Epidemology and Incidence of CRPS

Pain is the most important factor leading to disability. The reported incidence of CRPS type I is 1-2% after various fractures1-5% after peripheral nerve injury. The incidence of CRPS is 12% after a brain injury and 5% after a myocardial infarction. Females experience CRPS more commonly than males do by a ratio that varies from 2:1 to 4:1.CRPS is distributed across age groups, but reaches its peak incidence between 37 and 50 years. CRPS has an increased incidence in adolescents, compared with children, with females affected more frequently at a ratio of 4:1 and increased occurrence in the lower extremities rather than the upper by a ratio of 5.3:1.The highest incidence of the disease appears to be in adults aged 40-49 years. CRPS appears frequently in almost every age group except children. CRPS type I has been seen in children, but the incidence is much lower than in adults.

DIAGNOSIS

As per IASP diagnostic criteria CRPS is characterized by:

Severe, chronic pain often described as stinging or burning, Sensory abnormalities such as allodynia (pain due to a stimulus which does not normally provoke pain) or hyperesthesia (increased sensitivity to stimuli) ,motor impairment such as weakness, tremor, stiffness, or decreased range of motion, edema (tissue swelling) and hyperhydrosis (excessive sweating),progressive trophic changes to skin, hair, nails, muscle, and bone (such as thinning of bones or changes in how hair and nails grow) and, increasing dysfunction of the affected limb ¹.CRPS causes great suffering and distress in most patients. In addition to severe pain, which in some people remains chronic and unremitting, patients may also experience serious physical disabilities and reduction in their quality of life leading to depression, fear, anxiety CRPS diagnosis is based upon clinical criteria and that there is so far no gold standard or any objective diagnostic tool. At least 1 sign is to be observed at the time of evaluation in at least 2 of the following categories:

a.) Sensory: Evidence of hyperalgesia (to pinprick), allodynia (to light touch, temperature sensation, deep somatic pressure, or joint movement)

(b.)Vasomotor: Evidence of temperature asymmetry (>1°C), skin color changes or asymmetry

(c.) Sudomotor/edema: Evidence of edema, sweating changes, or sweating asymmetry Evidence of decreased range of motion, motor dysfunction (eg, weakness, tremor, dystonia), or trophic changes (eg, hair, nail, skin) ².The categories of clinical signs and symptoms that are important for diagnosis, know the interpretation of these diagnostic criteria for clinical use and the sensitivity and specificity (sensitivity 0.85, specificity 0.60).The diagnostic tests which may aid the diagnosis of CRPS are X-ray, three-phase bone scan, quantitative sensory testing (QST),autonomic testing, and thermography which is a test to show temperature changes and lack of blood supply ³in the affected limb ^4,5.Revised diagnostic criteria of CRPS ^:Diagnosis is based on the whole clinical picture. A number of investigations can be used to aid diagnosis by demonstrating altered blood flow or changes in sweating or bone mineralization. These include X-ray, MRI, radionuclide bone studies, vascular studies, and electro-diagnostic techniques. Research tools include micro-neurography, quantitive pseudomotor axon reflex testing, and the resting sweat output.⁶.Some patients typically presents with a triad of clinical findings: sensory abnormalities, perfusion abnormalities and alterations in motor function. Since some of these findings are seen in the other disease states, the diagnosis is often not clear, some findings show analysis of clinical samples to identify protein or patterns of protein changes associated with a disease state, blood samples were collected for protein and gene expression (RNA) analysis⁷ which indicates the presence of disease, this is under clinical phase validating the diagnostic accuracy of this method.

PATHOPHYSIOLOGY OF CRPS

The reason why only some patients develop CRPS is still unclear, there is also no comprehensive theory that can explain the diversity and heterogeneity of the symptoms (edema, central nervous symptoms, joint involvement etc.).Current attempts only explain theory behind single symptom but not the overall picture. An essential hypothesis about the main patho mechanism for developing CRPS includes inflammatory process. A recent finding showed that the fundamental cause of the abnormal pain sensations is ischemia and inflammation due to micro vascular pathology in deep tissues, leading to a combination of inflammatory and neuropathic pain processes.⁸

