Pediatr Drugs 2003; 5 (4): 229-241 1174-5878/03/0004-0229/$30.00/0

THERAPY IN PRACTICE

© Adis Data Information BV 2003. All rights reserved.

Pain Management in Children with Sickle Cell Disease Jennifer Stinson and Basem Naser Department of Anaesthesia, The Hospital for Sick Children, Toronto, Ontario, Canada

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 1. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 2. Barriers to Effective Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 3. Approaches to Pain Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 3.1 Pain Assessment Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 4. Principles of Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5. Pharmacologic Approaches to Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5.1 Acetaminophen (Paracetamol) and NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5.2 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.2.1 Choice of Opioid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.2.2 Methods of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.3 Guidelines for the Management of Acute Episodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 6. Nonpharmacologic Approaches to Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

Abstract

Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. The disease is characterized by chronic hemolytic anemia, as well as acute and chronic complications. One of the most intractable problems encountered by children with SCD is the painful episode that results from tissue ischemia due to vaso-occlusion. Pain related to SCD is unique among pain syndromes due to the unpredictable, recurrent, and often persistent nature of the disease, as well as the recurring and essential need for the use of opioids. Painful vaso-occlusive episodes (VOE) are a principal cause of morbidity and account for a significant number of emergency department and hospital admissions. When untreated or inadequately managed, the pain of VOE may cause both short- and long-term consequences. Despite the fact that pain is an almost universal feature of the disease, children with SCD may form one of the most undertreated and understudied populations. One of the factors contributing to poor pain management is conflicting perceptions between patients, their families, and healthcare professionals about pain that is reported and analgesia that is required. Pain management guidelines have recently been published in an effort to overcome barriers in the assessment and management of pain related to SCD. Although there is considerable variability in the way SCD pain is managed, the standard treatment protocol for painful episodes has been rest, rehydration, and analgesia. However, pain control for children with SCD is often a difficult and complex process, and one that requires frequent systematic pain assessments and continuous adjustment of comfort measures, especially analgesics. There are a variety of analgesic agents to choose from, such as acetaminophen (paracetamol), oral or parenteral nonsteroidal anti-inflammatory drugs, and oral or parenteral opioids. Each of these options has advantages and disadvantages to their use. Continuous infusions of analgesics and patient controlled analgesia have been shown to be effective and widely used in hospital settings

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to manage severe pain. However, the opioid dose required to achieve pain relief varies considerably within each painful episode, from one episode to another, and between individual patients. Although not yet curable in humans, pain related to SCD can be effectively managed in most patients by using a comprehensive approach that incorporates pharmacologic, psychologic, behavioral, and physical pain management strategies.

Sickle cell disease (SCD) is one of the most common genetic disorders, affecting mainly populations of African descent as well as other ethnic groups, such as those from the Caribbean, the Mediterranean, the Arabian Peninsula, and India.[1] In many treatment centers, SCD accounts for a notable proportion of visits to emergency departments and admissions to general pediatric and hematology units.[2] One of the most common problems experienced by children with SCD is pain associated with the unpredictable and relentless vaso-occlusive crisis (VOC) or episode (VOE). An episode can be triggered by many factors, including hypoxia, acidosis, dehydration, or infections, resulting in the polymerization of deoxygenated hemoglobin S and sickling of the sickle erythrocyte. These deformed sickle cells enter capillaries readily and adhere to the vascular endothelium. These adhesions, coupled with trapping of dense sickle cells, compromise blood flow. The resultant ischemia leads to tissue damage and cell necrosis, which in turn gives rise to nociceptive pain.[1,3] While the pain of SCD is primarily nociceptive in nature, it is important to recognize that pain may originate from many sources (e.g. musculoskeletal, visceral) and that children experience both acute and chronic pain (e.g. aseptic necrosis, bony infarction). 1. Clinical Features Children may experience painful VOE as early as 6–12 months of age. As hemoglobin F decreases during the first 2 years of life, the initial symptoms of SCD, such as splenomegaly, acute chest syndrome (ACS), and dactylitis (e.g. hand-foot syndrome) become evident. Young infants and toddlers with dactylitis may be irritable, refuse to walk, or cry when their hand or foot is touched. Typically, after the first few years of life, interruption of blood flow occurs in the larger bones of the extremities, vertebrae, rib cage, and periarticular structures, producing painful crises of the bones and joints.[1] In adolescents, common painful sites are the abdomen, chest, and lower back. Often the pain episodes are intermittent, recurrent, and acute in nature. On average, painful crises persist for 4 or 5 days, although protracted episodes may last for 2–3 weeks.[1] The pain is typically described as being worse than postoperative pain and as intense as pain associated with terminal cancer.[4,5] Children often use word descriptors such as ‘aching’, ‘sore’, and ‘pounding’ to describe the physical sensation © Adis Data Information BV 2003. All rights reserved.

