Improving pain treatment for patients with sickle cell disease is primary goal

MACC Fund support aids Dr. Brandow in landing two major grants

Note: This story originally appeared in the Spring 2014 edition of MACC Fund Today, a publication of Midwest Athletes Against Childhood Cancer, Inc., and is being reprinted with permission.

June 12, 2014 College News - Dr. Amanda Brandow spends most of her time dealing with pain in patients with sickle cell disease and working on ways to better understand and treat those suffering from it.

That’s because the board-certified Pediatric Hematologist-Oncologist at Children’s Hospital of Wisconsin, with a special interest in providing comprehensive and compassionate care for children with sickle cell disease (SCD), is keenly focused on understanding and developing better ways to assess and treat the pain that plagues her patients with SCD.   

“It’s my passion,” said Dr. Brandow, a Chicago native who has been a Medical College of Wisconsin faculty member at Children’s since 2008.  “I became interested in SCD when I was a resident here.  I stayed here for my fellowship because I really wanted to focus on hematology.  I discovered I enjoyed the patient care aspect of SCD and working with that population.” 

The majority of people with SCD in the United States are African American. It is a disease inherited genetically and transcends their whole life.

Dr. Brandow spends approximately 75% of her time researching SCD and the other 25% in the clinical setting working face-to-face with families providing inpatient and outpatient care.  The SCD program at Children’s Hospital includes approximately 350 children (mainly from the Milwaukee central city and some from northern Illinois) ranging in age from two months old to 18 years.  Dr. Brandow sees these patients with the remainder of the SCD team during hospitalizations and in the outpatient clinic when they are doing well.

Dr. Brandow’s first contact with the family is usually when their child is two months of age after the diagnosis of SCD is made on the state newborn screen. There are four common genotypes of SCD ranging from mild to most severe.  The hallmark of any genotype, but especially the most severe form, is pain. 

“That’s really my interest and what I research…how to better measure and evaluate pain, determine the underlying cause of pain and eventually how to develop novel treatments for pain.” 

There are exacerbations of pain that are acute in onset and come out of the blue that very often require IV narcotics in the emergency room or hospital.  Patients often require significantly high doses of narcotics just to get them comfortable. This pain can last two, three, four or more days.”

There are other complications that can occur such as lung problems (acute chest syndrome), strokes (about 10% of children with SCD have a stroke before age 20 years that can affect gross motor function or their ability to learn) as well as life threatening infections. “These children experience a lot of repeated events that bring them to the emergency room or hospital,” Dr. Brandow said. 

The only cure for SCD is a bone marrow transplant with the ideal donor being a fully matched brother or sister. 

“Unfortunately, many of our patients do not have the benefit of a matched sibling thus their only option is a matched unrelated donor that is often difficult to find. The only proven disease modifying therapy for SCD is hydroxyurea, an oral medication taken once daily that has been proven to decrease or prevent pain events and is safe.  However, hydroxyurea will not treat a pain event once it has started as it is not a pain medicine.” 

The average life expectancy for a patient with severe SCD is the mid-forties. Many times patients die acutely.  They may come to the hospital with what seems like a pain event and then go into multiple organ failure. “We don’t know why exactly they die more acutely vs. chronically.”

Hence the treatment for SCD pain goes back to square one. 

“Where it is now, where it’s been, unfortunately it’s the same,” Dr. Brandow admits.  SCD was discovered over 100 years ago.  Patients suffering from pain then were given morphine and fluid.  “Today if we admit someone to the hospital for pain we give them morphine and fluid to treat their pain. We do not have any other therapies to offer them- either treatment or preventative measures. We also see the pattern of their pain get worse over time. The pain from SCD can transition from being acute exacerbations of pain in childhood where pain comes, lasts, goes away and later repeats, to more chronic daily pain in teenagers and adults.  Teenagers with daily pain, for example, may have trouble going to school or holding down a job when they get older.

 “My interest is driven by the desire to discover why patients with SCD have pain,” said Dr. Brandow, herself a mother of a 2-year-old son (Oliver) and as of this writing was expecting a newborn. “The treatment has not changed and we don’t have a lot of novel treatments to give kids for pain.”

In the past it was believed the cause of pain was the “sickle” shape red blood cells (half mooned sickle and very rigid vs. very flexible) which got stuck in the small vessels leading to decreased blood flow with resultant long bone pain or deep organ pain. 

“We’re realizing it’s a lot more complicated than that,” Dr. Brandow said.  “I really want to understand the underlying biology of their pain. This understanding will potentially lead to new treatments for their pain.  We want to do more than just treat the end result (using morphine) but actually working on the prevention or cure side.