Aberrant healing and exaggerated inflammation

Classic inflammation is marked by typical immune cells such as lymphocytes, phagocytes, and mast cells, which excrete classic pro-inflammatory cytokines. In fluid derived from artificially produced blisters on CRPS affected extremities, compared to unaffected sides, levels of interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and tryptase were increased. Analysis of blister fluid with a multiplex array, testing for 25 different cytokines, revealed an even stronger pro-inflammatory expression profile, with increased markers for activated monocytes and macrophages.A pro-inflammatory cytokine expression profile was also demonstrated in liquor (IL-1β and TNFα increased) and occasionally in venous blood messenger ribonucleic acid [mRNA] levels of TNFα and IL-2 increased; levels of soluble TNFα receptor increased; of inflammation that are usually applied in clinical settings, including white blood cell count and C-reactive protein, are normal in CRPS patients⁹

Neurogenic inflammation is mediated by neuropeptides, which are excreted by nociceptive C-fibers in response to various triggers and which possess vasoactive and immunologic properties. The secretory nerve endings of these nociceptives are mainly located in the distal parts of extremities, the typical location for CRPS.However, primary afferent depolarization can also induce neuropeptide release within the dorsal horn, where they can mediate central sensitization. Cardinal mediators in neurogenic inflammation are substance P (SP) and calcitonin gene-related protein (CGRP).In rats, SP application induced or increased CRPS-like symptoms, while in humans, CRPS patients’ intradermal SP administration provoked abnormal plasma extravasation.Both SP and CGRP have been measured systemically elevated in CRPS patients. Bradykinin, another peptide involved in inflammation and peripheral nociceptor sensitization, was four times higher in venous blood of CRPS patients compared with controls. Neuropeptide Y and perhaps angiotensin converting enzyme (ACE) have been suggested as potential modulators of the neuroinflammatory responses. The involvement of vasoactive intestinal protein has also been suggested but could not be demonstrated. Compared with controls, CRPS patients displayed a facilitated neuro inflammatory response upon electrical C-fiber stimulation, even in the unaffected extremity, as measured by plasma protein extravasation and axon-reflex vasodilation. Increased systemic CGRP levels in patients with acute CRPS suggest neurogenic inflammation as a pathophysiologic mechanism contributing to vasodilation, edema, and increased sweating. However, pain and hyperalgesia, in particular in chronic stages, were independent of increased neuropeptide concentration ^10.Neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and nerve growth factor (NGF) might be involved in the pathophysiology of neuropathic pain.¹¹.Recent findings show that neuroplastic changes in the brain also are responsible for this disease.

A hypothesis for the cause of complex regional pain syndrome-: pain due to deep-tissue microvascular pathology.

Recent findings have developed an animal model (chronic post-ischemia pain) that creates CRPS-I-like symptomatology. The model is produced by occluding the blood flow to one hind paw for 3 hours under general anesthesia. Following reperfusion, the treated hind paw exhibits an initial phase of hyperemia and edema. This is followed by mechano-hyperalgesia, mechano-allodynia, and cold-allodynia that lasted for at least 1 month. Light microscopic analyses and electron microscopic analyses of the nerves at the site of the tourniquet show that the majority of these animals have no sign of injury to myelinated or unmyelinated axons. However, electron microscopy shows that the ischemia-reperfusion injury produces a microvascular injury, slow-flow/no-reflow, in the capillaries of the hind paw muscle and digital nerves. The slow-flow/no-reflow phenomenon initiates and maintains deep-tissue ischemia and inflammation, leading to the activation of muscle nociceptors, and the ectopic activation of sensory afferent axons due to endoneurial ischemia and inflammation,the fundamental cause of the abnormal pain sensations is ischemia and inflammation due to microvascular pathology in deep tissues, leading to a combination of inflammatory and neuropathic pain processes. ⁸

The Role of Genomic Oxidative-Reductive Balance as Predictor of Complex Regional Pain Syndrome Development: A Novel Theory

Nuclearfactor2 Single Nucleotide Polymorphisms (SNP’s) may occur in a subpopulation of patients with CRPS and that the occurrences of these SNPs may contribute to factors that may make these patients more susceptible to develop CRPS than the generalpopulation. CRPS is a complex disorder and thus, a SNP association could be due to the effects of other polymorphisms, both within Nrf2 and at nearby loci. Marzec et al ¹² identified functional polymorphisms in the promoter of Nrf2 that are found in relatively high frequency among multiple ethnic populations. In a nested case-control study, patients with the –617 A SNP had a significantly higher risk for developing ALI after major trauma relative to patients with the wild type (–617 CC).The author proposed that the -617 variant and/or other functional polymorphisms may be instrumental in contributing to suboptimal Nrf2 activity and thus to patients that may represent humans who are at risk or susceptible to develop complex regional pain syndrome. If confirmed, this information could be clinically important, as it could enable patients and health care providers to help make more informed clinical decisions affecting lifestyle and potential therapeutic strategies. Additionally, clinicians may decide to aggressively treat these patients extremely early — at the first sign of any symptoms/trauma. Also, clinicians may decide to perform a “prophylactic”/pre-emptive preoperative sympathetic block for such a patient undergoing surgery on an extremity (although the article which showed this technique to be potentially beneficial in patients undergoingsurgery with a history of CRPS may have had falsified data .Contrariwise, subjects who possess the AC genotype at position -1221 in the NQO1 gene with decreased transcription of NQO1 may potentially be less susceptible to the development of CRPS and perhaps could be observed by clinicians or treated by future translational investigations into the role of -617 variant and various other functional polymorphisms contributing to suboptimal Nrf2 activity and increasing susceptibility for developing CRPS as well as roles in other oxidant related conditions or disease processes. These investigations could conceivably lead to the development of novel prevention or intervention strategies for CRPS ¹³