of nociceptive pain due to tissue damage.[2] Pain that is described as burning, shooting, lancinating, or tingling in nature suggests a neuropathic component. Other clinical signs may include fever, swelling, and tenderness over affected sites and joint effusions, as well as changes in laboratory parameters.[2] More extensive VOE may progress to gross ischemic damage, resulting in bone marrow or bone, splenic, pulmonary, renal, and cerebral infarcts. ACS is another important sequelae of VOE. ACS is characterized by fever, tachycardia, tachypnea, cough, dyspnea, chest pain, leucocytosis, pulmonary infiltrates, and a poor response to antibacterial agents.[1,6,7] Although the exact mechanisms underlying the pathophysiology of ACS remain unknown, it may result from one, or a combination, of the following: atelectasis, infection, bone marrow embolization, rib infarction, microvascular occlusion, or lung infarction.[1,8] Clinicians are often reluctant to use opioids due to concerns that opioids may cause ACS. While opioid use does not cause ACS, its use may further exacerbate hypoxia in patients with ACS, especially when used in the high doses that are often needed to treat these painful episodes.[8,9] From our clinical experience, the cautious but rationale use of opioids, in combination with appropriate monitoring of vital signs, oxygen saturation and pain intensity, enables effective and safe treatment of the underlying painful event. There is a wide variation in the severity of SCD; some patients experience frequent hospitalizations and complications, while others manifest limited clinical symptomatology. The vast majority of pain in children with SCD is managed in the home setting. Children typically arrive at the emergency room department when their pain is severe and unmanageable at home with oral analgesics and comfort measures.[10-12] One of the more debilitating aspects of these painful episodes is its unpredictable nature in terms of frequency, intensity, affected sites, and duration of pain. This unpredictability can have adverse effects on attendance and education, activities of daily living, and undermine the child or adolescent’s sense of well-being and quality of life.[10,13-15] For example, during acute episodes, pain has most often been found to interfere with school and appetite, and less commonly with passive activities such as sleeping and watching television.[16] Moreover, psychologic factors, such as self-esteem, social assertiveness, and coping, are important modifiers of the pain experience and adaptation to the chronicity of SCD.[17,18] Because pain is a multifaceted, Pediatr Drugs 2003; 5 (4)

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complex, and inherently subjective experience, a one-to-one relationship between the physiologic event and the severity of pain is lacking. No laboratory markers for the presence or severity of pain exist, therefore, the gold standard for assessment is the patient’s self report.[19] 2. Barriers to Effective Care Despite the fact that pain is an almost universal feature of SCD, children with SCD are often undertreated.[4,20,21] One of the factors contributing to poor pain management is conflicting perceptions between patients, their families, and healthcare professionals about pain that is reported and analgesia that is required.[20-22] For example, children may experience pain for long periods (days to weeks), with high levels of pain either at home or in the hospital.[5,16] They often face long waits for care in emergency departments that do not have designated day-hospital or fast-track programs.[23] Once admitted to hospital, they are often weaned too quickly from intravenous analgesics.[20] Moreover, these children often face healthcare providers who are suspicious about the truth or validity of their pain scores. Healthcare providers often believe that children who are watching TV, playing, or sleeping are not in as much pain as they report or that these children always report high levels of pain. Children often use these strategies as a means of coping with pain. Therefore, this disparity between the patient’s self-report and their affect and behavior leads to distrust on the part of the healthcare providers. Moreover, unfamiliarity with the effective use of analgesics and fear of adverse effects, such as respiratory depression or addiction, may affect the clinician’s use of analgesics and often results in a cycle of undertreatment of pain related to SCD.[8,24,25] These factors can lead to seemingly aberrant behaviors in children and adolescents with SCD (e.g. clock-watching, requesting specific medications and doses), which are misunderstood by clinicians as drug-seeking, when in fact they are pain relief-seeking behaviors. This phenomenon has been referred to as pseudoaddiction[26] and these behaviors disappear with adequate pain control and weaning.[27] Therefore, it is essential to establish trusting, mutually respectful relationships between patients, family, and the healthcare team in order to optimise the assessment and management of pain related to SCD. 3. Approaches to Pain Assessment Accurate assessment of pain is the cornerstone of effective care for children with pain related to SCD.[19,20,27,28] While few in number, previous investigations of SCD pain in pediatric patients suggest that establishing a comprehensive assessment strategy is the critical first step in developing effective clinical interventions.[5,16,19,29] A thorough approach to assessment of SCD pain © Adis Data Information BV 2003. All rights reserved.

