Acupressure alleviates pain and clinical symptoms in patients with sickle cell disease Open Access

TO THE EDITOR:

Sickle cell disease (SCD) is an inherited blood disorder characterized by chronic pain and recurrent, severely painful vaso-occlusive crises (VOCs). Current pain management strategies often rely on high-dose opioid therapy, which carries significant risks of tolerance, opioid-induced hyperalgesia, and diminished quality of life (QoL), and are otherwise limited in available treatment approaches. Acupressure is a noninvasive integrative therapy that involves applying pressure to specific acupoints, using fingers or other probes. Acupressure has demonstrated efficacy in managing pain and improving QoL¹ associated with cancer,² dysmenorrhea,³ and labor.⁴ Recent studies also showed that self-administered acupressure improves pain and comorbidities in individuals with lower back pain⁵ and survivors of breast cancer.⁶ Many individuals with SCD self-manage their pain^7,8 and VOCs⁹ at home, largely owing to barriers in the health care system. There is an urgent need to develop safe, effective, and cost-efficient telehealth strategies for SCD pain management. This study reports some preliminary findings from our ongoing randomized controlled trial (RCT) (ClinicalTrials.gov identifier NCT06511453) evaluating the feasibility and effectiveness of self-administered acupressure for the management of SCD pain and comorbidities.

A total of 45 participants with SCD, aged 13 to 64 years (1 patient aged 13 years was included in the analysis, a minor deviation of inclusion criteria), were screened and enrolled from 2 sites (Indiana University, Indianapolis, IN and University of California, Irvine, CA). The study was approved by the institutional review board at Indiana University, and all participants gave electronic written informed consent. Demographic information is shown in Table 1. Twelve participants were initially enrolled into the acupressure group to assess feasibility, followed by 33 randomized to receive either 5-week self-administered acupressure in conjunction with usual care or usual care alone (supplemental Figure 1). All study communications were conducted virtually via video/phone calls, text messages, and emails. Participants in the acupressure arm received training and access to Health Insurance Portability and Accountability Act-compliant refresher materials. A 30-minute acupressure training was provided by a trained research assistant before the first treatment. Participants administered acupressure on each acupoint to confirm training fidelity. Those in the acupressure arm completed a 6-month follow-up (monthly), whereas those receiving usual care alone were followed monthly for 3 months. The study team maintained routine communications to facilitate adherence and data collection. Participants experiencing a VOC at the time of enrollment did not initiate treatment until the VOC was resolved.

Participants who were randomized to the acupressure group received training to administer the acupressure treatment every other day for 5 weeks. The acupoints used in this trial (ST36, SP6, SP10, LR3, LI4, LI11, DU24, DU20, and Yin Tang) were selected from the main acupoints of our acupuncture RCT (ClinicalTrials.gov identifier NCT05045820).

Patient-reported outcome measures were collected before, during (weekly), and after the 5-week treatment period to evaluate changes in pain and comorbidities. The Brief Pain Inventory was used to assess pain severity. Pain interference, anxiety, depression, fatigue, and sleep disturbance were assessed using PROMIS-29. The Widespread Pain Index evaluated the spatial extent of pain by the number of body sites endorsed as painful on a body map. QoL was determined using the Pediatric QoL Inventory (both pediatric and adult versions).

Linear mixed-effects models were applied to analyze the treatment's effectiveness by comparing the clinical outcomes among 23 acupressure participants and 14 usual care-only participants compared to their respective baseline at (1) pretreatment and posttreatment; and (2) individual time points before, during, and after treatment phases. Under the same mixed-effects models, patient-reported outcome measure results at time points after pretreatment were further compared to their pretreatment levels for each group separately. Participant-level random intercepts were included to account for within-participant correlations. Time points were included as a categorical variable for potentially nonlinear temporal trends. Given that VOCs and other major events may confound outcomes, models also evaluated the presence of a stressor at each time point (coded as yes or no). Analyses were conducted in SAS 9.4 (SAS Institute, Cary, NC). Two-sided P values < .05 were considered statistically significant. Because this was a hypothesis-generating pilot study, no adjustments for multiple comparisons were made.

Of the 45 participants consented, 5 were lost to follow-up, and 1 withdrew. Thirty-nine individuals (nonrandomized to treatment, n = 9; randomized, n = 30; average retention rate, 82.95%) completed the follow-up phase, and 2 were excluded from this analysis for poor data quality based on incongruent responses between similar surveys (supplemental Figure 1). There were no significant differences in age, body mass index, or sex between the 2 groups. Among the 391 scheduled treatment sessions for the 23 participants with SCD receiving acupressure, only 35 treatment sessions were missed (91.0% adherence). These adherence rates support the feasibility of the treatment. No participants in the treatment group reported side effects.

