Banner MD Anderson Cancer Center
Scientific Presentation, May 9, 2014
Rebecca Armendariz, MD

Disclosures

Objectives

Background
• World Health Organization (WHO) projects >
15 million new cancer cases by 2020 1
• > 60% Pain prevalence in metastatic, advanced or terminal phases of cancer,
~ 30% in survivors 2
• Cancer pain not adequately treated in a significant percentage of patients, ranging from 56 to 82.3% 3,4
• Most advanced cancer patients have at least two types of cancer-related pain
• Incidence of Chemotherapy Induced
Peripheral Neuropathy (CIPN) is widely variable

Background
®

Background
®

Background
– Physician Procedure Code 0278T, Transcutaneous electrical modulation pain reprocessing with placement of electrodes
– ICD-9 Codes: 338.3 - Neoplasm-related pain, 355.9 -
Mononeuritis of unspecified site & 357.7 - Polyneuropathy

Background
TENS
• Uses linear standard impulses with on-off biphasic current to excite A-Beta fibers
• High Frequency > 50 Hz with low
Intensity below motor contraction
• Or low frequency < 10 Hz with intensity that produces motor contraction
CALMARE
• Uses a proprietary algorithm to assemble strings of patterns that create a “non-pain” signal
(artificial neuron)
• Creates 16 different synthetic action potentials similar to endogenous waveforms
• Translated into 4 different phases creating variable nonlinear waveforms that stimulate C and A-
Delta fibers (width > 5 msec)

Background
TENS
• Continuous pulse pattern, square wave
• Pulse width of 200 microsecs & pulse freq of 80 Hz
• Increased until pt feels sensation
• Gate-Control Theory
– Melzack & Wall, 1965
CALMARE
• Charge per phase is 38.8 microcoulombs
• Phase duration is 6.8 - 10.9 microsecs with pulse rate of 43-52
Hz
• Frequency never exceeds 52 Hz
• Mean energy delivered per sec <
TENS device

Background
A-Beta Fiber
• A-Class thinly myelinated afferent fiber
• Muscle spindle secondary endings (muscle length)
• Touch & kinesthesia
A-Delta Fiber
• A-Class thinly myelinated afferent fiber
• Sensory afferent fiber
• Cold, pressure and acute sharp pain
C-Fiber
• C-Class non-myelinated afferent fiber
• Thermal, mechanical & chemical sensory fiber

Background
QuickTime™ and a
decompressor are needed to see this picture.

Background
QuickTime™ and a
decompressor are needed to see this picture.

Background
Substantia
Gelatinosa
Nucleus
Proprius
QuickTime™ and a
decompressor are needed to see this picture.

Background
QuickTime™ and a
decompressor are needed to see this picture.

Background

Background

What is it used for?
– Peripheral Neuropathy
– Post-Herpetic Neuralgia
– CRPS / RSD
– Carpal Tunnel Syndrome
– Phantom limb pain
– Chronic back pain
– Pudendal Pain
– Failed Back Surgery Synd
– Fibromyalgia
– Post-Surgical pain
– Perineal Pain
– Sciatica
– Chemo Induced Periph Neuropathy
– Radiation Plexopathy
– Pain from bone mets
– Drug-resistant pain

Contraindications?
• Patients with metal implants such as pacemakers, automatic defibrillators, aneurysm clips, vena cava clips and skull plates, have a seizure disorder or or pregnant.
• Patients with undiagnosed pain.
• Electrodes should not be placed on the carotid sinus, head, A/P thorax or over the heart.
• Can be used on patients with metal implants such as total knee, hip, shoulder and other joint replacements as well as on patients with implanted pins, clips, screws, plates and cages used for orthopedic repair.

