Relationship between painful manifestations and the use of hydroxyurea in children and adolescents with sickle cell disease

To analyze the profile of pain, its triggering factors, and the relationship with the use of hydroxyurea in children and adolescents with sickle cell disease. This was an analytical crosssectional study of 80 patients with sickle cell disease, both male and female, aged 6 to 18 years, seen at the Center for Hematology and Hemotherapy of Pernambuco, Brazil. To assess the pain profile, forms with the adapted visual scale from the “Fear of Dental Pain Questionnaire – Short Form” were used. Fisher's exact test was used to evaluate the Research, Society and Development, v. 9, n. 10, e6949109046, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.9046 2 association between pain manifestations and the use of hydroxyurea. Pain was reported by 68.7% of the patients and 52.7% of them reported severe pain, which eventually affected their daily routines. Physical triggers presented the highest rate (78.2%). The most frequent sites of pain were the trunk (80%) and lower extremities (54.5%), and constricting (40%) and deep (40%) pain were the most frequent types. Thirty percent of the patients reported being treated with hydroxyurea for prevention of painful events. It is concluded that the patients with sickle cell disease showed a high rate of painful events and physical factors, such as cold temperature, trauma and physical effort, were considered to be the most prevalent. There was no association between the use of hydroxyurea and pain improvement.


Introduction
Sickle cell disease (SCD) is a single-gene genetic and inherited disorder. It is caused by a mutation in the gene that produces hemoglobin A, converting it to sickle hemoglobin (HbS). Sickle cell anemia (SCA) is considered the most common type of SCD (Campelo et al., 2018). SCD is recognized by the World Health Organization (WHO) as a serious public health problem, having a large impact on the morbidity and mortality of affected individuals if it is left undiagnosed or is not treated properly (McGann, 2014). It has been estimated that 2 million Brazilians carry the HbS gene and 25,000 to 50,000 are believed to have the homozygous form. The distribution of SCD in Brazil is quite heterogeneous, but the northern and northeastern regions have the highest prevalence rates (6 to 10%) owing to the predominance of the African American ethnic group, a risk factor that is well established in the literature (Jesus, 2010).
Painful vaso-occlusive crisis, a marker of SCD, is the main cause of morbidity and the most common reason for emergency care and hospital admission. It may occur at a very early age, in the first months of life (Sousa et al., 2015;Fixler & Styles, 2002;Dumaplin, 2006).
To date, there is no specific treatment for SCD. The available drugs help relieve the symptoms, improving the patient's quality of life. One of these drugs, hydroxyurea, improves blood flow, increases fetal hemoglobin levels, and acts as an exogenous source of nitric oxide, reducing HbS concentration and the frequency of painful episodes (Silva-Pinto et al., 2013).
The aim of this study was to assess the profile of pain, its triggering factors and its response to hydroxyurea in children and adolescents with SCD.

Methods
This is an analytical cross-sectional study. The census sample was compound of 80 male and female patients aged 6 to 18 years with clinical and laboratory diagnosis of SCD, seen between February and June 2019 at the Center for Hematology and Hemotherapy of Pernambuco (HEMOPE), a referral center for the treatment of these patients. As a result of the specificity of the study population and the difficulty associated with random selection of patients with SCD, we used a nonprobability (convenience) sample. Patients diagnosed with attention deficit disorder and/or cognitive disorders were excluded from the study because these conditions might bias its results.
A form validated by the face validity method was applied to ensure the reliability of the data. A single researcher applied it so as to ensure the reliability of the collected data (Anastasi, 1982). This validation was conducted with 20% of the parents and/or legal guardians. The visual scale adapted from the Fear of Dental Pain Questionnaire -Short Form (S-FDPQ) was used to assess pain intensity. S-FDPQ was translated and validated for use with Brazilian children and adolescents (Ferreira & Colares, 2011). The visual scale consists of five faces that represent: 1-no pain, 2-mild pain, 3-moderate pain, 4-severe pain, and 5unbearable pain.
All of the children/adolescents and their parents/legal guardians answered questions about the presence and site of pain experienced in the past 3 months. A drawing of a doll with segments of human body parts was used for easier identification of the site of pain, and Research, Society and Development, v. 9, n. 10, e6949109046, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.9046 5 patients were asked to point to the affected region. Data were collected to determine the frequency and duration of pain; possible triggering factors such as cold temperature, trauma, and physical effort; psychological factors; fever and infection; type of pain; interference of pain with the daily routine; the approach to pain relief; and treatment used.
This study was approved by the Research Ethics Committee of HEMOPE (process number: 2.934364). The parents or legal guardians and the adolescents were informed about the research methodology and only those who signed the free informed consent form were eligible to participate.

