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Exploratory pilot study of electrical stimulus as a treatment option for chronic phantom limb pain

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Title:
Exploratory pilot study of electrical stimulus as a treatment option for chronic phantom limb pain
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Fitzgerald, Kelsey Sebring ( author )
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Denver, Colo.
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University of Colorado Denver
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English
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Master's ( Master of science)
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University of Colorado Denver
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Department of Bioengineering, CU Denver
Degree Disciplines:
Bioengineering

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Phantom limb ( lcsh )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Review:
There are nearly 2 million people with limb loss solely in the USA, commonly caused by trauma, cardiovascular disease, diabetes, cancer, and congenital limb deficiency. Phantom limb pain (PLP) is characterized as the pain occurring in the missing limb following an amputation and occurs in up to 80% of amputees. There are many current treatments for PLP that are often invasive and do not provide long lasting solutions. Patterned electrical neuromuscular stimulation (PENS) is a non-invasive surface electrical stimulation that has been used for pain management and re-education of muscle action. It has been beneficial in treatment of other injuries and may be applied to PLP. ( ,, )
Review:
In this study the Omnistim FX2 Pro was used to apply PENS at a low frequency and short phase duration to the residual limb in two lower limb amputee subjects. The electrical stimulation delivered through the surface electrodes was increased to a non-painful level of intensity that elicited a motor contraction in the antagonistic muscles of the residual limb for a duration of 15 minutes over 15 sessions. Pain data was collected using a 10-point numerical rating pain scale (NRS) before and after each treatment session. Presence of the characteristics of PLP including cramping, stabbing, shooting, and burning pain were tracked each week.
Review:
A one sided dependent T-test showed PENS effectively reduced the PLP in the two participants by over 85% (p<.05). Both participants began the study with severe PLP (8-10 NRS) and obtained sustained relief lasting up to 3 weeks from the therapy at little to no pain (1-2 NRS). PENS therapy was able to alleviate cramping, stabbing, and shooting PLP symptoms. The therapy was well accepted and participants commented that nothing had been able to relieve their PLP before this. The beneficial preliminary results from this pilot study should be expanded into a larger clinical trial to improve the significance of the effects, include application to upper limb amputees, as well as include a control.
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Includes bibliographic resource.
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System requirements: Adobe Reader.
Statement of Responsibility:
by Kelsey Sebring Fitzgerald.

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University of Colorado Denver
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Auraria Library
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on1020495386
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Full Text
EXPLORATORY PILOT STUDY OF ELECTRICAL
STIMULUS AS A TREATMENT OPTION FOR CHRONIC PHANTOM LIMB PAIN By
KELSEY SEBRING FITZGERALD B.A., University of Colorado, Boulder, 2015
A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfilment of the requirements for the degree of Master of Science Bioengineering Program
2017


2017
KELSEY SEBRING FITZGERALD
ALL RIGHTS RESERVED


Thesis for the Master of Science degree by Kelsey Sebring Fitzgerald has been approved for the Bioengineering Program By
Richard Weir, Chair Cathy Bodine Frank Palermo
Date: July 29, 2017-06-29


Fitzgerald, Kelsey Sebring (M.S., Bioengineering)
Exploratory Pilot Study of Electrical Stimulus as a Treatment Option for Chronic Phantom Limb Pain
Thesis directed by Associate Professor Richard Weir
ABSTRACT
There are nearly 2 million people with limb loss solely in the USA, commonly caused by trauma, cardiovascular disease, diabetes, cancer, and congenital limb deficiency. Phantom limb pain (PLP) is characterized as the pain occurring in the missing limb following an amputation and occurs in up to 80% of amputees. There are many current treatments for PLP that are often invasive and do not provide long lasting solutions. Patterned electrical neuromuscular stimulation (PENS) is a non-invasive surface electrical stimulation that has been used for pain management and re-education of muscle action. It has been beneficial in treatment of other injuries and may be applied to PLP.
In this study the Omnistim FX2 Pro was used to apply PENS at a low frequency and short phase duration to the residual limb in two lower limb amputee subjects. The electrical stimulation delivered through the surface electrodes was increased to a non-painful level of intensity that elicited a motor contraction in the antagonistic muscles of the residual limb for a duration of 15 minutes over 15 sessions. Pain data was collected using a 10-point numerical rating pain scale (NRS) before and after each treatment session. Presence of the characteristics of PLP including cramping, stabbing, shooting, and burning pain were tracked each week.
IV


A one sided dependent T-test showed PENS effectively reduced the PLP in the two participants by over 85% (p<.05). Both participants began the study with severe PLP (8-10 NRS) and obtained sustained relief lasting up to 3 weeks from the therapy at little to no pain (1-2 NRS). PENS therapy was able to alleviate cramping, stabbing, and shooting PLP symptoms. The therapy was well accepted and participants commented that nothing had been able to relieve their PLP before this. The beneficial preliminary results from this pilot study should be expanded into a larger clinical trial to improve the significance of the effects, include application to upper limb amputees, as well as include a control.
The form and content of this abstract are approved. I recommend its publication.
Approved: Richard Weir
v


ACKNOWLEDGMENTS
This human subjects research project was approved by COMIRB under protocol 16-1063. Thank you to the people at COMIRB for helping me through the initial approval process and subsequent amendments. This project would not have been possible without the help from the faculty in the Bioengineering Department, the staff at Childrens Hospital Colorado, and Accelerated Care Plus for donating the equipment. Many thanks to Dr. Sarah Sibbel, Dr. Travis Heare, Dr. Nathan Donaldson, and Dr. Matthew Mayer at Childrens Hospital for serving on this study and prescribing the therapy to the participants. Also thanks to my advisor Dr.
Richard Weir and committee members Dr. Cathy Bodine and Dr. Frank Palermo for their guidance and editing of numerous revisions. And finally, thanks to my parents and friends who encouraged me along this process and got me to the finish line.
VI


TABLE OF CONTENTS
CHAPTER
I. INTRODUCTION......................................................................1
II. HYPOTHESIS.......................................................................3
Specific Aims......................................................................3
III. BACKGROUND......................................................................4
Muscle Physiology..................................................................4
Effect of Amputation...............................................................5
Phantom Limb Pain..................................................................8
Originating in the Peripheral Limb..............................................9
Disruptions in the Spinal Cord.................................................10
Cortical Reorganization........................................................11
Predisposing Factors...........................................................13
Treatments........................................................................14
Opioids........................................................................14
Mirror Therapy.................................................................15
Transcutaneous Electrical Nerve Stimulation....................................17
Electrical Stimulation Therapy....................................................18
Increased Intensity Electrical Stimulus........................................18
Patterned Electrical Neuromuscular Stimulation.................................19
Electrical Stimulation Effects on the Body.....................................21
Tolerance to Electrical Stimulation............................................22
Clinimetrics......................................................................22
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Visual Analog Scale
23
Numerical Rating Scale............................................................23
Study Design........................................................................24
IV. MATERIALS..........................................................................25
Omnistim FX2 Pro....................................................................25
Numerical Rating Pain Scale.........................................................26
Questionnaire.......................................................................27
V. METHODS............................................................................28
Human Subjects......................................................................28
Inclusion Criteria................................................................28
Exclusion Criteria................................................................28
Electrical Stimulation Therapy......................................................29
Data Analysis.......................................................................31
VI. RESULTS............................................................................32
Effect of Electrical Stimulation Therapy on Decreasing Pain.........................32
Short Term Pain Relief..............................................................33
Reduction in Pain...................................................................35
Sustained Relief....................................................................37
Changes in the Characteristics......................................................38
Participant Testimonies.............................................................39
VII. DISCUSSION........................................................................41
Limitations of the Study............................................................44
viii
Unforeseen Obstacles
45


Future Developments.....................................................46
REFERENCES................................................................47
APPENDIX: COMIRB PROTOCOL.................................................51
IX


LIST OF TABLES
TABLE
1. Placement of the anterior and posterior surface electrodes on the residual limb
if the participant is an above or below the knee amputee.......................29
2. Pre and Post therapy max and min NRS pain scores for the 2 participants were
used to calculate percent decrease. Average reduction in pain is the reduction due to each treatment session averaged over all the completed sessions for each participant. The p-value was computed using a one-sided paired t-test to test for a significant reduction in pain.......................................36
3. Characteristics of PLP including cramping, burning, stabbing, and shooting pain
in the missing limb were tracked over time. Data was collected at the start of each treatment week and the characteristics are marked as Present (X) or Absent ( ).....................................................................39
x


LIST OF FIGURES
FIGURE
1. Muscles insert across a joint and movement is achieved when the muscle
shortens and bends the joint. (Pearson Education Inc., 2011)............4
2. Proprioceptors are sensors that receive information about the body in space
relay information to the central nervous system including the thalamus and somatosensory cortex where the sensory information is received. (Pearson Education Inc., 2011)...................................................8
3. Neuromagnetic source imaging used to map the mouth and hand regions
displaying cortical reorganization of the primary somatosensory cortex in an arm amputee (Flor, 2002. Permission received from ScienceDirect)........12
4. Mirror therapy works by placing the intact limb in front of the mirror and the
missing limb behind the mirror. The patient perceives their missing limb as the image reflected in the mirror.......................................16
5. The Visual Analog Scale is a 100mm horizontal line with pain extremes marked
at each end. The patient is asked to mark on the line where their pain is at before and after the treatment and the difference is recorded in mm.23
6. Application of the PENS protocol to the agonist and antagonist muscles and
their activity recorded using EMG. Output A is the surface electrode stimulating the agonist muscle and output B stimulates the antagonist muscle. The phase duration of the stimulation is the time in milliseconds. (ACP, 2007)....26
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7. Self-reported numerical pain scale that was given to the participant before and
immediately following the treatment to assess short term changes in phantom limb pain............................................................27
8. Surface electrode placement on the residual limb for an above-the-knee
amputation. Anterior electrodes placed on the vastus medialis (black) and rectus femoris (red). Posterior electrodes were placed inline on the major biceps femoris of the hamstrings............................................30
9. Pre and Post Treatment NRS pain values for each participant show the
reduction of pain during each treatment session. The relief of PLP following a treatment session was significant for both participants..............34
10. Average phantom limb pain reduction per treatment session based on a
numerical rating pain scale before (pre) and after (post) the patterned electrical neuromuscular stimulation for the two participants with standard error bars. For the first subject the PLP was reduced on average by 1.375 points and the second subject had a reduction of 1.727 points each treatment session. indicates that the reduction is significant based on the literature......35
11. Numerical rating pain scale data collected before the patterned electrical neuromuscular stimulation was applied to the residual limb. The pain decreased until it plateaued at little to no pain for both subjects. Both participants saw a
significant reduction in pain.
36


12. Days of relief from PLP following an electrical stimulation treatment session.
The length of relief in days increased exponentially (R= 0.81215) with the number of treatment sessions attended by the participants. Data displayed here is from the first participant who experienced 21 consecutive days without PLP
after only 8 treatment sessions.
38


LIST OF ABBREVIATIONS
PLP Phantom Limb Pain
ACP Accelerated Care Plus
EMG Electromyography
DRG Dorsal Root Ganglion
CNS Central Nervous System
EEG Electroencephalogram
VAS Visual Analog Scale
NRS Numerical Rating Scale
TENS Transcutaneous Electrical Nerve Stimulation
SCS Spinal Cord Stimulation
PENS Patterned Electrical Neuromuscular Stimulation
XIV


CHAPTER I
INTRODUCTION
Phantom limb pain (PLP) is a term that was first described in 1552 by Ambrose Pare, a sixteenth century French military surgeon, and then later coined in the 19th century by Silas Weir Mitchell, a famous surgeon (McGimpsey & Bradford, 2010; Subedi & Grossberg, 2011). Phantom limb pain is characterized as the pain occurring in the missing limb following an amputation. The reported rate of PLP was originally low due to a stigma behind the disease of appearing mentally unstable. According to the Amputee Coalition of America (2017), there are nearly 2 million people with limb loss solely in the USA, and that number has remained high since the start of the of the conflict overseas in Iraq and Afghanistan (Weeks, Anderson-Barnes & Tsao, 2010). Amputations are common in trauma such as war time injuries as well as cardiovascular disease, diabetes, cancer, and congenital limb deficiency. Each year, there are approximately 185,000 amputation surgeries performed and nearly an 80% prevalence of PLP in amputees (Flor, 2002). This equates to 148,000 new cases of PLP each year just in the United States. Of the 185,000 amputation surgeries performed each year, 54% of them are due to cardiovascular disease and diabetes (Amputee Coalition, 2017). The prevalence of cardiovascular disease increases from 40% in people ages 40-59, to 70-75% in people ages 60-79, and then again to 86% for those over the age of 80 in both men and women (Lloyd-Jones, Adams, Carnethon, et al., 2009). Because of the increase in occurrence of cardiovascular disease with age, there is also a direct correlation between age and likelihood of an amputation. More than 65% of amputations are performed on people
1


age 50 and older (McGimpsey & Bradford, 2010). With individuals living longer, the growing US population in those aged 60 and older is expected to dramatically increase in the next 30 years. This will lead to an increase in people with cardiovascular disease, more amputations, and a larger population living with PLP (Yazdanyar & Newman, 2009). Ziegler-Graham, MacKenzie, Ephraim, Travison & Brookmeyer (2008) predicted the number of people living with a limb loss in the U.S. to increase to 3.6 million by 2050 using incidence rates of amputations and assumptions based on age, sex, and race.
People with PLP are currently using pharmacologic drugs, anesthesia, additional surgeries and other non-invasive techniques such as mirror therapy to reduce their pain. While there are many treatments for PLP, they are sometimes invasive and do not provide long lasting solutions. Patterned electrical neuromuscular stimulation is a non-invasive surface electrical stimulation that has been used for pain management and re-education of muscle action. It has been beneficial in treatment of other injuries and may be applied to phantom limb pain (Accelerated Care Plus [ACP], 2007). A developed protocol to physically exercise the muscles of the residual limb and in turn increase the local blood flow may decrease stiffness and co-contraction and reduce PLP for amputees. There is no available research on the effects of Patterned Electrical Neuromuscular Stimulation on PLP which leaves a need for investigation and will be addressed with this exploratory pilot study on its effectiveness in reducing chronic PLP.
2


CHAPTER II
HYPOTHESIS
Patterned electrical neuromuscular stimulation applied at an intensity that elicits a muscle motor contraction in the antagonistic muscles of the residual limb may mitigate chronic phantom limb pain based on a numerical rating scale.
Specific Aims
Specific Aim One: Employ a Patterned Electrical Neuromuscular
Stimulation protocol with adjusting changes in intensity of the electrical stimulus to elicit a motor contraction in the residual limb. Electrical stimulus has many parameters including frequency, intensity, wavelength, stimulation patters, etc. The Omnistim FX2 Pro utilizes a low frequency of 50 Hz and an alternating stimulation pattern with a phase duration of 40 \is that is advantageous for clinical use due to the ease of skin penetration at lower intensities. For our study we want to establish an electrical stimulation protocol on changes in intensity of the electrical stimulus and the effect it has on chronic phantom limb pain. This will be accomplished by increasing the intensity to a non-painful level that elicits a motor contraction in the muscle for a duration of 15 minutes. According to the device manual it is standard-of-care to elicit a moderate muscle twitch for therapeutic purposes with the Omnistim FX2 Pro.
Specific Aim Two: Examine short term effects of Patterned Electrical
Neuromuscular Stimulation. Short term effects of the therapy will be examined at an intensity that promotes motor contraction on human subjects with chronic phantom limb pain through the use of a numerical rating scale administered before each treatment session and directly following.
Specific Aim Three: Assess the effect that Patterned Electrical
Neuromuscular Stimulation has on the characteristics of PLP.
The characteristics of PLP include cramping, stabbing, burning, and shooting pain in the missing portion of the limb. The effects will be assessed through a short answer questionnaire administered at the start of each treatment week. These questions will ask the participant which characteristics of the pain are present. This will provide insight into the effect that the treatment has on the different
3


characteristics/symptoms of phantom limb pain in preparation for a future study.
CHAPTER III
BACKGROUND
Muscle Physiology
Skeletal muscle makes up the largest percent of muscle in the human body and is responsible for movement through voluntary control. An individual muscle is composed of subunits called muscle fascicles which are made up of muscle fibers; the smallest subunit being the myofibrils which are made up of actin and myosin. Muscle fibers are innervated by motor neurons and together combine to form a functional motor unit. Motor neurons project into the muscle fibers and send voluntary control signals from the brain through the spinal cord to trigger the muscle for contraction. Muscles are actuators that remain unstimulated unless commanded to contract by a motor neuron. They can only shorten in length and perform the bending of joints by working together with synergistic and antagonistic muscles, inserting across the joint as displayed in Figure 1.
Figure 1: Muscles insert across a joint and movement is achieved when the muscle shortens and bends the joint. (Pearson Education Inc., 2011)
02011 Poarion Education Inc
4


In 1954, Andrew Huxley and Hugh Huxley published separate papers proposing that muscle contraction was due to the sliding of the thin filaments (actin) and thick filaments (myosin) past one another (Herzog, Powers, Johnston & Duvall, 2015). This became known as the Sliding Filament Theory which is still accepted today as the method of muscle contraction. Later in 1957, this theory was expanded by Andrew Huxley to describe the attachment between the filaments and the active force produced during contraction; this is known as the Cross-Bridge Theory (Huxley, 1957). Today, there is continued research in this area by Dr. Walter Herzog and others to explain the passive force produced by muscle through the protein titin and eccentric contraction where the muscle fibers are lengthened (Herzog et al. 2015). Muscles are essential to the bodys movement and function, and during an amputation that ability to contract is compromised.
Effect of Amputation
During an amputation, the limb is severed and so are the muscles and motor neurons. The amputation procedure varies depending on how much of the limb is being amputated as well as the site of amputation. Doctors try to preserve as much of the residual limb as they can and take many factors (limb temperature, coloring and sensitivity) into account before amputating a limb. During the procedure, the surgeon will remove the diseased tissue and crushed bone, smooth the new end of the bone, seal off blood vessels and nerves, and finally cut and shape the muscles so that the residual limb can be fitted with a prosthesis before closing the skin and dressing the wound (Johns Hopkins Medicine, n.d.). Many times, this final step of
5


the amputation involves connecting the antagonistic muscles to one another or wrapping one around the stump in order to tie them down (the processes of myoplasty and myodesis). This often results in co-contraction, tension, and stiffness in the muscles of the residual limb (Seyedali, Czerniecki, Morgenroth, & Hahn, 2012). Muscles tend to co-contract to increase stability and protect the joint leading to a more rigid limb.
Seyedali et al. (2012) tested this theory of co-contraction by observing nine unilateral trans-tibial (lower leg) amputees utilizing their prescribed prosthetic and comparing their co-contraction to five control intact-limbed individuals in all phases of gait analysis. In their study they looked separately at co-contraction of the ankle and knee joints. Using surface electromyography (EMG), they recorded activation of the tibialis anterior, medial gastrocnemius, vastus lateralis and biceps femoris. Seyedali et al. (2012) found co-contraction of the ankle and knee muscles to be more pronounced in the residual limb of the amputees than the control limbs. They concluded that amputees may be co-contracting as a way to stiffen the residual limb and increase stability which is necessary for their gait and single limb support in walking or running (Seyedali et al., 2012). This effect of co-contraction and limb stiffening may be adding to phantom limb pain and discomfort (Subedi & Grossberg, 2011).
When a limb is missing, the brain recognizes an unfamiliar sensation in the proprioceptors (muscle spindles) of the residual limb. Proprioceptors provide sensory information about the limbs location in space including: muscle length, muscle tension, and joint angle (Sherwood, 2015). As shown in Figure 2, these
6


