Evaluation of non-opioid therapies for pain management of sickle cell disease: a literature-based review

Abstract

Pain is a debilitating complication of sickle cell disease (SCD), driven by recurrent vaso-occlusive crises and chronic pain syndromes involving central sensitization and neuropathic mechanisms. Although opioid medications remain first-line therapy for acute pain, there are limitations that highlight the need for effective adjunctive approaches. Available data support non-opioid pharmacologic therapies including acetaminophen and nonsteroidal anti-inflammatory drugs as components of multimodal analgesia, with emerging evidence for therapies targeting neuropathic and centralized pain. Non-pharmacologic interventions such as cognitive behavioral therapy have also demonstrated potential benefits as adjunctive strategies in SCD pain management. This literature review examines evidence supporting non-opioid pharmacologic and non-pharmacologic therapies for pain management in SCD and is based on structured searches of PubMed, MEDLINE, and Cochrane databases.

Background

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy that impacts millions of people globally. According to the 2021 Global Burden of Disease Study, SCD prevalence increased by 41.4% from an estimated 5.46 million individuals in 2000 to 7.7 million in 2021 [1]. The global incidence of SCD remains high, with over 500,000 affected births annually, the majority occurring in low- and middle-income regions [1]. According to the Centers for Disease Control and Prevention in the United States, SCD affects approximately 100,000 individuals, making it the most common inherited blood disorder in the country [2]. SCD arises from a mutation in the β-globin gene resulting in the production of hemoglobin S (HbS) [3, 4]. Under conditions of deoxygenation, HbS polymerizes, leading to red blood cell sickling, membrane damage, cellular dehydration, and increased rigidity of erythrocytes [3]. Sickled erythrocytes promote endothelial adhesion, vascular inflammation, and microvascular occlusion, resulting in ischemia-reperfusion injury and chronic tissue damage [3, 4]. Recurrent vaso-occlusive events contribute to both acute pain crises and chronic pain syndromes through mechanisms involving peripheral sensitization, central sensitization, and ongoing inflammatory signaling [3, 4]. SCD is a complex multisystem disease associated with progressive end-organ damage, variable pain episodes, and reduced life expectancy [1].

Pain is the most common and disabling complication of SCD. Acute vaso-occlusive crisis (VOC) pain arises from ischemia–reperfusion injury and inflammation, while many patients also experience chronic daily pain and acute-on-chronic pain that may involve neuropathic mechanisms and central sensitization. Due to variable pain presentation in SCD, there has been difficulty in finding consistent pain management treatment strategies for patients [5]. Beyond pain, individuals with SCD are at increased risk for complications such as acute chest syndrome (ACS), stroke, and progressive end-organ damage, further compounding functional impairment and overall disease burden [6].

The mainstay treatments that have contributed to improved life expectancy and disease management in SCD have advanced in the last decade [1, 4, 7]. Disease modifying therapies such as hydroxyurea, which increases fetal hemoglobin (HbF) production and reduces erythrocyte sickling, and crizanlizumab, a monoclonal antibody targeting P-selectin-mediated cellular adhesion, have demonstrated reductions in VOC and improved disease outcomes [4, 7]. Additional adjunctive therapies including L-glutamine and arginine supplementation have also demonstrated benefit in reducing oxidative stress, endothelial adhesion, VOC, and analgesic requirements in patients with SCD [4]. In addition to improved access to transfusion therapies, enhanced disease surveillance, and emphasis on multidisciplinary medical care, these advances have resulted in earlier recognition of organ damage, decreased mortality, and improved morbidity [4, 8]. Despite these improvements in survival and disease management, pain remains prevalent and is a major driver of healthcare utilization and morbidity [9, 10].

Acute VOC pain is commonly managed with opioid and non-opioid analgesics like nonsteroidal anti-inflammatory drugs (NSAIDs). Opioids exert analgesic effects primarily through activation of central and peripheral µ-opioid receptors, reducing pain signaling and pain perception[5, 6], while NSAIDs reduce inflammation-associated pain through inhibition of cyclooxygenase (COX) enzymes and decreased prostaglandin synthesis [5, 11, 12]. The goal of this literature-based review is to examine the current medical landscape of sickle cell pain management in conjunction with evaluation of current non-opioid pharmacotherapy and non-pharmacologic therapies to aid in effective SCD pain management.

Burden of pain in sickle cell disease

In the United States, patients with SCD account for over 200,000 emergency department (ED) visits annually, the majority related to acute VOC [9]. It is estimated that approximately 60% of patients with SCD require hospitalization for at least one VOC each year, and nearly 25% seek hospital treatment for five or more VOC episodes within a single year [9]. Ballas and Dampier reported that over a five-year period, 68% of ED visits for SCD-related pain were attributable to only 19% of patients, highlighting a subset of individuals with disproportionately high ED utilization [9]. Reliance on ED-based care is suboptimal for both patients and health systems, as effective management of chronic disease in emergency settings is limited by discontinuity of care, prolonged wait times for analgesia, exposure to infectious environments, and evidence of poorer clinical outcomes [9]. Limited access to specialized sickle cell treatment centers or outpatient infusion services further necessitates ED utilization, contributing to increased visit volumes, longer wait times, and higher health care costs. The burden of SCD therefore extends beyond the individual patient, affecting families, caregivers, workplaces, and broader health-system resources.

