Complex Regional Pain Syndrome

Part
01
of two
Part
01

Complex Regional Pain Syndrome - Part One

The most common cause of complex regional pain syndrome is as a result of an abnormal response to an injury caused by bone fractures, sprains and strains, burns, and cuts. Overall CRPS incidence rate is 26.2 patients per 100,000 person-years.

RESEARCH STRATEGY

Initially, we started looking for information on epidemiology, demographic statistics, and disease history of Complex Regional Pain Syndrome (CRPS) in various credible sources of Complex Regional Pain Syndrome organizations, and reputable healthcare publications. We could locate information on epidemiology, demographic statistics, and disease history of complex regional pain syndrome (CRPS) pre-compiled.
With respect to incidence and the prevalence rate the articles published in 2017-2019, the study data they carried was from 2003. We exhaustively searched the latest information but all the latest sources such as National Institute of Neurological Disorders and Stroke, Medscape (eMedicine), and RSD Foundation quote the same information on the incidence and the prevalence rate. We, therefore, added three latest credible sources, which quote the same information on the incidence and the prevalence rate and state that there is no recent survey conducted, for due diligence.

EPIDEMIOLOGY

INCIDENCE:
  • Overall CRPS incidence rate: 26.2 patients per 100,000 person-years.
The combined incidence rate for both CRPS types I and II is four times greater at 26.2 instead of 6.28 per 100,000 person-years. This result has been brought about by the differences in socioeconomic and ethnic background of the cohort and diagnostic criteria application.

PREVALENCE:
  • CRPS type I: The prevalence rate recorded was 21 per 100,000 person-years.
  • CRPS type II: The prevalence rate recorded was 4 per 100,000 person-years.
From this data, it's clear that the incidence of CRPS type II is lower than that of CRPS type I.

DEMOGRAPHIC STATISTICS

There is no difference in prevalence or incidence that has been recorded regarding the effect of CRPS on different races. However, CRPS is more common in females than males by a varying ration of 2:1 to 4:1. There is a notable CRPS experience in various age groups, although it’s distributed across age groups. CRPS has a higher incidence in adolescents as compared to children and at the age of between 37 and 50 years, it reaches its peak incidence. Adults at the age of between 40 to 49years have portrayed the highest CRPS incidence. In pediatrics, CRPS is more common in girls of white ethnicity who are around puberty.

DISEASE HISTORY/CAUSALITY

DISEASE HISTORY
Complex regional pain syndrome roots its history from back in 1864 when Silas Weir Mitchell first reported CRPS, which corresponds to the current SRPS type II (Causalgia). Paul Sudeck from Hamburg Germany, in 1901, stated that CRPS is the “acute reflex bone atrophy that occurs after an injury and inflammation of the extremities and their clinical appearances.” This definition by Sudeck corresponds to what is now referred to as “CRPS type I without nerve lesion.” In 1936, James A. Evans coined “reflex sympathetic dystrophy” to refer to CRPS. However, in 1995, at a conference in Orlando, to avoid claims about pathophysiology, the descriptive phrase “Complex Regional Pain Syndrome” was agreed upon.

CAUSALITY
The most common cause of complex regional pain syndrome is as a result of an abnormal response to an injury caused by bone fractures, sprains and strains, burns, and cuts. CRPS may also occur when there is immobilization of limb (with plaster cast) after surgery. CRPS type I occur after an illness caused after limb nerve injury while CRPS type II occurs after distinct nerve injury.

Many cases of CRPS are as a result of a forceful trauma to a leg or an arm, which may include fracture, injury or amputation. Other minor and major traumas such as heart attacks, surgery, sprained ankles, and infections can also cause CRPS. However, not every person who experiences such traumas develops CRPS.
Part
02
of two
Part
02

Complex Regional Pain Syndrome - Part Two

There are two types of treatments for CRPS and they include medications and therapies. Medications are further classified as pain relievers, anti-depressants and anticonvulsants, corticosteroids, bone-loss medications, sympathetic nerve-blocking medication, and intravenous ketamine. Therapies are further classified as heat therapy, topical analgesics, physical therapy, mirror therapy, transcutaneous electrical nerve stimulation (TENS), biofeedback, spinal cord stimulation, and intrathecal drug pumps. Corticosteroids, calcium-regulating drugs, and opioids are some of the effective treatments for CRPS. Some of the unmet needs of CRPS patients include better diagnosis, treatment, and management.