signals are sent to the thalamus and somatosensory cortex. The thalamus relays the sensory signals from the body to the somatosensory cortex of the cerebral cortex for interpretation of the pain stimulus. In the textbook Human Physiology: From Cells to Systems, Sherwood comments on phantom limb pain and proposes the idea that severed endings of the muscle spindles and afferent nerve pathways can trigger action potentials that are then misinterpreted in the somatosensory cortex as pain in the missing region. Sherwood adds that phantom limb pain may also be a result from reorganization of the somatosensory cortex following an amputation (Sherwood, 2015). A study by Davis, Kiss, Luo, Tasker, et al. (1998) demonstrated that an amputation can affect the perception of the body in the thalamus and cerebral cortex.
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2011 Pearson Education, Inc
Figure 2: Proprioceptors are sensors that receive information about the body in space relay information to the central nervous system including the thalamus and somatosensory cortex where the sensory information is received. (Pearson Education Inc., 2011)
Phantom Limb Pain
Phantom limb pain (PLP) has been described as cramping, burning, stabbing, or shooting pain that occurs in the missing limb following an amputation. PLP is different from stump pain which occurs in the remaining portion of the limb, or non-painful sensations such as tingling, hot and cold sensations, and pressure that may also occur (Flor, 2002). It has been acknowledged that PLP occurs from a disconnect in the communication between the sensory pathway and the brain. Three
8


leading originations for the cause of PLP are: neuromas in the residual stump formed from deafferentation of the severed nerve, severing of peripheral nerves which results in disruptions in the afferent nerve input to the spinal cord, and cortical reorganization in the brain (Flor, Nikolajsen, & Jensen, 2006).
Originating in the Peripheral Limb
There is no well-accepted answer to the origin of phantom limb pain, but many researchers believe that some of the pain is initiated in the peripheral limb. Following an amputation, the nerves that once innervated the missing limb may be left severed or unconnected and can form neuromas in the peripheral limb (Flor et al., 2006). A neuroma is a growth of the nerve tissue that generates abnormal activity that does not originate at the nerve ending, and is sensitive to both mechanical and electrical stimuli (Bek, Demiralp, Kbmurcu, Atesalp, 2006). The injured nerve may have altered electrical properties that effect the voltage-sensitive sodium and potassium channels (Viswanathan, Phan, & Burton, 2010). Flor et al. (2006) found injections of a systemic adrenergic blocking agent at the site of the neuroma to reduce PLP and injections of adrenaline to increase PLP. Adrenergic blocking agents work by blocking sympathetic stimulation and production of epinephrine (adrenaline) which aggravates neuronal activity.
A study by Bek et al. (2006) evaluated the relationship between neuromas and PLP. 14 patients who developed neurinoma (a tumor of the nerve sheath) and PLP after a limb amputation were enrolled in the study to undergo a neurectomy to remove the neurinoma. Before the procedure the PLP mean visual analog score (VAS) was an 8.4 out of 10. The neurectomy was performed on all 14 patients and a
9


follow-up was conducted on average 71.5 months after the procedure. At the time of the follow-up, Bek et al. observed complete relief from PLP (0 VAS) and the disappearance of the neuroma symptoms. They concluded that to prevent neuromas and PLP the best approach to an amputation is to cut the nerve at a proximal position on the limb in order to leave the nerve ending furthest from the stump where most contact occurs (Bek et al., 2006).
The peripheral limb may not be the source of phantom limb pain since the pain can persist in the absence of neuromas but it may have a role in exacerbating it. (Subedi & Grossberg, 2011). Flor et al. (2006) proposed that a source for PLP was a combination of the damaged nerve endings with distorted activity in the dorsal root ganglia (DRG) which is responsible for relaying information to the central nervous system (CNS). For this reason, many researchers have looked for other sources of phantom limb pain including disruptions in the spinal cord and loss of input from the limb (Vaso et al., 2014).
Disruptions in the Spinal Cord
The dorsal root ganglion (DRG) is a collection of cell bodies that receives afferent sensory signals from the peripheral system before relaying it to the central nervous system which is made up of the brain and spinal cord. Damage to the DRG can result in spinal hyperactivity such as increased firing of dorsal horn neurons or decreased spinal cord inhibitory processes (Flor et al., 2006). Since 1969, spinal cord stimulation (SCS) has been used as a treatment for PLP (Viswanathan, Phan, and Burton, 2010). Viswanathan et al. (2010) tested the effectiveness of SCS in four lower limb amputee subjects and found the overall PLP to be reduced by over 80%
10


using the Brief Pain Inventory. In the study, the participant received implanted octopolar leads near the spinal cord that administered the stimulation to induce paresthesia in the area of pain. They concluded that this therapy was effective in reducing PLP but found other issues with it such as allergic dermatitis to the implant and infection at the site of implantation that resulted in two of the four subjects eventually having the implant removed.
Vaso et al. (2014) researched the idea that PLP was caused by an exaggeration of sensory input to the DRG rather than a loss of sensory input. They performed a study on 31 lower limb amputees using an intraforaminal epidural block of lidocaine injected in the DRG to prevent ectopic signals produced from reaching the CNS. They found the intraforaminal block consistently reduced both PLP and non-painful phantom limb sensations compared to a sham injection. Using the anesthetic injection, they were able to suppress the sensory input and saw a reduction in pain which supported their hypothesis that PLP may be caused by an amplification of sensory input (Vaso et al., 2014).
Cortical Reorganization
Previous studies have found PLP to be closely linked to maladaptive cortical plasticity (cortical reorganization) and changes in the primary somatosensory cortex of the brain as seen in Figure 3. Specifically, there is a connection between arm amputees and reorganization to the mouth region (Flor, Denke, Schaefer, &
Grusser, 2001).
11


Mouth
Amputated
Mirrored hand
Intact
Hand
Mouth
Figure 3: Neuromagnetic source imaging used to map the mouth and hand regions displaying cortical reorganization of the primary somatosensory cortex in an arm amputee (Flor, 2002. Permission received from ScienceDirect).
Flor et al. (2001) looked at the effect of sensory discrimination training on cortical reorganization and phantom limb pain. Their study consisted of 10 individuals, both male and female, ages 31 -74, with arm amputations on either side who were randomly put into an experimental group or control group. The control group received medical treatment consisting of analgesic medicine, transcutaneous nerve stimulation, or physical therapy while the experimental group began 10 daily 90 minute sessions over two weeks of sensory discrimination training. In the sensory training, the subject had to discriminate between the frequency or location of a non-painful high intensity electrical stimulus applied through eight surface electrodes
12


attached to the residual limb (Flor et al., 2001). Flor et al. (2001) saw a significant decrease in cortical reorganization which was measured using neuroelectric source imaging; the use of EEG (electroencephalogram) signals to map localizations of somatosensory evoked potentials in the brain. They also saw a decrease in PLP using a multidimensional pain inventory; a self-reported measure of chronic pain and the affect it has on an individuals life (West Flaven-Yale). With these findings, they concluded that there was a positive correlation between changes in sensory discrimination, cortical reorganization, and PLP (Flor et al., 2001). This study supports the idea that PLP may originate at the level of the brain and could be caused by cortical reorganization.
Predisposing Factors
There are many factors which have been associated with the onset of PLP including site of amputation, presence of pre-amputation pain, age and gender (Subedi & Grossberg, 2011). The incidence of pre-amputation pain has been reported to increase the likelihood of developing PLP (Hanley et al., 2007).
Research has found PLP to be more common among upper limb amputees than lower limb, and in women more often than men. (Subedi & Grossberg, 2011). PLP can present within hours following the amputation procedure or even a month or a year after the amputation is performed (Schley et al., 2008). It has also been recorded that stress, anxiety, exhaustion, and depression can exacerbate PLP (Berger & Bacon, 2009). The greatest determining factor of PLP appears to be the presence of pain in the limb before amputation (Hanley et al., 2007).
13


Treatments
Since PLP is such a prevalent problem, there have been many attempts at treatments including pharmacological prescriptions, additional surgeries, anesthesia doses, psychological treatments, transcutaneous electrical nerve stimulation (TENS), mirror therapy, massage and heat application (Flor, 2002). Some of the pharmacological prescriptions are opioids, ketamine, antidepressants, and muscle relaxants. These are used to block the pain signals from the afferent pathway back to the CNS and suppress the pain sensation. Anesthesia works in a similar manner by numbing the nerve ending and blocking the afferent pain stimulus. These treatments have showed only a slight decrease in pain and for a short period of time following administration (Kim & Kim, 2012).
Opioids
Opioids are a class of drugs that act on opioid receptors in the body to mimic morphine effects. They act on the central nervous system to reduce pain and have been proposed to inhibit cortical reorganization which can cause phantom limb pain (Turcios, Tran, Tu, & Lie, 2013). A major concern with opioid use is the risk of physical and mental dependence and also dosage tolerance and escalation. This tends to decrease recommendations for long-term use (Turcios et al., 2013).
A case study conducted by Kumar et al. (2015) included a 72-year-old male who had an above the knee amputation after being diagnosed with a cancerous tumor on his tibia. After being discharged following surgery he was administered 5 mg of morphine every four hours. After a week, his pain was still intense and his self-reported pain score was an 8 out of 10 on a visual analog scale (VAS). Kumar et
14


al. (2015) started the subject on oral morphine of 10 mg every four hours with progressive increase in concentration to 120 mg over a period of four weeks in order to manage the pain down to a score of 1-2 VAS. The subject then acclimated to the dosage and it was increased to 300 mg/4hrs to maintain a pain score VAS < 4.
Other interventions such as nerve blocks were attempted to reduce the pain and had little effect so the morphine dosage was increased again by gradual titration to 540 mg/4hrs. At this dosage the PLP remained diminished, but any attempt to decrease the morphine dose caused the pain to return so the researchers maintained the high-level dose (a high-level dose is considered as morphine >299mg/day). Researchers were able to achieve an optimal morphine dose to reduce the subjects PLP, but it required daily high-dose morphine which can have other health implications. According to the U.S. Department of Health and Human Services as many as 1 in 4 patients using long-term opioid therapy for chronic pain struggle with dependence. Morphine dosage over 50 mg/day doubles an individuals risk for an overdose and the Centers for Disease Control and Prevention suggests that maximum dosage of morphine should be no greater than 90 mg/day (Centers for Disease Control and Prevention [CDC], 2016).
Mirror Therapy
Mirror therapy was first discovered in 1996 by Ramachandran and Rogers-Ramachandran. It is used as a treatment for PLP by resolving the dissociation in visual-proprioceptive sensors in the brain created during an amputation (Ramachandran & Rogers-Ramachandran, 1996). It is one of the more widely known treatments for PLP because it is affordable and has shown immediate short-
15


term relief. The treatment requires only a mirror that is placed at the individuals midline. The individual places their intact limb on the side with the mirror and their amputated limb behind it. Upon moving and manipulating their intact limb, they see in the mirror the reflected limb which is perceived as the amputated limb (Figure 4). This helps to reduce pain by sensing movement in the amputated limb.
Figure 4: Mirror therapy works by placing the intact limb in front of the mirror and the missing limb behind the mirror. The patient perceives their missing limb as the image reflected in the mirror.
Kim and Kim (2012) tested the effects of mirror therapy on phantom limb pain in a human trial with one subject. The individual presented with pain at an 8 out of 10 VAS after receiving a variety of medication and nerve block treatments. They had the subject come in 4 times a week for 15-minute sessions where the subject would perceive the movement of their missing limb as if it were intact moving in the mirror image. Immediately after the mirror treatment, the subjects VAS pain score decreased to a 7 out of 10 VAS. After 1 month of treatment, the pain score had decreased to a 5 out of 10 VAS and some of the symptoms of PLP the subject was
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experiencing such as cramping and rotation of the limb were almost gone. Following 3 months of continued treatment, the subjects pain score remained at a 4 out of 10 VAS and was described as much more manageable. The researchers were able to conclude that mirror therapy had a more significant effect in decreasing phantom limb pain than prescribed medications and nerve blocks, and determined it was a better solution to the pain since it is low cost and can be performed at home (Kim & Kim, 2012). The limitation of this study is that there was only one subject, which lowers the significance. Additionally, the reduction in PLP plateaued at a 4 out of 10 VAS which the researchers cited as manageable but is still persistent pain. Transcutaneous Electrical Nerve Stimulation
Transcutaneous electrical nerve stimulation (TENS) therapy is the use of an electrical current delivered to the muscles through the skin using surface electrodes. TENS utilizes a low frequency (80 to 100 Hz) at a shorter phase duration (10 to 250 ps) to target thick afferent nerve fibers for stimulation (den Adel and Luykx, 2005). The electrodes are attached to the skin using adhesive pads and send alternating electrical pulses to the nerve endings in the muscle at a variety of frequencies and intensities.
There have been numerous studies conducted on the effect of TENS for phantom limb pain in amputees, investigating the optimal frequency and intensity. Cruccu et al. (2007) found a combination of low-frequency and high-intensity TENS therapy to be more effective than other doses. Other studies have also looked at the application of TENS to the intact portion on the opposite limb which targets the
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visual-proprioceptive sensors in the brain in attempts to disentangle them, similar to mirror therapy (Desantana, Walsh, Vance, Rakel & Sluka, 2008).
Mulvey et al. (2013) found TENS to be beneficial in reducing phantom pain and stump pain. They ran a pilot study with 10 trans-tibial amputee subjects with persistent moderate-to-severe phantom and/or stump pain of at least a 3 out of 10 on a numeric rating pain scale (NRS). They placed the electrodes on the stump and projected the TENS into the most painful site at a pulse duration of 80 ps and a pulse frequency of 100 Hz. For the study, they had the participants connected to the TENS electrodes for 60 minutes and at the 30-minute mark they were asked to perform a painful movement. They found the mean standard deviation change following the 60 minutes relative to baseline to be -1.8 NRS pain points at rest and -3.9 NRS points on movement (Mulvey et al., 2013). While these findings are statistically significant and the researchers concluded that TENS was an acceptable and tolerated treatment there was no control group. The 60 minutes TENS therapy was only tested once per participant, and no comments on the lasting effect were documented.
Electrical Stimulation Therapy
Increased Intensity Electrical Stimulus
The intensity of electrical stimulation can be varied from the level of sensory to motor. Sensory intensities are at a level where the subject feels a strong but comfortable sensation without any motor contraction. Increasing the electrical stimulation to a high intensity achieves a non-painful motor contraction (DeSantana et al., 2008). In general, higher frequency stimulation is delivered at a sensory
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intensity and low frequency stimulation is delivered at a motor intensity. Increased intensity electrical stimulation utilizes electrical pulses to induce motor contraction in muscle and as a result, exercises the residual limb muscles and increases local blood flow (Gulick, Castel, Palermo, & Draper, 2011). Higher intensity electrical stimulus has been used for treatment in sports muscle injuries by exercising the muscle to regain strength (Snyder-Mackler, Delitto, Stralka, & Bailey, 1994). Snyder-Mackler et al. (1994) ran a 4-week study on 52 subjects ages 15-43 who had anterior cruciate ligament surgery. They had they subjects perform rehabilitation with different intensities of electrical stimulus and looked at their electrically elicited knee extension torque. For the electrical stimulation they used a Versastim 380 with a carrier frequency of 2.5 kHz, pulse duration of 300 ps, and triangular alternating current at a burst rate of 75 bps. The amplitude of the current was set at the maximum tolerance for each subject (between 70-100 mA). Following the therapy, they assessed the subjects isometric muscle torque and found a linear response in the strength of the quadriceps femoris relative to the electrical stimulus intensity. The higher training intensity directly corresponded to increased isometric muscle force (Snyder-Mackler et al., 1994). They concluded that a higher intensity electrical stimulus increased muscle strength and the speed of recovery.
Patterned Electrical Neuromuscular Stimulation
Patterned electrical neuromuscular stimulation (PENS) has been marketed for neuromuscular re-education and treatment of muscular atrophy (ACP, 2007; Gulick, Castel, Palermo, & Draper, 2011). PENS replicates the normal firing patterns of walking by inducing a contraction in the agonist and antagonist muscles of the limb
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(ACP, 2007). The timed triphasic sensory input targets sensory and motor neurons and muscle stretch receptors that are active during voluntary activity such as walking (Gulick etal., 2011).
PENS utilizes an asymmetric biphasic square wave based on electromyographic patterns that consists of a non-identical triphasic low frequency pulse rate of 50 or 100 Hz (ACP, 2007). This stimulation is applied at a phase duration between 40-100 ps that provides the best penetration with decreased interference. Each tissue in the body has a resistance that slows the current or flow of ions between the surface electrodes. More than 99% of the bodys resistance to current occurs at the level of the skin (Fish & Geddes, 2009). Because of this, it is ideal to use a shorter phase duration to lower the resistance through the skin and into the muscle and nerve. Phase durations shorter than 200 ps are also able to target motor and sensory nerves for stimulation without stimulating pain nerves (den Adel & Luykx, 2005). Targeting the motor neurons with a high enough intensity promotes motor contraction in the muscle and can have therapeutic effects.
The PENS modality on the Omnistim FX2 has been beneficial in reducing muscle atrophy in other injuries and illnesses including patients with severe chronic obstructive pulmonary disease (COPD). A randomized controlled trial by Bourjeily-Habr, Rochester, Palermo, Snyder and Mohsenin (2002) looked at the effects of electrical muscle stimulation on the lower extremities in patients with COPD. In their study, 18 patients were randomly placed in the control (n=9) or the treatment group (n=9). The participants came in 3 times a week for 6 weeks and all had two surface electrodes from the Omnistim FX2 applied to each of the quadriceps, hamstrings,
20


and calf muscles. Each session the control group received no stimulation but was unaware and the treatment group received 20 minutes of electrical stimulation at a high intensity to promote a visible muscle contraction. After 6, weeks they noted that the maximum quadriceps and hamstrings strengths improved significantly and there was an increase in the shuttle walking distance test in the treatment group compared to the control group. The electrical stimulation had no statistically significant effect on lung function, peak work load, or peak oxygen consumption (Bourjeily-Habr et al., 2002). From these results they concluded that electrical stimulation of the lower extremities is a beneficial source of exercise training for COPD patients concurrent with pulmonary rehabilitation and may improve the exercise capability in patients who are unable to routinely exercise (Bourjeily-Habr et al., 2002).
Electrical Stimulation Effects on the Body
Electrical stimulation devices such as the Omnistim FX2 Pro conducts electricity that is passed from the device through impulses to the surface electrodes that are placed on the body using adhesive. The skin typically offers a high resistance except when the voltage is changing rapidly in the case of an alternating current, and then it allows more current to flow through (Fish & Geddes, 2009). Specifically, for the PENS therapy the device conducts a low frequency patterned current that is sent through the two output channels to the surface electrodes placed on the skin. Electrical impulses travel from one lead (anode) through the skin and subcutaneous layers to the underlying muscle beneath the second lead (cathode) where it mimics an action potential and elicits a contraction. Electrical current travels from positive to negative since it has a negative charge.
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Tolerance to Electrical Stimulation
When applying electrical stimulation to the muscles there is the possibility for the body to build up a tolerance, which is when the muscles become acclimated to the stimulus and no longer respond. Vance, Dailey, Rakel, and Sluka (2014) found that electrical stimulation applied daily at either a low frequency or high frequency with the same phase duration and intensity produced tolerance by the muscle fibers in both mice and humans. This can be avoided by alternating between low frequency and high frequency or by increasing the intensity daily (Vance et al., 2014).
Clinimetrics
Clinimetrics is a term coined by Yale Professor Alvan R. Feinstein M.D. to develop metric indexes utilized for clinical data. He defines it as the measurement of clinical phenomena which can either be acquisition of raw data (mensuration) or collection of raw data into groups for comparison (quantification) (Feinstein, 1987). Feinstein mentions in his book Clinimetrics that there are many aspects to take into account when creating an index for clinical data including the condition of the patient and the condition of the interviewer. If the patient has an impairment such as an amputation they may not be able to answer a written assessment. The condition of the interviewer comes in to play when oral responses of the patient are recorded.
The interviewer may add a bias to the answers as they are recorded and their tactics for asking the questions may prompt the patient in one way or another. Feinstein suggest a way to avoid this is to provide a self-administered index or create an ordinal/categorical index for the patient to assign their response. Two of the most common pain assessments that are self-administered and utilize an ordinal index
22


are the visual analog scale or the numerical rating scale (Williamson & Hoggart, 2005).
Visual Analog Scale
The visual analog scale (VAS) was first developed in 1921. It is a 100 mm horizontal line with pain extremes marked at each end as seen in Figure 5. The patient is asked to mark on the line where their pain is at before and after the treatment. The difference in pain is measured between the two points and recorded in mm. Limitations to this index is the lack of categorical values. The data on the VAS is not normally distributed and reproducibility is difficult to achieve with no set intervals (Williamson & Hoggart, 2005). The patient may not know where their initial mark was placed based on the style of the data collection and may not be able to accurately mark their decrease/increase in pain.
Vfeiurf Analog Scale (V.A.S) t
Mo Pain As Bad
Pain As It Could
Possibly Bo
Figure 5: The Visual Analog Scale is a 100mm horizontal line with pain extremes marked at each end. The patient is asked to mark on the line where their pain is at before and after the treatment and the difference is recorded in mm.
Numerical Rating Scale
The numerical rating scale (NRS) is an ordinal pain scale that is categorically separated into numbers from 0 to 10. The patient is asked to rate their pain before and after the treatment by selecting a number on the scale. This scale similarly has
23


