Complex Regional Pain Syndrome After

Zhongyu Li, MD, PhD, Beth P. Smith, PhD*, Christopher Tuohy, MD, Thomas L. Smith, PhD, L. Andrew Koman, MD

KEYWORDS  Chronic pain  Upper extremity  Fracture

After an emergent or elective upper extremity 5% after carpal tunnel surgery,4,5 and 22% to surgery, complex regional pain syndrome (CRPS) 39% after distal radius fracture.6 may complicate recovery, delay return to work, Current dogma states that early recognition and diminish health-related quality of life, and increase treatment of CRPS improves the prognosis for full the likelihood of poor outcomes and/or litigation. recovery; however, the term ‘‘early’’ is not well The clinical entity of CRPS is chronic pain that defined. In a population-based study in Olmsted persists in the absence of ongoing cellular damage County, 74 patients were diagnosed with CRPS and is characterized by autonomic dysfunction, type I between 1989 and 1999 and 74% of these trophic changes, and impaired function. In the peri- cases ‘‘resolved.’’2 Another study that followed operative period, the physiologic consequences of outcomes after distal radius fractures found that CRPS in the upper extremity contribute to or create the stiffness noted at 12 weeks (‘‘early’’ diagnosis one or more of the following: clinically significant of CRPS) correlated with residual symptoms at 10 osteopenia, delayed bony healing or nonunion, years.7 In addition, individuals who smoke have stiffness, tendon adhesions, arthrofibrosis, a poor prognosis compared with nonsmokers.8 pseudo-Dupuytren palmar fibrosis, swelling, and atrophy. This article discusses the diagnosis, phys- iology, and management of postsurgical CRPS that DIAGNOSIS occurs after hand surgery. CRPS is a clinical syndrome without a pathogno- INCIDENCE AND SIGNIFICANCE monic marker. CRPS type 1, also known as classic reflex sympathetic dystrophy, is defined as Although the exact incidence and prevalence of chronic pain without identifiable nerve involve- CRPS after hand surgery is unknown, the re- ment. CRPS type 2, also known as causalgia, ported incidence of CRPS is 5.5 to 26.2 per includes pain with identified nerve involvement. 100,000 person years, and the prevalence is re- In addition to pain, both syndromes are often ported as 20.7 per 100,000 person years.1,2 associated with autonomic dysfunction (abnormal Women are more frequently affected than men, vasomotor activity, inappropriate piloerector with a ratio of 3:1 to 4:1; the upper extremity is activity, abnormal sweat gland activity, and inap- involved more frequently than the lower extremity; propriate arteriovenous shunting) and functional and fracture is the most common causative impairment. Trophic changes may occur but vary event.1,2 The following rates of upper extremity with the severity of the precipitating event, the CRPS have been reported: 4.5% to 40% after time after injury, or the degree of extremity fasciectomy for Dupuytren contracture,3 2% to compromise.

Department of Orthopaedic Surgery, Wake Forest University School of , Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA * Corresponding author. E-mail address: [email protected]

Hand Clin 26 (2010) 281–289 doi:10.1016/j.hcl.2009.11.001

0749-0712/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved. hand.theclinics.com 282 Li et al

