"Efficacy of Botulinum Toxin Injection in Reducing Limb Pain in Patients With Complex Regional Pain Syndrome"

PROJECT DESCRIPTION Principal Investigator: Hajime Tokuno, MD

Project Title: "Efficacy of botulinum toxin injection in reducing limb pain in patients with
Complex Regional Pain Syndrome"

Purpose: Complex Regional Pain Syndrome is a condition affecting anywhere from 1 to 5 million
Americans including members of our veteran population for which there are woefully few
effective therapeutics options. The investigators hypothesize that they can reduce overall
pain levels in patients with Complex Regional Pain Syndrome (CRPS) using botulinum toxins.
Reduction in the VAS score will be the primary outcome measure. Additionally they hypothesize
that the quality of life will improve and disability will decrease, thus these two parameters
both quality of life and disability will serve as the main secondary outcome measures.
Additional secondary outcome measures include thermography, goniometry, algometry, electrical
impedance myography, and a modified VAS scale designed by the investigators.

Background:

CRPS is a poorly defined medical entity that consists of a number of different signs and
symptoms including neuropathic pain (or allodynia), ischemic pain, sympathetically mediated
pain, and myofascial pain. There have been a number of therapeutic options such as
anticonvulsants to treat neuropathic pain. Sympathetic mediated central pain has been treated
with sympathetic ganglion blocks.

There are two similar forms called CRPS-I and CRPS-II with the same symptoms and treatments.
CRPS-I has previously been known as RSD or Reflex Sympathic Dystrophy Syndrome and involves
individuals without confirmed nerve injury. CRPS-II has previously been known as causalgia
and involves individuals whose symptoms appeared after a confirmed nerve injury.

CRPS can appear at any age. It is rare in the elderly and more common in women. Occasionally
CRPS can develop without any known injury. There is no specific single diagnostic test to
confirm CRPS and diagnosis is made based on the affected individual's medical history and
signs/symptoms that match the definition; it is a diagnosis of exclusion. (Borchers 2014).

The component of CRPS largely ignored has been the myofascial pain component. Patients in the
VA CRPS clinic at West Haven, CT have been found to have a myofascial pain component and
responded positively to Botox injections. In one anecdotal case, the patient claimed that
botulinum toxin injection was the only drug that ever helped her overall pain albeit in a
limited fashion. Botulinum toxins are compounds known to relax tightly contracted muscles by
blocking the release of acetylcholine, the sole neurotransmitter that initiates muscle
contraction at the neuromuscular junction (Kalandakanond & Coffield 2001). They are a
well-established class of neurotoxin with a wide variety of FDA approved medical applications
including muscle relaxation, headache prevention and bladder control (Chen 2012). There are
only a handful of studies assessing botulinum toxin A injections for the treatment of CPRS
related pain. The results are mixed. There are two studies utilizing intramuscular botulinum
toxin, one by Safarpour et al 2010 comprising of two patients and the other by Argoff 2002
consisting of 11 patients. Patients demonstrated overall pain improvement with the
intramuscular Botox injections similar to the investigators' results.

In this study, the investigators are utilizing four novel devices; goniometry to assess range
of motion of the upper or lower extremity limb joints, infrared thermography to assess heat
production in affected body regions, algometry to quantify pressure-pain thresholds, and
electrical impedance myography to assess atrophy in a quantitative manner.

A goniometer is a simple mechanical tool used by physiotherapists that can quickly and safely
assess passive range of motion of individual limb joints. The units of measure will be
recorded in degrees change from the resting position to the fully flexed or extended position
for a given joint. For upper extremity CPRS, the investigators will assess arm flexion, arm
extension, wrist extension, wrist flexion for both the affected limb as well as the normal
limb. The normal will serve as the internal control. For lower extremity CRPS, they will
assess leg flexion, leg extension, dorsiflexion, plantar flexion. They will obtain a measure
of rotational range of motion of a joint using degrees of change compared to the unaffected
limb.

The investigators will be using a digital goniometer known as the Baseline Absolute Axis 360
Degree Goniometer. For this study, one physical therapist will carry out all the measurements
in order to avoid inter-examiner variability. She will obtain the mean of 3 separate
measurements at each joint.

