New epidemiological findings recast pain in sickle-cell disease (SCD) as being more often a chronic manifestation than was previously thought, although acute pain is still the hallmark of the disease. SCD pain intensity, the number of painful locations, and the frequency of hospitalizations due to SCD pain may worsen with age. In adults and even in children, the quantity and severity of SCD pain may be vastly underestimated, because most of the “iceberg” of SCD pain is “submerged” at home, and only the tip of the iceberg is seen by health care providers when acute SCD care is rendered in emergency rooms and hospitals. Implications of this “iceberg phenomenon” are significant for clinicians, researchers, employers, policy makers, and the public. Nevertheless, both emergency room and hospital utilization for SCD pain remain prevalent. Often, utilization recurs early, perhaps emblematic of poor acute pain management. New data show the protean impacts of SCD pain on health-related quality of life, sleep, and psychological and social health. The relationship of the severity of SCD pain to the severity of underlying sickle vasculopathy is unclear, but epidemiologic evidence and patient descriptors suggest a temporal evolution of pain mechanisms. At first, increasingly worse nociceptive pain from vaso-occlusion and local lesions may evolve over the first two decades of life. Then, in the third and following decades, central neuropathic pain may also evolve due to past and continuing nociceptive stimuli. New findings confirm environmental contributors to SCD pain, including seasonal (colder) temperatures, barometric pressure, and wind speed.

Frequency and Chronology of Pain

Pain is the most common symptom reported by the approximately 100,0001  Americans with sickle-cell disease (SCD), and this pain may be disabling. Previously, SCD hospitalizations and medical contacts were described in longitudinal studies. “Pain” as defined in these studies was found to be infrequent2  and to be the result of vaso-occlusive crises: severe, acute pain from vaso-occlusion and its inflammatory and ischemic consequences.

However, SCD pain may actually occur quite frequently. Adult respondents in the Pain in Sickle Cell Epidemiology Study (PiSCES) reported SCD pain on 54.5% of the 31,017 days surveyed. Importantly, 29.3% of respondents had pain on greater than 95% of the days surveyed.3  Dampier et al. studied children and adolescents (ages 6–21 years) with SCD for a total of 18,377 days, and found less frequent, but still surprisingly common pain; those studied reported 514 distinct SCD pain episodes occurring over 2592 days and 2326 nights.4  In a related report, children and adolescents reported SCD pain alone 8.4% of the time (1515 d), whereas other pain occurred 2.7% of the time (490 d), and both SCD and other pain 5.7% of the time (1041 d).5  These results show that acute pain is definitely the hallmark of SCD, but that chronic pain occurs far more often than was previously realized.

Severity of Pain

Pain in SCD is not only common, but also severe. In adults enrolled in PiSCES, SCD pain intensity was measured on a 0 to 9 numeric scale, but was also classified into three mutually exclusive severity categories: pain resulting in emergency room or hospital utilization (mean intensity, 5.9 ± 0.1); pain described by the patients as a crisis, but not resulting in emergency room or hospital utilization (mean intensity, 5.0 ± 0.1); and pain not described as a crisis (mean intensity, 3.9 ± 0.1).

Patients who described more frequent pain also described more intense pain on average. Those who described being in pain on 96% to 100% of days reported a mean pain intensity of 5.1 ± 0.2 on pain days and 6.2 ± 0.2 on crisis days, whereas those who described pain on 5% or fewer of days reported an intensity of 3.5 ± 0.4 on pain days and 4.5 ± 0.6 on crisis days. Opioid use was strongly correlated with pain intensity.