Hypoxia

The presence of hypoxia in CRPS is endorsed by several observations. In skin, employing micro-light guidespectrophotometer has revealed decreased capillary oxygenation ¹⁴, and dermal microdialysis has demonstrated increased lactate levels¹⁵. In muscle, nuclear magnetic resonance spectroscopy revealed signs of acidosis and impaired high-energy phosphate metabolism¹⁶.CRPS affected limbs display histopathological characteristics consistent with oxidative stress¹⁷. Hypoxia leads to acidosis and free radical formation, which are well-known triggers for primary afferents to cause severe painful sensations. In CRPS patients, experimentally induced tissue acidosis increased pain¹⁸. However, blood oxygen was not deprived as was demonstrated with capillary blood gas analysis.¹⁹

Hypoxia in CRPS has been proposed to be caused by extreme vasoconstriction, either sympathetically thriven or resulting from a local dysbalance between endothelial factors.In the latter case, nitric oxide (NO) and endothelin (ET-1) are opposite mediators, whereas NO induces vasorelaxation and ET-1 induces vasoconstriction. In CRPS patients, venous ET-1 levels were found equal between the affected and unaffected sides, but in blister fluid, ET-1 levels were increased at the affected side, while NO levels were decreased. As these were findings in chronic CRPS patients, they suggest a role of hypoxia induced by endothelial dysfunction in ongoing CRPS. Consequently, NO donors have been proposed as therapeutic agents ^20,21, the involvement of free radicals is likely in view of the positive outcomes of randomized clinical trials in human CRPS wherein scavengers, such as dimethylsufoxide, N-acetylcysteine ²², and vitamin C, were effective in the early treatment.

Genetics

The risk of CRPS may depend on susceptibility for exaggeration of the underlying disease mechanisms, such as inflammation and sensitization. This idea is supported by the observation of abnormal neuro inflammatory responses to triggers in the unaffected limbs of CRPS patients, such as an increased NO release from peripheral monocytes upon stimulation with cytokines and an enhanced axon-reflex vasodilation upon electrical C-fiber stimulation . As these were findings in the unaffected limbs, they suggest that the abnormal responses are innate and do not evolve from the CRPS itself. Hypothesizing that CRPS patients might share a pro-inflammatory genetic profile, polymorphisms have been studied of genes that code for potential mediators of inflammation in CRPS, including TNFα (increased in blisters from CRPS patients)and Angiotensin converting enzyme which is a modulator of Substance P and bradykinin .Primarily warm CRPS was associated with a polymorphism in one of the TNFα promoter genes. Polymorphisms in the human leukocyte antigen (HLA) system have also been studied, and loci from all three HLA classes have been reportedly associated with CRPS onset treatment resistance, or related dystonia.The associations with the HLA-DR and HLA-DQ polymorphisms were particularly remarkable in view of the similar findings in patients with multiple sclerosis and narcolepsy.^23,24

TREATMENT FOR CRPS

An emergency physician's primary role with patients who have complex regional pain syndrome (CPRS)/reflex sympathetic dystrophy syndrome (RSDS) is to recognize the possibility of the diagnosis and refer such patients to colleagues who are capable of using available therapies. Breaking through the pain cycle early increases the likelihood of a better outcome. The 3 basic modes of therapy include pain management, rehabilitation including physical therapy, and psychological therapy. Once the diagnosis is established, a number of treatment modalities that have been proven helpful are available. CRPS experts and researchers have looked at many treatment possibilities.

