Acute vaso-occlusive pain management in sickle cell disease

INTRODUCTION — Acute pain episodes are the most common reason for individuals with sickle cell disease (SCD) to seek medical attention. The frequency of pain episodes is likely to be underestimated because these episodes are managed at home, especially as individuals with SCD grow older and learn how to manage pain on their own.

Our approach to the acute management of painful episodes in children and adults with SCD is discussed here. Prevention of pain and treatment of chronic pain are discussed in detail separately. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

Separate topic reviews also discuss other aspects of SCD care including evaluation for complications that present with pain, mechanisms of vaso-occlusive pain, and other aspects of the management of sickle cell disease:

●Evaluation for complications that present with pain – (See "Evaluation of acute pain in sickle cell disease".)

●Pain mechanisms – (See "Pathophysiology of sickle cell disease".)

●Clinical manifestations – (See "Overview of the clinical manifestations of sickle cell disease".)

●General management – (See "Overview of the management and prognosis of sickle cell disease".)

●General management (children) – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

●Acute chest syndrome – (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

●Bone and joint complications – (See "Acute and chronic bone complications of sickle cell disease".)

●Investigational therapies – (See "Investigational therapies for sickle cell disease".)

OVERVIEW OF THE ROLE OF PROVIDER ATTITUDES ON EFFECTIVE TREATMENT

Provider misperceptions that interfere with the assessment — Several studies have demonstrated that negative health care provider attitudes interfere significantly with adequate assessment of pain and in turn may lead to insufficient treatment [1].

Examples include not believing the patient's self-report of pain or assuming the patient is drug-seeking because they know which pain medications work best for them. These assumptions can interfere with accurate pain assessment by disrupting trust between the individual in pain, family members, and health care providers [2]. (See 'Clinical assessment of pain' below.)

As discussed below, the rate of opioid misuse in individuals with SCD is lower than in other chronic pain conditions and lower than in the general population. (See 'Opioid side effects' below.)

Stigmatizing or biased language used in the medical record may adversely affect the assessment (and hence the treatment) of pain. In a 2018 trial, 413 physicians in training (medical students or residents in internal medicine or emergency medicine) were randomly presented with one of two hypothetical medical record notes that differed only in the terminology used to describe pain, and they were then asked to choose from four options for pain control [3]. Examples of the language used in the notes included the following:

●Neutral language – Physician note: "He has about 8 to 10 pain crises per year, for which he typically requires opioid pain medication in the ED… On physical exam, he is in obvious distress." Where the authors of the study used the term "crisis," we would say "acute pain episodes."

Nurse note: "He is not tolerating the oxygen mask and still has 10/10 pain…His girlfriend is by his side but will need to go home soon."

●Biased language – Physician note: "He is narcotic dependent and in our ED frequently. At home he reportedly takes 100 mg OxyContin BID and oxycodone 5 mg for breakthrough pain… On physical exam, he appears to be in distress."

Nurse note: "He refuses to wear his oxygen mask and is insisting that his pain is 'still a 10'…His girlfriend is lying on the bed with shoes on and requests a bus token to go home."

Compared with those who received the note that used neutral language, those who read the note that used biased language selected less aggressive pain-control options for the patient (pain treatment score 5.3 versus 4.7, p<0.001) and had more negative attitudes towards the patient (score on the positive attitudes towards sickle cell patients scale [PASS] 25.1 versus 20.3, p<0.001). More negative attitudes also correlated with more years of training.

The scope of misconceptions about SCD-associated pain among practicing clinicians is illustrated in the following examples:

●In a 2005 survey study, 86 percent of physicians in teaching hospitals did not believe that self-report is the most reliable indicator of pain among individuals with SCD [4].

●In a 1997 survey of emergency department physicians and hematologists, 50 and 23 percent, respectively, believed that individuals with SCD were addicted to opioids [5].

●In a 2001 survey of 77 nurses who treat individuals with SCD, 63 percent believed that addiction develops frequently; this belief was especially prevalent in nurses with less clinical experience and less education [6]. Thirty percent of respondents were reluctant to provide high-dose opioids, many believing they were not indicated for SCD pain. Additional barriers to adequate pain management identified by the survey included insufficient time to provide psychologic support, a narrow range of available analgesics, physicians' reluctance to prescribe opioids, and a belief that individuals with SCD are drug addicts.

These misconceptions about opioid abuse in individuals with SCD must be addressed on the clinical service to deliver optimal care. Short educational videos are available to facilitate understanding of sickle cell pain and the influence of provider attitudes on care [7,8]. In a 2010 trial that randomly assigned 276 clinicians (nurses, house staff, attending physicians) to view or not view these videos and then take a survey of their attitudes about sickle cell pain, simply viewing the videos reduced negative attitudes [9].

As discussed below, there is no combination of clinical and laboratory findings that can be used to determine that an individual is or is not in pain; the gold standard for pain assessment is the patient's (or family's) report. A placebo should never be administered to "test" the amount of pain as it undermines the patient/physician relationship and lengthens the duration of pain. (See 'Clinical assessment of pain' below.)

Terms and language we avoid — We specifically avoid the following terms:

●Sickler – The term "sickler" has a pejorative connotation in some countries such as the United States and is linked to negative attitudes toward individuals with SCD, which in turn may be associated with reduced treatment of pain and/or distrust of the patient's report of pain [10].

●Pain crises – We refer to acute pain in individuals with SCD as "painful episodes" or "acute pain episodes" rather than pain "crises." This terminology reflects the nature of the pain, which may begin as severe pain rather than a crisis event and which should be treated at the outset rather than waiting for a crisis to develop. Further, the term "pain crisis" has a connotation that individuals with SCD do not have the ability to manage their acute pain and only present when they are in a crisis, when in fact, pain can often be (and often is) actively self-managed in individuals with SCD. "Pain catastrophizing" has been used to describe a pain experience that is exaggerated. In a 2018 study, individuals with SCD who had higher pain catastrophizing scores used higher doses of short-acting opioids for pain management [11]. Individuals who have increased negative thinking about pain and are not active in the medical management of their pain have been found to have higher levels of pain and greater health care use [12,13].

●Frequent flier – We do not refer to individuals with the disease that often come to the emergency department or hospital as frequent fliers. This is a derogatory and dehumanizing term that has no place in medicine. If an individual has a high utilization of health care resources, we quantify the number of visits to the emergency department or hospitalization using neutral language, or we simply state that the individual has an increased rate of health care usage when compared with other individuals with SCD.

OVERVIEW OF ACUTE PAIN MANAGEMENT — Early, aggressive, adequate treatment of pain is an essential component of the management of SCD (algorithm 1) [14-17].

Key features of acute pain management include the following, which are summarized in a rapid overview table (table 1):

●Home therapy – Every person with SCD should have an individualized plan for treating pain that includes information on how to treat pain at home and whom to contact for prescriptions and/or pain that cannot be controlled at home. (See 'Management at home' below and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Individualized care plan'.)

●Rapid and thorough assessment – For those who present to the emergency department or day hospital, there should be rapid assessment of pain and SCD comorbidities that may require additional treatment. (See 'Clinical assessment of pain' below and 'Possible contributing comorbidities' below.)

●Rapid and effective analgesia – Analgesia should be provided rapidly and its efficacy assessed frequently. Individuals whose pain is not adequately treated should be admitted to the hospital for continuous opioids (preferably using patient-controlled analgesia [PCA]). As noted in the 2020 American Society of Hematology (ASH) guideline, standardized protocols are useful to ensure rapid analgesia for all individuals with sickle cell disease [17]. (See 'Initial pain control' below and 'Continuous opioids/patient-controlled analgesia (PCA)' below.)