In the above childhood study, analgesic medication was taken on 88% of the reported pain days and 76% of reported pain nights. A single oral analgesic was used on 58% of these days. On the remaining days, multiple analgesics were used in a variety of combinations. More frequent analgesic dosing was reported on days with more intense pain. In a related report on this sample, pain intensity was reported on a 0 to 10 scale, and was 3.9 ± 0.5 in 12 younger children (ages 5–9 years), but 5.3 ± 0.4 in 18 older children (ages 10–19 years).6 

Researchers have organized evidence supporting a theory of distinct phases (e.g., evolving, inflammatory, resolving) of a painful vaso-occlusive episode that results in hospitalization, and the underlying biology associated with rises and falls in pain severity during such an episode.7  Recent evidence adds to this theory. Even after hospital discharge, resolution of a painful episode may take quite some time, and may be associated with significant dysfunction, resulting in more days taken off of school or work than necessitated by hospitalization.8  Further, readmission soon after hospitalization is not uncommon.9  The above theory predicts that episodes typically last for 7 to 9 d, but Table 1 shows that, nationally, hospital lengths of stay are only 5 d when averaged overall, worsening from 3 to 6 d with age. Thus, readmission could represent failure of an original episode to resolve, inadequate supply of analgesia for pain occurring after discharge, or even hyperalgesia from opioid withdrawal.

Table 1.

Age-stratified number of discharges and length of stay for SCD*

Age-stratified number of discharges and length of stay for SCD*
Age-stratified number of discharges and length of stay for SCD*

*ICD-9-CM principal diagnosis code(s) 282.60–282.60, 282.61–282.61, 282.62–282.62, 282.63–282.63, 282.69–282.69), 2005. (From Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality.10 )

Location(s) of Pain

In adults enrolled in PiSCES, an average of 3.3 out of 16 sites (25%) were painful on the days surveyed. The number of pain sites varied by age, depression, frequency of pain days, crisis, and unplanned hospital/emergency room utilization. Pain was located in the lower back, knee/shin, and hip on average for more than one-third of pain days, while jaw and pelvis pain were infrequent (fewer than 10% of days). The odds of patients self-designating pain as a crisis were greater (odds ratio [OR] > 1.5) when pain was in the arm, shoulder, upper back, sternum, clavicle, chest, or pelvis. Unplanned utilization was substantially more likely (OR > 2.0) when pain was in the sternum, clavicle, or chest.11  Dampier et al. found fewer pain sites on average in children: 2.2 ± 0.3 in younger children and 1.9 ± 0.2 in older children.

Responses to Pain

Visiting a health care provider for pain relief is a rational response. Not surprisingly, pain is responsible for the majority of SCD medical visits. Platt et al. studied rates of medical visits for pain among 3578 patients in the Cooperative Study of Sickle Cell Disease (CSSCD). Above age 20, higher-utilizing adults were at higher risk of death. Utilization due to SCD pain increased as patients grew older, from 0 to 30 years, and declined thereafter.2  Combining the above results with studies showing that the frequency, severity, and number of sites of pain are greater in adults than in children suggests that the frequency of pain rises with the androgen-associated rise (especially in males) of hematocrit with the onset of puberty.12 

Despite the above statistics, the utilization of formal health care resources in response to SCD pain is infrequent when the denominator of all pain experienced by patients is included. Most SCD pain, even “crisis” pain, is managed at home, without emergency room or hospital utilization.13  Further, SCD pain that does result in health care utilization may be indistinguishable from pain managed at home. In PiSCES, while pain (with or without crisis or utilization) was reported on a total of 54.5% of days, crises without utilization were reported on 12.7% of days, and utilization for pain on only 3.5%. Significantly, the rate at which utilization days coincided with crisis days was far below what would be the expected if the two were essentially identical.3 

A substantial minority of SCD patients are high utilizers of hospitals and emergency rooms, and in fact are responsible for most of the visits; these patients are more severely ill, as measured by laboratory variables, pain, distress, and/or quality of life.14,15  In PiSCES, after controlling for severity and frequency of pain, high emergency room utilizers (35% of the sample) did not use opioids more frequently than other SCD patients.15 

