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Complex regional pain syndrome (CRPS) is any of several painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. Usually starting in a limb, it manifests as extreme
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
, swelling, limited range of motion, and changes to the skin and bones. It may initially affect one limb and then spread throughout the body; 35% of affected people report symptoms throughout their whole bodies. Two types exist: reflex sympathetic dystrophy (RSD) and causalgia. Having both types is possible.


Classification

The classification system in use by the
International Association for the Study of Pain The International Association for the Study of Pain (IASP) is an international learned society promoting research, education, and policies for the understanding, prevention, and treatment of pain. IASP was founded in 1973 under the leadership of ...
(IASP) divides CRPS into two types. It is recognised that people may exhibit both types of CRPS.


Signs and symptoms

Clinical features of CRPS have been found to be inflammation resulting from the release of certain proinflammatory chemical signals from the nerves, sensitized nerve receptors that send pain signals to the brain, dysfunction of the local blood vessels' ability to constrict and dilate appropriately, and maladaptive neuroplasticity. The signs and symptoms of CRPS usually manifest near the injury site. The most common symptoms are extreme pain, including burning, stabbing, grinding, and throbbing. The pain is out of proportion to the severity of the initial injury. Moving or touching the limb is often intolerable. With diagnosis of either CRPS types I or II, patients may develop burning pain and
allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
. Both
syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paired ...
s are also characterized by autonomic dysfunction, which presents with temperature changes (usually localized, but can be global), cyanosis, and/or edema. The patient may also experience localized swelling; extreme sensitivity to nonpainful stimuli such as wind, water, noise, and vibrations; extreme sensitivity to touch (by themselves, other people, and even light clothing or bedding/blankets); abnormally increased sweating (or absent sweating); changes in skin temperature (alternating between overly warm and cold); changes in skin colouring (from white and mottled to bright red or reddish-violet); changes in skin texture (waxy, shiny, thin, tight skin); softening and thinning of bones; joint tenderness or stiffness; changes in nails and hair (delayed or increased growth, brittle nails/hair that easily break); muscle spasms; muscle loss (atrophy); tremors; dystonia; allodynia; hyperalgesia; and decreased/restricted ability and painful movement of affected body part. Drop attacks (falls), almost fainting, and fainting spells are infrequently reported, as are visual problems. The symptoms of CRPS vary in severity and duration. Since CRPS is a systemic problem, potentially any organ can be affected. Symptoms may change over time, and they can vary from person to person. The more dynamic symptoms, especially vascular aspects (edema, temperature) and location of pain, can change numerous times a day. Previously, CRPS was considered to have three stages however more recent studies suggest people affected by CRPS do not progress through sequential stages and the staging system is no longer in wide use. Growing evidence instead points towards distinct sub-types of CRPS.


Cause

Complex regional pain syndrome is uncommon, and its cause is not clearly understood. CRPS typically develops after an injury, surgery, heart attack, or stroke. Investigators estimate that 2–5% of those with peripheral nerve injury, and 13-70% of those with
hemiplegia Hemiparesis, or unilateral paresis, is weakness of one entire side of the body ('' hemi-'' means "half"). Hemiplegia is, in its most severe form, complete paralysis of half of the body. Hemiparesis and hemiplegia can be caused by different medic ...
(paralysis of one side of the body) will develop CRPS. In addition, some studies have indicated that
cigarette smoking Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is believ ...
was strikingly present in patients and is statistically linked to RSD. This may be involved in its pathology by enhancing sympathetic activity, vasoconstriction, or by some other unknown neurotransmitter-related mechanism. This hypothesis was based on a retrospective analysis of 53 patients with RSD, which showed that 68% of patients and only 37% of controls were smokers. The results are preliminary and are limited by their retrospective nature. 7% of people who have CRPS in one limb later develop it in another limb.


