M a n a g e m e n t o f C h ro n i c P a i n

Following Nerve Injuries/CRPS

Typ e I I
Ian Carroll, MD, MSa, Catherine M. Curtin, MDb,c,*

KEYWORDS
 Chronic pain  Complex regional pain syndrome  Neuropathic pain  Nerve injuries

KEY POINTS
 Perioperative interventions can reduce incidence of postoperative chronic pain: prevention is much
more desirable than treating complex regional pain syndrome (CRPS)/neuropathic pain.
 There is a critical time window in treating the patient with CRPS/neuropathic pain: early intervention
is better.
 Surgeons need to be comfortable beginning treatment of CRPS/neuropathic pain.

Every incision and every fracture injures some sen- we present information from randomized con-
sory nerve. Most of the time, these nerves recover trolled trials (RCTs). Given the diversity and the
from this insult without long-term consequences; breadth of the topic, we hope that this overview
however, for some people, pain continues long provides an information foundation and the re-
after the wounds have healed. This chronic pain views presented will direct the reader to more
then affects quality of life, limits the patient’s ability detailed information.
to participate in therapy, and adversely affects
functional outcomes. Chronic postoperative pain DEFINITIONS
is a particularly frustrating problem for the surgeon
because it is hard to anticipate, ruins a technically The first step when discussing pain is to under-
perfect procedure, and the surgeon may be unsure stand terminology.
of the next steps of treatment. There is much infor-
Neuropathic Pain
mation on chronic pain and its treatment, but this
literature is often published outside of surgery This article focuses on pain associated with nerve
and diffusion of this information across disciplines injuries: neuropathic pain. The International Associ-
is slow. This article synthesizes some of this litera- ation for the Study of Pain (IASP) Neuropathic Pain
ture and provides a systematic presentation of the Special Interest Group has defined neuropathic
evidence on pain associated with peripheral nerve pain arising as a direct consequence of a lesion or
injury. disease affecting the somatosensory system.1,2 It
Chronic pain and complex regional pain syn- has typical characteristics that help separate it
drome (CRPS) are large topics and we have from other types of pain, such as joint pain from
divided this article into sections. When available, osteoarthritis. A recent Delphi survey of experts
we have presented pooled data for each subsec- defined neuropathic pain as having a clinical history
tion, including consensus statements and system- of nerve injury and the pain should demonstrate
atic reviews. When pooled data are not available, typical characteristics: (1) prickling, tingling, pins

a
Department of Anesthesia, Stanford University, 450 Broadway, Redwood City, CA 94603, USA; b Department
hand.theclinics.com

of Surgery, Palo Alto VA, 3801 Miranda Avenue, Palo Alto VA, Palo Alto, CA 94304, USA; c Division of Plastic
Surgery, Stanford University, Suite 400, 770 Welch RD Palo Alto, CA 94304, USA
* Corresponding author. Division of Plastic Surgery, Stanford University, Suite 400, 770 Welch RD Palo Alto, CA
94304.
E-mail address: [email protected]

Hand Clin 29 (2013) 401–408

http://dx.doi.org/10.1016/j.hcl.2013.04.009
0749-0712/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
402 Carroll & Curtin

and needles; (2) pain with light touch; (3) electric diagnostic test for CRPS. Given that CRPS is a
shocks or shooting pain; (4) hot or burning pain; clinical diagnosis, there has been a much research
and (5) Brush allodynia.3 For the researcher, there on what clinical signs are most specific to this
are several validated measures to differentiate diagnosis. The IASP guidelines state that the pa-
neuropathic pain.4 For more detailed information tient must have pain disproportionate to the injury
on how to assess neuropathic pain, we refer you and there is no other diagnosis that explains the
to a recent guideline, which provides detailed infor- pain. Box 1 presents the most recent clinical
mation on recommended measures.5 criteria for diagnosis of CRPS.8

