Letter to the Editor
Our patient’s initial ketamine infusion rate of 10 mg/h was
a common starting rate noted in a large review of keta-
mine infusions for CRPS [7]. The authors of this study rec-
ommended a duration of three to five days and a
maximum infusion rate of 25 to 50 mg/h. The true optimal
dose is unclear, and another well-studied initial rate is
0.07 mg/kg/h (5 mg/h for a 70 kg patient), titrated to a
maximum of 0.43 mg/kg/h (30 mg/h for a 70 kg patient) for
a total of five days [4]. It is important to note that our pa-
tient’s ketamine dose as well as duration of treatment prior
to the onset of psychiatric symptoms fell within these pro-
posed ranges. Ketamine is being explored as a novel
rapid-acting treatment for depression, with one common
protocol being 0.5 mg/kg IV ketamine infusion given over
40 minutes [8]. In this setting, there have also been case
reports of ketamine inducing an affective switch [9,10].
We described here the case of a woman with a history
of depression and opioid use disorder in remission who
received a ketamine infusion for treatment of CRPS and
developed a prolonged manic episode. Further studies
into risk factors for development of mania or psychosis
are needed. In certain individuals, prophylactic use of
neuroleptic medications to prevent such symptoms may
be beneficial [7].
MALA C. MANDYAM, MD AND NEERA K. AHUJA, MD
General Medicine Disciplines, Stanford University
School of Medicine, Stanford, California, USA
References
1 Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR.
Proposed new diagnostic criteria for complex re-
gional pain syndrome. Pain Med 2007;8(4):326–31.
2 Beerthuizen A, Stronks DL, Huygen FJ, et al. The
association between psychological factors and the
development of complex regional pain syndrome
type 1 (CRPS1)—a prospective multicenter study.
Eur J Pain 2011;15(9):971–5.
LETTER TO THE EDITOR
Pain Medicine 2017; 18: 2041–2045
doi: 10.1093/pm/pnx063
Perineural Injection Therapy in the Management of Complex Regional Pain Syndrome: A Sweet
Solution to Pain
Dear Editor,
Perineural injection therapy (PIT) is one of the latest
advancements in regenerative medicine. It targets
3 Bussa M, Guttilla D, Lucia M, Mascaro A, Rinaldi S.
Complex regional pain syndrome type I: A compre-
hensive review. Acta Anaesthesiol Scand 2015;59
(6):685–97.
4 Sigtermans MJ, van Hilten JJ, Bauer MC, et al.
Ketamine produces effective and long-term pain re-
lief in patients with complex regional pain syndrome
type 1. Pain 2009;145(3):304–11.
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5 Ricke AK, Snook RJ, Anand A. Induction of pro-
longed mania during ketamine therapy for reflex
sympathetic dystrophy. Biol Psychiatry 2011;70(4):
e13–4.
6 Nichols SD, Bulman M, Tisher A, Campbell JJ 3rd.
A case of possible iatrogenic ketamine-induced
mania in a patient being treated for postoperative
pain. Psychosomatics 2016;57(5):543–6.
7 Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut
RE. Subanesthetic ketamine infusion therapy: A
retrospective analysis of a novel therapeutic ap-
proach to complex regional pain syndrome. Pain
Med 2004;5(3):263–75.
8 McGirr A, Berlim MT, Bond DJ, et al. A systematic
review and meta-analysis of randomized, double-
blind, placebo-controlled trials of ketamine in the
rapid treatment of major depressive episodes.
Psychol Med 2015;45(4):693–704.
9 Banwari G, Desai P, Patidar P. Ketamine-induced
affective switch in a patient with treatment-resistant
depression. Indian J Pharmacol 2015;47(4):454–5.
10 Alison McInnes L, James-Myers MB, Turner MS.
Possible affective switch associated with intravenous
ketamine treatment in a patient with bipolar I dis-
order. Biol Psychiatry 2016;79(9):e71–2.
cutaneous nerves as a potential pain generator. First
described by Dr. Paul Pybus and Dr. Roger Wyburn-
Mason, PIT targets neurogenic inflammation in subcuta-
neous nerves that potentially generates pain [1,2]. PIT
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Thor et al.
was further refined by Dr. John Lyftgoft using dextrose
injection, which provided substantial pain control in a
series of 300 Achilles tendinopathy [3]. However, this
treatment approach remains largely unknown; thus we
sought to document the effect of PIT in the manage-
ment of complex regional pain syndrome (CRPS) and its
outcome on pain and functional restoration.
Three patients who fulfilled the Budapest Criteria for
CRPS were treated with series of PIT. The cutaneous
nerves were palpated along its course until tender
chronic constrictive injury (CCI) points were encoun-
tered. (CCI points are formed by cutaneous nerve swel-
ling proximal to its point of penetration of the fascial
layer at the fascial transition zone [FTZ].) Once identified,
the CCI points were cleansed with alcohol skin prep;
using a 25G hypodermic needle, 2 to 5 mL of 5% dex-
trose was administered subcutaneously directly at the
CCI points. On average, the patients received 1 to 1.3
