Pediatr Drugs DOI 10.1007/s40272-017-0263-z

REVIEW ARTICLE

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease Latika Puri1 • Kerri A. Nottage2 • Jane S. Hankins1 • Doralina L. Anghelescu3

Ó Springer International Publishing AG 2017

Abstract Acute vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Multiple complex pathophysiological processes can result in pain during a VOC. Despite significant improvements in the understanding and management of SCD, little progress has been made in the management of pain in SCD, although new treatments are being explored. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment of VOC pain, but new classes of drugs are being tested to prevent and treat acute pain. Advancements in the understanding of the pathophysiology of SCD and pain and the pharmacogenomics of opioids have yet to be effectively utilized in the management of VOC. Opioid tolerance and opioid-induced hyperalgesia are significant problems associated with the long-term use of opioids, and better strategies for chronic pain therapy are needed. This report reviews the mechanisms of pain associated with acute VOC, describes the current management of VOC, and describes some of the new therapies under evaluation for the management of acute VOC in SCD.

Key Points Vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Mechanisms underlying VOC are complex and not completely understood. Pain-management strategies for VOC are welldefined, albeit not sufficient in their current state, as VOC pain remains the most common cause of hospitalization. With better understanding of the pathophysiology of VOC and pharmacogenomics, newer treatments are being explored and may translate into improved pain management and quality of life in patients with SCD.

1 Introduction Electronic supplementary material The online version of this article (doi:10.1007/s40272-017-0263-z) contains supplementary material, which is available to authorized users. & Doralina L. Anghelescu [email protected] 1

Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, USA

2

Janssen Research and Development, Raritan, NJ, USA

3

Division of Anesthesia, Department of Pediatric Medicine, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS 130, Memphis, TN 38105-3678, USA

Sickle cell disease (SCD) is an autosomal recessive disorder caused by a homozygous missense mutation in the HBB gene, which encodes the b-globin subunit of adult hemoglobin (HbA). This mutation produces the abnormal HbS. Deoxygenated HbS forms rigid polymers, resulting in stiff, brittle sickle-shaped red blood cells (SS-RBCs) that form a characteristic sickle shape, are unstable, and occlude microcirculation, causing vaso-occlusion and downstream tissue ischemia. Cellular dehydration accelerates the formation of HbS polymers, whereas re-oxygenation of erythrocytes alters the HbS polymer and

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restores the normal shape. Frequent sickling and un-sickling eventually causes irreversible RBC damage, leading to intravascular hemolysis or extravascular removal by the spleen [1]. Intravascular hemolysis results in release of free hemoglobin, nitric oxide depletion, and oxidative stress. Moreover, the mutated globin can undergo auto-oxidation and precipitate on the inner surface of the RBC membrane, causing membrane damage via iron-mediated generation of oxidants [2]. Although the molecular basis of SCD is well characterized, the mechanisms underlying the vaso-occlusive crisis (VOC) are complex and involve many different pathways and cell lines; some are not yet fully understood [3].

2 The Acute Painful Crisis The acute VOC is a hallmark of SCD and the most common cause of hospitalization [4]. A single institution longitudinal study of 136 adult patients with 1540 admissions over 5 years showed that 95% of admissions were secondary to acute painful crisis [4]. Furthermore, approximately 50% of the patients admitted for acute VOC in this study were readmitted within 1 month of discharge for a previous VOC, emphasizing the frequency of this complication in SCD [4]. A different study noted a similar pattern of readmission for VOC pain in children [5]. The first VOC may occur as early as 6 months of age, often presenting as dactylitis, which manifests as painful edema of hands and feet. Later in life, VOCs occur with variable frequency and a range of locations [4–6]. Clinical features include sudden onset of pain in extremities, chest, lower back, or joints. The painful crisis evolves through four distinct phases: prodromal, initial, established, and resolving [7]. Episodes of VOC are usually precipitated by various known risk factors, including hypoxemia, inflammation, stress, trauma, increased blood viscosity, dehydration, and exposure to cold. Occasionally, they are unpredictable and the trigger remains unknown. Acute VOC can be associated with various complications, most commonly acute chest syndrome (ACS) and, in severe cases, multi-organ failure and sudden death. In addition to acute pain episodes, patients may experience persistent pain between episodes of VOC. This is more common in adolescents and adults [7]. Such pain is challenging to manage as it does not correlate with typical markers of disease severity, does not respond well to disease-modifying therapies such as hydroxyurea [7], and is associated with a high somatic symptom burden [8]. These patients use both long- and short-acting opioids at home without significant relief and often require frequent hospitalizations to treat acute exacerbations [7].