Socioeconomic disparities further complicate effective SCD management. Individuals with SCD are predominantly of African, Asian and Middle Eastern descent [13]. These populations are historically disadvantaged, medically underserved, understudied, and experience worse health outcomes [14]. Structural barriers such as limited access to specialty care, under-resourced settings, and bias in acute care may contribute to delayed treatment and poorer outcomes [14]. Adult age, Medicaid use, higher baseline pain burden, and increased comorbidities are significant predictors of high ED utilization among patients with SCD [1, 9, 10]. Patients frequently report missed school or work and, in some cases, job loss due to disease-related complications or caregiving responsibilities [1]. These disruptions can exacerbate financial strain and social instability and have been associated with mental and emotional burnout, post-traumatic stress disorder (PTSD), and additional barriers to consistent medical care. Chronic pain syndromes including avascular necrosis (AVN), central sensitization, post-VOC hyperalgesia, and opioid-induced hyperalgesia are commonly associated with VOC and further complicate pain management in the SCD population [6, 15, 16].

Methods

This literature-based review was conducted using structured searches of PubMed, MEDLINE, and Cochrane databases for english-language studies related to pain management in SCD, with an emphasis on non-opioid pharmacologic and non-pharmacologic therapies that were published from January 1, 2009 to June 1, 2026. Literature reviewed included randomized controlled trials (RCTs), cohort studies, observational studies, retrospective analyses, case series, guideline statements, and narrative reviews relevant to acute and chronic SCD pain management. Priority was given to higher-quality evidence, including RCTs and evidence-based guideline recommendations, when available. However, due to the limited number of large-scale RCTs evaluating pain management strategies in SCD, especially for chronic pain and non-opioid therapies, observational studies and smaller cohort analyses were also included to provide broader context regarding emerging treatment modalities and multimodal analgesic approaches.

The current evidence base for SCD pain management remains limited by a relative scarcity of high-quality RCTs, particularly for chronic pain and non-opioid therapies. Consequently, many therapeutic recommendations rely on observational studies, extrapolated chronic pain literature, and expert consensus guidelines, including the American Society of Hematology (ASH) recommendations. Additional limitations include small sample sizes, heterogeneous methodologies, inconsistent outcome measures, and limited long-term prospective data in SCD-specific populations.

Table 1.

Table of Evidence for Non-Opioid Pain Management Strategies in Sickle Cell Disease

Therapy	Evidence Type	Key Findings	Major Limitations
NSAIDs [5, 11, 12]	RCTs, reviews	Useful adjuncts in multimodal analgesia; opioid-sparing effects in some cohorts	Limited long-term safety data; renal/gastrointestinal risks
Acetaminophen [5, 24]	Small RCTs, reviews	May reduce opioid requirements and hospitalization duration	Limited adult-specific data
Ketamine [25–28]	Small RCTs, cohort studies, case series	Reduced pain scores and possible opioid-sparing effects in acute and refractory VOC	Heterogeneous protocols; limited large-scale RCT data
Lidocaine Infusion [29]	Retrospective studies, case series	Potential reduction in pain scores and opioid use	Small sample sizes; lack of RCTs
Antidepressants (TCAs/SNRIs) [19, 31, 32]	Observational studies, extrapolated evidence	Potential benefit for chronic and neuropathic pain	Minimal SCD-specific RCT data
Gabapentinoids [6, 35]	Meta-analysis, extrapolated evidence	Reported reductions in pain scores	Sparse pediatric and functional outcome data
Acupuncture [23–36]	Cohort and observational studies	Modest reductions in reported pain scores	Small uncontrolled studies
CBT/Digital CBT/Virtual Reality (VR)[37–42]	RCTs, multicenter trials, feasibility studies	Improved coping, reduced pain burden, promising early VR-associated reductions in pain and anxiety	Variable patient engagement, limited long-term outcome data
Physical Therapy/TENS/Massage [6, 13]	Small RCTs, observational studies	Potential functional and supportive pain benefit	Limited high-quality evidence