· The treatment of chronic CRPS includes tricyclic antidepressants, anticonvulsants, topical lidoderm, mexiletine, NMDA-receptor blockers, and capsaicin cream. Opioids can also be used in refractory cases.^25,26

· Intravenous infusion of iloprost a prostacyclin analogue²⁷ and immunoglobulin.²⁸

· Safety and efficacy analyses indicated that lacosamide 400 mg/d provided an optimal balance between efficacy and side effects in patients with painful diabetic neuropathy.²⁹

· Administration of an oxygen radical scavenger decreases this inflammatory reaction. Efficacy of intravenous mannitol used a hydroxyl radical scavenger to influence the symptoms of CRPS is negligible. Although, an improvement in the oedema of the affected limb was observed.³⁰

Medication Summary

Specialists in pain management usually an anesthesiologist or physiatrist commonly perform neural blockade. Use of pain modifying agents, such as cyclic antidepressants and gabapentin, usually is left to the primary care physician or pain management team. However, these patients experience severe pain and should be given sufficient analgesia to provide relief. Narcotics usually are required , meperidine provides some euphoria and also has an active metabolite that may accumulate. Agents with a short duration of action (e.g., fentanyl) are not usually appropriate.Some pain specialists prefer methadone for its long duration of action and mechanism of action benefit. This agent is an NMDA antagonist and may therefore be more effective in neuropathic pain syndromes. Other long-acting agents include sustained-release forms of oxycodone and morphine. Corticosteroids may be helpful in reducing pain and inflammation. They may be given as a short-term treatment in the early stages of CRPS.

Biphosphonates and calcitonin: People with CRPS commonly have bone loss in their CRPS-involved limb. Bone loss causes the bones to become soft, brittle and easier to break. Causes of bone loss may include not moving your limb enough and decreased blood flow to the CRPS-involved area. Biphosphonates and calcitonin help to decrease bone loss and control calcium levels in your blood. A number of research studies have been done to test biphosphonates as a treatment for CRPS. biphosphonates can greatly decrease pain in some People with CRPS, while calcitonin may offer mild pain relief.. The antinociceptive effect of bisphosphonates is primarily due to their capacity to inactivate osteoclasts and antagonize osteoclastogenesis may be simplistic. They inhibit prostaglandin E2, proteolytic enzymes, and lactic acid but not proinflammatory cytokines.Clodronate, pamidronate, and alendronate have specifically been used to treat CRPS, residronate and ibandronate can also be administered orally.^31,32

Dimethyl Sulfoxide (DMSO) and N-acetylcysteine (NAC): Free radicals are unstable oxygen atoms that form when they lose an electron. Electrons like to be in pairs. The loss of one electron literally puts the atom into orbit. It becomes a scavenger looking for another oxygen atom so that it can rob or steal the necessary electron. The result is a cascade of damage to the cells as new radicals are formed in order to salvage the damaged oxygen atoms. Compounds like DMSO, vitamin C, and Mannitol work by getting rid of free radicals. Inflammatory reactions are reduced by eliminating free radicals. The end-result is to limit the amount of tissue damage that occurs from inflammation. In some studies, corticosteroids and free radical scavengers were used together.³³

Antihypertensive Medication:

Antihypertensive medications, including calcium channel blockers and ACE inhibitors, that could increase the risk of developing CRPS. ACE inhibition blocks the degradation of substance P and bradykinin; thus its loss could lead to an accumulation of substance P and bradykinin that could result in an up regulation of the bradykinin receptors. ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin .The researchers were able to show that being on an ACE inhibitor could be a predictor of developing CRPS. They may also help to decrease pain by exerting some chemical effect on nerve cells in the spinal cord and brain. ^{34, 35}

Schwartzman ketamine therapy:

There is recent interest in the use of “ketamine coma” to treat CRPS. This is a dangerous procedure that has been used mostly in Europe and is not approved in the U.S. by the FDA. We are awaiting further outcome studies. Schwartzmann investigated bilateral cingulumotomy, thalidomide, and ketamine as possible new treatments for severe and refractory CRPS patients. Today, his research favors the drug ketamine, long used to treat chronic pain, as the answer to combat pain in his CRPS patients. The ketamine dosage included levels of 250-300 ug/dl for at least 4.5 days where “This level of treatment results in a medically induced coma.” The patients received a neurophysiological evaluation before their treatment and again six weeks after their treatment to assess “intellectual and academic abilities, executive functioning/processing speed, attention, learning and memory, and motor functioning. Mood/affect and personality were also evaluated.” The encouraging results of the experiment show that by the six week marker of deep ketamine therapy, patients had effective relief of pain “and there were no adverse cognitive effects to extended treatment with deep ketamine infusion.” .³⁶

Effect of Botulinum toxin :

