The last few years have been exciting times for CRPS. Many new
labs have been studying various aspects of CRPS .There is a dizzying
array of possibilities and we applaud all the dedicated researchers.
Ketamine treatments have been developing since 2002 when ketamine
was accidentally discovered to help CRPS. Read about it here.
RELIEF FOR WORST MAY LIE WITH KETAMINE COMA
LAS VEGAS-For the most severe cases of reflex sympathetic
dystrophy (RSD), inducing a five-day coma may be the only effective
The method is akin to rebooting the central nervous systems of patients
whose nerve cells have gone haywire. The FDA has yet to approve
coma therapy, which is induced by administering large bolus injections
of ketamine and midazolam at up to 50 times the normal dose. But
that has not stopped U.S. doctors from pioneering the use of a "ketamine
coma" in American patients treated at hospitals in Germany
For the better part of four years, Robert Schwartzman, MD, chairman
of the Department of Neurology at Drexel University College of Medicine
in Philadelphia, and colleagues have been studying the effects of
ketamine treatment, including induced comas, in patients with RSD.
Their results suggest that the coma therapy may provide long-term
and perhaps permanent relief in as many as half of the most severe
Ketamine first won FDA approval in 1970 as an anesthetic. It quickly
became known on the street as "Special K," a powerful
hallucinogen similar to LSD and PCP. Clinicians in the United States
can legally give the drug to patients with RSD-also known as complex
regional pain syndrome (CRPS) type I-who are under conscious sedation.
In this group, relief typically lasts no more than six months, Dr.
Ketamine is the most potent clinically available inhibitor of N-methyl-D-aspartate
(NMDA) receptors. These receptors permit the transfer of electrical
signals between neurons in the brain and the spinal column. Studies
support the idea that RSD results from a dynamic change in the physiology
and structure of central pain neurons mediated by NMDA receptors.
When these receptors malfunction, enzymatic and metabolic cascades
occur in pain cells, and the degree of pain is magnified out of
proportion to the physical injury causing it.
In a study of infusions of low-dose ketamine (Pain Physician 2005;8:175-179),
Dr. Schwartzman and colleagues found that a critical factor in central
sensitization seems to be the release of magnesium on the NMDA receptor,
with an influx of calcium and the initiation of intracellular cascades.
As an NMDA antagonist, ketamine blocks central sensitization. Drugs
such as dextromethorphan, amantadine and memantine (Namenda, Forest
Pharmaceuticals) also could be used, but they appear to have a low
potential for blocking the sensitization process.
Ketamine has long been known to be able to prevent RSD/CRPS following
surgery, said Scott Reuben, MD, professor of anesthesiology and
pain medicine at Tufts University School of Medicine in Boston and
director of pain management at Baystate Medical Center in Springfield,
"If it [ketamine] can prevent CRPS, the thought was, 'can
we use it to treat it?' " said Dr. Reuben, who serves as an
adviser to the Mexico study. "This is just the stepping stone.
Unfortunately, all we have are case reports and retrospective studies.
We need prospective studies."
Only the Worst Patients
RSD affects between 200,000 and 1.2 million Americans, according
to the Reflex Sympathetic Dystrophy Association. The disorder develops
without any apparent explanation in 1% to 2% of patients with fractures
and in 2% to 5% of patients with peripheral nerve injuries. The
RSD group claims that roughly 50,000 new cases develop each year.
For the Mexican and German research, doctors chose patients with
the most severe cases of RSD who had tried everything-including
blocks and hyperbaric chambers-for their pain.
Frustrated physicians from around the world refer patients to Dr.
Schwartzman. "I only see the worst patients," said Dr.
Schwartzman, who took on the challenge of RSD after being unable
to cure one of his patients with the condition. "Some have
gone through up to 100 doctors."
Failure in More Than Half
Dr. Schwartzman has sent a total of 38 patients to Germany for
treatment with the ketamine coma, which was discovered serendipitously
by Ralph-Thomas Kiefer, MD, and Peter Rohr, MD, in Tübingen.
The two physicians had induced a coma in a patient with RSD and
severe head trauma. When the patient awoke, the pain syndrome had
The five-day coma is induced with large bolus injections of ketamine
(1-1.5 mg/kg) and midazolam (2.5-7.5 mg). The coma is maintained
with infusions of ketamine (3-7 mg/kg per hour) and midazolam (0.15-0.3
mg/kg per hour), which are tapered toward the end.