HISTORY AND PHYSICAL EXAMINATION disease and is not related to any known psycho- logical profile.6 Because CRPS is, in effect, an In patients diagnosed with postoperative CRPS, abnormal prolongation of normal physiologic the details of the initiating injury or process are responses to injury in the periphery, in the spinal critical in developing a management plan. There- cord, and throughout the central nervous system, fore, the events leading to surgery should be re- there is the potential for it to occur in any patient viewed to ascertain any preexisting conditions, after surgical intervention. past traumatic injuries or pain issues, and preex- isting subclinical problems; all these variables PHYSICAL EXAMINATION may affect symptoms that occur after the surgery. For example, for patients with mild compression The physical examination of patients suspected of neuropathies (eg, ), quies- having postsurgical CRPS should be compared cent CRPS may be exacerbated in the periopera- with their preoperative examination. Tight wound tive period and serve as a neuropathic event. dressings or casts should be avoided. The exami- Concomitant injuries or preexisting mechanical nation needs to assess from the neck to the derangements may also potentiate nociceptive fingers, including all aspects of the affected stimulation and contribute to the dystrophic extremity. The extremity inspection should include process. There are no firm temporal relationships palpation; assessments of skin integrity, range of between the time of injury and the time of surgery, motion, joint stability, and motor power; and that is, early or late intervention has not been neurologic, vascular, and sensibility assessments. demonstrated to affect the incidence of CRPS. The extremity examination should also assess The time of onset of CRPS after surgery varies, stiffness, edema, atrophy of hair and nails, hyper- with symptoms appearing as early as in the post- sensitivity, and dexterity. Hand and extremity care unit (recovery room) or several postures should be observed at rest and during weeks after surgery. Similar to nonsurgically activity or gait. Neuropathic or nociceptive contrib- related CRPS, the presentation may be obvious, utors to the pain process should be investigated with severe classic pain and swelling, or it may and identified. New exacerbations of preexisting be insidious. Symptoms of CRPS are often subclinical compression neuropathy should be nonspecific; pain, numbness, swelling, and stiff- evaluated by motor examination, sensory testing, ness are the normal symptoms reported by most and mechanical indications (ie, Tinel signs). postoperative patients. Therefore, clinical vigi- Part of the physical examination should be lance and acumen are crucial to discern CRPS focused on the identification of possible nerve within the context of nonspecific symptoms and injuries. Carpal tunnel syndrome may occur after signs and to evaluate the responses of these distal radial fracture surgery or hand/ recon- symptoms to the treatment and the passage of struction, and it may require nonoperative or oper- time. Recognizing the clinical character of CRPS ative treatment. Iatrogenic nerve injury with is often crucial. In a classic presentation, this char- neuromas-in-continuity and neuromas or perineural acter includes pain that (1) is often described as irritation of mixed nerves or sensory branches can burning, throbbing, and searing; (2) does not also act as powerful drivers of CRPS. Commonly respond to narcotics; and (3) awakens patients at reported nerve injuries associated with CRPS night or prevents normal sleep. Patients with include those that are associated with the palmar CRPS are irritable and have difficulty with rehabil- cutaneous branch of the median nerve, the superfi- itation programs. In subtle or indolent presenta- cial radial nerve and its branches, and the dorsal tions of CRPS, patients are often described as branch of the ulnar nerve and its branches. ‘‘uncooperative.’’ They may complain of stiffness, However, injury or irritation of any nerve can swelling, cold sensitivity, hyperalgesia, and allody- contribute to a dystrophic process. nia. Return to work or normal activities is resisted, and patients may appear listless and forlorn. They Inspection and Observation are often irritated by family, coworkers, and The of patients with CRPS may be swollen, medical providers, and this feeling is often mutual. obscuring the dorsal veins, and/or the hands may In contrast, patients who present with massive appear dry or damp; the posture of the hand is swelling of their extremity, especially associated generally intrinsic minus (metacarpophalangeal with a zone of demarcation, multiple sores, unex- [MP] extended and proximal interphalangeal plainable wound breakdown, and/or abnormal [PIP] joint slightly flexed). Dystonia, posturing, or hand clenching, need to be evaluated carefully to tremors are also occasionally observed. For a thor- rule out a diagnosis of a fictitious disorder or malin- 9 ough examination, the should be gering. However, CRPS is not a psychiatric observed at rest, during activity, and during Complex Regional Pain Syndrome 283 ambulation. Surgical sites should be inspected for Vascular Examination signs of wound or surgical complications Vascular examination is important to identify any that vary from the expected usual complications. vascular deficiencies and should not be neglected.

