The Management of Sickle Cell Pain Robert E. Richard, MD, PhD

Corresponding author Robert E. Richard, MD, PhD Seattle Cancer Care Alliance, Adult Sickle Cell Clinic, Puget Sound Health Care System, Division of Hematology, University of Washington School of Medicine, 1600 South Columbian Way, S-111-Hem, Seattle, WA 98108, USA. E-mail: [email protected] Current Pain & Headache Reports 2009, 13:295–297 Current Medicine Group LLC ISSN 1531-3433 Copyright © 2009 by Current Medicine Group LLC

Treatment of pain in the setting of sickle cell disease remains unsatisfactory. The approach remains to treat the pain symptomatically with escalating doses of non-opioid and opioid medications while any underlying inciting process is investigated. For the majority of patients with sickle cell disease, pain will always be part of their lives. Advances in the treatment of sickle cell pain will depend on multiple approaches, including both pharmacologic and nonpharmacologic.

Introduction Sickle cell disease (SCD) can be described as the fi rst disease understood at the molecular level. However, the treatment of the disease as well as the disease’s main manifestation, pain, lags far behind the science. The approach to sickle cell–related pain has for far too long been centered in the acute setting and occurs in the emergency department. Although guidelines for the treatment of SCD pain exist, many patients report undertreatment of pain and interactions with caregivers who question their need for aggressive treatment [1,2]. There has been improved understanding of the biology of the sickle cell painful crisis and the complex interactions that occur between the red blood cell and the other components of whole blood as well as the vascular wall. Overall, these results have documented the important effects of the only drug approved specifically for the treatment of SCD, hydroxyurea [3]. Unfortunately, new medications that mitigate the painful episode have not been forthcoming. As the science of pain improves, practitioners who care for people with SCD will need to institute measures developed for other chronic pain syndromes. Improvements in pain treatment will require improvements in care delivery, availability of social services, and improved medications.

Epidemiology of the Sickle Cell Disease Painful Episode SCD is one of the most common genetic disorders, seen primarily in persons of African heritage. One in 700 newborns of African heritage is affected. The understanding of the natural history of sickle cell pain episodes is due to the landmark Cooperative Study of Sickle Cell Disease, which is now almost 20 years old [4]. Data were collected on 3578 children and adults with SCD: 12,290 separate pain episodes were recorded, allowing the researchers to describe more fully the patient with the severe disease phenotype. Patients with hemoglobin SS and hemoglobin S β0 -thalassemia (a complete loss of hemoglobin expression from the thalassemia gene) had more frequent pain episodes compared to patients with hemoglobin SC and hemoglobin S β+-thalassemia (some hemoglobin A production). Interestingly, it was a minority of patients who made up the majority of visits to the hospital. Of these patients, 1% averaged six or more hospitalizations for pain. This result has encouraged investigations into the “severe” sickle cell phenotype [5]. Admissions to the hospital turn out to be the tip of the iceberg for patients who suffer from sickle cell pain. PiSCES (Pain in Sickle Cell Epidemiology Study) is a recently published study in which patients kept a pain diary and recorded their level of pain intensity every day [6••]. Over a 2-year period the study enrolled 308 adult patients. Patients fi lled out diaries every day for at least 6 months, resulting in a total of 31,017 analyzed patient days. Patients reported significant levels of pain 54.5% of the days, and 29.3% of patients reported some level of pain on more than 95% of reported days. Patients reported to their physician, emergency department, or required hospitalization in only 3.5% of the reported pain episodes. This study has confi rmed what many sickle cell patient care providers suspected, that patients spend a great deal of time at home in pain and significantly underreport pain intensity.

Understanding of the Pathophysiology of a Painful Episode The pain of SCD can be directly related to vaso-occlusion, the hallmark of a painful crisis. Long thought to be simply due to sickle red cells blocking small vessels, it is now understood to be a vascular adhesive process that involves erythrocytes, leukocytes, and platelets, as well as changes in important coagulation factors [7,8]. A major shift in

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the understanding of sickle disease has been the description of the role of nitric oxide (NO) in vascular tone. Scavenging of NO by free hemoglobin is now believed to play a central role in the end organ damage that shortens the lives of patients. This has led investigators to propose two main phenotypes of people with SCD, the vaso-occlusive phenotype and the hemolytic phenotype [5,9••]. In the hemolytic phenotype, NO is scavenged by free hemoglobin, resulting in a higher incidence of pulmonary hypertension, priapism, and leg ulcers. Patients with the vaso-occlusive phenotype have higher hematocrits and more frequent painful episodes that are presumably more responsive to hydroxyurea. By defi ning the major pathological processes in each individual patient, care providers may have the ability to tailor therapy to the patient. Drugs such as L-arginine and phosphodiesterase-5 inhibitors that increase the concentration of NO are being tested in patients with SCD [10].