Chronic Pain
EPIDEMIOLOGY
Acute pain after injury is a normal and healthy
response. It serves the purpose of limiting activity Severe complex regional pain syndrome is a rare
and protecting the injured areas to allow the tissue occurrence, but chronic pain after injury to sensory
to heal. Yet at some point, pain transitions to a nerves is more frequent. CRPS may be the severe
pathologic process, no longer serving the protec-
tive role, and the pain becomes chronic or intrac-
table. Much effort has been devoted to define Box 1
Clinical criteria for complex regional pain
when pain has transitioned to this chronic state.
syndrome
Smith and colleagues’3 consensus study felt
neuropathic pain was intractable when the pain Must report at least one symptom in 3 of the 4
persisted despite trials of at least 4 drugs of following categories
known effectiveness in neuropathic pain. The 1. Sensory: Reports of hyperalgesia and/or
most frequently cited definition for chronic pain allodynia
was produced by the IASP, which states that
2. Vasomotor: Reports of temperature asym-
chronic pain is pain that has persisted beyond
metry and/or skin color changes and/or skin
the normal tissue healing time and often 3 months color asymmetry
is set as the convenient cutoff.1
3. Sudomotor/Edema: Reports of edema and/or
sweating changes and/or sweating
CRPS
asymmetry
The definition of complex regional pain has under- 4. Motor/Trophic: Reports of decreased range
gone a long evolution as our understanding of the of motion and/or motor dysfunction (weak-
process has evolved. During the Civil War era, it ness, tremor, dystonia) and/or trophic
was known as causalgia. In 1946, this type of changes (hair, nail, skin)
pain was referred to as Reflex Sympathetic Dystro-
Must display at least 1 signa at time of evalua-
phy,6 and during the 1990s, the nomenclature was
tion in at least 2 of the following categories
changed to the current term: CRPS. There has
been much debate on the criteria to make this 1. Sensory: Evidence of hyperalgesia (to
pinprick) and/or allodynia (to light touch
diagnosis. Both the IASP and a consensus state-
and/or deep somatic pressure and/or joint
ment called the Budapest criteria present fairly
movement)
similar lists of what a patient should display to
have a diagnosis of CRPS.7,8 The IASP defines 2. Vasomotor: Evidence of temperature asym-
metry and/or skin color changes and/or
CRPS as a syndrome characterized by a con-
asymmetry
tinuing (spontaneous and/or evoked) regional
pain that is seemingly disproportionate in time or 3. Sudomotor/Edema: Evidence of edema and/
degree to the usual course of pain after trauma or or sweating changes and/or sweating
asymmetry
other lesion. The pain is regional (not in a specific
nerve territory or dermatome) and usually has a 4. Motor/Trophic: Evidence of decreased range
distal predominance of abnormal sensory, motor, of motion and/or motor dysfunction (weak-
sudomotor, vasomotor edema, and/or trophic ness, tremor, dystonia) and/or trophic
changes (hair, nail, skin)
findings.7 This article focuses on the CRPS type II
associated with nerve injury; however, it is not a
A sign is counted only if it is observed at time of
hard to imagine that CRPS type I may be mediated diagnosis.
by similar pathways by injury to smaller unnamed Data from Harden RN, Oaklander AL, Burton AW,
et al. Complex regional pain syndrome: practical diag-
nerves in the bone and soft tissue. nostic and treatment guidelines. Pain Med 2013
This diagnosis of CRPS is based on history Feb;14(2):180–229.
and physical examination: there is no specific
 Chronic Pain Following Nerve Injuries 403