Review

Current SCD pain management landscape

VOCs are a defining feature of SCD and are responsible for recurrent episodes of severe pain, progressive organ damage, and complications including acute chest syndrome, splenic sequestration, hepatic and renal injury, and multi-organ failure[8, 17, 18]. Pain in SCD arises from both VOC-related and non-VOC mechanisms [17]. Nociceptive pain remains the most commonly reported pain type during acute VOC episodes [13]. However, increasing evidence characterizes SCD pain as chronic, heterogeneous, and influenced by individual pain phenotypes and sensitization processes [3]. Chronic pain represents a major contributor to SCD-related morbidity and is closely associated with central nervous system sensitization [3]. Central sensitization involves amplification of pain signaling, increased N-methyl-D-aspartate (NMDA) receptor activity, reduced pain thresholds, and heightened pain perception [3, 8]. Recurrent VOC-associated ischemic injury to peripheral nerves further contributes to neuropathic pain [13, 17, 18]. Poorly controlled pain is associated with impaired sleep, fatigue, mental health burden, reduced quality of life, and diminished academic and occupational functioning [19].

Acute pain management

Opioids remain the cornerstone of acute pain management in SCD, as outlined in the 2014 National Heart, Lung, and Blood Institute (NHLBI) expert panel report and the 2020 American Society of Hematology (ASH) SCD pain management guidelines. Opioids exert analgesic effects primarily through activation of µ-opioid receptors, reducing pain signaling and pain perception [5, 6]. Acute VOC management emphasizes rapid and aggressive analgesia, with the NHLBI report recommending initiation of analgesic therapy within 30 min of triage or 60 min of registration and reassessment of pain and sedation every 15–30 min [13]. The 2020 ASH guidelines similarly recommend prompt treatment of acute VOC pain within 60 min of emergency department arrival, use of the fastest acting administration route, and consideration of baseline pain regimens and prior effective therapies [6]. Studies have evaluated both intermittent intravenous opioid administration and patient-controlled analgesia (PCA) for management of VOC-related pain, with PCA offering individualized titration and improved patient autonomy in select hospitalized patients, although high-quality comparative evidence remains limited [12, 20, 21]. Despite opioids remaining first-line therapy for severe acute VOC pain, direct RCTs comparing opioid-centered regimens with non-opioid multimodal strategies in SCD remain limited [6, 22]. Most available studies evaluate non-opioid therapies as adjuncts within multimodal analgesic protocols, focusing on opioid-sparing effects, pain score reduction, or hospitalization outcomes rather than direct comparisons against opioid-based treatment strategies [5, 6, 22].

Chronic pain management

Chronic pain in SCD is identified as an area with limited supporting literature; nevertheless, current SCD practice guidelines endorse individualized pain management plans, annual assessment of chronic pain status, and consideration of opioid therapy during severe pain exacerbations when clinically appropriate [6, 13]. For chronic pain in adults, the 2020 ASH guidelines suggest consideration of neuropathic analgesic agents such as serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) including amitriptyline, and gabapentinoids, with recommendations largely extrapolated from fibromyalgia literature and not extended to pediatric populations due to insufficient evidence [6].

Despite their central role, opioid therapies are limited by adverse effects, risks of tolerance, physical dependence, and misuse [6, 8]. Adverse effects include respiratory and central nervous system depression, gastrointestinal side effects, and clinically significant drug interactions [8]. Opioid-induced hyperalgesia has been proposed as a contributing mechanism to chronic pain amplification in SCD, with much of the supporting evidence derived from preclinical and mechanistic studies, including murine SCD models [15]. In addition, patients with SCD frequently encounter stigma related to opioid use and pain reporting [9]. Stigma and bias may contribute to delayed analgesia reinforcing the need for standardized, multimodal approaches [9]. Advances in SCD research increasingly emphasize integrative and individualized pain management strategies, including non-opioid pharmacologic targets and non-pharmacologic therapies. Neuropathic pain has emerged as a critical and previously under-addressed treatment target. Non-pharmacologic interventions such as acupuncture, transcutaneous electrical nerve stimulation, physical therapy, sleep optimization, and cognitive behavioral therapy have gained attention as potentially beneficial adjuncts to pharmacologic management [23].

Although opioid-based therapy remains the mainstay of pain management in SCD, the importance of expanding treatment beyond opioids to include adjunctive pharmacologic therapies, non-pharmacologic interventions, and lifestyle-based strategies cannot be overstated. Multidisciplinary approaches and multimodal analgesia are essential for achieving comprehensive pain control. Multimodal analgesia is defined as the concurrent use of two or more analgesic therapies (pharmacologic or non-pharmacologic) intended to improve pain outcomes while reducing reliance on opioid medications [18]. This approach enables targeting of multiple pain pathways implicated in SCD, including inflammatory, nociceptive, neuropathic, and centrally sensitized mechanisms [12, 18, 22]. In acute VOC, overlapping pain processes such as inflammatory signaling, ischemic nociception, and neuropathic injury are likely to occur simultaneously. Multimodal strategies are also relevant for chronic pain management, particularly in addressing NMDA receptor activation and impaired descending inhibitory pathways involved in central sensitization and mixed-mechanism pain syndromes [18]. The need to expand non-opioid targets reflects the complex pain biology of SCD, the psychological burden associated with chronic pain and stress, and persistent inadequacies in current pain management approaches, underscoring the importance of protocol-driven integration of multimodal analgesic therapies.

