Evaluation and Treatment of Neuropathic Pain Syndromes

Introduction

Neuropathic pain comprises a wide range of heterogeneous conditions. Various types of neuropathic pain may have distinct pathophysiologic causes and different clinical signs and symptoms. Despite the diversity of conditions classified as “neuropathic pain,” many potentially share common underlying mechanisms of nociception, including neuronal hyperexcitability, but others may not. This may, in part, explain why certain analgesic agents are relatively effective for a wide range of neuropathic pain states but why notable exceptions exist that appear to be resistant to conventional “neuropathic” pain therapy. A group has been assembled to address the inconclusive research on “neuropathic” pain and to operationalize and specify definitions and criteria for conditions to be referred to as neuropathic pain ( Box 34.1 ). This work should lead to a more reductionist approach to the study of neuropathic pain and effective therapies for specific disease processes.

BOX 34.1

Updated Definition of Neuropathic Pain

IASP Definition: 2017

“Pain caused by a lesion or disease of the somatosensory nervous system”

Revised Research and Clinical Definition: 2007

“Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” IASP, International Association for the Study of Pain.

This chapter focuses on some of the more common states of “neuropathic” pain as defined by the sensitive but non-specific definition of the International Association for the Study of Pain (IASP). These conditions include postherpetic neuralgia (PHN), painful diabetic peripheral neuropathy (DPN), human immunodeficiency virus (HIV) painful sensory neuropathy, and chemotherapy induced peripheral neuropathy (CIPN). While complex regional pain syndrome (CRPS) is considered nocicplastic in nature, it is also discussed in this chapter.

Complex Regional Pain Syndrome

The term CRPS , which denotes both types one and two, originated from a history of different names appointed by individuals who made particular observations. In 1864 Silas Weir Mitchell made an important observation of Civil War soldiers when he noticed that they suffered from burning pain and muscle atrophy at the sites of their injuries caused by gunshot wounds. He called this “causalgia,” which is derived from the Greek words kausis (burning) and algos (pain). In 1900 at a lecture in Germany, Paul Sudeck stated that this syndrome could not only extend from the initial insult but also had an inflammatory component. The name Sudeck’s dystrophy was applied in his honor. Half a century passed before the discovery that invasive procedures that block the sympathetic nervous system provide further relief of pain symptoms. Because of the success of these methods, Evans renamed the syndrome “reflex sympathetic dystrophy.” Over the years, cases arose in which patients lacked a trophic component, sympathetic involvement was absent, or there was no evidence of reflex involvement. These exceptions led to a meeting in 1993 by the IASP at which the term “ complex regional pain syndrome ” was formulated and subsequently published the following year. The most commonly used clinical diagnostic criteria for CRPS types one and two are low in specificity but high in sensitivity, which has led to overdiagnosis of the pain syndrome. This has made it difficult to obtain accurate epidemiologic data for CRPS or to perform rigorous studies of the pathologic state. In 2007, research criteria (also known as the Budapest criteria) were published that included objective signs of pathology characteristic of patients with CRPS ( Box 34.2 ). These criteria had good specificity and sensitivity. Although they were initially intended for research use, this was later revised to include both a clinical and research set of criteria commonly used for diagnosis.

BOX 34.2

Difference Between the IASP Criteria and the Budapest Criteria for the Diagnosis of CRPS

IASP Criteria for the Diagnosis of CRPS*

1
Presence of an initiating noxious event or reason for immobilization
2
Disproportional pain, allodynia, or hyperalgesia from a known inciting event
3
Sign or symptom of any evidence showing edema, skin changes, blood flow, or abnormal sudomotor activity in the region of the pain
4
No other condition that would otherwise explain the degree of pain or dysfunction

Budapest Criteria for Diagnosis of CRPS

1
Presence of continued disproportional pain from the known inciting event
2
Must report at least one symptom in three of these four categories:
- Sensory: hyperesthesia, allodynia
- Vasomotor: temperature asymmetry, changes in skin color
- Sudomotor/edema: edema, changes in sweating, sweating asymmetry
- Motor/trophic: decreased range of motion, motor dysfunction (tremor, weakness, dystonia), trophic changes (hair, nail, skin)
3
Must report at least one sign in two or more of these categories at the time of evaluation:
- Sensory: hyperalgesia to pinprick, allodynia to touch, or joint movement
- Vasomotor: temperature asymmetry, color asymmetry
- Sudomotor/edema: edema, asymmetric sweating, sweating changes
- Motor/trophic: decreased range of motion, motor dysfunction, trophic changes
4
No other condition that would otherwise explain the degree of pain or dysfunction

Budapest Clinical Criteria ^,

At least one symptom in three or four symptom categories
At least one sign in two or more sign categories

Budapest Research Criteria

At least one symptom in all four symptom categories
At least one sign in two or more sign categories

*If seen without any major nerve damage, the diagnosis is CRPS type one; if seen with evidence of nerve damage, the diagnosis is CRPS type two.