The frequently excruciating pain is difficult to treat, and the natural history of CRPS is marked by unremitting worsening of the pain .The most widely known action of botulinum toxin A (BtxA) is its relaxing effect on skeletal muscles. BtxA is therefore widely used for the symptomatic relief of spasticity, dystonias, and other movement disorders. Recently there has been great interest in the use of BtxA for chronic pain. This interest stems from the fact that BtxA seems to have an early anti-nociceptive action that is independent of its muscle relaxing action and may be due to inhibition of central and peripheral sensitization. It has been previously hypothesized that the anti-nociceptive action of BtxA may be beneficial in CRPS. Botulinum toxin type A (BTA) prevents release of acetylcholine from cholinergic nerve terminals. This inhibition is long lasting but not permanent, and it does not result in cytotoxicity or neural loss. Preganglionic sympathetic nerves are cholinergic, and animal data indicate that BTA can induce prolonged sympathetic block when placed on surgically exposed sympathetic ganglia.^{37, 38}

Intravenous immunoglobulin’s:

Low-dose intravenous immunoglobulin (IVIG) reduces pain and improves autonomic limb symptoms in patients with long-standing, refractory complex regional pain syndrome (CRPS), a small but randomized study of long-standing, refractory CRPS patients shows. An average decrease of 1.55 units in pain scores vs saline after IVIG infusion during the subsequent 14 days, with no serious adverse effects were observed .³⁹ IVIG may "emerge as an effective and safe novel clinical treatment option for otherwise refractory disease, [although] confirmatory trials are required." Intravenous immunoglobulin Intravenous immune globulin (Human) (IGIV) (CarimuneNF, Flebogamma, Gammagard Gammar P .I.V., Gamunex, IveegamEN, Octagam, PanglobulinNF, PolygamS/D, Privigen) has been proposed as treatment for CRPS. It is theorized that modulating the immune system may alleviate CRPS. ⁴⁰

Intrathecal Drug Delivery:

Intrathecal drug delivery with a subcutaneous pump is a treatment that is considered when conservative measures have been tried, failed or there is a contraindication. The purpose of this route of drug delivery is to improve the therapeutic ratio of these medications by administering a higher concentration of medication near the spinal cord and less in the brain and periphery. The two most common medications that are used are morphine and baclofen⁴¹ . Intrathecal administration with subcutaneous pump is a treatment that should be considered when pain associated with CRPS is intractable and other conservative measures have been attempted and have failed, or when there is a contraindication.

Baclofen (Lioresal) has been proposed when CRPS is associated with the presence of severe dystonia, which is a rare development in CRPS has been considered an effective treatment for patients with spasticity. Some patients received a subcutaneous pump for continuous intrathecal administration of baclofenresulted in complete or partial resolution of focal dystonia of the hands but little improvement in the legs, dystonia associated with CRPS responds markedly to intrathecal Baclofen ⁴²

Ziconotide (Prialt) is in a class of non-opioid analgesics known as N-type calcium channel blockers. It is the synthetic equivalent of a naturally occurring cono peptide found in a marine snail known as Conus magus. It is administered intrathecally through appropriate programmable micro-infusion pumps that can be implanted or external, and which release the drug into the fluid surrounding the spinal cord. Ziconotide has a novel mechanism of action, and it offers a unique analgesic therapy for patients with severe intractable pain. However, its use should be limited to only those patients not responding to other therapies because it has the potential to produce serious neurologic and psychiatric side effects.^43,
44

Vitamin C: Vitamin C has been shown to reduce the prevalence of complex regional pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is recommended. The public health cost impact of complex regional pain syndrome type I (CRPS I) is considerable in both emergency and scheduled orthopaedic surgery. ⁴⁵

Complementary techniques- Treatment advances

Complementary medicine refers to medical care that may be used in addition to the more traditional forms of treatment. Complementary approaches include,

Acupuncture. Acupuncturists believe that a healthy body contains channels through which energy flows. When these channels are blocked, energy cannot flow and bad health can occur. Needles are inserted into the blocked areas to correct imbalances and open up the energy channels again.

Hypnosis Using hypnosis to treat pain may help to alter your physical sensations. Self-hypnosis involves inducing an altered state of consciousness – and thus controlling pain sensation by self.

Manipulation–Manipulation involves the movement of tissue by the laying on of hands. When done gently, it may be referred to as "mobilization." Doctors of Chiropractic and Osteopathy often do manipulations that are called "adjustments." People may feel short-term pain relief from this therapy. Many prefer these interventions because they avoid the possible side effects of medicines or problems related to surgery. Long-term and on-going dependence on these therapies for pain relief is discouraged.