Non-opioid analgesic therapy

NSAIDs

NSAIDs are an integral component of non-opioid adjunct therapy in multimodal analgesic protocols, specifically because of their COX inhibition and anti-inflammatory properties [5, 11, 12]. NSAIDs inhibit COX enzymes and reduce prostaglandin synthesis and inflammatory mediators[5, 11, 12]. In the context of SCD, COX inhibition may mitigate inflammatory and vasoconstrictive pathways that accompany ischemia during acute VOC [11]. NSAIDs reduce nociceptive pain and peripheral sensitization secondary to VOC, and can be administered orally (PO), intramuscularly (IM), intravenously (IV), or topically. IV administration route offers the most rapid and reliable analgesia effects. NSAIDs as intravenous administration are effective in moderate to severe pain as adjuncts to opioids in VOC management [5, 12]. RCTs suggest NSAIDs are assistive to multimodal analgesia protocols and are opioid reducing in some cohorts with acute VOC [5, 12].

NSAID use is limited mostly by their side effect profile and risk of renal impairment, gastrointestinal adverse effects, peptic ulcer disease, uncontrolled hypertension, bleeding abnormalities, or other significant cardiovascular disease [11, 12]. NSAIDs must be used in caution with patients taking antiplatelet agents or anticoagulation therapies because of the compounded bleeding risk. Inconsistent trial results and important side effect profile safety concerns require cautious and optimized treatment strategies for long term efficacy and literature supported treatment. The 2020 ASH guidelines suggest a course of 5–7 days of NSAID therapy added to opioids for both adults and pediatric patients with acute VOC related pain [6]. This is a conditional recommendation, as more research is needed to evaluate quantifiable improvement in SCD pain scores and its longitudinal safety profile in this population. Additional RCTs controlling for pain phenotypes, pediatric and adult populations, increased long term safety, and studies highlighting drug-drug interactions from NSAID use are needed in SCD specific populations.

Acetaminophen

Acetaminophen’s (APAP) analgesic effect is believed to involve inhibition of prostaglandin synthesis and modification of descending serotonergic pathways[5, 24]. APAP is available in PO, IV, and rectal formulations, and is advantageous for pain management in SCD due to high availability, low cost, minimal gastrointestinal impacts, ease of dosing, and minimal renal toxicity [5, 6, 24]. APAP is indicated for mild to moderate nociceptive pain and can be utilized as an adjunct to opioid use in severe pain during VOCs[5, 6, 24]. APAP is indicated for use in both pediatric and adult populations. A pediatric RCT with 104 children experiencing VOC, randomized 1:1 to IV APAP (n = 52) vs. IV diclofenac (n = 52) reported that when compared with IV diclofenac, IV APAP had superior analgesia and was able to decrease the length of hospitalization, use of opioids, and side effects of opioid use [24].

Practice guidelines recommend the use of APAP as a component in multimodal analgesia protocols for acute and chronic pain management in SCD [6, 13]. However, caution is required in patients with hepatic disease and concurrent alcohol use. Research gaps with APAP therapy still exist within mostly adult population, with less literature comparing IV APAP to other non-opioid therapies in VOC and scarce long-term data in frequency of use of APAP with both adult and pediatric populations [6].

Anesthetics

Ketamine is an NMDA receptor antagonist that inhibits glutamatergic transmission, thereby reducing central sensitization and modulating inflammatory signaling [25]. Ketamine is used as an adjunctive therapy for hospitalized patients with severe refractory pain that is inadequately controlled with opioids or in those experiencing opioid intolerance or suspected opioid-induced hyperalgesia. Low-dose, subanesthetic IV ketamine infusions have demonstrated potential benefit in SCD patients with breakthrough pain that is poorly responsive to opioid therapy [25, 26]. Small cohort studies have reported clinically meaningful, rapid-onset reductions in pain scores and opioid requirements when low-dose ketamine infusions are incorporated into multimodal analgesic regimens [25]. Additionally, RCTs evaluating low-dose ketamine during acute VOC management demonstrated analgesic efficacy comparable to morphine-based regimens, with some studies suggesting opioid-sparing potential, although adverse neuropsychiatric effects and heterogeneous study protocols remain important limitations [27, 28]. These acute single-dose ketamine protocols differ substantially from prolonged infusion approaches typically used in refractory pain crises.