CRPS , Complex regional pain syndrome; IASP, International Association for the Study of Pain.

Pathophysiology

There are two types of CRPS, known as type one and type two ( Box 34.3 ). They differ because type two has evident nerve injury, whereas type one assumes an injury to the nerve or nerves. A consistent finding in both types of CRPS is the discrepancy between the severity of the symptoms and the severity of the inciting injury. In addition, symptoms have the propensity to spread in the affected limb in a pattern not restricted to the specific nerve’s area of innervation. CRPS is characterized by intense burning pain with resultant hyperalgesia or allodynia. It may be associated with local edema and autonomic involvement, such as changes in skin color and sweating and increased or decreased skin temperature in the affected area. There may also be trophic changes in the skin, hair, and nails in the affected site (see Box 34.3 ). Although many questions about the pathophysiology of this syndrome are still unanswered, three main principles remain at the core of CRPS: abnormalities in both somatosensory and sensory pathways and sympathetic nervous system involvement.

BOX 34.3

Difference Between CRPS Type One and Two

CRPS Type One (Reflex Sympathetic Dystrophy)*

1
The presence of an initiating noxious event or a cause of immobilization
2
Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event
3
Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain
4
This diagnosis is excluded by conditions that would otherwise account for the degree of pain and dysfunction

CRPS Type Two (Causalgia) ^†

1
The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve
2
Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain
3
This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction

CRPS , Complex regional pain syndrome.

*Criteria two to four must be satisfied.

^† All three criteria must be satisfied.

Somatosensory Abnormalities

Inciting injury to either the upper or lower extremity is an important trigger of CRPS. Studies have shown that changes in cutaneous innervation of the injured extremities occur even when no nerve injury is found. Albrecht et al. performed a study where skin biopsy samples were obtained from the affected limbs of patients with CRPS type one. A lower density of C and A fibers were found in the affected limbs than in the unaffected limbs, which led to sensory deficits in the affected limbs. Brain plasticity is another important factor found to be associated with somatosensory abnormalities. Data suggest that patients with CRPS have decreased activity in the somatosensory cortex of the affected side. These patients also tend to have tactile mislocation because of somatotopic reorganization, which was found to be directly correlated with hyperalgesia. Changes occurring within the primary somatosensory (SI) cortex are dependent on pain and have been shown to be reversible after recovery from the pain. Recently, a study published by Azqueta-Gavaldon et al. where 20 patients with sensory and motor deficits attributed to chronic CRPS (> six months of pain) underwent a battery of tests including functional magnetic resonance imaging, showed that patients with sensory and motor deficits had bilateral decreases in gray matter in the putamen. They theorize that putamen alterations may explain the pain and motor impairment seen in patients with chronic CRPS.

Sensory Pathways (Central Nervous System Sensitization, Peripheral Sensitization)

Central sensitization occurs when pain perception increases because of the constant firing of painful stimuli to the central nervous system. Neuropeptides such as substance P and bradykinin are released in response to nociceptive stimuli and activate N -methyl- d -aspartate (NMDA) receptors, leading to hyperalgesia and allodynia. Chronic exposure to these neuropeptides may influence and remodel normal neuroanatomy. Glial cells (namely microglia and astrocytes) are immunocompetent CNS cells that are activated after tissue injury. In a cadaveric study of an individual with CRPS comparing spinal cord anatomy to four control cadavers, significant posterior horn cell loss along with microglial and astrocyte activation was found at the level of the original injury and entire spinal cord.