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requires a developmental and biopsychosocial framework that takes into consideration the child’s past, present, and anticipated pain experiences. Moreover, it should include an evaluation of the sensory, affective, behavioral, and sociocultural components of the pain experience. For these reasons, two clinical formats for pain assessment have been proposed. The first is a comprehensive multifaceted pain assessment designed to individualize care and examine the overall needs of the child and their family. Some clinicians have recommended that patients carry a ‘passport’ that summarizes this information. For example, the passport could include a recent history, recommended pain management routines, and brief descriptions of a typical VOE for that person. The second is a rapid assessment for use during acute painful episodes; this assessment is shorter and can be quickly used to check for pain intensity and response to treatment, as well as complications.[19,29] A simple measure of pain intensity that can be rapidly completed and takes into account the child’s developmental stage and cognitive abilities, is essential. Pain intensity should be assessed initially, after the peak effect of the medication, and at frequent intervals until the adequacy and duration of the medication effects have been determined. In addition to the regular assessment of vital signs, and presence or absence of complications of SCD (e.g. infections), healthcare providers should also inquire about pain relief, changes in the quality of pain (e.g. sharp, dull, achy), location, or distribution of the pain, as well as its affect on mood, sleep, and appetite. Documentation of these assessments is crucial so that the effectiveness of the treatment can be evaluated in a timely fashion. When there is disparity between the patient’s verbal self-report of pain and their associated behaviors and ability to function, further assessment should be carried out to determine the reason for such a discrepancy.[19] 3.1 Pain Assessment Tools

The subjectivity of pain makes the child’s report the best window into understanding their pain experience. However, pain assessment poses many challenges in infants and preverbal children with SCD because of the subjective and complex nature of vaso-occlusive pain, as well as developmental and language limitations that preclude comprehension and self-report. There are currently no well-validated tools for sickle cell pain in these vulnerable age groups. Typically, clinicians have relied on assessment of motor ability and the parent’s judgment of how their child’s behavior is different from their usual activity or temperament as indirect measures of pain.[29] There are several observational behavioral tools that have been developed and validated for other pain populations (e.g. in the postoperative setting) and which can be used for infants and young children, e.g. the Facial expresPediatr Drugs 2003; 5 (4)

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sion, Leg movement, Activity, Cry, Consolability (FLACC) pain scale (2 months to 7 years of age)[30] and the Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) [1–7 years of age].[31] A brief behavioral observation method developed for adults with SCD, which includes guarding, bracing, rubbing, grimacing, and sighing, may be appropriate for older school-aged children and adolescents.[32] By the age of 3–4 years, most children can use a self-report tool to rate pain intensity. There are a number of self-report methods such as visual analog, verbal, numerical, and facial scales. Some appropriate measures for preschool and young school-age children include the photographic scale of the African-American version of the Oucher scale[33] and the Wong-Baker Faces Pain Rating Scale.[34] Older school-aged children and adolescents who understand concepts of order and numbering are capable of providing more detailed ratings of intensity and descriptions of the quality (e.g. sharp, dull, achy) and location of pain. Two of the most commonly used multidimensional measures in this age group are the Adolescent Pediatric Pain Tool[35] and the Pediatric Pain Questionnaire.[36] It is important to chose one tool and use it routinely so that the child and healthcare provider become familiar with its significance to an individual patient.[27] For example, in our institution we use the FLACC for infants and pre-school children (2 months to 5 years of age), the Oucher scale for children 3–12 years of age, and the numerical rating scale for adolescents (12–18 years of age). Finally, for a more comprehensive review of reliable and valid pain measures in infants, children, and adolescents, the reader is referred to the review article by Franck et al.[28] 4. Principles of Pain Management The ultimate goal of pain management is adequate pain control, as defined by the child and their family.[21] In order to optimize acute pain relief, there are several key principles that guide the use of analgesic drugs in children. Painful episodes should be expeditiously and aggressively managed to reduce pain and enable children to attain maximum functional ability.[19] Other principles include a pre-emptive approach, as well as tailoring the drug, dose, route of administration, and anticipated adverse effects to the individual needs of the child.[21] The stepwise approach recommended by the World Health Organization for the management of cancer pain[37] is applicable to the management of sickle cell pain.[4,19,21] In this approach, mild pain is treated with acetaminophen (paracetamol) or nonsteroidal anti-inflammatory drugs (NSAIDs), which interrupt the transmission of painful stimuli along peripheral and central fibers. Moderate pain is treated with NSAIDs and a weak opioid, and severe pain is treated with a © Adis Data Information BV 2003. All rights reserved.

strong opioid. Finally, a multi-modal treatment approach that uses a combination of pharmacologic (e.g. opioids, NSAIDs) and nonpharmacologic (e.g. cognitive-behavioral and physical therapies) treatment strategies should be employed.[8] Opioid and nonpharmacologic strategies, such as biofeedback and hypnosis, work by altering the perception of pain at the level of the CNS.[9] 5. Pharmacologic Approaches to Pain Management 5.1 Acetaminophen (Paracetamol) and NSAIDs