extremes at either end but can also include intermediate categories including mild and moderate pain.
A review by Williams and Hoggart (2005) looked at the three most commonly used pain scales: the visual analogue scale, numerical rating scale, and verbal rating scale. In their analysis, they compared the pain scales based on the available research through MedLine via Pubmed. They concluded that the numerical rating scale provides the most sensitivity to changes in pain and that is the most liked among patients in a clinical and research setting for ease of use (Williamson & Hoggart, 2005).
The VAS is similar to the NRS in length and differs in that it is a continuous scale marked by the pain extremes and not the full ordinal scale. According to a study performed by Kelly (2001) the minimal clinically significant difference in VAS pain score was found to be 12mm on a 100mm scale. This correlates to a significant decrease of slightly larger than 1 point on the numerical rating pain scale. However clinically the interest is in a decrease from one pain category to another, for example, decreasing from severe pain to moderate pain (Feinstein, 1987).
Study Design
The research presented in this background section led to the hypothesis that a patterned electrical neuromuscular stimulation applied at a low frequency and a high intensity that promotes a motor contraction, when applied to the antagonistic muscles of the residual limb in amputee subjects, may decrease phantom limb pain. There is no available research on the effects of PENS on PLP which will be the aim in this study based off the above findings.
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CHAPTER IV
MATERIALS Omnistim FX2 Pro
The Omnistim FX2 Pro electrical stimulation device has been developed by Accelerated Care Plus (ACP) and is designed as a patterned electrical neuromuscular stimulation (PENS) system used for pain management and nerve blocking therapies (ACP, 2007). Omnistim FX2 Pro has many uses including: relaxation of muscle spasms, re-education of muscle action, prevention of disuse atrophy, increased local blood circulation, and maintaining or increasing range of motion. This device contains multiple modalities: pain management, neurological reeducation, muscle re-education, and functional re-education through the implementation of PENS, interferential current (IFC), medium frequency alternating current (MFAC), or low voltage pulsed current (LVPC). For this study, the neuromuscular re-education protocol was selected to apply triphasic PENS to the upper or lower residual limb. This stimulation employs a low frequency patterned current to stimulate the agonist and antagonist muscles in order to resemble the live firing pattern of walking in muscles. Triphasic PENS is used because it supports early restoration of agonist/antagonist muscular timing patterns to enhance recovery of function (ACP, 2007). Figure 6 displays an EMG recording of the agonist and antagonist muscle contractions when stimulated with output A (agonist) or B (antagonist) under the PENS protocol.
For the application of the Omnistim FX2 Pro, each output consists of two electrode leads that attach to the surface electrodes: a positive anode electrode lead
25


(red) and a negative cathode electrode (black). The red electrode is placed over the nerve that activates the muscle and the black electrode is placed over the area that will contract due to the stimulation as seen in Figure 8. The electrical impulse travels
from the red electrode lead to the black one and stimulates the muscle.
UPPER AND LOWER EXTREMITY FUNCTIONAL PROGRAMS; i iminii wm
i mrnnoiu m u d\rn^o iv^ AGONIST -ANTAGONIST EMG emu nuumo < EMG ANTAGONIST OUTPUTA OUTPUT B j 111111111111111
SIMULATED PATTERNS j mini
. SIMULATED WALKING AND i iiiiiiiii
CYCLING BASED FUNCTIONAL PATTERNS 100 200 300 Time Milliseconds
Figure 6: Application of the PENS protocol to the agonist and antagonist muscles and their activity recorded using EMG. Output A is the surface electrode stimulating the agonist muscle and output B stimulates the antagonist muscle. The phase duration of the stimulation is the time in milliseconds. (ACP, 2007)
For this study the intensity of the electrical stimulus was adjusted as necessary per session to promote motor contraction and avoid tolerance to the electrical stimulation that was previously mentioned. Achieving a visible motor contraction in the residual limb due to the electrical stimulation each treatment session verified that there was no effect of tolerance.
Numerical Rating Pain Scale
The numerical rating scale (NRS) is an ordinal measurement scale that was used to report the severity of phantom limb pain from no pain to worst pain. For this study a 10-point scale (Figure 7) was divided into no pain (1-2), moderate pain (3-5), severe pain (6-8) and worst possible pain (9-10). Subjects were asked before and after the treatment to assign their pain to one of the numbers. Smiley faces were
26


added as graphic aids for comprehension and written descriptions provided a categorical reference.
Please circle the appropriate response for right now:
No Moderate Severe Worst
Pain Pain Pain Possible
What is the current level of phantom limb pain you are experiencing? 1 2 3 4 5 6 7 8 9 10
Figure 7: Self-reported numerical pain scale that was given to the participant before and immediately following the treatment to assess short term changes in phantom limb pain.
Questionnaire
The questionnaire was administered weekly to the participants in order to monitor changes in the characteristics of their phantom limb pain as well as how the pain was impacting their daily lives. A few of the questions were modeled from the validated Patient-Reported Outcomes Measurement Information System (PROMIS) pain behavior and interference questionnaires including (HealthMeasures, 2017):
1. How much does the pain interfere with your daily activities
2. How much does the pain interfere with your social interactions with others
3. How much does the pain interfere with the things you usually do for fun These questions were rated on a categorical scale of not at all, a little bit, somewhat, quite a bit, and very much. Short answer questions were also asked about the characteristics of the pain including: symptoms of phantom limb pain, if the pain is worse at a particular time in the day, what relieves the pain, if they are taking any medications for the pain, and if they are having any residual limb pain or non-painful sensations. These questions helped to determine if the treatment was effective for a particular characteristic of phantom limb pain over another.
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CHAPTER V
METHODS Human Subjects
Two self-identified adult volunteers, a male and a female with lower limb deficiencies who were experiencing chronic phantom limb pain were enrolled in the study. The first subject was a male multiple limb amputee of 5 years, but complained of phantom limb pain only in the lower limb. He presented with an above-the-knee amputation secondary to a car accident. The second subject was a female below-the-knee amputee of 6 months, resultant from an infection.
The study protocol (Appendix A) was approved by the University of Colorado Scientific Advisory & Review Committee and the Colorado Multiple Institution Review Board. The therapy was prescribed by a physician and written informed consent was obtained prior to subjects participation.
Inclusion Criteria
Between the ages of 18 and 85
Have a limb amputation
Have a well healed amputation site and sensation in the remaining portion of the limb
Experiencing at least a 4 out of 10 of chronic phantom limb pain based on a numeric 10-point pain scale
Understand and follow directions in English
Exclusion Criteria
Those unable to come to the facility
Anyone with a cardiac demand pacemaker and/or implanted defibrillator
Anyone without a well healed amputation site or without sensation in their residual limb
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Electrical Stimulation Therapy
The experiments took place at the BioMechatronics Development Laboratory in Childrens Hospital on the University of Colorado Anschutz Medical Campus. The electrical stimulation device used in this study was the Omnistim FX2 Pro from ACP for the purpose of exercising the muscles of the residual limb and increasing local blood flow. The participant was asked to come in for 15 sessions over a period of 5 weeks, 3 sessions per week. During the first session, a study physician assessed the participant and their residual limb and prescribed the therapy.
For the therapy, the participant had the Omnistim FX2 Pro surface electrodes attached to the limb segment anatomically superior to the level of amputation as described in Table 1. The low extremity (LE) triphasic PENS was selected from the neurological re-education modality on the Omnistim FX2 Pro. The triphasic PENS parameters consisted of asymmetrical biphasic square wave at a frequency of 50 Hz and a phase duration of 70 ps (ACP, 2007). Electrodes were placed on major muscles over the motor end plate on both the anterior and posterior sides of the body on antagonist muscles as seen in Figure 8. The full protocol can be referenced in Appendix A.
Table 1: Placement of the anterior and posterior surface electrodes on the residual limb if the participant is an above or below the knee amputee.
Amputation Level Anterior Surface Electrode Placement Posterior Surface Electrode Placement
Below the knee Tibialis Anterior Gastrocnemius
Rectus Femoris Biceps Femoris
Above the knee Vastus Medialis Biceps Femoris
Rectus Femoris Biceps Femoris
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Figure 8: Surface electrode placement on the residual limb for an above-the-knee amputation. Anterior electrodes placed on the vastus medialis (black) and rectus femoris (red). Posterior electrodes were placed inline on the major biceps femoris of the hamstrings.
The red (positive) electrode is placed over the nerve that activates the muscle and the black (negative) electrode is placed over the area that contracts due to the stimulation. In order to best place the electrodes, the participants residual limb was palpated to assess the muscle location and muscle mass. The electrodes passed an electrical current of low frequency through the skin and into the muscle first at a low intensity for 5 minutes to allow the subject to adjust to the sensation. The amplitude of the current was gradually increased to an intensity level sufficient to elicit a non-painful motor contraction for another 15 minutes (highest level of current is 140 mA). The motor contraction electrical stimulus physically exercises the muscle using an alternating electrical pulse between electrical current outputs placed on the anterior and posterior sides. It has been previously determined through experience by Dr.
Frank Palermo of ACP that 15 sessions is a long enough period to produce results for
30


other injuries and if no results are seen by 15 sessions then there is likely not going to be a response.
Data Analysis
Pain level data was collected using a numerical rating pain scale as seen in Figure 7 before and after each session. Data pertaining to the characteristics of the PLP was collected at the beginning of each treatment week through the questionnaire to track any changes. Characteristics of phantom limb pain that were monitored include cramping, stabbing, burning, and shooting pain in the missing portion of the limb.
Data was processed with standard techniques including data analysis tools in Excel and MATLAB (Mathworks, Inc.) in order to evaluate the effect that patterned electrical neuromuscular stimulation therapy has on decreasing chronic phantom limb pain. A one sided t-test was used for within subject testing looking at pre and post NRS measurements to quantify a decrease in pain. The characteristics of the phantom limb pain where monitored each week and represented in a binary scale as present or absent. Trends in the qualitative data were noted to depict if the therapy had a greater effect on one symptom over another.
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CHAPTER VI
RESULTS
The two participants who reached out with interest in the study presented with chronic phantom limb pain in their lower extremity of at least a 4 out of 10 on a numerical rating scale (NRS). Both participants were experiencing cramping, burning, stabbing, and shooting phantom limb pain that most often presented at night. At the time of enrolling in the study, neither participant was taking any over the counter or prescribed medications for pain.
In the pre-screening questionnaire the male above-the-knee amputee described the PLP as a crushing sensation in the outside of his foot. The pain occurred daily and he rated it up to an 8 out of 10 NRS on occasion. The female below-the-knee amputee experienced phantom limb pain, telescoping of the limb, and restless leg syndrome. She was experiencing all symptoms of phantom limb pain and rated her pain as varying and up to a 10 out of 10 NRS at times.
Effect of Electrical Stimulation Therapy on Decreasing Pain
The Omnistim FX2 Pro Electrical Stimulator using the neuro re-education lower extremity patterned electrical neuromuscular stimulation decreases chronic phantom limb pain. The PENS therapy was comfortable for both participants and there was no report of pain or irritation during the treatment sessions from the Omnistim FX2 Pro device. Both participants felt a warmth in their residual limb following the electrical stimulation but noted that it was not uncomfortable. Muscle cramping presented in the residual limb as a side effect of the electrical stimulation in both participants. The cramping began in the major muscle on the distal part of
32


the limb that was being stimulated after the first few sessions but resolved itself in both participants with continued therapy.
The Omnistim FX2 Pro surface electrodes were placed over the major muscles on the anterior and posterior of the residual limb. Black and red leads were positioned in order to achieve motor contraction in the desired area of the residual limb. The placement of electrodes and black and red leads were determined at each session to best achieve motor contraction, avoid electrical stimulation tolerance, and reduce muscle cramping in the residual limb.
Short Term Pain Relief
The level of pain the participants were experiencing before the treatment that was cited on the pre-treatment pain scale depended on the time of day and what they had previously been doing, such as after physical therapy. Following each treatment session, the participants experienced a notable decrease in their phantom limb pain. The second participant commented that her phantom limb and telescoping foot would completely disappear following the application of PENS. The first participant had a significant average decrease in pain of 1.3 points per treatment session on the 10-point NRS and the second participant had a significant average decrease of 1.7 points on NRS per treatment session (Figures 9,10). This was calculated by averaging the decrease in pain on the NRS from the pre-treatment score to the post-treatment score over all treatment sessions for each participant. Over time, the decrease in PLP from each treatment session was retained which can be seen in the decrease in pre-treatment PLP scores in Figure 11.
33


Subject 1 Reduction in Pain
Treatment Session
Subject 2 Reduction in Pain
Treatment Session
Figure 9: Pre and Post Treatment NRS pain values for each participant show the reduction of pain during each treatment session. The relief of PLP following a treatment session was significant for both participants.
34


AVERAGE PAIN REDUCTION
<
SUBJECT
Figure 10: Average phantom limb pain reduction per treatment session based on a numerical rating pain scale before (pre) and after (post) the patterned electrical neuromuscular stimulation for the two participants with standard error bars. For the first subject the PLP was reduced on average by 1.375 points and the second subject had a reduction of 1.727 points each treatment session. indicates that the reduction is significant based on the literature.
Reduction in Pain
Percent decrease in PLP was calculated using the largest pre-therapy NRS pain score that was reported by the subject and the final post-therapy NRS pain score. The first participant saw a decrease in pain from their severe pain rating of an 8 to no pain, a 1 on NRS. This resulted in an 87.5% decrease in pain after 8 treatment sessions. The second participant began with their max pain at a 10 NRS and saw a reduction to no pain (1 NRS). Their pain decreased 90% after 11 treatment sessions.
35


Table 2: Pre and Post therapy max and min NRS pain scores for the 2 participants were used to calculate percent decrease. Average reduction in pain is the reduction due to each treatment session averaged over all the completed sessions for each participant. The p-value was computed using a one-sided paired t-test to test for a significant reduction in pain.
Subject 1 Subject 2
Pre-Therapy Max Pain (NRS) 8 10
Post-Therapy Min Pain (NRS) 1 1
Percent Decrease in Pain 87.5% 90%
Average Reduction in Pain per Session 1.375 1.727
P-Value .01816 .000102
Phantom Limb Pain Pre Treatment
_a>
is
u
i/>
c
10
9
8
7
6
5
4
3
2
1
1
2
3 4 5 6 7 8
Treatment Day
Subject 1 Subject 2
Figure 11: Numerical rating pain scale data collected before the patterned electrical neuromuscular stimulation was applied to the residual limb. The pain decreased until it plateaued at little to no pain for both subjects. Both participants saw a significant reduction in pain.
A one sided paired t-test with a 95% confidence interval was used to evaluate the significance of the reduction in pain resulted from the therapy in each participant. A p-value less than .05 is considered statistically significant. The first participant had
36


a significant reduction in pain after 8 treatment sessions (p = .01816). During the first two weeks of therapy the participant saw a decrease in PLP (p = .00978) before reaching continuous relief (rating of a 1 NRS). The second participant experienced a significant reduction in PLP after 11 treatment sessions (p = .000102). Similarly, after 2-3 weeks the participant also reached continuous relief of a 1 or 2 on the NRS.
Sustained Relief
The duration of the relief from PLP following the treatment sessions increased over time as more sessions were conducted. In the early stages of the treatment, participants commented that the pain would remain absent the rest of the day following the treatment but would return the next day. After a few more sessions, the relief began lasting two days, roughly until the next treatment session. This sustained relief continued to increase exponentially and last through the later treatments. The first participant went 21 days with no phantom limb pain after only half the recommended treatment sessions (Figure 12) and the second participant maintained relief for over two weeks after stopping treatment.
37


Figure 12: Days of relief from PLP following an electrical stimulation treatment session. The length of relief in days increased exponentially (R= 0.81215) with the number of treatment sessions attended by the participants. Data displayed here is from the first participant who experienced 21 consecutive days without PLP after only 8 treatment sessions.
Changes in the Characteristics
Both participants responded that they were experiencing all four characteristics of PLP prior to the therapy. The questionnaire was administered at the beginning of each treatment week and the characteristics that were present at the time are noted in Table 3. For consistency the questionnaire was always given during the first session of the week which varied based on the participants schedule and any cancelations. The PENS therapy alleviated the characteristics of PLP, specifically cramping, stabbing and shooting pain. The burning sensation presented occasionally for the below-the-knee amputee but was mild to moderate and not persistent. Additionally, the burning pain was relieved immediately following each
38


treatment session with the PENS. Cramping phantom limb pain as well as cramping in the residual limb were both mitigated by the PENS therapy.
Table 3: Characteristics of PLP including cramping, burning, stabbing, and shooting pain in the missing limb were tracked overtime. Data was collected at the start of each treatment week and the characteristics are marked as Present (X) or Absent ( ).
Participant Treatment Session Cramping Burning Stabbing Shooting
Subject 1 1 X X X X
3 X
6
Subject 2 1 X X X X
4 X X
6 X
9 X
11 X
Participant Testimonies
Overall, the Omnistim FX2 Pro PENS therapy was well received by the participants in the study. After attempting a variety of other treatments including mirror therapy, prescribed opioids, heat/cold application, massage, and TENS, the participants found this therapy to be the only treatment that provided any relief from their PLP. The male above-the-knee amputee commented that the application of the PENS felt like a massage that would relax (his) limb. The female below-the-knee amputee remarked that she felt like (she) was getting a workout in and was slightly fatigued after a PENS treatment session. The participants in this study have been living with PLP from 6 months up to 5 years and have found none of these other treatments to relieve their PLP; they were thrilled with the results of this study.
39


Have to tell you because I am totally stoked right now. About 4 hours after the treatment I had to lay down and I fell asleep in a sleep I never get, no one could wake me up at all I slept for 4 hours... I think the reason I slept so hard yesterday was due to the relief of the pain disappearing!
- Below-the-knee amputee
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CHAPTER VII
DISCUSSION
Patterned electrical neuromuscular stimulation significantly decreases chronic phantom limb pain in lower limb amputees. Participants in the study experienced a similar timeline of results. Upon initially starting the treatment, both participants felt an immediate decrease in PLP. Following sessions over the next two weeks, the subjects noted a variety of muscle cramping in the residual limb that was relieved with continued treatment. After completion of at least half of the designated 15 treatment sessions, participants then noted on the numerical rating pain scale that they had little to no PLP (1 -2 NRS) both before and after the treatment session. The PLP relief was then sustained at a low level for the duration of the study and even up to 3 weeks after the last treatment session.
On average, participants experienced a reduction in pain on the NRS of 1.55 points per treatment session. Subject one had an average reduction in pain of 1.375 NRS points and subject two had a reduction of 1.727 NRS points per treatment session. As mention in the background, Kelly (2001) ran a study with 156 patients and found the minimal clinically significant difference to be 12mm on a 100mm visual analog scale. This correlates to a 1-point decrease in pain on the NRS from 1-10 that was developed for this study. Clinically, participants began with pain that was severe and persistent, and by the conclusion of the therapy they were experiencing little to no pain that presented occasionally. Participants commented that when the PLP did occur it was less intense than it previously had been and would resolve itself after a short while. The above-the-knee amputee had a percent decrease in
41


