Chronic Pain Versus ‘Rare’ Disease: The Case of CRPS

Chronic Pain Versus ‘Rare’ Disease: The Case of CRPS

By Terri Lewis, PhD.

Terri A Lewis, PHD

Terri A Lewis, PhD

(Editor’s Note: A Conference is being held this month in Chicago with the goal of trying to develop a reference protocol for the use of ketamine to treat CRPS—and perhaps to inspire some clinical studies. We’ll report on that this coming week. We asked Dr. Lewis for some thoughts about why more attention from industry or government hasn’t been focused on CRPS-or chronic pain generally- and she provided this background)

Guidance assists sponsors of drug and biological products intended to treat or prevent rare diseases to conduct efficient and successful development programs through a discussion of selected issues commonly encountered in the identification and treatment of drugs for rare diseases.  Within the context of drug development programs, it is more difficult to address the context of a rare disease with which there is often little medical experience or recognition.  These issues are more acute when the disease is rare or there is an overt refusal to acknowledge that the disorder exists at all – as often seems to be the case with chronic pain and its associated syndromes.

All drug development and treatment identification programs should have a firm scientific foundation.  Because of both the numbers of persons affected, and the dispersal of clinical experience among a small number of clinical referral centers, the natural history of the majority of rare diseases is often poorly described if not simply ignored.  This problem is compounded by chronic pain derived from medical harm or iatrogenic injuries.

A rare disease is defined by the Orphan Drug Act of 1983 as a disorder or condition that affects less than 200,000 persons.  Most rare diseases, however, affect far fewer persons.  However, chronic pain in all of its forms is estimated to affect 116 million adults in the USA (roughly 1 in 3) over the course of their lifetimes (Institute of Medicine, 2011,1999) making it among the most common under addressed healthcare challenges.  More than 200 common and rare diseases generate chronic lifelong pain in affected individuals.

The majority of pain generating disorders are serious conditions with no FDA approved treatments, leaving substantial unmet medical needs for patients.  Because these diseases may themselves occur at a low frequency, physicians often correlate the lack of curative treatment for the disease with a lack of need to treat associated chronic pain generated by the disease itself.  It is not uncommon for patients to hear that because there is no treatment for the disease, pain care is taken off the table as an option. Increasingly, the public discussion confuses treatment for palliation with addiction and dependence.  This flawed logic drives the development of impaired public policy and creates substantial challenges for affected consumers who have to live with the lifelong effects of progressive disease.  In the aggregate, these diseases and the roughly 400,000 iatrogenic injuries that occur annually to add to this chronic pain generating total, create an urgent need to understand and address chronic pain in all of its expressions within the population.

Guidance exists to address important aspects of drug development for rare diseases and the design of treatment protocols. There must be an adequate description and understanding of the disease’s natural history, an important element in this foundation.  Very little research has captured the development of the natural history of chronic pain development in humans, although animal studies are replete with observations and reports using animal models.  Whether the natural history observed in animal studies is comparable to the experience of humans is unknown, but it does offer an excellent opportunity for patient generated research conducted in collaboration with researchers to develop an adequate understanding of the pathophysiology of both diseases that generate chronic pain and chronic pain as a disease process in and of itself.

Determination of a drug’s proposed mechanism of action, and identification of the nonclinical pharmacotoxicology considerations to support the proposed clinical investigation is derived from the study of the natural history of the disease.  Knowledge about the disease’s natural history can inform important aspects of drug development by defining the disease population, the full range of disease manifestations, and identification of important disease subtypes. It is important to understanding critical elements in clinical study design, such as study duration and choice of subpopulations. Researchers must develop and select outcome measures that are more sensitive to determining whether the intervention results reflect changes in the manifestations of the disease or impact on symptoms associated with resulting pain as a symptom.

Developing biomarkers to support proof-of-concept (POC) information, guide treatment selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy is an important outcome of these efforts. In some cases, these biomarkers can be used to help us understand associations between disease and manifested chronic pain symptoms.  At this time, there is no agreed single set of data elements for chronic pain that adequately addresses all rare diseases – and insofar as chronic pain is concerned, the epidemiology work has not been done to identify these data elements or biomarkers.

