Developing an Implementation Blueprint for the NIH HEAL Initiative GRACE Trial: Perspectives on Acupuncture and Guided Relaxation for Chronic Sickle Cell Disease Pain.

Objective: This study aimed to explore perspectives of people living with sickle cell disease (SCD) and SCD clinic providers and staff about the use of acupuncture and guided relaxation for treating chronic SCD pain. Data obtained were to inform an implementation blueprint for an effectiveness implementation clinical trial (GRACE Trial) testing whether acupuncture or guided relaxation reduces chronic pain when compared with usual care. Design: Qualitative research design. Methods: We conducted 33 semistructured interviews with people with SCD and SCD clinic providers and staff. Interviews were transcribed and coded. A deductive content analysis process was used to identify themes. Results: Four themes were identified: Receptivity to Acupuncture and Guided Relaxation, Limited Awareness, Complementary and Integrative Health (CIH) Therapy Preference, and Access Barriers. Both patients and clinic providers and staff were open to the use of acupuncture and guided relaxation for chronic pain treatment. After learning about these CIH therapies, some patients expressed a preference for one therapy over the other. They also discussed their ability to successfully engage with each therapy. There is a need to dispel misconceptions about the therapies by increasing understanding of how each therapy is implemented and functions to reduce pain. We identified several potential barriers that might affect the success of the trial and future health system integration, including time, transportation, and technology. Conclusion: This study is one of the first to present perspectives of both patients with SCD and clinic providers and staff on the use of acupuncture and guided relaxation for chronic SCD pain. Stakeholders' early input and perspectives highlighted that they welcome nonpharmacological CIH therapies. Implementation of a clinical trial and future health system integration will require the addressing misinformation and identifying strategies to overcome access barriers. Clinical trial registration number: NCT04906447.

Hybrid effectiveness-implementation trial of guided relaxation and acupuncture for chronic sickle cell disease pain (GRACE): A protocol.

Background: People with sickle cell disease frequently use complementary and integrative therapies to cope with their pain, yet few studies have evaluated their effectiveness. The 3-arm, 3-site pragmatic Hybrid Effectiveness-implementation Trial of Guided Relaxation and Acupuncture for Chronic Sickle Cell Disease Pain (GRACE) has 3 priorities: (1) evaluate guided relaxation and acupuncture to improve pain control; (2) determine the most appropriate and effective treatment sequence for any given patient based on their unique characteristics; and (3) describe the processes and structures required to implement guided relaxation and acupuncture within health care systems. Methods: Participants (N = 366) are being recruited and randomized 1:1:1 to one of 2 intervention groups or usual care. The acupuncture intervention group receives 10 sessions over approximately 5 weeks. The guided relaxation intervention group receives access to video sessions ranging from 2 to 20 min each viewed daily over 5 weeks. The usual care group receives the standard of clinical care for sickle cell disease. Participants are re-randomized at 6 weeks depending on their pain impact score. Assessments occur at 6 weeks, 12 weeks, and 24 weeks. The primary outcome is the change in pain impact score and secondary measures include opioid use, anxiety, depression, sleep, pain catastrophizing, substance use, global impression of change, constipation, and hospitalizations. The GRACE study uses the Consolidated Framework for Implementation Research to plan, execute, and evaluate the associated implementation processes. Conclusion: The results from GRACE will represent a critical step toward improving management of pain affecting patients with sickle cell disease.ClinicalTrials.gov Identifier: NCT04906447.

Acupuncture for chronic pain in adults with sickle cell disease: a mixed-methods pilot study.