PLP of 87.5% and the below-the-knee amputee saw a 90% decrease in their pain. Farrar and Young (2001) found an average reduction of 30% on the NRS represented a clinically significant reduction.
The duration of the relief also increased with an increased number of treatment sessions and was eventually sustained following the therapy. This could be due to the effect that PENS has on the afferent signaling pathway and cortical reorganization of the somatosensory cortex that are potential sources for PLP. The body responded better to the therapy with increased number of sessions for both participants. Participants in the study felt the electrical stimulation and were able to achieve a motor contraction in the residual limb at a lower intensity with each sequential treatment. This is caused by the reactivating of latent nerves and atrophied muscles in the residual limb during the initial treatment sessions.
An underlying reason for why this therapy works may be due to norepinephrine and the role it plays in increasing pain and co-contraction. According to Dr. Frank Palermo with ACP, proprioceptors send signals to the basal ganglia and thalamus about the bodys location in space. Following an amputation, the brain is attempting to relocate the missing limb in space and sends norepinephrine to the site in order to obtain homeostasis. However, since it has been amputated, it is not possible to attain the original normal state and the muscles of the residual limb will continue to receive norepinephrine and stay rigid increasing the PLP. The PENS therapy may be redefining the bodys boundaries by stimulating the residual limb and realigning the somatosensory cortex and in turn reducing norepinephrine production and phantom limb pain. There is little information on this hypothesis for
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the mechanism that norepinephrine contributes to PLP and should be explored further.
The below-the-knee participant in the study also experienced increased definition of the residual limb. They noted sensations becoming more spatially accurate on the residual limb as well as an increase in muscle tone. Before the therapy, they would touch the posterior side of the residual limb and feel the sensation on the anterior side near the surgical suture. After continued electrical stimulation treatments, the gap between the site of touch and sensation decreased. This may also be an effect of cortical reorganization due to the electrical stimulation. Flor et al. (2006) found sensory discrimination training using high intensity electrical stimulation to improve the cortical reorganization in the somatosensory cortex and improve the ability to discriminate the location of the stimulus. Bourjeily-Habr et al. (2002) found PENS to increase muscle mass by increasing the capillary/fibre ratio and the fibre cross sectional area.
Applying patterned electrical neuromuscular stimulation to the residual limb resulted in slight muscle soreness in the major muscles. Participants in the study commented of tiredness and muscle cramping within the first two weeks after beginning the therapy. In the TCEMS COPD study, patients in the treatment group also reported muscle soreness in their legs following stimulation (Bourjeily-Habr et al., 2002). This is most likely caused by exercising atrophied muscles since participants in the current exploratory pilot study of electrical stimulation therapy for PLP experienced a reduction in muscle soreness with continued treatment.
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A one sided paired t-test was used to evaluate the significance of the reduction in pain caused by the therapy in each participant. Since the participant is likely to use the same criteria to rate their pain before and after the treatment a with in-subject standardization of pre and post data on the numerical rating scale was used to measure a decrease in pain. Both participants saw a significant reduction (p<.05) in PLP that was sustained after their last treatment session up to 3 weeks. A consistent significant decrease in pain for each participant allows the decreased rating for the therapy to be standardized as a whole (Feinstein, 1998).
The therapy appeared to have the greatest effect on shooting and stabbing PLP. It also relieved cramping that presented in the residual limb in addition to cramping PLP. The first participant experienced relief from the crushing sensation they felt in their foot and the second participant was relieved from their telescoping sensation. Burning PLP is the only characteristic that PENS didnt effectively reduce. This pain was similar to the burning pain from the infection that the participant experienced in her lower limb before the amputation. As previously mentioned, preamputation pain increases the likelihood of developing PLP and recurring pain that was similar to pain before the amputation isnt uncommon. The burning could also be caused by neuromas or nerve inflammation that may be present in the residual limb (Bek et al., 2006).
Limitations of the Study
One limitation to the study was the variability in an individuals pain tolerance and as a result their reported pain levels. This was accounted for by using a within-subject standardization of pre and post data on the numerical rating scale to
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measure a decrease in pain. There was also no control group to compare the effectiveness of PENS, but we can compare the results here to the participants previous attempts with other treatments and inability to experience PLP relief.
Another limitation is the difficulty in recruiting an adequate number of subjects for the study to reach significance and also working around patients schedules and the commitment to 3 sessions per week for 5 weeks. Only two participants enrolled in the study, likely due to the inconveniences of the location and the length of the study.
Unforeseen Obstacles
The first participant in the study had to leave town midway through the study after 8 treatment sessions. They were experiencing sustained relief from their PLP before stopping treatment. This relief lasted for another 3 weeks after the last treatment session before any symptoms of PLP returned. The second participant was scheduled for surgery after completion of 11 sessions. At this point in the therapy, their PLP remained improved before being prescribed tramadol (an opioid) for their unrelated shoulder pain prior to surgery. The participant returned to complete the remaining treatment sessions 10 days after surgery. At this time, she was taking a prescribed dose of oxycodone every 4 hours and tramadol as needed. As a result, she was barely able to feel the electrical stimulation even at a high intensity and no visible motor contraction was achieved. Opioids such as oxycodone and tramadol inhibit afferent pain signals and previous studies have found tramadol to directly decrease PLP which may be added to the exclusion criteria for a future study.
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Future Developments
The beneficial preliminary effects from this study have been used to respond to a Veterans Affairs grant proposal on a study inquiring about treatments for PLP. There has also been close work with the Physical Therapy Department at University Hospital in Aurora who are excited to continue the electrical stimulation therapy concurring with physical therapy sessions to relieve patients of their PLP.
It is recommended that the exploratory pilot study described here be expanded into a larger clinical trial to improve the significance of the effects. This therapy should be applied to upper limb amputees as well as include a control. Future studies should assess PENS against other electrical stimulation therapies for the treatment of PLP.
The planned duration of the therapy for this study consisted of 15 electrical stimulation treatments for the participant. During the therapy, a low numerical rating pain score was achieved and maintained. A future longitudinal study following the participants of the current study would provide insight into the long term effects of the therapy. It would also provide data on the benefits of continuing treatments and the appropriate frequency of treatments to maintain PLP relief.
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Hanley, M.A., Jensen, M.P., Smith, D.G., Ehde, D.M., Edwards, W.T., & Robinson, L.R. (2007). Preamputation pain and acute pain predict chronic pain after lower extremity amputation. Journal of Pain, 8(2), 102-109.
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Kelly, A-M. (2001). The minimum clinically significant difference in visual analogue scale pain score does not differ with severity of pain. Emerging Medicine Journal, 18, 205-207.
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Electrical Stimulation to Enhance Recovery of Quadriceps Femoris Muscle Force Production in Patients Following Anterior Cruciate Ligament Reconstruction. Physical Therapy, 74(10), 901-907.
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APPENDIX: COMIRB PROTOCOL
COMIRB
APPROVED
02-Mar-2017
CAMPUS BOX F-490 TELEPHONE: 303-724-1055 Fax: 303-724-0990
COMIRB Protocol
COLORADO MULTIPLE INSTITUTIONAL REVIEW
BOARD
Protocol #: 16-1063
Project Title: Exploratory Study of Electrical Stimulus as a Treatment Option for Chronic Phantom Limb Pain
Principal Investigator: Richard Weir Version Date: 02/07/2017
I. Hypotheses and Specific Aims:
The purpose of the research project is to conduct a pilot study to explore the efficacy of an electrical stimulus regimen on the treatment of chronic phantom limb pain using a standard-of-care electrical stimulation system provided by ACP-Accelerated Care Plus Corporation1. The basis for this project is the observation that the ACP high intensity electrical stimulator (Omnistim FX2 Pro1) has shown improvement in pain and the treatment of other injuries as well as anecdotal evidence2 from the stimulator creator Dr. Frank Palermo, founder and owner of ACP, on the effectiveness of the ACP system in the management of pain for persons with limb amputations. These observations suggest that appropriate stimulation applied to the surface of the residual limb of persons with limb amputations can attenuate their phantom limb pain. We wish to explore in a more systemic manner whether this is indeed the case and to identify the parameter of interest needed to enable us to develop a full clinical trial. Self-identified adult volunteers will be used for the population served.
Specific Alms
1) Electrical stimulus has many parameters including frequency, intensity, wavelength, stimulation patters, etc. The Omnistim FX2 Pro utilizes a medium frequency (between 1,000 to 10,000 Hz) and an alternating stimulation pattern that is advantageous for clinical use due to the ease of skin penetration at lower intensities. For our study we want to establish an electrical stimulation protocol on changes in intensity of the electrical stimulus and the effect it has on chronic phantom limb pain. This will be accomplished by increasing the intensity to a non-painful level that elicits motor contraction in the muscle for a duration of 15 minutes. According to the device manual it is standard-of-care to
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elicit a moderate muscle twitch for therapeutic purposes with the Omnistim FX2 PRO.
2) Examine short term effects of electrical stimulus medium frequency alternating current at an intensity that promotes motor contraction on human subjects with chronic phantom limb pain through the use of a numerical pain scale administered before the treatment session and directly following.
3) Assess the effectiveness of reducing chronic phantom limb pain long term using an electrical stimulus treatment that promotes motor contraction over a period of 15 sessions. This will be assessed through a numerical pain scale and short answer questions about the characteristics of the pain. This will provide insight into the duration required for a future study.
II. Background and Significance:
In 2010 there were an estimated 1.9 million people with limb loss solely in the USA according to the National Institute of Standards and Technology (NIST), and that number has increased since the start of the of the conflict over seas in Iraq and Afghanistan (S.R. Weeks, 2010). Amputations are common in trauma such as war time injuries as well as cardiovascular diseases, diabetes, cancer, and congenital limb deficiency. Each year, there are approximately 185,000 amputation surgeries performed and there is up to an 80% prevalence of phantom limb pain (PLP) in amputees (Flor, 2002).
Phantom limb pain (PLP) is classified as burning, stabbing, shooting, and/or cramping in the missing portion of the limb. Current treatments for PLP include pharmacological drugs, anesthesia, additional surgery, mirror therapy, transcutaneous electrical nerve stimulation (TENS) and others. TENS, as usually implemented, has been used as an electrical stimulus therapy to effectively reduce pain in numerous spots of the body, but has shown little effect in reducing phantom limb pain especially long term even with varying the frequency and intensity. Furthermore, it is reported that many individuals with an amputation are reluctant to have an additional surgery to improve their pain and many also dont want to rely on drugs because of their added side effects (Subedi and Grossberg, 2011). Current non-medical treatments havent proven to be a long term solution and typically only offer immediate relief (Flor, 2002). Also many of these treatments that require prescriptions or surgery arent available for all types of people and amputations occur among all socioeconomic classes as well as ages and genders (McGimpsey and Bradford, 2010). Using an electrical stimulator at an intensity that promotes muscle contraction has proven to reduce pain and increase healing in numerous sports and joint related injuries (Snyder_Mackler, 1994). Anecdotally, we have learned that a similar treatment protocol when applied to persons with phantom limb pain can mitigate their pain2. We seek to test this anecdote.
The goal of this pilot study is to assess the effectiveness of electrical stimulation in the management of chronic PLP and also to acquire data to inform us to the most appropriate study design and power for a future more formal clinical trial. To accomplish this, we will utilize the ACP Omnistim FX2 Pro1 electrical stimulator and use it to physically exercise the muscles of the residual limb and
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hence increase the local blood flow and explore its potential for treatment of phantom limb pain both in the short term and the long term.
III. Preliminary Studies/Progress Report:
This is a pilot studying to inform on the study design and power of a future clinical trial to explore the effectiveness of electrical stimulation on managing phantom limb pain. Research on higher intensity electrical stimulus has been shown to relieve pain in other areas of the body and improve the healing in patients who have had ACL surgery (Snyder_Mackler, 1994). Specifically, the Omnistim FX2 Pro is used for relaxation of muscle spasms, re-education of muscle action, prevention of disuse atrophy, increased local blood circulation, and maintaining or increasing range of motion. In order to obtain preliminary data on the effect this electrical stimulation technique has on chronic phantom limb pain we propose to collect data from 10 subjects. This will allow us to gain an understanding of the issues involved in using this technique.
IV. Research Methods
A. Outcome Measure(s):
Outcome measures include reduced phantom limb pain short term directly following 20-minute treatment session as assessed on a numeric 10-point pain scale and sustained long term pain reduction relative to a baseline pain level as assessed using a self-reported numeric pain scale and short answer to record changes in pain characteristics. These outcome measures will help us to better determine if a full clinical trial should be pursued.
B. Description of Population to be Enrolled:
The subject population will consist of self-identified adult volunteers with a limb deficiency, a well healed site of amputation and who have sensation in their residual limb and are experiencing at least a 4 out of 10 of chronic phantom limb pain based on a numeric 10-point pain scale. The subjects can be of any ethnicity, age (18-85 years), and gender. 10 subjects will be enrolled to allow us to assess efficacy of the treatment protocol. The subjects must be able to understand and follow directions in English, assessed by their ability to respond during the recruitment and consent process. Exclusion criteria include any subjects that are not able to understand the procedures or are unable to come to the facility and anyone with cardiac demand pacemakers and/or implanted defibrillators. Also anyone without a well healed amputation site or sensation in their residual limb for placement of the surface electrodes will be excluded. Subjects will be recruited via flyers placed at the University of Colorado Anschutz or Auraria campuses, flyers emailed to organizations that work with our target population, or in-person at conferences and events to which we have been invited.
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C. Study Design and Research Methods
The experiments will take place at the Biomechatronics Development Laboratory in the Childrens Hospital on Anschutz campus. The participant will come for 15 sessions over a period of 6 weeks, and each session will last for up to 1 hour. During this session the study physician will prescribe the treatment and they and the primary contact and PI will monitor the patient throughout each session. The participant will have Omnistim FX2 Pro surface electrodes attached to the limb segment superior to the level of amputation. Electrodes will be placed on the major muscles over the motor endplate on both the anterior and posterior sides of the body. Standard of care procedure involves palpation of the subject's residual limb which will be used to locate the best position for the surface electrodes. The electrodes will pass an electrical current through the skin and into the muscle first at a low intensity for 5 minutes to allow the subject to adjust to the sensation. The current will then be gradually increased to a level sufficient to elicit a non-painful motor contraction. The subject will sit in a relaxed position as the electrical stimulator contracts the muscles for a duration of 15 minutes. It has been determined that 15 sessions is a long enough period to produce results for other injuries and if no results are seen by 15 sessions then there is likely not going to be a response.
D. Description, Risks and Justification of Procedures and Data Collection Tools:
Pain level data will be collected using a self-reported pain scale before and immediately after each session. Data pertaining to the characteristics of the pain will be collected once a week using short answer questions and a pain scale to evaluate any long term changes. The data will be recorded for all sessions and allow us to observe long term effects. Risks of surface electrical stimulus include possible minor skin discomfort from the adhesive used to attach electrodes to the skin as well as minor discomfort from the motor contraction caused by the electrical stimulator. Absent or diminished sensation in the limb should be avoided for electrode placement or treated with caution. Stinging, burning or other painful sensations under the electrodes on normal or desensitized areas is indications of increased current density. Skin irritation and burns beneath the electrodes have been reported with the use of other powered muscle stimulators. The level of intensity of electrical stimulation will result in slight tingling of the area up to non-painful motor contraction. If it becomes painful the subject should inform the operator immediately and the intensity level will be reduced. Soreness of the muscles may occur from the promotion of muscle contraction. When the procedure is finished, the electrodes will be removed. All equipment will be sterilized in accordance to standard of care procedures. If you feel that you have been harmed while participating in this study, you should inform Richard Weir at 847-912-1032 immediately.
E. Potential Scientific Problems:
Potential scientific problems include a lack of subjects with limb amputation.
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F. Data Analysis Plan:
Data will be processed with standard techniques in MATLAB (Mathworks,
Inc.) in order to evaluate the effect that high intensity electrical stimulus has on decreasing phantom limb pain. T-tests will be used for within subject testing looking at pre and post treatment measures to quantify a decrease in pain and Anovas will be used to look at trends in post treatment measures over time. This will allow us to assess if this electrical stimulation therapy is an effective treatment for phantom limb pain.
This is an exploratory studying to inform on the study design and power of a future more formal clinical trial to explore the effectiveness of electrical stimulation on managing chronic phantom limb pain. In order to obtain preliminary data on the effect this electrical stimulation technique has on phantom limb pain we propose to collect data from 10 subjects. This will allow us to gain an understanding of the issues involved in using this technique.
G. Summarize Knowledge to be Gained:
The development of a less invasive and widely available treatment for phantom limb pain that will enhance the quality of life for individuals with a limb amputation.
H. References:
Flor, Herta. (2002). Phantom-limb Pain: Characteristics, Causes, and Treatment. The Lancet Neurology, 1.3, 182-89.
McGimpsey, G., & Bradford, T. (2010). Limb prosthetics services and devices. Worcester, MA: Bioengineering Institute Center for Neuroprosthetics, Worcester Polytechnic Institution. Retrieved from
http://www.glb.nist.gov/tip/wp/pswp/upload/239_limb_prosthetics_services_d
evices.pdf
Snyder-Mackler, L., Delitto, A., Stralka, S. W., & Bailey, S. L. (1994). Use of Electrical Stimulation to Enhance Recovery of Quadriceps Femoris Muscle Force Production in Patients Following Anterior Cruciate Ligament Reconstruction. Physical Therapy, 74(10), 901-907.
Subedi, Bishnu, and Grossberg, George T. (2011). Phantom Limb Pain: Mechanisms and Treatment Approaches. Pain Research and Treatment 2011, 1-8.
Weeks, S.R, Anderson-Barnes, V. C., and Tsao, J. W. (2010). Phantom limb pain: theories and therapies. Neurologist, 16 (5), 277-286.
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Full Text

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EXPLORATORY PILOT STUDY OF ELECTRICAL STIMULUS AS A TREATMENT OPTION FOR CHRONIC PHANTOM LIMB PAIN By KELSEY SEBRING FITZGERALD B.A., University of Colorado, Boulder, 2015 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfilment of the requirements for the degree of Master of Science Bioengineering Program 2017

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ii 2017 KELSEY SEBRING FITZGERALD ALL RIGHTS RESERVED

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iii Thesis for the Master of Science degree by Kelsey Sebring Fit zgerald has been approved for the Bioengineering Program By Richard Weir Chair Cathy Bodine Frank Pale r m o D ate: July 29, 2017 06 29

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iv Fitzgerald Kelsey Sebring (M.S., Bioe ngineering) Exploratory Pilot Study of Electrical Stimulus as a Treatment Optio n for Chronic Phantom Limb Pain Thesis directed by Associate Professor Richard Weir ABSTRACT There are nearly 2 million people with limb loss solely in the USA, com monly caused by trauma, cardiovascular disease, diabetes, cancer, and congenital limb deficiency. Phantom limb pain (PLP) is characterized as the pain occurring in the missing limb following an amputation and occurs in up to 80% of amputees There are many current treatments for PLP that are often invasive and do not provide long lasting solutions. Patterned electrical neuromuscular stimulation (PENS) is a non invasive surface electrical stimulation that has been used for pain management and re education of muscle action. It has been beneficial in treatment of other injuries and may be applied to PLP In this study the Omnistim FX 2 Pro was used to apply PENS at a low frequency and short phase duration to the residual limb in two lower limb amputee subjects. T he electrical stimulation delivered through the surface electrodes was increased to a non painful level of intensity that elic ited a motor contraction in the antagonistic muscl e s of the residual limb for a duration of 15 minutes over 15 sessions. Pain data was collected using a 10 point numerical rating pain scale (NRS) before and after each treatment session Presence of the c ha racteristics of PLP including cramping, stabbing, shooting, and burning pain were tracked each week.

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v A one sided dependent T test showed PENS effectively reduced the PLP in the two participants by over 85% (p<.05) Both participants began the study with se vere PLP (8 10 NRS) and obtained sustained relief lasting up to 3 weeks from the therapy at little to no pain (1 2 NRS) PENS therapy was able to alleviate cramping, stabbing, and shooting PLP symptoms The therapy was well accepted and p articipants commen ted that nothing had been able to relieve their PLP before this. The beneficial preliminary results from this pilot study should be expanded into a larger clinical trial to improve the significance of the effects, include application to upper limb amputees, as well as include a control. The form and content of this abs tract are approved. I recommend its publication. Approved: Richard Weir

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vi A CKNOWLEDGMENTS This human subjects research project was approved by COMIRB under protocol 16 1063. Thank you to the people at COMIRB for helping me through the initial approval process and subsequent amendments. This project would not have been possible without the help from the faculty in the Bioengineering Department, the staff equipment. Many thanks to Dr. Sarah Sibbel, Dr. Travis Heare Dr. Nathan and prescribing the therapy to the participants. Also thanks to my advisor Dr. Richard Weir and committee members Dr. Cathy Bodine and Dr. Frank Palermo for thei r guidance and editing of numerous revisions. And finally, thanks to my parents and friends who encouraged me along this pr ocess and got me to the finish line.