Palpation Sensibility Examination Patients may experience hyperpathia, allodynia, Assessments of pain threshold (monofilaments) numbness, or hyperalgesia. Therefore, it is impor- and innervation density (2-point discrimination) tant to palpate the arm and hand to determine if may be beneficial and can suggest a neuropathic these symptoms have a dermatomal distribution component to the pain syndrome (CRPS type 2). or if they are diffuse. If the symptoms are diffuse, the patient should be reevaluated after sympatho- DIAGNOSTIC EVALUATION lytic treatment. Mechanical Testing Skin Integrity Pain threshold evaluations may be performed using algometers, dolorimeters, computer-assis- The skin and any wounds around the affected area ted stimulation devices, and thermal threshold should be assessed carefully for signs of altered machines.10 It is difficult to obtain these evalua- sensibility, abnormal autonomic function, and tions except in large medical centers; however, trophic changes. when available, they provide clinically useful, objective information. Von Frey monofilaments Motor Testing can also be used to determine pain thresholds. An evaluation of motor power must be performed to determine if there are weakness or endurance Autonomic Function Evaluation issues. Computerized endurance testing may be Autonomic function of the hands may be assessed beneficial for collecting this information. Both by an evaluation of vasomotor control after the intrinsic and extrinsic motor testing must be application of a stressor (ie, exposure to cold) as evaluated. part of an isolated cold stress testing.5 Sweat production may be determined by measuring Range of Motion resting sweat output and by the quantitative sudo- 11 The range of motion of all joints, including the motor axon reflex test. Thermography, when shoulder, should be evaluated and recorded. used with a physiologic stressor, provides valu- 12 Adhesive capsulitis or restricted range of motion able confirmatory information. These tests of the shoulder is common in patients with long- provide objective measures of autonomic function; standing CRPS. In patients with long-standing however, they are only available at selected CRPS of the hand, intrinsic muscle contractures tertiary referral centers. are also common. Therefore, the hand should be Radiologic Testing evaluated for any evidence of contracture. Many investigators have recommended 3-phase Joint Stability scans as a diagnostic tool for CRPS. Positive scan results support the clinical diagnosis of Joints should be assessed for global stability. Joint CRPS. A positive 3-phase bone scan result in instability may elicit or contribute to nociceptive patients with CRPS is characterized by increased stimuli that contribute to CRPS. Instability of ulno- third phase bone scan periarticular uptake in all humeral, radiohumeral, distal radioulnar, radiocar- joints. Evidence of vasomotor instability and pal, intercarpal, and finger joints may all contribute abnormal patterns of flow distribution may also to significant nociception. In addition, tears in the be evident on phase I and phase II bone scans. triangular fibrocartilage complex or chronic However, these scans document vasomotor sprains and strains may contribute to CRPS. abnormalities, and therefore, they are not diag- nostic for CRPS. The difficulty in using bone scans Neurologic Examination as a diagnostic tool for CRPS is that the scans may A careful neurologic examination should be per- have insufficient sensitivity and specificity in formed to identify any possible neuropathic patients with partially treated CRPS or in patients involvement, especially spinal cord or brachial with variant presentations of the syndrome. These plexus involvement. In addition, the patient should findings have led to Lee and Week’s13 analysis of be evaluated for movement disorders, such as the existing literature and their conclusion that ‘‘a dystonia. three phase bone scan is not a prerequisite for 284 Li et al