Every patient in whom a coma is induced does well initially, Dr.
Schwartzman said, but the pain returns in 55% to 60% of cases. Still,
of the 38 patients treated in Germany, at least 12 have had minimal
or no pain for more than five years. Three of the 12 required occasional
subanesthetic boosters of ketamine.
"We're blocking the RSD," Dr. Schwartzman said. "The
maintaining thing is still there. If you don't block the maintaining
problem, the same molecular genetic cascade occurs."
A study of the full ketamine coma in the patients treated in Germany
will soon appear in Pain Medicine. Of the 20 patients featured in
the study who underwent the therapy, 16 experienced complete remission
lasting at least six months. "While the trial suggests improvements
in pain reductions," the researchers concluded, "a randomized
controlled study will be necessary to prove its efficacy."
The coma's side effects-precipitous weight loss, sleep disruption,
anxiety, weakness and the usual complications of critical care medicine-are
potentially serious. The bottom line, Dr. Schwartzman said, is that
"the procedure has proven to be very safe but clearly has inherent
South of the Border
A study in Mexico has started, with a protocol similar to that
used in the German study; patients are sent to the San José
Technological Hospital, which is affiliated with the Tec de Monterrey
School of Medicine in Monterrey, Mexico, a few hours' drive from
the Texas border. Patients pay about $20,000 for the treatment,
which is not covered by insurance.
Leading the Mexican medical team is Fernando Cantœ Flores,
MD, an anesthesiologist and specialist in pain management who was
trained at the University of Texas.
The study was originally approved in the United States by the institutional
review boards of the University of South Florida and Tampa General
Hospital, but the FDA refused to grant an exemption to its international
new drug application. Rather than embark on a process that would
likely cost $3 million and delay treatment for their patients, the
study was moved to Mexico. A review board in Monterrey also approved
So far, eight patients have been treated in Mexico. The main difference
from the German study is that pain thresholds are measured with
a force gauge. The German study relied on self-reporting.
Low-Dose Conscious Sedation
A less dramatic treatment option for severe cases of RSD is a subanesthetic
infusion of low-dose ketamine (10-30 mg per hour titrated according
to side effects such as amnesia, blurred vision and vomiting). Dr.
Schwartzman has performed close to 200 of these-about one each week
for the past four years-at Hahnemann University Hospital in Philadelphia.
The treatment costs about $10,000, and insurance companies will
not pay for it. Dr. Schwartzman estimated that he performs 95% of
all such procedures in the country. He also treats about 10 outpatients
per week with lower doses in his clinic.
The infusions succeed in 70% to 80% of cases. But even in the most
responsive patients, pain typically returns after approximately
six months. A study published in Pain Medicine (2004;5:263-275)
found similar results.
A two-hour infusion of low-dose ketamine can also be used to manage
RSD or as a booster after treatment with the coma. Pretreatment
with 0.2 mg of I.V. glycopyrrolate (the only other drug needed)
is administered along with a ketamine drip at 100 mg per hour, supplemented
with 5- to 40-mg I.V. bolus injections of ketamine. An average adult
will require a total of 400 to 600 mg of ketamine over a two-hour
For patients with the most intractable cases of RSD, the full coma
treatment may still be the only hope. In a study published online
in Pain Medicine in July 2007 (online early article), Dr. Schwartzman
and his German colleagues found that an "awake" version
of the ketamine infusion at higher doses (50-500 mg per day) over
a 10-day period in four patients with extreme RSD did not relieve
Cause for Optimism
Shannon Stocker, MD, an Orlando, Fla., RSD patient, underwent coma
therapy in Mexico. Dr. Stocker said the concern she felt about going
into the treatment was "overwhelmed by a desire to get better
because the pain was so bad it was worth all the risk. The burning
pain was constant. But when there was anything like raindrops, it
felt like ice picks stabbing me."
The ketamine coma may be the key to curing other conditions directly
related to either RSD or similar nerve dysfunction. As a result
of her RSD, Dr. Stocker had skin ulcers all over her arms, which
began to clear up while she was still in the coma.
Jim Broatch, executive director of the RSD Syndrome Association,
called ketamine therapy "promising" but added that more
data are needed. "We're saying the jury is still out."