end stage of a spectrum of pain processes after One of the most important predictors of high post-
nerve injury. Epidemiologic studies of complex operative pain is high preoperative pain level:
regional pain syndrome are often flawed because these patients already have a nociceptive system
of the infrequency of the diagnosis. The largest that is primed. Thus, if the surgeon is caring for a
study was from the Netherlands using a general patient with several risk factors, it is helpful to
population database.9 The investigators looked consider perioperative interventions.
at 217,000 patients and found the overall inci- The next section reviews perioperative interven-
dence of CRPS was 26 per 100,000 person years. tions that have data from RCTs that support their
Women were affected at least 3 times more often role in reducing postoperative chronic pain.
than men and the upper extremity was affected Preemptive use of local anesthetics can reduce
more frequently than the lower limb. the number of patients who have chronic postop-
Chronic pain after nerve injury is far more com- erative pain. A study on patients who had breast
mon than CRPS. There are no large studies as- surgery found that the group that received regional
sessing the incidence of pain after major nerve anesthetic block had significantly decreased pain
injury. Case series in brachial plexus injuries have at 1 month, 6 months, and 12 months after surgery
found that nearly all patients experience pain after when compared with the control group.13 Another
injury. A recent case series of patients with nerve trial found decreased pain months after surgery in
injuries found a high prevalence of pain (66%), the group that had a preoperative block before
with many having severe pain.10 Yet even smaller thoracotomy.14 There are several other studies
injuries, such as the trauma associated with carpal indicating that anesthetizing the nerve with local
tunnel syndrome, have a 20% rate of pain at analgesia before incision affects long-term chronic
3 months.11 Although the pain after carpal tunnel pain.15
release is not a direct nerve injury, the pain is often Vitamin C has also been found to reduce the
burning and the scar is sensitive to light touch: fea- transition to CRPS after distal radius fractures.
tures consistent with a neuropathic process. Many Vitamin C is a free radical scavenger, which re-
of these may be because of injury to branches of duces vascular permeability after trauma. It has
the palmar cutaneous branch of the median nerve. also may decrease tumor necrosis factor alpha
Thus, for the hand surgeon, understanding and interleukin-6, which are important inflamma-
methods to prevent and treat chronic pain associ- tory cytokines. Zollinger and colleagues16 evalu-
ated with a nerve injury is important to improve ated vitamin C in the treatment of distal radius
outcomes. fractures in an RCT of 123 patients. They deter-
mined 500 mg of vitamin C for 50 days provided
PREVENTION a statistical benefit, with decreased pain in these
patients. They next looked at dosing study and
The hand surgeon should understand preventive found that the odds ratio of developing CRPS after
measures that can influence the postoperative distal radius fracture was 0.22 among those who
pain course and identify the patients/procedures received vitamin C. Statistically significant benefit
that would be at higher risk for postoperative was seen at 500 mg per day and 1500 mg per
pain so perioperative measures can be instituted. day.17 Another quasiexperimental study on foot
So who is at risk? There has been extensive and ankle patients found that after institution of a
work to stratify characteristics associated with perioperative vitamin C regimen, the rate for
the development of chronic pain. First is the type CRPS decreased from 9.6% to 1.7%.18 These 3
of injury. Major nerve trauma bombards the studies support the use of vitamin C at 500 mg
spinal cord and central nervous system with noci- per day as part of the perioperative regimen.
ceptive stimuli and, not unexpectedly, these pa- There are several other medications that show
tients are at high risk of pain. Then there are also promise for reducing the transition to chronic
specific injuries, such as distal radius fracture, pain, including gabapentin and ketamine. There
which have a high rate of development of are good data for improvement with these medica-
CRPS.12 Patient factors also are associated with tions in acute pain after surgery, but because of
risk of chronic pain. CRPS is more frequently wide heterogeneity in the literature, there is still a
seen in women.9 Psychological factors before lack of evidence on their impact on chronic pain.
injury have long been thought to increase the risk There is a new meta-analysis of gabapentin and
chronic pain. The theory is that a patient with an pregabalin, supporting their use for chronic
increased basal rate of catecholamines will be pain.19 At this time, we would advise the surgeon
more easily sensitized to pain, but the data that these medications may reduce chronic pain
are lacking and, at this time, the link between psy- and the surgeon should consider using these med-
chological traits and CRPS risk is still speculative. ications despite weaker levels of evidence. Our
404 Carroll & Curtin