3 Pathophysiology of Vaso-occlusive Crisis (VOC) The vaso-occlusion model has evolved from polymerization-based concepts to a multistep pathway involving complex interactions among the SS-RBCs, leukocytes, endothelial cells, and plasma proteins. Both in vitro and in vivo studies suggest that the SS-RBC has abnormal adhesive properties and activation of adhesion receptors (e.g., E-selectin, P-selectin, basal cell adhesion molecule— Lutheran blood group [BCAM/Lu], intercellular adhesion molecule [ICAM]-4, and cluster of differentiation [CD]-44) [9–12]. Additionally, reperfusion injury in SCD results in endothelial damage and activation, oxidant generation, and elevated cytokines and tissue factors [13, 14]. Interaction of SS-RBCs with vascular endothelium may lead to production of abnormal oxygen species by the endothelial cells and oxygen-dependent activation of transcription factor nuclear factor (NF)-jB. In turn, NF-jB causes an increase in adhesion molecules such as E-selectin, vascular cell adhesion molecule (VCAM)-1 and ICAM-1 on the surface of the endothelium, facilitating SS-RBC adhesion. Endothelial damage also leads to leukocyte recruitment. Circulating white blood cells in SCD exhibit an activated phenotype [15, 16] and potential interactions with SS-RBCs as have been demonstrated in sickle cell mice [17–19]. Additionally, platelet activation contributes to inflammatory pathways as well as activation of the coagulation cascade [20]. Thus, a complex interplay of events leads to the formation of heterocellular aggregates involving the SS-RBC, leukocytes, and platelets [21]. Collectively, the cascade of events mediated by inflammatory markers leads to cell–cell interactions that cause vascular occlusion with tissue ischemia, episodes of recurrent pain, and eventual organ damage (Fig. 1). Recent studies suggest that vascular occlusion and the consequent inflammation are the possible root causes of sickle cell pain [22, 23]. Release of inflammatory mediators from damaged tissue sensitizes nociceptors, which in turn transform the chemical energy generated by the inflammation to an electrochemical impulse in the primary afferent nociceptors. The electrical painful stimulus is then transmitted through the Ad and C fibers to the dorsal horn of the spinal cord via the dorsal root ganglion. Transmission of this painful stimulus is facilitated by glutamate, an excitatory neurotransmitter and inhibited by gamma-amino-butyrate (GABA) [24, 25]. At the level of the dorsal horn, the pain stimulus crosses to the contralateral side and ascends along the spino-thalamic tract to the brainstem, hypothalamus, thalamus, and limbic system, when pain sensation is perceived (Fig. 2). The severity of pain stimulus and type of receptors involved in processing of the stimuli may play a role in determining the nature of VOC [24]. Electrical stimuli in intermittent VOC are weak and mainly involve the a-

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease

Fig. 1 Pathophysiology of vaso-occlusion in sickle cell disease. 1 Red blood cells with deoxygenated HbS form rigid polymers, resulting in brittle sickle-shaped red blood cells (SS-RBCs). 2 The SS-RBCs have abnormal adhesive properties because of activation of adhesion receptors (e.g., E-selectin, P-selectin, ICAM-4, etc.) and increased phosphatidylserine exposure and, thus, increased interactions with leukocytes, platelets, and endothelial cells, resulting in the formation of heterocellular aggregates that cause vaso-occlusion. 3

Vaso-occlusion results in tissue ischemia and inflammation, with subsequent release of inflammatory biomarkers that sensitize nociceptors and result in pain. Inflammatory biomarkers mentioned here are well known to be elevated in sickle cell disease. Research is ongoing to describe various other biomarkers that contribute to inflammation in sickle cell disease. ICAM intercellular adhesion molecule, IL interleukin, TGF transforming growth factor, TNF tumor necrosis factor, VCAM vascular cell adhesion molecule

amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). There is only mild depolarization, and the Nmethyl-D-aspartic acid (NMDA) channels usually remain blocked with magnesium. With stronger and frequent pain stimuli, the NMDA channel is activated by expelling magnesium and a subsequent influx of calcium [24]. Calcium activates a series of intracellular signaling cascades that facilitate transmission of painful stimuli. Furthermore, central sensitization and neuroplasticity also alter the perception of pain by the brain [26–28]. Central sensitization is a process by which excessive nociceptive signals from the periphery to the central nervous system cause changes in the brain and spinal cord that result in continuous amplification of the pain sensation [26, 29]. This is clinically manifested as a reduced pain threshold and allodynia, expanded receptive fields, and persistence of pain even after the original injury has resolved [7]. Various neuroimaging studies also support the important role of central sensitization in pain in SCD [30–32]. Conversely, the descending inhibitory pathways contribute to modulation of pain transmission via serotonin, norepinephrine, encephalin, b-endorphin, and dynorphin.

