Pain and Opioid Use after Reversal of Sickle Cell Disease Following Hematopoietic Stem Cell Transplant
Authors: Darbari Deepika S. , Liljencrantz Jaquette , Ikechi Austin , Martin Staci , Marie Claire Roderick , Fitzhugh Courtney D. , Tisdale John F , Thein Swee Lay , Hsieh Matthew 
Published: April 2021

Abstract
Introduction: Pain is the most common symptom of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is currently the only curative therapy for SCD; however, some patients continue to report pain requiring opioid treatment despite hematologic cure following successful HSCT. Knowledge of factors associated with continued pain and opioid use may help reduce post-HSCT pain-related morbidity. We analyzed data from a cohort of SCD patients who have been successfully treated by nonmyeloablative HLA-matched sibling allogeneic HSCT. Our goal was to investigate pre-HSCT factors that are associated with continued pain and opioid use at 12 months after a successful HSCT.
Methods: Detailed data on the clinical course, pain, opioid use, and laboratory values were collected from medical records at 3 months pre-HSCT and 12 months post-HSCT (n=35). Patient Reported Outcomes Measurement Information System (PROMIS) measures were available in a subgroup of these patients (n=20), also collected at the same time points. Patients with pre-HSCT pain were classified using Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy (AAPT) guidelines into one of three pain categories: 1. Chronic pain without contributory SCD complication; 2. Chronic pain explained by contributory SCD complication, eg. avascular necrosis; 3. Chronic pain with a mixed pain phenotype (eg. some pain explained by a contributory SCD complication but also pain occurring in unrelated sites). Patients who only experienced acute episodic pain were grouped separately (Episodic pain only).
Results: The median age of the cohort was 30.5 years (range: 16-65 years) and 21 (60%) patients were male. Pre-HSCT, all patients experienced intermittent episodes of pain. Forty-six% of the patients experienced acute episodic pain only, 26% also had chronic pain with a contributory SCD complication and 28% also had chronic pain without contributory SCD complication or a mixed pain phenotype. Post-HSCT, median pain-related admissions decreased significantly (from 3 admissions/year (range 0-24) pre-HSCT to 0 (range 0-3) post-HSCT; (p&lt;0.001)). There were significant reductions in the prescription of both short- and long-acting opioids pre- vs post-HSCT (91% to 40% for short acting and 40% to 14% for long acting opioids; p&lt;0.001). While 14 out of 35 (40%) reported pain at 12 months post-HSCT, examination of continued opioid use patterns across the AAPT groups showed that in the group of chronic pain patients without contributory SCD complications, 90% continued to use opioids to manage their pain whereas none of the patients in the episodic pain only group received opioids post-HSCT and for the group of patients with chronic pain related to a SCD complication, 50% stopped using opioids post-transplant.
Analysis of PROMIS data, showed significant improvement in the subscales of Pain Intensity (p=0.03), Pain Impact (p=0.007), Satisfaction with Social Role (p= 0.03), and Physical Function (p= 0.004) following HSCT but no significant changes were seen for Fatigue (p=0.09), Anxiety, Depression or Sleep Disturbance (which may be explained by the small sample size not having enough variance). However, when comparing patients with persistent pain and opioid use without related SCD complications (n=6) versus those with resolved pain post-HSCT (n=9), pre-HSCT Anxiety ratings were significantly higher in the group with unexplainable, persistent pain (p=0.05). For those same groups, additional pre-HSCT factors that were associated with unexplainable, persistent pain post-HSCT were higher burden of pain as defined by higher median pain admissions/year (2 (0-10) vs. 5.5 (3-9); p=0.04); higher overall numerical pain rating on a 0-10 scale (2 (0-5) vs. 6 (5-7); p=0.02) and treatment with long acting opioids (0% vs. 86%; p&lt;0.001).
Conclusions: SCD patients with higher pre-HSCT pain burden (more pain admissions and higher pain intensity ratings), long-acting opioid use and certain psychological traits (anxious disposition) may be at risk for persistent pain and continued opioid use post-HSCT. Future studies should evaluate outcomes beyond 12 months of follow up, further characterize underlying mechanisms and evaluate potential interventions to reduce pain and opioid use related morbidities in this subset of patients.

Disclosures
No relevant conflicts of interest to declare.