Treatment of Sickle Cell Pain

Karen F. Marlowe, PharmD., Michael F. Chicella, PharmD.


Pharmacotherapy. 2002;22(4) 

In This Article

Treatment Modes

Most physicians in sickle cell centers prefer the intravenous route for providing analgesics.[27] Administering analgesics as needed is not appropriate for sickle cell pain because the pain is sustained; however, scheduled fixed doses do not address the variability seen in patients with sickle cell disease.[3,6] For sickle cell pain, patient-controlled administration of an analgesic drug is equal in efficacy to intermittent dosing. Patient-controlled administration can decrease nursing time, shorten time between pain perception and drug administration, and lower patient anxiety.[28]

Several concerns limit intramuscular adminis-tration of an analgesic. Although it may be useful before intravenous access is obtained, repeated intramuscular injections may result in muscle damage and formation of sterile abscesses. An evaluation of pharmacokinetics of meperidine after intramuscular administration reported a 2- to 3-fold variation in time to peak.[14] Thus, the intramuscular route should be avoided whenever possible.

Oral analgesics for treating sickle cell pain crises have not been evaluated extensively but have met with some success. One study that evaluated intravenous versus oral morphine in children with vasoocclusive episodes found equal efficacy and safety in both groups.[29] In another study, oral morphine was administered in combination with a nonsteroidal antiinflammatory agent for treatment of acute pain episodes in an emergency department. Compared with historical controls, admission rates decreased with this treatment.[30] In most cases the oral route should be reserved for patients with mild-to-moderate pain or those in the latter stages of recovery who can tolerate oral intake. Physicians may find intravenous or patient-controlled bolus doses useful as a bridge to conversion to oral therapy.[3] Patients who are discharged receiving oral therapy should be provided with enough drug to last until their follow-up appointment.

Transdermal fentanyl has been suggested as an alternative for both acute and chronic pain control. Transdermal administration has two potential drawbacks. First, it takes 12 hours to achieve steady state, and patients still require treatment for breakthrough pain. Second, titrating the dosage to the patient's fluctuating pain is difficult.[14] However, the transdermal route might be effective when venous access is difficult.

Epidural pain control may be an alternative route for patients with acute pain that is unresponsive to other routes and adjunctive therapies. Epidural pain control could avoid some side effects of intravenous or patient-controlled administration of opiates. Epidural administration is most effective when the pain is located below the fourth dermatome.[3,31]

Table 1 summarizes several studies evaluating different opiates and routes of administration.[19,28,29,30,32,33,34,35]

Opiates. Most opiates have comparable efficacy and safety profiles, making them difficult to differentiate.[3] Morphine is considered the drug of choice for treatment of acute sickle cell pain crisis.[6] However, morphine's pharmacokinetics, and thus dosing, vary among patients.[7] One study of patients with sickle cell disease reported an 8-fold variation in morphine clearance (6.2-59.1 ml/min/kg).[36] Patients with sickle cell disease have more rapid plasma clearances and shorter half-lives for morphine than other patients, such as those with cancer and those undergoing surgery. In addition, patients with severe symptoms have significantly faster clearances than those with moderate symptoms (23.4 ml/min/kg and 36.3 ml/min/kg, respectively, p=0.042).[36] More rapid clearance may result in a weaker analgesic response from commonly administered doses.[36]

Meperidine often is the opiate of choice for patients with sickle cell pain crisis; however, its use has been discouraged due to the risk of seizures. In fact, this patient population may be particularly vulnerable to seizures because of reduced renal function, high meperidine dosages, and altered meperidine pharmacokinetics.[3,27] The drug's short half-life requires frequent dosing to maintain adequate levels of analgesia. One pharmacokinetic evaluation found that patients with sickle cell disease had significantly lower meperidine levels at all time points than a control group of patients with abscesses.[37]

Hydromorphone has fewer side effects than morphine and may be an alternative for patients who experience nausea or pruritus with morphine.[3] However, no controlled studies have evaluated administration or pharmacokinetics of hydromorphone in this patient population.

Administration of an agonist-antagonist drug for patients with acute sickle cell pain is controversial; however, the efficacy of nalbuphine has been evaluated in children with sickle cell disease. A retrospective chart review of nalbuphine versus meperidine in 16 children and young adults found that pain control with nalbuphine was similar to that achieved with meperidine.[7,38] However, some practitioners question whether administration of an agonist-antagonist drug is ethically appropriate considering the severity of sickle cell pain.[7] Another concern is the possible development of a withdrawal-like syndrome in patients receiving long-term therapy with opiate agonists.

Oral opiates such as methadone, morphine, codeine, oxycodone, and hydroxycodone provide alternatives for outpatient treatment and pain management for patients discharged from the hospital. Although these drugs are administered routinely to patients with sickle cell disease, their efficacy and safety have not been evaluated for treatment of acute pain crisis. These drugs are given as an oral analgesic for treatment of mild-to-moderate pain at home, as transitional therapy between hospital treatment and home manage-ment, or for management of chronic pain.

