Learning Objectives/Outcomes:After participating in this CME/CNE activity, the provider should be better able to:

1. Identify the physiologic mechanisms of pain for patients with sickle cell disease.

2. Summarize the different ways in which coping impacts pain outcomes in patients with sickle cell disease.

3. Compare effectiveness of nonpharmacologic treatments for pain related to sickle cell disease.

Pain as defined by the International Association for the Study of Pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage."1 For individuals with a condition that causes repeated episodes of pain throughout their lives, the emotional component of pain must not be underestimated. In addition, pain is an individual experience that is perceived within the context of the patient's environment. Therefore, a more holistic view of pain assessment and treatment is necessary to address the biopsychosocial needs of the individual in pain or at risk for pain.

This article reviews the complex physical and psychological complications in sickle cell disease and how nonpharmacologic treatment of pain may enhance quality of life and pain control.

Pathophysiology of Sickle Cell Pain

Sickle cell disease (SCD) is a group of genetic hemoglobin disorders that affect approximately 100,000 Americans. It is more common in certain ethnic groups, including people of African descent.2 A mutation in the hemoglobin gene causes the red blood cell (RBC) to polymerize, or become a sickle shape, when deoxygenated.3 The effect of the polymerization causes the RBC to become more fragile and hemolyze, or break apart, triggering an inflammatory cascade and anemia. This polymerization effect also causes the RBCs to adhere to other cells, leading to vaso-occlusion; the sickled RBCs adhere to blood vessels and block blood flow.

Endothelial cell activation resulting from the interaction between the sickled RBC and the vessel wall causes the release of inflammatory mediators. Increased production of inflammatory mediators, together with increased extravasation of cells, such as monocytes, mast cells, and macrophages in the surrounding tissue contributes to an inflammatory environment that triggers nociceptor activation. Increased sensitivity to cold and heat with thermal hyperalgesia and cold allodynia suggests sensitization of pain pathways in patients with chronic SCD-related pain. The vaso-occlusion and inflammation cause the hallmark pain associated with SCD.4

Pain in SCD can begin in infancy and is unpredictable and typically severe.3 Often the pain requires emergency department use or hospitalization, and high rates of readmission exist in this patient population.5 In addition, patients have frequent episodes of moderate pain managed at home. Pain in young children can greatly impair quality of life, including mood, sleep, school performance, and social development, and place them at risk for chronic pain conditions later in life.6

Complications in Sickle Cell Disease

Physical Complications

In addition to pain, patients with SCD are at risk for many other physical problems as a result of the chronic hemolysis in their blood vessels.7 Patients are at greater risk of avascular necrosis of the large joints, skin ulcers, retinopathy, pulmonary hypertension, and significant infections. Growth and sexual development are often delayed. Short stature and delayed puberty can be especially stressful for adolescent boys and can contribute to bullying and social stigmatization.8

Fatigue is also a significant symptom of SCD. Chronic anemia, hypoxemia, inflammation, and sleep disruption all contribute to SCD fatigue.9 The relationship between sleep and SCD pain and fatigue is especially important. Valrie et al10 showed that greater daytime pain was related to poor sleep that night, which in turn was related to greater pain the next day. Ameringer and Smith9 demonstrated a significant association between fatigue and anxiety and depression; the associations in their 60 adolescents and young adults was moderate to strong.

Psychological Complications

Children with SCD are at risk for psychological dysfunction due to both their pain and complications.8 Vasculopathy in the vessels of the brain can lead to stroke. Nearly 30% of children with SCD have a silent or overt stroke by the age of 18 years, which can cause physical and cognitive challenges.11 Executive function and memory are especially affected; this cognitive dysfunction, especially without overt physical signs, can pose a challenge in adolescence and during transition to adult care, with major impact on adherence to medical care and function.8

As with other chronic pain conditions, SCD mutually exists with surrounding psychosocial factors.12 Many studies have demonstrated higher rates of depression and anxiety in children and adolescents with greater frequency and intensity of SCD pain.13 In their study of 75 children and adolescents, Graves et al14 demonstrated that overall, there was a greater incidence of anxiety in patients with SCD than in the general population, and that quality-of-life scores were negatively associated with symptoms of depression, anxiety, and school phobia.

Coping and Adjustment in Sickle Cell Disease

Many patients with SCD go on to live full and productive lives, whereas some have severe disease and high health care utilization. Both physical and psychological health can have an impact on quality of life and functional ability of the patient with SCD. Often, the difference is how well the patient is able to process and cope with the many challenges of SCD.