A burst of literature has appeared that has further characterized the utilization of hospitals and emergency rooms for SCD pain. Most studies used national, administrative claims-based datasets containing unselected, highly representative patient samples and/or surveys.16  For example, a study of administrative claims data from eight geographically dispersed states representing 33% of the US population with SCD (21,112 patients) updates Platt's original, smaller CSCCD report of decades ago. The CSSCD relied on recruited patients and used primary data collection to measure utilization events.2  The 8-state study reported a rate of acute care encounters, 2.59 per patient per year, that was 2 to 3 times higher than in the CSCCD. There were 1.52 hospitalizations and 1.08 treat-and-release emergency room visits per year. Approximately 29% of the population had no encounters, while 16.9% had 3 or more encounters per year. In the CSSCD, 40% of the population had no encounters in a year, while 5% accounted for a large proportion of utilization. Further, re-hospitalization rates for the 8-state study were frequent: 22.1% and 33.4% at 14 and 30 d, respectively. Both utilization rates and re-hospitalization rates were highest for 18- to 30-year-olds.17 

Other studies have shown that hospitalizations for SCD pain are more frequent and hospital lengths of stay are longer among older children than younger children,18,19  although the percentage of all emergency room visits resulting in hospitalization actually dropped in one study among older compared with younger children.20  SCD children also demonstrate unmet health care access needs and show higher odds of frequent severe headaches or migraines, intellectual disabilities, regular use of prescription medication, and fair or poor health status compared with African-American controls.21 

Another rational response to pain is analgesic use, and in SCD, use appears rational. In PiSCES, home opioid analgesic use varied widely: a total of 39 out of 232 (16.8%) of patients studied did not use opioids at home during any of the days surveyed, whereas 88 (37.9%) used them on 1% to 49% of days, and 104 (44.8%) used them on 50% or more of days. Opioid use independently predicted pain, crises, and hospital and emergency room utilization.3 

In children, Dampier et al. found that cognitive-behavioral or physical pain-management activities were used alone on 7.5% of pain days and with analgesics on 77%. Female gender and increasing pain intensity were associated with an increased number of pain-management activities used. Increasing pain intensity was also associated with the use of several specific pain-management activities.22 

Depression, Psychological, and Neurological Impacts

Many studies have documented that depression and anxiety disorders are common in SCD and may be correlated with SCD symptoms.23  More recent, however, is the notion that chronic pain, via neurological changes in the prefrontal cortex (see discussion of neuroplasticity and remodeling below), may affect emotion. This could as easily be true in SCD as in any other chronic painful disease. For example, having chronic back pain or fibromyalgia is also associated with decreased grey matter in the prefrontal cortex, which may be associated with a decreased ability to inhibit the experience of pain.24 

Health-Related Quality of Life

New research reconfirms that individuals with SCD have poor baseline health-related quality of life, and painful episodes have a further negative impact.25  This is most striking in the physical functioning and pain domains. Worse health-related quality of life in SCD patients is associated with disease severity and pain intensity.26 

Sleep

Aside from emerging relationships between nocturnal hypoxia, sleep-disordered breathing (including sleep apnea), and pulmonary hypertension identified in SCD patients,27  anecdotal reports from patients and new research suggests that there are sleep disturbances related primarily to SCD pain, and vice versa, in SCD patients.28 

Local Mechanisms

The above epidemiologic research, combined with new research in other disease states, suggest the need to revisit theories about how SCD pain evolves over time and to revisit approaches to pain management in SCD. The most important finding is that pain in SCD is more often chronic than was previously realized, although acute pain is still the hallmark SCD presentation. Figure 1 is a conceptual, hypothetical model of pain in SCD, beginning with age 120 months (10 years) and showing evolution with time. The first two types of pain, as depicted by the legend to Figure 1, represent known, recurrent, nociceptive pain (defined below) experienced due to vasculopathic and necrotic conditions, respectively. The final two types of pain described in the legend depict neurological pain manifestations hypothesized to develop later in life in response to prior recurrent nociceptive pain or in response to opioid therapy.

Figure 1.

Conceptual model of etiologies and temporal evolution of pain in SCD. Multiple etiologies may be present in any one patient.

Figure 1.

Conceptual model of etiologies and temporal evolution of pain in SCD. Multiple etiologies may be present in any one patient.