●Other considerations – Attention should be paid to hydration status, venous thromboembolism prophylaxis, renal and hepatic function, and potential opioid side effects. (See 'Hydration, adjuvant therapies, and medication management' below.)

The benefit of early and aggressive treatment of pain (eg, treating SCD pain similarly to cancer pain) was demonstrated in a study that compared emergency department visits and hospitalization before and after institution of an aggressive approach to pain management in 50 individuals with SCD [18]. The intervention involved rapid intravenous morphine with controlled-release (CR) opioids added as needed; staff and study participants were instructed regarding the new procedure. Following the intervention, emergency department visits decreased substantially in the entire cohort, and hospital admissions and length of stay declined dramatically in a subset of 15 individuals with the greatest frequency of acute pain episodes (77 versus 35 admissions over a six-month period; 173 versus 462 days in the hospital), without any compensatory changes in the use of other services.

CARE OUTSIDE OF THE EMERGENCY DEPARTMENT

Management at home — Home management is the most frequent setting for acute (and chronic) pain management in SCD (table 2). Evidence to support home management as the most common location for acute vaso-occlusive pain is demonstrated in a prospective series of 232 adults with SCD who completed a daily pain diary for up to six months (the Pain in Sickle Cell Epidemiology Study [PiSCES]) [19,20]:

●Daily pain was reported by 29 percent

●Severe pain that prompted medical attention was reported on 3.5 percent of days

●Pain was managed exclusively at home (without medical attention) on 38 percent of days, approximately 80 percent of which included use of opioids

The authors concluded that pain was the rule rather than the exception, despite relatively infrequent emergency department (ED) or office visits for pain control.

Home management should include access to short- and long-acting opioids, with a clear plan and instructions for when to seek medical attention.

●Individuals not receiving chronic opioids are given a prescription to fill and a plan that is tailored to the pain level and the therapies available (table 2).

•Non-opioid therapy is used for mild pain (table 3). Medications may include acetaminophen or a nonsteroidal antiinflammatory drugs (NSAID) in selected individuals with mild pain, as suggested by an expert panel from the National Heart, Lung, and Blood Institute (NHLBI), as well as other expert reviews [14,15,21]. In the Pain in Sickle Cell Epidemiology Study (PiSCES), at least 10 percent of the adults with SCD used non-opioid analgesics for pain control [20].

•Adjuvant therapies such as relaxation and breathing exercises and/or local measures such as heat are included. Ice and cold compresses should be avoided because they may precipitate sickling.

•As pain severity increases, opioids of escalating strengths are used (table 4 and table 5).

•When pain is severe, continuous opioid therapy is needed (table 6).

●For individuals with chronic pain who are already receiving opioids, the home management of pain should begin with a dose of opioids that gave relief during prior pain events and escalate from there. Individuals who require long-acting opioids on a regular basis should have additional short-acting medication for breakthrough pain such as morphine, oxycodone, or hydromorphone (Dilaudid). (See 'Pain medication outside the ED' below.)

●Clear guidance regarding warning signs of more serious complications and when to seek medical attention should be provided, along with easy access to telephone numbers.

•Medical attention should be sought for fever, cough, or other signs of infection. Emergency medical attention should be sought for associated symptoms suggesting stroke, acute chest syndrome (ACS), splenic sequestration, aplastic crisis, or other severe SCD complication.

•There should be a clear plan for when to seek medical services and whom to contact if oral analgesics at home do not provide adequate pain relief. This may involve evaluation by the primary clinician, emergency department familiar with the care of individuals with SCD, or day hospital.

Day hospital/infusion center — SCD day hospitals are staffed by clinicians familiar with SCD care who can provide rapid evaluation and treatment of uncomplicated pain using a pain plan tailored to the individual's analgesic history. Studies suggest that management in an experienced day hospital or infusion center rather than the ED results in better outcomes:

●A study from 2021 that compared pain management in 483 adults with SCD who were treated in an infusion center versus the ED found better outcomes with infusion center treatment (faster administration of pain medication, greater likelihood of rapid reassessment, lower likelihood of hospitalization) [22]. Four infusion center sites were included: two dedicated to SCD and two that also see other hematology-oncology patients. Since infusion centers were closed on weekends, only weekday visits were evaluated, resulting in data for 1441 visits in 269 individuals. The time to first dose of pain medication was 132 minutes in EDs and 62 minutes in infusion centers (70 minutes faster, 95% CI, 54-98 minutes). Pain reassessment at 30 minutes was 3.8 times greater in infusion centers (95% CI, 2.6-5.6). Patients were four times more likely to be discharged home from the infusion center than the ED (95% CI, 3-5 times). Findings were consistent across infusion center sites.

These data clearly demonstrate and reinforce the clinical practice in many SCD centers for children and adults with SCD. The ED is not the best place for management of SCD-related acute and chronic pain. Many SCD centers have either a formal strategy for management of acute pain in their hematology-oncology clinics during the day or in a day hospital, and this study confirms the clinical efficiency of an infusion center when compared with the option of sending individuals with acute vaso-occlusive pain to the ED.

●A study from 2000 that compared pain management in a day hospital (2259 visits) with the local ED (2401 visits) found that those treated in the day hospital had a shorter visit for initial pain control (4.5 versus 13 hours), lower hospital admission rate (8 versus 51 percent), and similar rate of revisit (9.5 percent for each) [23].

●Another study reported a reduction in hospitalization rate from 207 to 104 annually during five years of day hospital implementation [24].

Pain medication outside the ED — Opioid therapy includes controlled-release (CR) agents such as oxycodone and morphine, along with short-acting agents for breakthrough pain.

●For more severe pain, hydrocodone can be used, followed by immediate-release morphine, followed by a long-acting agent such as CR-morphine or CR-oxycodone.

●CR products have different onsets of action. CR-morphine products such as MS Contin can take two to four hours until peak onset, whereas the CR-oxycodone product OxyContin will take only approximately half an hour to peak onset. Thus, if CR-morphine is used for severe pain, it can be accompanied by immediate-release morphine to use until the long-acting product becomes effective. In addition to the shorter time to onset of pain relief, CR-oxycodone has a longer duration of action than CR-morphine (approximately 12 versus approximately 8 hours). Treatment with CR opioids can be continued for the duration of the pain event and then discontinued.

●Opioid with acetaminophen combinations is not recommended but if used, should be limited to a fixed duration of time (eg, 48 to 72 hours) to avoid acetaminophen toxicity and/or masking of fever from a concurrent infection.

●Codeine and acetaminophen combinations are no longer recommended in the routine management of pain in children under 12 years of age. In older children, these agents should be used with caution because of the association with difficulty breathing and death [25].

●Codeine will not provide adequate pain relief for many individuals who have a cytochrome P450 gene polymorphism that decreases metabolism to the active opioid. In a study of 73 children with SCD for whom codeine was ineffective, 42 (58 percent) had reduced-function alleles in CYP2D6 [26]. Codeine should only be used for individuals for whom it is previously known to be effective.

Many individuals self-medicate with cannabinoids or other adjuvant therapies (see 'Adjuvant therapies' below and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Cannabinoids'). These may be helpful for selected individuals, and it is important for clinicians to be aware of the approaches each individual is using and whether the therapy is a helpful addition for that person.

MANAGEMENT IN THE ED AND HOSPITAL

Clinical assessment of pain — Pain in SCD is intense; it can begin as early as six months of age and typically lasts throughout life [2,27]. The vast majority of individuals with SCD have true, severe, often incapacitating lifelong pain, use pain medication appropriately, and do not have drug-seeking behavior or a substance abuse disorder. The cornerstone of evaluating a pain episode in an individual with SCD is the trust between the individual and the treating health care provider(s). The lack of trust between a patient in acute pain and a provider is common in the emergency department (ED) and hospital, where individuals caring for the patient may be less familiar with SCD and may be meeting the patient for the first time.