Thus, the overall outcome of tissue ischemia depends on the extent of the tissue damage and the net balance of pain stimulators versus pain inhibitors [7]. Animal models have provided some insight into pain in SCD [33]. Transgenic mice expressing various levels of HbS were noted to have increased pain behaviors in response to ischemic/reperfusion injury and also demonstrated increased sensitivity to cold, heat, and mechanical stimuli when compared with their age-matched controls [23, 33]. Neurochemical changes in the skin and molecular alterations in the spinal cord and peripheral nerve fibers in the skin support the existence of inflammatory and neuropathic pain in sickle mice [23].

4 Pain Management Overview The clinical outcomes of SCD have improved significantly over the years. The advent of universal newborn screening, better vaccines and antibiotics, penicillin prophylaxis, hydroxyurea, and comprehensive multidisciplinary care have collectively worked to decrease pediatric mortality

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[34, 35]. However, management of acute painful crisis has not significantly changed, and the prevention and treatment of VOC remain suboptimal. The advancements in understanding of the pathophysiology of pain and the pharmacogenomics of opioids have not adequately translated to management of VOC in SCD. The literature supports the use of opioids [36, 37] and non-steroidal anti-inflammatory drugs (NSAIDs), which remain the mainstay of therapy for VOC.

5 Principles of Acute VOC Management Management of an acute VOC should begin with a thorough but rapid assessment of the patient’s pain on presentation, including evaluation of causes of pain other than VOC and the patient’s recent use of analgesics [38]. Analgesic therapy should be initiated within 30 min of triage or 60 min of registration and is a quality care measure for treating patients with SCD [38]. Patients who present with mild to moderate pain and achieve adequate relief with NSAIDs should continue treatment with NSAIDs. However, if pain is severe, with partial to minimal relief from NSAIDs, parenteral opioids should be initiated promptly. Choice of analgesic therapy should consider multiple factors such as recent analgesic use and the patient’s knowledge of effective agents and previous side effects. The use of individualized treatment plans as formulated by a patient’s sickle cell provider is recommended to ensure rapid and effective pain management [38]. Several randomized clinical trials and observational studies support the use of around-the-clock dosing of analgesics with patient-controlled analgesia (PCA) versus intermittent analgesic administration in treating VOCs [39–41]. Patients should be periodically assessed every 15–30 min for response to therapy using validated ageappropriate pain-assessment tools, such as the FLACC scale (face, legs, activity, cry, consolability) [42], the FPS-R (FACES Pain Scale-Revised) [43], or a numeric pain scale [44], for ages \4, 4–7, and [7 years, respectively. Administration of opioids can be repeated at the same or higher doses as deemed necessary to obtain effective pain control, and reassessments should occur within 30 min of each opioid dose [45]. Sedation should also be monitored. In addition to initiation of analgesic therapy, patients should receive supportive care, including parenteral hydration, antihistamines for opioid-induced pruritus, antiemetics, incentive spirometry, and close monitoring of vital signs. The type of intravenous hydration (hypotonic vs. isotonic) is a topic of debate, and although there is some evidence that hypotonic fluids may be beneficial, there is no consensus on the type of fluid to be administered during a VOC event [46, 47]. Bolus amounts should be

administered only if the patient is hypovolemic. Over-hydration should be avoided as it can be associated with the development of ACS [48]. Evidence is lacking regarding an appropriate level of hydration that should be maintained during a VOC. At our institute, we start with 1.59 maintenance (including intravenous and oral fluid intake) and titrate it down as the patient’s pain improves during hospitalization. Adjunctive nonpharmacological measures, such as application of heat and distractive tools, should be used whenever available. Meperidine is no longer recommended for the treatment of acute VOC pain because of concerns about neurotoxicity. Erythrocyte transfusion is also not routinely indicated for the treatment of acute VOC.

6 Pharmacological Management of Pain during VOC Pharmacological approaches to the treatment of acute VOC pain should (1) aim to address the factors that triggered or initiated the VOC episode (i.e., infection, dehydration); (2) include general supportive measures (i.e., hydration); and (3) target the pathophysiologic pathways of pain. Each class of medications used to treat acute VOC pain addresses a different pathophysiological mechanism as outlined in the following sections (Fig. 2). 6.1 Clinical Pathways Interventions aimed at improving the quality of care during VOC include rapid triage; early administration of pain medications; the availability of a clinical protocol to promote rapid, effective, and safe management of pain; and monitoring response to pain medications [38]. Aggressive multimodal management of acute VOC pain has been identified as one of three areas targeted for improvement in pain outcomes, in addition to improved pain assessment and documentation using valid pain tools and better education and support for pain management at home. This recommendation was based on the finding that, during VOC treatment, 95% of opioid doses used were sub-therapeutic or in the low therapeutic range [49]. Therefore, the use of institutional-based clinical protocols, i.e., clinical pathways, for treating VOC has been strongly recommended [49–51]. In our own institutional experience, clinical pathway algorithms are used for the treatment and monitoring of patients with VOC (Appendices I–IV in the Electronic Supplementary Material [ESM]). The implementation of a clinical pathway for VOC management in children in a pediatric emergency department was found to reduce the time interval to first analgesic from 74 to 42 min (P = 0.012) and the time to first opioid from 94 to 46 min (P = 0.013). The percentage of patients who received