The Orphan Drug Act provides incentives associated with orphan-drug designation to make developing drugs for small numbers of patients financially viable;  however, the statutory standard for the approval of orphan drugs is not different from the standard for developing drugs for common conditions.  The application of currently approved drugs to off-label uses is not addressed by the Orphan Drug Act, but is covered under experimental treatment under CFR Title 21.

In October, a group of physicians will gather in Chicago to examine the use of Ketamine, an anesthetic medication used widely for surgical applications described at this link -  The disease of concern is Complex Regional Pain Syndrome or CRPS (ICD-10 G90.5).  This is characterized as a rare neurologic syndrome characterized by burning pain, tenderness, swelling, and changes in the skin color and temperature of a body part or extremity.  Often caused by crushing injury, bone fracture, or surgery, the syndrome is characterized by severe burning pain in an extremity accompanied by sudomotor, vasomotor, and trophic changes in bone without an associated specific nerve injury.  The skin over the affected region is usually swollen, changes color, and demonstrates hypersensitivity to tactile stimuli and erythema.  In 2006, de Mos, et al., estimated the incidence of CRPS in the population at 26.2 per 100,000 persons.  It may take several years to achieve proper diagnosis, which causes pronounced suffering, permanent disability, and frustration in affected persons.

All drugs and clinical protocols – for both rare and common conditions – must be based on demonstration of substantial evidence of effectiveness in treating or preventing the condition and evidence of safety for that use. Evidence of effectiveness should be obtained from one or more adequate and well-controlled studies in identified populations.  The Reflex Sympathetic Dystrophy Association ( is sponsoring the discussion in the hopes that a standardized protocol can be designed that will yield meaningful data for direction of sponsored research and treatment.

Additional reading -

Institute of Medicine (2011,1999). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research (Institute of Medicine Report)

Rare Diseases: Common Issues in Drug Development Guidance for Industry. Retrieved from

  1. de Mos et al., The incidence of complex regional pain syndrome: …, Pain (2006), doi:10.1016/j.pain.2006.09.008

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Authored by: Terri A Lewis, PhD.

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Dear Donna. No I never heard of that nexatrone medicine??? I read your comment I am very happy my comment made you mentally feel better.. Even if only for a short time. I don’t know what I said to help you.. Maybe God guided me? Anyway my heart goes out to you and pray your treatments help you. If I allow this disease to kill me from the pain… It would… But I am a fighter and always fighters want to help others too. But sometimes fighters get weak.. Mess up.. Need a hug… Anger others cause we are different. We want to fix the world and try to in small ways. .and we mess up. …maybe by talking too loud cause no one ever understands..or repeat ourselves.. Annoying people who don’t help when they should do so… When we see something is wrong. So we end up trying to help and get a broken heart… Feelings really hurt by others. When we can volunteer in some way we talk about what is wrong and they get tired of hearing it…. But no one does anything to fix it. We are not afraid to speak up but the bad we see… No one helps. Long story but it is about a fighter for Good things and what is right. We are alone and don’t want to be a part of the bad we see or experienced. Again I could write a thick book as many of you could do too. God Bless all of us.. If it means anything I care about you too! 😇

