Conflict of interest: The views expressed do not necessarily represent those of the funding agency or official findings of the South Carolina, Department of Health and Human Services (Medicaid).
Pain management in children and adolescents with sickle cell disease†
Article first published online: 14 OCT 2010
Copyright © 2010 Wiley-Liss, Inc.
American Journal of Hematology
Volume 86, Issue 1, pages 82–84, January 2011
How to Cite
Jerrell, J. M., Tripathi, A. and Stallworth, J. R. (2011), Pain management in children and adolescents with sickle cell disease. Am. J. Hematol., 86: 82–84. doi: 10.1002/ajh.21873
- Issue published online: 17 DEC 2010
- Article first published online: 14 OCT 2010
- Accepted manuscript online: 16 SEP 2010 01:36PM EST
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].
Materials and Methods
Medical and pharmacy claims for the calendar years January 1, 1998 through December 31, 2006 were used to identify a cohort of child and adolescent patients (ages 17 and under) enrolled in and eligible for Medicaid for a minimum of 9 months in each calendar year included in this analysis, who had a service encounter with a diagnosis of SCD (thalassemia and SC trait were not included). The selection date was the date of the first encounter in which the SCD diagnosis was documented in the Medicaid system. No information was available on their treatments before this start date. This procedure yielded a total N = 2194 pediatric SCD cases during the 11-year period. Medicaid medical claims were used to identify a service encounter, date of service, and the International Classification of Diseases, 9th Clinical Modification diagnosis codes related to that visit. Pharmacy claims identified the medication dispensed, and the date the prescription was filled. This study was approved by the University of South Carolina Institutional Review Board as exempt from human subject research guidelines (45 Code of Federal Regulations part 46).
Primary or secondary diagnosis codes for VOC inpatient or ER pain visits and for blood transfusions, an adenotonsillectomy, and the percent of services received from an SCD specialty clinic were obtained from the Visits file. Prescriptions of HU, NSAIDs, weak and stronger opioids, anticonvulsants, and antidepressants were coded from the Pharmacy file. The analgesics examined were prescribed acetaminophen, NSAIDS (naproxen, ibuprofen, motrin, etc.), weak opioids (codeine or hydrocodone, with or without acetaminophen), or stronger opioids (morphine or oxycodone, with or without acetaminophen). Antidepressants were categorized as SSRIs for citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, or SNRIs/ heterocyclics for bupropion, duloxetine, maprotiline, mirtazapine, nefazodone, trazodone, or venlafaxine. Anticonvulsants were coded for gabapentin, pregabalin, carbamazepine, valproic acid, and phenytoin. The SSRI and SNRI/heterocyclic antidepressants were prescribed for diagnosed depression, and the anticonvulsants were prescribed for seizures, not for the treatment of VOC pain.
To examine the relative impact of pain medication categories over time on frequency of acute pain episodes, a negative binomial regression model (for non-normally distributed count data; PROC GENMOD facility in SAS version 9.1; SAS Institute, Cary, NC) was employed to calculate a ratio of the log rate of VOC acute pain visits per total years in the Medicaid data set with prescribed NSAIDs, opioids, antidepressants, or anticonvulsants as the independent variables. Individual risk factors (age, gender, race), receipt of HU or an adenotonsillectomy (dichotomously coded as yes/no), which might be associated with hypoxic episodes correlating with the onset of pain crises [26, 27], mean number of blood transfusions per year, and the percentage of SCD services received from a specialty clinic for SCD were used as control variables to explain differences in total pain episodes. Interaction terms between the strong opioids and antidepressants or anticonvulsants were used to examine the combined effect of these medications. Resulting model estimates, 95% confidence intervals, and P-values are reported for statistical significance.
Data analysis was supported by the University of South Carolina School of Medicine Departments of Neuropsychiatry, Pediatrics, and Internal Medicine.
- 1National Institutes of Health Consensus Development Conference Statement: Hydroxyurea treatment for sickle cell disease. Ann Intern Med 2008; 148: 932–938., , , et al.
- 2Pain management and quality of life in sickle cell disease. Expert Rev Pharmacoecon Outcomes Res 2009; 9: 347–352., , .