Non-opioids are the backbone in the management of mild pain and should be used in conjunction with opioids for moderate to severe pain.[19,38] Non-opioids are prostaglandin-synthesis inhibitors, interfering with the function of the enzyme cyclo-oxygenase (COX), which prevents the conversion of arachidonic acid to prostaglandins.[38] In the peripheral nervous system, prostaglandins can contribute to the sensitization of nociceptors to noxious stimulation.[19] Non-opioid analgesics have several advantages over opioids. They can provide additive analgesia when combined with opioids or adjuvants, and have an opioid-sparing effect. In addition, the patient or family can administer them at home, with some being relatively inexpensive and not requiring a prescription or access to medical staff. Their disadvantages include a ceiling effect (a dose beyond which further drug administration will produce no substantial improvement in analgesia) and greater likelihood of adverse systemic effects than with the use of opioids.[19] Acetaminophen is the most commonly used analgesic in the treatment of mild to moderate pain in children. Although acetaminophen inhibits the synthesis of prostglandins, its effects are primarily central, providing analgesia and antipyresis, with little anti-inflammatory action.[38] Because it lacks a peripheral effect, it has a very low adverse effect profile, and has no adverse effects on renal, gastrointestinal, or platelet function. Acetaminophen is probably the safest analgesic; however the daily dose should be decreased in the presence of hepatic dysfunction.[19] Patients should also be educated not to exceed the recommended daily dose. Finally, the effect on the liver of long-term administration in moderate doses is unknown.[21] NSAIDs differ from one another in their analgesic, antipyretic, and anti-inflammatory effects. The adverse effects of NSAIDs may vary depending on the specific drug and the patient’s preexisting medical conditions.[38] NSAIDs are contraindicated in patients with gastritis, peptic ulcers, coagulopathies, and renal failure. In addition, all NSAIDs are administered orally, except for ketorolac, which can be used orally or parenterally. Several Pediatr Drugs 2003; 5 (4)

Pain Management in Sickle Cell Disease

NSAIDs are also available in rectal preparations, e.g. naprosyn and diclofenac. Data regarding the efficacy and adverse effects of ketorolac in pain related to SCD are sparse, therefore it is generally not used as a first-line agent.[19,39-41] Ketorolac can be added to opioids for additional analgesia in situations where opioids provide insufficient analgesia after optimal titration, or more commonly as an adjunct to opioid analgesia in the presence of opioidrelated adverse effects. However, ketorolac should not be used for more than 5 days because of increased potential for toxicity.[19] The new COX-2 inhibitors (e.g. celecoxib) show promise of eliminating some of the adverse systemic effects associated with NSAIDs.[19,21] Finally, there is very limited clinical experience with the use of other potent anti-inflammatory medications, such as corticosteroids, during VOC.[19,42] 5.2 Opioids

Opioids are the most commonly used analgesics in the treatment of moderate to severe acute pain due to VOC. Opioids are morphine-like drugs that produce pain relief by actions at peripheral and central opioid receptors. They include true opiates, or opium derivatives (e.g. morphine), and other drugs with similar pharmacologic action (e.g. codeine, oxycodone, hydrocodone, fentanyl, hydromorphone, and methadone). There are three major classes of opioids: agonists, partial agonists, and mixed agonistantagonists. Opioid agonists are most commonly used in the management of sickle cell pain. The role of agonist-antagonist preparations, such as nalbuphine,[43] has not been well defined, therefore they are not recommended for first-line therapy in SCD.[19] Opioid analgesics have less systemic adverse effects than NSAIDs; however, their use in SCD is often associated with many misbeliefs about drug-seeking behavior, addiction, and respiratory depression.[8] 5.2.1 Choice of Opioid

The choice of which opioid preparation to use should be based on the characteristics and expected duration of the pain, the setting of care, and the drug’s pharmacology, including duration of action, ease of administration, and adverse effects.[19,44] Painful events in the majority of children (up to 90%) can be successfully managed at home.[10] If the patient’s pain is typically of short duration (e.g. <24 hours), opioids or opioid preparations with short duration of action are appropriate. For oral administration, codeine with acetaminophen tends to be one of the most commonly used agents for relief of moderate pain in the home setting.[2,12] If pain is severe, or if there are intolerable adverse effects, then oxycodone, morphine, or hydromorphone can be used. All these agents are available in liquid form for patients who are unable to take pills. There are also short-acting opioid agonists available in combined © Adis Data Information BV 2003. All rights reserved.