Pathophysiology

Inflammation and alteration of pain perception in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all pa ...
are proposed to play important roles. The persistent pain and the perception of nonpainful stimuli as painful are thought to be caused by inflammatory molecules (IL-1, IL2, TNF-alpha) and neuropeptides (substance P) released from peripheral nerves. This release may be caused by inappropriate cross-talk between sensory and motor fibers at the affected site. CRPS is not a psychological illness, yet pain can cause psychological problems, such as anxiety and depression. Often, impaired social and occupational function occur. Complex regional pain syndrome is a multifactorial disorder with clinical features of
neurogenic inflammation Neurogenic inflammation is inflammation arising from the local release by afferent neurons of inflammatory mediators such as Substance P, Calcitonin Gene-Related Peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3). In such neurons, relea ...
(swelling in the central nervous system), nociceptive sensitisation (which causes extreme sensitivity or
allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
),
vasomotor Vasomotor refers to actions upon a blood vessel which alter its diameter. More specifically, it can refer to vasodilator action and vasoconstrictor action. Control Sympathetic innervation Sympathetic nerve fibers travel around the tunica media of ...
dysfunction (blood flow problems which cause swelling and discolouration) and maladaptive
neuroplasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it ...
(where the brain changes and adapts with constant pain signals); CRPS is the result of an "aberrant nappropriateresponse to tissue injury". The "underlying neuronal matrix" of CRPS is seen to involve cognitive and motor as well as nociceptive processing; pinprick stimulation of a CRPS affected limb was painful (mechanical hyperalgesia) and showed a "significantly increased activation" of not just the S1 cortex (contralateral), S2 (bilateral) areas, and insula (bilateral) but also the associative-somatosensory cortices (contralateral), frontal cortices, and parts of the anterior cingulate cortex. In contrast to previous thoughts reflected in the name RSD, it appears that there is reduced sympathetic nervous system outflow, at least in the affected region (although there may be sympatho-afferent coupling).DR WILL HOWARD FFPMANZCA, FFANZCA, DIP MED (PAIN MANAGEMENT) http://www.qld.anzca.edu.au/anzca/resources/college-publications/pdfs/ANZCA%20Blue%20Book%202011%20P9.pdf#page=10 Wind-up (the increased sensation of pain with time) and
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all pa ...
(CNS) sensitization are key neurologic processes that appear to be involved in the induction and maintenance of CRPS. Compelling evidence shows that the N-methyl-D-aspartate ( NMDA) receptor has significant involvement in the CNS sensitization process. It is also hypothesized that elevated CNS glutamate levels promote wind-up and CNS sensitization. In addition, there exists experimental evidence demonstrating the presence of NMDA receptors in peripheral nerves. Because immunological functions can modulate CNS physiology, a variety of immune processes have also been hypothesized to contribute to the initial development and maintenance of peripheral and central sensitization. Furthermore, trauma-related cytokine release, exaggerated neurogenic inflammation, sympathetic afferent coupling, adrenoreceptor pathology, glial cell activation, cortical reorganisation, and
oxidative Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
damage (e.g., by
free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spo ...
) are all factors which have been implicated in the pathophysiology of CRPS. In addition, autoantibodies are present in a wide number of CRPS patients and IgG has been recognized as one of the causes of hypersensitivity that stimulates A and C nociceptors, attributing to the inflammation. The mechanisms leading to reduced
bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optic ...
(up to overt
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone am ...
) are still unknown. Potential explanations include a dysbalance of the activities of sympathetic and
parasympathetic The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
autonomic nervous system The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies internal organs, smooth muscle and glands. The autonomic nervous system is a control system t ...
and mild
secondary hyperparathyroidism Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels), with resultant hyperplasia of these glands. This disorde ...
. However, the trigger of secondary hyperparathyroidism has not yet been identified. In summary, the
pathophysiology Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...
of complex regional pain syndrome has not yet been defined; CRPS, with its variable manifestations, could be the result of multiple pathophysiological processes.