Undoubtedly, the ultimate etiologic source of pain in SCD early in life is vaso-occlusion, which is ubiquitous. Vaso-occlusion is represented by the solid line in Figure 1. However, SCD pain episode rates vary between subjects, even within genotype. Further, the location, timing, and severity of pain episodes may be unpredictable. Logically, most attribute this variability to underlying variations in vaso-occlusion and their consequences. Epidemiologically, pain is paroxysmally severe, resulting in emergency room and hospital utilization, but it is also often prevalent at an intensity that is managed at home. It follows that vaso-occlusion may be chronic and may always be present at some low level. For some patients, the pain represented by the line in Figure 1 may never go to an intensity of zero.

Vaso-occlusion results in a complex progressive cascade of tissue ischemia and inflammation. This appears to result from impaired rheology due to the sickled shape of polymerized red blood cells in SCD, as opposed to their otherwise flexible, biconcave morphology that makes them capable of reaching arterioles and capillary beds of muscle and organ tissue. A conformational change in hemoglobin S also impairs its oxygen-carrying capacity compared with normal hemoglobin A. A panoply of processes result, including red-cell sickling, inflammation and adhesion, coagulation activation, stasis, deficient bioavailability and excessive consumption of nitric oxide, excessive oxidation, and reperfusion injury. Together, these processes are called sickle-cell vasculopathy.29  Pulmonary hypertension, priapism, fetal wastage and growth retardation, autosplenectomy, and chronic renal disease are all well-documented in SCD. Vasculopathy contributes to tissue ischemia and necrosis in these and other complications of SCD, potentially ending in organ failure of the spleen, kidneys, heart, lungs, brain, liver, and bone, and in early death.30 

Reliable biomarkers of chronic vasculopathy in SCD are being researched31 ; however, biomarkers able to distinguish the severity and temporal changes in stimuli underlying pain exacerbations have still not been identified. Dampier et al.'s longitudinal studies of SCD children demonstrate similar clinical features and similar predictive hematologic parameters of home-managed versus acute care-managed pain, implying a single underlying pain stimulus of variable intensity.6  However, no studies show body-location-specific changes in biomarkers associated temporally with changes in pain at that location. To date, we cannot “predict a crisis” reliably using biomarkers.

At least early in life, the neurologic mechanism linking underlying pain stimuli to pain experience in SCD is that of nociception. Nociception requires that pain be due to an identifiable pain stimulus that is potentially or actually damaging. The nociceptive nervous system involves the peripheral nerves, spinal cord, brain stem, thalamus, and cerebral cortex, and links recognition of a damaging stimulus to an adaptive behavioral response.32  A noxious or potentially damaging stimulus is linked to a sensation that is perceived as intense and unpleasant (pain), which is designed to allow an association of this sensation with something that must be avoided.

In acute pain, hyperalgesia ensures that contact with or movement of the affected structure will be minimized until healing is complete. This is a critically important adaptive mechanism in SCD, where widespread tissue damage is common. It involves four major pathophysiologic processes: transduction, transmission, modulation, and perception.33  This innate physiological response is likely repeated countless times during vaso-occlusive episodes in the first two decades of life. This repetitive stimulus is suspected of being one of the key precursors to the chronic pain experienced by some SCD patients later in life.

A second source of nociceptive pain in some SCD patients comes from a clearly localized source: tissue necrosis. Bone infarction of the spine and long bones, as well as avascular necrosis of the hip and shoulder, are frequent in SCD, and are localizable by clear radiographic findings. Bone infarction may wax and wane, and may be physically manifested by heat, swelling, rubor, tenderness of the extremities, or dactylitis. Chronic leg ulcers in SCD are painful. When they appear, they generally are in locations consistent with venous stasis rather than arterial insufficiency, and they anecdotally may sometimes respond to elevation, which is consistent with venous stasis ulcers. Pain from splenic infarction is localizable and discrete, and is often acute and disabling. The stimuli producing this nociceptive pain may be chronic and ongoing or may wax and wane.