Digital infrared thermography can record heat emanation from pre-defined regions of interest
(ROI) in affected area of the body, non-invasively. Studies of CRPS suggest that limb
temperatures are often elevated acutely and decreased chronically. There are mixed results
regarding the utility of thermography in the diagnosis of CRPS and the investigators of this
study are hoping to provide further insight into this matter. Because of the mixed results of
infrared imaging in pain patients (Ra et al 2013), they will use this parameter as a
secondary outcome measure. The specific device they will be utilizing is a FLIR A65 series
medical grade IR thermography unit. They will be utilizing quantitative thermography where
they will utilize the selected regions of interest (ROIs) and compare between the affected
and unaffected areas on the contralateral limb(s). They will be utilizing the Research IR Max
software to perform statistical analyses. Below are the defined ROIs:

flexor carpi radialis and flexor digitorum superficialis, extensor carpi radialis and
extensor carpi ulnaris, biceps, triceps, anterior compartment leg muscles, gastrocnemii
quadriceps hamstrings and hip adductors.

They have developed these ROIs based on their own observations in the CRPS clinic. They have
observed that the limb hypothermia localizes mostly to the large proximal muscles on the side
of a hand or foot experiencing allodynia. There was less correlation with the affected distal
limb segment where the allodynia was perceived. Similar observations were made by a group
that examined the reliability of IRT in the diagnosing CRPS (Choi et al 2013).

An algometer is a device that measures pain thresholds in affected areas. The investigators
will be utilizing a digital algometer designed by Wagner Instruments called the Force One
Digital Force Gauge. They will be recording the minimal pressure required to trigger a pain
response at several pre-designated site. The physical therapist on their team will obtain the
measurements and will record the average of three readings. The operator of the device will
apply a steady force at a predefined site on an affected limb, and a digital readout of the
pain threshold will be recorded in kilopascal units (kPa = Newtons/m2) per second. They will
utilize the same muscle groups laid out in the ROIs above. In all instances, the central
belly of the muscle will be targeted and pressure will be applied to the central belly until
the patient perceives pain at that site. The pressure readout will be recorded for later
comparison and correlation with other primary and secondary measures. They are focusing on
the central belly because this is where the majority of trigger points are located (Margoles
1999).

They will also utilize electrical impedance myography (EIM) in this study. EIM assesses
disease-induced changes in muscle tissue, including myocyte atrophy and loss, muscle edema,
and fatty infiltration. It is a new technology that is non invasive and safe. EIM uses
high-frequency, low intensity electrical currents to quantify disuse atrophy and other muscle
pathology. The low intensity of the current prevents the muscle and nerve depolarization
threshold, and therefore, the patient experiences no unpleasant sensation during the study.
This is especially important with the CRPS patients who are chronically experiencing
tremendous pain. Rutkove et al demonstrated that leg atrophy following limb immobilization as
well as restoration of normal muscle bulk was measureable with an EIM device. Rutkove used a
parameter was called θ which is a measure of both resistance and capacitance θ = arctan (X/R)
where X = 1/capacitance and R = resistance.

The investigators wish to quantify the muscle atrophy in CRPS patients using the same
technology. Clinical experience has shown that the painful limbs are often atrophic and cold.
The investigators are interested in understanding the relationship between heat production
and muscular atrophy and if EIM can give them a more precise and representation of this
phenomenon. (Tarulli et al 2009).

Significance:

The potential benefits are overall pain reduction in the painful extremity as demonstrated by
reduced score on the VAS. Additionally there may be improvement of quality of life and
reduction in disability. This project may contribute to the utilization of a new treatment
modality for CRPS that may reduce limb pain more so than any current modality.

Research Plan:

Methods:

This is a double blinded, randomized cross-over study that will be conducted over an
estimated 7 month period for each study participant. It is a pilot study that will include
twenty subjects recruited from the Neurology CRPS clinic at VA Connecticut and also from the
area VA hospitals within a 150 mile radius. Subjects will receive an intramuscular injection
Treatment A which is only 1% lidocaine or Treatment B which is mixture of botulinum toxin A +
1% lidocaine in the affected limb only. This is a cross over study where patients will
receive Treatment A or B initially during the first of four study visits and during the third
study visit will receive whichever treatment not given during the first visit. Dr. Sameer
Ali, VA neurology fellow, will be blinded when administering the treatments. Dr. Hajime
Tokuno, VA neurologist who is the principal investigator of the trial will prepare the
treatments. Clinical pharmacy will be randomizing the treatments. Dr. Tokuno will not be
blinded as he needs to know which treatment has been given in case of complications.