Diagnosis

Diagnosis is primarily based on clinical findings. The original diagnostic criteria for CRPS adopted by the International Association for the Study of Pain (IASP) in 1994 have now been superseded in both clinical practice and research by the "Budapest Criteria" which were created in 2003 and have been found to be more sensitive and specific. They have since been adopted by the IASP. The criteria require there to be pain as well as a history and clinical evidence of Sensory,
Vasomotor Vasomotor refers to actions upon a blood vessel which alter its diameter. More specifically, it can refer to vasodilator action and vasoconstrictor action. Control Sympathetic innervation Sympathetic nerve fibers travel around the tunica media of ...
,
Sudomotor Sudomotor function refers to the autonomic nervous system control of sweat gland activity in response to various environmental and individual factors. Sweat production is a vital thermoregulatory mechanism used by the body to prevent heat-related ...
and Motor or Trophic changes. It is also stated that it is a
diagnosis of exclusion A diagnosis of exclusion or by exclusion (''per exclusionem'') is a diagnosis of a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from history, examination ...
. To make a clinical diagnosis all four of the following criteria must be met: # Continuing pain, which is disproportionate to any inciting event # Must report at least one symptom in ''three of the four'' following categories.. #* Sensory: Reports of
hyperesthesia Hyperesthesia is a condition that involves an abnormal increase in sensitivity to stimuli of the sense. Stimuli of the senses can include sound that one hears, foods that one tastes, textures that one feels, and so forth. Increased touch sensitiv ...
#* Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry #* Sudomotor/Edema: Reports of
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
and/or sweating changes and/or sweating asymmetry #* Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness,
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...
,
dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often int ...
) and/or trophic changes (hair, nail, skin) # Must display at least one sign at time of evaluation in two or more of the following categories #* Sensory: Evidence of
hyperalgesia Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...
(to pinprick) and/or
allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
(to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement) #* Vasomotor: Evidence of temperature asymmetry (>1 °C) and/or skin color changes and/or asymmetry #* Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry #* Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin) # There is no other diagnosis that better explains the signs and symptoms


Diagnostic adjuncts

No specific test is available for CRPS, which is diagnosed primarily through observation of the symptoms. However, thermography, sweat testing, X-rays, electrodiagnostics, and sympathetic blocks can be used to build up a picture of the disorder. Diagnosis is complicated by the fact that some patients improve without treatment. A delay in diagnosis and/or treatment for this syndrome can result in severe physical and psychological problems. Early recognition and prompt treatment provide the greatest opportunity for recovery.


Thermography

Presently, established empirical evidence suggests against
thermography Infrared thermography (IRT), thermal video and/or thermal imaging, is a process where a thermal camera captures and creates an image of an object by using infrared radiation emitted from the object in a process, which are examples of infrared ...
's efficacy as a reliable tool for diagnosing CRPS. Although CRPS may, in some cases, lead to measurably altered blood flow throughout an affected region, many other factors can also contribute to an altered thermographic reading, including the patient's smoking habits, use of certain skin lotions, recent physical activity, and prior history of trauma to the region. Also, not all patients diagnosed with CRPS demonstrate such "vasomotor instability" — particularly those in the later stages of the disease. Thus, thermography alone cannot be used as conclusive evidence for—or against—a diagnosis of CRPS and must be interpreted in light of the patient's larger medical history and prior diagnostic studies. In order to minimise the confounding influence of external factors, patients undergoing infrared thermographic testing must conform to special restrictions regarding the use of certain
vasoconstrictors Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...
(namely,
nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
and
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
), skin lotions, physical therapy, and other diagnostic procedures in the days prior to testing. Patients may also be required to discontinue certain pain medications and sympathetic blockers. After a patient arrives at a thermographic laboratory, he or she is allowed to reach thermal equilibrium in a 16–20 °C, draft-free, steady-state room wearing a loose fitting cotton hospital gown for approximately twenty minutes. A technician then takes infrared images of both the patient's affected and unaffected limbs, as well as reference images of other parts of the patient's body, including his or her face, upper back, and lower back. After capturing a set of baseline images, some labs further require the patient to undergo cold-water autonomic-functional-stress-testing to evaluate the function of their
autonomic nervous system The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies internal organs, smooth muscle and glands. The autonomic nervous system is a control system t ...
's peripheral vasoconstrictor reflex. This is performed by placing a patient's unaffected limb in a cold water bath (approximately 20 °C) for five minutes while collecting images. In a normal, intact, functioning autonomic nervous system, a patient's affected extremity will become colder. Conversely, warming of an affected extremity may indicate a disruption of the body's normal thermoregulatory vasoconstrictor function, which may sometimes indicate underlying CRPS.