Neuropathic Pain Mechanisms and Neuroplasticity

Chronic pain has been defined as that resulting when there is an uncoupling of nociceptive processes from noxious stimulation or healing.32  Chronic pain has also been defined temporally as pain lasting for more than 6 months.34 Figure 1 shows that, by either definition, pain in SCD may be chronic. In addition to nociceptive pain, chronic neuropathic pain may well complicate acute pain in SCD. In general, neuropathic pain occurs as a result of malfunction or injury in the peripheral or central nervous system. Temporally, it may be acute or chronic. Neuropathic pain has been demonstrated in many diseases, notably herpetic neuralgia,32  diabetic neuropathy,35  fibromyalgia,36  chronic low back pain,37  phantom limb pain,38  and functional bowel disease.39  In SCD, neuropathic pain may result from prior nociceptive painful episodes. Specifically, in other disorders, nociceptive input can sensitize supraspinal areas involved in pain processing, causing them to become more active during future events of noxious stimulation, which is expressed phenotypically as a lowering of the pain threshold.24  Subsequently, there may actually be parallel anatomical brain changes in the surrounding glia (astrocytes and microglia) called neuroplasticity or remodeling, which contribute to the maintenance of an altered, neuronal phenotype. While Figure 1 emphasizes this mechanism as producing chronic pain, it may be that the severity of acute nociceptive pain episodes is intensified by this same neuropathic mechanism after remodeling has occurred.

Neuropathic pain can be inferred when patients use certain pain descriptors (e.g., burning, tingling, shooting, numbness, and lancinating) to describe their pain.40  It can also be documented experimentally by demonstrating sensations of pain in the absence of an experimental stimulus and/or by demonstrating abnormal (hyperalgesic) pain responses from standardized pain stimuli.41  Using these criteria, there are few studies so far demonstrating neuropathic pain in SCD. Epidemiological studies of pain have not asked patients to use pain descriptors, nor have they included psychophysical testing. One study of transplanted patients ages 16 to 45 years with severe SCD who achieved cure showed that they still had pain after transplantation, which lasted for months.42  This pain was attributed to opioid withdrawal, but testing was not done to confirm if the pain was possibly neuropathic. A recently published phenotypic classification system for SCD allowed for the existence of neuropathic pain due to “nerve ischemia from vaso-occlusion,”43  but listed only one publication reporting neuropathic pain in SCD, and it referred only to peripheral neuropathy.44  Only one recent study has employed pain descriptors, which revealed that SCD patients choose descriptors commonly used to describe neuropathic pain and nociceptive pain to describe their SCD pain.45 

Figure 1 shows that neuropathic pain in SCD likely does not manifest itself until early or late adulthood, and only in patients with sufficient prior nociceptive pain; longitudinal studies that begin in childhood may be necessary to confirm these hypotheses. If they are confirmed, then further studies would be required to determine if more effective disease and pain management in adolescents and young adults reduces the incidence and severity of both acute and chronic SCD pain in older adults.

Finally, Figure 1 shows a fourth potential source of SCD pain: that from chronic and/or acute opioids given to treat pain. Opioid-induced hyperalgesia is considered to be due to the administration of opioids, and is different from the hyperalgesia described above, which is provoked by prior nociceptive stimuli. Opioids temporarily reduce central responsivity to any pain stimulus. Although not yet proven in SCD, evidence from experimental laboratory studies and opioid treatment in other diseases suggest that acute or chronic opioid administration may cause hyperalgesia.46  The SCD pain stimulus no doubt continues in the face of palliation of pain using opioids. In cancer, this effect is usually short-lived, ending in the death of the patient, so any opioid-generated hyperalgesia is less important; however, in SCD, opioid-induced hyperalgesia could go on for decades, depending on the severity of the pain and the chronicity and intensity of opioid therapy.33  Like neuropathic pain from prior nociceptive pain, opioid administration in SCD may alter future nociceptive pain, exaggerating the innate hyperalgesic response that is part of nociception.