The acupressure group exhibited significant reductions in all measures after the 5-week treatment (Figure 1), compared to the usual care-only group including pain severity (mean reduction, –2.60; 95% confidence interval [CI], –3.95 to –1.24; P < .001), pain interference (mean reduction, –3.22; 95% CI, –5.66 to –0.78; P = .011), physical dysfunction (mean reduction, –2.51; 95% CI, –4.44 to –0.58; P = .012), fatigue (mean reduction, –4.98; 95% CI, –7.83 to –2.13; P = .001), sleep disturbance (mean reduction, –4.02; 95% CI, –6.29 to –1.75; P = .001), anxiety (mean reduction, –2.14; 95% CI, –4.05 to –0.23; P = .029), depression (mean reduction, –3.13; 95% CI, –4.85 to –1.40; P = .001), and widespread pain (mean reduction, –2.98; 95% CI, –4.91 to –1.04; P = .004). QoL also signified improvement in the treatment group (mean improvement, 9.43; 95% CI, 2.64 to 16.21; P = .008). Stressors significantly affected pain severity (mean effect, +2.94; P < .001), pain interference (mean effect, +2.43; P = .043), and widespread pain (mean effect, +2.46; P = .015) when present.

Longitudinally, participants receiving acupressure in addition to usual care demonstrated greater and more sustained improvement in symptoms than those receiving usual care alone (Figure 1). Pain severity, pain interference, widespread pain, fatigue, anxiety, and depression declined from baseline to week 5 and remained lower throughout follow-up in the acupressure group. Physical dysfunction improved steadily from week 1 and remained significant throughout the follow-up period. Sleep disturbance did not show significant change until week 2, then continued to improve and remained significant throughout follow-up in the acupressure group.

Participants who underwent acupressure reported reduced pain, emotional distress, fatigue, sleep disturbances, physical dysfunction, and improved QoL. Symptom improvements typically reached their peak by the fifth week of treatment and lasted at least 3 months. This hypothesis-generating study achieved its primary goal of demonstrating feasibility and preliminary efficacy of self-administered acupressure, documenting high adherence for 5 weeks, with no adverse effects reported.

This pioneering study primarily investigating feasibility had limitations in study design compared to a randomized double-blinded controlled trial. Given the small sample size and the pilot nature of this study, randomized and nonrandomized participants were aggregated to increase the power (supplemental Figure 1), which might introduce residual confounding. Furthermore, the remote treatment introduces potential confounding factors associated with treatment consistency, because participants must accurately identify acupoints and maintain consistent administration at each session. Although participants were trained and had access to training materials, deviations in protocol are potential confounding factors. The open-label design limits our ability to isolate specific treatment effects from potential placebo effects; however, this limitation is inherent to pilot trials. Large-scale sham-controlled RCTs incorporating SCD populations are needed to validate these preliminary findings and further elucidate the potential of acupressure as an effective telehealth approach for SCD pain management.

Acknowledgment: This research received funding from the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative (Y.W.).

Contributions: L.H. drafted the manuscript and assisted with data collection; A.Q.P. coordinated study procedures, assisted with data collection, and helped revise the manuscript; M.J. assisted with recruitment and data collection of participants recruited at the California site; Z.L. performed data analysis; Y.W. and A.R.W.O. directed patient recruitment at the Indiana site; Z.P. directed patient recruitment at the California site and revised the manuscript; S.E.H. and R.E.H. helped revise the manuscript; and Y.W. revised the manuscript, developed the conceptual framework, and directed the overall performance and quality of the clinical investigation.

Conflict-of-interest disclosure: S.E.H. has consulted for Aptinyx, Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Wayne State University, Indiana University Indianapolis, and the University of Glasgow; and reports grant funding from the National Institutes of Health (NIH), Arbor Medical Innovations, and Aptinyx. R.E.H. has previously consulted for Pfizer and Aptinyx; and reports grant funding from Pfizer, Aptinyx, Cerephex, and NIH. Z.P. has consulted for Vertex, Alexion, Agios Pharmaceutical, and Pharming; has been the site Principal Investigator for clinical trials with Novartis, Novo Nordisk, GBT Pharma, and Pfizer; and a speaker for Agios Pharmaceuticals and Sobi. The remaining authors declare no competing financial interests.

Correspondence: Ying Wang, Department of Anesthesia, Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W 15th St, Indianapolis, IN 46202; email: ywa12@iu.edu.