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vii TABLE OF CONTENTS CHAPTER I INTRODUCTION ................................ ................................ ................................ ................ 1 II HYPOTHESIS ................................ ................................ ................................ .................... 3 Specific Aims ................................ ................................ ................................ ................................ 3 III BACKGROUND ................................ ................................ ................................ ................ 4 Muscle Physiology ................................ ................................ ................................ ........................ 4 Effect of Amputation ................................ ................................ ................................ .................... 5 Phantom Limb Pain ................................ ................................ ................................ ...................... 8 Originating in the Peripheral Limb ................................ ................................ ........................... 9 Disruptions in the Spinal Cord ................................ ................................ ............................... 10 Cortical Reorganization ................................ ................................ ................................ .......... 11 Predisposing Factors ................................ ................................ ................................ .............. 13 Treatments ................................ ................................ ................................ ................................ 14 Opioids ................................ ................................ ................................ ................................ ... 14 Mirror Therapy ................................ ................................ ................................ ....................... 15 Transcutaneous Electrical Nerve Stimulation ................................ ................................ ........ 17 Electrical Stimulation Therapy ................................ ................................ ................................ ... 18 Increased Intensity Electrical Stimulus ................................ ................................ .................. 18 Patterned Electrical Neuromuscular Stimulation ................................ ................................ .. 19 Electrical Stimulation Effects on the Body ................................ ................................ ............. 21 Tolerance to Electrical Stimulation ................................ ................................ ........................ 22 Clinimetrics ................................ ................................ ................................ ................................ 22

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viii Visual Analog Scale ................................ ................................ ................................ ................ 23 Numerical Rating Scale ................................ ................................ ................................ .......... 23 Study Design ................................ ................................ ................................ ............................... 24 IV MATERIALS ................................ ................................ ................................ ................... 25 Omnistim FX 2 Pro ................................ ................................ ................................ ....................... 25 Numerical Rating Pain Scale ................................ ................................ ................................ ....... 26 Questionnaire ................................ ................................ ................................ ............................. 27 V METHODS ................................ ................................ ................................ ...................... 28 Human Subjects ................................ ................................ ................................ .......................... 28 Inclusion Criteria ................................ ................................ ................................ .................... 28 Exclusion Criteria ................................ ................................ ................................ .................... 28 Electrical Stimulation Therapy ................................ ................................ ................................ ... 29 Data Analysis ................................ ................................ ................................ .............................. 31 VI RESULTS ................................ ................................ ................................ ....................... 32 Effect of Electrical Stimulation Therapy on Decreasing Pain ................................ ..................... 32 Short Term Pain Relief ................................ ................................ ................................ ................ 33 Reduction in Pain ................................ ................................ ................................ ........................ 35 Sustained Relief ................................ ................................ ................................ .......................... 37 Changes in the Characteristics ................................ ................................ ................................ ... 38 Participant Testimonies ................................ ................................ ................................ .............. 39 VII DISCUSSION ................................ ................................ ................................ ................ 41 Limitations of the Study ................................ ................................ ................................ ............. 44 Unforeseen Obstacles ................................ ................................ ................................ ............ 45

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ix Future Developments ................................ ................................ ................................ ................. 46 REFERENCES ................................ ................................ ................................ ...................... 47 APPENDIX: COMIRB PROTOCOL ................................ ................................ ........................ 51

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x LIST OF TABLES TABLE 1 Placement of the anterior and posterior surface electrodes on the residual limb if the participant is an above or below the knee amputee. ................................ ... 29 2 Pre and Post therapy max and min NR S pain scores for the 2 participants were used to calculate percent decrease. Average reduction in pain is the reduction due to each treatment session averaged over all the completed sessions for each participant. The p value was computed using a one sided paired t test to test for a significant reduction in pain. ................................ ................................ ....... 36 3 Characteristics of PLP including cramping, burning, stabbing, and shooting pain in the m issing limb were tracked over time. Data was collected at the start of each treatment week and the characteristics are marked as Present (X) or Absent ( ). ................................ ................................ ................................ ..................... 39

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xi LIST OF FIGURES FIGURE 1. Muscles insert across a joint and movement is achieved when the muscle shortens and bends the joint. (Pearson Education Inc., 2011) ............................... 4 2. Proprioceptors are sensors that receive information about the body in space relay information to the central nervous system including the thalamus and somatosensory cortex where the sensor y information is received. (Pearson Education Inc., 2011) ................................ ................................ ................................ ..... 8 3. Neuromagnetic source imaging used to map the mouth and hand regions displaying cortical reorganizati on of the primary somatosensory cortex in an arm amputee (Flor, 2002. Permission received from ScienceDirect). ......................... 12 4. Mirror therapy works by placing the intact lim b in front of the mirror and the missing limb behind the mirror. The patient perceives their missing limb as the image reflected in the mirror. ................................ ................................ ...................... 16 5. The Visual Analog Scale is a 100mm horizontal line with pain extremes marked at each end. The patient is asked to mark on the line where their pain is at before and after the treatment and the difference is recorded in mm. ................ 23 6. Application of the PENS protocol to the agonist and antagonist muscles and their activity recorded using EMG. Output A is the surface electrode stimulating the agonist muscle and output B stimulates t he antagonist muscle. The phase duration of the stimulation is the time in milliseconds. (ACP, 2007) .................... 26

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xii 7. Self reported numerical pain scale that was given to the participant before and immediately following the treatment to assess short term changes in phantom limb pain. ................................ ................................ ................................ ....................... 27 8. Surface electrode placement on the residual li mb for an above the knee amputation. Anterior electrodes placed on the vastus medialis (black) and rectus femoris (red). Posterior electrodes were placed inline on the major biceps femoris of the hamstrings. ................................ ................................ ........................... 30 9. Pre and Post Treatment NRS pain values for each participant show the reduction of pain during each treatment session. The relief of PLP following a treatment session was significant for both participants. ................................ ........ 34 10. Average phantom limb pain reduction per treatment session based on a numerical rating pain scale before (pre) and after (post) the patterned electrical neuromuscular stimulation for the t wo participants with standard error bars. For the first subject the PLP was reduced on average by 1.375 points and the second subject had a reduction of 1.727 points each treatment session. indicates that the reduction is significant based on the literat ure. ........................ 35 11. Numerical rating pain scale data collected before the patterned electrical neuromuscular stimulation was applied to the residual limb. The pain decreas ed until it plateaued at little to no pain for both subjects. Both participants saw a significant reduction in pain. ................................ ................................ ....................... 36

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xiii 12. Days of relief from PLP following an electrical stimulation treatment session. The length of relief in days increased exponentially (R= 0.81215) with the number of treatment sessions attended by the participants. Data displayed here is from the first participant who experienced 21 consecutive days without PLP after only 8 treatment sessions. ................................ ................................ ................. 38

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xiv LIST OF ABBREVIATIONS PLP Phantom Limb Pain ACP Accelerated Care Plus EMG Electromyography DRG Dorsal Root Ganglion CNS Central Nervous System EEG Electroencephalogram VAS Visual Analog Scale NRS Numerical Rating Scale TENS Transcutaneous Electrical Nerve Stimulation SCS Spinal Cord Stimulation PENS Patterned E lectrical Neuromuscular Stimulation

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1 CHAPTER I INTRODUCTION Phantom limb pain (PLP) is a term that was first described in 1552 by Ambrose Pare, a sixteenth century French military surgeon, and then later coined in the 19 th century by Silas Weir Mitchell, a famous surgeon (McGimpsey & Bradford, 2010; Subedi & Grossberg, 2011 ). Phantom limb pain is characterized as the pain occurring in the missing limb following an a mputation. The reported rate of PLP was originally low due to a stigma behind the disease of appearing mentally unstable. According to the Amputee Coalition of America (2017), there are nearly 2 million people with limb loss solely in the USA, and that num ber has remained high since the start of the of the conflict overseas in Iraq and Afghanistan (Weeks, Anderson Barnes & Tsao, 2010). Amputations are common in trauma such as war time injuries as well as cardiovascular disease, diabetes, cancer, and congeni tal limb deficiency. Each year, there are approximately 185,000 amputation surgeries performed and nearly an 80% prevalence of PLP in amputees (Flor, 2002). This equates to 148,000 new cases of PLP each year just in the United States. Of the 185,000 amputa tion surgeries performed each year, 54% of them are due to cardiovascular disease and diabetes (Amputee Coalition, 2017). The prevalence of cardiovascular disease increases from 40% in people ages 40 59, to 70 75% in people ages 60 79, and then again to 86 % for those over the age of 80 in both men and women (Lloyd Jones, Adams, Carnethon, et al., 2009). Because of the increase in occurrence of cardiovascular disease with age, there is also a direct correlation between age and likelihood of an amputation. Mo re than 65% of amputations are performed on people

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2 age 50 and older (McGimpsey & Bradford, 2010). With individuals living longer, the growing US population in those aged 60 and older is expected to dramatically increase in the next 30 years. This will lead to an increase in people with cardiovascular disease, more amputations, and a larger population living with PLP (Yazdanyar & Newman, 2009) Ziegler Graham, MacKenzie, Ephraim, Travison & Brookmeyer (2008) predicted the number of people living with a limb loss in the U.S. to increase to 3.6 million by 2050 using incidence rates of amputations and assumptions based on age, sex, and race. People with PLP are currently using pharmacologic drugs, anesthesia, additional surgeries and other non invasive techniqu es such as mirror therapy to reduce their pain. While there are many treatments for PLP, they are sometimes invasive and do not provide long lasting solutions. Patterned electrical neuromuscular stimulation is a non invasive surface electrical stimulation that has been used for pain management and re education of muscle action. It has been beneficial in treatment of other injuries and may be applied to phantom limb p ain (Accelerated Care Plus [ACP], 2007). A developed protocol to physically exercise the mus cles of the residual limb and in turn increase the local blood flow may decrease stiffness and co contraction and reduce PLP for amputees. There is no available research on the effects of Patterned Electrical Neuromuscular Stimulation on PLP which leaves a need for investigation and will be addressed with this exploratory pilot study on its effectiveness in reducing chronic PLP.

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3 CHAPTER II HYPOTHESIS Patterned electrical neuromuscular stimulation applied at an intensity that elicits a muscle motor contraction in the antagonistic muscles of the residual limb may mitigate chronic phantom limb pain based on a numerical rating scale. Specific Aims Specific Aim One: Employ a Patterned Electrical Neuromuscular Stimulation protocol with adjusting changes i n intensity of the electrical stimulus to elicit a motor contraction in the residual limb. Electrical stimulus has many parameters including frequency, intensity, wavelength, stimulation patters, etc. The Omnistim FX 2 Pro utilizes a low frequency of 50 Hz and an alternating stimulation pattern with a phase duration of 40 s that is advantageous for clinical use due to the ease of skin penetration at lower intensities. For our study we want to establish an electrical stimulation protocol on changes in intensity of the electrical stimulus and the effect it has on chronic phantom limb pain. This will be accomplished by increasing the intensity to a non painful level that elicits a motor contraction in the muscle for a duration of 15 minutes. According to the device manual it is standard of care to elicit a moderate muscle twitch for therapeutic purposes with the Omnistim FX 2 Pro. Specific Aim Two: Examine short term effects of Patterned Electrical Neuromuscular Stimulation. Short term effects of the thera py will be examined at an intensity that promotes motor contraction on human subjects with chronic phantom limb pain through the use of a numerical rating scale administered before each treatment session and directly following. Specific Aim Three: Assess the effect that Patterned Electrical Neuromuscular Stimulation has on the characteristics of PLP. The characteristics of PLP include cramping, stabbing, burning, and shooting pain in the missing portion of the limb. The effects will be assessed through a short answer questionnaire administered at the start of each treatment week. These questions will ask the participant which characteristics of the pain are present. This will provide insight into the effect that the treatment has on the different

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4 character istics/symptoms of phantom limb pain in preparation for a future study. CHAPTER III BACKGROUND Muscle Physiology Skeletal muscle makes up the largest percent of muscle in the human body and is responsible for movement through voluntary control. An individual muscle is composed of subunits called muscle fascicles which are made up of mu scle fibers; the smallest subunit being the myofibrils which are made up of actin and myosin. Muscle fibers are innervated by motor neurons and together combine to form a functional motor unit. Motor neurons project into the muscle fibers and send voluntar y control signals from the brain through the spinal cord to trigger the muscle for contraction. Muscles are actuators that remain unstimulated unless commanded to contract by a motor neuron. They can only shorten in length and perform the bending of joints by working together with synergistic and antagonistic muscles, inserting across the joint as displayed in Figure 1. Figure 1 : Muscles insert across a joint and movement is achieved when the muscle shortens and bends the joint. (Pearson Education Inc., 2011)

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5 In 1954, Andrew Huxley and Hugh Huxley published separate papers proposing that muscle contraction was due to the sliding of the thin fila ments (actin) and thick filaments (myosin) past one another ( Herzog, Powers, Johnston & Duvall today as the method of muscle contraction. Later in 1957, this theory was expa nded by Andrew Huxley to describe the attachment between the filaments and the active (Huxley, 1957). Today, there is continued research in this area by Dr. Walter Herzog and oth ers to explain the passive force produced by muscle through the protein titin and eccentric contraction where the muscle fibers are lengthened ( Herzog et al. amputation that ab ility to contract is compromised. Effect of Amputation During an amputation, the limb is severed and so are the muscles and motor neurons. The amputation procedure varies depending on how much of the limb is being amputated as well as the site of amputat ion. Doctors try to preserve as much of the residual limb as they can and take many factors (limb temperature, coloring and sensitivity) into account before amputating a limb. During the procedure, the surgeon will remove the diseased tissue and crushed bo ne, smooth the new end of the bone, seal off blood vessels and nerves, and finally cut and shape the muscles so that the residual limb can be fitted with a prosthesis before closing the skin and dressing the wound (Johns Hopkins Medicine, n.d.). Many times this final step of

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6 the amputation involves connecting the antagonistic muscles to one another or wrapping one around the stump in order to tie them down (the processes of myoplasty and myodesis). This often results in co contraction, tension, and stiffne ss in the muscles of the residual limb (Seyedali, Czerniecki, Morgenroth, & Hahn, 2012). Muscles tend to co contract to increase stability and protect the joint leading to a more rigid limb. Seyedali et al. (2012) tested this theory of co contraction by observing nine unilateral trans tibial (lower leg) amputees utilizing their prescribed prosthetic and comparing their co contraction to five control intact limbed individuals in all phases of gait anal ysis. In their study they looked separately at co contraction of the ankle and knee joints. Using surface electromyography (EMG), they recorded activation of the tibialis anterior, medial gastrocnemius, vastus lateralis and biceps femoris. Seyedali et al. (2012) found co contraction of the ankle and knee muscles to be more pronounced in the residual limb of the amputees than the control limb s They concluded that amputees may be co contracting as a way to stiffen the residual limb and increase stability wh ich is necessary for their gait and single limb support in walking or running (Seyedali et al., 2012). This effect of co contraction and li mb stiffening may be adding to phantom limb p ain and discomfort (Subedi & Grossberg, 2011) When a limb is missing, the brain recognizes an unfamiliar sensation in the proprioceptors (muscle spindles) of the residual limb. Proprioceptors provide sensory information about the limbs location in space including: muscle length, muscle tension, and joint angle ( Sherwood, 201 5) As shown in Figure 2, these

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7 signals are sent to the thalamus and somatosensory cortex. The thalamus relays the sensory signals from the body to the somatosensory cortex of the cerebral cortex for interpretation of the pain stimulus. In the textbook Hum an Physiology: From Cells to Systems, Sherwood comments on phantom limb pain and proposes the idea that severed endings of the muscle spindles and afferent nerve pathways can trigger action potentials that are then misinterpreted in the somatosensory corte x as pain in the missing region. Sherwood adds that phantom limb pain may also be a result from re organization of the somatosensory cortex following an amputation ( Sherwood, 2015) A study by Davis, Kiss, Luo, Tasker, et al. (1998) demonstrated that an amp utation can affect the perception of the body in the thalamus and cerebral cortex.

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8 Figure 2 : Proprioceptors are sensors that receive information about the body in space relay information to the central nervous system including the thalamus and somatosensory cortex where the sensory information is received. (Pearson Education Inc., 2011) Phantom Limb Pain Phantom limb pain (PLP) has been described as cramping, burning, stabbing, or shooting pain that occurs in the missing limb fo llowing an amputation. PLP is different from stump pain which occurs in the remaining portion of the limb, or non painful sensations such as tingling, hot and cold sensations, and pressure that may also occur (Flor, 2002). It has been acknowledged that PLP occurs from a disconnect in the communication between the sensory pathway and the brain. Three

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9 leading originations for the cause of PLP are: neuromas in the residual stump formed from deafferentation of the severed nerve, severing of peripheral nerves wh ich results in disruptions in the afferent nerve input to the spinal cord, and cortical reorganization in the brain (Flor, Nikolajsen, & Jensen, 2006). Originating in the Peripheral Limb There is no well accepted answer to the origin of phantom limb pain, but many researchers believe that some of the pain is initiated in the peripheral limb. Following an amputation, the nerves that once innervated the missing limb may be left severed or unconnected and can form neuromas in the peripheral limb (Flor et al., 2006). A neuroma is a growth of the nerve tissue that generates abnormal activity that does not originate at the nerve ending, and is sensitive to both mechanical and electrical stimuli (Bek, Demiralp, Kmrc, Atesalp, 2006). The injured nerve may have al tered electrical properties that effect the voltage sensitive sodium and potassium channels (Viswanathan, Phan, & Burton, 2010). Flor et al. (2006) found injections of a systemic adrenergic blocking agent at the site of the neuroma to reduce PLP and inject ions of adrenaline to increase PLP. Adrenergic blocking agents work by blocking sympathetic stimulation and production of epinephrine (adrenaline) which aggravates neuronal activity. A study by Bek et al. (2006) evaluated the relationship between neuroma s and PLP. 14 patients who developed neurinoma (a tumor of the nerve sheath) and PLP after a limb amputation were enrolled in the study to undergo a neurectomy to remove the neurinoma. Before the procedure the PLP mean visual analog score (VAS) was an 8.4 out of 10. The neurectomy was performed on all 14 patients and a

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10 follow up was conducted on average 71.5 months after the procedure. At the time of the follow up, Bek et al. observed complete relief from PLP (0 VAS) and the disappearance of the neuroma sym ptoms. They concluded that to prevent neuromas and PLP the best approach to an amputation is to cut the nerve at a proximal position on the limb in order to leave the nerve ending furthest from the stump where most contact occurs (Bek et al., 2006). The peripheral limb may not be the source of phantom limb pain since the pain can persist in the absence of neuromas but it may have a role in exacerbating it. (Subedi & Grossberg, 2011). Flor et al. (2006) proposed that a source for PLP was a combination of t he damaged nerve endings with distorted activity in the dorsal root ganglia (DRG) which is responsible for relaying information to the central nervous system (CNS). For this reason, many researchers have looked for other sources of phantom limb pain includ ing disruptions in the spinal cord and loss of input from the limb (Vaso et al., 2014). Disruptions in the Spinal Cord The dorsal root ganglion (DRG) is a collection of cell bodies that receive s afferent sensory signals from the peripheral system before r elaying it to the central nervous system which is made up of the brain and spinal cord. Damage to the DRG can result in spinal hyperactivity such as increased firing of dorsal horn neurons or decreased spinal cord inhibitory processes (Flor et al., 2006). Since 1969, spinal cord stimulation (SCS) has been used as a treatment for PLP (Viswanathan, Phan, and Burton, 2010). Viswanathan et al. (2010) tested the effectiveness of SCS in four lower limb amputee subjects and found the overall PLP to be reduced by o ver 80%

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11 using the Brief Pain Inventory. In the study, the participant received implanted octopolar leads near the spinal cord that administered the stimulation to induce paresthesia in the area of pain. They concluded that this therapy was effective in red ucing PLP but found other issues with it such as allergic dermatitis to the implant and infection at the site of implantati on that resulted in two of the four subjects eventually having the implant removed. Vaso et al. (2014) researched the idea that PLP was caused by an exaggeration of sensory input to the DRG rather than a loss of sensory input. They performed a study on 31 lower limb amputees using an intraforaminal epidural block of lidocaine injected in the DRG to prevent ectopic signals produced from reaching the CNS. They found the intraforaminal block consistently reduced both PLP and non painful phantom limb sensations compared to a sham injection. Using the anesthetic injection, they were able to suppress the sensory input and saw a reduction in p ain which supported their hypothesis that PLP may be caused by an amplification of sensory input (Vaso et al., 2014). Cortical Reorganization Previous studies have found PLP to be closely linked to maladaptive cortical plasticity (cortical reorganization) and changes in the primary somatosensory cortex of the brain as seen in Figure 3. Specifically, there is a connection between arm amputees and reorganization to the mouth region (Flor, Denke, Schaefer, & Grusser, 2001).

