In a cohort of 2,194 children with sickle cell disease (SCD) treated in community-based services, we explored the types of medications used to treat vaso-occlusive (VOC) pain episodes, and the relative effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and adjunctive antidepressants or anticonvulsant medications on reducing acute VOC pain visits over time. Pharmacologic treatments for VOC pain consisted mainly of NSAIDs and weak opioids. Significantly more patients with more than 3 inpatient or ER VOC pain visits during their first year of SCD treatment were prescribed stronger opioids, SSRIs, SNRI/heterocyclics, and anticonvulsants. Prescription of both stronger opioids and SSRI antidepressants or anticonvulsants was significantly associated with lower cumulative rates of acute VOC pain visits over time. Using an observational study design and existing clinical data, these findings are intended to illustrate the potential clinical advantages of combining adjunctive antidepressants or anticonvulsants with primary pain medications for relief of acute VOC pain over time.
In children with SCD, erythrocytes become deoxygenated, dehydrated, and crescent-shaped, and tend to aggregate or stick to blood vessel walls, blocking blood flow in bones and organs, and causing recurring, VOC pain episodes . With recurring acute VOC pain episodes, severe SCD represents a chronic pain condition . For effective long-term management, pharmacological interventions for acute VOC pain  could be combined with adjunctive interventions for chronic pain .
The chronology of pain in children with SCD includes eight phases . The first three phases involve specific pain sites (e.g., dactylitis), prodromal signs of VOC pain, and an early, mild form of VOC pain. A mild oral analgesic may be given (e.g., acetaminophen), and NSAIDs may be effective in reducing bone and joint pain. Phase 4 is characterized by pain accelerating to a moderate level, interfering with daily activities, and requiring stronger oral analgesics (e.g., weak opioids [codeine, hydrocodone]). In Phase 5, VOC pain increases to a severe level and plateaus for an extended time period, requiring hospitalization and intravenous (IV) opioids (e.g., morphine, oxycodone). The acute phase of VOC pain episodes may last 3–5 days. The VOC pain starts to decrease in Phase 6 and in Phase 7 decreases rapidly, as treatment with of IV analgesics is gradually decreased and the use of sustained-release oral opioids is initiated. In Phase 8, VOC pain is resolved or decreased to a “tolerable level,” treated at home, using mild to moderate strength analgesics. Some patients may require “breakthrough” oral opiates (e.g., morphine elixir).
Hydroxyurea (HU) has been shown to reduce episodes of VOC pain in observational and randomized controlled trials [5–10], and regular blood transfusions are used for prevention of recurrent pain in patients who have not responded to HU [2, 4]. Pharmacotherapies for chronic pain include agents from multiple drug classes (simple analgesics, NSAIDs, opioids, anticonvulsants, and antidepressants) . The tricyclic antidepressants [11–13] as well as the serotonin norepinephrine reuptake inhibitors or heterocyclic (SNRI/ heterocyclic) antidepressants venlafaxine, bupropion, and duloxetine [14–17] are efficacious in the management of chronic pain. The SNRI/ heterocyclics produce fewer side effects in children and adolescents and, when used as adjunctive analgesics, they effectively improve patient overall quality of life . When used solely for pain management, the selective serotonin reuptake inhibitors (SSRIs) have either been less robust (i.e., paroxetine, citalopram) or lacked any efficacy at all (i.e., fluoxetine) [11, 18]. Two anticonvulsants, gabapentin and pregabalin, are backed by the strongest evidence as analgesics for multiple types of pain  but others may be used. No systematic studies of the combined effects of these classes of agents on VOC pain were found in the literature.
This pediatric SCD cohort was 60% African American, 53% male, entered into the Medicaid data set at 5–6 years of age, and remained in the data set for about 7 years. Most were prescribed NSAIDs or weak opioids (Table I). The majority of patients treated with NSAIDs were taking ibuprofen, motrin, and naproxen. The weak opioids prescribed were codeine/acetominophen and hydrocodone. The stronger opioids prescribed were morphine and oxycodone. Those prescribed SSRIs were taking citalopram, escitalopram, paroxetine, fluoxetine, or sertraline. Prescribed SNRI/heterocyclic agents were mainly venlafaxine, mirtazapine, bupropion, or duloxetine. The primary anticonvulsants prescribed were carbamazepine, valproic acid, gabapentin, or phenytoin, with fewer patients receiving pregabalin (Table I). Ten percent of the pediatric SCD cohort had more than three acute VOC pain visits during their first year of SCD treatment, and significantly more of these were prescribed stronger opioids, SSRIs, SNRI/heterocyclics, and anticonvulsants (Table II). As shown in Table III, only those children prescribed both stronger opioids and SSRI antidepressants or anticonvulsants had significantly lower cumulative rates of acute VOC pain visits over time, controlling for other interventions, which could impact VOC pain.
