New analgesic therapies for sickle cell disease
Myron Yaster MD, Rita Agarwal MD, and Elliot J. Krane MD
The October 2024 issue of Scientific American has many articles devoted to Innovations in Sickle Cell Disease (SCD). Admittedly, I’ve been interested in sickle cell disease since my internship in pediatrics almost 50 years ago. I was always mystified by it. It seemed simple enough to account for with what should be a simple explanation – a single gene causes a mutant hemoglobin protein to clump together into fibers, which deform red blood cells into the shape of sickles. These clumps of “sickled” cells get stuck inside the microvasculature, interrupting blood flow and prompting intense pain (vaso-occlusive crisis, VOC), and ultimately tissue necrosis, end organ (liver, kidney, CNS, lung, bone) damage and even organ failure.
In today’s PAAD, we review the article by Emily Sohn1 on new solutions to ease sickle cell’s extreme pain. There are several other articles in this issue discussing new cures for this disease, interviews with researchers who are revolutionizing sickle cell care, and interviews with people living with sickle cell and how the disease affects them. For those of you who train medical, nursing, and anesthesia assistant students, these articles are must-reads. Also recommended is the article by Sara Reardon,2 for those of you interested in new therapies that are being used to treat and even cure this disease. Indeed, if you stay tuned, the Reardon article is to be reviewed in the coming weeks.
Because pain management is one of the core missions in the practice of pediatric anesthesia, of all of the articles in this issue, I’ve chosen the article by Emily Sohn for today’s PAAD as our starting point. Additionally, I’ve asked the PAAD’s executive council’s pain mavens Drs. Elliot Krane and Rita Agarwal to assist. Myron Yaster MD
Original article
Sohn E. Ease the Pain: The excruciating pain of sickle cell disease is difficult to prevent or treat. Researchers are working on new ways to provide relief. Sci Am. 2024 Oct 1;331(3):94. doi: 10.1038/scientificamerican102024-1EhD9cAv41AF6vmBB5nn0G. PMID: 39292912.
Let’s start today’s PAAD with a simple question: “When patients with sickle cell disease are not experiencing an acute painful episode are they pain free?” I think most of us think they are. We assume they are either pain free or suffering from intermittent painful episodes. Actually, SCD pain may actually occur quite frequently. Adult respondents in the Pain in Sickle Cell Epidemiology Study (PiSCES) reported SCD pain on 54.5% of the 31,017 days surveyed.3 Importantly, 29.3% of respondents had pain on greater than 95% of the days surveyed.”4 Thus, what we see in the hospitalized patient with acute debilitating pain is just the tip of the iceberg. Most patients have chronic, recurring or unremitting pain – the submerged iceberg.4 Even in children and adolescents, chronic pain occurs much more frequently than most of us realize.5 Thus, pain is the rule rather than the exception.
Even after discharge after an acute painful episode requiring hospitalization, “resolution of a painful episode may take quite some time, and may be associated with significant dysfunction, resulting in more days taken off of school or work than necessitated by hospitalization.”6 Further, readmission soon after hospitalization is not uncommon.7 Prevailing experience is that sickle cell crises typically last for 7 to 9 days, but nationally, hospital lengths of stay are only 5 d when averaged overall, varying from 3 to 6 d with age. Thus, readmission may represent failure of an original episode to resolve, inadequate supply of analgesia for pain occurring after discharge, or even hyperalgesia from opioid withdrawal.4
I (MY) learned this lesson the hard way. As the director of the pediatric pain service at the Johns Hopkins hospital in the 1990s, my colleagues and I instituted IVPCA for hospitalized patients with an acute painful episode. It wasn’t a great solution but better than what existed. Unfortunately, the length of stay during these hospitalizations increased and we were essentially fired by the hematologists who insisted that 5 days was the maximum required for these episodes.
“For now, people typically have a home protocol they start at the onset of an acute event. It usually includes opioids (such as oxycodone), heat, and ibuprofen or other over-the-counter pain relievers. If those approaches fail, more intensive hospital care can include intravenous opioids and fluids, ketamine and local anesthesia, among other strategies. Yet even with those efforts, patients often remain in pain after discharge.”1 The need for opioids, often in large dose, has in our opinion perverse implications. It often results in bigoted suspicion and accusations of drug seeking by medical professionals, many of whom associate opioid abuse with the African-American population. In fact, providers often accuse patients of faking or magnifying their pain to get drugs.