OBJECTIVE: Chronic pain is a common symptom experienced among patients with sickle cell disease (SCD). Our aims were to assess the feasibility and acceptability of performing acupuncture for the treatment of chronic pain in adults with SCD. METHODS: This was a single-arm, prospective pilot study of six adults with SCD. Participants reported ⩾ 3 months of chronic pain and were > 18 years of age. Per protocol, acupuncture was to be administered twice per week for 5 weeks, for 30 min per session. All treatments were performed in the acupuncture treatment laboratory at the University of Illinois Chicago College of Nursing. Pain intensity, pain interference, and other symptoms were measured at baseline and after the intervention. Participants completed a semi-structured interview and a protocol acceptability questionnaire after the acupuncture intervention. RESULTS: Six participants (mean age 52.5 years, six Black) were enrolled. Although the study was suspended due to COVID-19 and not all participants completed the 10-session protocol, completion rates were high with no missed appointments. One participant did not complete the study due to hospitalization unrelated to acupuncture. No adverse events were reported. At completion of the intervention at 4-5 weeks post-baseline, all participants had reduced pain intensity and pain interference. The mean acceptability score on the protocol acceptability questionnaire was 82%. CONCLUSION: It was feasible and acceptable to implement acupuncture in adults with SCD. This study can be used to guide a larger randomized controlled trial to evaluate the effect of acupuncture on reducing chronic pain in adults with SCD.Trial registration number: NCT04156399 (ClinicalTrials.gov).

Oral administration of the LSD1 inhibitor ORY-3001 increases fetal hemoglobin in sickle cell mice and baboons.

Increased levels of fetal hemoglobin (HbF) lessen the severity of symptoms and increase the life span of patients with sickle cell disease (SCD). More effective strategies to increase HbF are needed because the current standard of care, hydroxyurea, is not effective in a significant proportion of patients. Treatment of the millions of patients projected worldwide would best be accomplished with an orally administered drug therapy that increased HbF. LSD1 is a component of corepressor complexes that repress γ-globin gene expression and are a therapeutic target for HbF reactivation. We have shown that subcutaneous administration of RN-1, a pharmacological LSD1 inhibitor, increased γ-globin expression in SCD mice and baboons, which are widely acknowledged as the best animal model in which to test the activity of HbF-inducing drugs. The objective of this investigation was to test the effect of oral administration of a new LSD1 inhibitor, ORY-3001. Oral administration of ORY-3001 to SCD mice (n = 3 groups) increased γ-globin expression, Fetal Hemoglobin (HbF)-containing (F) cells, and F reticulocytes (retics). In normal baboons (n = 7 experiments) treated with ORY-3001, increased F retics, γ-globin chain synthesis, and γ-globin mRNA were observed. Experiments in anemic baboons (n = 2) showed that ORY-3001 increased F retics (PA8695, predose = 24%, postdose = 66.8%; PA8698: predose = 13%, postdose = 93.6%), γ-globin chain synthesis (PA8695: predose = 0.07 γ/γ+ß, postdose = 0.20 γ/γ+ß; PA8698: predose = 0.02 γ/γ+ß, postdose = 0.44 γ/γ+ß), and γ-globin mRNA (PA8695: predose = 0.06 γ/γ+ß, postdose = 0.18 γ/γ+ß; PA8698: predose = 0.03 γ/γ+ß, postdose = 0.33 γ/γ+ß). We conclude that oral administration of ORY-3001 increases F retics, γ-globin chain synthesis, and γ-globin mRNA in baboons and SCD mice, supporting further efforts toward the development of this drug for SCD therapy.

Risk factors for vitamin D deficiency in sickle cell disease.

Vitamin D deficiency (VDD), 25-OHD levels <20 ng/ml, is prevalent among patients with sickle cell disease (SCD) and is linked to acute and chronic pain and bone fracture in this population. There is limited literature regarding VDD-associated risk factors for SCD. We examined potential clinical and genomic parameters associated with VDD in 335 adults with SCD in a cross-sectional study. VDD was present in 65% of adult SCD patients, and 25-OHD levels independently and positively correlated with older age (P < 0·001) and vitamin D supplementation (P < 0·001). 25-OHD levels were higher in SCD patients over 40 years of age compared to the general African-American population. Both lower 25-OHD levels and increased pain frequency were associated with increased expression of SLC6A5 encoding glycine transporter-2 (GlyT2), a protein involved in neuronal pain pathways. Lower 25-OHD levels were also associated with increased expression of CYP3A4, and with decreased expression of GC (also termed DBP) and VDR, three genes involved in vitamin D metabolism. We conclude that vitamin D supplementation should be an almost universal feature of the care of young adults with SCD, and that further research is warranted into genomic factors that regulate vitamin D metabolism in SCD.

