Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by persistent pain that does not follow a particular nerve pattern. It often develops after an injury and is accompanied by changes in skin temperature, color, and swelling in the affected region. CRPS results from abnormal inflammatory and pain processing responses to the initial injury. It involves sensitization of both the peripheral and central nervous systems, autonomic nervous system dysfunction, and potentially autoimmune mechanisms. Treatment focuses on medications like gabapentin to reduce nerve sensitization, bisphosphonates to inhibit bone changes, and nerve blocks or spinal cord stimulation for pain relief.

1. Complex Regional Pain Syndrome
(CRPS)
Aditya Johan Romadhon, SST.Ft,
M.Fis

2. Introduction
Persists beyond the usual expected time for tissue healing
Pain does not follow a particular dermatome or myotome but is rather regional
Inflammatory, immunological, central, and peripheral sensitization, as well as autonomic changes, have been studied in CRPS
Scientific evidence does not point to a single principal mechanism, the underlying mechanism seems to be multifactorial
Multiple pathophysiologic mechanisms have been described in the literature so far to explain CRPS
Characterized by allodynia, hyperalgesia, sudomotor and vasomotor abnormalities, and trophic changes
Complex Regional Pain Syndrome (CRPS) is a neuropathic pain
https://www.ncbi.nlm.nih.gov/books/NBK430
719/

3. Epidemiology
Minnesota found an incidence of 5.46 per 100,000 person-years for CRPS type I and
0.82 per 100,000 person-years for CRPS type II (Sandroni et al, 2013)
In the Netherlands, found the incidence to be much higher at 26.2 cases per 100,000
person-years (Mos et al, 2006)
The Netherlands study reported a peak incidence at 61–70 years of age, while the
American study found the median age of onset to be 46 years
Upper extremities were found to be more commonly involved than lower in both
studies
The most common trigger for the disorder was found to be a fracture, associated with
44 to 46% of the cases
https://www.ncbi.nlm.nih.gov/books/NBK430
719/

4. Clinical manifestation
Whilst appearing to be a neuropathic pain condition, CRPS is mostly unresponsive to standard neuropathic pain treatments
Often with chronicity, the symptoms (especially pain) progress proximally up the limb, often to the shoulder/hip but not beyond
CRPS is almost universally restricted to the limb (upper or lower) & favors the distal extremities,
Each patient displaying different symptoms and signs such as warm or cold limb, oedema, allodynia, hyperalgesia, abnormal
sweating and skin and nail tissue changes
Type I occurs in the absence of nerve trauma, while type II occurs in the setting of known nerve trauma
CRPS has two subtypes: type I, formerly known as reflex sympathetic dystrophy, and type II, formerly known as causalgia
https://doi.org/10.1016/j.mehy.2018.07.
026

5. Etiology
Dupuytren contracture surgeries 4.5 to 40% chance of developing CRPS
Carpal tunnel surgeries were noted to have a 2 to 5%
In patients undergoing closed reduction of distal radius fracture, 32.2 % patients developed CRPS
Symptoms improved in many patients at 3 months, but no significant improvement was noted at about a year
prospective cohort study found that CRPS developed within 8 weeks after a noxious event
CRPS has been noted to be commonly associated with extremity fractures, large multicenter prospective study found that 48.5% of
patients developed CRPS

6. Clinical presentation
In the acute phase, the injured limb is
usually extremely painful, red, warm
(although sometimes it quickly
becomes relatively cold) and swollen
Allodynia and hyperalgesia mechanical
and thermal, changes in sweating,
changes in hair and nail growth, and
muscle weakness
Voluntary motor reduce, hyperpathia
may occur and negative sensory signs
(hypoesthesia, hypoalgesia,
hypothermesthesia)
CRPS seems to be characterized by a
mixture of noxious sensations
(“positive symptoms”) and sensory loss
(“negative symptoms”)

7. Over months, the relatively warm limb often
becomes relatively cold, dystonia, tremor and
myoclonus may also develop
Activity of the limb typically exacerbates signs
and symptoms
Over time, clinical features spread proximally
(but not distally) and can even emerge on the
opposite limb or the ipsilateral limb
in chronic cases with longer disease durations
(>5 years) other features are sometimes noted,
such as urological symptoms,syncope, and
even mild cognitive deficits
Dystonia
CRPS