Radiography

Scintigraphy, plain radiographs, and magnetic resonance imaging may all be useful diagnostically. Patchy osteoporosis ( post-traumatic osteoporosis), which may be due to disuse of the affected extremity, can be detected through X-ray imagery as early as two weeks after the onset of CRPS. A
bone scan A bone scan or bone scintigraphy is a nuclear medicine imaging technique of the bone. It can help diagnose a number of bone conditions, including cancer of the bone or metastasis, location of bone inflammation and fractures (that may not be vis ...
of the affected limb may detect these changes even sooner and can almost confirm the disease.
Bone densitometry Dual-energy X-ray absorptiometry (DXA, or DEXA) is a means of measuring bone mineral density (BMD) using spectral imaging. Two X-ray beams, with different energy levels, are aimed at the patient's bones. When soft tissue absorption is subtracted ...
can also be used to detect changes in bone mineral density. It can also be used to monitor the results of treatment since bone densitometry parameters improve with treatment.


Ultrasound

Ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...
-based osteodensitometry (ultrasonometry) may be potential future radiation-free technique to identify reduced
bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optic ...
in CRPS. Additionally, this method promises to quantify the bone architecture in the periphery of affected limbs. This method is still under experimental development.


Electrodiagnostic testing

Electromyography Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyo ...
(EMG) and nerve conduction studies (NCS) are important ancillary tests in CRPS because they are among the most reliable methods of detecting nerve injury. They can be used as one of the primary methods to distinguish between CRPS types I and II, which differ based on evidence of actual nerve damage. EMG and NCS are also among the best tests for ruling in or out alternative diagnoses. CRPS is a "diagnosis of exclusion", which requires that no other diagnosis can explain the patient's symptoms. This is very important to emphasise because patients otherwise can be given a wrong diagnosis of CRPS when they actually have a treatable condition that better accounts for their symptoms. An example is severe carpal tunnel syndrome (CTS), which can often present in a very similar way to CRPS. Unlike CRPS, CTS can often be corrected with surgery to alleviate the pain and avoid permanent nerve damage and malformation. Both EMG and NCS involve some measure of discomfort. EMG involves the use of a tiny needle inserted into specific muscles to test the associated muscle and nerve function. Both EMG and NCS involve very mild shocks that in normal patients are comparable to a rubber band snapping on the skin. Although these tests can be very useful in CRPS, thorough informed consent must be obtained prior to the procedure, particularly in patients experiencing severe allodynia. In spite of the utility of the test, these patients may wish to decline the procedure to avoid discomfort.


Classification

* Type I, formerly known as reflex sympathetic dystrophy (RSD), Sudeck's atrophy, or algoneurodystrophy, does not exhibit demonstrable nerve lesions. As the vast majority of patients diagnosed with CRPS have this type, it is most commonly referred to in medical literature as type I. * Type II, formerly known as causalgia, has evidence of obvious nerve damage. Despite evidence of nerve injury, the cause or the mechanisms of CRPS type II are as unknown, as the mechanisms of type I. Patients are frequently classified into two groups based upon temperature: "warm" or "hot" CRPS in one group and "cold" CRPS in the other group. The majority of patients (about 70%) have the "hot" type, which is said to be an acute form of CRPS. Cold CRPS is said to be indicative of a more chronic CRPS and is associated with poorer McGill Pain Questionnaire scores, increased central nervous system involvement, and a higher prevalence of
dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often int ...
. Prognosis is not favourable for cold CRPS patients; longitudinal studies suggest these patients have "poorer clinical pain outcomes and show persistent signs of central sensitisation correlating with disease progression".


Prevention

Vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...
may be useful in prevention of the syndrome following
fracture Fracture is the separation of an object or material into two or more pieces under the action of stress. The fracture of a solid usually occurs due to the development of certain displacement discontinuity surfaces within the solid. If a displ ...
of the forearm or foot and ankle.


Treatment

Treatment of CRPS often involves a number of modalities.