Peripheral sensitization is the counterpart of central sensitization. When a nerve injury occurs, multiple pro-inflammatory factors such as glial cell activation, substance P, bradykinin, tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), prostaglandin E ₂ , and nerve growth factor are activated, which results in increased nociceptive sensitivity and a decreased threshold for the firing of nociceptive stimuli. A study where immunoglobulin G (IgG) from patients with chronic CRPS was injected into mice showed increased edema and paw hyperalgesia with concomitant sustained microglial and astrocyte activation in the spinal cord dorsal horn and pain-related regions of the brain. Furthermore, this was found to be IL-1β mediated as IL-1 receptor antagonists, and IL-1β floxed mice prevented these changes when exposed to IgG of CRPS patients.

Together, central and peripheral sensitization results in the allodynia and hyperesthesia seen in patients with CRPS. There are other important factors in the inflammatory pathway, such as the role of nuclear factor kappa B (NFκB) upstream in the pro-inflammatory pathway observed in animal studies. To date, anatomic, biomolecular, and immunohistologic studies such as those mentioned above illustrated the multifactorial influences in the development of central and peripheral sensitization of this disease along with their effect on neuroanatomy.

Neuroinflammation

An emerging hypothesis for the mechanism for CRPS development is neurogenic inflammation. As mentioned previously, many pro-inflammatory factors are released during nerve injury, evidenced in patients and animal models. This early stage of CRPS (“warm phase”) results in vascular symptoms, trophic changes, and pain mediated by neuropeptides with resultant production of high levels of cytokines, nerve growth factors, and mast cells. Studies on IL-6 and TNFα levels in patients with CRPS have shown elevated levels in blisters and skin that decrease once the patient’s condition has become chronic. Dendritic cells whose roles include activating helper T cells have been hypothesized as the primary mediator for neuroinflammation. A study by Russo et al. utilizing mass cytometry immunophenotyping found that in 14 patients with Budapest criteria supported clinically diagnosed CRPS showed an increased level of central memory CD4 and CD8 T cells implicating a possible role of antigen mediated T-lymphocyte response in the development of CRPS. Although further studies are needed to further validate this pathway, it is possible that neuroinflammation itself plays a role in the evolution of this condition.

Altered Sympathetic Nervous System Function

Involvement of the sympathetic nervous system is thought to be responsible for the limbs in patients with CRPS becoming cool, blue, and painful secondary to vasoconstriction because of excessive outflow from the sympathetic nervous system. In an animal study, rats with chronic post ischemic pain that had norepinephrine injected into their hind paws experienced increased nociceptive firing, supporting the notion that pain can be sympathetically maintained. Interestingly, norepinephrine levels were found to be lower in the affected extremity than the normal contralateral extremity in patients with chronic CRPS. Several studies evaluating the effect of adrenergic receptor stimulation on the vasculature in patients with CRPS have indicated an increased response to an adrenergic stimulus. However, this provides little evidence in support of sympathetic maintenance of CRPS pain.

Coupling of sympathetic neurons may occur not only to nociceptive afferents but also to non-nociceptive mechanosensitive or cold-sensitive neurons. Sympathetic afferent coupling, considered the cause of sympathetically maintained pain, occurs in cutaneous and deep somatic tissues, but during the acute event of CRPS, the deep somatic tissues are of greater importance. Although coupling occurs in some patients with CRPS, a subset of patients with clinically identical CRPS have sympathetically independent pain. These patients exhibit little to no response to sympathetic blockade either pharmacologically with phentolamine or via interventional blockade of the sympathetic ganglia.

Epidemiology

Multiple studies of CRPS type one have shown that the male-to-female ratio ranges between 1:2 and 1:4, thus suggesting that females are at higher risk for the development of the syndrome. ^, However, the male-to-female ratio for most other pain syndromes is similar. A retrospective, cross-sectional analysis study showed that the male-to-female ratio was 1:4 and that the most common initiating events were bone fractures, sprains, and trauma. In a prospective study, it was found that CRPS incidence four months after a wrist fracture was 3.8%. This group generated a prediction rule to identify high risk patients based on a 25 min assessment evaluating pain, response time, dysynchiria, and swelling one week after wrist fracture. This study found that a pain score of ≥ five within the first week of injury was nearly as accurate as performing the 25 min assessment in identifying wrist fracture patients at high risk for developing CRPS.