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12 Figure 3 : Neuromagnetic source imaging used to map the mouth and hand regions displaying cortical reorganization of the primary somatosensory cortex in an arm amputee ( Flor, 2002 Permission received from ScienceDirect). Flor et al. (2001) looked at the effect o f sensory discrimination training on cortical reorganization and phantom limb pain. Their study consisted of 10 individuals, both male and female, ages 31 74, with arm amputations on either side who were randomly put into an experimental group or control g roup. The control group received medical treatment consisting of analgesic medicine, transcutaneous nerve stimulation, or physical therapy while the experimental group began 10 daily 90 minute sessions over two weeks of sensory discrimination training. In the sensory training, the subject had to discriminate between the frequency or location of a non painful high intensity electrical stimulus applied through eight surface electrodes

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13 attached to the residual limb (Flor et al., 2001). Flor et al. (2001) saw a significant decrease in cortical reorganization which was measured using neuroelectric source imaging; the use of EEG (electroencephalogram) signals to map localizations of somatosensory evoked potentials in the brain. They also saw a decrease in PLP usin g a multidimensional pain inventory; a self reported measure of chronic pain and Yale). With these findings, they concluded that there was a positive correlation between changes in sensory discriminatio n, cortical reorganization, and PLP (Flor et al., 2001). This study supports the idea that PLP may originate at the level of the brain and could be caused by cortical reorganization. Predisposing Factors There are many factors which have been associated w ith the onset of PLP including site of amputation, presence of pre amputation pain, age and gender (Subedi & Grossberg, 2011). The incidence of pre amputation pain has been reported to increase the likelihood of developing PLP (Hanley et al., 2007). Resear ch has found PLP to be more common among upper limb amputees than lower limb, and in women more often than men. (Subedi & Grossberg, 2011). PLP can present within hours following the amputation procedure or even a month or a year after the amputation is p erformed (Schley et al., 2008). It has also been recorded that stress, anxiety, exhaustion, and depression can exacerbate PLP (Berger & Bacon, 2009). The greatest determining factor of PLP appears to be the presence of pain in the limb before amputation (H anley et al., 2007).

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14 Treatments Since PLP is such a prevalent problem, there have been many attempts at treatments including pharmacological prescriptions, additional surgeries, anesthesia doses, psychological treatments, transcutaneous electrical nerve s timulation (TENS), mirror therapy, massage and heat application (Flor, 2002). Some of the pharmacological prescriptions are opioids, ketamine, antidepressants, and muscle relaxants. These are used to block the pain signals from the afferent pathway back to the CNS and suppress the pain sensation. Anesthesia works in a similar manner by numbing the nerve ending and blocking the afferent pain stimulus. These treatments have showed only a slight decrease in pain and for a short period of time following adminis tration (Kim & Kim, 2012). Opioids Opioids are a class of drugs that act on opioid receptors in the body to mimic morphine effects. They act on the central nervous system to reduce pain and have been proposed to inhibit cortical reorganization which can ca use phantom limb pain (Turcios, Tran, Tu, & Lie, 2013). A major concern with opioid use is the risk of physical and mental dependence and also dosage tolerance and escalation. This tends to decrease recommendations for long term use (Turcios et al., 2013). A case study conducted by Kumar et al. (2015) included a 72 year old male who had an above the knee amputation after being diagnosed with a cancerous tumor on his tibia. After being discharged following surgery he was administered 5 mg of morphine every four hours. After a week, his pain was s till intense and his self reported pain score was an 8 out of 10 on a visual analog scale (VAS). Kumar et

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15 al. (2015) started the subject on oral morphine of 10 mg every four hours with progressive increase in concentration to 120 mg over a period of four w eeks in order to manage the pain down to a score of 1 2 VAS The subject then acclimated to the dosage and it was increased to 300 mg/4hrs to maintain a pain score VAS < 4. Other interventions such as nerve blocks were attempted to reduce the pain and had little effect so the morphine dosage was increased again by gradual titration to 540 mg/4hrs. At this dosage the PLP remained diminished, but any attempt to decrease the morphine dose caused the pain to return so the researchers maintained the high level d ose (a high level dose is considered as morphine >299mg/day). Researchers were able to achieve an optimal morphine dose to reduce the subjects PLP, but it required daily high dose morphine which can have other health implications. According to the U.S. Dep artment of Health and Human Services as many as 1 in 4 patients using long term opioid therapy for chronic pain struggle with overdose and the Centers for Disease Control and Pr evention suggests that maximum dosage of morphine should be no greater than 90 mg/day (Centers for Disease Control and Prevention [CDC], 2016). Mirror Therapy Mirror therapy was first discovered in 1996 by Ramachandran and Rogers Ramachandran. It is used as a treatment for PLP by resolving the dissociation in visual proprioceptive sensors in the brain created during an amputation (Ramachandran & Rogers Ramachandran, 1996). It is one of the more widely known treatments for PLP because it is affordable and h as shown immediate short

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16 midline. The individual places their intact limb on the side with the mirror and their amputated limb behind it. Upon moving and manipulating thei r intact limb, they see in the mirror the reflected limb which is perceived as the amputated limb (Figure 4 ) This helps to reduce pain by sensing movement in the amputated limb. Kim and Kim (2012) tested the effects of mirror therapy on phantom limb pain in a human trial with o ne subject. The individual presented with pain at an 8 out of 10 VAS after receiving a variety of medication and nerve block treatments. They had the subject come in 4 times a week for 15 minute sessions where the subject would perceive the movement of the ir missing limb as if it were intact moving in the mirror decreased to a 7 out of 10 VAS. After 1 month of treatment, the pain score had decreased to a 5 out of 10 VAS and some of the symptoms of PLP the subject was Figure 4 : Mirror therapy works by placing the intact limb in front of the mirror and the missing limb behind the mirror. The patient perceives their missing limb as the image reflected in the mirror.

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17 experiencing such as cramping and rotation of the limb were almost gone. Following VAS and was described as much more manageable. The re searchers were able to conclude that mirror therapy had a more significant effect in decreasing phantom limb pain than prescribed medications and nerve blocks, and determined it was a better solution to the pain since it is low cost and can be performed at home (Kim & Kim, 2012). The limitation of this study is that there was only one subject, which lowers the significance. Additionally, the reduction in PLP plateaued at a 4 out of 10 VAS which the researchers cited as manageable but is still persistent pai n. Transcutaneous Electrical Nerve Stimulation Transcutaneous electrical nerve stimulation (TENS) therapy is the use of an electrical current delivered to the muscles through the skin using surface electrodes. TENS utilizes a low frequency (80 to 100 Hz) at a shorter phase duration (10 to 250 s ) to target thick afferent nerve fibers for stimulation (den Adel and Luykx, 2005). The electrodes are attached to the skin using adhesive pads and send alternating electrical pulses to the nerve endings in the mus cle at a variety of frequencies and intensities. There have been numerous studies conducted on the effect of TENS for phantom limb pain in amputees, investigating the optimal frequen cy and intensity. Cruccu et al. (2007) found a combination of low frequen cy and high intensity TENS therapy to be more effective than other doses. Other studies have also looked at the application of TENS to the intact portion on the opposite limb which targets the

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18 visual proprioceptive sensors in the brain in attempts to disen tangle t hem, similar to mirror therapy ( Desantana, Walsh, Vance, Rake l & Sluka, 2008). Mulvey et al. (2013) found TENS to be beneficial in reducing phantom pain and stump pain. They ran a pilot study with 10 trans tibial amputee subjects with persistent m oderate to severe phantom and/or stump pain of at least a 3 out of 10 on a numeric rating pain scale (NRS). They placed the electrodes on the stump and projected the TENS into the most painful site at a pulse duration of 80 s and a pulse frequency of 100 Hz. For the study they had the participants connected to the TENS electrodes for 60 minutes and at the 30 minute mark they were asked to perform a painful movement. They found the mean standard deviation change following the 60 minutes relative to baselin e to be 1.8 NRS pain points at rest and 3.9 NRS points on movement (Mulvey et al., 2013). While these findings are statistically significant and the researchers concluded that TENS was an acceptable and tolerated treatment there was no control group. The 60 minutes TENS therapy was only tested once per participant, and no comments on the lasting effect were documented. Electrical Stimulation Therapy Increased Intensity Electrical Stimulus The intensity of electrical stimulation can be varied from the level of sensory to motor. Sensory intensities are at a level where the subject feels a strong but comfortable sensation without any motor contraction. Increasing the electrical stimulation to a high intensity achieves a non painful motor contraction (DeSa ntana et al., 2008). In general, higher frequency stimulation is delivered at a sensory

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19 intensity and low frequency stimulation is delivered at a motor intensity. Increased intensity electrical stimulation utilizes electrical pulses to induce motor contrac tion in muscle and as a result, exercises the residual limb muscles and increases local blood flow ( Gulick, Castel, Palermo, & Draper, 2011) Higher intensity electrical stimulus has been used for treatment in sports muscle injuries by exercising the muscl e to regain strength ( Snyder Mackler, Delitto, Stralka, & Bailey, 1994) Snyder Mackler et al. (1994) ran a 4 week study on 52 subjects ages 15 43 who had anterior cruciate ligament surgery. They had they subjects perform rehabilitation with different inte nsities of electrical stimulus and looked at their electrically elicited knee extension torque. For the electrical stimulation they used a Versastim 380 with a carrier frequency of 2.5 kHz, pulse duration of 300 s, and triangular alternating current at a burst rate of 75 bps. The amplitude of the current was set at the maximum tolerance for each subject (between 70 100 mA). Following the therapy, they assessed the isometric muscle torque and found a linear response in the strength of the quadrice ps femoris relative to the electrical stimulus intensity. The higher training intensity directly corresponded to increased isometric muscle force (Snyder Mackler et al., 1994). They concluded that a higher intensity electrical stimulus increased muscle str ength and the speed of recovery. Patterned Electrical Neuromuscular Stimulation Patterned electrical neuromuscular stimulation (PENS) has been marketed for neuromuscular re education and treatment of muscular atrophy (ACP, 2007; Gulick, Castel, Palermo, & Draper, 2011). PENS replicates the normal firing patterns of walking by inducing a contraction in the agonist and antagonist muscles of the limb

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20 (ACP, 2007). The timed triphasic sensory input targets sensory and motor neurons and muscle stretch receptors that are active during voluntary activity such as walking (Gulick et al., 2011). PENS utilizes an asymmetric biphasic square wave based on electromyographic patterns that consists of a non identical triphasic low frequency pulse rate of 50 or 100 Hz (ACP, 2007). This stimulation is applied at a phase duration between 40 100 s that provides the best penetration with decreased interference. Each tissue in the body has a resistance that slows the current or flow of ions between the surface electrodes. More t han 99% of the resistance to current occurs at the level of the skin (Fish & Geddes, 2009). Because of this, it is ideal to use a shorter phase duration to lower the resistance through the skin and into the muscle and nerve. Phase durations shorter than 200 s are also able to target motor and sensory nerves for stimulation without stimulating pain nerves (den Adel & Luykx, 2005). Targeting the motor neurons with a high enough intensity promotes motor contraction in the muscle and can have therapeuti c effects. The PENS modality on the Omnistim FX 2 has been beneficial in reducing muscle atrophy in other injuries and illnesses including patients with severe chronic obstructive pulmonary disease (COPD). A randomized controlled trial by Bourjeily Habr, R ochester, Palermo, Snyder and Mohsenin (2002) looked at the effects of electrical muscle stimulation on the lower extremities in patients with COPD. In their study, 18 patients were randomly placed in the control (n=9) or the treatment group (n=9). The par ticipants came in 3 times a week for 6 weeks and all had two surface electrodes from the Omnistim FX 2 applied to each of the quadriceps, hamstrings,

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21 and calf muscles. Each session the control group received no stimulation but was unaware and the treatment group received 20 minutes of electrical stimulation at a high intensity to promote a visible muscle contraction. After 6, weeks they noted that the maximum quadriceps and hamstrings strengths improved significantly and there was an increase in the shuttle walking distance test in the treatment group compared to the control group. The electrical stimulation had no statistically significant effect on lung function, peak work load, or peak oxygen consumption (Bourjeily Habr et al., 2002). From these results th ey concluded that electrical stimulation of the lower extremities is a beneficial source of exercise training for COPD patients concurrent with pulmonary rehabilitation and may improve the exercise capability in patients who are unable to routinely exercis e (Bourjeily Habr et al., 2002). Electrical Stimulation Effects on the Body Electrical stimulation devices such as the Omnistim FX 2 Pro conducts electricity that is passed from the device through impulses to the surface electrodes that are placed on the body using adhesive. The skin typically offers a high resistance except when the voltage is changing rapidly in the case of an altern ating current, and then it allows more current to flow through (Fish & Geddes, 2009). Specifically, for the PENS therapy the device conducts a low frequency patterned current that is sent through the two output channels to the surface electrodes placed on the skin. Electrical impulses travel from one lead ( anode ) through the skin and subcutaneous layers to the underlying muscle beneath the second lead ( cathode ) where it mimics an action potential and elicits a contraction. Electrical current travels from po sitive to negative since it has a negative charge.

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22 Tolerance to Electrical Stimulation When applying electrical stimulation to the muscles there is the possibility for the body to build up a tolerance, which is when the muscles become acclimated to the stimulus and no longer respond. Vance, Dailey, Rakel, and Sluka (2014) found that electric al stimulation applied daily at either a low frequency or high frequency with the same phase duration and intensity produced tolerance by the muscle fibers in both mice and humans. This can be avoided by alternating between low frequency and high frequency or by increasing the intensity daily (Vance et al., 2014). Clinimetrics Clinimetrics is a term coined by Yale Professor Alvan R. Feinstein M.D. to develop metric indexes utilized for clinical data. He defines it as the measurement of clinical phenomena which can either be acquisition of raw data (mensuration) or collection of raw data into groups for comparison (quantification) (Feinstein, 1987). Feinstein mentions in his book Clinimetrics that there are many aspects to take into account when creating an index for clinical data including the condition of the patient and the condition of the interviewer. If the patient has an impairment such as an amputation they may not be able to answer a written assessment. The condition of the interviewer comes in to play when oral responses of the patient are recorded. The interviewer may add a bias to the answers as they are recorded and their tactics for asking the questions may prompt the patient in o ne way or another. Feinstein suggest a way to avoid this is to provide a self administered index or create an ordinal/categorical index for the patient to assign their response. Two of the most common pain assessments that are self administered and ut ilize an ordinal index

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23 are the visual analog scale or the numerical rating s cale (Williamson & Hoggart, 2005). Visual Analog Scale The visual analog scale (VAS) was first developed in 1921. It is a 100 mm horizontal line with pain extremes marked at each end as seen in Figure 5 The patient is asked to mark on the line where their pain is at before and after the treatment. The difference in pain is measured between the two points and recorded in mm. Limitations to this index is the lack of categorical values. The data on the VAS is not normally distributed and reproducibility is difficult to achieve with no set intervals (Williamson & Hoggart, 2005). The patient may not know where their initial mark was placed based on the style of the data collection and may n ot be able to accurately mark their decrease/increase in pain. Figure 5 : The Visual Analog Scale is a 100mm horizontal line with pain extremes marked at each end. The patient is asked to mark on the line where their pain is at before and after the treatment and the difference is recorded in mm. Numerical Rating Scale The numerical rating scale (NRS) is an ordinal pain scale that is categorically separated into numbers from 0 to 10. The patient is asked to rate their pain before and after the treatment by selecting a number on the scale. This scale similarly has

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24 extreme s at either end but can also include intermediate categories including mild and moderate pain. A review by Williams and Hoggart (2005) looked at the three most commonly used pain scales: the visual analogue scale, numerical rating scale, and verbal rating scale. In their analysis they compared the pain scales based on the available research through MedLine via Pubmed. They concluded that the numerical rating scale provides the most sensitivity to changes in pain and that is the most liked among patients i n a clinical and research setting for ease of use (Williamson & Hoggart, 2005). The VAS is similar to the NRS in length and differs in that it is a continuous scale marked by the pain extremes and not the full ordinal scale. Accor ding to a study performed by Kelly (2001) the minimal clinically significant difference in VAS pain score was found to be 12mm on a 100mm scale. This correlates to a significant decrease of slightly larger than 1 point on the numerical rating pain scale. However clinically the interest is in a decrease from one pain category to another, for example, decreasing from severe pain to moderate pain (Feinstein, 1987). Study Design The research presented in this background sec tion led to the hypothesis that a patterned electrical neuromuscular stimulation applied at a low frequency and a high intensity that promotes a motor contraction, when applied to the antagonistic muscles of the residual limb in amputee subjects, may decre ase phantom limb pain. There is no available research on the effects of PENS on PLP which will be the aim in this study based off the above findings.

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25 CHAPTER IV MATERIALS Omnistim FX 2 Pro The Omnistim FX 2 Pro electrical stimulation device has been developed by Accelerated Care Plus (ACP) and is designed as a patterned electrical neuromuscular stimulation (PENS) system used for pain management and nerve blocking therapies (ACP, 2007). Omnistim FX 2 Pro has m any uses including: relaxation of muscle spasms, re education of muscle action, prevention of disuse atrophy, increased local blood circulation, and maintaining or increasing range of motion. This device contains multiple modalities: pain management, neuro logical re education, muscle re education, and functional re education through the implementation of PENS, interferential current (IFC), medium frequency alternating current (MFAC), or low voltage pulsed current (LVPC). For this study, the neuromuscular re education protocol was selected to apply triphasic PENS to the upper or lower residual limb. This stimulation employs a low frequency patterned current to stimulate the agonist and antagonist muscles in order to resemble the live firing pattern of walking in muscles. Triphasic PENS is used because it supports early restoration of agonist/antagonist muscular timing patterns to enhance recovery of function (ACP, 2007). Figure 6 displays an EMG recording of the agonist and antagonist muscle contractions when stimulated with output A (agonist) or B (antagonist) under the PENS protocol. For the application of the Omnistim FX 2 Pro, each output consists of two electrode leads that attach to the surface electrodes: a positive anode electrode lead

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26 (red) and a negat ive cathode electrode (black). The red electrode is placed over the nerve that activates the muscle and the black electrode is placed over the area that will contract due to the stimulation as seen in Figure 8. The electrical impulse travels from the red electrode lead to the black one and stimulates the muscle. For this study the intensity of the electrical stimulus was adjusted as necessary per session to promote motor contraction and avoid tolerance to the electrical stimulation that was previously mentioned. Achieving a visible motor contraction in the residua l limb due to the electrical stimulation each treatment session verified that there was no effect of tolerance. Numerical Rating Pain Scale The numerical rating s cale (NRS) is an ordinal measurement scale that was used to report the severity of phantom limb pain from no pain to worst pain. For this study a 10 point scale (Figure 7) was divided into no pain (1 2), moderate pain (3 5), severe pain (6 8) and worst possible pain (9 10). Subjects were asked before and after the treatment to assign their pain to one of the numbers. Smiley faces were Figure 6 : Application of the PENS protocol to the agonist and antagonist muscles and their activity recorded using EMG. Output A is the surface electrode stimulating the agonist muscle and output B stimulates the antagonist muscle. The ph ase duration of the stimulation is the time in milliseconds. (ACP, 2007)

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27 added as graphic aids for comprehension and written descriptions provided a categorical reference. Figure 7 : Self reported numerical pain scale that was given to the participant before and immediately following the treatment to assess short term changes in phantom limb pain. Questionnaire The questionnaire was administered weekly to the participants in order to monitor changes in the characteristics of their phantom limb pain as well as how the pain was impacting their daily lives. A few of the questions were modeled from the validated Pati ent Reported Outcomes Measurement Information System (PROMIS) pain behavior and interference questionnaires including (HealthMeasures, 2017): 1. H ow much does the pain inter fere with your daily activities 2. H ow much does the pain interfere with your social in teractions with others 3. H ow much does the pain interfere with th e things you usually do for fun These questions were rated on a categorical scale of not at all, a little bit, somewhat, quite a bit, and very much. Short answer questions were also asked abou t the characteristics of the pain including: symptoms of phantom limb pain, if the pain is worse at a particular time in the day, what relieves the pain, if they are taking any medications for the pain, and if they are having any residual limb pain or non painful sensations. These questions helped to determine if the treatment was effective for a particular characteristic of phantom limb pain over another.

