is limited to case reports regarding use in phantom limb pain • Katayam et al. (2001) studied the effect of SCS, DBS, and MCS on 19 patients with phantom pain • Satisfactory long term pain control was achieved in 6 of 19 (32%) by SCS, 6 of 10 (60%) by DBS and 1 (20%) of 5 by MCS. • No evidence of an advantage of MCS over SCS and DBS of the thalamus

Other modalities • Acupuncuture has demonstrated mixed and inconsistent results. • Other treatments reported to have mixed results include anesthetic and surgical neuroablation as well as psychologic interventions • Vaso et al. (2014) demonstrated spinal and intraforaminal block (n=31) consistently attenuated, and often completely eliminated both phantom pain and sensation in lower limb amputees

Mirror Therapy • Ramachandran et al. proposed the use of mirrors in 1996 • Patient views the reflection of their intact limb moving in a mirror placed strategically to mimic movement on the affected side • Chan et al. (2007) performed a randomized, sham-controlled crossover study showing significant decrease in pain for patients who underwent mirror therapy in comparison to 2 control groups • mental visualization was ineffective and may actually worsen pain • Ramachandran poses that the mirror resolves the visual-proprioceptive dissociation proposed as an explanation for phantom pain. • Mechanism remains unclear

Mirror Therapy • Rizollati et al. (2006) demonstrated the existence of “mirror neurons” in macaques that fire both when the animal performs an action, as well as when it observes the same action performed. • Ramachandran et al. (2008) further demonstrated that touching the virtual image in the mirror is sufficient to elicit tactile sensation in the phantom limb • Activation of mirror neurons modulates somatosensory inputs and may block pain perception in the phantom limb.

Mirror Therapy • Deconinck et al. (2014) performed a systematic review to asses the effect of mirror therapy on brain activation during a motor task • Mirror therapy increases neural activity in areas involved with allocation of attention and cognitive control (dorsolateral prefrontal cortex, posterior cingulate cortex, S 1 and S 2, precuneus). • Evidence for ipsilateral projections from the contralateral M 1 to the untrained/affected hand as a consequence of training with mirrors • Apart from activation in the superior temporal gyrus and premotor cortex, there is little evidence it activates the mirror neuron system. • Mirror therapy can exert a strong influence on the motor network, mainly through increased cognitive penetration in action control. • Variance in methodology and the lack of studies that shed light on the functional connectivity between areas still limit insight into the actual underlying mechanisms

Conclusion • Further research is needed to determine the relationship between proposed mechanisms of phantom pain • Treatment plan should be targeted to symptoms as well as underlying mechanisms

Thank You

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Weeks S. , et al. “Phantom Limb Pain: Theories and Therapies” The Neurologist 2010; 16: 277– 286 Vaso et al. “Peripheral nervous system origin of phantom limb pain” Pain 21 April 2014; Epub ahead of print Uustal, H. , et al. “Pain Issues and Treatment of the Person with an Amputation” Phys Med Rehabil Clin N Am 25 (2014) 45– 52 Mc. Cormick et al. “Phantom limb pain: A Systematic Neuroanatomical-Based Review of Pharmacoloigcal Treatment” Pain Medicine 2014; 15: 292– 305 Nikolaijsen, L. , et al. “The influence of preamputation pain on postampuation stump and phantom pain” Pain 1997; 72: 393– 405 Melzack R. “Prolonged relief of pain by brief, intense transcutaneous somatic stimulation. ” Pain. 1975; 1: 357– 373. Carabelli R, Kellerman W. “Phantom limb pain: relief by application of TENS to contralateral extremity” Arch Phys Med Rehabil. 1985 Jul; 66(7): 466 -7 Finsen V, Persen L, Lovlien M, et al. “Transcutaneous electrical nerve stimulation after major amputation. ” J Bone Joint Surg Br. 1988; 70: 109 – 112. Mulvey M, Radford H, et al. “Transcutaneous Electrical Nerve Stimulation fo Phantom Pain and Stump Pain in Adult Amputees. ” Pain Practice (2013); 13(4); 289 -296. Broggi G, Servello D, Dones I, Carbone G. “Italian multicentric study on pain treatment with epidural spinal cord stimulation” Stereotact Funct Neurosurg 1994; 62(1 -4): 273 -8 Bittar R, et al. “Deep brain stimulation for phantom limb pain. ” Journal of Clinical Neuroscience (2005); 12(4): 399 -404 Perreira E, Boccard S, et al. “Thalamic deep brain stimulation for neuropathic pain after amputation or brachial plexus avulsion. ” Neurosurgical Focus (2013) 35(3): E 7