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preparations with acetaminophen or aspirin (acetylsalicylic acid). However, aspirin is contraindicated in children in the presence of fever or other viral disease, due to its association with Reye’s syndrome.[38] For patients whose pain requires many days to resolve, a sustained release preparation may be more convenient and provide more consistent analgesia.[45] However, short-acting opioids may have to be used for breakthrough pain, as well as early in the treatment until the sustained-release preparation reaches steady-state levels. Failure to achieve adequate outpatient pain relief signals the need to use parenteral medications.[19] There is little empirical evidence that supports one opioid over another in terms of efficacy in relieving painful episodes. In equipotent doses, most opioids produce the same clinical effects, and induce similar adverse effects.[8] However, morphine sulfate is an effective, inexpensive, and familiar opioid and is, therefore, the preferred treatment for VOC in the management of moderate to severe pain requiring parenteral administration in our institution. Sustained release oral morphine preparations have been shown to provide effective analgesia;[45] however, they require titration and are, therefore, more commonly used for prolonged episodes of painful crises. Alternatives to morphine include hydromorphone, fentanyl, and methadone. Hydromorphone and fentanyl are useful for patients who cannot tolerate morphine due to excessive pruritus and nausea. Methadone is difficult to titrate, and the risk of respiratory depression negates its use in sickle cell pain.[4] In the past, meperidine (pethidine) was the most commonly prescribed opioid due to its euphoric effects and misbeliefs that it produced less biliary spasm and respiratory depression.[8] Although meperidine is still widely used,[46] it should be reserved for very brief treatment courses in patients who have reported and demonstrated its effectiveness, or who have allergies or uncorrectable intolerances to other opioids, such as morphine and hydromorphone.[19] Repetitive administration over several days may result in seizures and central nervous system hyperexcitability due to an accumulation of the metabolite normeperidine.[19,21,44,47] The effective use of opioids requires achieving an often delicate balance between optimizing pain relief and minimizing adverse effects.[19] Sedation, respiratory depression, nausea, vomiting, constipation, and pruritus are anticipated adverse effects of all opioids. Given that each opioid may not produce the same adverse effects, trying a different opioid may lessen symptoms. Alternatively, changing the administration regimen by decreasing the concentration of each intravenous bolus while shortening the time interval, may abate adverse effects.[47] In addition, the use of adjuvants such as antiemetics, antipruritic agents, and stool softeners/laxatives can be used to ameliorate these adverse effects. Close monitoring of vital signs, in particular respiratory rate and oxygen saturation levels, is essential in avoiding potential serious adverse Pediatr Drugs 2003; 5 (4)

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Table I. Intravenous patient controlled analgesia (PCA): indications, advantages, disadvantages, and implications for practice (reproduced from Palozzi and Stinson,[55] with permission) Patient selection criteria

Advantages

Disadvantages

Implications

Understands concept of PCA (e.g. age ≥7 years)

Allows enhanced control by child

Child may not use PCA effectively due to fear of addiction, and lack of understanding of PCA

Provide education to children and families outlining how the pump works, when to press the button, safety features and that the child cannot overdose

Child willing and co-operative

Child able to titrate analgesic to desired level (e.g. use of bolus dose)

Parents may discourage their child to use the button, or press the button for the child when it is not indicated

Hourly sedation score and respiratory rate

Physically able to activate button

Continuous infusion often used only at night

Risk of medication error at initial programming and when changing from one opioid to another (e.g. morphine 1 mg/ml to meperidine [pethidine] 10 mg/ml)

Record number of PCA attempts, doses actually received, and total volume infused hourly

Parents understand concept of PCA

Reduces delay in analgesic administration

Check intravenous lines regularly

In some special situations, nurse- or parent-controlled analgesia may be used for young children or those who are physically unable to press the button[56]

Can prevent pain associated with movement, physiotherapy, etc.

Regularly assess pain score

Lockout intervals (every 5–10min) and maximum dose limits (1–4h) provide for safe administration

Evaluate the child’s understanding of the use of PCA and reinforce teaching as indicated

Reduces fear associated with intramuscular injections

Observe for adverse effects and provide appropriate interventions

Intravenous and subcutaneous use Suitable for many types of acute pain

effects. All patients should have naloxone readily available for treatment of respiratory depression. However, it is important to administer naloxone cautiously to avoid precipitation of profound withdrawal, seizures, and severe pain.[19] 5.2.2 Methods of Administration

Medications for the management of severe VOC pain should be administered intravenously by patient controlled analgesia (PCA) pumps,[48-52] or through the use of a continuous infusion[53,54] or oral sustained-released preparation,[45] with intermittent breakthrough doses as needed to provide maximal pain control. Yaster and colleagues[8] argue that fixed doses of intravenous opioids administered around-the-clock make little sense and often result in inadequate analgesia due to the enormous individual variations in pain perception and opioid metabolism. Moreover, the use of an ‘as needed’ schedule relies on the child to ask for the morphine, © Adis Data Information BV 2003. All rights reserved.

which may result in peaks and valleys of plasma levels and inadequate analgesia. Subcutaneous routes can also be used when there is poor venous access and the child is not dehydrated, while intramuscular injections should be avoided. A variety of administration schedules are possible using combinations of oral and parenteral administration; however, these schedules should be tailored to the individual needs and preferences of the child and family.[4,19] The use of PCA has increased in popularity as a well tolerated and effective method of analgesic administration in children >7 years of age with SCD.[48-52] The indications, advantages, and disadvantages, as well as implications for practice, are outlined in table I.[55] Proper use of PCA requires a coordinated system of management, usually by acute pain teams, with nursing protocols and ongoing education. PCA should be started only after satisfacPediatr Drugs 2003; 5 (4)