Have a meeting with RSD CRPS patients in a big forum. You will learn much!!!! It’s such a horrible disease that is hard to deal with unless we can share and learn from each other. Only my Dr. Who is an MD. Dr. Took the time to research RSD CRPS even calling specialists out of our State on three way calls to discuss how to keep me alive and meds to ease the indescribable pain. The people I met at an outdoor fundraiser out of my state I went to told me they were on same meds as me. To relieve the pain so we can at times do good… Volunteer at areas that needed help etc. But this disease only allows us to do so much and the body warns one the disease is attacking. Our body tells us to stop and get to bed. It’s a weird disease!!! Symptoms that happen only once or twice or more in a period of seven years. One never knows where else in your body it attacks. Again maybe only once or on a regular basis if one falls asleep leaning too hard on a part of your body. Then one wakes up… Cannot move an inch due to the severe pain in any part of body leaned on too hard while asleep.. Then one yells in pain trying hard not to… Then slowly move inch by inch screaming until one can stand up. Slowly the pain eases up and just gets sore. Rubbing it helps but the meds are what saves us from dying!!! They ease the pain in the damaged area. The body knows where to put the meds. Never ever did I ever get high on the meds!! With the right medicine the RSD CRPS major area takes the meds and eases the pain. Weird things happen from nerve damage Rsd Crps but never are constant things. But the disease itself is constant. Relief is all we want!!! Ketamine works if given early in the disease… If later the Ketamine lasts for anywhere from minutes to almost a day. One never knows. But Ketamine should really be studied by scientists after listening to Victims because while it is working one is in heaven… The RSD CRPS goes away completely!!!!! What is in Ketamine that may be a cure for RSD?? Should people who have RSD a long time get regular shots of Ketamine to see if it eventually cures it??? It does work but you have to help those who have it a longer time. I pray you organize a big get together for people who have this horrible suffering disease. In the beginning without meds I was crying.. Yelling… Begging for help… My eyes red from the pain!!! No one understands what we go through other than others who also have it.! We repeat ourselves if no one understands what we are talking about. It’s due to we are alone with our suffering and we still are expected… Read more »

War On Pain Patients

My heart goes out to all who suffer with chronic pain in today’s opiophobic environment. Those of us with rare diseases are less likely to be treated appropriately early in the disease process due to the time taken to obtain a proper diagnosis. In today’s restrictive prescribing environment, I fear more and more will go on to develop centralized pain. In addition to centralized pain, I fear more widespread use of invasive procedures that can cause even more rare diseases and pain (i.e., epidural steroid injections -> Arachnoiditis as Cathy Maccoux sadly knows). I’m relieved to see that some are researching treatments for CRPS, it gives me hope. Thank you to all involved in Ketamine research!

If you or a loved one is living with the devastation of CRPS, it’s not your fault. Hang in there because help may be right around the corner.

Thank you, Terri Lewis and National Pain Report for keeping us informed and giving us hope.

Just tweeted a link to this article, with postings to @WarOnPainPts @ThePainComm @NIHPainResearch. Thanks for sharing, Terri.

Donna Rubinetti

Good God Joan your post actually made me feel better, mentally! I hear of many CRPS patients who seem to be high functioning despite their pain. I can barely withstand it, it is soooo bad. CRPS has spread throughout my body. I am attempting to wean myself from the meds in order to take low dose naltrexone which sounds like a “miracle” drug. So few people understand this because I “look fine.” Do you know anything about LD naltrexone? At this point, opiates don’t even work for me. Thanks for your post.

Sharon Romenesko

High Dose Ketamine infusions took me form existence to living. Walking to get my mail instead of using a scooter. Being able to be touched and hugged almost 8 1/2 years. i was able to volunteer a few times, socialize, attend church, give back to the world. Joy, pure joy and true laughter and smiles. People heard it in my voice, saw it in my face and boldy movements. I am so grateful to everyone who plays a part in putting together these conferences and the medical professionals who take the time to share what they have learned that REALLY WORKS and what doesn’t. I Thank You all! Being a human guinea pig is not pleasant to say the least, more like torturous, After 8 1/2 years I was losing hope. I am so grateful for Dr. Pradeep Chopra and Dr Ricardo Alvarad and other physicians who care enough to want to help and do what works instead of what only makes the facility money at a patients cost and continued pain. These conferences bring knowledge and awareness to people who suffer but also to medical professionals who care and want to learn more about how to help treat their patients and bring quality of life to us. Plus share what they have learned. I thank you! I appreciate each persons contribution to making these conferences possible. I am even more grateful it is happening in the upper midwest -WI, MI, MN and other surround states need much guidance on how to identify, understand, and treat CRPS patients with compassion and treatments that work. I know Wisconsin really, really needs educating on all areas of CPRS.
God Bless each and everyone one of you, I wish i could be there - one of these years I hope I am able to attend. Namaste


Truth Honor and Integrity,

What value (truth, honor and integrity) does your quoting of the unscientific rantings of a prehistoric physician have to do with this painful condition?! Your behavior is abominable! Granted, biofeedback and meditation might have some affect on the condition, no treatment, so fsr, can eliminate the horrific symptoms!