- 3Hemoglobinopathies. In KliegmanRM, BehrmanRE, JensonHB, StantonB, editos. Nelson Textbook of Pediatrics,18th ed. Philadelphia, PA: WB Saunders Elsevier; 2007. Available at http://www.mdconsult.com/das/book/body/143898456-9/853444084/1608/1067.html#4-u1.0-B978-1-4160-2450-7..50464-3--cesec19_8724. Accessed June 17,2009., .
- 4The assessment and management of chronic pain in children. Paediatr Drugs 2002; 4: 737–746., , , .
- 5Hydroxyurea for treatment of severe sickle cell anemia: A pediatric clinical trial. Blood 1996; 88: 1960–1964., , , et al.
- 6Safety of hydroxyurea in children with sickle cell anemia: Results of the HUG-KIDS study, a phase I/II trial.Pediatric Hydroxyurea Group. Blood 1999; 94: 1550–1554., , , et al.
- 7Hydroxyurea for sickle cell disease: A systematic review for efficacy and toxicity in children. Pediatrics 2008; 122: 1332–1342., , , et al.
- 8Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood 2001; 97: 3628–3632., , , et al.
- 9Long-term hydroxyurea therapy for infants with sickle cell anemia: The HUSOFT extension study. Blood 2005; 106: 2269–2275., , , et al.
- 10Use of hydroxyurea in children ages 2 to 5 years with sickle cell disease. J Pediatr Hematol Oncol 2000; 22: 330–334., , , et al.
- 11Antidepressant pharmacotherapy: Considerations for the pain clinician. Pain Pract 2003; 3: 135–143., .
- 12Psychiatry in chronic pain: A review and update. Curr Psychiatr Rep 2005; 7: 213–219., .
- 13Management of neuropathic pain: Translating mechanistic advances and evidence-based research into clinical practice. Clin J Pain 2006; 22: S2–S8..
- 14Painful peripheral neuropathy and its nonsurgical treatment. Muscle Nerve 2004; 30: 3–19., .
- 15Antidepressant and anticonvulsant medication for chronic pain. Phys Med Rehabil Clin N Am 2006; 17: 381–400., .
- 16Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 2007; 27: 1571–1587., .
- 17Neuropathic agents and pain: New strategies. Biomed Pharmacother 2006; 60: 318–322., .
- 18Pharmacotherapy of chronic pain: A synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry 2009; 31: 206–219., , .
- 19Hematologic problems in psychosomatic medicine. Psychiatr Clin North Am 2007; 30: 739–759., , , et al.
- 20Validation of diagnostic codes for outpatient-originating sudden cardiac death and ventricular arrhythmia in Medicaid and Medicare claims data. Pharmacoepidemiol Drug Saf 2010; 19: 555–562., , , , , , , .
- 21Identification and validation of lupus nephritis cases using administrative data. Lupus 2010; 19: 741–743., , .
- 22Pharmacogenetics of morphine: Potential implications in sickle cell disease. Am J Hematol 2007; 83: 233–236., , , .
- 23Hospitalization rates and costs of care of patients with sickle-cell anemia in the state of Maryland in the era of hydroxyurea. Am J Hematol 2006; 81: 927–932., , , .
- 24The course and correlates of high hospital utilization in sickle cell disease: Evidence from a large, urban Medicaid managed care organization. Am J Hematol 2009; 84: 666–670., , , .
- 25The cost of health care for patients with sickle cell disease. Am J Hematol 2009; 84: 320–322..
- 26Chronic tonsillitis, tonsillectomy and sickle cell crises. J Laryngol Otol 1987; 101: 467–470., .
- 27Obstructive sleep apnea syndrome in sickle cell disease. Ann Otol Rhinol Laryngol 1989; 98: 174–178., , , .
Jeanette M. Jerrell*, Avnish Tripathi, James R. Stallworth, * Department of Neuropsychiatry and Behavioral Science, University of South Carolina School of Medicine, South Carolina, Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health, South Carolina, Department of Pediatrics, University of South Carolina School of Medicine, South Carolina.