8. Underlying mechanism
Inflammation
Pain
sensitization
Autonomic
changes
Immunological
changes

9. Trauma results in nociception with activation of mechanical
nociceptors at the site of trauma
Pathological pain processing at the cortical and subcortical
regions of the brain occurs in CRPS
Reconciliation of pain processing with basal ganglia outputs
to autonomic, endocrine and motor function
Trauma and atrophy release Danger Associated Molecular
Pattern, which are captured by dendritic cells, which then
migrate to the regional lymph node (regional not
dermatomal)
Autonomic imbalance (symphathetic hyperactivity)
T-cells and B-cells are activated and dendritic cells and
macrophages release inflammatory cytokines (i.e. TNFα, IL-
1, IL-18)
This initiates a regional immune response with activation of
osteoclasts and monocytes and colony expansion of
immune cells that results in further secondary injury

10. Inflammation
Inflammatory
Elevated levels of
pro-inflammatory
cytokines in serum
and cerebrospinal
fluid
Elevated levels of
neuropeptides
released from
peripheral nerve
endings
The elevated levels
of inflammatory
markers and
neuropeptides lead
to vasodilation and
tissue extravasation
CRPS trigger
neurogenic
inflammation

11. Pain sensitization
Sensitization of the
peripheral nervous system
is triggered by the release
of pro-inflammatory
markers (TNF-α ) after the
initial injury reduce the
stimulation threshold,
leading to local
sensitization and
hyperalgesia in CRPS
(peripheral sensitization)
Hyperalgesia and
allodynia develop as a
result of sensitization, the
release of substance-P,
bradykinin, and glutamate
play an important role in
this process (central
sensitization)

12. Autonomic Changes
Upregulation of sympathetic receptors on
nociceptive nerve fibers (sympathetic-afferent
coupling)
Sympathetic hyperactivity leads to increased pain
and sympathetic sensitivity of nociceptive nerves
Local swelling, color, and temperature variations
associated with this disorder suggest an
involvement of the autonomic nervous system
Widespread autonomic dysregulation in CRPS can
affect heart rate and lead to orthostatic dysfunction
In warm CRPS, vasodilation occurs as a result of
reduced catecholamine release, and the opposite
phenomenon occurs in cold CRPS
Dey S, Guthmiller KB, Varacallo M. Complex Regional Pain Syndrome. [Updated
2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;

13. The role of vasomotor dysfunction
Vasomotor dysfunction is common in CRPS
The affected limb is usually warmer than the healthy limb early-on, and colder than the healthy limb
later on
This shift in relative temperature suggests that the activity in vasoconstrictor neurons changes over
time in CRPS
Fewer than 6 months duration, the ‘warm’ type, the affected limb was warmer than the contralateral
limb, even massive body cooling failed to activate sympathetic vasoconstrictor neurons
Greater than 6 months duration, the ‘cold’ type, temperature on the affected limb were consistently lower
than those on the contralateral limb
doi: 10.1016/S1474-
4422(11)70106-5

14. Immunological Changes
Autoantibodies against beta-2-adrenergic
receptor, alpha -1a-adrenergic receptor,
and muscarinic-2 receptor have been
found in CRPS
A significant
improvement in pain
following intravenous
immunoglobulin
treatment in CRPS
patients. which further
supports potential
autoimmune
pathophysiology
doi: 10.7326/0003-4819-152-3-201002020-
00006.

15. Cortical reorganization
Cortical reorganization and maladaptive plasticity in
patients with CRPS
Panel (A): The distance between the peak response
over the contralateral somatosensory cortex to
stimulation of the first digit (D1) and fifth digit (D5) on
the affected and healthy hands in a patient with CRPS
Note that the distance between D1 and D5 is less for
the affected limb
Panel (B): Normalisation of primary sensory cortex
reorgnisation occurs in association with the resolution
of CRPS symptoms
Maihöfner C, Handwerker HO, Neundörfer B, Birklein F. Cortical
reorganization during recovery from complex regional pain syndrome.
Neurology. 2004 Aug 24;63(4):693-701. doi:

16. Treatment
Gabapentin is the most widely
studied medication in this class, it
works by inhibiting the alpha 2-
delta subunit of voltage-gated
calcium channels
Bisphosphonates his class of
medication is used routinely in
bone-related problems as it inhibits
osteoclastic activity, inhibition of
bone marrow cell proliferation and
migration as well as inflammation
modulation
Lumbar sympathetic nerve blocks
are routinely used in the treatment
of lower extremity symptoms
Stellate ganglion sympathetic
blocks are used for the management
of upper extremity symptoms of
this syndrome
Spinal cord stimulation involves
delivering electric stimulation to
the dorsal column of the spinal cord
by the placement of electrodes in
the epidural space
Multiple mechanisms : inhibition of
nociceptive neural conduction in
the spinal cord, adrenergic
inhibition, vasodilation, and
reversal of cortical maladaptive
neuroplastic changes
https://doi.org/10.31138/mjr.30.1
.16

17. THANKS