The gold standard for assessment of pain is the individual's (or family's) report; no combination of clinical and laboratory findings exists to determine (or confirm) whether an individual with SCD is in pain [2,14]. Specifically, the absence of hemolysis or stability of the hemoglobin level should not be used to justify withholding of pain medication or administration of a lower dose. This is especially true in individuals with hemoglobin SC (Hb SC) disease, whose pain episodes may be triggered by hyperviscosity and who may present with a low-normal or normal hemoglobin level. Failure to adequately assess and appreciate the intensity and cause(s) of pain may lead to unnecessary withholding of opioids, which in turn may worsen pain and coping mechanisms [2].

The perspective of the individual in pain (or parent/family member) should be sought regarding whether the pain is typical or atypical of usual pain episodes. Pain that is not typical raises greater concern about other sources of pain in addition to vaso-occlusion. (See 'Possible contributing comorbidities' below.)

Acute pain should be assessed rapidly so as not to delay analgesia (table 1). Pain should be characterized according to location, severity, duration, exacerbating factors, and potential comorbidities:

●Location – The locations of pain vary between individuals and at different times for the same individual. The main locations for acute vaso-occlusive pain include long bones, abdomen, and chest; multiple sites are often involved [28,29]. These and other common sites of pain are illustrated in the figure (figure 1) and described in the following reports.

Infants and toddlers may present with dactylitis (pain and swelling from infarctions involving the hands and feet) [30].

In a series of 145 outpatient adults with SCD who were asked to describe the characteristics of their typical pain, the sites most commonly involved were [31]:

•Upper back – 63 percent

•Left arm – 61 percent

•Right arm – 35 percent

•Legs – 30 to 40 percent

•Chest – 26 percent

•Abdomen – 26 percent

•Lower back – 12 percent

Similar locations were documented in a series of hospitalized adults [32].

●Intensity and quality – The intensity of SCD pain can vary from mild to debilitating [2]. The Cooperative Study of Sickle Cell Disease (CSSCD) defined a pain episode as pain related to SCD lasting at least two hours and leading to a clinic visit or hospitalization [28]. However, this underestimates the true degree of pain because many individuals have pain that is treated at home and hence does not lead to a clinic or emergency department visit.

Assessment of pain intensity depends on the age of the individual. Toddlers and young children may exhibit irritability or pain on palpation but may be unable to provide a verbal description. For older children and adults, the severity of pain may be assessed using a tool such as a the Wong-Baker FACES scale (for young children) (figure 2) or a visual analog scale (for adolescents and adults) (figure 3); other scales such as the African American Oucher Scale or a simplified five-point scale have also been used [2,33,34]. While these tools are helpful and important, their use should not delay prompt analgesia.

Neuropathic pain, which may include components of central sensitization, peripheral nerve injury, and/or hyperalgesia, increases with age and is likely underdiagnosed in individuals with SCD [35]. Symptoms include hypersensitivity to touch with increased pain from normal stimuli (allodynia), often with extreme sensitivity to temperature. Therapies directed at neuropathic pain are discussed below. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Chronic pain'.)

●Duration – SCD pain may last for hours to days; some people with SCD never become completely pain-free.

One study described four phases of a painful episode (figure 4) [1]. These include a prodromal phase consisting of numbness, aches, and/or paresthesias lasting up to 24 hours before the development of acute pain; an initial/infarctive phase of acute pain lasting two to three days; a postinfarctive inflammatory phase; and a resolving/recovery phase.

Hospitalization for uncomplicated acute pain in children and adults with sickle cell disease is approximately 4.5 [36-38] and 7 days, respectively. Children and adults with SCD with uncomplicated acute pain episodes in the hospital beyond six days and 10 days, respectively, should be evaluated for secondary causes of pain or altered pain sensation. Such an evaluation should not include denial of pain. Acute pain episodes that last for a period of several weeks are atypical and warrant alternative explanations, including consideration of comorbidities, such as depression.

Possible contributing comorbidities — Failure to appreciate complications associated with pain such as ACS or acute stroke may lead to serious and potentially life-threatening complications. As noted in a 2014 guideline from the National Heart, Lung, and Blood institute (NHLBI), individuals with SCD presenting with acute pain are at risk for other complications such as ACS, which often require other interventions in addition to pain control [14]. Evaluation for other sources of somatic and visceral pain is discussed in detail separately. (See "Evaluation of acute pain in sickle cell disease".)

Comorbidities may also develop during hospitalization; individuals with SCD who are in pain often develop acute pulmonary events or hypoxic episodes, and ongoing or intermittent assessment of pulse oximetry should be part of the routine vital signs for these individuals, along with close monitoring for clinical changes including tachypnea, wheezing, intercostal muscle retraction, and/or nasal flaring. If these findings develop, immediate reassessment of oxygen saturation and pulmonary status is required.

Initial pain control — Most individuals with SCD-associated pain will only present to the emergency department or day hospital when their pain has exceeded what they can manage at home with oral opioids. Thus, pain is likely to have been escalating; prompt treatment is needed (algorithm 1). Management is based on the cardinal principles outlined by the American Pain Society (APS) and an evidence-based guideline from the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) [2,14,21,39]. These principles include the following components:

●Prompt administration of pain medication (within 30 minutes) – Acute pain should be treated in the emergency department or day hospital as an Emergency Severity Index (ESI) of 2 (table 1). Triage wait time should be within 15 minutes, and analgesia should be provided as soon as possible, in less than 30 minutes [14,40]. Opioids are used. The intravenous route is preferred; subcutaneous or intranasal administration can be used for those with difficult intravenous access.

•For individuals who have previously been treated for a pain episode, the individual's pain treatment plan should be followed; the starting dose of opioid is chosen based on the intensity of current pain compared with previous pain and effective doses.

•For those for whom the previous opioid dose is unknown, there may be an institutional pain plan for people with sickle cell disease.

•Options for opioid therapy include intravenous morphine (0.1 to 0.15 mg/kg; maximum initial dose 10 mg) or intravenous hydromorphone (0.02 to 0.05 mg/kg; maximum initial dose 1.5 mg), with rapid reassessment of pain after the dose is administered [2,41]. Caution should be used in situations where the previous starting dose was greater than the upper limit of the typical standard dose (eg, >10 mg for morphine or >1.5 mg for hydromorphone) due to risks of sedation.

•Intranasal fentanyl has been safely used in the initial acute emergency department management of SCD pain, particularly in pediatrics [42]. This agent is rapid-acting, has a short duration of action, and avoids delays associated with obtaining intravenous access. It should be part of a standardized emergency room protocol in which patient eligibility, triage plans, and follow up medication is well defined. Intranasal fentanyl should be restricted to two doses. A 2014 Cochrane review of the use of intranasal fentanyl found it to be effective for pain control in children >3 years of age without SCD who had moderate to severe pain [43]. For children who weigh ≥10 kg, two doses of 1.5 mcg/kg administered 5 to 10 minutes apart (maximum single dose 100 mcg) have been administered [42]. Use of this agent requires knowledge of substantial differences in the pharmacologic profile compared with other fentanyl preparations. In contrast to children, there is a lack of high-quality randomized controlled trials in adults with SCD addressing the efficacy and risks of intranasal fentanyl.

•Some pain protocols are incorporating ketamine for initial pain control in the emergency department. This may be appropriate depending on institutional protocols. A trial involving 278 adults with SCD who presented to the emergency department with acute pain and still had pain after treatment with a non-opioid analgesic (intravenous acetaminophen or an NSAID) after 30 minutes randomly assigned participants to receive a single dose of morphine (0.1 mg/kg) or ketamine (0.3 mg/kg) and found comparable reductions in pain over the next two hours [44]. A review of pediatric practices that included seven adolescents with SCD found that low dose ketamine (1 to 10 micrograms/kg/min) was associated with reductions in pain [45]. The authors commented that ketamine seemed to be effective for some patients and not others. More efficacy data are needed. Ketamine may also be used for pain that does not respond to opioids. (See 'Ketamine for acute pain not responsive to opioids' below.)