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease

ketorolac increased from 57 to 82% (P = 0.03), and the time to subsequent pain score assessment and the change in pain score did not improve [50]. 6.2 Non-Opioid Medications NSAIDs are the first line of therapy for acute VOC pain of mild to moderate intensity. They should be initiated before arrival to the hospital, ideally in the home care setting, and should be included in the clinical algorithms for emergency room departments. Studies of NSAIDs in patients with SCD are limited. The use of intravenous ketorolac for the management of VOC pain crisis was first reported in 1991 with an emphasis on the lack of respiratory depression, sedation, and constipation compared with opioids; it has been suggested that its analgesic effect is equivalent to that of morphine [52]. One small randomized controlled trial of ketorolac added to meperidine compared with meperidine alone showed a reduction in the dose of meperidine used [53]. When compared with intravenous morphine, the dual regimen of ketorolac and morphine showed no additional benefit [39]. However, they are used concurrently as standard of care for management of VOC pain based on their distinct mechanisms of action and different targets along the pain pathways (Fig. 2). The role of selective cyclooxygenase inhibitors in VOC pain has not been explored. 6.3 Opioid Medications Based on strong evidence, prompt initiation of parenteral opioids is highly recommended for severe pain not controlled by NSAIDs or home use of opioids. Any of the available intravenous opioids, except meperidine, (morphine, hydromorphone, fentanyl, nalbuphine) are acceptable as initial therapy for VOC. The decision regarding which intravenous opioid to administer during acute VOC pain is based on individual comorbidities and the patient’s prior response to opioids during previous VOC episodes. For instance, for cases of severe pruritus with morphine and hydromorphone, nalbuphine may be considered an adequate alternative, with potency equal to that of morphine. Individuals with SCD tend to have accelerated morphine plasma clearance, up to twice as high as that of healthy individuals [54], since patients with SCD have increased hepatic and renal blood flow as a consequence of increased cardiac output associated with chronic anemia [55–57]. There is evidence that the glomerular filtration rate is significantly increased in children with SCD, and it progressively decreases with advancing age [54]. These differences should be considered when prescribing opioids, in regards to both dosing and frequency of use. Accepted standard equi-analgesic ratios lead to opioid conversions expressed as equipotent

doses. For adult patients, 10 mg of intravenous or subcutaneous morphine is equivalent to 1.5 mg of intravenous or subcutaneous hydromorphone and to 100 lg of intravenous or subcutaneous fentanyl 100 lg or 20 mg oral oxycodone [58]. 6.3.1 Timing of Opioid Administration as a Quality Indicator The National Institutes of Health (NIH) guidelines recommended the first dose of opioid to be given within 60 min from registration [38]. In a single-center retrospective study of 177 subjects with 414 visits for VOC, the time to opioid administration was independently associated with the area under the curve for pain scores at 4 h, total length of stay in the emergency department, and total dose of intravenous opioids. This suggests that the reduction of time to opioid administrations significantly impacts pain outcomes [59]. 6.3.2 Oral vs. Intravenous Route of Opioid Administration Oral opioids are therapy option in the outpatient setting (home therapy) and occasionally in the hospital setting if pain is considered of low intensity. The most common oral opioids used in the home setting are codeine, oxycodone, and hydrocodone. All are compounded with or without an NSAID or acetaminophen. Codeine use has been recently restricted in the USA to patients aged[12 years because of concerns with over-sedation and respiratory depression leading to death [60]. Similarly, in the EU, the European Medicines Agency has limited the use of codeine to children aged [12 years, for moderate pain, and only after acetaminophen (paracetamol) or ibuprofen have been used first. However, use of codeine informed by the patient’s ability to properly metabolize the drug through typing of the cytochrome P450 (CYP)-2D6 phenotype should guide prescription of this medication to avoid toxicity and maximize its efficacy [61]. It seems intuitive that acute severe VOC pain would be better treated with intravenous opioids. Nevertheless, a study evaluating two regimens of opioid administration for VOC in the emergency department (one regimen of intravenous morphine every 4 h, and another regimen of a first dose administered intravenously followed by oral doses every 4 h for the duration of the stay in the emergency department) found that patients treated with oral morphine had a shorter stay in the emergency department, experienced better pain relief, had lower admission rates, and developed ACS less frequently than patients receiving all morphine doses intravenously. These findings were interpreted to be multifactorial: environmental, cultural, psychological, and pharmacogenetic [62].