After conducting an in-depth search, we have established that the information on the effectiveness of each of the treatments for CRPS and the names of any key opinion leaders that would see patients does not exist in the public domain. Below we have discussed our research methodology including how we searched and why some of the required information is not available publicly.

METHODOLOGY

We were able to find information regarding the currently available treatments for CRPS and the unmet needs of CRPS patients. For the effectiveness of the available treatments for CRPS, we were able to locate information on some of these treatments. However, there wasn't enough information in the public domain to see the effectiveness of each of the treatments for CRPS.

In order to identify the required information, we initially started by looking into reliable medical journals such as FreeMedicalJournals, The BMJ, NCBI, Clinical Science, Journal of Clinical Pathology, and others. These journals tend to publish the latest information and research studies on health conditions and diseases. Although these sources did not provide the desired information, we found significant information in NCBI on why the required information is not available in the public domain and a few treatments that work for CRPS.
Our next strategy involved looking into the medical meta-search engines, and media sources that commonly publishes medical news. These sources include CrossRef, RefSeek, MedicalNewsToday, ScienceDaily, WebMD, HealthLineNetworks, Ganfyd, MedScape, and others. Most of the information found was outdated and was related to the diagnosis, treatments, and causes of the disease and did not talk specifically about the effectiveness of the treatments of CRPS. However, an article from MedScape provided some light on why the requested information may not be available in the public domain and also provided a list of medications that are effective in the treatment of CRPS.
As our third strategy to find statistical data on treatments that are effective for CRPS, we looked into statistics portals and research analysis websites such as Statista, FutureMarketInsights, PRNewswire, Transparency Market Research, and other similar sites. All the sources that we found were paywalled. These sources also provided the list of KOLs that research institutions rely on during CRPS clinical trails. Based on information aforementioned, we have concluded that the effectiveness of treatments for CRPS is scarce in the public domain.
Following this, we moved on to find the information regarding the key opinion leaders that clinical research institutions rely on. Initially, we looked into clinical trials directories such as ClinicalTrialsGov, CenterWatch, NIH, and others to analyze each of the clinical trials pertaining to CRPS, hoping to find the names of the KOLs. But this did not reveal the names of KOLs. Also, only two of the clinical trials that we came across were from the year 2018 and the rest were from 2015, 2013, and older than that. So, we moved on to our next strategy.

Next, we looked into a market research analysis portal and found a detailed report covering all aspects of CRPS such as treatments, diagnosis, unmet needs of the patients, the KOLs and their views, etc. It is a paywalled report, but a sample can be requested after providing name, address, email ID, and other information. No information was available about the cots of the report.
Then, we decided to broaden the research criteria and looked for the opinion leaders that research institutions rely on during clinical trials pertaining to all the 'chronic pain' diseases such as Rheumatoid arthritis, osteoarthritis, fibromyalgia, and CRPS itself. We looked into reliable medical journals, media sources, and medical news websites such as Forbes, NINDS, FrontiersIn, UpToDate, MedicalNewsToday, ScienceToday, The BMJ, NCBI, etc. These sources also did not provide any information on who the KOLs that see the patients and research institutions that perform CRPS clinical trials.
After conducting in-depth research, it was clear that only a few clinical trials have been performed related to CRPS and this could be the possible reason that there is not much information available in the public domain about the KOLs and the effectiveness of each treatment that is currently available for CRPS.

Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is "a chronic (lasting greater than six months) pain condition that most often affects one limb (arm, leg, hand, or foot) usually after an injury." The main cause of CRPS is due to the "damage to, or malfunction of, the peripheral and central nervous systems. It is divided into two types CRPS-I and CRPS-II. This classification is based on the nerve injury involved in the condition. CRPS, where there is no confirmed nerve injury is known as CRPS-I which was previously known as "reflex sympathetic dystrophy syndrome" whereas, CRPS-II that was "previously known as causalgia" occurs when there is an association with nerve injury. Some research revealed nerve injury in CRPS-I as well. However, the treatment for both CRPS I & II is similar.