the diagnosis of complex regional pain Currently, there are no drugs for CRPS that are syndrome.’’ Quantitative scintigraphies (bone labeled by the Federal Drug Administration (FDA), scans) have demonstrated that there are both and few drugs are approved for chronic neuro- cortical and cancellous osteopenia that appear in pathic pain. However, based on clinical experience excess of that observed with entry-matched and the literature, the following classes of drugs controls treated with casting.14 with a sympatholytic component have been recom- mended for use in patients with CRPS: antidepres- Sympatholytic Challenge Testing sants, anticonvulsants, membrane stabilizing Sympathetically maintained pain (SMP) may be agents, and adrenergic agents. The most common differentiated from sympathetically independent oral agents in these categories are listed in pain by a sympatholytic challenge provided by Table 2. The types of oral medications that an intravenous injection of phentolamine, which are prescribed depend, in part, on the patient’s presentation. For a hot, swollen hand, an antide- is a combination of a1- and a2-adrenergic receptor blockers. In patients with SMP, the injection pressant combined with an anticonvulsant is results in transient pain relief.15 Similarly, stellate prescribed in conjunction with hand . ganglion blocks, single cervical epidural blocks, Commonly used drugs include a tricyclic antide- sympathetic brachial plexus blocks, or scalene pressant in low doses (ie, amitriptyline [Elavil], blocks may provide temporary relief of pain in 25 mg three times a day, or amitriptyline, 50 patients with SMP. In patients who respond during mg, at bedtime for a normal-sized adult) the block, pain is relieved, whereas motor function combined with phenytoin (Dilantin), 100 mg remains. Although single blocks provide a useful three times a day, or pregabalin (Lyrica), 75 to diagnostic test, they are associated with signifi- 100 mg twice a day or three times a day. For cant false-negative rates. However, they are help- patients with cold, stiff hands, a mild antidepres- ful in differentiating patients with SMP from sant is often combined with a calcium channel patients with sympathetically independent pain. blocker. Another common drug regimen is amitriptyline combined with amlodipine TREATMENT (Norvasc). For patients with acute hyperalgesia or allodynia Early recognition of CRPS and the prompt initia- and mild to moderate edema, an adrenergic agent tion of treatment seems to improve patient (eg, clonidine [Catapres]) may be of benefit. A outcomes. However, diagnosis and treatment of clonidine patch (0.1 mg) is applied over the most CRPS within 6 to 12 weeks of the onset of symp- sensitive area; the application of the patches is toms is not common in most patients; delays in combined with hand therapy, including a stress diagnosis and treatment are especially common loading program. Steroid dose packs are used in patients with milder variants of CRPS. In addi- by many and have demonstrated effi- tion, patients who develop CRPS after fractures, cacy in reducing symptoms. Corticosteroids act especially of the distal radius, seem to have to stabilize membranes and to decrease inflamma- a worse prognosis even when the CRPS is discov- tory pain (Table 1). ered early and treated promptly. Treatment decisions are guided by the patients’ Prophylactic Treatment symptoms and whether their pain is sympatheti- cally maintained or sympathetically independent. Vitamin C taken prophylactically at a dose of 500 In addition, the presence of an identifiable noci- mg/d has been shown to decrease the incidence ceptive or neuropathic component may require of CRPS in patients who sustain distal radius frac- surgical intervention. Treatment is often multi- tures.16 However, the role of other vitamins in the factorial and involves a combination of therapy, treatment of CRPS is unclear. oral medications, parenteral medications, and surgery. Hand therapy and various treatment Parenteral Agents modalities are usually combined with oral medica- tions. Commonly, hand therapy including active Generally, parenteral agents are administered by and passive range of motion, splinting, and anesthesiologists. However, recent controlled contrast baths (alternating heat and cold) is studies have not demonstrated the efficacy of used. Other interventions that are beneficial for intravenous treatment of CRPS.17,18 Intravenous some patients are transcutaneous nerve stimula- agents, such as guanethidine, cortisone, reser- tors, H-wave therapy, and stress loading.10 pine, lidocaine, and bretylium, have been used Oral pharmacologic intervention is used previously. Of these drugs, bretylium tosylate frequently to manage the symptoms of CRPS. was the only drug labeled by the FDA for this Complex Regional Pain Syndrome 285

Table 1 Definitions

Nociception Detection of an unpleasant (noxious) stimulus that produces pain in human subjects under normal circumstances Allodynia Pain in a specific dermatomal or autonomous distribution associated with light touch to the skin; a stimulus that is not normally painful Hyperalgesia Increased sensitivity to pain (includes allodynia and hyperesthesia) Hyperesthesia Increased sensitivity to stimulation (pain on response to a mild nonnoxious stimulus) Sympathetic pain Pain in the presence of and/or associated with over action of the sympathetic pain fibers; by definition, the pain is relieved by sympatholytic interventions Hypoesthesia Decreased sensitivity to stimulation Hyperpathia Abnormally painful reaction to a stimulus (especially repetitive); often includes extended duration of pain, frequently with a delay Dysesthesia An unpleasant, abnormal sensation Paresthesia An abnormal sensation

