Impact of chronic pain on acute pain trajectories in sickle cell disease: Insights from the sickle cell disease treatment with arginine therapy (STArT) randomized controlled trial

Abstract

Abstract Background/Methods: STArT (NCT04839354) was a phase-3 double-blind, randomized placebo-controlled trial of intravenous (IV) arginine therapy in participants aged 3-21 years with sickle cell disease (SCD) and vasoocclusive episode (VOE) pain requiring IV opioids. STaRT was conducted at 10 US sites utilizing the Pediatric Emergency Care Applied Research Network (PECARN). Enrolled participants were randomized 1:1 to receive either study drug or placebo within 12 hours of receiving their first dose of IV opioid. The primary outcome was time-to-crisis- resolution defined as the time in hours from study drug delivery to the last dose of IV opioid. Secondary outcomes included total parenteral opioid & patient reported outcomes (PROMIS) at admission, discharge, and 7-12 days post-discharge. Participants were classified at enrollment as having chronic pain (CP) if they experienced pain on ‘15 or more days of the month’ or ‘atleast half the days of the month’ for the last 6 months. Methods: We compared demographic and clinical characteristics and change in pain score (enrollment-discharge) by CP group. We then examined pain intensity trajectories of the highest daily pain score (0-10) during hospitalization in study participants by CP status at enrollment; to do so, we included CP status as a main effect and CP status X follow-up day as an interaction term in linear mixed models. Similar models were also examined with sex as a main effect. Finally, a four-level sex-CP variable as a main effect and sex-CP X follow-up day as an interaction were assessed. Unadjusted models were examined, as were models adjusted for total opioid received in IV morphine milligram equivalent/kilogram body weight. Results: Two hundred and seventy-one participants were randomized and received study drug (129-arginine, 142-placebo), and data on presence of CP was available for 268 participants. The median age of participants was 15.1 years (IQR 11.2-17.7), 71.3% (n=191) of participants were age 12 and older, and 51.9 %, (n=139) were male. Most had Hemoglobin SS genotype (70.1%, n=188). Most participants were prescribed HU (75.7%, n= 203) and 21.1% (n=54) received chronic transfusion therapy. About half (51%) reported that they experienced CP, and 77.2% (n=207) experienced 3 or more healthcare visits for pain in the 12 months prior to enrollment. Almost all reported a pain score of 6 or higher at arrival to the Emergency Department. Clinical characteristics at enrollment were similar across CP groups, except that the CP group was more likely to have a history of acute chest syndrome (p=0.013) and asthma (p=0.026). Participants in the CP group were also more likely to report 3 or more healthcare visits for pain in the 12 months prior to enrollment (p<0.001). We found a significantly lower change in pain score (enrollment-discharge) in the CP group (mean 3.9, SD 3.2) compared to the non-CP group (mean 4.8, SD 3.4, p=0.018). Participants with CP were more likely to return to the ED within 28-days. The mean number of follow-up number of days with pain score assessments was 3.82 days (SD 1.99 days). Examining trends in highest pain intensity score during hospitalization, we found a significant decrease in pain score for the entire cohort (p<0.001), with an average 0.18-point decrease (slope estimate -0.18, 95% CI: -0.28, -0.08) in highest pain score for every day of measurement. There was no difference in decrease in pain score by sex. The interaction between CP X follow-up day was significant (p<0.001), indicating a difference in trends by CP status; the CP group had a slower decrease in pain (slope estimate -0.05, 95% CI -0.19, 0.08) as compared to non-CP group (slope estimate -0.42, 95% CI -0.58, -0.26). The interaction between follow-up day and sex-CP was significant (p=0.007), indicating that pain trajectories over time differ by sex-CP level. Both male and female participants with CP experienced a significantly smaller decline in daily high pain scores over time compared to those without CP. Conclusion: About half of children and young adults hospitalized with SCD VOE have CP. Children and young adults with CP, compared to those without CP, experience a smaller magnitude of change in pain score and a slower decline in pain during hospitalization. These findings should be considered in the study design and selection of study outcomes for future SCD acute pain clinical trials.