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6.3.3 Safety of a High-Dose Opioid Protocol The use of high doses of opioids in patients with SCD may be necessary and justified based on the likelihood of having developed some degree of opioid tolerance, since approximately 50% of adults with SCD are on chronic opioid regimens at home for management of chronic pain [6]. The possibility of opioid tolerance is further supported by an investigation of patterns of opioid use in patients with SCD, which showed that only 25% were not prescribed opioids for chronic use, whereas 47% were prescribed short-acting opioids, and 25% were prescribed both shortacting and long-acting opioids. Investigators have explored the safety-related outcomes of a high-dose opioid regimen during emergency department care and hospitalization and have concluded that this practice is safe for patients with SCD [58]. The protocol allowed up to three doses of intravenous/subcutaneous opioids every 20 min, the second and third doses of which were double the initial standard acceptable adult dose. The larger the dose administered and the shorter the time interval, the more likely patients were to exhibit an abnormal vital sign; nevertheless, no interventions were necessary to correct the vital signs, leading the authors to recommend this practice as safe [58]. 6.3.4 Opioid Use via Patient-Controlled Analgesia It has been shown that PCA is better than an intermittent on-demand opioid regimen [63, 64]. However, evidence to guide the optimal dosing of PCA to treat VOC is lacking. A multicenter, randomized, single-blind, two-arm inpatient trial investigated a higher-demand dose low-infusion (HDLI) regimen compared with a lower-demand dose higher-infusion (LDHI) regimen, using demand dose to infusion dose ratios of 3:1 versus 1:3. The primary outcome measure was time to significant change (25 mm) in average daily pain intensity on a scale of 0–10 during hospitalization. In adults, the outcome was achieved within 2 days for both groups, with a larger decrease (45 mm) within 4.5 days in the HDLI treatment group, and 3 days in the LDHI treatment group, with a significant hazard ratio of 0.245 (P = 0.023), suggesting that infusions rather than demand dosing may achieve or maintain high levels of opioid analgesia. The 12 pediatric participants showed slower improvement in pain intensity than adults, and no difference between treatment arms was noted for this small sample [65]. In a small retrospective chart review of children with SCD treated with opioid PCA, the high-dose bolus with low infusion appeared to be more effective and associated with faster pain control and reduced hospitalization duration than the low bolus dose with high infusion [66].

6.3.5 Alternative routes of Fentanyl use: Transbuccal and Intra-Nasal The accelerated clearance of morphine in patients with SCD supports the evaluation of alternative or additional therapies for acute VOC pain management. The analgesic value of a fentanyl buccal tablet was studied in a crossover comparison during two separate VOC episodes in 20 patients. This study investigated a continuous infusion of intravenous ketorolac plus tramadol compared with fentanyl buccal tablet doses of 100 lg added to the ketorolac plus tramadol, as one to four total doses at least 30 min apart. In both treatment arms, pain was significantly reduced at 6 h as measured by visual analog scale scores. After the initial pain reduction during the first 6 h post-intervention, the ketorolac–tramadol protocol induced a plateau in pain scores, whereas the buccal fentanyl protocol produced significantly and continuously lower pain scores at 6 and 12 h after treatment, suggesting that buccal fentanyl can provide superior control of breakthrough pain during acute VOC pain episodes [67]. Intranasal fentanyl is an attractive pain treatment option in the context of VOC. It has the advantage of a fast onset of action (20 min) and avoids the delays involved with obtaining intravenous access. This fast onset of action corresponds to the time of peak serum concentration [68]. In an urban pediatric emergency department, the use of intranasal fentanyl as the first parenteral medication as two doses 5–10 min apart, during 289 visits for VOC, led to a reduction in the time to first dose of parenteral opioid from 56 to 23 min and an increase in the proportion of patients discharged from 32 to 48%. No increase in 24-h readmission, respiratory depression, or inpatient length of stay was observed [69]. In a randomized, double-blind, placebo-controlled trial in children aged 3–20 years presenting to the emergency department for VOC, 24 patients received a single dose of intranasal fentanyl 2 lg/kg (maximum 100 lg) and 25 patients received an equivalent volume of intranasal saline in addition to the institutional standard of care for VOC. The fentanyl group experienced a greater decrease in median pain score at 20 min compared with placebo, and no serious adverse events were reported [70]. 6.3.6 Tramadol as a First-Line Therapy for VOC Tramadol is a synthetic, centrally acting analgesic agent with a dual mechanism of action as a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake, with analgesic efficacy potency between that of codeine and morphine. The use of a regimen of tramadol and ketorolac continuous infusions in adults has been reported. A pilot study investigated the efficacy of intravenous infusions of ketorolac 0.86 mg/kg/day and tramadol 0.30 mg/kg/h for a maximum of 72 h, combined with