Outcomes of the disease tended to be worse in patients with upper extremity injuries than in those with lower extremity injuries, injuries other than fractures, and “cold” (commonly chronic) CRPS rather than “warm” (acute) CRPS. Other risk factors that contribute to the development of CRPS are age, workplace, concomitant use of angiotensin-converting enzyme (ACE) inhibitors, history of migraines, history of asthma, and type of injury. The average age of patients ranges between 16 and 79 (median range, 41.6), with a higher incidence in the older population. Patients with motor nerve damage were found to be at higher risk for CRPS than those with sensory nerve damage. Fracture has been reported to be the most common initiating injury. The incidence of job-related injuries leading to CRPS was as high as 76%, which may indicate a psychosocial or secondary gain component in reporting of this pain. Studies report that CRPS develops in patients with a family history of CRPS at a higher incidence and younger age, suggesting that CRPS may have a genetic component. Another study showed that siblings of patients in whom CRPS developed before 50 years of age had a three-fold increased risk for development of the syndrome. Psychological factors such as depression, personality disorders, and anxiety have no correlation with CRPS patients, suggesting no specific type of CRPS personality.

Clinical Features

The pain must be greater in proportion to the inciting event. There must be at least one symptom in three of the following four categories: sensory (hyperesthesia/allodynia), vasomotor (changes in temperature or sweating in the affected limb than the normal limb), sudomotor/edema, and motor/trophic (demonstration of weakness, decreased range of motion, or trophic changes in hair, nails, or skin). At least one sign must be present at the time of evaluation in two or more of these four categories: sensory, vasomotor, sudomotor/edema, and motor/trophic. There must be no other diagnosis that better explains the patient’s signs and symptoms. This differs from the criteria proposed in 1993 by the IASP (see Box 34.3 ). A recent study in which the validity of CRPS was evaluated by comparing the Budapest criteria in patients with CRPS and those with neuropathy showed that the IASP criteria had a sensitivity of 1.0 and a specificity of 0.4, and the Budapest criteria had a clinical sensitivity of 0.99 and a specificity of 0.68. The newly revised criteria are also divided into clinical and research. The research criteria contain more inclusions, which allows a specificity of 0.96.

The current IASP taxonomy also divides CRPS into CRPS one (formerly known as reflex sympathetic dystrophy) and CRPS two (formerly known as causalgia). The distinction between CRPS one and two is the presence of a definable nerve lesion in patients with CRPS two. The signs and symptoms for both conditions are clinically indistinguishable and include sensory changes (allodynia, hyperalgesia, and hypoalgesia), edema, temperature abnormalities, and changes in sweating (see Box 34.3 ). Pain is the principal feature in both CRPS one and CRPS two. In patients with CRPS, the associated clinical signs are typically out of proportion to the inciting injury. Patients describe a burning, deep-seated ache that may be shooting in nature and associated with allodynia or hyperalgesia. Pain occurs in 81.1% of patients meeting the CRPS criteria. Patients also frequently complain of sensory abnormalities such as hyperesthesia in response to the typical mechanical stimuli encountered in day-to-day activities (such as dressing) involving the affected limb.

In CRPS two (i.e. CRPS with associated major nerve injury), patients often report hyperesthesia around the injured nerve in addition to electric shock-like sensations, shooting pain, and allodynia. Symptoms indicative of vasomotor autonomic abnormalities (including color changes) occurred in 86.9% of patients; temperature instability occurred in 78.7%. Sudomotor symptoms of hyperhidrosis and hypohidrosis were reported in 52.9%. Trophic changes in skin, nail, or hair patterns were reported in 24.4%, 21.1%, and 18%, respectively. Edema was reported in 79.7%, with decreased range of motion in 80.3% and motor weakness in 74.6%.

Over time, symptom severity changes reflecting stability or progression of disease. In 2010 Harden et al. developed a CRPS symptom severity score (CSS) to help categorize the degree of CRPS for aiding in clinical decision making, which was validated by an international prospective multi-site study. ^, In the study, they found that changes in CSS correlated with greater changes in fatigue, pain intensity, social functioning, ability to take physical roles, and overall wellbeing, indicating the possible role of this score in clinical monitoring and research. Eventually, approximately three-quarters of all CRPS cases resolve even without treatment, with the resolution of microvascular signs and symptoms resolving before resolution of pain.