Therapy

Physical and occupational therapy have low-quality evidence to support their use. Physical therapy interventions may include
transcutaneous electrical nerve stimulation Transcutaneous electrical nerve stimulation (TENS or TNS) is the use of electric current produced by a device to stimulate the nerves for therapeutic purposes. TENS, by definition, covers the complete range of transcutaneously applied currents ...
, progressive weight bearing, graded tactile desensitization,
massage Massage is the manipulation of the body's soft tissues. Massage techniques are commonly applied with hands, fingers, elbows, knees, forearms, feet or a device. The purpose of massage is generally for the treatment of body stress or pain. In Eu ...
, and
contrast bath therapy Contrast bath therapy, is a form of treatment where a limb or the entire body is immersed in hot (but not boiling) water followed by the immediate immersion of the limb or body in cold ice water. This procedure is repeated several times, alternatin ...
. In a retrospective cohort (unblinded, non-randomised and with intention-to-treat) of fifty patients diagnosed with CRPS, the subjective pain and body perception scores of patients decreased after engagement with a two-week multidisciplinary rehabilitation programme. The authors call for randomised controlled trials to probe the true value of multidisciplinary programs for CRPS patients.


Mirror box therapy

Mirror box Mirror therapy (MT) or mirror visual feedback (MVF) is a therapy for pain or disability that affects one side of the patient more than the other side. It was invented by Vilayanur S. Ramachandran to treat post-amputation patients who had phantom ...
therapy uses a mirror box, or a stand-alone mirror, to create a reflection of the normal limb such that the patient thinks they are looking at the affected limb. Movement of this reflected normal limb is then performed so that it looks to the patient as though they are performing movement with the affected limb. Mirror box therapy appears to be beneficial at least in early CRPS. However, beneficial effects of mirror therapy in the long term is still unproven.


Graded motor imagery

Graded motor imagery appears to be useful for people with CRPS-1. Graded motor imagery is a sequential process that consists of (a)
laterality The term laterality refers to the preference most humans show for one side of their body over the other. Examples include left-handedness/right-handedness and left/right- footedness; it may also refer to the primary use of the left or right he ...
reconstruction, (b)
motor imagery Motor imagery is a mental process by which an individual rehearses or simulates a given action. It is widely used in sport training as mental practice of action, neurological rehabilitation, and has also been employed as a research paradigm in cog ...
, and (c)
mirror therapy Mirror therapy (MT) or mirror visual feedback (MVF) is a therapy for pain or disability that affects one side of the patient more than the other side. It was invented by Vilayanur S. Ramachandran to treat post-amputation patients who had phantom ...
. Transcutaneous Electrical Nerve Stimulation (TENS) Transcutaneous Electrical Nerve Stimulation (TENS) is a therapy that uses low voltage electrical signals to provide pain relief through electrodes that are placed on the surface of the skin. Evidence supports its use in treating pain and edema associated with CRPS although it does not seem to increase functional ability in CRPS patients.


Medications

Tentative evidence supports the use of
bisphosphonates Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they h ...
,
calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates. in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing th ...
, and
ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...
. Nerve blocks with guanethidine appear to be harmful. Evidence for sympathetic nerve blocks generally is insufficient to support their use. Intramuscular
botulinum Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium '' Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromu ...
injections may benefit people with symptoms localized to one extremity.


Ketamine

Ketamine, a dissociative anesthetic, appears promising as a treatment for CRPS. It may be used in low doses if other treatments have not worked. No benefit on either function or depression, however, has been seen.


Bisphosphonate treatment

As of 2013, high-quality evidence supports the use of
bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
s (either orally or via IV infusion) in the treatment of CRPS. Bisphosphonates inhibit
osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
which are cells involved in the resorption of bone. Bone remodeling, via osteoclast activity in resorption of bone, is thought to sometimes be hyperactive in CRPS. It is hypothesized that bone resorption causes acidification of the intercellular milieu and this activates nerves involved in
nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, ...
that densely innervate bone causing pain; therefore inhibiting bone resorption and remodeling is thought to help with regards to pain in CRPS. CRPS involving high levels of bone resorption, as seen on
bone scan A bone scan or bone scintigraphy is a nuclear medicine imaging technique of the bone. It can help diagnose a number of bone conditions, including cancer of the bone or metastasis, location of bone inflammation and fractures (that may not be vis ...
, is more likely to respond to bisphosphonate therapy.


