Abstract
Background
Mechanism of Disease
Polymerization of deoxy-sickle hemoglobin injures the erythrocyte, leading to premature extravascular and intravascular hemolysis.1,2 Acute and chronic vascular endothelial changes facilitate adhesion of sickle erythrocytes and other blood cells, release of inflammatory mediators, vaso-occlusion, and end-organ damage, ultimately shortening the life span of affected individuals. 2
Disease Treatment
Disease treatment involves preventive care and supportive therapies, including hydration, judicious use of blood transfusions, and prophylactic antibiotics. The only FDA-approved therapy for SCD, hydroxyurea, increases levels of fetal hemoglobin and total hemoglobin and reduces frequency of pain crises, blood transfusions, and acute chest syndrome (ACS) episodes. 3 In select patients with severe disease, hematopoietic stem cell transplantation can be curative. 4
Pain and Vaso-Occlusive Crises
As fetal hemoglobin production diminishes around six months of age, painful vaso-occlusive crises (VOC) begin and recur with great variability in frequency and severity. 5 Higher hematocrit, lower fetal hemoglobin, and presence of α-thalassemia trait are associated with increased rates of VOC. While many episodes have no clear trigger, common identifiable precipitants include dehydration, infections, psychological stress, menses, and weather changes. Recent data show one-third of patients having no VOCs for a year, and 17% having more than three, with a 30-day rehospitalization rate of 33%. 6 Frequent VOCs are associated with early mortality, and can lead to chronic and intractable pain syndromes, greatly impacting sleep, mood, and social and physical functioning. 7
Management of the Acute Pain Crisis
Successful pain management in VOCs depends on patient and clinician establishing trust, clearly defined expectations, and reasonable clinical goals. 8 Negative provider attitudes towards acute pain in SCD as well as misperception of pain behaviors as red flags for analgesic addiction lead to undertreatment of pain. 8 Clinicians more familiar with managing acute pain crises are more likely to believe patients' pain ratings. 8
• Pain crises last on average 9–11 days for hospitalized adults (four to five days in pediatric populations). 9
• The physical exam can reveal erythematous, swollen, and tender superficial bony areas (e.g., sternum, spine, ribs, wrists) but more often offers nonspecific findings (e.g., soft, tender abdomen). Although patients may have ‘target’ joints or areas of pain recurrence, they commonly report shift in locations of pain during a hospitalization.
• Management consists of supportive care with fluid hydration and aggressive pain control.1,10
• Rapid initiation and titration of opioid therapies remains a cornerstone for managing acute VOC pain.9,11 If IV access is challenging, parenteral opioids may easily be delivered subcutaneously. One small, randomized trial showed patient-controlled analgesia use was associated with similar analgesia but lower overall opioid use and side effects compared to continuous infusion. 12 Earlier retrospective studies linking morphine use to development of ACS have been refuted. 13
• Many patients' VOC pain is predictable enough to establish patient-specific pain protocols, which give dosing guidelines to clinicians such as emergency department staff who may not be familiar with the patient.
• Nonsteroidal antiinflammatory drugs (NSAIDs) may enhance relief and recovery, 10 although large randomized controlled trials are lacking. There is no proven analgesic benefit to corticosteroids, neuropathic adjuvant agents, or red blood cell transfusions.
• While supplemental oxygen has no proven therapeutic role in patients with normal saturations, hypoxia in VOC may herald serious complications (e.g., ACS, stroke, pulmonary embolism). Incentive spirometry may prevent pulmonary complications leading to ACS. 14
• Low-dose intravenous naloxone infusion may relieve opioid-induced pruritis without affecting pain control. 15
Chronic Pain in SCD
• Chronic pain in SCD is widespread and demonstrated to negatively impact functional status and quality of life. 16 Nearly one-third of patients report pain on most days and most pain exacerbations occur outside of health care settings. 17 Although no evidence supports higher rates of opioid addiction in SCD patients compared with the general population, 18 prescriber fears about addiction remain a barrier to adequate opioid administration. 18 Tensions between SCD patients and clinicians around opioid prescribing more likely reflect pseudoaddiction.18,19
• Chronic pain can develop from objective disease complications (leg ulcers, avascular necrosis) or a less well-understood transformation from persistent repeated acute VOCs into a chronic pain syndrome. 12 Permanent opioid therapy is necessary for some patients.
• Although specific guidelines are lacking, experts recommend an interdisciplinary approach to chronic pain management, and combining intervention modalities, including both pharmacologic (e.g., acetaminophen, NSAIDs, anticonvulsants, tricyclic antidepressants, judicious use of opioids) and nonpharmacologic treatments (e.g., heat, massage, relaxation therapies, distraction, self-hypnosis, prayer/meditation, and acupuncture).8,16