Adverse Side Effects

Evidence

Evidence
• Marineo, G. - 2003 first published trial involving 11 patients with cancer with resistant visceral pain 5
– Pain reduced from 8.6 out of 10 before the first treatment to 2.3 out of
10 after the first treatment and to less than 0.5 out of 10 at the end of
10 sessions (P < 0.0001 by paired t-test)
– 9 of the 11 pts stopped pain meds within 5 sessions (until death)
– No toxicities or adverse side effects
• Sabato, A.F. & Marineo, G - 2005 trial with 226 patients with neuropathic pain 6
– Reported 80% of pts had > 50% pain relief, 10% responded with pain relief from 25% to 49%, and 10% had no response (P < 0.0001 by paired t-test)
– No toxicities or adverse side effects
• FDA clearance based on these studies

Evidence
• Smith, T.J. et al - 2010 - Pilot trial of a Patient-Specific Cutaneous
Electrostimulation Device (MC5-A Calmare
®
) for CIPN 7
– 18 patients given 10 days of treatment, 16 completed
– Mean age 58.6 years, 4 men, 14 women
– CIPN range 3 months - 8 years
– Predominant study agents taxane and bortezomib
– Primary Objective: reduce CIPN pain by 20% based on threshold used in the Cancer Pain Trial 12
– Repeated-measures random-effects analysis of variance for adjusted pain score
– Daily pain score variability

Evidence
• Smith, T.J. et al - 2010 Pilot trial for treatment of CIPN 7
– Pain score (NRS) fell 59% from 5.81 + 1.11 before treatment to 2.38 +
1.82 at the end of 10 days (P < 0.0001 by paired t-test)
– Strong statistically significant difference between the pre and post-daily pain scores (P < 0.001)

Evidence
• Smith, T. et al - 2010 Pilot trial for treatment of CIPN 7
– No toxicity was seen
– Some responses were durable
– Improved sensation, gait and motor function
– Return to ‘normal’ sensation & partial relief of numbness

Evidence
• Smith, T. et al - 2010 Pilot trial for treatment of CIPN 7
– Four patients had their CIPN reduced to zero
– Only two had complete resolution without maintenance
Secondary Endpoint measures showed:
– No change in morphine oral equivalent dose (3 decreased)
– No other formal QOL or symptom, other than pain, changed significantly

Evidence
• Ricci, M., et al. 2012 Managing Chronic Pain: results from an openlabel study sing MC5-A Calmare
® device 8
– 73 pts: 40 with cancer & 33 without cancer
– Median age 66 yrs (28 - 87 range), 38 male, 35 female
– Pain present > 3 months in 81% of patients (75% continuous)
– Assess efficacy and tolerability of the device
– NRS assessed weekly during Tx and weekly for 2 week follow-up

Evidence
• Ricci, M., et al. 2012 Managing Chronic Pain 8

Evidence
• Ricci, M., et al. 2012 Managing Chronic Pain 8

Evidence
• Ricci, M., et al. 2012 Managing Chronic Pain 8

Evidence
• Ricci, M., et al. 2012 Managing Chronic Pain 8

Evidence
• Marineo, G, Smith, T. et al - 2012 - Scrambler Therapy May Relieve
Chronic Neuropathic Pain More Effectively Than Guideline-Based
Drug Management: Results of a Pilot, RCT 9
– 52 pts randomized to either 10 day Calmare Tx vs pharm
– Pain matched (post surg neuropathic pain, PHN, spinal stenosis)
– VAS pain scores at 1, 2, 3 months, med use, allodynia
– Control group (Pharm) managed based on European Federation of
Neurological Societies (EFNS) Clinical Practice Guidelines
– Most common baseline therapy: Amitryptyline, Gabapentin & Tramadol -
> switched to Amitriptyline, Clonazepam and Oxycodone

Evidence
• Marineo, G, Smith, T. et al - 2012 Pilot RCT Calmare vs Drugs 9
– Results: 1 Mos = VAS reduced 28% in control and 91% in Scrambler
(P<0.0001)

Evidence

Evidence

Evidence
• Marineo, G, Smith, T. et al - 2012 Pilot RCT Calmare vs Drugs 9
– Opioids eliminated in 11 of 17 cases, halved in 1 case, 5 unvaried
– Anticonvulsants eliminated in 17 of 24 cases, reduced in 1 case, 6 unvaried
– Antidepressants eliminated in 9 of 19 cases, reduced in 4 cases, 6 unvaried
– Overall drug consumption reduced by 72% in Calmare group

Evidence
• Marineo, G, Smith, T. et al - 2012 Pilot RCT Calmare vs Drugs 9
– Allodynia was reduced in Calmare group from 77% to 15%
– Clinically significant