injections per week to tender CCI points of the cutane-
ous nerves supplying the dermatomes overlying the
affected area or joint.
Table 1 summarizes the clinical features of the PIT
recipients. The first patient sustained a left anterior
talo-fibular ligament injury six months prior and pre-
sented with recalcitrant ankle pain with left foot and
toes swelling, skin changes, and allodynia affecting
gait. The second patient presented with left shoulder
pain after a fall onto the left shoulder. At presentation
six months later, she had limited neck, shoulder, and
elbow range of motion and would prevent any han-
dling of the left shoulder and upper limb. The third
patient sustained a traumatic amputation of his right
fourth and fifth distal interphalangeal joints with severe
unrelieved pain at two months post-trauma, with allo-
dynia and edema involving the amputated fingers up
to the right elbow, loss of all third finger joints, loss of
fourth and fifth metacarpo-phalangeal and proximal
interphalangeal joints’ range of motion, and skin
changes. Pain was assessed prior to PIT and weekly
thereafter; pain score evolution is summarized in
Figure 1. Figure 2, A and B, graphically documents
the physical findings of the first patient prior to and
upon completion of PIT. Figure 3 depicts the tender
CCI palpated and injected in the first case. At the end
of the PIT series, all three patients had resolution of
their presenting CRPS features and were able to
actively participate in therapy.
Neurogenic inflammation plays an important role in the
occurrence of CRPS and is the basis of managing
CRPS with PIT [4]. Soft tissues are innervated by pepti-
dergic sensory nerves with transient receptor potential
vanilloid-type 1 (TRPV-1) receptors. Upregulation of
TRPV-1 receptors in response to pro-inflammatory
signals from injured tissues leads to production of sub-
stance P and calcitonin gene-related peptide (CGRP) by
2042
the peptidergic nerves [1]. Substance P is responsible
for pain while CGRP causes breakdown of soft tissue
structures, neurogenic inflammation, and inflammation
of the surrounding tissues. The nerve supply to the
nerves called nervi nervorum can also release similar
neurodegenerative peptides onto the C fibers while in a
pathological state [5].
Nerve irritation can happen through repetitive muscular
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contractions and the sudden change in direction of sen-
sory nerves travelling between muscle and fascial layers,
predisposing the TRPV-1 nerves to irritation or trauma.
Irritation to a superficial nerve supplying cutaneous sen-
sation over a joint may cause transmission of ectopic
impulses in prodromic and antidromic directions.
Prodromic transmission leads to pain perception via the
somatosensory cortex and generation of reflex muscle
spasm through the spinal cord ventral horn cells. The
antidromic transmission toward the blood vessels
releases substance P [6]. Trauma to the superficial
nerve can affect the deeper structures based on
Hilton’s law, which states that nerves supplying a joint
also supply both the muscles moving the joint and the
skin covering the articular insertion of those muscles
as a result of embryological development [7].
Cutaneous nerve trauma may precipitate nerve edema
proximal and distal to the injury. Swelling along the
traumatized cutaneous nerve will reach the nerve’s fas-
cial penetration points, which will cause strangulation
of the affected nerve as it passes through the fascial
transition zone, creating a CCI point. These constric-
tions inhibit the flow of nerve growth factors essential
for nerve health and repair [8]. Repetitive muscle dys-
function also changes fascial tension and creates a
CCI point [1].
Dextrose binds to presynaptic calcium channels, inhibit-
ing the release of neurodegenerative peptides, thus
decreasing neurogenic inflammation. This results in pain
reduction, regression of soft tissue swelling, and relief of
CCI constrictions, restoring normal nerve growth factor
flow, facilitating nerve repair, and providing almost
instantaneous analgesic effect lasting from hours to
days [9]. In our observations, repeated PIT results in a
stepwise decrease of pain in patients with CRPS.
We have demonstrated the effectiveness of PIT in man-
aging CRPS and the various mechanisms underlying the
therapeutic effects of subcutaneous dextrose injections.
The treatment cost was nominal, with minimal setup
required in the outpatient clinic. No adverse events were
encountered, and the clients’ acceptance of the proce-
dure was good. We believe further clinical acceptance
and research of this therapeutic modality will help
advance understanding of neurogenic inflammation’s
role in neuropathic pain conditions. We believe that this
therapeutic modality holds promise to more effective
pain management.
 Table 1 Clinical parameters of patients receiving perineural injection therapy for CRPS
Case 1 Case 2 Case 3
Budapest Criteria Pre Post Pre Post Pre Post