According to Sarafino and Smith15 "coping is the process by which people try to manage the perceived discrepancy between the demands and resources they appraise in a stressful situation." The coping process is not a single event, but a constant cognitive and behavioral negotiation with the environment.15

Coping for patients can include both emotion-focused and problem-focused strategies, with behavioral and cognitive approaches. Emotion-focused coping controls the emotional response to the stressor. Behavioral approaches include seeking support, engaging in activities, or using stress management techniques such as relaxation, deep breathing, or yoga. Cognitive approaches include appraisals of the stressor and defense mechanisms such as denial or avoidance. Problem-focused coping involves finding the resources to cope with the stressor and includes such approaches as seeking treatment and learning new skills.

To assess coping in SCD, Gil et al16 developed a Pain Coping Strategies Questionnaire that assesses 3 domains of coping: coping attempts, negative thinking, and passive adherence:

1. Coping attempts include distraction, calming statements, praying, and reinterpreting pain.17

2. Negative thinking includes catastrophizing, fear statements, anger statements, and isolation.

3. Passive adherence or illness-focused coping includes using heat, massage, rest, fluids, and prayer to ameliorate SCD pain.17

The transactional model of stress by Lazerus and Folkman helps to understand the process of adaptation to a stressor (SCD) through coping.18 There is a relationship between SCD factors, demographics, and adaptation processes that the family and patient use to deal with stress. The mediators of stress and illness factors are the coping strategies.

In their study of 87 children and adolescents, Gil et al17 demonstrated that coping strategies used by patients to deal with pain, even after factoring in pain frequency, predicted adjustment. They demonstrated that these coping strategies were flexible over time and children were less likely than adults to have fixed negative coping patterns. Therefore, children may be more open to interventions that are aimed at improving coping strategies. Such interventions would be especially important before the transition to adolescence, when negative thinking and illness-focused strategies are used more often.19

Catastrophizing

Catastrophizing is an exaggerated negative mental state seen in response to real or anticipated pain.20 In response to pain, there is a heightened focus on pain, greater emotional response, and component of fear that in turn all amplify the pain experience. It is seen frequently in chronic pain states such as fibromyalgia and functional abdominal pain.20 There is conflicting evidence as to whether the phenomenon of catastrophizing contributes to SCD. Some studies have shown a modest correlation between pain, but no correlation between adjustment and mood and catastrophizing.21

Interestingly, a complex relationship between parental catastrophizing and children's pain and functional disability has been shown. Sil and colleagues19 studied 100 youth with SCD and their parents and demonstrated that when youth had low scores on a pain-catastrophizing scale, functional disability was decreased more if the parental catastrophizing score was high. In other words, even youths who were not catastrophizing much on their own appeared to show less functional ability if their parent was a catastrophizer. Conversely, youths with high levels of catastrophizing had greater disability if their parents had low levels on the scale. Both of these findings demonstrate that there is an interaction between parent and child that uniquely affects the ability of the youth to cope with pain, and which is independent to their own perceptions. The authors' findings also reinforce the need for a thorough family assessment of pain, functioning, and coping. Families can affect coping by the ways in which they respond to their child's distress, model coping behaviors, and coach their child through stress.22

Self-Efficacy

To adapt and cope with SCD and prevent complications, patients need to practice positive health behaviors. Self-efficacy is the belief that one has the ability to achieve a certain health outcome.23 Furthermore, it emphasizes individuals' belief that they can exert control over their behaviors and internal and external environment.24 Studies have shown that higher self-efficacy in patients with SCD is associated with improved coping, lower incidence of symptoms, and decreased pain intensity.23

Management of Pain in Sickle Cell Disease

Management of sickle cell pain is multifactorial. The primary treatment of acute pain consists of opioid and nonsteroidal anti-inflammatory pain medications. Opioids have common and significant side effects, including hyperalgesia, tolerance, and dependence.25 Hydroxyurea is a medication that, when taken daily, prevents the sickling and hemolysis of RBCs by increasing the amount of fetal hemoglobin. It is a safe and effective treatment for all genotypes of SCD beginning at 9 months of age. It has been recommended that patients start hydroxyurea early in life to decrease the long-term sequelae (such as vasculopathy, pulmonary hypertension, and renal complications) that are associated with the disease. Hydroxyurea is also used as a treatment for secondary stroke prevention.