Pain Management in Sickle Cell Disease

tory pain relief has been achieved with an aggressive opioid titration schedule. PCA administration regimens for bolus doses and basal infusions are controversial; however, in general the approach differs from postoperative pain.[4,8,19] Two retrospective studies of children and adolescents with SCD who used PCA found that patients varied widely in the drug administered, use of basal infusions, individual doses, total amount of drug received, and patient satisfaction.[49,51] The empirical evidence does not support the use of continuous background infusions (e.g. increased morphine use without substantial reduction in pain compared with bolus-only regimens) in the management of sickle cell pain.[48-51] However, in the authors’ experience, the majority of patients benefit from low dose basal infusions to aid night-time pain relief, improve sleep, increase mobilization, and enhance patient/parent satisfaction. For example, in our center initial bolus doses of morphine sulfate may vary from 0.01–0.04 mg/kg, with basal infusions ranging from 0.01–0.07 mg/kg/h.[51] Indications for the use of alternative therapies, such as continuous epidural infusions and transdermal fentanyl, have not yet been established;[19] however, several authors reported that epidural analgesics with local anesthetics were effective in children whose sickle cell pain did not respond to conventional analgesia.[57,58] In addition, there is some evidence for the use of transdermal fentanyl in SCD;[59] however, it is rarely used as the serum drug concentration does not approach analgesic levels for about 12–16 hours after application, and the drug continues to be active for some time after the patch is removed. Both of these approaches remain controversial, and controlled studies are needed to define their role in the management of sickle cell pain. 5.2.3 Guidelines for the Management of Acute Episodes

Patients with pain related to SCD may need somewhat higher doses than that typically used for other patient groups.[19] Doses almost twice as high as those necessary for postoperative pain relief are often needed to relieve the pain of VOE.[21] This is, in part, due to the often higher pain intensity experienced in pain related to SCD than that of many other pain syndromes.[4] In addition, analgesics often have altered levels or duration of action because of the accelerated renal clearance and hepatic metabolism.[60] Finally, many patients develop some degree of pharmacologic tolerance. Given this, it is important to realize that opioid tolerance and physical dependence are expected with long-term opioid therapy, and should not be confused with psychologic dependence or addiction.[19] Therefore, the right dose has been described as the dose that relieves the pain.[21] This is achieved by titrating the opioid dose to a level that is deemed tolerable in order to relieve pain and minimize short- and long-term consequences of unrelieved pain. Clinicians can use a simple, 5-point Likert © Adis Data Information BV 2003. All rights reserved.

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scale[19] (0 = no relief, 1 = little, 2 = moderate, 3 = good, and 4 = complete relief) to determine relief from pain, where relief is usually indicated by a score of 2 or greater. One can also establish with the patient what a tolerable level of pain would be on a pain intensity scale (e.g. usually 50–60% reduction from the upper end of the scale). Titration should continue until the highest achievable pain relief score has been reached.[19] Finally, from our perspective, we have found it helpful to define for healthcare providers what is meant by mild, moderate and severe pain, as outlined in table II. Most pediatric centers have established guidelines or protocols for the management of acute painful episodes of SCD in the emergency department and in-patient units.[2] Table III and table IV outline a comprehensive treatment regimen and key guidelines for effective management of pain related to SCD, in the hospital setting. Suggestions for the management of pain in the home setting following discharge from hospital are outlined in table V. For more specific information on: (i) how to select an opioid starting dose for children who are opioid-naive; (ii) equianalgesic administration; (iii) calculation of rescue doses; (iv) intravenous titration approaches; and (v) weaning methods, clinicians are referred to the American Pain Society Guidelines.[19] 6. Nonpharmacologic Approaches to Pain Management A variety of nonmedical techniques exist to help reduce pain, distress, and pain-related disability (e.g. depression, school absenTable II. Definitions of mild, moderate, and severe sickle cell pain (reproduced from Friedman et al.,[2] with permission) A child with mild pain Rates his/her pain as 1–3 on a numerical pain scale of 0–10 Rates his/her pain as 10–30 on the Oucher Scale[33] May not appear uncomfortable, but complains of pain A child with moderate pain Rates his/her pain as 4–6 on a numerical pain scale of 0–10 Rates his/her pain as 40–60 on the Oucher Scale[33] May show facial grimacing, unhappiness, irritability, and a poor appetite May (according to parents) have been unable to carry out normal daily activities, or been uninterested in social interactions (e.g. school, playing with friends) A child with severe pain Rates his/her pain as >6 on a numerical pain scale of 0–10 Rates his/her pain as >60 on the Oucher Scale[33] Usually shows facial grimacing, guarding, irritability, and a poor appetite Usually unable to carry out normal daily activities, and is uninterested in social interactions