“As children age their pain gets worse.  Why is that?” Neuropathic pain, an abnormality in the nerves, could be one of the reasons where the etiology of their pain is not necessarily related to the red blood cell but may be at the level of the nervous system.  “A lot of patients describe their pain with very specific words that are very suggestive of neuropathic pain.  Words like ‘burning, shooting, shock-like’…a sort of pain that radiates, that is characteristic of nerve pain (vs. pain from, say, a broken leg which is more pounding or throbbing). 

“The reason that these pain descriptors and potential for neuropathic pain are intriguing is that there is a whole class of drugs that specifically treats neuropathic pain that have not been traditionally used to treat SCD pain.  This could potentially open up a whole new area of drugs already available that haven’t yet been tried.”

For years, anecdotally, patients with SCD avoid cold temperatures because they know that it stimulates pain.  Jumping into a pool or a rapid change in temperature from going into an air conditioned movie theater or climactic weather changes from warm to cold can trigger a pain event and they can end up in the emergency room the next day. “Why is that?” Dr. Brandow asks.  “We have no idea.  That got me intrigued.”

In studies completed at the Medical College of Wisconsin using mice with SCD, it has been shown that SCD mice have increased sensitivity to cold, heat and pressure suggesting there may be something wrong with their nerves that is consequently driving the pain. “I translated these laboratory findings to humans by evaluating sensitivity to cold, heat and pressure in both children and adults with SCD.” 

There are validated ways to measure these various sensitivities in children age 7 and up by applying a sensation of warm or cold temperature through a computer-driven thermode that provides this thermal stimulus and records patients’ responses to these stimuli. “What we found was patients with SCD were more sensitive to cold and heat than patients without SCD suggesting increased pain sensitivity, but why?”

This initial study led to a National Institute of Health (NIH) grant awarded to Dr. Brandow to continue building on this work to help answer the question of why these abnormalities are occurring and how they may be causing increased pain sensitivity in SCD patients.  Much of the work to this point that led to the NIH grant has been funded by the MACC Fund, allowing Dr. Brandow, along with her mentor Dr. Julie Panepinto, to obtain preliminary data, support a research coordinator to help recruit patients and perform testing and support other research costs.

“We’re looking at markers of inflammation called leukotrienes that are involved in the pathology of asthma.  We know they are increased in patients with SCD and that they are associated with neuropathic pain in patients without SCD.  By bringing all of this together with other pain sensitivity measures, we hope to figure out if there is an association that reveals inflammation may actually be driving the pain sensitivity in patients with SCD.” 

Currently there are existing drugs (i.e. Singlair) that are used to treat asthma that block the effects of leukotrienes; perhaps these or other drugs that modify leukotrienes could be used to treat SCD pain.  “The whole idea is to try and find novel ways to treat or prevent pain other than just treating the end point with opioids.”

Dr. Brandow received a second grant from the American Society of Hematology, an award for Junior Faculty, to support her research related to SCD and pain. “In this project we are looking at another marker that may also be linked to increased pain sensitivity,” she said.  “This marker is called ‘Substance P’ and could be another target for novel pain treatments.”

Pain research in SCD is difficult because of so many different variables. “How do you ‘standardize’ pain…pain is variable based on the patient and patients experience pain in different ways confirming the likelihood of varying levels of pain sensitivity.  Pain research is not well developed in SCD and that’s why treatments haven’t advanced.

“The model I have to study pain in patients with SCD is unique.  We are the first group of investigators to publish our work in looking at increased pain sensitivity in patients with SCD.  I want to take this research to the next level.”

Dr. Brandow plans to use the data gathered with support from these two grants to apply for additional grants to further her research.  “I would love to see my research move into the development of new novel treatments that treat the underlying cause of SCD pain or to start using drugs currently available that could treat neuropathic pain”.

“If I had a dream, or by the time I retire, I’d like to have a child with SCD who is in pain be given something to treat the pain besides morphine. We would be treating the underlying reason why they have that pain vs. treating the end result. We have to find better ways to treat and/or prevent the severe pain that causes our patients to suffer.”

The MACC Fund, as always, is playing a key role. “The MACC Fund has been instrumental in this work.  It has really helped to move our research forward.”

Dr. Marcio Malogolowkin, Medical Director of the MACC Fund Center, concurs.

“The two outstanding grants Dr. Brandow received epitomize what the MACC Fund is all about.   These grants would not have been possible were it not for the MACC Fund’s trust, confidence, unquestionable support, belief and support of these young investigators.  I’m extremely proud to be part of the MACC Fund.”

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