●Rapid reassessment and repeat dosing if needed – Reassessment is made shortly after the opioid administration is expected to take effect (approximately 20 minutes after administration for morphine, 30 minutes after hydromorphone). Rapid reassessment is critical because many individuals will not have relief of pain from initial dosing [46]. Individuals with severe pain may require repeated doses of intravenous morphine 0.02 to 0.05 mg/kg every 20 to 30 minutes to achieve pain relief.

•If pain relief is adequate with a single dose of opioids, it may be appropriate to discharge the individual home with a long-acting opioid such as CR-oxycodone with a prescription for a short-acting medication for breakthrough pain. (See 'Management at home' above.)

•Repeat dosing is used if pain relief is inadequate from the initial dose. Repeat dosing is typically at 20 percent of the initial dose (or up to 50 percent of the initial dose, based on clinical judgment and the patient's previous treatment). Reassessment should occur within 30 minutes and retreatment given if needed.

The opioid dose generally should not be adjusted sooner than approximately 20 minutes for morphine or 30 minutes for hydromorphone, as this may lead to significant side effects such as respiratory depression or somnolence.

•Fentanyl given intranasally can be used during triage to stabilize the patient and minimize suffering before the availability of standardized emergency room parenteral medication is available. It should be restricted to a maximum of two doses 5 to 10 minutes apart. This use applies to programs that have protocols for its use and not as a substitute for other therapies.

•If pain is not relieved with three or more doses of morphine or hydromorphone, hospitalization for around-the-clock parenteral analgesics is generally indicated. (See 'Continuous opioids/patient-controlled analgesia (PCA)' below.)

•The individual should be monitored by pulse oximetry and rapidly evaluated for changes in pain that may be associated with development of another SCD complication, as well as monitored for sedation. (See 'Possible contributing comorbidities' above and 'Opioid side effects' below.)

●Avoid ineffective therapies

•Placebo therapy should never be used as it undermines the patient/physician relationship and lengthens the duration of pain.

•Sedatives and anxiolytics should not be used to treat pain, as they will mask the behavioral response to pain without providing analgesia [2]. However, these medications may be appropriate for treating anxiety and/or insomnia, and they should not be withheld if the individual is taking them as an outpatient, due to risks of withdrawal, increased anxiety, and/or insomnia.

•We do not recommend the routine use of ketorolac in individuals hospitalized with acute painful episodes. Some programs use ketorolac as a narcotic-sparing therapy for individuals with SCD, and this practice may be reasonable when used in the emergency department for a short period of time (up to 12 hours). However, there is significant acute and chronic renal injury associated with this agent, and there are no randomized controlled trials demonstrating any efficacy of ketorolac in an inpatient setting for individuals receiving opioids to relieve pain. There are some limited reports of beneficial effects of ketorolac in SCD, particularly in patients experiencing bone pain [47].

Importantly, published as well as unpublished evidence indicates that even a single dose of ketorolac given during an acute vaso-occlusive pain event was associated with acute kidney injury (AKI) [48]. Among the patients who received at least one dose of ketorolac, the odds of developing AKI increased by 63 percent (odds ratio [OR] 1.63, 95% CI 1.08-2.47) for every additional day a participant received ketorolac. Thus, we believe the known toxicity of ketorolac, for even a short period of time, outweighs its unproven benefit for hastening recovery to baseline for acute vaso-occlusive pain events requiring hospitalization. Its use should be limited and designated for specific cases that demonstrate clinical efficacy, and even then, close monitoring of kidney function and assessment for intestinal bleeding should be repeated daily. (See 'Therapies we do not use' below.)

•NSAIDs other than ketorolac are generally not appropriate for individuals with pain requiring hospitalization, although their use should be assessed on a case-by-case basis and may be appropriate for selected individuals with mild pain who are expected to benefit based on prior experience. The true benefit of NSAIDs in SCD is uncertain and unproven; small observational studies have shown inconsistent results [49-53]. The risks of gastrointestinal bleeding, renal disease, and other complications are all reasons to avoid routine NSAID use in hospitalized individuals with SCD. NSAIDs compromise renal blood flow and reduce glomerular filtration rate (GFR) by approximately 15 percent [54]; this effect is highly dependent on increased prostaglandin production in SCD and increases the risk for NSAID-induced acute renal failure (see "Sickle cell disease effects on the kidney"). When used, the duration of NSAID therapy should be limited to four days [55]. NSAIDs should be avoided in individuals with renal insufficiency or those at risk of acute renal failure due to deleterious effects on renal blood flow [56,57]. In pregnant women, NSAIDs are avoided after 30 weeks gestation. (See 'Special populations (renal/hepatic dysfunction, pregnancy)' below.)

•Routine use of oxygen is not indicated during an acute vaso-occlusive pain episode unless there is evidence of a clinically significant decrease in hemoglobin oxygen saturation from the individual's baseline (typically, of more than four percentage points). The rationale for this approach is that when oxygen supplementation is provided unnecessarily and a decline in respiratory status subsequently occurs, the corresponding decline in hemoglobin oxygen saturation may be temporally masked because of the oxygen supplementation. (See 'Possible contributing comorbidities' above.)

•Routine blood transfusion is not indicated for isolated vaso-occlusive pain but may be appropriate if pain is accompanied by another complication such as stroke or ACS. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Continuous opioids/patient-controlled analgesia (PCA) — Around-the-clock (continuous or regularly scheduled) opioid therapy is used for individuals with uncontrolled pain that is not effectively treated with initial opioid doses in the emergency department (algorithm 1). Use of a clinical pathway with individualized dosing tailored to the individual's needs may improve the quality of care [58-61]. The success of these pathways is strongly dependent upon continuous education of the individual receiving the medications, nurses administering the medications, and physicians ordering the medications.

●Agent – Appropriate opioid agents include morphine or hydromorphone. Morphine is used most commonly in our practice. (See 'Special populations (renal/hepatic dysfunction, pregnancy)' below.)

●Schedule – Medication can be provided by intermittent dosing or continuous infusion. We prefer continuous infusion by patient-controlled analgesia (PCA) because it provides the most even pain control within the therapeutic window without side effects, along with the option for self-administration of additional doses for breakthrough pain. However, PCA administration requires rigorous monitoring and appropriate expertise to determine the correct settings and avoid complications.

Importantly, as-needed (PRN) pain medication should not be used as the sole source of pain relief, because such a practice will ensure that the individual will have subtherapeutic pain medication levels resulting in unnecessary pain. As-needed schedules may also result in substantial delays and/or sleep deprivation by requiring the individual in pain to remain awake most of the night asking for (and waiting for) pain medication. Some nursing protocols may allow up to one hour to administer an as-needed medication.

●Dose – The total daily dose is determined from the dosing required in the emergency department and/or records of previous dosing requirements. Dosing history from prior hospitalizations can be very helpful when determining initial dosing, but this does not substitute for a case-by-case analysis for each individual and each admission.

When using PCA, we use the strategy of the American Pain Society (APS) expert panel on treatment of pain, where the majority of the opioid dose is given by a continuous intravenous route and demand dosing is provided every 20 minutes at a dose equivalent to one-sixth of the hourly infusion dose. The demand dose is used for breakthrough pain and is not intended to substitute for a continuous infusion.