Continuous and H 
disproportionate pain
Sensory H 
Vasomotor H 
Sudomotor/oedema H 
Motor/trophic changes H 
Impairment Reduced left Full left
ankle aROM ankle aROM
Functional outcome TUG: 300 sec TUG: 20 sec
CCI points treated Left medial and lateral sural
cutaneous nerves CCI
aROM ¼ active range of motion; CCI ¼ chronic constrictive injury; CRPS ¼ chronic regional pain syndrome; DASH ¼ The Disabilities of the Arm, Shoulder and Hand score;
NRS ¼ numerical rating scale; TUG ¼ timed up and go test.
H  H 
H  H 
H  H 
  H 
H  H 
Reduced neck, left shoulder, Full aROM Loss of 3rd finger and Full left elbow aROM
and left elbow aROM left elbow aROM
DASH: 91.7 DASH: 5.0 DASH: 99.2 DASH: 4.2
Left medial, intermediate and posterior supraclavicular Right medial antebrachial and ulnar nerve CCIs
cutaneous nerves CCI and the left punctus nervosum
Letter to the Editor

2043
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Thor et al.

Evoluon of NRS with PIT

9

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5
NRS

0
Pre-PIT Post-1st PIT Post- 2nd PIT Post- 3rd PIT Post-4th PIT Post-5th PIT Post-6th PIT Follow up
PIT sessions

Case 1 Case 2 Case 3

Figure 1 Numeric rating scale evolution during the course of PIT in three in recipients with complex regional pain
syndrome. NPT ¼ ; NRS ¼ numerical rating scale of pain; PIT ¼ perineural injection therapy.

Figure 2 Patient 1 with complex regional pain syndrome affecting her left foot and ankle. (A) Pre–perineural injec-
tion therapy (PIT). (B) Post-PIT.

2044

Figure 3 (A) Medial and lateral sural cutaneous
nerves. (B) Saphenous cutaneous nerve. Dots indicates
the chronic constrictive injury sites, which are injected
subcutaneously.
JU ANN THOR, MD, NOR HANIM MOHAMED HANAPI, MBBS,
HAZWANI HALIL, BSC, AND ANWAR SUHAIMI, MBBS, MREHABMED
Department of Rehabilitation Medicine, Faculty of
Medicine, University of Malaya, Kuala Lumpur,
Malaysia
LETTER TO THE EDITOR
Pain Medicine 2017; 18: 2045–2047
doi: 10.1093/pm/pnx071
A Cervical Epidural Abscess After the Racz Procedure in a Patient with Failed Cervical Surgery
Syndrome
Dear Editor,
A 55-year-old man visited our pain clinic complaining of
pain, burning, and prickling that involved both shoulders
and forearms and increased with movement. He had un-
dergone a three-level posterior laminectomy and discec-
tomy. Physical examination showed neuropathic pain in
the C4-C5-C6 dermatomes and motor strength of 3 out
of 5 in the right upper extremity and 4 out of 5 in the left
upper extremity. His neuropathic pain was more
Letter to the Editor
References
1 Reeves KD, Lyftogt J Prolotherapy: Regenerative Injection
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Raton, FL: CRC Press; 1996.
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dinopathy: The best solution? Aust Musculoskeletal
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(CRPS). Neurosci Lett 2008;437(3):199–202.
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refractory knee, shoulder and lateral elbow pain. Aust
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and osteoarthritis. Arthritis Trust Am 1989;9–22.
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Ferrara, Italy: The Hackett Hemwall Foundation and
the Italian Society for Prolotherapy; 2010.
prominent in the left shoulder and arm. The patient was
prescribed pregabalin 300 mg/day (Lyrica 300 mg Pfizer,
Freiburg, Germany), paracetamol 1500 mg/day (Parol
500 mg, Atabey, Istanbul, Turkey), and tramadol HCl
150 mg/day (Contramal 50 mg, Abdi Ibrahim, Istanbul,
Turkey). He had no concomitant disease, and the Racz
procedure was scheduled for cervical epidural lysis.
With the patient prone on the operating table, conscious
sedation was obtained with 50 mcg fentanyl and 2 mg
2045