Visual imagery – This technique is the practice of using your imagination to create mental pictures that may help reduce stress and relieve your pain. Typically, this involves closing your eyes and picturing something in your mind. For example, you may picture a healing energy washing over your body, or the “wires” to the pain being cut.⁴⁶

Regional anaesthetic techniques: Regional anesthetic, also known as nerve blocks, involves the injection of local anesthetic alone or in combination with steroids into a peripheral nerve or sympathetic ganglion. The site of the injection is determined by the location of the pain. It is noted that there is scant evidence regarding the proper timing, number, necessity or appropriateness of nerve blocks for diagnosis or treatment of CRPS. Techniques for regional nerve blocks include: selective sympathetic ganglion blockade, stellate ganglion block for the upper extremity and lumbar sympathetic block for the lower extremity, intravenous regional guanethidine/bretylium block, and intravenous phentolamine infusion. Blocks may be used primarily to provide a pain-free period so that patients may progress in the functional restoration portion of treatment, lumbar sympathetic blocks or stellate ganglion blocks may be used as components of the multimodal treatment of CRPS if used in the presence of consistent improvement and increasing duration of pain relief. A review was performed regarding the use of regional anesthetic for CRPS with three objectives: to determine the likelihood of pain alleviation after sympathetic blockade with local anesthetics in the patient with CRPS; to assess how long any benefit persists; and to evaluate the incidence of adverse effects of the procedure. sympathetic blockade is considered the gold standard for treatment of CRPS, but the efficacy is unknown.⁴⁶

Sympathetic nerve blockade:

Sympathetic blocks are particularly useful in the early stages of CRPS.. Local anaesthetic blockade is carried out at the sympathetic paravertebral ganglion, which innervates the site of the CRPS, for example the stellate ganglion or lumbar sympathetic chain for upper and lower limbs, respectively. Pain relief from these blocks generally lasts longer than the duration of action of the local anaesthetic. Intravenous regional analgesia (IVRA) using agents such as lidocaine, clonidine, guanethidine, reserpine, and bretylium have all been described. Randomized controlled trials have shown that IVRA is no better than placebo; however, despite this, they continue to be commonly used. SMP can be treated using surgical sympathectomy; radiofrequency techniques have also been described recently. An important problem with permanent sympathectomy techniques is the recurrence of symptoms and neuralgia 6 months to 2 years following the procedure. The techniques work better if performed within 12 months of the original injury. ⁴⁷

Transcutaneous electrical nerve stimulation: Different studies show varying success rates for the use of transcutaneous electrical nerve stimulation (TENS). This is a non-invasive, simple, and safe technique; therefore, it is always worth considering as an adjunct. ⁴⁷

Neuromodulation (Spinal Cord Stimulation (SCS) and Peripheral Nerve Stimulation (PNS) :

Neuromodulation can involve spinal cord or peripheral nerve stimulation. Spinal cord stimulation affects sensory dorsal nerve roots as well as the descending inhibitory pain pathways within the spinal cord. It may also induce the endogenous release of opioids. A clinical trial showed that it has a modest effect on pain at 6 months when combined with physical therapy but did not affect quality of life or function. However, it may be of use in carefully selected patients and the technique is employed in several centres. SCS and PNS have been used in the treatment of CRPS. These modalities are recommended for patients who have tried and failed, who have been judged to be unsuitable, or when there is a contraindication for conservative treatment modalities. SCS, also known as dorsal column stimulation, involves surgical implantation of electrodes in the epidural space on the dorsal aspect of the spinal cord; electrical current from the electrode induces paresthesias, a sensation that suppresses the pain.^{48, 49}

Motor Cortex and Deep brain stimulation:

Motor cortex and deep brain stimulation have been proposed as a treatment for intractable neuropathic pain. A review of the literature indicates that there is lack of clinical trials that evaluate this treatment. The guidelines have shown that the results are equivocal and require further competitive trials .Patients with CRPS treated with medical treatment (analgesics, adjuvants etc)plus repetitive transcranial magnetic stimulation (RtMS) to the motor cortex .Assessment was performed by Visual Analogical Scale (VAS) there was a significant reduction in the VAS scores favoring the r-rTMS group.^50,51

Radiofrequency Ablation:

Radiofrequency ablation (RFA) has been proposed as a treatment for CRPS. RFA is a procedure in which nerves are destroyed with the use of heat generated by an electric current. A review indicates that an RF-SG block is most likely to be of benefit for patients suffering from CRPS type II, ischemic pain, cervico-brachialgia, or post-thoracotomy pain; however clinical efficacy remains to be proven in a randomized controlled trial. “The radiofrequency ablative techniques are much more controllable than neurolytic solution injections, and less invasive than surgical ablation.⁵²