TREATMENTS

There is no cure for CRPS. The following treatments only help in relieving the pain:
MEDICATIONS
Pain relievers: Over-the-counter (OTC) pain relievers such as aspirin, ibuprofen (Advil, Motrin IB, others), and naproxen sodium (Aleve) can be used to ease mild pain and inflammation associated with CRPS. Doctors may prescribe stronger pain relievers if OTC drugs aren't helpful. Opioid medications might be an option.

Anti-depressants and anticonvulsants: Sometimes antidepressants, such as amitriptyline, and anticonvulsants, such as gabapentin (Neurontin), are used to treat pain that originates from a damaged nerve (neuropathic pain).
Corticosteroids: Prednisone and other steroid medications may help reduce "inflammation and improve mobility in the affected limb."
Bone-loss medications: These medications help prevent bone loss. Bone loss medications include alendronate (Fosamax) and calcitonin (Miacalcin).
Sympathetic nerve-blocking medication: An "anesthetic to block pain fibers" may be injected in the affected nerves to relieve pain.
Intravenous ketamine: Based on research studies "low doses of intravenous ketamine" which is a strong anesthetic can be given to substantially reduce pain.

Although these medications help in reducing pain, there is no improvement in limb function.
THERAPIES
Heat therapy: The application of heat might be helpful in relieving "swelling and discomfort on skin that feels cool."
Topical analgesics: A number of topical treatments are available to reduce hypersensitivity. These are available as over-the-counter ointments such as capsaicin cream, or lidocaine cream or patches (Lidoderm, LMX 4, LMX 5).
Physical therapy: Physical therapy i.e. "gentle, guided exercising of the affected limbs might help decrease pain and improve range of motion and strength." It is important to start exercising as early as possible for better relief.
Mirror therapy: A mirror is used to help "trick the brain." Mirror therapy can also be helpful to improve function and reduce pain n people with CRPS.
Transcutaneous electrical nerve stimulation (TENS): Chronic pain is sometimes eased by applying electrical impulses to nerve endings.
Biofeedback: In biofeedback, a patient learns to become more aware of the human body which can help relax the body and relieve pain.
Spinal cord stimulation: Doctor inserts tiny electrodes along the spinal cord which help reduce pain.
Intrathecal drug pumps: Intrathecal drug pump involves pumping medications into the spinal cord fluid of the patient relieving pain.
CRPS is also known to recur because of "exposure to cold or an intense emotional stressor." Recurrence may be treated with small doses of an antidepressant or other medication.

EFFECTIVENESS OF TREATMENT

According to MedScape which is one of the most reputed medical websites, "due to a lack of information on the pathophysiology of CRPS and the similar absence of consistent objective diagnostic criteria, clinical trials that demonstrate effective therapies are difficult to perform." Therefore, currently, only "a few evidence-based treatment regimens" are available. The report further added that only four literature reviews and outcome studies were found with "very little consistent information regarding the pharmacological agents and methods available for the treatment of CRPS". This explains that not many clinical trials have been performed to identify all the effective treatments for CRPS.
According to NCBI, Complex regional pain syndrome (CRPS) is "a descriptive term for a complex of symptoms and signs typically occurring following the trauma of the extremity." Typical symptoms of CRPS include "severe pain, swelling, vasomotor instability and functional impairment of the affected limb." Currently, there are no effective methods of treatment for this. Although "a large number of treatments have been investigated, major multicentre randomized controlled trials are lacking."
1. Corticosteroids: Pulsed doses of steroids (60-80 mg/d for 2 wk) have been reported as beneficial for CRPS in a small, uncontrolled case series. Two small, single blind trials of 10 and 17 patients with early-stage CRPS (within 2-3 months of injury) also reported clinical improvement after 4 or 12 weeks of oral corticosteroid therapy. These studies did not report long-term follow-up data in these cases.

Based on clinical trials, in those patients "who have had symptoms for more than 6 months with CRPS", the use of corticosteroids has little efficacy. Also, in many cases, the corticosteroid treatment was found to cause the return of pain and other symptoms in those patients. However, according to some experts, the use of corticosteroids might be effective in the early stages of CRPS.