algorithm for the perioperative management of provide sensory reorganization and desensitiza-
pain, based on the available literature, is provided tion, and extinguish the pathologic pain pathways.
in Tables 1 and 2. There are a few randomized trials demonstrating
benefits for therapy when compared with con-
TREATMENT trols.22–24 Two meta-analyses looking at physical
therapy modalities for the treatment of CRPS
Despite the most meticulous care, the surgeon will have been performed. Although these studies
still be faced with the patient who has lingering were hindered by the heterogeneity of the litera-
chronic pain well after the soft tissue has healed. ture, they did find evidence that graded motor im-
If the physician feels the patient meets the criteria agery and mirror therapy reduced pain.25,26
for CRPS treatment, referral to a pain specialist Acupuncture has been studied as an adjunct treat-
should be initiated immediately. However, the real- ment for chronic pain. At this point, evidence is
ity of practice is such that there is often a delay lacking for the treatment of CRPS but a large study
before a pain specialist sees the patient and thus in Germany found that acupuncture reduced pain
the hand surgeon should start treatment. In addi- for a variety of conditions.27 There are many other
tion, the surgeon may have patients with neuro- modalities that have been described for the treat-
pathic pain who do not fully meet the criteria for ment of CRPS, but at this time, strong evidence
CRPS but require additional treatment for their does not exist (eg, myofascial releases, stress
pain. The animal studies are clear that there is a loading).
window of opportunity with pain; thus, if a patient
is having pain disproportionate to expectations,
therapy should be initiated promptly in attempt to Medications
break the process.19 The next paragraph reviews
Pharmacologic treatments are a second arm in
evidence-based treatments for chronic neuro-
management of CRPS and neuropathic pain. Dur-
pathic pain/CRPS.
ing the acute phase of CRPS, corticosteroids have
The surgeon should always begin with a thor-
been used as burst therapy, which has been sup-
ough physical examination to rule out treatable
ported in some randomized trials.28,29 Most other
causes of the pain, such as carpal tunnel syn-
medications that have been studied were in those
drome. There have been several case series that
with a chronic presentation of CRPS/neuropathic
have shown patients who present with CRPS
pain. A mainstay in treatment for chronic pain is
may have a nerve entrapment that responded to
gabapentin, which was originally produced as an
surgical release.20,21 Practitioners should have a
antiseizure medication and has become a useful
low threshold for obtaining additional electrodiag-
pain management tool.30 It binds to the alpha-2
nostic testing if there is a suspicion of nerve
delta subunit of presynaptic P/Q-type voltage-
entrapments.
gated calcium channels, modulating the traffic
and function of these channels. This may directly
Therapy
modulate release of excitatory neurotransmitters
The first arm of treatment is therapy and other non- from activated nociceptors. Alternatively, some
pharmacological modalities, which are keystones data suggest that gabapentin’s antinociceptive
in neuropathic pain management. The goal is to mechanism may arise through activation of

Table 1
Authors’ perioperative treatment algorithm

All Patients 1. Preoperative local anesthetic administration

(at site of incision or using a block)
Moderate concern for chronic postoperative 1. Preoperative local anesthetics
pain 2. Vitamin C 500 mg daily for 50 d
High concern for chronic postoperative pain 1. Preoperative local anesthetics
(patient with high preoperative pain, nerve 2. Gabapentin 900 mg 2 h before surgery
manipulation, high anxiety) 3. Gabapentin 300–600 mg 3 times a day for 14–30 d
(if tolerated by patient)
4. Vitamin C 500 mg daily for 50 d
5. If a general anesthetic: we ask the
anesthesiologist about possibility of
intraoperative ketamine administration
 Chronic Pain Following Nerve Injuries 405

Table 2
Authors’ treatment algorithm for patient presenting with CRPS/neuropathic pain