New therapies are on the horizon and in active study trials. Will they work? We can only hope but having been in the business for a long time we are skeptical about “breakthroughs”.
“Rivipansel targets an adhesion molecule called E-selectin with the goal of preventing leukocytes from sticking to blood vessels. In a phase 3 trial,8 those who took rivipansel showed a 61 percent reduction of E-selectin levels in their blood. Patients who took the drug within 26 hours of an acute attack’s onset had shorter hospital stays and spent half as long on IV opioids compared with those who took it after that window—two days instead of four.”1
“Imatinib is a cancer drug that appears to reduce inflammation. It inhibits a neuropeptide called substance P, which activates mast cells, causing inflammation and pain. Imatinib reduces VOC pain in mouse models of sickle cell disease and has shown potential to do the same in people. Studies show that adding imatinib to outpatients’ treatment protocol reduced the number of VOCs and hospitalizations and shortened hospital stays.9 The drug also reduced the use of pain relievers significantly.”1
“Cannabinoids may alleviate chronic pain by reducing inflammation and interrupting key pathways. Anecdotally, many sickle cell patients report self-treating with—and achieving relief from—cannabinoid drugs.”1
FDA commercially-approved gene therapy was used for the first time just this summer in a 12-year-old with SCD, which will be the first cure of a genetic disease with this modality.10 There is something sweet about the irony that this revolutionary treatment was successfully used for the first time in the treatment of a disease that occurs almost exclusively in the African-American population, a population that has been denied adequate access to medical care, and often any access to medical care, for centuries in this country.
Additionally, “It is particularly important to focus on children and adolescents before their brains develop a “nociplastic pain pattern,” pain sensitivity that sets in after years of repetitive acute attacks. This won’t necessarily require new drugs. Rather, doctors could prevent chronic pain, or at least diminish it, by providing better treatment to patients at younger ages.”1
Finally, “other factors that exacerbate chronic pain are loneliness, depression, malnutrition and social isolation, all common issues for people with sickle cell disease. Depression in particular affects between 20 and 60 percent of people with sickle cell, and studies suggest that treatment with antidepressants may reduce pain episodes. Companionship and a healthy diet might help, and those changes may also decrease the dose of opioids required to relieve pain.”1
Send your thoughts and comments to Myron who will post in a Friday reader response.
References
1. Sohn E. Ease the Pain: The excruciating pain of sickle cell disease is difficult to prevent or treat. Researchers are working on new ways to provide relief. Sci Am 2024; 331(3): 94.
2. Reardon S. New Treatments for Sickle Cell Disease: After years of little progress, new therapies to treat or even cure the disease are reaching patients. Sci Am 2024; 331(3): 85.
3. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Annals of internal medicine 2008; 148(2): 94-101.
4. Smith WR, Scherer M. Sickle-Cell Pain: Advances in Epidemiology and Etiology. Hematology 2010; 2010(1): 409-15.
5. Dampier C, Ely E, Brodecki D, O'Neal P. Home management of pain in sickle cell disease: a daily diary study in children and adolescents. J Pediatr Hematol Oncol 2002; 24(8): 643-7.
6. Brandow AM, Brousseau DC, Panepinto JA. Postdischarge pain, functional limitations and impact on caregivers of children with sickle cell disease treated for painful events. Br J Haematol 2009; 144(5): 782-8.
7. Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. Am J Hematol 2005; 79(1): 17-25.
8. Dampier CD, Telen MJ, Wun T, et al. A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis. Blood 2023; 141(2): 168-79.
9. Karimi M, Bahadoram M, Mafakher L, Rastegar M. Impact of Imatinib on reducing the painful crisis in patients with sickle cell disease. Hematol Transfus Cell Ther 2024; 46(4): 387-92.
10. " First Patient Begins Newly Approved Sickle Cell Gene Therapy." The New York Times, May 6, 2024.