purpose; however, marketing of bretylium in the is important to confirm that the pain is predomi- United States has been discontinued. nantly SMP and that it can be controlled with Epidural clonidine and corticosteroids have medications or continuous blocks. been used successfully in patients with refractory Surgery to release compressed nerves, to symptoms.19,20 The blockade may be achieved correct or cushion neuromas-in-continuity, or to by indwelling catheters located in the epidural relieve perineural fibrosis may offer significant space or contiguous with portions of the brachial benefits to some patients.29,30 Another option, plexus or peripheral nerves. These continuous the surgical ablation of sympathetic nerves by blocks may be used for 1 to 5 days as an outpa- reversible means, such as phenol injections or ra- tient treatment when used to target peripheral diofrequency ablation, may provide symptom re- nerves. lief. In other patients, neurolysis and blockade of Some of the newer treatments for CRPS include peripheral nerves may be efficacious. Spinal cord the use of free radical scavengers, including stimulation provides effective pain relief in 50% dimethyl sulfoxide, vitamin C, and N-acetyl- of patients.31 Use of implantable nerve stimulators cysteine.16,21 Their mechanism of action is and dorsal column stimulators are valuable as hypothesized to be related to their ability to inter- salvage procedures in selected patients with fere with oxygen radical–mediated inflammatory refractory symptoms.6,32,33 Other salvage proce- response.22 Calcitonin,23 bisphosphonates,24–26 dures for the most difficult cases include the use and N-methyl-D-asparate antagonists (eg, ket- of dorsal column stimulators and gray matter stim- amine, memantine)27,28 have been used to treat ulators and cingulotomy.34 patients with CRPS, with reported reduction in symptoms. However, controlled trials will be Psychological Treatment required to determine the efficacy of these drugs. Counseling, biofeedback, and adaptive therapy Surgical Treatment can be beneficial for certain patients with CRPS. Although CRPS is not a psychiatric disease, Surgery to correct neuropathic or nociceptive sites chronic pain does affect health-related quality of plays an important role in the treatment of patients life. Patients with CRPS may experience reactive with CRPS. If indicated, surgery may be performed depression as a result of their symptoms. early if the CRPS symptoms cannot be controlled medically. The dictum that surgery is inappropriate LATE MANAGEMENT OF COMPLICATIONS and doomed to failure in patients with CRPS is RELATED TO CRPS incorrect and deprives patients of valuable and necessary interventions. However, surgical proce- Surgery on the extremities of patients with CRPS is dures should be used with caution, and care appropriate if pain cannot be managed using other should be taken in determining the appropriate methods. Assuming that perioperative pain control choice of surgical intervention. Before surgery, it is possible using sympatholytic interventions, 286 ie al et Li

Table 2 Oral medications

Major Short-Term Disadvantage Drug Usual Dosage Mechanism or Contraindications Amitriptyline 25 mg tid or 50 mg qhs Inhibits amine pump-decreased Drowsiness With guanethidine hydrochloride (Elavil) norepinephrine reuptake sulfate Amlodipine (Norvasc) 5–10 mg qd Ca11 channel blocking agent; prevents Headache arteriovenous shunting; increases Postural hypotension nutritional flow Corticosteroids 20–80 mg/d; prednisone Stabilizes membranes; increases nutritional Adrenal suppression equivalents  5–40 d flow; decreases inflammatory pain Avascular necrosis (dose related) Fluoxetine (Prozac) 20 mg/d AM Serotonin reuptake inhibitor Minimal drowsiness Gabapentin (Neurontin) 300–600 mg tid Dizziness Renal disease; patients Somnolence must be carefully Ataxia monitored Nifedipine (Procardia) 10 mg tid, may increase Ca11 channel blocking agent; prevents Headache slowly to 30 mg tid arteriovenous shunting; increases Postural hypotension nutritional flow