Dose adjustments to the PCA are typically made when additional demand medication is required more than three times an hour for two or more consecutive hours. The continuous and breakthrough doses may both be increased. The new continuous hourly dose is started at the level of the previous total hourly amount of medication used (continuous plus demand doses), provided that side effects are not limiting. The new demand dose should remain at one-sixth of the new continuous dose, allowing for all of the clinical personnel to double- and triple-check the amount of opioid provided. The goal is to provide the medication in the therapeutic window without requiring the patient to awaken from sleep to add more medication. This strategy requires all personnel to work as a team to ensure that the individual remains comfortable and not overly sedated. As the PCA is weaned, long-acting oral opioids may be required in some cases and may be continued following discharge from the hospital. (See 'Tapering of opioids and discharge' below.)

If PCA (or sufficient expertise or resources for its use) is not available, regularly scheduled intravenous doses of morphine or hydromorphone can be given every two to three hours. Intervals longer than two to three hours should be avoided because they may lead to increased pain before the next scheduled dose. Individuals with renal insufficiency receiving morphine may require dose reductions.

●Treatment for breakthrough pain – It is critical to make additional treatment available for breakthrough pain (defined as transitory pain that occurs intermittently while the individual is receiving opioid therapy, may last only a few minutes to an hour, and is difficult to distinguish from the persistent pain). The hallmark of breakthrough pain is the swift increase in pain while the individual is being treated with continuous or around-the-clock opioid therapy.

All individuals hospitalized with pain episodes should have written orders for breakthrough pain medication to maintain a therapeutic effect when the breakthrough pain occurs. The best approach is to provide immediate access to pain medication without requiring the individual to call the nurse and wait for additional medication. This is most easily achieved using PCA with a demand-dose option.

Two of the more common mistakes in treating breakthrough pain are overtreating the episode by increasing the around-the-clock/continuous hourly dose, which is likely to result in overtreatment of pain and excessive side effects (figure 5), or allowing a delay in the treatment of the breakthrough pain, such that medication is administered after the pain has escalated further or subsided. As noted above, management of breakthrough pain with as-needed (PRN) pain orders is often inadequate.

●Neuropathic pain – Neuropathic pain may exacerbate acute pain episodes, and therapies directed at neuropathic pain should be included if appropriate. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Management of chronic pain'.)

●Ongoing assessment – All individuals should be assessed with objective pain tools and sedation scales to ensure that analgesia is adequate and oversedation does not occur. Hemoglobin oxygen saturation monitoring is also helpful in managing severe painful episodes. Orders should include temporary cessation of analgesia and physician notification if the hemoglobin oxygen saturation level decreases by more than four percentage points from the individual's baseline or if bradypnea occurs. Other potential complications of opioids, including gastrointestinal effects and pruritus, should also be anticipated and managed appropriately. (See 'Opioid side effects' below.)

Evidence for the benefit of PCA compared with other schedules comes from several small randomized trials and observational studies:

●A trial that randomly assigned 20 young adults with SCD to PCA versus intermittent intravenous morphine (4 mg every 30 to 60 minutes) found that the PCA group had a reduced time between pain onset and treatment (7 versus 18 hours) and a reduced length of stay [62]. Total morphine use was similar.

●A trial that randomly assigned 19 adults to receive morphine by PCA versus continuous infusion found that those assigned to PCA had less morphine consumption per hour (0.5 versus 2.5 mg) and overall (33 versus 260 mg), less nausea and vomiting, and a nonsignificant trend towards shorter hospitalization time (six versus nine days) [63].

●A study that assessed satisfaction before and after institution of a PCA protocol in 50 children and adolescents or their parents found that 48 (96 percent) preferred PCA [64].

Additional information about the use of PCA to manage acute pain is presented separately. (See "Management of acute pain in the patient chronically using opioids for non-cancer pain".)

Hydration, adjuvant therapies, and medication management — Factors that may worsen the severity of SCD pain include insufficient use of opioids due to side effects or concerns about dependence, alterations in opioid metabolism, psychologic or neuropathic components, hypoventilation, insomnia, or decreased fluid intake.

Individuals receiving hydroxyurea prior to hospitalization should continue it at their regular dose unless there is a hydroxyurea-induced cytopenia or laboratory change [14]. A decrease in hemoglobin level with a high reticulocyte count during an acute event is rarely caused by hydroxyurea. For individuals not receiving hydroxyurea at the time of hospitalization, the possibility of starting hydroxyurea to reduce future pain episodes is generally discussed on an outpatient basis when the individual is feeling well. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Disease-modifying medications' and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Importance of prevention'.)

Hydration — Individuals with SCD are frequently hypovolemic during pain episodes; hydration may improve pain control and reduce the likelihood of other complications. Reduced oral intake, increased insensible losses, and reduced urinary-concentrating ability of the kidney (hyposthenuria) may contribute to a negative fluid balance [65] (see "Sickle cell disease effects on the kidney", section on 'Acute kidney injury'). Individuals with SCD should pay close attention to adequate hydration. Fluid intake, urinary output, and daily weights should be monitored closely during hospitalization.

For treatment of hypovolemia, we generally give an initial intravenous bolus of 0.5 to 1 L of normal saline. Many adults with SCD have underlying renal and cardiac dysfunction, and close monitoring of vital signs is essential due to the increased risks of heart failure and pulmonary edema [66-68]. In addition, renal disease, including renal tubular dysfunction, increases the risk of metabolic acidosis and electrolyte abnormalities including hyperkalemia, hyperuricemia, hyperchloremia, and hyperphosphatemia [69-71]. Hypernatremia should be avoided because it induces red blood cell (RBC) dehydration and sickling [72]. Thereafter, we use a maintenance rate of combined intravenous and oral fluid that contains at least one-quarter normal saline (roughly 2 L/m² per day), targeted to a net even or slightly positive daily fluid balance and a roughly stable body weight. Hospitalized individuals should be encouraged to drink fluids; it is important to place the fluids within reach because individuals in severe pain will be largely confined to the bed. High-quality evidence to support a specific route, type, or quantity of hydration is lacking, as discussed in a 2012 Cochrane review [73].

Ketamine for acute pain not responsive to opioids — Ketamine may be appropriate in individuals with severe pain not responsive to standard opioid analgesics, as suggested in the 2020 American Society of Hematology (ASH) guideline [17]. It is also indicated in individuals with hyperalgesia syndrome. Some institutional protocols include ketamine for initial pain management in the emergency department. Individual pain protocols embedded in the electronic medical record allows inclusion of ketamine in the initial pain plan for individuals whose pain is less responsive to opioids and/or when ketamine is preferred by the patient and providers. (See 'Initial pain control' above.)

Ketamine is not an opioid. It prevents glutamate activation of the N-methyl-D-aspartate (NMDA) receptor, which may mitigate opioid tolerance. Its analgesic benefits are seen in low, subanesthetic doses. Ketamine is increasingly being used for severe pain in SCD as well as other settings (eg, cancer, bur).

Ketamine can be used in the emergency department intranasally at 0.25 mg/kg to a maximum of 1 mg/kg per dose. In limited studies, continuous intravenous infusion has been reported to be safe and effective in SCD. Our inpatient treatment protocol consists of continuous infusion of ketamine at approximately 3 to 5 mcg/kg/min (0.3 mg/kg/hour).

Ketamine is also noted to have an antidepressive effect, which may help in the transition to pain prevention and management of chronic pain. (See 'Transition to pain prevention' below and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Chronic pain'.)

Ketamine can have side effects, including dysphoria and nystagmus, but they are uncommon at low doses. Ketamine should only be used by programs experienced and trained with its use and following a standardized protocol [74-76].

Adjuvant therapies — Adjuvant therapies are an important component of the management of acute and chronic pain. Importantly, these therapies are intended to supplement analgesics rather than to replace them. These interventions should be one component of a comprehensive pain management strategy, tailored to the needs of the individual and family and should be allowed to change over time according to the needs of the individual [17].