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Table III. Comprehensive regimen to manage severe episodes of sickle cell pain in the hospital[2,9,61]ab Initial therapy in the emergency department Moderate to severe pain: morphine 0.1–0.15 mg/kg/dose IV (dose limit = 7.5mg). Repeat in 60min if inadequate relief if adequate relief for 2h with one or two doses of morphine, consider giving acetaminophen (paracetamol) and codeine (± NSAID), and discharge home if able to take oral analgesics and fluids. If more than one or two doses of morphine required, then consider admission to hospital Maintenance therapy with opioid analgesics for in-patients with severe pain Continuous infusion morphine sulfate: start at 0.04 mg/kg/h; titrate to relief q8h by increments of 0.02 mg/kg/h, to a maximum of 0.1 mg/kg/h hydromorphone: 0.004 mg/kg/h; titrate to relief q8h by increments of 0.002 mg/kg/h, to a maximum of 0.01 mg/kg/h meperidine (pethidine): 0.4 mg/kg/h; titrate to relief q8h by increments of 0.2 mg/kg/h, to a maximum of 1.0 mg/kg/h (recommended for patients who are truly intolerant of morphine or hydromorphone, or for treatment of very brief episodes) Oral controlled release morphine (e.g. MS Contin) 1.9 mg/kg q12h (doses rounded off to nearest available strength – 15mg, 30mg, 60mg) Patient controlled analgesia pump parameters morphine sulfate: bolus dose of 0.01–0.04 mg/kg, lockout interval 6–10min, ± basal infusion of 0.01–0.04 mg/kg/h, with the 2h dose limit set at 80% of total 2h dose hydromorphone: bolus dose of 0.003–0.005 mg/kg, ± basal infusion of 0.001 mg/kg/h meperidine: bolus dose of 0.1–0.4 mg/kg, ± basal infusion of 0.1–0.25 mg/kg/h Non-opioid analgesics Acetaminophen: 10–15 mg/kg q4h, with a maximum dosage of 65 mg/kg/day Ibuprofen: 10 mg/kg q6–8h, with a maximum dosage of 40 mg/kg/day Naproxen: 5 mg/kg q12h, with a maximum dosage of 1 g/day Ketorolac: initial IV loading dose of 1.0 mg/kg, then 0.5 mg/kg q6h to a maximum of 2 mg/kg/day; PO 10mg q4–6h, to a maximum of 40 mg/day Rescue therapy for breakthrough pain Morphine sulfate: 0.05 mg/kg/dose IV q1–2h prn Hydromorphone: 0.015–0.020 mg/kg/dose IV q3–4h prn Immediate release oral morphine: 0.15–0.3 mg/kg q2–3h prn Meperidine: 0.5 mg/kg/dose IV q1–2h prn Adjuvant therapies Antipruritics Diphenhydramine 5 mg/kg/day PO/IV divided into four doses Hydroxyine 2 mg/kg/day PO divided into three or four doses Antiemetics Dimenhydrinate 5 mg/kg/day PO/IV divided into four doses Laxatives Docusate sodium 5 mg/kg/day PO, divided into three doses or as a single daily dose; usual adult dosage is 100–200 mg/day Other supportive measures Hydration (oral and intravenous) 1.5 × maintenance requirement Heating pads, hot water bottles Hydrotherapy Transcutaneous electrical stimulation

Continued next page

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Table III. Contd

Guided imagery Relaxation Distraction Play therapy a

This table only includes the usual dose for children whose bodyweight is <50kg.

b

Published tables vary in the suggested doses that are equianalgesic to morphine. Clinical response (e.g. pain relief) is the criterion that must be applied for each patient; titration to clinical response is necessary. Because there is not complete cross-tolerance among these drugs, it is usually necessary to use a lower than equianalgesic dose when changing drugs, and to retitrate to response.[19]

IV = intravenous; MS Contin = morphine sulfate contin (a sustained release preparation); NSAID = nonsteroidal anti-inflammatory drug; PO = orally; prn = as needed; qxh = every x hours.

teeism, negative self-esteem) in children with SCD, while improving coping and overall level of functioning.[19,62-64] However, extremely few empirical studies have been conducted to evaluate their effectiveness in controlling pain related to SCD.[17,62,63,65-70] In general, these approaches are classified as physical, behavioral and psychologic interventions. Physical therapies consist of hydration, heat massage, physical therapy, transcutaneous electrical stimulation, and acupuncture. Behavioral strategies include deep breathing, relaxation exercises, biofeedback, and behavior modifi-

cation. Finally, psychologic pain control techniques include education, distraction, guided imagery, hypnotherapy, and psychotherapy. The main purpose of these strategies is to: (i) modify the child’s subjective pain experience; and (ii) help maximize adaptive behaviors while minimizing maladaptive behaviors. It is important to select the techniques based on an assessment of the child’s pain, developmental level, and physical condition. While these strategies are not a substitute for pharmacologic therapies in