Adjunctive Therapy for Acute Pain. Several adjunctive treatments have been used as combination or primary therapy for acute episodes of sickle cell pain. Nonsteroidal antiinflammatory agents such as ketorolac, piroxicam, and ibuprofen have been evaluated for monotherapy and in combination with opiates for vasoocclusive crises. Ketorolac is a successful primary treatment for patients unable to tolerate opiates.[7,39] In a blinded, crossover trial with 20 children, ketorolac provided superior pain control and with fewer side effects than meperidine.[7,39,40] Another report evaluated the effects of a single dose of ketorolac given to patients in an emergency department. These patients received no less narcotic therapy than their counterparts, but continued ketorolac administration may have provided increased benefit.[41] No significant difference was found between patients with sickle cell pain treated with a combination of a single dose of ketorolac in addition to morphine and a control group receiving morphine as monotherapy.[42] The group receiving ketorolac and morphine experienced the same degree of pain, rate of hospital admission, and total opiate dose as the morphine monotherapy group.

A more recent study evaluated efficacy of intravenous ketorolac for treatment of acute sickle cell crises in a pediatric emergency department.[43] In 70 episodes treated, more than half resolved with ketorolac and fluids only. An initial pain score greater than 7 out of 10 or the presence of four or more pain sites were predictors of failure of monotherapy with ketorolac. A Nigerian trial found that piroxicam for treatment of vasoocclusive crisis was as effective as aspirin and had fewer side effects.[44] Ibuprofen was suggested as an addition to traditional pain management regimens.[30] However, possible detrimental effects of nonsteroidal antiinflammatory agents on bone healing is a concern.[3] Although these agents should address the inflammatory component of sickle cell pain, further study is needed to evaluate the best role for them in treatment of acute sickle cell crises.

Methylprednisolone was administered with standard therapy in a randomized, double-blind trial involving 56 episodes of pain crisis in children and adolescents.[45] In the steroid group, in which patients received methylprednisolone 15 mg/kg up to a maximum dose of 1000 mg, the duration of inpatient analgesic therapy was significantly reduced compared with the placebo group. However, the steroid group experienced more recurrences of pain than the placebo group shortly after therapy was completed. No adverse effects were reported. As with nonsteroidal antiinflammatory drugs, effects of glucocorticoid agents on bone healing and frequency of avascular necrosis are of concern.[3]

Stimulants have been suggested for adjunctive therapy in acute pain crises. Methylphenidate and dextroamphetamine are thought to have intrinsic analgesic properties and may enhance analgesia provided by opiates. They also may counteract some of the somnolence associated with opiates, allowing for administration of higher dosages of analgesics.[3] These agents have not been evaluated in a controlled manner for patients with sickle cell pain.

Tricyclic antidepressants and anticonvulsants are given for various pain syndromes, including neuropathic pain, and they have been included in several reported treatment protocols. However, their efficacy has not been directly evaluated for treatment of acute and chronic sickle cell pain.[3]

Providing adequate hydration is a component of almost every treatment protocol for vasoocclusive crises. Dehydration is one of the principal precipitating factors for pain crises. However, overcorrection of fluid balance can have a negative effect, including possibly increasing the risk of acute chest syndrome. This syndrome, characterized by cough, chest pain, dyspnea, fever, and radiographic changes, is the most common cause of death for patients with sickle cell disease.[3,46] Hydration should be provided to correct deficits, replace any ongoing losses, and maintain euvolemia. Mild pain may improve with oral hydration.[6]

Both psychological and behavioral therapies have been provided as adjuncts to traditional analgesics. Psychological strategies include distraction, guided imagery, hypnotherapy, psychotherapy, and patient education about pain.[3] An evaluation of a program to teach coping skills (breathing, relaxation, and distractions) found that when patients used coping skills, their use of health care resources decreased. However, the benefit of instruction decreased without reinforcement.[47] Behavioral techniques may include relaxation, biofeedback, behavior modification, and deep breathing exercises.[3] Pain-behavior contracts, which have been used mainly with patients whose actions are perceived as inappropriate, may provide a way to define limits and expectations for patient and care provider and may place responsibility on the patient for adhering to the treatment plan. These contracts can be used with adolescents and adults to decrease maladaptive behaviors, improve compliance with care plans, and maximize pain control. Contracts can address types of analgesics to be administered; compliance with other interventions, such as incentive spirometry; and activities of daily living, such as remaining mobile.[22,27] No randomized trials have been performed to evaluate their efficacy.

Polymerization of hemoglobin S is dependent on its concentration. Other types of hemoglobin, specifically fetal hemoglobin (hemoglobin F), are resistant to sickling. Hydroxyurea, the most recent advance in prevention of the sequelae of sickle cell disease, increases the concentration of hemoglobin F in erythrocytes. Hemoglobin F forms soluble polymers with hemoglobin S, reducing the overall concentration of hemoglobin S and the likelihood of polymerization and sickling of the cell. Hydroxyurea causes significant reduction in the incidence of acute pain crises (from 4.5 to 2.5 crises/year, p<0.001), acute chest syndrome (from 51 to 25 episodes/ year, p<0.001), and need for transfusions (from 73 to 48 transfusion/year, p=0.001).[48]

Hydroxyurea has been evaluated for use in adult and pediatric populations.[48,49,50] In most protocols, hydroxyurea is started at 10-15 mg/kg and then titrated to an effective dosage. Efficacy is evaluated by monitoring for an increase in hemoglobin F concentrations or mean corpuscular volume.[11] Dosages are titrated over several months, with monitoring of complete blood counts every 2 weeks at the start of therapy and then regularly throughout therapy. Efficacy of hydroxyurea depends on patient adherence to the treatment regimen and on close monitoring for side effects such as myelosuppression.[10,11,48]


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