Ketamine should be avoided or used with caution in patients with elevated intracranial or intraocular pressure, uncontrolled hypertension, active psychotic disorders, or significant cardiovascular disease. Administration requires close monitoring by clinicians experienced in ketamine use and management of associated adverse effects [6, 25, 26]. The 2020 ASH guidelines recommend against the routine first-line use of ketamine infusions for acute VOC pain but acknowledge the potential benefit of low-dose ketamine for pain refractory to opioid treatment [6]. Accordingly, these recommendations remain conditional, reflecting the need for additional high-quality RCTs and the level of monitoring required to ensure safe administration.

Systemic lidocaine exerts analgesic effects primarily through sodium channel blockade and produces anti-inflammatory and anti-hyperalgesic effects [29]. Lidocaine also modulates NMDA receptor activity and attenuates sympathetic overactivity, mechanisms that may be beneficial in both nociceptive and neuropathic pain associated with acute and chronic SCD [29]. IV lidocaine is used as an adjunctive therapy in hospitalized or monitored clinical settings for patients with pain refractory to opioid treatment [29]. In the context of SCD, lidocaine is administered as a continuous low-dose IV infusion, as oral lidocaine is not utilized for SCD pain management. Topical lidocaine formulations, including patches and creams, may provide limited relief for superficial somatic pain but are generally insufficient for moderate to severe pain syndromes [5, 20, 30].

Adjunctive lidocaine infusions have been associated with reductions in pain scores and opioid requirements during VOC management [29]. In a small retrospective review, 8 of 15 lidocaine infusions resulted in clinical success, defined as a ≥ 20% reduction in pain scores, with a corresponding 32.2% reduction in morphine-equivalent dose (MED) among successful treatments [29]. These findings suggest that lidocaine infusions may serve as a valuable component of multimodal analgesia, potentially reducing opioid burden during acute VOC episodes [29]. However, available evidence remains limited by small sample sizes, heterogeneous outcome measures, inconsistent pain phenotyping, and a lack of RCTs. Data on the use of lidocaine infusions for chronic SCD pain are also sparse. Current SCD guidelines do not provide specific recommendations regarding lidocaine use in SCD pain management [6]. Additionally, IV lidocaine is contraindicated in patients with unstable cardiac conduction disorders, and requires caution in patients with hepatic dysfunction, or significant drug interactions with antiarrhythmic agents, necessitating continuous cardiac monitoring during administration [29].

Other pharmacologic adjuncts

Antidepressants

Antidepressants, specifically TCAs and SNRIs, may have promising utility in the management of chronic SCD pain via upregulation of descending inhibitory pathways related to neuropathic pain and central sensitized pain [6, 31–33]. TCAs and SNRIs may provide relief for patients with chronic pain syndromes that develop after recurrent VOC episodes. Modulation of central pain pathways implicated in these SCD associated chronic pain syndromes may contribute to improved analgesic effect[32, 33]. Limited evidence suggests antidepressants may improve chronic pain symptoms, reduce opioid reliance, alleviate neuropathic pain, and help address psychosocial complications associated with SCD [13, 17, 32, 33]. Oral antidepressants are typically inexpensive, covered by insurance, and are easily accessible to the adult patient population.

Practice guidelines suggest the use of antidepressants in adult SCD patients given the increased prevalence of chronic pain complaints in this patient population and the psychosocial comorbidities associated with chronic pain [6]. Due to limited literature, recommendation for the use of antidepressants for the pediatric population were not provided [6]. TCAs may potentiate opioid-related adverse effects and carry risks of prolonged QT syndrome, orthostasis, anticholinergic effects and impaired cognitive function [32]. SNRIs have been associated with side effects including sexual dysfunction, increased bleeding/bruising, leukocytosis, thrombocytopenia, anemia, and increased risk of suicidal ideation in patients less than 25 years of age [32]. Although these hematologic side effects are uncommon, they have not been studied specifically in patients with SCD, so it is unknown if this risk changes within this patient population. In addition, due to the increased risk of suicidal ideation in the under 25 age group, there remains uncertainty if antidepressant use can be recommended for pediatric and younger adult SCD patients. This again necessitates increased monitoring in pediatric and younger adult populations.

Corticosteroids

Corticosteroids have historically been explored as potential adjunctive therapies in SCD due to their anti-inflammatory effects; however, their use remains controversial and potentially harmful in this patient population [34]. A meta-analysis evaluating corticosteroid use in patients with SCD and acute complications showed an increased risk of hospital readmission with corticosteroid use when compared to standard treatment [34]. Consistent with these findings, the 2020 ASH guidelines recommend against corticosteroid use for acute VOC pain management [6]. The guidelines note that corticosteroids may still be indicated for non-SCD related conditions, such as asthma exacerbations, but recommend avoiding corticosteroids specifically for SCD pain management because of associated risks [6].