Table IV. Guidelines for the effective management of acute episodes of sickle cell pain[9,19] Conduct initial clinical assessment for cause of pain and/or complications Identify and treat any precipitating factors Select appropriate opioid analgesic, its dose, route, and frequency of administration based on prior history, current assessment, and site of care[19] Titrate to relief while minimizing adverse effects. Determine with patient the measure to be used in determining response to therapy (e.g. Oucher, VAS). Titration should continue to the highest achievable relief score using a combination of pharmacologic, psychologic, behavioral and physical therapies as required[19] Maintain relief with around-the-clock administration, rather than on a prn basis[19] Give rescue doses (e.g. 1/4–1/2 around-the-clock dose) as needed for breakthrough pain every 1–3h if adequate pain relief is not achieved[19] If three or more rescue doses are needed in ≤24h, increase the maintenance dose by 25–50% Give non-opioid analgesics and adjuvant analgesics in combination with opioid analgesics to provide balanced analgesia If the acute painful episode is improved and pain is relieved to a tolerable level then the patient may be discharged home. However, failure to achieve adequate pain relief after aggressive therapy for 6–8h is an indication for hospital admission Consider treating adverse effects of opioids with adjuvants, such as dimenhydrinate for nausea and diphenhydramine for pruritis Monitor sedation and vital signs with special attention to RR and oxygen saturation. Observe for signs of opioid toxicity As the patient improves, gradually transition to oral analgesics. This enables the patient to more rapidly resume normal activities of daily living. The patient must be able to tolerate oral intake. Calculate the total daily opioid administered intravenously and convert that amount to an equivalent PO dose (e.g. IV : PO dose conversion ratio for morphine is 1 : 3). Administer this dose at intervals appropriate for the drug chosen to ensure successful transition from IV to PO. For example: continuous infusion: decrease the maintenance dose by 25% every 12–24h and replace with an oral opioid in regular divided doses PCA: stop basal infusion and substitute with around-the-clock or sustained release oral opioid preparations and continue with PCA bolus doses for another 12–24h Evaluate and document the following regularly: pain severity, pain relief, mood, adverse events and their treatment Design a discharge plan with outpatient follow-up if pain adequately controlled with oral analgesics, taking fluids well by mouth and resolution of concurrent problems IV = intravenous; PCA = patient controlled analgesia; PO = orally; prn = as needed; RR = respiratory rate; VAS = visual analogue scale.

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Table V. Suggestions for the management of pain at home following hospital discharge Pain management should include both pharmacologic and nonpharmacologic strategies Patients should be instructed to monitor pain intensity and relief at home using the same assessment tools that were used in the hospital. If pain escalates or does not improve within 48h, patients should contact their doctor or go to the emergency department Examples of analgesic agents and administration regimens include: short-acting preparations (e.g. codeine or oxycodone with acetaminophen [paracetamol]) around the clock for 48 hours then re-evaluate. If pain is mild, may administer prn sustained release preparations (e.g. controlled-release morphine, codeine, or oxycodone). Need to prescribe short-acting opioid doses for breakthrough pain. Note that some patients may be on these preparations for several weeks, therefore, the dose should be gradually reduced by 10–20% per day. When the lowest dose is reached, use short-acting opioid doses and gradually increase the administration interval until an interval of once daily has been reached, then discontinue NSAIDs (e.g. naprosyn, ibuprofen) can be administered alone for mild pain, or in combination with both short-and long-acting preparations for moderate pain prn = as needed.

acute pain management, they should be integrated into a comprehensive care plan to provide optimal pain relief.[8,19] 7. Conclusions Pain is the hallmark clinical feature of SCD. The severity and unpredictability of the pain, lack of objective markers, and conflicting perceptions between patients, families, and healthcare professionals make pain in SCD particularly challenging to manage.[21] However, pain can be effectively managed in most children by aggressive use of currently available treatment approaches. Effective management requires frequent assessment to maintain pain control, make adjustments due to tolerance or adverse effects of opioid therapy, and identify exacerbations of pain and/or other complications. Once a thorough assessment has been completed, a comprehensive management approach, including appropriate pharmacologic, psychologic, behavioral, and physical strategies can be implemented to reduce pain, improve functional ability, and enhance well-being.[19] Future research on these specific pharmacologic and nonpharmacologic approaches is needed in order to optimize the reduction of pain and pain-related disabilities associated with SCD in children. Acknowledgements The authors would like to acknowledge Dr J. Friedman, Department of Paediatric Medicine, and Lori Palozzi, RN, MScN, ACNP, Department of Anaesthesia, The Hospital for Sick Children, for their thoughtful feedback in the preparation of this manuscript. Jennifer Stinson is funded by the Canadian Nurses Foundation/Hospital for Sick Children’s Foundation/Canadian Institute of Health Research, and the Hospital for Sick Children Clinician Scientist Fellowship. The author has no conflicts of interest that are directly relevant to the content of this manuscript. © Adis Data Information BV 2003. All rights reserved.

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Correspondence and offprints: Jennifer Stinson, Department of Anaesthesia, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail: [email protected]

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