Patients with SCD also look to alternative therapies for pain relief, especially nonpharmacologic techniques such as cognitive-behavioral therapy, guided imagery, and relaxation. Use of complementary and alternative medicine (CAM) by children with SCD is common.26 Sibinga et al27 demonstrated that, among 57 patients with SCD in a cross- sectional survey study, more than half used a form of CAM. The most common therapies were prayer, relaxation techniques, and imagery. The study also demonstrated that there was a very high parental interest in CAM therapies (83%) but a perceived low interest in CAM from the child's health care provider. Similar results were demonstrated by Yoon and Black26 in their cross-sectional survey with the addition of massage as a frequent CAM therapy used by pediatric patients.

The use of CAM to control pain in SCD was studied by Thompson and Eriator,28 who reported that there are benefits to CAM use by adults with SCD. In other studies, patients reported their perceptions that CAM had fewer side effects, was more cost-effective, and was more holistic [than traditional medical treatment]. CAM use increased the perceived control the patients had over their health and pain and led to patient empowerment. CAM therapies have been tested in the SCD population and have been shown to improve self-efficacy and positive coping strategies and decrease pain.5

CAM use in SCD primarily falls into 3 categories:

1. Bioenergy (prayer, reiki),

2. Mind-body (relaxation, imagery, cognitive-behavioral therapy, biofeedback), and

3. Biomechanical (massage, acupuncture).27

A brief description of the body of CAM research for SCD follows in terms of efficacy and potential to decrease pain and stress.

Mind-Body Therapies

Guided Imagery

Guided imagery involves using a mental picture to evoke a state of relaxation or pain reduction.29 In pediatrics, studies have examined guided imagery for pain control postoperatively.5 Dobson and Bryne5 studied the effect of daily practice of guided imagery on pain and self-efficacy in a cohort of 20 school-aged children with SCD. The authors demonstrated that self-efficacy scores were positively correlated with frequency of guided imagery use. Pain scores had also decreased significantly postintervention. Negative trends were also seen in pain medication use, acute care use, and school absences. Although this study was quasiexperimental and a small sample, it is promising that a short intervention and daily practice of guided imagery can have a positive impact on young children. The increase in self-efficacy can be especially important, because boosting their confidence in controlling their pain at young age can have lasting effects on childrens' health and psychological adjustment.

Biofeedback

Biofeedback uses "technology to provide the user with information (feedback) on physiologic states such as muscle tension, galvanic skin temperature, and brain waves, so that the user can manipulate these states through conscious mental control."30 In SCD, biofeedback has been as an adjunctive pain treatment for relaxation. One study of 10 children with SCD measured the effect of biofeedback-assisted relaxation training (BART) on peripheral body temperature, health-related quality of life, and pain frequency and disability.31 Although all measures were positively correlated with BART, this was a small pilot study, and, therefore, results are difficult to generalize. Biofeedback as a CAM therapy is less utilized, probably due to the specific equipment and personnel involved.

Relaxation and Deep Breathing

Progressive muscle relaxation is a technique that teaches patients to tense a group of muscles and then release, creating a mind and body calm.30 It is conducted by a trained professional or through a recording of a guided script. Progressive muscle relaxation has been shown to be effective in both pain and anxiety, although those effects are diminished when more rigorous methods are applied.

Deep breathing is deliberate and mindful, and it is used to manage stress and anxiety; it is also an important component of other CAM therapies such as yoga and meditation. Deep breathing is commonly used in CAM practice, with research finding it useful in panic disorder, asthma, and menopause.30

In SCD, relaxation and deep breathing have been studied both alone and in conjunction with "self-management" skills.32 Ezenwa et al29 demonstrated significantly lowered pain scores but no change in stress intensity after a guided relaxation intervention. The pilot study of 28 patients with SCD randomly assigned the participants in a guided relaxation intervention group or an attention control group. The intervention consisted of 12-minute video clips that were delivered on tablets that the participants then used at home for daily practice for 2 weeks. The study's findings suggest that guided relaxation could be a cost-effective and efficacious way to reduce pain, and possibly stress; however, larger and longer randomized controlled trials (RCTs) are needed to replicate findings.