Gabapentinoids

Gabapentinoids, including gabapentin and pregabalin, bind to the α2δ subunit of voltage-gated calcium channels and reduce the release of excitatory neurotransmitters involved in central pain signaling. Their potential role in SCD pain management is based on the contribution of central sensitization, chronic pain amplification, and neuropathic pain mechanisms observed in some patients with SCD [35]. Available evidence supporting gabapentinoid use in SCD remains limited, and much of the rationale for their use is extrapolated from chronic pain conditions with overlapping features of centralized pain processing, particularly fibromyalgia. According to Häuser et al., a meta-analysis of randomized controlled trials in fibromyalgia patients demonstrated significant patient-reported reductions in pain with gabapentin and pregabalin therapy; however, the studies did not consistently evaluate physical function or long-term outcomes [35].

These findings informed subsequent recommendations for chronic SCD pain management despite limited disease-specific evidence. Practice guidelines suggest gabapentinoids as an option for adults with SCD-related chronic pain, emphasizing that this recommendation is based largely on indirect evidence from fibromyalgia studies because of the limited availability of SCD-specific trials [6]. The guidelines further highlight side effects including weight gain, dizziness, somnolence, and peripheral edema, and note that recommendations remain conditional because of limited evidence evaluating long-term efficacy and safety in SCD populations [6]. Due to the lack of pediatric studies available, the guidelines were unable to make a recommendation regarding gabapentinoid use in children with chronic SCD pain [6].

Non-pharmacologic and integrative interventions

Acupuncture

Acupuncture modulates pain via multiple pain pathways that are especially implicated in SCD including peripheral nerve stimulation and local release of endogenous opioids, alteration of limbic pain processing, and reduction in inflammatory cytokines implicated in VOC related pain [23, 31, 36]. These pain modulating mechanisms within acupuncture make this treatment plausible for implementation into multimodal analgesia protocols for both nociceptive signaling targets and chronic central sensitization of pain. Clinical interest in acupuncture for SCD is further supported by the variety of approaches available (e.g., electroacupuncture, acupressure, and traditional acupuncture) and the potential flexibility of delivery across inpatient, outpatient, and home settings [36]. Acupuncture can be useful in patients seeking to reduce opioid use or those with difficulty accessing opioid therapies, those unable to increase medication doses, those experiencing medication-related side effects, and those with chronic central sensitization of pain and post-VOC hyperalgesia [23, 31].

Modest pain reduction has been observed in select studies, particularly within pediatric populations. A prospective cohort study of 24 pediatric patients (90 acupuncture treatments; 55 treatments had documented pre/post pain scores) reported pain reduction in 65.5% of recorded treatments [23]. Thirteen treatments utilized a pain scale of 0–10 and resulted in a mean pain score decrease from 7.31 ± 1.75 to 6.08 ± 1.85 (p = 0.11). Forty-two treatments utilized a 0–4 pain scale and observed a mean pain decrease from 3.31 ± 0.72 to 2.33 ± 0.98 (p< 0.0001) [23]. However, interpretation of these findings is limited by small sample size, lack of blinding, and reliance on pre- and post-intervention comparisons, which may introduce placebo effects and other sources of bias. Although the available data remain limited and more robust RCTs are needed, early literature suggests acupuncture may provide modest adjunctive benefit for some patients with SCD [23]. Acupuncture is best incorporated as an adjunctive treatment into multimodal analgesia protocols rather than as a primary therapy.

Acupuncture is generally considered safe when performed by trained practitioners [36]. Limitations of acupuncture therapies include patients with coagulopathy, although the risk of bleeding within acupuncture is generally minimal. Specifically related to SCD, risk assessment should consider increased negative outcomes with infections and potential bleeding disorders. Practical barriers remain, including limited insurance coverage, variable availability of trained providers, and reduced accessibility compared with other non-pharmacologic modalities. The 2020 ASH guidelines were unable to provide a recommendation for or against the use of acupuncture in SCD because of limited available literature [6]. The 2014 NHLBI report similarly did not provide a recommendation regarding acupuncture utility but identified acupuncture as a potential non-pharmacologic treatment option requiring additional high-quality SCD-specific trials [13].

Behavioral and psychological therapies

Behavioral and psychological therapies, specifically CBT, have demonstrated encouraging evidence for reduction in pain intensity, improvement in coping strategies, and applications across both pediatric and adult SCD populations [37, 38]. CBT targets maladaptive thoughts and behaviors and helps patients restructure pain perception and behavioral responses to chronic pain [19, 37]. CBT may also help mitigate central sensitization and improve perceived pain burden. Growing interest in behavioral interventions for SCD has led to larger RCTs evaluating both in-person and digitally delivered CBT-based therapies as supportive adjunctive treatments in pediatric, adolescent, and adult SCD pain management [37, 38]. More recently in the CaRISMA trial, mobile and web-based behavioral pain management platforms have been explored in SCD populations as technology-assisted approaches intended to improve accessibility, patient engagement, and non-pharmacologic coping strategies [38]. However according to Oluwole et al., reported outcomes remain heterogeneous, with variability in patient engagement, adherence, and sustained clinical benefit across studies [38]. These approaches are also consistent with multidisciplinary and behavioral health principles emphasized in the recent National Alliance of Sickle Cell Centers (NASCC) consensus recommendations for comprehensive SCD care [39].