Evidence
Figure 4. Effect of Therapy by Mono-or Polyneuropathy

Evidence
• Pachman, D.R., et al. 2012 ASCO Abstract - Pilot study for treatment of chemotherapy induced peripheral neuropathy.
10
– 11 pts, mean age 57, 3 men 8 women
– majority symptoms > 2 years, various agents
– Daily NRS, 10 Txs of 30 mins each

Evidence
• Smith, T.J., et al. 2012 ASCO Abstract - Treatment of post-herpetic pain with scrambler therapy, a patient-specific neuro-cutaneous electrical stimulation device.
11
– 10 pts mean age 54 + 13 yrs, 6 men 4 women
– Mean PHN duration 15.6 months (2.5 - 48 months range)
– NRS at 1, 2, & 3 months
Results:
– Baseline pain score 7.64 + 1.46 diminished to 0.42 + 0.89 at one month
(1.93 at 2 months and 2.21 at 3 months)
– Achieved maximum pain relief with < 5 treatments
– Continued relief at 2 and 3 months
– 5 out of 10 pts had continued complete disappearance of pain
– Most patients were able to stop or reduce pain medications

Evidence
• Sparadeo, F. et al. 2012 - Scrambler Therapy: An Innovative and
Effective Treatment for Chronic Neuropathic Pain 12
– 173 pts treated for 10 days with Calmare ® device
– Follow-up analysis on 91 patients
– VAS before and after each treatment
– VAS & Brief Pain Inventory at baseline and again 3 to 6 months post treatment
– Single site spine pain, neuralgia, CRPS, multi-site pain patients

Evidence
• Results: Mean VAS score before starting treatment was just over 7.24 and diminished to 3 after the 10th session.
VAS Scores before and after Calmare

Evidence
• Results: BPI score means by diagnosis showed statistically significant improvement across all four groups after 10 treatments (p< .01) paired t-tests.

Evidence
• Results: Mean scores in all variables of the BPI were diminished after
Calmare tx (P<.0001) and dropped by over 50% .

Evidence
• Results: Analysis of Variance results with means comparisons on all dependent variables (BPI & VAS) within the four diagnostic groups .

Evidence

Evidence

Evidence

Who Is Using Calmare?
• Dept of Defense has 14 machines
• Andrews Air Force Base is using
Calmare ®
• Navy base in San Diego (Balboa) has integrative Medicine Clinic and is offering Calmare
®
• Walter Reed is utilizing Calmare ® for undisclosed Pain syndromes

Who Is Using Calmare?
• Naval Medical Center Portsmouth
Portsmouth, VA 23708-2111
• Naval Medical Center San Diego
San Diego, CA 92134-5000
• Naval Medical Center Bethesda
Bethesda, MD 20889
• Naval Hospital Camp Lejeune
Camp Lejeune, NC 28547-0100
• Naval Hospital Pensacola
Pensacola, FL 32512-0001
• Naval Hospital Bremerton
Bremerton, WA 98312-1898
• Naval Hospital Jacksonville
Jacksonville, FL 32214-5000
• Naval Hospital Camp Pendleton
Camp Pendleton, CA 92055-5008
• U.S. Naval Hospital Okinawa
Chatan-cho, Okinawa 904-0103

Who Is Using Calmare?
• Massey Cancer Center at the
Virginia Commonwealth University
Richmond, VA
• Stephen J. D'Amato, MD, FACEP
West Warwick, RI http://cprcenters.com/
•
•
Paul Carbone Cancer Center at the
University of Wisconsin
Madison, WI
Mayo Clinic
Rochester, MN
• Jack D'Angelo MD, MBA, Perry
Drucker MD, and Christopher
Perez MD
Staten Island, NY http://www.sirehab.com/Scrambler%20Thera py%20Clinical%20Research%20and%20Pre sentations.html
• Hunter Holmes McGuire Veteran’s
Hospital, Richmond, VA
• University of Virginia, Charlottesville,
VA
• Spero Pain Clinic, St. George, UT http://www.sperotherapy.com/
• 32 Calmare
®
Treatment Centers listed w/ Competitive Technologies