●Psychosocial support – As with any condition that produces chronic pain, SCD pain may be associated with various psychosocial stresses that contribute to depression and social isolation. This may be especially true during transition from pediatric to adult care. Psychosocial support should be appropriate to the individual's needs and may include cognitive-behavioral approaches, relaxation or breathing exercises, yoga, or self-hypnosis [14,17,40,77-79].

For chronic pain, muscle relaxation and self-hypnosis have been suggested in the NHLBI guidance on managing SCD [14]. These approaches are discussed in more detail separately. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Psychological therapy'.)

●Local therapies – Some individuals may benefit from heat packs [14]. Ice packs and cold compresses should be avoided in the setting of acute vaso-occlusive pain because cold may precipitate sickling.

●Insomnia treatment – Insomnia can be a serious problem that may be exacerbated by anxiety and inadequate pain control, and in turn, it may contribute to emotional distress and pain perception. Additional disorders may contribute to insomnia in SCD, including unrecognized sleep-disordered breathing (eg, obstructive sleep apnea, nocturnal hypoventilation) with hypoxia and/or restless legs syndrome [80]. Interventions to address these disorders may help reduce pain as well as other SCD complications. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Sleep-disordered breathing' and "Restless legs syndrome and periodic limb movement disorder in children" and "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)

●Antidepressants – Antidepressant therapy is not part of the acute pain management plan in individuals with intermittent pain; however, mental health assessment should be included for all individuals with chronic pain as part of comprehensive care. (See 'Transition to pain prevention' below.)

The time required in determining the individual's needs and providing education may be substantial; the benefits in overall pain management as well as other aspects of comprehensive care are also likely to be great.

Role of NSAIDs — A 2020 guideline from the American Society of Hematology (ASH) suggests a short course (five to seven days) of a nonsteroidal antiinflammatory drug (NSAID) in addition to opioids for acute pain management in children and adults with SCD [17]. As stated in the guideline, this is a conditional recommendation based on very low certainty in the evidence for benefit.

While we agree that a short course of ibuprofen is likely to be safe for the majority of outpatients without concomitant kidney disease and for selected inpatients, evidence suggests that many individuals with SCD are at risk for acute tubular necrosis (ATN), especially when dehydrated. Determining which individuals are at risk for ATN is especially challenging because common measures of kidney function do not perform well in individuals with SCD due to hyperfiltration. As noted in the ASH guideline, risk for kidney injury may be increased in individuals with other comorbidities such as peptic ulcer disease or cardiovascular disease or in those receiving an anticoagulant. (See "Sickle cell disease effects on the kidney", section on 'Accurate estimation of kidney function'.)

We interpret existing evidence and the ASH guideline to suggest that an NSAID may be used selectively after reviewing the individual's kidney function, risk factors for ATN, and pain history, but NSAIDs should not be used routinely and should not be included in routine standing orders for vaso-occlusive pain. (See 'Therapies we do not use' below.)

VTE prophylaxis — All adults with SCD admitted to the hospital with an acute medical illness should receive venous thromboembolism (VTE) prophylaxis. We generally do not use VTE prophylaxis in children with SCD (eg, <18 to 21 years). This is discussed separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis'.)

THERAPIES WE DO NOT USE — We avoid therapies known or suspected to cause harm and those not demonstrated to provide benefit [16]:

●Ice – Ice and cold compresses should be avoided because they may precipitate sickling.

●Meperidine – We do not use meperidine (pethidine) because multiple doses are associated with accumulation of the metabolite normeperidine, which can cause central nervous system toxicity including twitching, multifocal clonus, and seizures [2,14,21].

●Ketorolac, other NSAIDs – We avoid ketorolac in adults with SCD hospitalized for pain because the efficacy of adding an NSAID to morphine for inpatient management has not been demonstrated [55]. As noted above, we may use ketorolac briefly in the emergency department, in selected individuals with low risk for acute tubular necrosis (ATN), or in selected settings in which it is important to avoid opioids. (See 'Initial pain control' above and 'Role of NSAIDs' above.)

Ketorolac has a number of toxicities that are especially concerning in individuals with SCD, including Boxed Warnings regarding appropriate use (limited to five days, not for children, not for chronic pain); gastrointestinal, cardiovascular, and bleeding risks; renal toxicity; and others [81]. Renal toxicity, including irreversible renal failure, can occur in individuals with and without compromised renal function. In a retrospective review involving 97 children and adolescents with SCD-related pain and acute kidney injury (AKI), the likelihood of AKI increased in a dose-dependent manner for each day of ketorolac therapy [48]. Importantly, the estimated GFR calculated from serum creatinine levels in SCD are an overestimate, approximately 29 percent above the actual GFR [54]. Thus, estimated GFR cannot be used as a basis to give ketorolac safely. (See "Sickle cell disease effects on the kidney", section on 'Accurate estimation of kidney function'.)

We generally avoid other NSAIDs in individuals hospitalized with acute pain for similar reasons, although NSAIDs may be appropriate in selected cases. The lack of efficacy for NSAIDs in improving pain control was demonstrated in a trial that randomly assigned 54 adults with vaso-occlusive pain to the intravenous NSAID ketoprofen or placebo; all received intravenous morphine and acetaminophen [55]. Resolution of the vaso-occlusive pain and morphine use was similar in both groups.

●Transfusion – Red blood cell (RBC) transfusion is not a treatment for uncomplicated vaso-occlusive pain without symptomatic anemia. Importantly, however, vaso-occlusive pain may accompany other SCD complications for which transfusion is indicated. If pain and a complication requiring RBC transfusion are present, pain control and transfusion should be administered concurrently. Adequate analgesia for pain should not be delayed while administering a transfusion because transfusion does not treat pain. In contrast to acute pain, there may be some individuals with chronic pain or frequent pain episodes who benefit from chronic transfusions, as discussed below and separately. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Refractory pain: Role of regular transfusions' and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

●Magnesium – Magnesium was proposed as a potentially safe method of treating pain due to its potential role in ion flux, which may affect RBC hydration and propensity for sickling (see "Investigational therapies for sickle cell disease", section on 'Increasing RBC hydration (senicapoc, memantine)'). However, a randomized trial in 208 children with acute pain (MAGnesium for children in Crisis [MAGiC]) did not show any benefit in hospital length of stay from magnesium (40 mg/kg intravenously every eight hours up to six doses) compared with placebo [82].

●Glucocorticoids – Glucocorticoids are commonly used to treat inflammation. Only one randomized trial has addressed use in SCD, in which 36 children with SCD who were admitted to the hospital for acute pain were randomly assigned to receive intravenous methylprednisolone or placebo (all received morphine) [83]. The duration of inpatient therapy was shorter in the glucocorticoid group (41 versus 71 hours). However, a greater number in the glucocorticoid group were readmitted to the hospital within one week of discharge (3 versus 15 percent). Thus, we do not use glucocorticoids for acute pain, similar to the 2020 ASH guideline [17].

Glucocorticoids may be associated with rebound pain and adverse effects that are especially concerning in this population (gastrointestinal bleeding, avascular necrosis of bone), further reducing enthusiasm. A trial in which 54 individuals with SCD were randomly assigned to receive inhaled glucocorticoids or placebo suggested that the inhaled glucocorticoids might be a promising way to treat pain while avoiding systemic toxicities [84]. Validation of benefit in a larger cohort would be required for glucocorticoids to be incorporated into routine practice.

●Oxygen – We do not use oxygen during uncomplicated vaso-occlusive events when the individual's oxygen saturation is at baseline and there are no pulmonary symptoms. However, we monitor closely for these complications and administer oxygen for hypoxemia and/or respiratory indications, as discussed above. (See 'Possible contributing comorbidities' above.)