Opioids

Opioids such as
oxycodone Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonl ...
,
morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. The ...
,
hydrocodone Hydrocodone, also known as dihydrocodeinone, is an opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe eno ...
, and
fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine, ...
have a controversial place in treatment of CRPS. These drugs must be prescribed and monitored under close supervision of a physician, as these drugs will lead to physical dependence and can lead to addiction. Thus far, no long-term studies of oral opioid use in treating neuropathic pain, including CRPS, have been performed. The consensus among experts is that opioids should not be a first line therapy and should only be considered after all other modalities (non-opioid medications, physical therapy, and procedures) have been trialed.


Surgery


Spinal cord stimulators

Spinal cord stimulator appears to be an effective therapy in the management of patients with CRPS type I (level A evidence) and type II (level D evidence). While they improve pain and quality of life, evidence is unclear regarding effects on mental health and general functioning. Dorsal root ganglion stimulation is type of neurostimulation that is effective in the management of focal neuropathic pain. The
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
approved its use in February 2016. The ACCURATE Study demonstrated superiority of dorsal root ganglion stimulation over spinal (dorsal column) stimulation in the management of CRPS and causalgia.


Sympathectomy

Surgical, chemical, or radiofrequency sympathectomy — interruption of the affected portion of the sympathetic nervous system — can be used as a last resort in patients with impending tissue loss, edema, recurrent infection, or ischemic necrosis. However, little evidence supports these permanent interventions to alter the pain symptoms of the affected patients, and in addition to the normal risks of surgery, such as bleeding and infection, sympathectomy has several specific risks, such as adverse changes in how nerves function.


Amputation

No randomized study in medical literature has studied the response with amputation of patients who have failed the above-mentioned therapies and who continue to be miserable. Nonetheless, on average, about half of the patients will have resolution of their pain, while half will develop phantom limb pain and/or pain at the amputation site. As in any other chronic pain syndrome, the brain likely becomes chronically stimulated with pain, and late amputation may not work as well as it might be expected. In a survey of 15 patients with CRPS type 1, 11 responded that their lives were better after amputation. Since this is the ultimate treatment of a painful extremity, it should be left as a last resort.


Prognosis

The prognosis in CRPS is improved with early and aggressive treatment; with the risk of chronic, debilitating pain being reduced with the early treatment. If treatment is delayed, however, the disorder can quickly spread to the entire limb, and changes in bone, nerve, and muscle may become irreversible. The prognosis is worse with the chronic "cold" form of CRPS and with CRPS affecting the upper extremities. Disuse of the limb after an injury or psychological distress related to an injury are also associated with a poorer prognosis in CRPS. Some cases of CRPS may resolve spontaneously (with 74% of patients undergoing complete resolution of symptoms (often spontaneously) in a population based study in Minnesota), but others may develop chronic pain for many years. Once one is diagnosed with CRPS, should it go into remission, the likelihood of it resurfacing after going into remission is significant. Taking precautions and seeking immediate treatment upon any injury is important.


Epidemiology

CRPS can occur at any age, with the average age at diagnosis being 42. It affects both men and women; however, CRPS is three times more frequent in females than males. CRPS affects both adults and children, and the number of reported CRPS cases among adolescents and young adults has been increasing, with a recent observational study finding an incidence of 1.16/100,000 among children in Scotland.


History

The condition currently known as CRPS was originally described during the
American Civil War The American Civil War (April 12, 1861 – May 26, 1865; also known by other names) was a civil war in the United States. It was fought between the Union ("the North") and the Confederacy ("the South"), the latter formed by states ...
by Silas Weir Mitchell, who is sometimes also credited with inventing the name "causalgia". However, this term was actually coined by Mitchell's friend
Robley Dunglison Robley Dunglison (4 January 1798 – 1 April 1869) was an English-American physician, medical educator and author who served as the first full-time professor of medicine in the United States at the newly founded University of Virginia from 1824 ...
from the Greek words for heat and for pain. Contrary to what is commonly accepted, it emerges that these causalgias were certainly major by the importance of the vasomotor and sudomotor symptoms but stemmed from minor neurological lesions. In the 1940s, the term reflex sympathetic dystrophy came into use to describe this condition, based on the theory that sympathetic hyperactivity was involved in the pathophysiology. In 1959, Noordenbos observed in causalgia patients that "the damage of the nerve is always partial." Misuse of the terms, as well as doubts about the underlying pathophysiology, led to calls for better nomenclature. In 1993, a special consensus workshop held in Orlando, Florida, provided the umbrella term "complex regional pain syndrome", with causalgia and RSD as subtypes.