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exchange transfusions, in seven adults with acute VOC pain. This study found that pain scores decreased significantly in all patients and no additional morphine was required [71]. Subsequently, the addition of buccal fentanyl to this regimen during early phases of VOC demonstrated significant improvements in pain [67]. In children, the use of an intravenous infusion of tramadol at a dose of 0.25 mg/kg/h in combination with acetaminophen 40–60 mg/kg/day and ibuprofen 20 mg/kg/day promoted resolution of acute VOC pain [72]. 6.3.7 Nalbuphine Nalbuphine, albeit not commonly used in the USA as a first-line opioid for VOC pain, is the opioid most commonly used for the treatment of moderate VOC pain in France. Questionnaire responses from 81 emergency departments in France indicated that nalbuphine and morphine were used in 71.6 and 85% of centers for moderate and severe VOC pain, respectively. The majority (91.7%) of responders indicated a belief that intravenous morphine provided relief for severe pediatric VOC, but only 30.9% thought intravenous nalbuphine provided relief [73]. The use of nalbuphine as compared with morphine appeared to be associated with a lower incidence of ACS in two retrospective studies. In the first study, the authors identified the use of nalbuphine versus morphine in patients aged 5–19 years admitted for VOC. In 37 (21%) admissions, a diagnosis of ACS was also made (26 [29%] and 11 [12%] in the morphine and nalbuphine groups, respectively; P \ 0.01). The second study was a retrospective chart review of 988 admissions for VOC episodes, which indicated that the incidence of ACS in patients treated with morphine versus nalbuphine was 10.8 versus 2.1%, respectively [74, 75]. If VOC symptomatology is not resolved and admission is necessary for pain control, the use of opioid PCA may be necessary; upon discharge, consideration should be given to a slow wean of the oral opioid regimen based on the short-term use of a long-acting opioid to supplement the asneeded doses of immediate-release opioid (Appendix II in the ESM).

[76, 77]. Ketamine is a phencyclidine derivative, which is a noncompetitive antagonist of NMDA receptors. Low-dose ketamine has been considered a safe adjuvant to opioid analgesia and has occasionally been used in SCD for the treatment of VOC [78]. A literature review [79] based on a few studies [80–82] evaluating either intravenous or oral ketamine in acute VOC pain in 17 adults and children indicated significant improvement in pain and a reduction in opioid consumption in 83% of patients [79]. Low-dose ketamine could be an effective option for patients with opioid-induced hyperalgesia, but larger controlled trials are needed. 7.2 Gabapentin There is emerging recognition that vaso-occlusive pain has both nociceptive and neuropathic components [83]. Gabapentin has been used successfully to treat both neuropathic [84–86] and nociceptive pain [87], and it has synergism with morphine [88]. The mechanism of action is binding of the a2-d subunits of the voltage-dependent calcium ion channels, which blocks the development of hyperalgesia and central sensitization [89, 90]. No data are currently available on the use of gabapentin for acute VOC in patients with SCD. An ongoing phase II clinical trial is investigating gabapentin in addition to standard of care therapy for acute vaso-occlusive pain episodes (NCT01954927) [91]. 7.3 Magnesium Magnesium has vasodilator activity and anti-inflammatory properties. As an NMDA antagonist, it has been shown in some clinical settings to reduce opioid consumption [92, 93]. Magnesium sulfate was used for the treatment of VOC in two small studies with conflicting results [94, 95]. To further investigate, a randomized controlled trial investigated magnesium for the treatment of VOC in children. The primary endpoint was length of stay from the time of first study drug infusion. The study did not demonstrate a significant benefit of magnesium in addition to standard therapy for VOC [96]. 7.4 Rivipansel

7 Pharmacological Management of Acute VOC Pain: Novel Treatment Options and Ongoing Clinical Trials 7.1 Ketamine Opioid tolerance and opioid-induced hyperalgesia can develop because of the activation of the NMDA receptor, resulting in the downregulation of opioid receptors

Rivipansel is a pan-selectin inhibitor that interferes with RBC and leukocyte adhesion which promulgates VOC. A phase II study of rivipansel did not demonstrate a difference in the primary endpoint of time to resolution of VOC, but there was a clinically meaningful reduction in mean and median time to VOC resolution [97]. These findings were sufficient to warrant further evaluation in a phase III trial to definitively determine efficacy in reducing the duration of acute VOC (NCT02187003).

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7.5 Sevuparin Sevuparin is a chemically modified heparin that has retained anti-adhesive properties while minimizing antithrombin properties, reducing bleeding risk. Mouse models have demonstrated normalization of blood flow during VOC with sevuparin use [98]. A phase II trial is currently evaluating the role of sevuparin during acute VOC (NCT02515838) in patients aged C12 years. The primary endpoint is time to resolution of VOC.