●Antiplatelet agents – Available data do not support the use of antiplatelet agents for pain management in SCD. The DOVE trial (Determining effects Of platelet inhibition on Vaso-occlusive Events), which randomly assigned 341 children and adolescents with SCD to receive prasugrel or placebo for prevention, showed a trend toward a lower rate of acute pain episodes or ACS that did not reach statistical significance (2.30 versus 2.77 events per person-year; rate ratio 0.83, 95% CI 0.66-1.05) [85]. A subsequent randomized trial of ticagrelor versus placebo also did not show a reduction in vaso-occlusive pain events (annualized rate of pain episodes 2.7 versus 2.6 with placebo; rate ratio 1.06, 95% CI 0.75-1.50) [86].

Antiplatelet agents may be used in other settings in SCD (eg, administration of low-dose aspirin during pregnancy to reduce the risk of preeclampsia). (See "Sickle cell disease: Obstetric considerations", section on 'During pregnancy'.)

●Investigational therapies – A number of other agents are under investigation in SCD, some of which are being tested for treating acute pain. In general, we would not use these agents outside of a clinical trial. (See "Investigational therapies for sickle cell disease".)

SPECIAL POPULATIONS (RENAL/HEPATIC DYSFUNCTION, PREGNANCY) — Individuals with renal and/or hepatic insufficiency require special attention due to altered metabolism of opioids.

●In renal insufficiency, morphine has a higher risk of adverse effects that appear to be due to accumulation of the sedating metabolite morphine-6-glucuronide [87-89]. Hydromorphone is safer than morphine, but a metabolite that may cause agitation, confusion, or hallucinations (hydromorphone-3-glucuronide) may accumulate [90-93].

●In hepatic insufficiency, metabolism of opioids is reduced, resulting in higher levels of morphine or hydromorphone.

Care should involve input from a qualified pain expert or anesthesiologist. Close monitoring of renal and hepatic function is needed.

Pregnant women with SCD who have an acute pain episode are generally treated similarly to nonpregnant individuals, although NSAIDs are avoided after 30 weeks gestation. This is discussed in detail separately. (See "Sickle cell disease: Obstetric considerations".)

DISCHARGE/OUTPATIENT CONSIDERATIONS

Tapering of opioids and discharge — We provide enough pain medication for a three- to five-day taper upon discharge. We advise all patients to fill opioid prescriptions for home use before discharge (typically, on the second day of hospitalization and before the weekend). To support outpatient management after discharge, we typically schedule a telemedicine visit or face-to-face visit within seven days after discharge.

Evidence-based strategies for opioid tapering have not been developed for SCD; adherence to common-sense principles can provide the basis for a successful transition from the hospital to ambulatory setting with adequate pain control. These include:

●Do not taper opioids in the first 24 hours unless there is respiratory depression or increased lethargy

●Taper opioids during the day when appropriate assessment of pain can be performed

●Taper opioids incrementally, approximately 10 to 20 percent of the opioid dose at a time

●Taper opioids by decreasing the dose rather than by increasing the interval between doses

●Convert to oral pain medication when the intravenous dose is roughly equivalent to home doses of oral medications (table 5 and table 7)

Typically, individuals can be discharged from the hospital when pain is adequately controlled on oral analgesics. Many individuals with SCD are managed with a combination of long-acting and short-acting opioids. If the individual does not usually require long-acting opioids at home, we recommend discontinuing the long-acting opioids when the pain event subsides. However, if the individual requires long-acting opioids at home, these should be made available. (See 'Management at home' above.)

When tapering to an oral regimen, the opioid dose and schedule during the last 12 to 24 hours of hospitalization should be matched to what will be given at home. This strategy ensures that the home regimen will be effective [94]. Avoiding undertreatment for pain (due to concerns about addiction that may not apply) and overtreatment for pain (without addressing the root cause, such as avascular necrosis or menstrual pain) are both important and should be incorporated into an individual protocol specific to the patient that is reviewed regularly by their clinician.

We strongly advise that all individuals with SCD receive their prescription from the outpatient hospital pharmacy to ensure they have the appropriate medication prior to leaving the hospital. On more than one occasion, individuals have been sent home on the weekends or at other times of the week and are unable to fill their prescription at the neighborhood pharmacy, which has the potential to lead to recurrence of pain and rehospitalization. Discharge without opioid prescriptions (eg, with NSAIDs alone) has been shown to be associated with a higher 30-day readmission rate than discharge with adequate home medication [95,96]. Prescription monitoring programs are being implemented increasingly; these should not restrict the use of prescriptions nor limit the appropriate size of prescriptions for individuals with SCD.

All individuals need a follow-up visit in the outpatient clinic within two weeks of discharge [97]. A review of rehospitalization rates for 408 children with SCD admitted with acute pain episodes found that having an outpatient visit was associated with lower rates of readmission to the hospital at two weeks and one month (hazard ratios [HRs] 0.23, 95% CI 0.12-0.41 and 0.44, 95% CI 0.33-0.59, respectively) [98]. In a single-center pediatric case control study, the greatest risk factor for readmission was no outpatient hematology follow-up within 30 days of discharge (odds ratio [OR] 7.7, 95% CI 2.4-24.4) [97].

As noted above, individuals already receiving hydroxyurea should continue it upon discharge; those for whom hydroxyurea will be initiated should do so during outpatient follow-up when they are well. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Hydroxyurea'.)

Transition to pain prevention — As noted above, all individuals require follow-up soon after discharge and discussion of a comprehensive plan to prevent or reduce pain in the future.

This may include:

●Medications that reduce vaso-occlusion

●Adjunctive therapies

●Psychosocial support

●Antidepressant medications

These interventions are discussed separately. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Chronic pain'.)

OPIOID SIDE EFFECTS — Certain aspects of managing opioid complications are unique to individuals with SCD due to the lifelong unremitting nature of the pain and chronic requirement for opioids in some individuals. The frequency of chronic opioid requirement varies with the population and may be as high as 50 percent.

Sedation — Sedation is common, and respiratory depression is especially concerning due to the increased risk of acute chest syndrome (ACS) and/or hospital-acquired respiratory infections. It is also especially important to distinguish opioid-induced central nervous system changes from cerebrovascular complications of SCD. The clinical differences are usually obvious (eg, timing relative to drug administration, abrupt versus gradual onset). (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

A reasonable plan for monitoring and risk reduction during an acute hospitalization includes [14,21]:

●Pulse oximetry, monitored during administration of intravenous opioids in the hospital

●Incentive spirometry, performed every two hours while awake

●Ambulation and activity, encouraged as soon as possible

Sleep impairment increases pain sensitivity and the risk of hyperalgesia syndrome. While opioids alter the quality of sleep, insufficient sleep is probably more detrimental than reduced-quality sleep. Therefore, we recommend continued analgesia during the night in the individual with pain, rather than relying on having the patient wake up to request an as-needed (PRN) medication, as long as they are monitored closely and are responsive [99-101].

Other sedating medications should be avoided when possible. For nausea, we prefer a selective 5-hydroxytryptamine (5-HT₃) receptor antagonist (eg, ondansetron) rather than a phenothiazine; for insomnia, we prefer melatonin and good sleep hygiene habits. Some individuals receiving diphenhydramine may continue it, as long as they are aware of potential risks and benefits. (See "Poor sleep and insomnia in hospitalized adults".)

The key to success with incentive spirometry is having hospital personnel engage the individual and provide sufficient instruction; often, this is best achieved using an established nursing protocol. In selected cases, intermittent positive pressure breathing therapy may be appropriate. The benefit of incentive spirometry in preventing respiratory complications during pain episodes was demonstrated in a trial that randomly assigned 29 children and young adults with SCD to receive incentive spirometry (10 maximal inspirations every two hours while awake) versus no incentive spirometry [102]. Pulmonary complications were significantly reduced in those receiving incentive spirometry compared with controls (5 versus 42 percent).

