For the estimated 100,000 people living with sickle cell disease (SCD) in the United States, pain is a common occurrence. [1,2] In addition to the acute pain resulting from vaso-occlusive crises (VOCs), many of individuals with SCD suffer from chronic pain and associated comorbidities such as depression and anxiety. 
Studies have demonstrated that more than 55% of patients with SCD experience pain on more than 50% of days, and 29% experience pain nearly every day.2 These rates are likely even higher than these findings reflect, as chronic pain in SCD is typically managed at home and thus likely underreported.
While the precise mechanisms have not been elucidated, multiple “underlying causes of pain can contribute to the evolution of chronic pain in SCD, including repeated acute nociceptive pain from VOCs, inflammatory pain, neuropathic pain, and opioid-induced hyperalgesia… all of which lead to central sensitization,” stated Osunkwo and colleagues in a 2020 review. 
In the absence of other proven pain management strategies in SCD, opioid analgesics represent the standard treatment approach for acute and chronic pain in these patients. Nonetheless, increasing reports indicate that pain management in SCD has been complicated by efforts to stem the opioid epidemic. 
While necessary, these efforts have inadvertently “had an adverse effect by creating ‘opioidphobia’ amongst prescribers, thus denying opioids when required for sickle pain,” Kalpna Gupta, PhD, professor of medicine in the division of hematology/oncology at the University of California, Irvine, told us in an interview. 
In the context of the growing drug overdose crisis, a reliance on opioid analgesics may be conflated with drug abuse and addiction, according to Samir Ballas, MD, Emeritus Professor of medicine and pediatrics at Sydney Kimmel Medical College at Thomas Jefferson University in Philadelphia, PA. As he described in a 2016 paper, these negative and stigmatizing connotations have been unfairly applied to patients with SCD in a case of “guilt by association.” 
Across a range of studies, physicians and nurses surveyed suspected high rates of opioid abuse or addiction in patients with SCD.  As a result, some providers have begun to “underutilize or avoid prescribing opioids to treat sickle cell pain,” Dr Ballas told us.
In qualitative study published in 2019 in JAMA Network Open by Sinha and colleagues, 15 patients with SCD reported reduced opioid access, increased stigmatization regarding the use of opioids, provider preoccupation with opioid monitoring at the expense of comprehensive care, and increasing difficulty filling opioid prescriptions in pharmacies. 
As African Americans comprise the majority of the population with SCD in the US, the barriers related to the opioid crisis are likely to intersect with racial bias and discrimination by healthcare providers, thus intensifying the treatment challenges these individuals face. For example, “African American patients are more likely than white patients to be suspected of opioid abuse, subjected to more frequent urine screening, and referred to substance abuse services,” wrote Sinha and colleagues. 
Indeed, study participants reporting negative treatment experiences in the emergency department (ED) believed these were due to stigma which they attributed to racial bias (influencing perceptions of drug-seeking) and limited SCD-related knowledge among ED doctors.6 There is an ongoing need for “education of physicians on the unique pathophysiology as well as chronic and acute symptom management in the clinic and ED,” Dr Gupta said.
Of course, the potential exists for individuals with SCD to develop opioid abuse and addiction. However, it is crucial for providers to avoid making assumptions, check their biases, and adequately evaluate each patient on a case-by-case basis. “Most important in this regard is to differentiate addiction to opioids from opioid tolerance, the withdrawal syndrome, and opioid-induced hyperalgesia,” noted Dr Ballas, who wrote in detail on this topic in a 2020 review. 
In this paper, he explained that the chronic pain in SCD—which he proposed is more accurately described as persistent pain since it differs so greatly from chronic pain in other populations—is unique and thus not well-addressed in the CDC Guidelines for Prescribing Opioids for Chronic Pain.  In 2019, the CDC issued a clarification letter to emphasize the unique nature of pain management in SCD and cancer and stating that the guidelines are not applicable to these groups.
Rather, providers should adhere to the National Institutes of Health guidelines for the treatment of SCD.  Among other points, these guidelines recommend that clinicians respect patients’ self-reports about pain severity and base analgesic selection partly on the patient’s knowledge of the agents and doses that have been effective for them in the past. 
While opioids are currently the most effective therapy for pain in SCD, there is growing interest in identifying effective non-opioid treatment options for this population. Emerging research shows promise for nonpharmacologic approaches that could augment treatment when appropriate and available.
“Cognitive behavioral therapy and integrative approaches such as acupuncture, hypnosis, and other mind-body interventions have shown some effectiveness in clinical studies,” Dr Gupta stated.  Further investigation of these interventions is warranted, along with clinical trials on potentially effective novel pharmacologic therapies.
Dr Gupta reports receipt of consultancy fees and honoraria from several companies. Please see the original references for a full list of disclosures. 
 Centers for Disease Control and Prevention. Data & statistics on sickle cell disease. Updated December 16, 2020. Accessed online July 27, 2021. https://www.cdc.gov/ncbddd/sicklecell/data.html
 Osunkwo I, O’Connor HF, Saah E. Optimizing the management of chronic pain in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2020;2020(1):562-569. doi:10.1182/hematology.2020000143
 Ballas SK. How I treat acute and persistent sickle cell pain. Mediterr J Hematol Infect Dis. 2020;12(1):e2020064. doi:10.4084/MJHID.2020.064
 Sagi V, Mittal A, Tran H, Gupta K. Pain in sickle cell disease: current and potential translational therapies. Transl Res. 2021;234:141-158. doi:10.1016/j.trsl.2021.03.007
 Ruta NS, Ballas SK. The opioid drug epidemic and sickle cell disease: guilt by association. Pain Med. 2016;17(10):1793-1798. doi:10.1093/pm/pnw074
 Sinha CB, Bakshi N, Ross D, Krishnamurti L. Management of chronic pain in adults living with sickle cell disease in the era of the opioid epidemic: a qualitative study. JAMA Netw Open. 2019;2(5):e194410. doi:10.1001/jamanetworkopen.2019.4410
 The ASCO Post. CDC issues clarification on guideline for prescribing opioids for chronic pain in patients with cancer and sickle cell disease. Published online April 9, 2019. Accessed online July 27, 2021. https://ascopost.com/News/59920
 National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report, 2014. Bethesda, MD: National Heart, Lung, and Blood Institute, US Department of Health and Human Services. Accessed online July 27, 2021.
 Sagi V, Argueta DA, Kiven S, Gupta K. Integrative approaches to treating pain in sickle cell disease: pre-clinical and clinical evidence. Complement Ther Med. 2020;51:102394. doi:10.1016/j.ctim.2020.102394