Continued robust RCTs are still needed to further define the long-term efficacy and implementation of CBT within guideline-level recommendations. Biofeedback and mindfulness-based interventions add mechanisms of autonomic regulation, sympathetic reduction, and altered attention to pain perception alongside CBT [6, 37, 38]. The practice of biofeedback and mindfulness may serve as useful adjuncts to multimodal SCD pain management and are generally considered low-risk interventions [37]. Barriers include insurance coverage, consistent patient engagement, scheduling costs, provider shortages, and continued measurable improvement in the patient’s overall condition [19, 37, 38]. Digital formats may improve access for some patients but still require reliable internet access, technological literacy, and safe environments for participation. Earlier randomized clinical trials evaluating smartphone-delivered CBT interventions in pediatric SCD populations demonstrated improvements in coping skills, pain management behaviors, and daily activity engagement, further supporting the feasibility of digitally delivered behavioral therapies in this patient population [40].

Emerging interest also exists in the use of virtual reality (VR) based interventions for SCD pain management. Preliminary studies evaluating both acute VOC-related pain and chronic home-based pain management suggest VR may reduce pain intensity, anxiety, and overall pain burden in select patient populations. A 2025 single-center prospective study of 63 adults hospitalized with severe VOC despite IV morphine therapy reported that a 20-minute VR session reduced mean pain scores from 6.4 ± 1.3 to 5.3 ± 1.8 immediately after intervention, with pain reduction sustained at 1 h follow-up (5.6 ± 1.6; p= 0.001) [41]. The proportion of patients reporting high anxiety scores also decreased from 42.9% before VR intervention to 17.8% immediately afterward [41]. Most patients (83.3%) reported high satisfaction with the VR experience, and reported VR-related adverse effects were mild and self-limited, consisting primarily of transient symptoms such as dizziness and visual discomfort [41]. Additionally, feasibility studies evaluating in-home VR interventions for chronic SCD pain management demonstrated acceptable tolerability and patient engagement, supporting the potential role of VR as an accessible adjunctive behavioral intervention [42]. However, current evidence remains limited by small sample sizes, feasibility-focused study designs, heterogeneous intervention protocols, and limited long-term outcome data. Additional larger-scale RCTs are needed to better define the role of VR as a non-pharmacologic adjunct within multimodal SCD pain management strategies.

Physical & supportive therapies

A major focus of movement-based interventions associated with SCD is to combat musculoskeletal deconditioning from reduced movement, reduce pain from AVN, and improve movement and overall function of the patient [6]. Pain associated with SCD may limit patients’ ability to consistently participate in physical activity. High-quality RCTs are limited in SCD specific patient populations. Additionally, supportive therapies such as heat therapies, TENS units, and massage therapies have all been implicated as being beneficial for SCD patients in the management of daily pain [6]. However, this area of study is also impacted by small sample sizes and limited RCTs available for literature support.

Current SCD guidelines do not explicitly provide a recommendation for support for the use of physical therapy and related movement-based interventions as an adjunctive treatment to utilize in SCD pain management due to the lack of RCTs available to substantiate the recommendation. Practice guidelines acknowledge the support of physical therapy in other chronic pain conditions and outline the need for additional research into the impact of physical therapy on SCD specifically.

Discussion

Evidence summary: what actually works?

Across the literature available at the time of this review, the strongest evidence for non-opioid pain management in SCD is supportive of the use of NSAIDs and APAP for acute pain and CBT for chronic pain. These adjunctive therapies are successfully included in multimodal analgesia and overall symptom management in this patient population. Although improved and more robust RCTs for NSAIDs, APAP, and CBT are still needed, the current modest evidence available shows meaningful reduction of pain reported by SCD patients. Additional RCTs are needed to better characterize pain phenotypes, evaluate broader age groups, quantify magnitude of benefit, and define optimal dosing strategies.

Ketamine and intravenous lidocaine represent promising adjunctive anesthetic-based therapies for sickle cell related pain, particularly in patients with opioid-refractory acute VOC or opioid-induced hyperalgesia [25–29]. Both agents target mechanisms implicated in central sensitization and mixed nociceptive–neuropathic pain, and small cohort studies suggest they may reduce pain intensity and opioid requirements when incorporated into multimodal analgesic regimens. However, their use is limited by the need for close monitoring, patient-specific contraindications, and a paucity of high-quality RCTs, underscoring the need for further research to better define efficacy, safety, and patient selection criteria in both acute and chronic SCD pain management.