Importantly, an opioid reversal agent (eg, naloxone) should not be given to an individual who is somnolent but easily arousable, as this may precipitate severe pain requiring greater opioid doses. Rather, the opioid should be held until somnolence lessens. Naloxone should be reserved for symptomatic respiratory depression and/or impending respiratory failure. If used, naloxone should be administered in small doses or as a low-dose infusion. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Sleep-disordered breathing'.)

Respiratory distress with tachypnea and anxiety is not a side effect of opioid therapy. This finding should prompt evaluation for other conditions such as pulmonary embolism or ACS. (See 'Possible contributing comorbidities' above.)

Gastrointestinal — Nausea and constipation are common. In a series of 145 adults with SCD who completed a pain questionnaire, nausea and constipation were the most troubling opioid side effects; these were reported in 83 and 80 percent, respectively [31]. We treat most individuals with SCD with stimulant laxatives, typically within the first 24 hours after initiating opioids. Details of administration and additional approaches such as opioid antagonists and lubiprostone are discussed in depth separately. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Constipation'.)

If treatment is needed for nausea, we prefer a selective 5-HT₃ receptor antagonist due to their nonsedating properties. Other therapies and approaches are presented separately. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Nausea and vomiting'.)

Naloxone may provide relief from the nausea and pruritus associated with opioid use when used by experienced practitioners [103-107]. Typically, low-dose infusional naloxone (0.25 mcg/kg/hour) is administered in conjunction with intravenous patient-controlled analgesia (PCA).

Pruritus — Pruritus is a common problem with all opioids, due to histamine release from skin mast cells (see "Mast cells: Surface receptors and signal transduction"). Management should be individualized based on symptoms.

●For individuals with pruritus on chronic opioid therapy, effective approaches include the use of nonsedating antihistamines, substitution of a different agent (eg, hydromorphone), or adding a 5-HT₃ receptor antagonist (eg, ondansetron, granisetron).

●For hospitalized individuals, continuous infusion of low-dose naloxone (0.25 mcg/kg/hour) has been helpful in decreasing pruritus without requiring opioid adjustment [108]. Morphine and naloxone are compatible in the same intravenous line and can be infused simultaneously.

Importantly, an individual should not be falsely labeled as having an opioid allergy solely on the basis of pruritus, because this may result in avoidance of therapy that is effective in controlling pain. Additional information and other options for treatment are presented separately. (See "Drug hypersensitivity: Classification and clinical features", section on 'Pseudoallergic reactions' and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Pruritus' and "Pruritus: Therapies for generalized pruritus".)

Opioid use disorder — The prevalence of opioid use disorder in individuals with SCD is routinely greatly overestimated by clinicians, despite evidence to the contrary. This may be in part because the majority of individuals with SCD manage their pain episodes at home or through their primary clinician. As a result, hospital staff may only encounter the one or two individuals with SCD who have an opioid use disorder from among the hundreds or thousands of individuals with SCD in the local population who do not. It is critical that clinicians not extrapolate from these one or two individuals to the rest of the SCD population.

The prevalence of opioid use disorders in individuals with SCD has been demonstrated to be similar to or lower than the general population [109]. Large academic centers in the United States and Europe have reported evidence of substance abuse in 0 to 9 percent of individuals with SCD; the incidence in comparable populations without SCD is 6 to 9 percent [18,109-114]. In a study of opioid-induced deaths that compared mortality of individuals with SCD to that in other chronic pain conditions over a 14-year period (1999 to 2013), individuals with SCD had a lower mortality than people with fibromyalgia, back pain, or migraine headache (0.77 percent of deaths in SCD, compared with 4.4, 2.1, and 4.5 percent, respectively) [114]. It is important for clinicians to understand that the use of opioids under appropriate medical supervision, regardless of amount or frequency, does not constitute an opioid use disorder. Increasing dose requirements due to changes in drug metabolism (ie, tolerance) or withdrawal symptoms upon discontinuation (ie, physical dependence) are normal physiologic reactions and do not indicate substance addiction. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment", section on 'Diagnosis'.)

When concerns about opioid use disorder or drug abuse occur, they are best raised and discussed outside an acute pain episode. A multidisciplinary approach is used, including a complete review of the opioid prescription history, hospital records of opioid usage, and a discussion with the primary care clinician and the rest of the clinical team (medical social worker, case worker, psychologist). A care plan for addressing these concerns should be created and implemented with subsequent episodes. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Individualized care plan'.)

Other general principles of managing opioid complications are similar to those used in other settings, the most similar being cancer pain [18]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sickle cell disease (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Provider attitudes – Provider attitudes play a significant role in the effective treatment of sickle cell disease (SCD) pain. The facilitation of trust and avoidance of stigmatizing or catastrophizing language can improve the effectiveness of pain assessment and pain control. (See 'Overview of the role of provider attitudes on effective treatment' above.)

●Pain assessment – The gold standard for assessment of pain is the individual's report; no combination of clinical and laboratory findings can determine whether an individual with SCD is in pain. Acute pain should be assessed rapidly to facilitate analgesia and determine whether other conditions are present, such as acute chest syndrome (ACS), bone infarction, or splenic sequestration (table 1). Placebo should never be used. (See 'Clinical assessment of pain' above and "Evaluation of acute pain in sickle cell disease".)

●Site of care – Home management is the most frequent setting for acute pain management. We use a stepwise approach (table 2). Individuals not receiving chronic opioids start with nonopioid therapy for mild pain (table 3) followed by opioids of escalating strengths (table 5 and table 7 and table 4), with additional short-acting medication for breakthrough pain. There should be a clear plan for when to seek medical services and whom to contact. Day hospitals or hematology-oncology infusion centers are the most effective locations for management of acute pain. In treating pain, the emergency departments (EDs) are not the preferred location, but may be the only option, particularly on weekends and holidays. (See 'Care outside of the emergency department' above.)

●ED and hospital treatment – Most individuals with SCD pain only present to the hospital or ED when pain cannot be controlled at home. Acute pain should be treated as an Emergency Severity Index (ESI) of 2 (<30-minute triage wait time) with rapid reassessment after initial opioid (algorithm 1). Appropriate therapies include intravenous morphine, hydromorphone, or intranasal fentanyl (see 'Initial pain control' above). If pain is not relieved with more than two doses, hospitalization is indicated, preferably using patient-controlled analgesia (PCA) with additional demand dosing for breakthrough pain. Attention should be paid to hydration status, venous thromboembolism (VTE) prophylaxis, and potential adverse effects of opioids. Ketamine may be used in some cases. (See 'Overview of acute pain management' above and 'Special populations (renal/hepatic dysfunction, pregnancy)' above.)

●Drugs to avoid – We generally do not use meperidine, ketorolac, other nonsteroidal antiinflammatory drugs (NSAIDs), or other therapies mentioned above due to potential toxicities and lack of benefit. Transfusion is not indicated for uncomplicated pain. (See 'Therapies we do not use' above and "Hydroxyurea use in sickle cell disease" and "Investigational therapies for sickle cell disease".)

●Discharge considerations – We provide enough pain medication for a three- to five-day taper upon discharge. We advise all patients to fill opioid prescriptions for home use before discharge (typically, on the second day of hospitalization and before the weekend). To support outpatient management after discharge, we typically schedule a telemedicine visit or face-to-face visit within seven days after discharge. Opioid tapering and discharge are discussed above; prevention is covered separately. (See 'Tapering of opioids and discharge' above and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

●Opioid side effects – Interventions may be needed for sedation, gastrointestinal effects, pruritus, and other side effects. Likelihood of opioid use disorder is greatly overestimated despite evidence to the contrary. (See 'Opioid side effects' above.)

ACKNOWLEDGMENTS — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.