Yvetta BarbeeMiles

For sensitivity and movement pain. Ketamine saved me. The study is good . I can at least manage.

Donna Rubinetti

Please continue to keep me up to date regarding RSD/CRPS information.
Thank you.
Donna Rubinetti

Truth Honor and Integrity

Sport is a preserver of health.

Our food should be our medicine and our medicine should be our food.

Get knowledge of the spine, for this is the requisite for many diseases

Truth Honor and Integrity

“The majority of pain generating disorders are serious conditions with no FDA approved treatments, leaving substantial unmet medical needs for patients.”

Illnesses do not come upon us out of the blue. They are developed from small daily sins against Nature. When enough sins have accumulated, illnesses will suddenly appear.

Leave your drugs in the chemist’s pot if you can heal the patient with food.

The way to health is to have an aromatic bath and a scented massage every day.

Everyone has a doctor in him or her; we just have to help it in its work. The natural healing force within each one of us is the greatest force in getting well. Our food should be our medicine. Our medicine should be our food. But to eat when you are sick, is to feed your sickness.

Michael R Kennedy

Thank you for keeping us all informed in so many ways. I look forward to additional blogs.

Cathy Maccoux

My name is Cathy Maccoux and I have a 25 yr old daughter who has been suffering with CRPS since she was 11 years old. She has it in both legs and arms. It flares up more then we would like it to. She is also a victim of the NECC fungal meningitis outbreak. We live in Minnesota and cannot find any doctor willing to try Ketamine. They did use it at Children’s Hospital on her but once she aged out of there no one is willing to try it. She did have two spinal cord stimulators, but because of the fungal meningitis they had to be permanently removed.
She would need a Ketamine infusion for flare ups. They worked great for her!
Please let me know how I could get information about the outcome of this conference and how we could get help for our daughter using Ketamine.

Thank you,
Cathy Maccoux

Please please don’t take away pain medicines away that work to allow us CRPS suffering humans to survive!!! CRPS is a weird disease! When we can…the meds ease the pain so we can do errands without anyone knowing we are we suffer so horribly! BUT this disease is always felt. We can be out so for awhile then the body starts warning you feeling the pain starting. The warning signs are one starts crying while the body tells you must get to bed lying down. One almost passes out to sleep once in bed. One must take a nap off and on around the clock. Therefore one is usually up at 2 a.m. if you lay your body wrong you wake up with excruciating pain in your groin area near legs or on your head. When this happens you want and do scream in pain and cannot move at all… But slightly move and rub the pain area sometimes. I have had so many odd things happen to my body…. Some only happened 2 times in 7 years I have CRPS. I could write a book. But I do know my meds are common for RSD CRPS and approved by Dr Chopra in Rhode Island and a CRPS scientist in Connecticut. Without these meds I never would have lived…one cannot handle the nerve damage pain!!! I do not bug my Dr. about my CRPS.. Don’t ask for anything cause I am surviving and have to accept this disease. My Dr. researched and talked to the above Dr’s. several times. I can see my grandchildren grow… Volunteer a tiny bit off and on when my body allows it. But believe me this disease is a nightmare until accepted. There are no words one can use to describe the pain !!!! It is like Hard labor delivery even worse at times. But the medicines ease the pain. I think positive…. Exercise everything good. I never once got high from my meds… Not once…. The body knows where to put the meds to ease the pain!!! I never took a street drug my entire life! Only God knows when I die not the government by taking away medicines discovered that work. Each of us CRPS suffering humans can be slightly different yet those I met said the same things I write to you. We have been abused by Dr’s. Etc… Many similar stories I say. We all could write a book!! Enough of no help for us… Many have it and are not diagnosed properly!!!