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28 CHAPTER V METHODS Human Subjects Two self identified a dul t v o lun t ee rs, a male and a female with lower lim b d e f ici e n cies who were experiencing chronic phantom limb pain were enrolled in the study. The first subject was a male multiple limb amputee of 5 years, but complained of phantom limb pain only in the lower limb. He pres ented with an above the knee amputation secondary to a car accident. The second subject was a female below the knee amputee of 6 months, resultant from an infection. The study protocol (Appendix A) was approved by the University of Colorado Scientific Advisory & Review Committee and t he Colorado Multiple Institution Review Board. The therapy was prescribed by a physician and written informed consent was Inclusion Criteria Between the ages of 18 and 85 Have a limb amputation Have a well healed amputation site and sensation in the remaining portion of the limb Experiencing at least a 4 out of 10 of chronic phantom limb pain based on a numeric 10 point pain scale Understand and follow directions in English Exclusion Criteria Those unable to come to the facility Anyone with a cardiac demand pacemaker and/or implanted defibrillator Anyone without a well healed amputation site or without sensation in their residual limb

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29 Electrical Stimulation Therapy The experiments took place a t th e Bi o M e ch a tron i cs De v e lopm e nt La b or a tor y in Childr e s H o spital o n the University of Colorado A nsch u tz Medical Cam p us. The electrical stimulation device used in this study was the Omnistim FX 2 Pro from ACP for the purpose of exercising the muscles of the residual limb and increasing local blood flow. The p a r ti c ipant was asked to co m e in for 15 sessions over a period of 5 weeks, 3 sessions per week. During the first session, a study physician as sessed the participant and their residual limb and prescribed the therapy For the therapy, the participant had the Omnistim FX 2 Pro surface electrodes attached to the limb segment anatomically superior to the level of amputation as described in Table 1. The low extremity (LE) triphasic PENS was selected from the neurological re education modality on the Omnistim FX 2 Pro. The triphasic PENS parameters consisted of asymmetrical biphasic square wave at a frequency of 50 Hz and a phase duration of 7 0 s (ACP, 2007). Electrodes were placed on major muscles over the motor end plate on both the anterior and posterior sides of the body on antagonist muscles as seen in Figure 8. The full protocol can be referenced in Appendix A. Table 1 : Pla cement of the anterior and posterior surface electrodes on the residual limb if the participant is an above or below the knee amputee. Amputation Level Anterior Surface Electrode Placement Posterior Surface Electrode Placement Below the knee Tibialis Anterior Rectus Femoris Gastrocnemius Biceps Femoris Above the knee Vastus Medialis Rectus Femoris Biceps Femoris Biceps Femoris

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30 The red (positive) electrode is placed over the nerve that activate s the muscle and the black (negative) electrode is placed over the area that contracts due to the stimulation. palpated to assess the muscle location and muscle mass. The electrodes passed an electrical current of low frequency through the skin and into the muscle first at a low intensity for 5 minutes to allow the subject to adjust to the sensation. The amplitude of the current was gradually increased to an intensity level sufficien t to elicit a non painful motor contraction for another 15 minutes (highest level of current is 140 mA). The motor contraction electrical stimulus physically exercise s the muscle using an alternating electrical pulse between electrical current outputs plac ed on the anterior and posterior sides. It has been previously determined through experience by Dr. Frank Palermo of ACP that 15 sessions is a long enough period to produce results for Figure 8 : Surface electrode placement on the residual limb for an above the knee amputation. Anterior electrodes placed on the vastus medialis (black) and rectus femoris (red). Posterior electrodes were placed inline on the major biceps femoris of the hamstrings.

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31 other injuries and if no results are seen by 15 sessions then there is likely not going to be a response. Data Analysis Pain level data was collected using a numerical rating pain scale as seen in Figure 7 before and after each session. Data pertaining to the characteristics of the PLP was collected at the beginning of each treatment week through the questionnaire to track any changes. Characteristics of phantom limb pain that were monitored include cramping, stabbing, burning, and shooting pain in the missing portion of the limb. Data was proce s sed with stand a rd t echniques including data analysis tools in Excel and MATLAB (Ma th w orks, Inc.) in o rder to evaluate the effect that patterned electrical neuromuscular stimulation therapy has on decreasing chronic phantom limb pain. A one sided t test was used for within subject test ing looking at pre and post NRS measurements to quantify a decrease in pain. The characteristics of the phantom limb pain where monitored each week and represented in a binary scale as present or absent Trends in the qualitative data were noted to depict if the therapy had a greater effect on one symptom over another.

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32 CHAPTER VI RESULTS The two participants who reached out with interest in the study presented with chronic phantom limb pain in their lower extremity of at least a 4 out of 10 on a numerical rating scale (NRS). Both participants were experiencing cramping, burning, stabbing, and shooting phantom limb pain that most often presented at night. At the time of enrolling in the study, neither participant was taking any over the counter or prescribed medications for pain. In the pre screening questionnaire the male above the knee amputee described the PLP as a crushing sensation in the outside of his foot. The pain occurred daily and he rated it up to an 8 out of 10 NRS on occasion. The female below the knee amputee experienced phantom limb pain, telescoping of the limb, and restl ess leg syndrome. She was experiencing all symptoms of phantom limb pain and rated her pain as varying and up to a 10 out of 10 NRS at times. Effect of Electrical Stimulation Therapy on Decreasing Pain The Omnistim FX 2 Pro Electrical Stimulator using the neuro re education lower extremity patterned electrical neuromuscular stimulation decreases chronic phantom limb pain. The PENS therapy was comfortable for both participants and there was no report of pain or irritation during the treatment sessions from t he Omnistim FX 2 Pro device. Both participants felt a warmth in their residual limb following the electrical stimulation but noted that it was not uncomfortable. Muscle cramping presented in the residual limb as a side effect of the electrical stimulation i n both participants. The cramping began in the major muscle on the distal part of

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33 the limb that was being stimulated after the first few sessions but resolved itself in both participants with continued therapy. The Omnistim FX 2 Pro surface electrodes wer e placed over the major muscles on the anterior and posterior of the residual limb. Black and red leads were positioned in order to achieve motor contraction in the desired area of the residual limb. The placement of electrodes and black and red leads were determined at each session to best achieve motor contraction, avoid electrical stimulation tolerance, and reduce muscle cramping in the residual limb. Short Term Pain Relief The level of pain the participants were experiencing before the treatment that w as cited on the pre treatment pain scale depended on the time of day and what they had previously been doing, such as after physical therapy. Following each treatment session, the participants experienced a notable decrease in their phantom limb pain. The second participant commented that her phantom limb and telescoping foot would completely disappear following the application of PENS The first participant had a significant average decrease in pain of 1.3 points per treatment session on the 10 point NRS a nd the second participant had a significant average decrease of 1.7 points on NRS per treatmen t session (Figures 9,10 ). This was calculated by averaging the decrease in pain on the NRS from the pre treatment score to the post treatment score over all treat ment sessions for each participant. Over time, the decrease in PLP from each treatment session was retained which can be seen in the decrease in pre t reatment PLP scores in Figure 11

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34 Figure 9 : Pre and Post Treatment NRS pain values for each participant show the reduction of pain during each treatment session. The relief of PLP following a treatment session was significant for both participants. 3 7 4 4 2 1 1 1 1 3 3 1 1 1 1 1 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 Numerical Rating Pain Scale Treatment Session Subject 1 Reduction in Pain Pre Post 8 6 5 6 8 7 6 2 2 1 2 5 3 4 4 5 5 4 1 1 1 1 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 11 Numerical Rating Pain Scale Treatment Session Subject 2 Reduction in Pain Pre Post

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35 Figure 10 : Average phantom limb p ain reduction per treatment session based on a numerical rating pain scale before (pre) and after (post) the patterned electrical neuromuscular stimulation for the two participants with standard error bars For the first subject the PLP was reduced on average by 1.375 points and the second subject had a reduction of 1.727 points each treatment session. indicates that the reduction is significant based on the literature. Reduction in Pain Percent decrease in PLP was calculated using the largest pre therapy NRS pain score that was reported by the subject and the fin al post therapy NRS pain score. The first participant saw a decrease in pain from their severe pain rating of an 8 to no pain, a 1 on NRS. This resulted in an 87.5% decreas e in pain after 8 treatment sessions. The second participant began with their max pain at a 10 NRS and saw a reduction to no pain (1 NRS) Their pain decreased 90% after 11 treatment sessions. 1 2 3 4 5 6 7 1 2 AVERAGE NUMERICAL RATING PAIN SCALE SUBJECT AVERAGE PAIN REDUCTION pre post

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36 Table 2 : Pre and Post therapy max and min NRS pain scores for the 2 participants were used to calculate p ercent decrease Average reduction in pain is the reduction due to each treatment session averaged over all the completed sessions for each participant. The p value was computed using a one sided paired t test to test for a significant reduction in pain. Subject 1 Subject 2 Pre Therapy Max Pain (NRS) 8 10 Post Therapy Min Pain (NRS) 1 1 Percent Decrease in Pain 87.5% 90% Average Reduction in Pain per S ession 1.375 1.727 P Value .01816 .000102 Figure 11 : Numerical rating pain scale data collected before the patterned electrical neuromuscular stimulation was applied to the residual limb The pain decreased until it plateaued at little to no pain for both subjects. Both participants saw a significant reduction in pain A one sided paired t test with a 95% confidence interval was used to evaluate the significance of the reduction in pain resulted from the therapy in each partic ipant. A p value less than .05 is considered statistically significant. The first participant had 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 11 Numerical Rating Pain Scale Treatment Day Phantom Limb Pain Pre Treatment Subject 1 Subject 2

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37 a significant reduction in pain after 8 treatment sessions (p = .01816). During the first two weeks of therapy the participant saw a decrease in PLP (p = .009 78) before reaching continuous relief (rating of a 1 NRS). The second participant experienced a significant reduction in PLP after 11 treatment sessions (p = .000102). Similarly, after 2 3 weeks the participant also reached continuous relief of a 1 or 2 on the NRS. Sustained Relief The duration of the relief from PLP following the treatment sessions increased over time as more sessions were conducted. In the early stages of the treatment participants commented that the pain would remain absent the rest of the day following the treatment but would return the next day. After a few more sessions the relief began lasting two days, roughly until the next treatment session. This sustained relief continued to increase exponentially and last through the later tre atments. The first participant went 21 days with no phantom limb pain after only half the recommended treatment sessions (Figur e 12 ) and the second participant maintained relief for over two weeks after stopping treatment.

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38 Figure 12 : Days of relief from PLP following an electrical stimulation treatment session. The length of relief in days increased exponentially (R= 0.81215) with the number of treatment sessions attended by the participants. Data displayed here is from the firs t participant who experienced 21 consecutive days without PLP after only 8 treatment sessions. Changes in the Characteristics Both participants responded that they were experiencing all four characteristics of PLP prior to the therapy. The questionnaire w as administered at the beginning of each treatment week and the characteristics that were present at the time are noted in Table 3. For consistency the questionnaire was always given during the first session of the week which varied based on the participan therapy alleviated the characteristics of PLP, specifically cramping, stabbing and shooting pain. The burning sensation present ed occasionally for the below the knee amputee but was mild to moderate and not persi stent Additionally, the burning pain was relieved immediately following each 1 1 2 2 3 3 4 21 R = 0.8121 0 5 10 15 20 25 1 2 3 4 5 6 7 8 Days of Relief Treatment Session Days of Relief

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39 treatment session with the PENS Cramping phantom limb pain as well as cramping in the residual limb were both mitigated by the PENS therapy. Table 3 : Characteristics of PLP including cramping, burning, stabbing, and shooting pain in the missing limb were tracked over time. Data was collected at the start of each treatment week and the characteristics are marked as Present (X) or Absent ( ). Participant Treatment Session Cramping Burning Stabbing Shooting Subject 1 1 X X X X 3 X 6 Subject 2 1 X X X X 4 X X 6 X 9 X 11 X Participant Testimonies Overall the Omnistim FX 2 Pro PENS therapy was well received by the participants in the study. After attempting a variety of other treatments including mirror therapy, prescribed opioids, heat/cold application, massage, and TENS the participants found this therapy to be the only treatment that provided any relief from their PLP. The male above the knee amputee commented that the application of the the knee g a workout in and was slightly The participants in this study have been living with PLP from 6 months up to 5 years and have found none of these other treatments to relieve their PLP; they were thrilled with the r esults of this study.

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40 hours after the treatment I had to lay down and I fell asleep in a sleep I never get, no one could wake me up at all I slept for 4 hard yesterday was due to the Below the knee amputee

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41 CHAPTER VII DISCUSSION Patterned electrical neuromuscular stimulation significantly decreases chronic phantom limb pain in lower limb amputees. Participants in the study experienced a similar timeline of results. Upon initially starting the treatment, both participants felt an immediate decrease in PLP Following sessions over the next two weeks, the subj ects noted a variety of muscle cramping in the residual limb that was relieved with continued treatment After completion of at least half of the designated 15 treatment sessions, p articipants then noted on the numerical rating pain scale that they had lit tle to no PLP (1 2 NRS) both before and after the treatment session. The PLP relief was then sustained at a low level for the duration of the study and even up to 3 weeks after the last treatment session On average participants experienced a reduction in pain on the NRS of 1.55 points per treatment session. Subject one had an average reduction in pain of 1.375 NRS points and subject two had a reduction of 1.727 NRS points per treatment session As mention in the background, Kelly (2001) ran a study with 1 56 patients and found the minimal clinically significant difference to be 12mm on a 100mm visual analog scale. This correlates to a 1 point decrease in pain on the NRS from 1 10 that was developed for this study. Clinically, participants began with pain th at was severe and persistent, and by the conclusion of the therapy they were experiencing little to no pain that presented occasionally. Participants commented that when the PLP did occur it was less intense than it previously had been and would resolve it self after a short while. The above the knee amputee had a percent decrease in

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42 PLP of 87.5% and the below the knee amputee saw a 90% decrease in their pain Farrar and Young (2001) found an average reduction of 30% on the NRS represented a clinically significant reduction. The duration of the relief also increased with an increased number of treatment sessions and was eventually sustained following the thera py This could be due to the e ffect that PENS has on the afferent signaling pathway and cortical reorganization of the somatosensory cortex that are potential source s for PLP. The body responded better to the therapy with increased number of sessions for b oth participants. Participants in the study felt the electrical stimulation and were able to achieve a motor contraction in the residual limb at a lower intensity with each sequential treatment. This is caused by the reactivating of latent nerves and atrop hied muscle s in the residual limb during the initial treatment sessions An underlying reason for why this therapy works may be due to norepinephrine and the role it plays in increasing pain and co contraction. According to Dr. Frank Palermo with ACP, pro prioceptors send signals to the basal ganglia and Following an amputation, the brain is attempting to relocate the missing limb in space and sends norepinephrine to the site in order to obtain homeostasis However, since it has been amputated it is not possible to attain the original normal state and the muscle s of the residual limb will continue to receive norepinephrine and stay rigid increasing the PLP The PENS aries by stimulating the residual limb and realigning the somatosensory cortex and in turn reducing norepinephrine production and phantom limb pain. The re is little information on this hypothesis for

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43 the mechanism that norepinephrine contributes to PLP and should be explored further. The below the knee participant in the study also experienced increased definition of the residual limb. They noted sensations becoming more spatially accurate on the residual limb as well as an increase in muscle tone. Before the therapy, they would touch the posterior side of the residual limb and feel the sensation on the anterior side near the surgical suture. After continued electrical stimulation treatments, the gap between the site of touch and sensation decreased. This m ay also be an effect of cortical reorganization due to the electrical stimulation. Flor et al. (2006) found sensory discrimination training using high intensity electrical stimulation to improve the cortical reorganization in the somato sensory cortex and i mprove the ability to discriminate the location of the stimulus. Bourjeily Habr et al. (2002) found PENS to increase muscle mass by increasing the capillary/fibre ratio and the fibre cross sectional area. Applying patterned electrical neuromuscular stimul ation to the residual limb resulted in slight muscle soreness in the major muscles. Participants in the study commented of tiredness and muscle cramping within the first two weeks after beginning the therapy. In the TCEMS COPD study, patients in the treatm ent group also reported muscle soreness in their legs following stimulation (Bourjeily Habr et al., 2002). This is most likely caused by exercising atrophied m uscles since participants in the current exploratory pilot study of electrical stimulation therap y for PLP experienced a reduction in muscle soreness with continued treatment.

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44 A one sided paired t test was used to evaluate the significance of the reduction in pain caused by the therapy in each participant. Since the participant is likely to use the sa me criteria to rate their pain before and after the treatment a within subject standardization of pre and post data on the numerical rating scale was used to measure a decrease in pain. Both participants saw a significant reduction (p<.05) in PLP that was sustained after their last treatment session up to 3 weeks A consistent significant decrease in pain for each participant allows the decreased rating for the therapy to be standardized as a whole (Feinstein, 1998). The therapy appeared to have the greatest effect on shooting and stabbing PLP. It also relieved cramping that presented in the residual limb in addition to cramping PLP. The first participant experienced relief from the crushing sensation they felt in their foot and the second p articipant was relieved from their telescoping This pain was similar to the burning pain from the infection that the participant experienced in her lower limb before the amputation. As previously mentioned, pre amputation pain increases the likelihood of developing PLP and recurring pain that was similar to pain The burning could also be caused by neuromas or nerve inflammation that m ay be present in the residual limb (Bek et al. 2006 ) Limitations of the Study tolerance and as a result their reported pain levels. This was accounted for by using a within subject standardization of pre and post data on the numerical rating scale to

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45 measure a decrease in pain. There was also no control group to compare the effectiveness of PENS previous attempts with other tr eatments and inability to experience PLP relief. Another limitation is the difficulty in recruiting an adequate number of subjects the commitment to 3 sessions per week fo r 5 weeks. Only two participants enrolled in the study, likely due to the inconveniences of the location and the length of the study. Unforeseen Obstacles The first participant in the study had to leave town midway through the study after 8 treatment sess ions. They were experiencing sustained relief from their PLP before stopping treatment. This relief lasted for another 3 weeks after the last treatment session before any symptoms of PLP returned. The second participant was scheduled for surgery after comp letion of 11 sessions. At this point in the therapy their PLP remained im proved before being prescribed t ramadol (an opioid) for their unrelated shoulder pain prior to surgery. The participant returned to complete the remaining treatment sessions 10 days after surgery. At t his time, she was taking a prescribed dose of o xycodone every 4 hours and tramadol as needed. A s a result she was barely able to feel the electrical stimulation even at a high intensity and no visible motor contraction was achieved. Opi oids such as oxycodone and t ramadol inhibit afferent pain signals and p revious studies have found t ramadol to directly decrease PLP which may be added to the exclusion criteria for a future study.

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46 Future Developments The beneficial preliminary effects from this study have been used to respond to a Veterans Affairs grant proposal on a study inquiring about treatments for PLP. There has also been close work with the Physical Therapy Department at University Hospital in A urora who are excited to continue the electrical stimulation therapy concurring with physical therapy sessions to relieve patients of their PLP. It is recommended that the exploratory pilot study described here be expanded into a larger clinical trial to improve the significance of the effects. This therapy should be applied to upper limb amputees as well as include a control. Future studies should assess PENS against other electrical stimulation therapies for the treatment of PLP. The planned duration of the therapy for this study consisted of 15 electrical stimulation treatments for the participant. During the therapy a low numerical rating pain score was achieved and maintained. A future longitudinal study following the participants of the current stud y would provide insight into the long term effects of the therapy. It would also provide data on the benefits of continuing treatments and the appropriate frequency of treatments to maintain PLP relief.

