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Complete Recovery From
Intractable Complex Regional Pain
Syndrome, CRPS-Type I, Following
Anesthetic Ketamine
and Midazolam
Ralph-Thomas Kiefer, MD*; Peter Rohr, MD†; Annette Ploppa, MD*,
Karl-Heinz Altemeyer, MD†; Robert Jay Schwartzman, MD‡
*Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University,
Tuebingen, Germany; †Department of Anesthesiology, Intensive Care and Emergency Medicine,
and Pain Therapy, Klinikum Saarbrücken, Teaching Hospital of the University of Saarland,
Saarbrücken, Germany; ‡Department of Neurology, Drexel University, College of Medicine,
Hahnemann University Hospital, Philadelphia, Pennsylvania, U.S.A.
Abstract
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 obtained 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.
Key Words: central sensitization, complex regional pain
syndrome, reflex sympathetic dystrophy, ketamine,
NMDA-receptor
148 • kiefer et al.
INTRODUCTION
The pathophysiology underlying complex regional pain
syndrome I (CRPS-I) is incompletely understood but
CRPS has recently been posited to be a disease of the
peripheral and central nervous system.1,2 In early stages
of the disease, nociceptive input may be maintained by
increased sympathetic activity.3 A prolonged intense
afferent barrage at the site of injury may initiate functional
and structural changes in nociceptive receptors
and pain transmission neurons at all levels of the
neuraxis. This leads to sensitization of peripheral and
central nociceptive pathways which initiate and maintain
chronic neuropathic pain states.4 At the level of the
dorsal horn, sensitization is primarily mediated by NMethyl-
D-Aspartate (NMDA)-receptor activation.1 The
role of NMDA-receptors in the generation and maintenance
of neuropathic pain and CRPS is suggested by
clinical and experimental studies and is supported by
the benefit of NMDA-receptor antagonists in the treatment
of some neuropathic pain.5
Clinical studies support the efficacy of ketamine in
the treatment of CRPS.6–9 The analgesic effects of ketamine
and its duration of action are dose-dependent.
Anesthetic doses of ketamine have not been investigated
in pain medicine because of concern for ketamine specific
side effects which are also dose-dependent.5,6 This
case report details successful treatment of refractory
CRPS with ketamine and midazolam utilized in anesthetic
doses that has lasted for 8 years.
CASE REPORT
A 17-year-old girl suffered a strain injury of the right
wrist and hand, which caused severe pain and edema.
Initial therapy consisted of immobilization, cooling, and
oral diclofenac (3 × 50 mg/day). The patient was reevaluated
after 10 days of treatment because of increasing
pain. Further physical therapy and nonsteroidal
drugs were continued after this re-evaluation. Severe
pain persisted and a low potency opioid (Valoron N®,
Pfizer Pharma GmbH, Karlsruhe, Germany: tilidine
hydrochloride 50 mg, naloxone hydrochloride 4 mg)
was added to her treatment regime, which also failed to
provide pain relief.
After 6 months, the patient was transferred to the
pain center in Saarbrücken Germany because of continued
severe pain, erythema, and edema. She presented
with massive edema of the right hand, intense spontaneous
superficial and deep pain (mean pain: visual analog
scale [VAS] 4, peak pain: VAS 6, on a 10 cm VAS,
endpoints: 0: no pain, 10: worst imaginable pain), as
well as static and dynamic allodynia of the entire right
hand and wrist. The extremity also demonstrated bluish
discolored cool skin (temperature difference: 0.5°C),
hyperhidrosis in the right forearm, and increased nail
and hair growth (Figures 1, 2, 3). A movement disorder
was noted that included the inability to initiate movement,
make a fist, or oppose the thumb and index finger.
The patient fulfillled both the 1993 IASP diagnostic
criteria for CRPS, and the 1999 modified research diagnostic
criteria for CRPS.7,8
Figure 1. Photographs A and B show the clinical signs of the
patient at admission to the pain center Saarbrücken. Swelling,
reddish discoloration, temperature asymmetry, hyperhidrosis,
asymmetric nail, and hair growth were observed. Hyperalgesia
and allodynia of the right hand and wrist were severe. Photograph
C: status of the patient at admission to the intensive care
unit, after the rapid contiguous spread of signs (massive edema,
bluish mottled discoloration) into the entire right arm.
A
B C
Figure 2. Fluoroscopic control of positioning of the brachial
plexus catheter (vertical infraclavicular approach), after the loss
of the analgesia 24 hours after its insertion and initial pain relief.
The contrast demonstrates correct placement of the catheter
with diffusion the infra- and supraclavicular components of the
brachial plexus.
Complete Recovery from Intractable CRPS-I • 149
Pain reduction (VAS 2) was obtained by continuous
brachial plexus analgesia (initial block: 20 mL mepivacaine
1% and 20 mL bupivacaine 0.375%; and then
by continuous infusion: of bupivacaine 0.25%, 8 mL/h)
in conjunction with physiotherapy. The following day
severe pain (VAS 6) recurred. A suspected catheter dislocation
was ruled out by fluoroscopy. Subsequent
attempts to relieve pain included stellate ganglion
blocks, local superior ganglion opioid analgesia, and
intravenous opioids, all of which were unsuccessful.
Severe edema and discolored skin as well as hyperalgesia
and static and dynamic mechanical allodynia were
rapidly spreading to her entire arm. She continued to
suffer excruciating and unbearable pain (VAS 9 to
9.5). A thrombosis was ruled out by Color-Doppler-
Sonography, which was confirmed by a negative magnetic
resonance angiogram.
The patient was transferred to the intensive care unit
(ICU) for ketamine treatment. Under standard ICU
monitoring conditions (continuous arterial blood pressure,
ECG, and pulse oximetry), treatment was started
with bolus injections of ketamine (1 mg/kg) and midazolam
(5 mg), which was then followed by continuous
infusions. The ketamine infusion was gradually
increased over the following days (3–5 mg/h), and a
midazolam infusion was dosed as clinically needed to
provide stable and deep sedation. There was rapid
regression of the edema and discolored skin, and the
patient started to move her hand and arm spontaneously.
This regimen was continued for 5 days, at which
time edema had completely resolved and spontaneous
movements appeared almost unimpaired. On day 6, the
infusion was slowly tapered. The patient emerged from
anesthetic doses of ketamine and midazolam completely
free of pain. She experienced psychomimetic side effects
during the first week following treatment that included
agitation, anxiety, and nightmares. The psychomimetic
side effects responded well to midazolam and completely
abated within 1 month.
The patient has remained pain-free and showed a
complete remission from associated CRPS signs and
symptoms. Her motor function steadily improved with
physiotherapy. The patient has maintained this full
remission for 8 years.