Diagnosis

There is currently no “gold standard” test for the diagnosis of CRPS. A very thorough history and physical examination are essential for evaluation and diagnosis. Patients with this condition will have the signs and symptoms mentioned. Many clinicians utilize the Budapest criteria ( Box 34.2 ) to help diagnose this condition. In 2018, a European Pain Federation Task Force developed standards for diagnosis and treatment of CRPS where they recommended the utilization of the Budapest criteria as the main tool to diagnosis the condition with further diagnostic tests only to exclude other diagnoses.

A physical examination must be performed to establish the sensory, motor, trophic, sudomotor/edema, and autonomic changes. Sensory changes such as allodynia may be evaluated by light touch and the application of warm/cold temperature to the affected area. Autonomic dysfunction may be confirmed by the presence of asymmetry in temperature and color. Trophic changes may be manifested as changes in skin, nails, and hair in the affected limb. Motor activity may be evaluated by examining motor strength and range of motion. Sudomotor/edema changes may be assessed by dragging a smooth object over the affected and unaffected limb, with the wetter limb allowing a smoother drag than the drier limb. Common diagnostic tools used for diagnosis, characterizing, and monitoring of CRPS include quantitative sensory testing, tests of autonomic function, and imaging for trophic changes.

Quantitative Sensory Testing (QST)

QST is a noninvasive means to evaluate sensory and pain perception to classify pain but cannot be used as the sole method to diagnose a particular pain pathology. There is variability in the ability to reproduce results, and as such, the precision and accuracy of this modality are still up for debate. Such testing includes the use of standardized psychophysical tests of the sensory and motor systems, thermal sensation, thermal pain, and vibratory thresholds to assess the function of myelinated small fiber and unmyelinated small fiber afferents. Patients with CRPS may have impaired paradoxical heat sensations, mechanical detection thresholds, mechanical pain thresholds to pinprick stimuli and blunt pressure, allodynia, and pain summation with the use of continuous pinprick stimuli. There is currently no definitive diagnostic sensory pattern in patients with CRPS, but this test can aid in distinguishing other neuropathies from CRPS. ^,

Tests of Autonomic Function

Thermoregulation and sudomotor regulation are the main systems tested in patients with CRPS for disorders in autonomic function. Thermoregulation is tested by using the thermoregulatory sweat test (TST) and infrared thermography or thermometry. The TST assesses calorimetric precipitation from a specific region of the body by adding a solution that changes color when enough heat is generated to produce sweat. Infrared thermography is direct visualization of the change in temperature of the affected site, and in infrared thermometry, a device is used to measure temperature through the detection of infrared energy. Changes in temperature in patients with CRPS versus those with other types of pain had a sensitivity of 76% and a specificity of 94%. Sudomotor regulation is tested by using the quantitative sudomotor axon reflex test (QSART), which measures sweat output from various regions of the skin. However, a recent retrospective review of patients who underwent QSART was found to have a sensitivity of 67.6% and specificity of 40.6%, with a not statistically significant odds ratio of 1.43.

Trophic Changes

Three-phase bone scintigraphy (TPBS) is a very valuable test for the detection of CRPS. Although joint and bone alterations are not part of the IASP inclusion criteria, they are very important in the outcome of the syndrome. TPBS detects alterations in periarticular bone metabolism, particularly increased bone metabolism, by detecting increase uptake of a periarticular tracer, which occurs predominantly within the first year. TPBS is low in sensitivity but high in specificity. Furthermore, TPBS may have a role in monitoring treatment effectiveness for CRPS as well, possibly predicting disease response to ketamine treatment. ^, Magnetic resonance imaging of the affected limb has also been used for detection of CRPS but has high sensitivity (97%) and low specificity (17%).

Treatment

Management of CRPS has been complicated by scant knowledge of the cause of the disease, which has resulted in few targeted therapies. Most of the medications initiated as first line therapy have been investigated for other non-CRPS neuropathic pain conditions and then applied to the treatment of CRPS, with mixed success. The historical approach to therapy for CRPS remains a multimodal, multi-disciplinary methodology. The predominant therapeutic modalities for the care of CRPS patients include physical therapy, pharmacologic agents, and interventional procedures.

Physical and Occupational Therapy

Physical and occupational therapy for restoration of function and improvement of limbs affected by CRPS has been studied widely. Physical exercises such as isometric strengthening, active range of motion, myofascial release, and stress loading are all tools that aid in restoring the functional capacity of the affected limb. A 2019 multi-disciplinary study utilizing physical therapy modalities (graded motor imagery and physiotherapy exercises) along with psychological treatment, memantine, and morphine treatment was successful in reducing some of the CRPS symptoms.