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47 REFERENCES den Adel, R.V. & Luykx, R.H.J. (2005) Low and Medium Frequency Electrotherapy. Enraf Nonius Therapy Manual 6 41. Accelerated Care Plus [ACP]. (2007). Omnistim FX 2 Pro: Patterned Electrical Neuromuscular Stimulator Product Specifications. Accelerated Care Plus Reno, Nevada, SPEC0205, R ev1. Amputation. Johns Hopkins Medicine Health Library. Web. 02 May 2016. www.hopkinsmedicine.org Amputee Coalition of America. (2017). Limb Loss Statistics. Web. 19 May 2017. www.amputee coalition.org/limb loss resource center/resources by topic/limb loss statistics Bek, D., Demiralp, B., Kmrc, M., & Atesalp, S., (2006). The relationship between phantom limb pain and neuroma. Acta orthop Traumatol Turc, 40(10), 44 48. Berger, I.H. & Bacon, D.R. (2009). Historical notes on amputation a nd phantom limb Gundersen Lutheran Medical Journal 6(1), 26 29. Bourjeily Habr, G., Rochester, C.L., Palermo,F., Snyder, P., & Mohsenin, V. (2002). Randomized controlled trial of transcutaneous electr ical musc le stimulation of the lower extremities in patients with chronic obstructive pulmonary disease. Thorax, 57(12), 1045 1049. Centers for Disease Control and Prevention. (2016). Factsheet CDC Guideline for Prescribing Opioids for Chronic Pain. U.S. Depart ment of Health and Human Services. Web. 12 June 2017. Cruccu, G., Aziz, T.Z., Garcia Larrea, L., Hansson, P., J ensen, T.S., Lefaucheur, J.P., Simpson, B.A., & Taylor, R.S. (2007). EFNS guide lines on neurostimulation therapy for neuropathic pain. European Journal of Neurology 14(9), 952 970. Davis, K.D., Kiss, Z.H.T., Luo, L., Tasker, R.R., Lozano, A.M., & Dostrovsky, J.O. (1998). Phantom sensations generated by thalamic microsimulation. Nature 391 385 3 87.

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48 Desantana J.M., Walsh, D.M., Vance, C., Rakel, B.A., & Sluka, K.A. (2008). Effectiveness of Transcutaneous Electrical Nerve Stimulation for Treatment of Hyperalgesia and Pain. Curr Rheumatol RepCurrent Rheumatology Reports 10.6, 492 499. Farrar, J.T., Young, J.P LaMoreaux, L., Werth, J.L., & Poole, R.M. (2001) Clinical importance of changes in chronic pain intensity measure on an 11 point numerical pain rating scale. Pain, 94(2), 149 158. Feinstein, Alvan R. (1987). Clinimetrics New Haven: Yale University Press. Print. Fish, R.M. & Geddes, L.A. (2009). Conduction of Electrical Current to and Trough the Human Body: A Review. Open Access Journal of Plastic Surgery, 9, 407 421 Flor, H., Denke, C., Schaefer, M., & Grusser, S. (2001). Effect of sensor discrimination training on cortical reorganization and phantom limb pain. Lancet, 357, 1763 1764. Flor, H. (2002). Phantom limb Pain: Characteristics, Causes, and Treatment. The Lancet Neurology, 1.3, 182 89. Flor, H., Nikolaksen, L., & Jensen, T. (200 6). Phantom li mb pain: a case of maladaptive CNS plasticity? Nature Reviews Neuroscience, 7, 873 881. Gulick, D.T., Castel, J.C., Palermo, F.X., & Draper, D.O. (2011). Effect of Patterned Electrical Neuromuscular Stimulation on Vertical Jump in Collegia te Athletes. Sports Health, 3(2), 152 157. Hanley, M.A., Jensen, M.P., Smith, D.G., Ehde, D.M., Edwards, W.T., & Robinson, L.R. (2007). Preamputation pain and acute pain pr edict chronic pain after lower extremity amputation. Journal of Pain 8(2), 102 109 HealthMeasures (2017). PROMIS: Patient Reported Outcomes Measurement Information System. Northwestern University. Web. 02 June 2017. Herzog, W., Powers, K., Johnston, K., & Duvall, M. (2015). A New Paradigm for Muscle Contraction. Frontiers in Physiology, 6, 174. Huxley, A. F. (1957). Muscle structure and theories of contraction. Progress in Biophysics and Biophysical Chemistry, 7, 255 318.

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49 Kelly, A M. (2001). The minimum clinically significant difference in visual ana logue sca le pain score does not differ with severity of pain. Emerging Medicine Journal, 18, 2 05 207. Kim, S. Y. & Kim, Y. Y. (2012). Mirror Therapy for Phantom Limb Pain. The Korean Journal of Pain 25 (4), 272 274. Kumar, V, Garg, R., Bharati S.J., Gupta, N., Bhatanagar, S., Mishra, S., & Balhara, Y.P.S. (2015). Long Term High dose Oral Morp hine in Phantom Limb Pain with No Addiction Risk. Indian Journal of Palliative Care, 21(1), 85 87. Limb Amputation: Reasons, Procedure, Recovery. WebMD WebM D, n.d. Web. 02 May 2016. Lloyd Jones, D., Adams, R., Carnethon, M., Simone, ( 2009). Heart disease and stroke statistics -2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 119(3), 21 181 McGimpsey, G. & Bradford, T. (2010). Limb prosthetics services and devices. Worcester, MA: Bioengineering Institute Center f or Neuroprosthetics, Worcester Polytechnic Institution Retrieved from h ttp://www.glb.nist.gov/tip/wp/pswp/upload/239_limb_prosthetics_servic es_devices.pdf Mulvey, M., Radford, H., Fawkner, H., Hirst, L., Neumann, V., & Johnson, M. (2013). Transcutaneous Electrical Nerve Stimulation for Phantom Pain and Stump Pain in Adult Amputees. Pain Practice, 13(4), 289 296. Ramachandran, V.S. & Rogers Ramachandran, D., (1996). Synaesthesia in phantom limbs induced with mirrors. Proceedings of the Royal Society B: Biological Sciences 263, 377 386. Schley, M.T., Wilm s, P., Toepfner, T., Schaller, H.P., Schmelz, M., Konrad, C.J., & Birbaumer, N. (2008). Painful and non painful phantom and stump sensations in acute traumatic amputees. The Journal of Trauma 65(4), 858 864. Seyedali, M., Czerniecki, J.M., Morgenroth D.C., & Hahn, M.E., (2012). Co contraction patterns of trans tibial amputee ankle and knee musculature during gait. Journal of NeuroEngineering and Rehbilitation, 9, 29.

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50 Sherwood, L., (2015). Human Physiology: From Cells to Systems. Brooks Cole, 9 th ed. 181 188. Print. Snyder Mackler, L., Delitto, A., Stralka, S. W., & Bailey, S. L. (1994) Use of Electrical Stimulation to Enhance Recovery of Quadriceps Femoris Muscle Force Production in Patients Following Anterior Cruciate Ligament Reconstruction Physical Therapy 74(10) 901 907 Subedi, B., & Grossberg, G. T. (2011). Phantom Limb Pain: Mechanisms and Treatment Approaches. Pain Research and Treatment 1 8. Trucios, J., Tran, J., Tu, K.N., & Lie J.D. (2013). Phantom Limb Pain: Current and Emerging Treatments. U.S. Pharmacist: A Jobson Publication, 38(3): HS14 HS16 Vance, C.GT, Dailey, D.L., Rakel, B.A., & Sluka, K.A. (2014). Using TENS for pain control: the state of the evidence. Pain Management, 4(3), 197 209. Vaso, A., Adahan, H.M., G jika, A., Zahaj, S., Zhurda, T., Vyshka, G., Devor, M. (2014). Peripheral nervous system origin of phantom limb pain. Pain, 155, 1384 1391. Viswanathan, A., Phan, P., & Burton, A. (2010). Use of spinal cord stimulation in the treatment of phantom limb pain: case series and review of the literature. World institute of Pain, 10(5), 479 484. Weeks, S.R, Anderson Barnes, V. C., & Tsao, J. W. (2010). Phantom limb pain: theories and therapies. Neurologist 16(5), 277 286. Willia mson, A. & Hoggart, B. (2005). Pain: a review of three commonly used pain rating scales. Journal of Clinical Nursing, 14, 798 804. Yazdanyar, A. & Newman, A. B. (2009). The Burden of Cardiovascular Disease in the Elderly: Morbidity, Mortality, and Costs Clinics in Geriatric Medicine 25 (4), 563 568. Ziegler Graham, K., Mackenzie, E.J., Ephraim, P.L., Travison, T.G. & Brookmeyer, R. (2008). Estimating the Prevalence of Limb Loss in the United States: 2005 to 2050. Archives of Physical Medicine and Rehabilitation, 89(3), 422 429.

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51 APPENDIX : COMIRB PROTOCOL COMIRB Protocol COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD CAMPUS BOX F 490 TELEPHONE: 303 724 1055 Fax: 303 724 0990 Protocol #: 16 1063 Project Title: Exploratory Study of Electrical Stimulus as a Treatment Option for Chronic Phantom Limb Pain Principal Investigator: Richard Weir Version Date: 02/07/2017 I. Hypotheses and Specific Aims : The purpose of the research project is to conduct a pilot study to explore the efficacy of an electrical stimulus regimen on the treatment of chronic phantom limb pain using a standard of care electrical stimulation system provided by ACP Accelerated Care Plus Corporation 1 The basis for this project is the observation that the ACP high intensity electrical stimulator (Omnistim FX 2 Pro 1 ) has shown improvement in pain and the treatment of other injuries as well as anecdotal evidence 2 from the stimulator creator Dr. Frank Palermo, founder and owner of ACP, on the effectiveness of the ACP system in the management of pain for persons with limb amputations. These observations suggest that appropriate stimulation applied to the surface of the residual limb of persons with limb amputations can attenuate their phantom limb pain. We wish to explore in a more systemic manner whether this is indeed the case and to identify the parameter of interest needed to enable us to develop a full clinical trial. Sel f iden t i f i e d adult volunteers will be used for t he pop ul a t i on s e rved. Specific Aims 1) Electrical stimulus has many parameters including frequency, intensity, wavelength, stimulation patters, etc. The Omnistim FX 2 Pro utilizes a medium frequency ( between 1,000 to 10,000 Hz) and an alternating stimulation pattern that is advantageous for clinical use due to the ease of skin penetration at lower intensities. For our study we want to establish an electrical stimulation protocol on changes in intensity of the electrical stimulus and the effect it has on chronic phantom limb pain. This will be accomplished by increasing the intensity to a non painful level that elicits motor contraction in the muscle for a duration of 15 minutes. According to the device manual it is standard of care to COMIRB APPROVED 02 Mar 2017

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52 elicit a moderate muscle twitch for therapeutic purposes with the Omnistim FX 2 PRO. 2) Examine short term effects of electrical stimulus medium frequency alternating current at an intensity that promotes motor contraction on h uman subjects with chronic phantom limb pain through the use of a numerical pain scale administered before the treatment session and directly following. 3) Assess the effectiveness of reducing chronic phantom limb pain long term using an electrical stimulus treatment that promotes motor contraction over a period of 15 sessions. This will be assessed through a numerical pain scale and short answer questions about the characteristics of the pain. This will provide insight into the duration required for a future study. II Background and Significance : In 2010 there were an estimated 1.9 million people with limb loss solely in the USA according to the National Institute of Standards and Technology (NIST), and that number has increased since the start of the of the conflict over seas in Iraq and Afghanist an (S.R. Weeks, 2010). Amputations are common in trauma such as war time injuries as well as cardiovascular diseases, diabetes, cancer, and congenital limb deficiency. Each year, there are approximately 185,000 amputation surgeries performed and there is u p to an 80% prevalence of phantom limb pain (PLP) in amputees (Flor, 2002). Phantom limb pain (PLP) is classified as burning, stabbing, shooting, and/or cramping in the missing portion of the limb. Current treatments for PLP include pharmacological drugs, anesthesia, additional surgery, mirror therapy, transcutaneous electrical nerve stimulation (TENS) and others. TENS, as usually implemented, has been used as an electrical stimulus therapy to effectively reduce pain in numerous spots of the body, but has shown little effect in reducing phantom limb pain especially long term even with varying the frequency and intensity. Furthermore, it is reported that many individuals with an amputation are reluctant to have an additional surgery to improve their pain and on drugs because of their added side effects (Subedi and Grossberg, 2011). Current non typically only offer immediate relief (Flor, 2002). Also many of these tre atments that amputations occur among all socioeconomic classes as well as ages and genders (McGimpsey and Bradford, 2010). Using an electrical stimulator at an intensity that pro motes muscle contraction has proven to reduce pain and increase healing in numerous sports and joint related injuries (Snyder_Mackler, 1994). Anecdotally, we have learned that a similar treatment protocol when applied to persons with phantom limb pain can mitigate their pain 2 We seek to test this anecdote. The goal of this pilot study is to assess the effectiveness of electrical stimulation in the management of chronic PLP and also to acquire data to inform us to the most appropriate study design and powe r for a future more formal clinical trial. To accomplish this, we will utilize the ACP Omnistim FX 2 Pro 1 electrical stimulator and use it to physically exercise the muscles of the residual limb and

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53 tial for treatment of phantom limb pain both in the short term and the long term. III. Preliminary Studies/Progress Report: This is a pilot studying to inform on the study design and power of a future clinical trial to explore the effectiveness of ele ctrical stimulation on managing phantom limb pain. Research on higher intensity electrical stimulus has been shown to relieve pain in other areas of the body and improve the healing in patients who have had ACL surgery (Snyder_Mackler, 1994). Specifically, the Omnistim FX 2 Pro is used for relaxation of muscle spasms, re education of muscle action, prevention of disuse atrophy, increased local blood circulation, and maintaining or increasing range of motion. In order to obtain preliminary data on the effect this electrical stimulation technique has on chronic phantom limb pain we propose to collect data from 10 subjects. This will allow us to gain an understanding of the issues involved in using this technique. IV. Research Methods A. Outcome Measure(s): O utcome measures include reduced phantom limb pain short term directly following 20 minute treatment session as assessed on a numeric 10 point pain scale and sustained long term pain reduction relative to a baseline pain level as assessed using a self repor ted numeric pain scale and short answer to record changes in pain characteristics. These outcome measures will help us to better determine if a full clinical trial should be pursued. B. Description of Population to be Enrolled: The subject popula t ion will cons i st o f self identified a dul t v o lun t ee rs with a limb d e f ici e n cy, a well healed site of amputation and who have sensation in their residual limb and are experiencing at least a 4 out of 10 of chronic phantom limb pain based on a numeric 10 point pain scale Th e su bjec t s can be of any e t hnici t y a g e (18 85 years) an d g e nd e r. 10 su bje c t s will be e nroll e d to allow us to assess efficacy of the treatment protocol. Th e su bje c t s m u s t be a b l e t o u nd e rstand a n d f ollow dire c t ions in E n glish, a ssessed b y their a b ili t y to respo n d d u ring th e r e crui tme nt a n d co n sent p r oce s s. Ex clusion criter i a include a ny subjec t s t ha t a r e n o t able t o u n ders t a n d the proc e dures or are unable to come to the facility and anyone with cardiac demand pacemakers and/or implanted defibrillators Also anyone without a well healed amputation site or sensation in their residual limb for placement of the surface electrodes will be excluded. Subjects will be recruited via flyers placed at the University of Colorado Anschutz or Auraria c ampuses, flyers emailed to organizations that work with our target population, or in person at conferences and events to which we have been invited.

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54 C. Study Design and Research Methods The experiments will take place a t th e Bi o m e ch a tron i cs De v e lopm e nt L a b or a tor y in th e Childr e s H o spital o n A nsch u tz cam p us. The p a r ti c ipant will co m e for 15 sessions over a period of 6 weeks, and each session will last for up to 1 hour. During this session the study physician will prescribe the treatment and they and the primary contact and PI will monitor the patient throughout each session. The participant will have Omnistim FX 2 Pro surface electrodes attached to the limb segment superior to the level of amputation. Electrodes will be placed on the major muscles over the motor endplate on both the anterior and posterior sides of the body. S ta nd ard o f c are proc e dure i n volves p a l p a t ion o f t he subject s residual limb which will be used to l oc a te t he best p ositio n fo r th e s u rf a c e electrodes. The electrodes will pass an electrical current through the skin and into the muscle first at a low intensity for 5 minutes to allow the subject to adjust to the sensation. The current will then be gradually increased to a level sufficient to elicit a non painful motor contraction. The subject will sit in a relaxed position as the electrical stimulator contracts the muscles for a duration of 15 minutes. It has been determined that 15 sessions is a long enough period to produce results for other injuries and if no results are seen by 15 sessions then there is likely not going to be a response. D. Description, Risks and Justification of Procedures and Data Collection Tools: Pain level data will be collected using a self reported pain scale bef ore and immediately after each session. Data pertaining to the characteristics of the pain will be collected once a week using short answer questions and a pain scale to evaluate any long term changes. The data will be recorded for all sessions and allow u s to observe long term effects. Risks of su r f a ce electrical stimulus include possible minor skin dis c o m fo r t f r o m the a dhesi v e used t o a t t a c h electrodes to the skin as well as minor discomfort from the motor contraction caused by the electrical stimulator Absent or diminished sensation in the limb should be avoided for electrode placement or treated with caution. Stinging, burning or other painful sensations under the electrodes on normal or desensitized areas is indications of increased current density. Sk in irritation and burns beneath the electrodes have been reported with the use of other powered muscle stimulators. The level of intensity of electrical stimulation will result in slight tingling of the area up to non painful motor contraction. If it becom es painful the subject should inform the operator immediately and the intensity level will be reduced. Soreness of the muscles may occur from the promotion of muscle contraction. When t he proc e dure is finished, t he el e ctrodes will be removed. All equipm e nt will be sterilized in a c cord a nce to st a nda r d of care proc e dures. If you feel t ha t y o u h a ve been h a rm e d wh i le p a r t i cip a ti n g in this s tud y you s h ould in f orm Rich a rd Weir a t 847 912 1 032 i m media t ely. E. Potential Scientific Problems: Po t e n t i a l scien t i f ic problems include a l ac k o f su bje cts wi t h limb a m pu t at i o n.

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55 F. Data Analysis Plan: Data will be proce s sed with stand a rd t echniques in MATLAB (Ma th w orks, Inc.) in o rder to evaluate the effect that high intensity electrical stimulus has on decreasing phantom limb pain. T tests will be used for within subject testing looking at pre and post treatment measures to quantify a decrease in pain and Anovas will be used to look at tr ends in post treatment measures over time. This will allow us to assess if this electrical stimulation therapy is an effective treatment for phantom limb pain. This is an exploratory studying to inform on the study design and power of a future more formal clinical trial to explore the effectiveness of electrical stimulation on managing chronic phantom limb pain. In order to obtain preliminary data on the effect t his electrical stimulation technique has on phantom limb pain we propose to collect data from 10 subjects. This will allow us to gain an understanding of the issues involved in using this technique. G. Summarize Knowledge to be Gained: The developme nt of a less invasive and widely available treatment for phantom limb pain that will enhance the quality of life for individuals with a limb amputation. H. References: Flor, Herta. (2002). Phantom limb Pain: Characteristics, Causes, and Treatment. The Lancet Neurology, 1.3, 182 89. McGimpsey, G., & Bradford, T. (2010). Limb prosthetics services and devices. Worcester, MA: Bioengineering Institute Center f or Neuroprosthetics, Worcester Polytechnic Institution. Retrieved from http://www.glb.nist.gov/tip/wp/pswp/upload/239_limb_prosthetics_services_d evices.pdf Snyder Mackler, L., Delitto, A., Stralka, S. W., & Bailey, S. L. (1994) Use of Electrical Stimulation to Enhance Recovery of Quadriceps Femoris Muscle Force Productio n in Patients Following Anterior Cruciate Ligament Reconstruction Physical Therapy, 74(10) 901 907 Subedi, Bishnu, and Grossberg, George T. (2011). Phantom Limb Pain: Mechanisms and Treatment Approaches. Pain Research and Treatment 2011, 1 8. Weeks, S.R, Anderson Barnes, V. C., and Tsao, J. W. (2010). Phantom limb pain: theories and therapies. Neurologist 16 (5), 277 286.