2. Calcium-regulating drugs: Calcitonin administered intranasally tid has been demonstrated to significantly reduce pain in patients with CRPS.
3. Opioids: Opioids are effective for the treatment of postoperative inflammatory, cancer-related pain, and many other painful conditions. However, these drugs have not been studied for the treatment of CRPS.
4. Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs have not been investigated for the treatment of CRPS; however, mild-to-moderate pain would be a common sense indication.
5. Sodium channel blocking agents: An IV lidocaine infusion has been shown to be effective in uncontrolled trials for reducing spontaneous and evoked pain with both CRPS types I and II.
6. Gamma-aminobutyric acid (GABA) agonists: Intrathecally administered baclofen has been shown to be an effective treatment for dystonia and CRPS.
7. Gabapentin: Two studies supported the analgesic effect of gabapentin in patients with CRPS.
8. Calcium channel blockers: A small, uncontrolled case series showed improvement in patients with CRPS using the calcium channel blocker nifedipine.
9. Beta-blockers: Clinical experience is poor; however, benefit was demonstrated in some case reports.
10. Oral sympatholytic agents: Like sympathetic blocks, oral sympatholytic agents should, in theory, provide symptom and pain relief for patients with CRPS and other neuropathic SMP.
11. Clonidine: Based on a study on patients with CRPS with SMP reported decrease in "allodynia from transdermal clonidine, but only in the skin directly under the transdermal patch."

12. The review of randomized controlled trials showed that only bisphosphonates were found to give uniformly positive effects, statistically significantly better than placebo.
Studies reported improvement in CRPS with "topical dimethyl sulfoxide, systemic steroids, spinal cord stimulation and graded motor imagery/mirror therapy programmes." The available evidence does not support the use of other treatments in CRPS, however, they are frequently used in clinical practice.

UNMET NEEDS OF CRPS PATIENTS

A new guideline published by the Royal College of Physicians in partnership with 28 other organizations, including the British Psychological Society, says patients with complex regional pain syndrome (CRPS) "need better diagnosis, treatment, and management of their condition from a wide variety of healthcare professionals." Due to the reason, CRPS is a rare condition and "can be confused with other causes of pain", there are "delays in diagnosis and getting the right treatment early."
CRPS often begins after an injury to the limb, but the cause of the continuing pain and other symptoms is unknown. Treatments can address the symptoms and help patients manage the condition but not the underlying cause. Most patients will improve spontaneously within about a year, bur some can be left with unrelenting pain for many years. Also, our understanding of aberrant neural signal processing is mainly descriptive—it is not entirely evident how these neural transmissions might be modified to reduce pain and lower the pain threshold. There is an urgent "unmet need in medicine to better come to grips with neuropathic pain, its mechanisms, and treatment." With that, a clearer understanding of CRPS may emerge.
For instance, the role of the inciting injury in CRPS requires more investigation, in that a subset of patients develop CRPS with no such trauma or at least no recollection of it. "Trophic symptoms, including very pronounced symptoms, might hold a clue to deeper understanding of CRPS but only a subset of patients develops them." Apart from this, the change in skin temperature has also been experienced in some CRPS patients but this may also be seen in various other health conditions as well. Therefore, this may "owe to the inflammatory response rather than a specific aspect of CRPS."

Overall, "a better knowledge of CRPS, its etiology, and its mechanisms are urgently needed." As a diagnosis of exclusion in a field where many rare and complex conditions predominate, it is likely that many patients diagnosed with CRPS may have other conditions. Treatment of CRPS is challenging and often ineffective. A more thorough understanding of the neuropathy and its origin are urgently needed to better define it, diagnose it, and ultimately treat it effectively.

PAYWALLED SOURCE — KEY OPINION LEADERS

A paywalled report was found published on Influential Business Man, 2018, titled as "Complex Regional Pain Syndrome (CRPS) Market Insights, Epidemiology and Market Forecast-2028." There is no information mentioned about the cost of the report but, a sample can be requested.