Phenoxybenzamine 40–120 mg/d a1-receptor blocking agent Orthostatic hypotension hydrochloride (Dibenzyline) Phenytoin (Dilantin) 100 mg tid Decreases resting membrane potentials; Ataxia inhibits amine pump; stabilizes synaptic Liver damage Pregnancy membrane Convulsion Pregabalin (Lyrica) 50–200 mg tid Dizziness Somnolence Peripheral edema Complex Regional Pain Syndrome 287 nociceptive and neuropathic foci may be managed these patients are often cool, and swelling may by appropriate neurolysis of compressed nerves, be minimal. Patient compliance is compromised repair of damaged nerves, or perineural fibrosis if active range of motion is restricted. These in correction of mechanical lesions. In addition, patients tend to request additional narcotics, and patients with CRPS may develop MP and PIP joint acquiescence to their demands by their treating contractures that can be managed by surgical physicians is rarely beneficial. Delayed union and release. Contracted intrinsic muscles are common osteopenia are often observed. Phase I and phase in these patients, and intrinsic releases may be II bone scans may show hyperperfusion (hot/warm beneficial. In addition, bony malunion or nonunion hand) and hypoperfusion (cool stiff hand); 3-phase may occur because of the CRPS-induced osteo- scans show increased uptake at the fracture site penia. For these patients, may be and in the periarticular areas of the hand and wrist. warranted to gain the necessary correction. In patients with CRPS after distal radius frac- Neuropathic foci are managed using the same tures, awareness of the vagaries of presentation techniques that are used for patients with neuro- is crucial. Because the onset of CRPS may occur pathic foci without CRPS. Nerve repair, neurolysis, later, patients may develop symptoms during the nerve wrapping, resection of neuromas, and 2- to 3-week period between their scheduled temporary blockade with phenol or cryoablation follow-up appointments. Therefore, are various techniques that can be used success- office staff and other providers (especially nurses, fully in these patients. nurse practitioners, physician assistants, and ther- apists) need to understand the importance of early diagnosis of CRPS based on symptoms reported SPECIFIC ENTITIES by the patients. In patients reporting pain and stiff- Distal Radius Fracture ness, a chart notation that addresses the presence The reported incidence of CRPS after distal radius or absence of CRPS is an important safeguard. If fracture ranges from 2% to 39% and is one of the CRPS is suspected, this concern should be noted, leading causes of poor outcomes and malpractice a sympatholytic medication should be prescribed, claims.6 The incidence of CRPS is increased as and consultation with a physician should be ar- a result of improper casting. The presence of ranged. In patients who have coexistent carpal CRPS and the resultant osteoporosis (in excess tunnel neuropathy, neurolysis of the median nerve of similarly treated non-CRPS fracture) contributes should be performed. to delayed healing and nonunion. The delay in heal- ing and the occurrence of nonunion is secondary to Carpal Tunnel Surgery and CRPS bone demineralization.14 Onset of CRPS after distal radius fracture is variable and often delayed; stiff- Severe chronic pain that occurs after carpal tunnel ness, difficulty sleeping, burning pain, and cold release surgery is classified as type 2 or neuro- sensitivity are the common symptoms. Median pathic CRPS. In this instance, CRPS may be asso- nerve involvement, often slow and insidious, may ciated with nerve irritations related to the provide a neuropathic component, and for these procedure (idiopathic), perineural fibrosis, or nerve patients, surgical release of the median nerve injury (neuropraxia, neuromas-in-continuity, nerve may be beneficial. In patients who are treated transection). Onset of symptoms may be rapid, with external fixators or who have radial incisions, and patient symptoms can be apparent in the irritation or injury of the superficial radial nerve recovery room. However, in most cases, symp- may create a neuropathic focus. Overdistraction, toms occur at 1 to 3 weeks after surgery. Injury radioulnar joint instability, intercarpal instability, to the palmar cutaneous nerve branch may occur unstable triangular fibrocartilage complex, and/or and may be problematic in patients with coexis- chondral injury may contribute as nociceptive tent CRPS. Patients present with pain, cold sensi- drivers of the pain process. tivity, variable swelling, and difficulty sleeping. The most common presentation of CRPS after Nonsurgical management is the first line of treat- distal radius fracture is a warm, swollen hand; hy- ment; however, for patients with refractory SMP, perpathia or allodynia; stiffness in which edema is surgical intervention may be needed after an responsive to elevation; and pain that is refractory appropriate period of medical intervention fails to to narcotics. The hot, swollen presentation usually control pain. occurs at 1 to 3 days after surgery, with associated If CRPS symptoms are only partially resolved after median nerve symptoms reported by many combinations of oral or parenteral pharmacologic patients. A more problematic alternative presenta- treatment and therapy, surgery for neuropathic tion of CRPS occurs when pain and stiffness are CRPS may be considered. Treatment options for the predominate symptoms. The extremities of perineural fibrosis include: (1) neurolysis alone, 288 Li et al

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