|Independent variable||SCD Cohort|
|African American||1305 (59.5%)|
|Non African Americana||889 (40.5%)|
|Mean age at SCD diagnosis as documented in Medicaid||5.7 (SD = 5.3)|
|Years in Medicaid||7.2 (SD = 3.1)|
|Percent receiving care at specialty clinic||13.4 (SD = 14.9)|
|SCD VOC pain treatments|
|Mean blood transfusions per year||1.6 (SD = 1.9)|
|Prescribed hydroxyurea: Yes||209 (9.5%)|
|Adenotonsillectomy performed: Yes||256 (11.7%)|
|Prescribed NSAID: Yes||740 (33.7%)|
|Prescribed weak opioid: Yes||1477 (67.3%)|
|Prescribed stronger opioid: Yes||494 (22.5%)|
|Prescribed SSRI antidepressant: Yes||122 (12.0%)|
|Prescribed SNRI/heterocyclic antidepressant: Yes||111 (10.9%)|
|Prescribed anticonvulsant: Yes||74 (3.4%)|
|Medication Prescribeda||VOC Pain First Year Severity–Low (N = 1972; 89.9%)||VOC Pain First Year Severity–High (N = 222; 10.1%)||P-value|
|NSAIDs||572 (29.0%)||168 (75.7%)||<0.0001|
|Weak Opioids||1258 (63.8%)||219 (98.7%)||<0.0001|
|Stronger Opioids||342 (17.3%)||152 (68.5%)||<0.0001|
|SSRIs||93 (4.7%)||29 (13.1%)||<0.0001|
|SNRI/heterocylics||91 (4.6%)||20 (9.0%)||0.005|
|Anticonvulsants||48 (2.4%)||26 (11.7%)||<0.0001|
|Predictor||Estimated Coefficient||95% Confidence Interval||P-value|
|Transfusions per year||0.17||(0.07, 0.26)||0.0003|
|Percent receiving specialty care||0.01||(0.009, 0.02)||<0.0001|
|Amount NSAIDs prescribed per year||0.01||(0.004, 0.02)||0.007|
|Amount weak opioids prescribed per year||0.08||(0.07, 0.10)||<0.0001|
|Prescribed stronger opioids and SSRIs||−0.02||(−0.04, −0.01)||0.0009|
|Prescribed stronger opioids and anticonvulsants||−0.0002||(−0.0003, −0.0001)||<0.0001|
Most of these psychotropic medications have infrequent but potentially important hematologic side effects or may interact with the anticoagulants used in medically ill patients . The SSRIs citalopram, paroxetine, fluoxetine, and sertraline as well as some SNRIs may inhibit platelet function and are associated with an increased risk of bleeding complications (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, hemorrhage) or bruising, especially with the concomitant use of aspirin or NSAIDs . Citalopram is associated with leukocytosis and leukopenia, whereas sertraline is associated with thrombocytopenia; both are associated with the development of anemia . The SNRI/heterocyclic agents, venlafaxine, mirtazapine, and bupropion, are associated with leukopenia. Furthermore, venlafaxine is associated with the development of anemia and leukocytosis, and mirtazapine is associated with the development of anemia, eosinophilia, agranulocytosis, pancytopenia, and thrombocytopenia, whereas duloxetine is only associated with bruising and bleeding . The anticonvulsants, carbamazepine, and phenytoin, carry an increased risk of agranulocytosis, leukopenia, and thrombocytopenia, carbamazepine is also associated with the development of anemia, eosinophilia, and leukocytosis, whereas valproic acid is associated with pure red cell aplasia (as is carbamazepine) and thrombocytopenia. Gabapentin is associated only with leukopenia and neutropenia .
While this SCD cohort represents a large, heterogeneous group of children and adolescents, and the long-term observational study provides information regarding important clinical interventions and their impact on pediatric VOC pain, the data were not gathered using a prospective, controlled design and structured clinical research interviews were not employed to confirm any of the assigned medical conditions. Previous studies have shown that although Medicaid databases provide much less detailed information on individuals and care than primary data collection, physician diagnoses and utilization data correspond to clinical medical record reviews in the majority of the cases [20, 21]. Furthermore, these results report associations and, as a result, directions of causality cannot be inferred. Pediatric SCD patients who dropped out of treatment or were periodically ineligible for Medicaid coverage are not represented in this data set and their outcomes may differ from those patients who remained in Medicaid over time.
Practitioners will need to evaluate the individual benefit-risk ratio of combining analgesics with antidepressants or anticonvulsants in SCD children and adolescents with severe pain, rather than solely increasing the opioid dose , and realize that none of these psychotropic agents is FDA-approved for pain management in children and adolescents. Controlled trials regarding the adjunctive use of psychotropics for VOC pain relief are needed to determine which agent combinations are safe, effective, improve quality of life, and reduce the personal and payer burden associated with multiple acute VOC pain episodes per year [23–25].