Research

The
National Institute of Neurological Disorders and Stroke The National Institute of Neurological Disorders and Stroke (NINDS) is a part of the U.S. National Institutes of Health (NIH). It conducts and funds research on brain and nervous system disorders and has a budget of just over US$2.03 billion. Th ...
(NINDS), a part of the National Institutes of Health, supports and conducts research on the brain and central nervous system, including research relevant to RSDS, through grants to major medical institutions across the country. NINDS-supported scientists are working to develop effective treatments for neurological conditions and ultimately, to find ways of preventing them. Investigators are studying new approaches to treat CRPS and intervene more aggressively after traumatic injury to lower the patient's chances of developing the disorder. In addition, NINDS-supported scientists are studying how signals of the sympathetic nervous system cause pain in CRPS patients. Using a technique called
microneurography Microneurography is a neurophysiological method employed to visualize and record the traffic of nerve impulses that are conducted in peripheral nerves of waking human subjects. It can also be used in animal recordings. The method has been succes ...
, these investigators are able to record and measure neural activity in single
nerve fiber An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
s of affected patients. By testing various hypotheses, these researchers hope to discover the unique mechanism that causes the spontaneous pain of CRPS, and that discovery may lead to new ways of blocking pain. Other studies to overcome chronic pain syndromes are discussed in the pamphlet "Chronic Pain: Hope Through Research", published by the NINDS. Research into treating the condition with mirror visual feedback is being undertaken at the Royal National Hospital for Rheumatic Disease in Bath. Patients are taught how to desensitize in the most effective way, then progress to using mirrors to rewrite the faulty signals in the brain that appear responsible for this condition. However, while CRPS can go into remission, the chance of it reoccurring is significant. The Netherlands has the most comprehensive program of research into CRPS, as part of a multimillion-Euro initiative called TREND. German and Australian research teams are also pursuing better understanding and treatments for CRPS.


In other animal species

CRPS has also been described in animals, such as cattle.


Notable cases

* Nia Frazier, ''Dance Moms'' star *
Paula Abdul Paula Julie Abdul (born June 19, 1962) is an American singer, dancer, choreographer, actress, and television personality. She began her career as a cheerleader for the Los Angeles Lakers at the age of 18 and later became the head choreographe ...
, singer, actor, TV personality * Jill Kinmont Boothe, US ski slalom champion * Gemma Collis-McCann, British paralympic fencer * Shin Dong-wook, South Korean actor and model *
Howard Hughes Howard Robard Hughes Jr. (December 24, 1905 – April 5, 1976) was an American business magnate, record-setting pilot, engineer, film producer, and philanthropist, known during his lifetime as one of the most influential and richest people in th ...
, American business tycoon, aviator, inventor, filmmaker, and philanthropist * Rachel Morris, British paralympic cyclist. * Cynthia Toussaint, author and media personality *
Danielle Brown Danielle Brown Order of the British Empire, MBE (born 10 April 1988) is a British Target archery, competitive archer and award winning children's author. She has competed in the Paralympic Games winning gold medals in Beijing and London and has ...
, British paralympic archer * Radene Marie Cook, former Los Angeles radio broadcaster, artist, and advocate * Marieke Vervoort, Belgian Paralympic athlete * Bruno Soriano, Spanish footballer


References


External links

* * {{DEFAULTSORT:Complex Regional Pain Syndrome Nerve, nerve root and plexus disorders Syndromes of unknown causes Chronic pain syndromes Neurocutaneous conditions Osteopathies Pain