The total dose of Treatment A or B per patient in the lower extremity or upper extremity will
be based on common doses given in spasticity patients in the neurology injection clinic. The
total dose per patient in the arm will be as follows: biceps 30 units, triceps 40 units,
flexor carpi radialis 20 units, extensor carpi radialis 20 units. The total dose per patient
in the leg will be as follows: vastus lateralis 50 units, rectus femoris 30 units, medial
gastrocnemius 40 units, tibialis anterior 40 units. The dosing pattern will be largely exam
dependent as we will inject the actual areas or proximal to the areas that are painful either
at rest or upon stretch. A maximum of 200 units of botulinum toxin A will be administered at
a time as to minimize the risk of side effects.

For the treatment B arm one vial of ONABOTULINUMTOXINA 200 UNITS/VIAL for each subject will
be drawn in two separate syringes of 100 units each and reconstituted with the 1% lidocaine.
For treatment A there will be two syringes filled with 1% lidocaine. Dr. Tokuno will prepare
the treatments and randomization and storage will be provided by the clinical pharmacy. The
reconstituting will be done in the clinic. Patients will be injected at the VA Connecticut
during CRPS clinic hours.

There will be a washout period of 4 months for the patients receiving the first round of
injections (lidocaine or botulinum toxin + lidocaine) prior to the crossover. There will be a
total of 4 visits to the VA. The first visit-either injection of Treatment A or B, the post
injection 1 month follow up. After 3 more months have gone by (4 months post
injection=washout period) then the treatment arm will switch and pt will again come in for
the injection and post injection 1 month follow up.

All four study visits will start with obtaining the VAS score, a modified VAS score we have
designed, pain disability index and quality of life scores. We will utilize a modified VAS
scale to ask patient the average level of pain in a day, the lowest and highest pain scores
for that day, and the exact contributions of various qualities of the pain specifically
myofascial and hypersensitivity pain.

We then will proceed by obtaining data with the utilization of thermography, goniometry,
algometry, EIM. Thermographic data will allow us to look at heat production in the affected
limb compared to unaffected limb and if there is a change after treatment A or B when
reassessed. Algometry will allow us to determine how much pressure is needed to allow for
realization of discomfort and if this changes post treatment. Goniometry will allow us to
determine the range of motion of both affected and unaffected muscles to see if there is a
difference as we are expecting decreased range in the affected limb. We can then see if the
range of motion will improve after either treatment. We also will utilize EIM to assess if
our treatments can alter changes of impedance in the affected limb.

The primary outcome measure is pain reduction reflected by the VAS scale and the secondary
outcome measures are quality of life and disability as well as thermography and range of
motion. This study will test the effects of a one-time botulinum toxin A injection.

Statistical analysis-. We will have patients come one month after each of the two injections
to reassess their functional status using goniometry, thermography and neurologic exam. The
primary outcome measure is pain reduction reflected by the VAS scale and the secondary
outcome measures are quality of life and disability as well as thermography and range of
motion. This study will test the effects of a one-time botulinum toxin A injection. The
Pierson product-moment correlation will be used to assess the pain via the VAS score over
time. The Spearman rank-order correlation will be used to assess the VAS scale and the
following secondary outcome measures-Range of motion, thermography, quality of life,
disability.

Inclusion Criteria:

1. All patients with documented diagnosis of CRPS per International Pain Society
Guidelines. Diagnosis must be made or confirmed in the neurology CRPS clinic prior to
recruitment.

2. Patients ages 18-80.

3. Patients may or may not have tried other therapeutics, will not affect study.

4. Veterans enrolled in the Veterans Hospital system of the United States.

5. Patients enrolled either type I or II CRPS of either upper or lower extremity.

Exclusion Criteria:

1. Prior history of adverse side effects with use of botulinum toxin.

2. Prior adverse reaction to lidocaine use.

3. CRPS involving multiple extremities.

4. Myasthenia gravis, myopathy, severe polyneuropathy or other causes of chronic muscle
weakness.

5. History of severe mental illness or dementia.