Should We Use It?
• Cost: ~ $85,000
• Options for lease vs purchase
• United Health Care, Blue Cross Blue
Shield and Medicare
• Medicare just lost appeal for
Calmare ®
• Charge $60 to $300 per session
• You would need 142 patients over the course of 2 years (6 pts/month) charged the minimum $60/session =
$85,000

Should We Use It?
• American Academy of Pain Medicine
– Released a position paper at its annual meeting calling insurance payers to provide adequate coverage for interdisciplinary pain care
– PT, Massage, Yoga, Acupuncture and other alternative therapies
• Clinical / ethical responsibility to offer alternative pain therapies
– Improve QOL and functionality
– Reduce medication use
– Outcomes help with decisions to start chemotherapy?
– Use for non-cancer neuropathic pain syndromes
• Research Potential
– Clinical Research Site?
– fMRI?
– Blood levels of prostaglandins, endorphins?
– Reduce inpatient LOS?

Demo

Demo

Demo
Placement of electrodes does not always follow the dermatome.
1
2
1
2 2
1
1
2
2
1
1
2
2
1
1
2
1
1

Demo

Demo
FIRST TREATMENT
Complete Analgesia No Response
Completes all
Treatments
Satisfactory
Analgesia
Duration
Non-Optimal
Analgesia
Duration
Requires
Treatments PRN
Carried out incorrectly or unfeasible
(False Non-Responsive)
Carried out correctly and actually non-responsive*

Chronic Benign Pain
Basic Cycle of two consecutive weeks of 10-
12 treatments
Demo
Follow Up
(1-3 Months)
Slow Relapse
(Seen in pluriradicular pain)
Absence of Pain
Possibility of Functional Recovery
(Typically observed in monoradicular pain syndromes)

Oncology Pain
Basic Cycle of two consecutive weeks of
10 treatments
Demo
Monitoring
Single Treatment when Needed
Absence of Pain
Possibility of Functional Recovery
(Typically observed in monoradicular pain syndromes)

Q & A

References
1.
Frankish H. 15 million new cancer cases per year by 2020, says WHO. Lancet 2003; 361: 1278
2.
Van den Beuken-van Everdingen MHJ, De Rijke JM, Kessels AG et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18: 1437 –1449.
3.
Costantini M, Ripamonti C, Beccaro M et al. Prevalence, distress, management and relief of pain during the last three months of cancer patients’ life. Results of an Italian mortality follow-back survey. Ann Oncol 2009; 20: 729–735.
4.
Breivik H, Cherny N, Collett F et al. Cancer-related pain: a pan European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009; 20: 1420 –1433.
5.
Marineo, G. Untreatable pain resulting from abdominal cancer: new hope from biophysics? JOP 4, 1 –10 (2003).
6.
Sabato, A.F., Marineo, G. & Gatti, A. Scrambler therapy. Minerva Anestesiol. 71, 479 –482 (2005).
7.
Smith, T.J., Coyne, P.J., Parker, G.L., Dodson, P. & Ramakrishnan, V. Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare ¨) for chemotherapy-induced peripheral neuropathy. J. Pain Symptom Manage.
40, 883 –891 (2010).
8.
Ricci, R., Pirotti, S., Scarpi E., Burgio M., Maltoni M., Sanson E., Amadori D. Managing chronic pain: results from an open-label study using MC5A Calmare® device. J Support Care Cancer. 20:405-412 (2012).
9.
Marineo, G., Iorno, V., Gandini, C., Moschini, V. & Smith, T.J. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial. J. Pain Symptom
Manage. 43:1, 87-95 (Jan 2012).
10. Pachman, D.R., et al. Pilot Study of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy.
2012 ASCO Annual Meeting, Abstract No 9075. J Clin Oncol 30, 2012 (supplemental).
11. Smith, T., Marineo, G. Treatment of post-herpeti pain with scrambler therapy, a patient-specific neuro-cutaneous electrical stimulation device. 2012 ASCO Abstract No e19564. J Clin Oncol 30, 2012 (supplemental).
12.
Sparadeo, F., Kaufman, C., D’Amato, S. Scrambler Therapy: An Innovative and Effective Treatment for Chronic
Neuropathic Pain. J Life Care Planning. 11:3, 3-15. (2012)

Thank You