ASH guidelines address ‘major gaps in our knowledge’ regarding sickle cell disease care
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Pain is one of the most common symptoms of sickle cell disease, and severe pain is the leading cause of ED visits and hospital stays among patients with this disease.
However, guidance on management of pain and other sickle cell disease (SCD) complications has been limited, leading to variability in clinical practice.
For that reason, ASH has issued new evidence-based guidelines for sickle cell disease, with the goal of helping providers and patients make informed decisions regarding individualized care.
In 2014, the NHLBI released an expert panel report that addressed issues related to SCD. The ASH guidelines, published in Blood Advances, expand upon the report and focus on other aspects of SCD management, according to Robert Liem, MD, chair of the ASH Sickle Cell Disease guideline coordination panel and director of the comprehensive sickle cell disease program at Ann & Robert H. Lurie Children’s Hospital of Chicago.
“The questions we addressed had to do with what we consider four major gaps in our knowledge of how best to manage patients with SCD,” Liem said in an interview with Healio. “We also wanted to make sure that we were developing recommendations in areas that hadn’t been covered by that initial NHLBI panel report.”
A ‘rigorous process’
The guidelines focused on cardiopulmonary and kidney disease, transfusion support, cerebrovascular disease, and management of acute and chronic pain. A guideline on hematopoietic stem cell transplantation is expected later this year.
“The transplant manuscript hasn’t come out yet, but that panel looks at how best to use transplant for the kinds of complications that we see in SCD,” Liem said.
To develop the guidelines, ASH assembled 61 clinical experts, five methodologists and 10 patient representatives. Each guideline panel consisted of 13 to 15 members, including a primary hematologist and a methodologist.
“We went through a very rigorous process in coming up with the recommendations after reviewing the literature,” Liem said. “We rely on experts in the methodology of how to review the literature to derive the recommendation.”
Each panel also included experts in the respective content areas, including clinicians specializing in anesthesia, pain management or psychiatry for the panel on pain management.
The patient representatives, two of whom served on each panel, were essential in the development of each recommendation, according to Liem.
“In deriving the recommendations, we take into consideration factors like patient values,” he said. “We consider the input of patient representatives very important in making our final recommendations.”
Liem said the cardiopulmonary kidney disease panel, with which he worked, evaluated screening requirements for complications such as pulmonary hypertension and chronic lung disease, as well as sleep disorders. The panel also considered how best to treat evolving kidney disease and the role of kidney transplantation for patients with SCD.
“Often, the evidence in the literature is not very clear,” Liem told Healio. “The questions we came up with were not necessarily based on how much evidence we thought was out there, but were meant to give us an opportunity to look at the available evidence in the literature so we could come up with the best recommendation.”
Acute and chronic pain
The pain guideline included several recommendations for managing both acute pain and chronic pain experienced by patients with SCD, according to panel member Amanda M. Brandow, DO, MS, professor of pediatrics in the section of hematology/oncology at Medical College of Wisconsin.
“We divided our guidelines into acute pain and chronic pain, because both are prevalent and likely distinct,” Brandow told Healio. “These types of pain are likely driven by different underlying mechanisms within the disease.”
Brandow said the panel developed questions regarding pharmacologic and nonpharmacologic treatment of each pain type.
She said because opioids are known as the backbone of acute pain treatment, the panel explored whether there were effective nonopioid-based pharmacologic therapies for acute pain that could be given to patients undergoing active treatment or those who are refractory to opioids. The panel also considered the role of opioids in treating chronic SCD pain.
The use of indirect evidence
Brandow and colleagues used the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) framework to rate the available evidence and develop the guidelines.
“We had experienced methodologists who worked with us to develop these guidelines, as did all of the ASH guideline panels,” Brandow said. “Eddy Lang, MD, who was our methodologist, helped shepherd us through the process of grading the evidence. We gathered the evidence for all our individual questions.”
However, Brandow and colleagues found a significant paucity of data to address their questions.
The panel then looked to indirect evidence. This involved evaluating studies of pain management among individuals without SCD.
The panel found indirect evidence especially useful in addressing questions about chronic pain. For its recommendation on management of SCD chronic pain without an identifiable cause, researchers examined evidence among patients with a parallel chronic pain condition.
“We reached the consensus in a very rigorous, standardized way, and the one we settled on was fibromyalgia,” Brandow said. “The reason why we chose fibromyalgia was that some of the basic science and clinical science data show chronic sickle cell disease pain is likely mediated by abnormal mechanisms in the peripheral and/or central nervous system. This was one of the pain populations that we felt we could extrapolate the data from in an indirect manner.”
After reviewing this indirect data, the panel identified classes of drugs that had strong, applicable evidence to support their use for SCD chronic pain without an identifiable cause. These included gabapentinoids, tricyclic antidepressants, and serotonin and norepinephrine reuptake inhibitors (SNRIs), which the panel conditionally recommended as options for pain management.
For chronic pain with an identifiable cause, such as avascular necrosis of bone, the panel used an osteoarthritis population as a source of indirect evidence. Based on this evidence, the panel conditionally recommended duloxetine, other SNRIs and NSAIDs as nonopioid pain management options.
The guidelines advise against the initiation of chronic opioid therapy for patients with newly diagnosed chronic SCD pain, except for those who do not respond to other pain treatments.
“We thought very long and very hard about this recommendation, and were very careful in how we put it forward,” Brandow told Healio. “We did not have a lot of data. It’s surprising, when you look at the data across painful conditions, that there isn’t a lot of data out there about chronic opioid therapy and how it treats chronic pain.”
The role of opioids
The panel’s recommendations for acute pain relied less on indirect evidence, Brandow said.
The guidelines recommended use of a standardized protocol to treat SCD pain in the acute care setting, including tailored opioid dosing, nonopioid pharmacologic treatments and nonpharmacologic therapies.
The panel conditionally recommended personalized opioid dosing based on baseline opioid treatment and previous effective treatment. It also suggested a 5- to 7-day course of NSAIDs in addition to opioids for acute SCD-related pain.
Nonpharmacologic recommendations included massage, yoga, transcutaneous electrical nerve stimulation, virtual reality and guided audiovisual relaxation along with standard pharmacologic treatment. These recommendations also were conditional based on very low certainty in the evidence.
Brandow said the panel ultimately could not make a recommendation on one of its key questions regarding opioids — whether they should be delivered via continuous infusion in addition to on-demand delivery.
“We felt the indirect evidence wasn’t appropriate to use, because most of it was coming from post-surgical patients,” Brandow said. “Our patients are not opioid-naive. The surgical patients are often using opioids for the very first time in their lives after they have had surgery. So, we decided not to use that evidence.”
Brandow said the guidelines are not intended to exclude opioids from the pain management armamentarium for patients with SCD.
“They were developed with the goal of trying to maximize all the options that exist in our toolkits,” Brandow said. “Opioids have a role for some patients, if they’re administered and monitored in the correct way.”
For more information:
Amanda M. Brandow, DO, MS, can be reached at 9000 W. Wisconsin Ave., Milwaukee, WI 53226; email: abrandow@mcw.edu.
Robert Liem, MD, can be reached at 225 E. Chicago Ave., Chicago, IL 60611.
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