Sources
Sources

From Part 01
Quotes
  • "The incidence rate of CRPS type I was 5.46 per 100000 person-years, and the incidence rate of CRPS type II was 0.82 per 100000 person-years, giving rise to a combined incidence rate for both CRPS types I and II of 6.28 per 100000 person-years. "
  • "However, a subsequent population-based study by de Mos et al. estimated the combined incidence rate of CRPS to be approximately four times greater at 26.2 per 100000 person-years "
Quotes
  • "Epidemiological data from 2 major studies show a CRPS incidence between 5.577 and 26.2 cases25 per 100,000 people per year."
Quotes
  • "an incidence of approximately 5.5 per 100,000 person-years at risk and a prevalence of about 21 per 100,000 for CRPS type I. [47] The same study showed an incidence of 0.8 per 100,000 and a prevalence of about 4 per 100,000 for CRPS type II. [47, 14] Therefore, the incidence of CRPS type I is higher than that of CRPS type II"
  • "The reported incidence of CRPS type I is 1-2% after various fractures [14] , while that of CRPS type II approximates 1-5% after peripheral nerve injury [14, 48] . The incidence of CRPS is 12% after a brain injury [49] and 5% after a myocardial infarction [50] ."
  • "CRPS affects all races; no differences in incidence or prevalence have been observed."
  • "CRPS is distributed across age groups, but reaches its peak incidence between 37 and 50 years."
  • "Females experience CRPS more commonly than males do by a ratio that varies from 2:1 to 4:1"
Quotes
  • "Type I typically arises from minor injury (sprain/fracture) • develops more commonly in girls of white ethnicity, with incidence rising around puberty"
  • "Type II indicates likelihood of specific nerve injury causing the symptoms • occurs in equal numbers in boys and girls "
Quotes
  • "It took approximately 100 years to form the acronym “CRPS.” In 1864, Silas Weir Mitchell reported on patients whose disease corresponds to what we now call complex regional pain syndrome (CRPS) type II (Causalgia).61 In 1901, Paul Sudeck from Hamburg, Germany, described the “acute reflex bone atrophy after inflammation and injuries of the extremities and their clinical appearances,” which corresponds to CRPS type I without nerve lesion"
  • "The next milestone in CRPS history was reached in 1936, when James A. Evans coined the phrase “reflex sympathetic dystrophy”, which has been used for decades.31 At a conference in Orlando, 1995, it was agreed to use the descriptive phrase “Complex Regional Pain Syndrome” to avoid claims about pathophysiology.86"
Quotes
  • "Type 1. Also known as reflex sympathetic dystrophy syndrome (RSD), this type occurs after an illness or injury that didn't directly damage the nerves in your affected limb. About 90 percent of people with complex regional pain syndrome have type 1."
  • "Type 2. Once referred to as causalgia, this type has similar symptoms to type 1. But type 2 complex regional pain syndrome follows a distinct nerve injury."
Quotes
  • "The condition usually seems to develop within a month of an injury, either minor or more serious. These can include: bone fractures sprains and strains burns cuts"
  • "One of the main theories suggests that CRPS is the result of a widespread abnormal response to an injury that causes several of the body's systems to malfunction"
  • "CRPS has also been known to occur after surgery to a limb or after part of a limb has been immobilised (for example, in a plaster cast)."
From Part 02
Quotes
  • "Sometimes antidepressants, such as amitriptyline, and anticonvulsants, such as gabapentin (Neurontin), are used to treat pain that originates from a damaged nerve (neuropathic pain)."
  • "Gentle, guided exercising of the affected limbs might help decrease pain and improve range of motion and strength. The earlier the disease is diagnosed, the more effective exercises might be."
  • "In some cases, learning biofeedback techniques may help. In biofeedback, you learn to become more aware of your body so that you can relax your body and relieve pain."
Quotes
  • "Complex regional pain syndrome (CRPS) is a chronic (lasting greater than six months) pain condition that most often affects one limb (arm, leg, hand, or foot) usually after an injury. CRPS is believed to be caused by damage to, or malfunction of, the peripheral and central nervous systems. "
  • "Although it is more common in women, CRPS can occur in anyone at any age, with a peak at age 40. CRPS is rare in the elderly. Very few children under age 10 and almost no children under age 5 are affected. "
  • "People with CRPS also experience changes in skin temperature, skin color, or swelling of the affected limb. This is due to abnormal microcirculation caused by damage to the nerves controlling blood flow and temperature. "
Quotes
  • "A new guideline published today by the Royal College of Physicians in partnership with 28 other organisations, including the British Psychological Society, says patients with complex regional pain syndrome (CRPS) need better diagnosis, treatment and management of their condition from a wide variety of healthcare professionals."