Photon Therapy: The photonic stimulator used in photon therapy or photodynamic therapy is a hand held device which emits infrared light and is held over specific points located on the body. The infrared light penetrates the skin to help increase blood flow and circulation. It is a non-invasive, safe, painless beam of light which activates or produces particular physiological results based on applied neuropsychological principles. For those with RSD/CRPS, the sympathetic nervous system is dysfunctional in that it does not properly control the cutaneous blood flow to the areas of the skin. These altered blood flow patterns look like hyperthermia (increased heat) or hypothermia (decreased blood flow). There is a temperature asymmetry in the body. The photonic stimulator can regulate blood flow and normalize temperature patterns. Photon therapy has been used to treat many conditions, injuries from sports, auto accidents work injuries, or painful diseases e.g. back/neck/hip/knee and CRPS (complex regional pain syndrome).The thermal imaging processor is a digital infrared imaging system that measures heat emanating from the body and is used to measure progress before and after treatment is completed, offering a unique form of visual feedback. Photon therapy works in four general ways: a) localized muscles relaxers, b) localized anti-inflammatory, c) localized pain reliever and d) to help injured nerves heal. Because there are no drugs used and it targets specific areas that are to be treated and there are no "all over the body" side effects and the patient feels relaxed. This is related to the restoration of the parasympathetic nervous system. Photon breaks the painful inflammatory cycle by dilating small blood and lymphatic vessels. This increase in circulation removes the irritating inflammatory products and results in accelerated healing and pain relief. the fibroblasts. immune system and nervous system are also stimulated by photon to increase activity--thereby repairing damaged tissues sooner.⁵³

Shockwave therapy: SW treatment has been shown to promote neo-angiogenesis, to have anti-inflammatory and anti-edemagenic properties, to have a collagen synthesis action, to induce an osteogenetic stimulus and to recruit stem cells by chemotaxis to differentiate along specific lines. Therefore, the application of a second course of SW could not only provide a cumulative effect on nerve fibers, with a longer-lasting anti-nociceptive effect , but could also act on the remaining alterations of ischemia and osteopenia in the damaged tissues, breaking the vicious circle of pain-ischemia-osteopenia of CRPS. Further studies should investigate their efficacy in the treatment of CRPS type I, in consideration of the deeper tissues being treated. The results of this study suggest that extracorporeal SW treatment is effective in treating CRPS type I, mainly through the modulation of pain.⁵⁴

Hyperbaric oxygen therapy (HBO) Therapy: In CRPS, hypoxia and acidosis reduced the pain threshold and tolerance. During HBO treatment hyperoxia causes vasoconstriction, decreases oedema, and increases the partial pressure of oxygen in the tissues. In addition, it stimulates the activity of depressed osteoblasts and decreases the formation of fibrosis tissue. Thus it breaks up the physiopathological mechanism that is the basis of CRPS. These features of HBO therapy led us to evaluate its efficacy for treating CRPS. A significant decrease in the severity of pain was detected in the patients receiving HBO treatment. Moreover, allodynia and edema decreased, the ROM of extremities affected by CRPS increased and skin colour returned to normal.⁵⁵

Physical methods

People with CRPS often avoid using their CRPS-involved limb because it hurts. If you do not use and move your CRPS-involved limb, it will become stiffer, and eventually, more disabled and more painful. Moving your limb and retraining it to do the things it normally does is key to getting better. Physical therapy (PT) is the most important part of CRPS treatment at almost any stage. You may begin therapy by having PT and occupational therapy (OT) that helps decrease pain, swelling, and sensitivity and increase movement. As you get better, physical therapists will help you increase movement, strength and flexibility in your limb. For example, the therapist working with a golfer may help him or her find clubs with a thicker grip or adjust his or her swing. Vocational and occupational therapists can help you get ready to return to work. They are trained to adapt work stations and equipment to help. Remember that PT and other therapies are often only a part of your CRPS treatment. You may need PT, medicines and other treatments for very long periods of time. CRPS treatment is most useful when the pain medicine physician is giving the right pain-relieving drugs or nerve blocks; the psychologist is helping with pain-related depression or anxiety and so on.