Modalities such as acupuncture, gabapentinoids, and antidepressants show early promise as adjunctive therapies to further aid in pain reduction. Current SCD practice guidelines, which expand discussion of chronic pain, neuropathic pain, and central sensitization, underscore the substantial evidence gaps that persist in SCD pain management. Existing trials are often small, consisting of heterogenous pain phenotypes, and are limited by short follow-up periods. SCD-specific evidence regarding gabapentinoid use remains sparse, and additional RCTs evaluating pain management strategies in SCD are necessary to better define its clinical utility.

More expansion of research into antidepressant effectiveness specifically within SCD is needed to be able to provide more evidence of backed recommendations for chronic pain management. Small sample sizes, limited RCTs with consistent and measurable outcomes, difficulty in standardizing pain phenotypes, and limited studies on pediatric populations all contribute to gaps in established literature [19, 32, 33]. Currently, antidepressants are best used as adjuncts to SCD treatment, both from pain management and psychosocial management. Physical and supportive therapies carry practical benefits in the day-to-day quality of life in SCD patients; however, remain under-studied and are not consistently implemented into SCD patient care plans.

Overall, the literature suggests that several modalities may provide meaningful improvements in pain scores and contribute to more personalized multimodal regimens for SCD patients. Therapies that target central sensitization, improve coping management, and address chronic pain pathways in conjunction with overall disease improvement should be the target of more robust investigation.

Limitations of the existing literature

Current literature on sickle cell pain management, both non-opioid pharmacologic and non-pharmacologic, is limited by a lack of robust data supporting their effectiveness. Literature is impacted by small sample sizes, short follow-up periods, and inconsistent outcome measures, particularly for quality of life and functional endpoints. Interpretation of many existing studies is further limited by reliance on pre- and post-intervention analyses or uncontrolled case series, as acute VOC naturally improve over time, making it difficult to distinguish treatment-specific benefit from the expected course of illness. Additional larger scale studies exploring treatment options on a more measurable scale are crucial in moving toward targeted and successful therapies. Practice guidelines further report that there exists an absence of data addressing chronic pain in pediatric populations which limit evidence-based recommendations for pediatric and adolescent populations that are undoubtedly also facing chronic pain and complications from recurrent VOCs [6]. The exact mechanisms of VOC cause, severity, and implications are still largely unknown. These gaps are particularly notable given recent NASCC consensus recommendations emphasizing standardized, longitudinal health maintenance and comprehensive outcome tracking in SCD [39].

Future directions

Moving forward in the pursuit of improved therapeutic management of SCD related pain management needs to include extensive research and validation of multimodal analgesic protocols. While these are emerging as potential interventions, the standardization, consistent implementation, and research-backed data require improvement. In addition to multimodal analgesia within pain management, non-pharmaceutical interventions need to be researched and further considered as mainstay treatment recommendations. Many non-pharmacologic therapies are currently not covered under most insurance plans, or patients have limited access to exploring these avenues. Improved access to these modalities in addition to further research exploring the effectiveness of these interventions is vitally important and needed for this patient population.

A priority for future research is the incorporation of patient reported outcomes and improved quality of life measures. Quality of life measures such as day-to-day functioning, sleep quality, impact on school or work, psychosocial burdens, financial impacts, and daily pain scores are inconsistently included in current SCD literature. Patients frequently report frustration with the daily impacts that SCD has on their lives outside of medical boundaries. Patient lived experiences should drive future research, or therapeutic strategies will continue to miss major influences of outcomes and patient success.

Conclusion

Non-opioid modalities are integral to a successful and comprehensive framework of SCD pain management. Sole opioid reliance is an unrealistic assumption for routine care, given side effect impact, potential contribution of opioid-induced hyperalgesia, and access limitations. The unpredictability of VOC and the difficulty of generalizing evidence across both adult and pediatric populations further complicate development of standardized, evidence-driven guidelines. Available evidence supports the adjunctive use of NSAIDs, APAP, CBT, with promising emerging evidence for the use of acupuncture in SCD pain management.

Importantly, the goal of this review is not to advocate cessation of opioid therapy in SCD; rather, it emphasizes the need to broaden therapeutic targets and integrate non-opioid pharmacologic and non-pharmacologic strategies into individualized care plans. A multimodal approach rather than opioid replacement alone represents the most promising pathway to improving pain outcomes in SCD. Although additional RCTs are needed to better evaluate non-opioid therapies in SCD, conducting high-quality RCTs in acute VOC care settings remains inherently challenging due to unpredictable pain crises, variability in patient pain phenotypes, and the need for rapid analgesic intervention.

Author contributions

A.A. and K.R conceptualized the review. K.R. and A.A. performed the literature review and drafted the initial manuscript. R.N. contributed to the clinical application and interpretation of the content. A.A. and R.N. critically revised the manuscript for important clinical content and accuracy. All authors read and approved the final manuscript.

Funding

The authors declare that no financial support was received for the research and/or authorship of this article.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.