Statistical analysis
Absolute and relative frequencies were estimated for the categorical variables, whereas mean, standard deviation, and median were calculated for the numerical variables.
Fisher's exact test was used to assess the association between variables. Statistical significance was set at 5%. The data were typed into an Excel spreadsheet and the statistical calculations were made using SPSS (Statistical Package for the Social Sciences) version 23.

Results
Eighty patients were assessed and 55% were male, 57.5% were aged 6 to 11 years, and 81.2% were of mixed ancestry. With respect to SCD, 95% of the patients had SCA and 5% had some subtype of hemoglobinopathy such as HbS-beta+thalassemia. History of stroke was found in 15.0% of the patients, and spleen and liver disorders accounted for 28.8% and 18.8%, respectively. Table 1 shows the frequency of painful events in SCD patients. Regarding hydroxyurea, 30% of the patients had been using it for over 6 months. All of the patients reported that pain was related to SCD and the triggering factors were mostly physical (78.2%). The most commonly affected sites were the trunk (80%) and lower extremities (54.5%); the most common types of pain were constricting (40%) and deep (40%); and 23.6% of the patients reported that the pain was very frequent (Table 2).
Research, Society and Development, v. 9, n. 10, e6949109046, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.9046 a The percentage was obtained from 55 patients who had reported pain in the past 3 months. b Given the possibility of more than one answer choice, the sum of frequencies is greater than the total number (55) of patients who reported pain. Source: Authors.
Most children/adolescents stated that pain would interfere in their daily routines.

Discussion
Pain was an apparent symptom among the children and adolescents who participated in the present study and it is an important clinical manifestation of SCD. The analysis of the perception of painful events associated with SCA among children and their caregivers demonstrated that assessing pain in terms of its characteristics, impact, and coping and management strategies is a protective measure, as such assessment allows adopting approaches that could minimize the potential detrimental effect of pain on child development (Dias et al., 2013).
All participants considered that pain was closely related to SCD, but the type and intensity of pain varied considerably. Deep and constricting pain were the most prevalent types. As for pain intensity, severe pain accounted for 52.7%. As with the results found in the present study, other studies revealed that pain is regarded as severe by most children and that constricting pain is reported by them quite frequently (Dias et al., 2013;National Institutes of Health, 2002;Yaster et al., 2000). Development, v. 9, n. 10, e6949109046, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.9046 11 The presence of pain was related to triggering factors, and physical triggers were the most prevalent. Previous studies have referred to painful events as frequently spontaneous, possibly triggered by infections, dehydration, acidosis, hypoxia, physical stress, fatigue, changes in temperature, and high altitude (Steinberg, 1999;Shapiro, 1989).
In relation to the pain site, most indicated that the trunk and lower extremities were mostly affected. A study has shown that preschool children with SCD felt pain predominantly in their extremities, whereas school-aged children and young adults complained of pain in the trunk (Shapiro, 1989).
Pain was considered a limiting factor for activities of daily living and for leisure activities, confirming the hypothesis that pain associated with SCD may cause physical and emotional imbalance (Schneider & Medeiros, 2012;Freire et al., 2015;Marques et al., 2015).
Also, this study demonstrated that 61.1% of the patients needed hospital admission, predisposing them to a higher risk of infections and to deterioration of their clinical picture, thus affecting their social life and their quality of life.
Some studies have shown changes in the quality of life of children and adolescents with SCD as a result of systemic involvement (spleen and liver disorders and stroke) (Araujo et al., 2013;Taryn et al., 2016;Roberti et al., 2010). In the present study; however, these changes were unremarkable.
Manifestations of pain in individuals with hemoglobinopathies include episodes that require drug treatment as an attempt to ameliorate symptoms and improve the clinical picture (Tostes et al., 2008;Voskaridou et al., 2010;Silva & Shimauti, 2006;Figueiredo, 2007). With the purpose of improving the quality of life of these patients, reducing the frequency of painful events, 30% of the children and adolescents in the present study were treated with hydroxyurea for prevention of painful events, showing a good treatment response, even though no significant association has been found between this medication and the intensity and frequency of pain. A study showed a reduction in the number of hospital admissions, painful events, and need of blood transfusions, but there was also no significant association with the use of hydroxyurea (Bandeira et al., 2004). Therefore, further studies with other designs should be conducted to assess the use of hydroxyurea in children and adolescents with SCD and the use of other drugs with the same benefits of hydroxyurea but without its toxicity, permitting a more comprehensive assessment of painful events. Research, Society and Development, v. 9, n. 10, e6949109046, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.9046

Conclusion
The patients with SCD investigated showed a high rate of painful events, most of which were found to be associated with physical factors. Notably, the painful manifestation of SCD is characterized by multiple adverse effects that affect children and adolescents and also their families, with several consequences for their daily lives. Strategies for the implementation of public policies aimed at the prevention of painful events are necessary in order to change positively the course of the disease and improve the quality of life of patients.