A randomized controlled pilot study feasibility of a tablet-based guided audio-visual relaxation intervention for reducing stress and pain in adults with sickle cell disease.

AIM: To test feasibility of a guided audio-visual relaxation intervention protocol for reducing stress and pain in adults with sickle cell disease. BACKGROUND: Sickle cell pain is inadequately controlled using opioids, necessitating further intervention such as guided relaxation to reduce stress and pain. DESIGN: Attention-control, randomized clinical feasibility pilot study with repeated measures. METHODS: Randomized to guided relaxation or control groups, all patients recruited between 2013-2014 during clinical visits, completed stress and pain measures via a Galaxy Internet-enabled Android tablet at the Baseline visit (pre/post intervention), 2-week posttest visit and also daily at home between the two visits. Experimental group patients were asked to use a guided relaxation intervention at the Baseline visit and at least once daily for 2 weeks. Control group patients engaged in a recorded sickle cell discussion at the Baseline visit. Data were analysed using linear regression with bootstrapping. RESULTS: At baseline, 27/28 of consented patients completed the study protocol. Group comparison showed that guided relaxation significantly reduced current stress and pain. At the 2-week posttest, 24/27 of patients completed the study, all of whom reported liking the study. Patients completed tablet-based measures on 71% of study days (69% in control group, 72% in experiment group). At the 2-week posttest, the experimental group had significantly lower composite pain index scores, but the two groups did not differ significantly on stress intensity. CONCLUSION: This study protocol appears feasible. The tablet-based guided relaxation intervention shows promise for reducing sickle cell pain and warrants a larger efficacy trial. TRIAL REGISTRATION: The ClinicalTrials.gov Identifier is: NCT02501447.

Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease.

Recent evidence of neuropathic pain among adults with sickle cell disease (SCD) reveals a need for adjuvant analgesic treatments for these patients. Ca(2+)/calmodulin protein kinase IIα (CaMKIIα) has a known role in neuropathic pain and trifluoperazine is a potent CaMKIIα inhibitor. The study aim was to determine trifluoperazine's acute effects, primarily on adverse effects and secondarily on pain intensity reduction, in adults with SCD. In a phase I, open-label study of 6 doses of trifluoperazine (0.5, 1, 2, 5, 7.5, 10mg), we obtained 7-hourly and 24-h repeated measures of adverse effects, pain intensity, and supplemental opioid analgesics in 18 adults with SCD (18 hemoglobin SS disease, 15 women, average age 35.8±8.9 years, ranged 23-53) each of whom received a single dose. Data were analyzed with descriptive statistics. Subjects reported moderate to severe sedative effects at 7.5 and 10mg doses, respectively. Eight subjects reported 50% reduction in chronic pain without severe sedation or supplemental opioid analgesics; one of these subjects had dystonia 24.5h after the 10mg dose. The analgesic effect lasted for at least 24h in 3 subjects. Sedation resolved with caffeine and dystonia resolved with diphenhydramine. Adults with SCD experienced minimal adverse effects at doses under 10mg. In this molecular mechanism-driven translational study, trifluoperazine shows promise as an analgesic drug that is worthy of further testing in a randomized controlled study of adults with SCD starting at a dose of 1mg in repeated doses to determine long-term adverse and analgesic effects.

Sickle cell disease: an opportunity for palliative care across the life span.

Sickle cell disease is a chronic illness that affects patients physically and emotionally and can do so at an early age. An ecological model of palliative care that involves improved communication among the health care team, patients, and their families can be beneficial. Open and honest communication regarding advance care planning, disease management, relief of pain and other symptoms, and bereavement and grief are all important for the patient, family, and health care team. Given the multiple acute and chronic complications of sickle cell disease, an approach to care that is holistic and comprehensive may help to improve a patient's biologic function and the perceived health, functional status, and quality of life of the patient and family.