New acute CRPS 1. Urgent referral to pain specialist

2. Solumedrol dose pack if acute presentation
3. Gabapentin 300–1200 mg 3 times a day (as tolerated by patient)a
4. Vitamin C 500 mg/d
5. Search for occult nerve injury: comprehensive nerve conduction studies
and evaluate for sensory nerve injuries easily missed on nerve con-
duction studies: (1) radial sensory branch injury, (2) palmar cutaneous
branch of the median, (3) cutaneous neuromas in scar.
Diffuse neuropathic pain 1. Gabapentin 300–1200 mg 3 times a day (as tolerated by patient)a
2. Desipramine 25 mg and increase each week by 25 mg until taking 100–
150 mg/d. Goal is serum plasma level 100–300 ng/mL. Desipramine can
have cardiac toxicity at higher doses, thus it is not for patients with
heart disease or family history of sudden death, and not for patients
taking other antidepressants.
3. If not candidate for tricyclic antidepressants because of heart disease,
consider duloxetine. Start 20 mg/d and increase to 60–120 mg/d.
4. Start therapy including myofascial releases
Diffuse neuropathic pain 1. Desipramine 25 mg and increase each week by 25 mg until taking 100–
(not tolerating or no 150 mg/d. Goal is serum plasma level 100–300 ng/mL. Desipramine can
effect of gabapentin) have cardiac toxicity at higher doses, thus it is not for patients with
heart disease or family history of sudden death, and not for patients
taking other antidepressants.
2. If not candidate for tricyclic antidepressants because of heart disease,
consider duloxetine. Start 20 mg/d and increase to 60–120 mg/d.
Tender scar to light touch 1. Inject intradermally with bupivacaine, if relief 5 scar problem
2. Therapy for scar management and desensitization
3. Trial of topicals, such as capsaicin
4. Potential Botox injectionb
5. Consider scar revision if conservative treatment fails
6. Some scar neuromas are not particularly tender but pain relief occurs
with intradermal injection.
a
Dosing of gabapentin is challenging; there is the balance of getting an efficacious does without having side effects,
such as drowsiness, which make the medication intolerable. We titrate up slowly starting 300 mg per day and increasing
every other day to a goal of 600 mg 3 times a day. Patients are counseled to stop increasing the dose when side effects
become too bothersome (ie, stop at dose they can live with). Some patients just do not tolerate higher doses of gabapen-
tin, we have found that for these patients starting very low (100 mg per day) and slowly titrating up can allow patients to
get benefit from this medication.
b
Botox in painful scars is an off-label use of this medication with only preliminary data at this time.

noradrenergic pain-inhibiting pathways in the spi- the patient to hold at the dose where side effects
nal cord and brain.31 Although there are limited become bothersome has increased patient accep-
data on gabapentin for CRPS, there is a wealth tance of this drug. Pregabalin shares the same
of literature on the treatment of chronic neuro- mechanism of action and side effects as gabapen-
pathic pain. A recent Cochrane review looked at tin; however, it is absorbed more efficiently by the
gabapentin for those with chronic neuropathic small intestines when given at higher doses.
pain and found that gabapentin gave a high level Switching from gabapentin to pregabalin may
of relief to about a third of the patients with mostly therefore be useful in patients who describe partial
tolerable adverse effects32; however one RCT of analgesia at 1200 mg of gabapentin 3 times a day
gabapentin in patients with CRPS I found only without the occurrence of dose-limiting side
mild effect.33 Gabapentin is a fairly safe medica- effects.
tion but has frequent side effects that can be intol- Bisphophonates have some of the best evi-
erable to the patient. The common side effects are dence showing benefit in the treatment of CRPS.
fatigue, dizziness, weight gain, and restlessness. They were proposed as a treatment for CRPS
More severe side effects are rare but include because they inhibit bone resorption, which is a
changes in mood and suicidal thoughts. We have common finding in patients with CRPS. Several
found that slow initiation of dosing and allowing studies have shown benefit from bisphosphonates
406 Carroll & Curtin