Dr. Schwartzman has now written more than 60 articles on RSD and
spoken about the disorder at more than 100 conferences, including
the 2007 annual meeting of the American Academy of Pain Management,
at which he delivered the keynote address.
The success of the various ketamine protocols has made him optimistic
about the prospects for patients with previously intractable RSD.
"It's wonderful to be able to successfully treat someone
in severe pain," he said. "That's why you go
to medical school."
Complete recovery from intractable complex regional pain
syndrome, CRPS-type I, following anesthetic ketamine and midazolam.
Kiefer RT, Rohr P, Ploppa A, Altemeyer KH, Schwartzman RJ.
Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls
University, Tuebingen, Germany. firstname.lastname@example.org
OBJECTIVE: To describe the treatment of an intractable
complex regional pain syndrome I (CRPS-I) patient with anesthetic
doses of ketamine supplemented with midazolam.
METHODS: A patient presented with a rapidly progressing
contiguous spread of CRPS from a severe ligamentous wrist injury.
Standard pharmacological and interventional therapy successively
failed to halt the spread of CRPS from the wrist to the entire right
arm. Her pain was unmanageable with all standard therapy. As a last
treatment option, the patient was transferred to the intensive care
unit and treated on a compassionate care basis with anesthetic doses
of ketamine in gradually increasing (3-5 mg/kg/h) doses in conjunction
with midazolam over a period of 5 days.
RESULTS: On the second day of the ketamine and
midazolam infusion, edema, and discoloration began to resolve and
increased spontaneous movement was noted. On day 6, symptoms completely
resolved and infusions were tapered. The patient emerged from anesthesia
completely free of pain and associated CRPS signs and symptoms.
The patient has maintained this complete remission from CRPS for
8 years now.
CONCLUSIONS: In a patient with severe spreading
and refractory CRPS, a complete and long-term remission from CRPS
has been btained utilizing ketamine and midazolam in anesthetic
doses. This intensive care procedure has very serious risks but
no severe complications occurred. The psychiatric side effects of
ketamine were successfully managed with the concomitant use of midazolam
and resolved within 1 month of treatment. This case report illustrates
the effectiveness and safety of high-dose ketamine in a patient
with generalized, refractory CRPS.
Rare care in Mexico eases woman's pain
A Mooretown woman was put in a "ketamine coma" after friends
and strangers raised $20,000.
By Shawn Jeffords
London Free Press
SARNIA-Strapped to a bed in a Mexican hospital, Heather Kennedy-Redmond
was battling shadows from the darkest corner of her mind.
Tubes pierced her body to feed and help her breathe, while beeping
monitors registered her vital signs.
After exhausting traditional medicine, the 26-year-old Mooretown
woman had travelled to Mexico for experimental treatment of chronic
She has a little-known condition called reflex sympathetic dystrophy,
The controversial treatment she underwent involved inducing a coma
by flooding her body for five days with ketamine, a powerful human
and veterinary anesthetic known to street users as Special K.
For the week, vivid hallucinations threatened to consume her. But
a year later, the pain she endured has now eased.
Parents Linda and Paul Kennedy and husband Ken Redmond hovered
over her for the week, hoping she'd emerge from the coma changed.
Looking back, Kennedy-Redmond recalls a simple gesture in that
hospital room in Monterey as a revelation. "I remember holding
my dad's hand and it didn't hurt."
Mother Linda Kennedy describes her family as quiet.
"We're very ordinary people. We're not the kind of people
to go through with coma treatments," she said.
But after seven years of few answers and even fewer viable treatment
options in Canada, even a radical long-shot seemed better than nothing.
"For my parents, the ketamine coma was not something they
wanted to do," Kennedy-Redmond said. "For me it was like,
'It can't get here fast enough. Let me do it now.' "
The pain of RSD first appeared following a routine injection in
July 2000. She'd just had her tonsils removed and the inter-muscular
shot in her right leg hurt for days.
The pain spread and grew intensified. Prescribed anti-inflammatory
medication did nothing to ease it, she said.
"We went to so many doctors. They were telling me I was crazy
and it was all in my head," she said.
The changes were devastating for a woman who filled her free time
at sports and preparing for 10-kilometre runs.
"Within two years it had spread across my body, from my scalp
to my toes."