8 Pharmacological VOC Prevention 8.1 Hydroxyurea Hydroxyurea is the only medication approved by the US FDA for the treatment of SCD in adults. There are no approved treatments for children, but hydroxyurea is used off-label and is recommended to be offered to all children with SCD beginning at 9 months of age, regardless of disease severity based on consensus guidelines [38]. The clinical benefit of hydroxyurea appears to be due to an increase in hemoglobin F (HbF). Numerous studies have demonstrated the clinical benefit of hydroxyurea as manifested by a reduction in frequency of VOC episodes [99], acute hospitalizations [100–102], transfusions [103], and mortality [45, 103–106], making it the most effective available treatment in reducing morbidity and mortality among patients with SCD. Hydroxyurea should be continued during the treatment of a painful crisis. Though anemia may be exacerbated during these episodes, it is generally not necessary to withhold hydroxyurea during acute VOC. For patients presenting with pain who have not been prescribed hydroxyurea, a discussion with the patient’s primary hematologist or sickle cell provider is warranted regarding initiation of this therapy. Other drugs that induce HbF, such as pomalidomide and decitabine, are in early phase studies; their efficacy in SCD remains unclear [21]. 8.2 Erythrocyte Transfusions RBC transfusions are not an effective therapy for uncomplicated acute painful episodes, and this clinical setting is the cause of the greatest misuse of transfusions in patients with SCD. Transfusions are not without risk, particularly in a population of patients who will likely require numerous transfusions over the course of their lifetime, so the benefits and risks of each transfusion must be carefully considered. For patients in whom hydroxyurea therapy has been maximized without sufficient reduction in painful episodes, chronic prophylactic monthly transfusion therapy (simple

or automated exchange transfusions) can be safely used to decrease the frequency of pain episodes [107, 108]. 8.3 Crizanlizumab Cellular adhesive molecules such as P- and E-selectins contribute to the cellular adhesion of SS-RBC and leukocytes to the vascular endothelium. The SUSTAIN trial was a phase II study that evaluated crizanlizumab, a humanized monoclonal antibody directed toward P-selectin, for the treatment of SCD [109]. The primary endpoint was the annual rate of VOC. Patients randomized to crizanlizumab had significantly fewer painful events over 1 year of treatment compared with placebo (1.63 vs. 2.98; P = 0.01). Adverse events were similar between the active and the control groups. This study indicated that crizanlizumab may have a role in the management of patients with SCD and frequent pain events. 8.4 Prasugrel Prasugrel, an oral agent that inhibits adenosine diphosphate (ADP)-mediated platelet adhesion and aggregation, was studied in children with SCD. Though the drug had a favorable safety profile, there was no significant difference in the rate of VOC between the treatment and placebo groups [110]. However, when stratified by age, children aged 12–17 years experienced a statistically significant reduction in VOC. This may suggest that platelet activation and adhesion is more central to the mechanism of VOC with aging and that this agent may have a role in older children as part of multimodal therapy. 8.5 Apixaban Apixaban is an oral factor Xa inhibitor that is being evaluated in an ongoing randomized, double-blind, phase III study (NCT02179177). The primary endpoint is a comparison of the mean daily pain score between the treatment and control arms. If apixaban is proven beneficial in treating acute VOC, it could be used as an adjuvant to opioids, especially among patients with renal insufficiency, in which NSAIDs are contraindicated. 8.6 Statins Inflammation is a critical component of acute and chronic pain in patients with SCD and contributes to long-term complications. Despite this, drugs targeting inflammation are not used on an ongoing basis. Statins have anti-inflammatory properties in addition to lipid-lowering effects and may have a role in the management of SCD. A small study of 19 patients treated with simvastatin demonstrated

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease

Fig. 2 Pain mechanisms. The red triangle indicates morphine, which provides analgesia via the l-opioid receptor. Location of action: 1 in the periphery (following inflammation), 2 spinal cord dorsal horn, pre- and post-synaptic; 3 brainstem, thalamus (ventral caudal nucleus), somatosensory cortex (role in the somatosensory component of pain), 4 anterior cingulate cortex (role in the affective component of pain), 5 descending inhibitory modulating system (periaqueductal gray, nucleus rapheus magnus, rostral ventral medulla). The red square indicates ketamine, which provides analgesia via antagonism

of the N-methyl-D-aspartic acid (NMDA) receptor. Location of action: 1 reduces transmission of nociceptive signals from the periphery to supraspinal levels, at the primary sensory afferent neuron; 2 modulates descending pathways. The red circle indicates nonsteroidal anti-inflammatory drugs, which provide analgesia via inhibition of the cyclooxygenase enzymes, inhibition of the production of prostanoids in the periphery, and prevention of the sensitizing action on peripheral sensory fibers

reductions in the frequency of pain, oral analgesic use, C-reactive protein, and other soluble inflammatory markers [111]. These data support further investigation of the use of statins in patients with SCD.