for CRPS.34–36 Indeed, a recent review of clinical stimulators. Sympathetic blocks have long been
trials to treat CRPS found that bisphosphonates used in the treatment of CRPS but the evidence
were the only medications with clear benefits for of its effectiveness is lacking. One study found
patients with CRPS.37 There has been concern that only 50% of sympathetic block performed
that long-term use of bisphosphonates may result actually blocked the sympathetic chain.41 Nerve
in pathologic fractures, but this complication is stimulators also are used in the treatment of
rare, and for the treatment of CRPS, many patients chronic pain. Spinal cord stimulators are the com-
need only a few months of treatment. Bisphosph- mon stimulators used for chronic pain with one
onates should be avoided in patients with poor RCT demonstrating initial efficacy compared with
dentition because of the risk of osteonecrosis of physical therapy alone, but those gains diminished
the jaw, and patients should be warned to report over time to nonsignificance at 5 years.42
any jaw, face, tooth, or head discomfort during Botox is an evolving tool in the treatment of pain.
treatment. It blocks the acetylcholine release and this seems
Tricyclic antidepressants (TCAs; amitriptyline, to reduce pain. It is being used intradermally to
desipramine, and imipramine) are also routinely reduce pain with some early success and may
used in the treatment of neuropathic pain. These be useful for cutaneous neuromas.43
medications augment the pain inhibitory pathways Finally, it is important to consider peripheral
and can have other beneficial side effects, such as nerve compression in patients with symptoms of
amitriptyline helping with sleep and desipramine CRPS. Placzek and colleagues44 reported on 8 pa-
helping with mood. The 2007 Cochrane review tients who developed CRPS following upper ex-
confirmed that TCAs were beneficial and these tremity surgery with clinical concerns for median
are tolerated well by most patients.38 Amitriptyline or combined median and ulnar nerve compres-
is safe at low doses and can be started while wait- sion, which were confirmed with electrodiagnostic
ing for the patient to be seen by a pain specialist. studies. They were treated with nerve decompres-
No one tricyclic is more effective than another, sion, which resulted in statistically significant
but they all seem to be more effective the higher decrease in pain and increase in Disabilities of
the dose that the patient is able to tolerate. In the Arm, Shoulder, and Hand (DASH) scores,
this regard, desipramine is particularly helpful with immediate relief of most other symptoms
because it has the least affinity for the muscarinic and improvement on motion and grip strength.
cholinergic and histamine receptors that mediate
side effects. Patients are therefore often able to SURGICAL PATIENTS WITH CRPS
tolerate a titration to 100 to 150 mg per day where
TCAs are more effective. A typical regimen starts Management of a patient who has CRPS or
at 25 mg per day and increases by 25 mg each chronic pain and may require additional surgical
week. However, with high doses there are cardiac procedure can be challenging, as those with a his-
side effects. So for the hand surgeon, starting out tory of CRPS are at risk for a recurrence/reactiva-
with 25 mg daily while waiting for a pain specialist tion of their pain with additional trauma and thus
is a safe and effective starting strategy. this group is approached with caution. The first
Topical medications have also been used for group of potential surgical candidates would be
chronic pain treatment, including EMLA cream, those patients with CRPS who also have a nerve
capsaicin ointment, and lidocaine patches. injury, which is the pain generator. These patients
Capsaicin has good evidence of efficacy in treat- include those with compression neuropathies or
ment of neuropathic pain. Its mechanism of action painful scar neuromas. Although there is no good
was once thought related to substance P but is evidence, most believe that surgery in this popula-
now thought to arise via the TRPV1 receptor. tion is appropriate. For these patients, we first
Overactivation of nocioceptors by capsaicin may attempt conservative treatments (physical ther-
cause some of these fibers to actually die back apy, medication, rest, splinting, desensitization).
from the skin surface. A 1997 meta-analysis of 5 tri- If these fail, then we proceed with surgery. At sur-
als determined that capsaicin had a positive effect gery, we give our entire perioperative regimen, and
compared with placebo and a more recent Co- if possible use an indwelling regional anesthetic
chrane review confirmed that capsaicin provided catheter for the first few postoperative days. If
pain relief.39,40 possible, we limit immobilization and begin ther-
apy shortly after surgery with the idea that it may
be important to have the nerve gliding in the oper-
Interventions
ative bed before scarring can tether or compress
The third arm of treatment is the more invasive in- it. The second group is patients who might need
terventions, such as sympathetic blocks and nerve surgery, but have had CRPS in the past. In general,
 Chronic Pain Following Nerve Injuries 407

this group should be approached with caution and 12. Puchalski P, Zyluk A. Complex regional pain syn-
unless the surgery has a high likelihood of drome type 1 after fractures of the distal radius: a
improving quality of life, we would advise patients prospective study of the role of psychological
against surgical intervention. factors. J Hand Surg Br 2005;30:574–80.
Every practicing hand surgeon will see patients 13. Kairaluoma PM, Bachmann MS, Rosenberg PH,
with chronic neuropathic pain and complex et al. Preincisional paravertebral block reduces the
regional pain syndrome. There is much literature prevalence of chronic pain after breast surgery.
on these processes but most is in the anesthesia Anesth Analg 2006;103(3):703–8.
journals and not always readily accessible to the 14. Obata H, Saito S, Fujita N, et al. Epidural block with
hand surgeon. We feel that the take-home mes- mepivacaine before surgery reduces long-term
sages are prevention for those at risk and that post-thoracotomy pain. Can J Anaesth 1999;
initiation of early treatment is something that 46(12):1127–32.
hand surgeons should be comfortable performing. 15. Lavand’homme PM, Eisenach JC. Perioperative
administration of the alpha2-adrenoceptor agonist
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