determined that hydroxyurea also prolonged the life expectancy of treated patients [17]. Hydroxyurea should be used to treat adults with sickle cell anemia who have moderate to severe disease, typically those with three or more acute painful crises or episodes of the acute chest syndrome in the previous year. Its use in children is increasing since its safety was demonstrated in the HUG-KIDS study [18]. Hydroxyurea therapy may decrease the risk of stroke in at-risk patients with SCD [19]. Therefore, all patients with SCD with moderate to severe disease should be considered for hydroxyurea therapy, and their dose should be titrated based on the myelosuppressive effect [20••]. Patients often require upwards of 30 to 35 mg/kg of hydroxyurea a day in order to get maximal benefit. Pain episodes that result in hospitalization are also significant because they often precede or occur concurrently with acute chest syndrome, a major cause of mortality in patients with SCD [21]. Early recognition of this catastrophic process is critical so that red cell exchange can be instituted.

Medicinal Therapies for the Management of Sickle Cell Pain Opioid medications are accepted as a necessary part of sickle cell pain management both for acute pain and chronic management. For severe acute crisis-related pain, opioids are the mainstay of treatment. However, it is important to remember that no evidence-based treatment strategies exist for the management of the acute painful episode. The use of clinical guidelines does improve care and should be part of a comprehensive approach to treating patients [11]. Initial treatment should include a non-opioid medication such as acetaminophen or ibuprofen. Most SCD patients in pain will require opioid medications, and for many in the emergency department they will need it delivered parenterally primarily for severity of pain intensity, titratability, and rapid onset of action. For inpatients, recent studies have prospectively evaluated the efficacy of patientcontrolled analgesia (PCA) in both children and adults with SCD [12,13•]. The use of PCA early in the hospitalization resulted in overall decreased opioid usage and improved patient satisfaction. PCA delivery of an opioid medication should now be considered the standard of care for an admitted patient with an acute sickle cell pain episode. Adjuvant medications include the use of antihistamines for the expected pruritis. Sedatives and anxiolytics should be used judiciously for agitated or frightened patients. Laxatives should be routinely prescribed for people receiving regular opioids. SCD is a prothrombotic state [14,15], and prophylactic anticoagulation should be considered for all patients who are at increased risk of thrombosis secondary to immobility or placement of a central venous catheter. The development of hydroxyurea as a treatment for SCD is one of the few success stories in the treatment of SCD. A pivotal study, the Multicenter Study of Hydroxyurea, was published in 1995 and confi rmed the effectiveness of hydroxyurea in preventing painful episodes [16]. Follow-up analysis of the study population

Adolescents With Sickle Cell Disease: A Unique Population Adolescents with SCD face a difficult transition as they move from pediatric care into the care of an adult clinic. Combined with the physical, emotional, and social growth and development that occurs during this period, it can be a critical time to ensure that the patients have a stable approach to their acute and chronic pain issues. Studies of this at-risk population have shown that the majority of pain is managed at home, resulting in school absenteeism and increased social isolation [22•]. Psychosocial issues are critical in adolescent compliance. Adolescents that have optimistic expectations for the future tended to have more successful outcomes [23]. Negative mood in adolescents resulted in higher pain scores and increased health care utilization. In particular, males are at increased risk of school failure. This population deserves increased attention and specialized treatment plans.

Opioid-induced Hyperalgesia in Patients With Sickle Cell Disease Increased sensitivity to pain may be observed in any clinical setting where acute or chronic pain requiring opioids occurs. Sickle cell patients who require escalating doses of opioid pain treatments may be suffering from the syndrome of opioid-induced hyperalgesia [24]. Paradoxically, the chronic administration of opioid analgesics to treat pain may result in worsening of the pain syndrome. When it occurs, the sickle cell patient is often labeled as drugseeking. This syndrome can be difficult to recognize, but the failure to identify this neurotoxicity syndrome could set off a spiral of increasing tension between caregiver and patient, resulting in undertreatment of the patient. Patients can present with delirium, agitation, or restlessness, and

The Management of Sickle Cell Pain

can appear to be irrational. Myoclonic jerks can occur, and the pain does not necessarily follow an expected distribution. The key to treatment is to change the treatment plan to use a different opioid, lower overall opioid doses, and consider including a non-opioid agent such as ketorolac. The addition of a low-dose benzodiazepine may be helpful.

Conclusions SCD pain remains a difficult clinical problem with major consequences for the patients as well as the burden on the health care system. Better understanding of the complex vaso-occlusive process should result in disease-specific therapies that improve upon the present standard of hydroxyurea. Until that time, health care practitioners that care for people with SCD will need to partner with pain specialists to help develop treatment approaches that are individualized for each patient. This is a lifelong endeavor and has been compared to the palliative care approach used in cancer care [25]. Ultimately, cell therapy– based approaches, such as cord blood transplant and induced pluripotent stem cells, will be necessary to affect a permanent cure.

Disclosure No potential confl ict of interest relevant to this article was reported.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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