Biomechanical Therapies

Massage

Therapeutic touch and massage have been used for centuries to augment health and decrease pain. Massage increases circulation to muscles and joints and produces relaxation and parasympathetic nervous system stimulation.33 The mechanism for pain relief is thought to be due to the activation of mechanoreceptors. This activation modulates pain through descending inhibition by blocking the release of substance P (an important pain-signaling neurochemical).34 The relaxation effect of massage also decreases muscle spasms and tightness that can cause or exacerbate pain.25

There have been few well-designed studies on the effects of massage therapy on pain in SCD; however, most studies have been small studies without the use of a control group.33 A study to assess the effects of massage therapy in youth with SCD included 34 children and their parents randomized to a massage or an attention control group; parents were taught to perform daily massages for 1 month.33 Both groups were assessed before and after the intervention to measure depression and anxiety, pain and care utilization, and functional status. The researchers demonstrated decreased depression and anxiety and increased functional status in children and adolescents receiving daily massage. However, there was also a corresponding increase in caregiver depression and anxiety, which may be due to the added stress of performing the daily therapy on children; although this stress may decrease with mastery of massage skills. Despite being a small study, the findings support the theory that massage can be a valuable tool for parents to help manage childrens' pain associated with SCD and enhance relaxation and well-being.

Acupuncture

Acupuncture is based on the theories of traditional Chinese medicine. It involves the insertion of fine needles into acupuncture points along designated meridians of energy in the body.34 These acupoints have been shown in studies to have bundles of C-fiber afferents and pain receptors. Essential to acupuncture analgesia is the sensation of de qi. De qi is achieved through both the twisting and pushing of the needle that leads to activation of the mechanoreceptors; the sensation is described as pressure, tugging, or a dull ache. It has been hypothesized that the mechanoreceptors transmit pain signals to the brain and modulate pain through descending inhibition.34

There have been few studies on the treatment effects of acupuncture in SCD. Many of the studies on pediatric pain syndrome, such as headache, low back pain, and fibromyalgia, have shown trends toward positive treatment effects of acupuncture.35 Unfortunately, there is limited substantial evidence, because the availability of RCTs is sparse. A retrospective review of acupuncture use for SCD pain by Lu et al36 showed promising, albeit limited, results for patients in both the inpatient and outpatient centers. This study only focused on pain assessment before and after acupuncture treatment and did not measure other effects such as decreased anxiety, improved mood, or functional status; all of which could be of importance in long-term functioning.

Adjunct Therapy

Considering that both peripheral and central mechanisms can affect pain in patients with SCD, cognitive-behavioral therapy can provide another avenue to reduce pain and improve functional outcomes.37 Supportive therapies to promote coping skills have been shown to positively improve pain outcomes and adherence to pharmacologic and nonpharmacologic treatments.38 Cognitive-behavioral therapy coping skills training, via technology such as smartphones, can be an effective way to engage youth in their treatment and reduce pain intensity.32

After an 11-week treatment protocol of cognitive-behavioral therapy that produced a significant improvement in clinical measures of pain and self-efficacy for coping with pain, the intrinsic functional connectivity of the brain was assessed.39 Compared with control participants who did not receive cognitive-behavioral therapy (n = 19 in the experimental and control groups each), the intrinsic functional connectivity decreased between brain regions involved in affective pain (amygdala/periaqueductal gray) and increased between the basal ganglia and the somatosensory cortex. These changes were associated with cognitive-behavior therapy-related improvements, suggesting that it can effectively facilitate relearning the interpretation of pain. Because CAM therapies work through different mechanisms,40,41 the potentially synergistic effects of combining both peripherally mediated and cognitive pain treatment may have a significant impact on pain outcomes.

Conclusion

Sickle cell disease is a unique condition in that it is characterized by lifelong unpredictable stress and pain.37 The stress of SCD is both physical and psychological and requires adaptation for the patient to remain healthy and functional. The assessment of a patient with SCD, therefore, should be careful to include the psychosocial aspects of his or her life. A careful evaluation of family functioning, coping abilities, and adjustment to pain is vitally important to understand both the disease and the patient's pathology.

Treatment of a patient with SCD should include all available modalities to address the disease process and to enhance pain management and psychosocial functioning. In addition to pain medications and hydroxyurea, CAM therapies should be considered part of a comprehensive biopsychosocial model of pain control for these patients. CAM therapies have the potential to improve pain, and to enhance coping and stress management.

The pediatric SCD population is an ideal one in which to start incorporating CAM therapies in standard hematology care. Children and adolescents are more likely to be open to new skills, are developing coping strategies, and have yet to have entrenched negative thinking. Children and families can learn how to adjust to the multiple psychosocial stressors that accompany SCD, such as pain, fatigue, school absence, repeated hospitalizations, and disruption of daily life. Coping and disease management skills have the potential to increase self-efficacy, which can lead to a well-adjusted and healthier adulthood.

References