In desperation the Kennedys turned to the Internet, searching for
anything that matched the symptoms. In 2003 they found a doctor
in Vero Beach, Fla., who treated chronic pain, and booked an appointment.
With diagnosis came shocking news: RSD has no cure.
"We just kept saying, there's always hope," said Linda
Her daughter began travelling to Hamilton every three weeks for
nerve blocks and epidurals, adding 30 needles to a daily regimen
of 17 pills.
The treatments threatened to do irreparable harm to Kennedy-Redmond's
body. Worse yet, the pain kept increasing.
Eventually the Kennedys' research led to ketamine. They read a
single, low-dose treatment was showing promise. Another more radical
"ketamine coma" left some patients in trials pain-free.
The U.S. Food and Drug Administration hasn't approved the treatment,
but a doctor in Mexico had secured the drug from German physicians.
"My parents didn't tell me about it," Kennedy-Redmond
said. "They were good about it, because they didn't want me
to get my hopes up and be excited and then be shot down."
Paul and Linda Kennedy talked to patients who'd had the treatment
and doctors who administered it. But the wait list for a low-dose
treatment was about 250 names and the first opening a decade away.
Family, friends, co-workers and strangers raised $20,000 for the
$50,000 treatment cost.
"There are just so many people to thank," Heather said.
They flew to Mexico last March. Heather returned feeling weak but
A year later, she's "60 percent" better. Though she'll
never be cured, she expects to be symptom-free soon. Not everyone
responds to the treatments, she cautioned.
copyright London Free Press
PLEASE NOTE: This treatment is not for
everyone, however, it brings us hope that even the most severe cases
can be treated.
PARC is monitoring this situation closely.
More studies are needed.
and Benett: Objectifying CRPS
et al Serum and salivary oxidative analysis in CRPS
Krumova, E MD: Skin Temperature Measurements
Seles, R PhD: Mirror Therapy
Swart, K MD: Cortical Changes in CRPS
DIAGNOSTIC TESTS FOR CRPS:
New research has found markers for CRPS.
this means that CRPS can now be diagnosed. From Boston, a skin biopsy
(3mm punch biopsy) can detect distal nerve damage (distal portion
of axons). Dr A L Oaklander at Mass. General Nerve Injury Unit is
studying this test further.
al et al Evidence of focal small fiber axonal degeneration in CRPS
al Needlestick Distal Nerve Injury in Rat Models of CRPS
From Haifa Israel, a simple saliva test
can measure high levels of LDH (lactate dehyrogenase), the same
substance found in heart attack victims and also albumin..
et al Serum and salivary oxidative analysis in CRPS Pain 2008.
New theory of chronic post-ischemic pain
(CPIP) as being the mechanism for CRPS, is outlined in this study:
et al CPIP: A novel animal model
DeMos, M MD :Medical History and Onset
DeMos: Siblings Study
Gazerani. P MD : Botox
Groenweg, G MD : Regulation of Peripheral
Blood Flow in CRPS
Hsu, E. MD Practical Management
Schwartzman, RJ MD: CRPS
Wrigley MD: CRPS
Wen-Wu, Li MD: Cytokines and NALP1
Bell and Moore: Review: IV
Harden, N MD: Severity Scale of
Kirkpatrick A MD: Response
to IV Ketamine
Moscovitz and Cooper: CRPS
Feliu et al Overview of CRPS
Smith, H MD: Genetic Link?
Teets, R MD: Integrative Approach
Tran,D.Q.H. MD: Treatment of CRPS
Wuppenhorst, N MD: Three Phase Bone
Scans for CRPS
Zhongyu, L MD: CRPS after Hand
Cacchio, A. MD: Mirror Therapy
Collins, S MS et al: IV Magnesium
Gustin: NMDA Receptor and Morphine
Jennifer: Brain Imaging
Moscovitz, P MD Overview of CRPS
Nama, S. MD: Ketamine and Dexmedetomidine
Notarincola, A MD: Shockwave
Plane, Jennifer PhD: Monocycline
Ruam, M BSW: Spinal Cord Stimulation
Safapour, D MD et al: Botox
Sakamoto, E MD:Orofacial CRPS
Sharma, A MD: Survey on CRPS
Vanijs, F MD Test for Spinal Cord Stimulation
Valeo, T. IVIG Treatment for CRPS
Walton, MD: CRPS
STUDIES 2012 coming soon.