Other methods of therapy are currently under study. In a large controlled study in which tactile acuity and pain on the application of a tactile stimulus were measured in patients with CRPS, and mirror images were used to show the reflection of the unaffected limb during the stimulus, a decreased two-point discrimination threshold and decreased pain acuity were observed. This suggests that therapies that improve functional restoration of the affected limb (including mirror therapy) may improve the outcome of CRPS. However, evidence for other forms of physiotherapy for the management of CRPS I and II is unclear. Despite ongoing studies and modeling, an optimal clinical physiotherapy algorithm to treat this condition has yet to be validated.

Pharmacologic Therapy

Membrane Stabilizers

Medications such as gabapentin and pregabalin have been shown to be effective in relieving neuropathic pain. ^, CRPS is considered neuropathic pain, and gabapentin is presumed to be effective in treating it, yet there are very limited studies showing its specific efficacy for CRPS. In a randomized, double blind, placebo controlled crossover study in which patients were treated for two three week periods with two weeks in between, gabapentin had minimal effect on pain, but it significantly reduced patients’ sensory deficits. In a case report of a 15-year-old female with left arm CRPS one, pregabalin was successful in the management of her pain after she failed treatment with gabapentin, selective serotonin anti-depressants, and stellate ganglion block. Although there is no clear evidence of efficacy for gabapentin, these neuroleptic medications are the first line therapy for neuropathic pain and are thus considered first line therapy for CRPS.

Corticosteroids

A large part of the pathophysiology in CRPS is the acute inflammatory process that occurs after an inciting event (see “Pathophysiology”). Because of this inflammatory course, corticosteroids have been used for treatment. In a 2006 randomized controlled trial comparing prednisolone with piroxicam, patients were given either medication for one month, and their shoulder-hand syndrome scores (measuring pain, distal edema, passive humeral abduction, and external rotation) were determined. In the prednisolone group, 83.3% showed improvement, and in the piroxicam group, only 16.7% improved. The shoulder-hand syndrome score in the steroid group was significantly lower than that in the piroxicam group. Other studies have shown that continuation of prednisolone treatment (two months) after an initial one month high-dose (40 mg) taper was successful in reducing post stroke CRPS one patients. Short term steroid use was further found to normalize microcirculation in response to remote ischemic conditioning (RIC, a non-damaging method to induce ischemia to an extremity) in CRPS patients (typically RIC causes an increased O ₂ extraction and decreased blood flow) implicating the anti-inflammatory role of steroids in CRPS.

Anti-depressants

These drugs have not been studied for use specifically with CRPS, but they have been widely studied for the control of neuropathic pain, and because CRPS is considered neuropathic pain, they are used in pain management. Anti-depressants such as tricyclic antidepressants (TCAs) and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) have been used to control neuropathic pain effectively. In a recent Cochrane review, TCAs were found to be effective in treating neuropathy, with a number needed to treat (NNT) of 3.6 and a relative risk (RR) of 2.1. Venlafaxine, an SSNRI, was also found to be effective, with an NNT of 3.1 and RR of 2.2. Further studies to investigate the drugs’ ability to specifically target CRPS are warranted. A recent study showed that the combination of gabapentin and nortriptyline was a more effective therapy than either medication alone for neuropathic pain (including CRPS). In children with CRPS, a randomized controlled trial comparing amitriptyline to gabapentin revealed no statistical difference between the efficacy of both medications in successfully decreasing pain intensity scores.

Opioids

Studies on the effects of opioids directly on CRPS are lacking, although some have shown opioids to improve neuropathic pain when used in high doses. However, a double blind, placebo controlled trial studying the efficacy of sustained-release morphine in CRPS patients for a total treatment of eight days showed that it was ineffective in decreasing pain, but the study had many limitations. In 2016, a Cochrane review evaluating fentanyl use for the treatment of neuropathic pain including CRPS and PHN showed that there was insufficient evidence to support or refute the use of the medication in those conditions. Substantial challenges to using opioid therapy for nonmalignant pain include nausea, constipation, cognitive impairment, tolerance, and hyperalgesia. ^, Therefore it should be used only until other therapies can be initiated. Studies of these medications in the CRPS population are lacking, and more is needed to demonstrate the efficacy of opioids.

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