8.7 GBT440 GBT440 is an agent under investigation in patients with SCD. The drug binds to the a-chain of hemoglobin and

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increases oxygen affinity. The oxygenated hemoglobin S impedes polymerization in hypoxic conditions. A murine model demonstrated that GBT440 increased the half-life of RBCs and led to a decrease in reticulocyte count [112]. An ongoing phase III trial (NCT03036813) is evaluating the impact of GBT440 on reducing hemolysis and the incidence of acute VOC. 8.8 Cannabinoids Cannabinoids are also being studied for chronic pain associated with SCD (NCT01771731) based on preclinical data suggesting cannabinoids attenuate pain in sickle mice [23].

9 Nonpharmacological Interventions for the Management of Pain during VOC Non-pharmacological therapies, including transcutaneous electrical nerve stimulation (TENS) [59], cognitive behavioral therapy, biofeedback, hypnosis, and massage have all been used as adjunct measures to treat pain in SCD. A literature review of 28 studies that evaluated the effect of non-pharmacological interventions on acute and chronic pain in SCD showed that 12 of these studies reported significant improvement in pain [60]. Over the last decade, virtual reality (VR) has been increasingly used as an adjunctive measure in a variety of clinical settings, ranging from the management of acute and chronic pain [61] to the treatment of psychiatric disorders [62]. It is a technologically advanced system wherein the user is completely immersed into a simulated environment using a head-mounted display, headphones with environmental sound and/or noise reduction, and a head-tracking system. This distracts the user and shifts the focus from pain to the interactive environment, thus resulting in decreased pain perception. This can reduce pain and anxiety during an acute VOC. Its role in the management of VOC pain is yet to be studied. Overall, there is still a strong need for further evaluation of nonpharmacological interventions in VOC.

10 Conclusions The treatment of VOC in patients with SCD has remained unchanged for many years. Hydroxyurea was approved by the FDA nearly 20 years ago and remains the only drug approved to reduce the frequency of painful crises. For treatment to evolve, further early drug development and clinical trials are needed. Fortunately, we are experiencing an era of substantial interest among researchers in

academia and industry, leading to growth in the number of clinical trials to address pain in SCD. Even so, clinical trials of acute pain are challenging to conduct. Numerous study-related procedures need to be completed expeditiously, including informed consent, enrollment/randomization, and delivery of treatment while the patient’s pain needs are being addressed. Around-the-clock availability of research staff and collaboration with emergency medicine colleagues is often required to enroll patients in the acute care setting. Since these studies are resource and labor intensive, many have succumbed to premature termination [65, 113, 114]. National guidelines for the management of VOC are a priority and have been implemented in many regions worldwide with improvement in care [115]. It should be noted that this review is centered around systems and practices in developed countries and may not translate fully to treating patients with SCD in less developed countries. In total, 75% of the global disease burden is centered in sub-Saharan Africa, where the infrastructure needed to provide care is lacking [116]. Despite a disproportionate number of patients with SCD in Africa, these patients have only recently been included in clinical trials for VOC pain [110]. Adult patients with SCD are often well-versed in the treatment of pain given their lifelong experience with painful crises. This is frequently misperceived by healthcare providers as opioid-seeking behavior and a sign of addiction. On the other hand, some patients may be stoic because of developing coping mechanisms and may not exhibit the behaviors expected by healthcare providers. This may result in delays to administration of analgesic medication and mistrust of medical providers [117]. Better education of medical providers, particularly triage personnel, emergency physicians, and advanced practice providers, and the implementation of standardized care pathways and individualized treatment plans can help overcome these challenges. As healthcare providers, we need to be cognizant not to underestimate or delegitimize the pain experienced by patients with SCD. In summary, pain management strategies for VOC are well-defined, albeit insufficient in their current state, as VOC pain remains the most common cause of hospitalization. Though much more work is necessary, with better understanding of the pathophysiology of VOC and pharmacogenomics, newer treatments are being explored and may translate into improved pain management and quality of life in patients with SCD. Acknowledgements The authors would like to thank Brandon Stelter, Sr. Graphic Designer, St. Jude Biomedical Communications, for preparation of the figures.

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease Compliance with Ethical Standards Conflict of interest Latika Puri, Jane S. Hankins, and Doralina L. Anghelescu have no conflicts of interest. Kerri A. Nottage is employed by Janssen Research and Development, Raritan, NJ, USA.

17.

18. Funding No funding sources were used. 19.

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