The Feldenkrais Method: The Feldenkrais method is a type of bodywork that uses gentle movements to promote personal awareness of the body, increase flexibility and improve coordination. One of the key philosophies of the Feldenkrais method is that there is no separation between the mind and body and that, as the body strengthens and gains new forms of movement, the mind will also strengthen and improve. Unlike manipulative physical therapies such as massage or Rolfing, Feldenkrais practitioners generally view the work as a way to expand one’s knowledge of self and promote the connection between the mind and the body. Classes – called “Awareness through Movement” – focus on teaching small, precise movements that can be beneficial to people of all fitness levels and abilities. One-on-one Feldenkrais is called “Functional Integration.” Many people find the experience relaxing and helpful.⁵⁶

ELUSIVE AND EMERGING THERAPIES

Improvement has been reported with dimethyl sulfoxide, steroids, epidural clonidine, intrathecal baclofen, spinal cord stimulation, and motor imagery programs⁵⁷. Immunomodulation remains elusive. The acute administration of high dose corticosteroids continues to be theoretically desirable since emerging mechanisms of the disease appear to include immune mediated pathways. But corticosteroids are ineffective for the middle and late stages of the condition and their use requires acute phase diagnosis and administration. There is good reason to think that a close relative of reincarnated thalidomide would be helpful against CRPS, but, as of this writing, the search for an immune modulator that is effective in treating CRPS continues. Recent reports that reveal a relationship between the activation of spinal cord glia and the enhanced transmission and experience of neuropathic pain foretell of possible future treatments.^{58, 59} Immune mediated mechanisms will one day be a target of CRPS therapy⁶⁰. The science is incomplete and there is no practical application of this work presently. There is a special irony in the observation that a potent antagonist to glial activation is a medication whose patent protection has long ago expired. There can be no commercial incentive for a pharmaceutical manufacturer to sponsor complex and expensive clinical trial of the modulation. The direct current signal changes of photoplethysmography between both feet during one side lumbar sympathetic block were studied. The hypothesis is that signal changes occur earlier than other indices to decide whether it is successful following lumbar sympathetic block on only one-side, this study is still in clinical phase and results are being analyzed.⁶¹

Researchers working on mice have found an enzyme in the brain that appears to make pain last after nerve injury and they hope to use it as a new target to treat chronic pain in people. In a paper published in Science magazine Friday, the scientists in Canada and South Korea said they managed to alleviate pain after blocking the enzyme. “It provides us with basic understanding of the brain mechanism for chronic pain,” lead author Min Zhuo, a physiology professor at the University of Toronto, wrote in an email.“It not only provides a new possibility to design new pain medicine, but it also helps us to understand why many drugs fail to control chronic pain.”Although painkillers have existed for long periods of time, management of chronic pain in hospitals, and for conditions like cancer and end-of-life palliative care, is far from adequate in many places.Zhuo and colleagues found raised levels of the enzyme “protein kinase M zeta” in a region of the brain called the anterior cingulate cortex of the injured mice. To confirm the enzyme’s function, they knocked out a gene in another group of mice which they believed was responsible for triggering the production of the enzyme. They subsequently found that those mice experienced less or no chronic pain at all after nerve injury.“The knockout mice without this enzyme may experience less or no chronic pain”. Zhuo and his team hope their work will help in the design of a new class of drugs that blocks this enzyme. ⁶²“Many painkillers do not work for chronic pain, especially neuropathic pain. There is great need for new drugs that can effectively control chronic pain.

CONCLUSION:

The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health (NIH), supports and conducts research on the brain and central nervous system, including research relevant to CRPS, 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 RSDS patients. Using a technique called micro-neurography; these investigators are able to record and measure neural activity in single nerve fibers 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.Hopefully, recent research findings will inspire pain researchers and clinicians to consider endothelial cells and the microvasculature as important potential generators of the noxious inputs critical for CRPS, and put to rest not only the name, reflex sympathetic dystrophy, but the misguided theories, research, and limited treatment it spawned. Research into treating the condition with Mirror Visual Feedback is being undertaken at the Royal National Hospital for Rheumatic Disease. Patients are taught how to desensitize in the most effective way then progress on to using mirrors to rewrite the faulty signals in the brain that appear responsible for this condition. New non pharmacologic treatments include graded motor imagery, mirror virtual feedback exercises, and de-sensitization ,all focused on restoring normal nervous system function, assessing both peripheral and central sensitization. At present diverse recommendations exist as the ‘treatment of choice’ in a given stage of the disease. Although the dream of conquering this perplexing disease is still farfetched, the future certainly looks bright.

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Received on 16.03.2012

Modified on 29.03.2012

Accepted on 05.04.2012

Research J. Pharmacology and Pharmacodynamics. 4(3): May-June, 2012, 133-143