Environment: Weather, Barometric Pressure, and Wind Speed

Two multi-site studies have continued research into the effects of climate and environment on SCD pain. The first failed to find a significant relationship between temperature and the occurrence of painful episodes, but did find that higher wind speeds during the preceding 24 h were associated with the onset of pain.47  Conversely, the Multicenter Study of Hydroxyurea found positive, direct associations between other climate conditions and SCD pain. Adults with SCD reported exacerbated SCD pain during seasonably colder temperatures, but not during days with lower barometric pressure. Colder seasons were significantly associated with greater pain intensity but not frequency. Higher average monthly temperatures were statistically significantly associated with lower pain intensity and lower pain frequency. Both pain intensity and pain frequency were statistically significantly higher when the average monthly barometric pressure was higher. Northern geographic residence was not statistically associated with higher pain intensity and frequency compared with southern residency, although the differences did suggest a trend.48 

Genetic Predictors

Beyond the scope of this article is a discussion of genetic predictors of response to SCD therapies.49  However, recent data provide evidence that pain phenotypes in SCD have more complex underlying genetic explanations than simple hemoglobin type. Within the hemoglobin S genotype, haplotypes of the S gene appear to be related to specific phenotypes of the disease, including pain phenotypes.50 

Psychological Predictors

In addition to being an outcome of pain in SCD, psychological factors may also be predictive of pain. Cognitive factors (e.g., catastrophizing, or irrational thought that something is far worse than it actually is) and psychological factors (e.g., depression and coping) influence the central representation of pain.51  We found that SCD subjects had higher mean catastrophizing scores than those found in studies of other chronic pain conditions that are not lifelong or life-threatening.52 

Two recent studies advanced the understanding of the impact of depression on pain.53,54  The latter study found that depressed subjects had pain on significantly more days than non-depressed subjects. When in pain on non-crisis days, depressed subjects had higher mean pain, higher distress from pain, and more interference from pain.52 

Over two decades ago, coping strategies among SCD adults were found to be important predictors of pain and adjustment. Individuals with high scores on the negative thinking and passive adherence categories had more severe pain, were less active and more distressed, and used more health care services. Individuals with high scores on coping attempts were more active during painful episodes.55  A more recent study has found that active coping is positively associated with pain frequency, while passive adherence coping is related to pain intensity. Psychological coping was shown to be unrelated to health service utilization. The degree of impairment was associated with affective coping.56 

Taken together, the above research advances lead to the conclusion that pain in SCD is far more common and severe, with more significant effects on all aspects of life, than was previously reported. For many SCD patients, pain is the rule rather than the exception, and is likely multifactorial in etiology, not simply vaso-occlusive. Pain prevalence is probably vastly underestimated by health care providers, resulting in misclassification, distorted communication, undertreatment, possible unnecessary loss of employment and productivity by patients and caregivers, and mistrust even from family members and friends of patients. While a discussion of the measurement and treatment of SCD pain is beyond the scope of this article, results from the above epidemiology and etiology studies demand that clinicians, researchers, employers, policy makers, and the public rethink the measurement and treatment approaches to pain in SCD.

Conflict-of-interest disclosure: The authors declare no competing financial interests. Off-label drug use: None disclosed.

Wally R. Smith, MD, Professor, Division of General Internal Medicine, Virginia Commonwealth University, P.O. Box 980306, Richmond, VA 23298-0306; Phone: (804) 828-6938; Fax: (804) 828-4862; e-mail: wrsmith@vcu.edu

1
Hassell
KL
Population estimates of sickle cell disease in the U.S
Am J Prev Med
2010
4
38
4 Suppl
S512
S521
2
Platt
OS
Thorington
BD
Brambilla
DJ
et al
Pain in sickle cell disease. rates and risk factors
N Engl J Med
1991
325
11
16
3
Smith
WR
Penberthy
LT
Bovbjerg
VE
et al
Daily assessment of pain in adults with sickle cell disease
Ann Intern Med
2008
148
94
101
4
Dampier
C
Ely
E
Brodecki
D
O'Neal
P
Home management of pain in sickle cell disease: a daily diary study in children and adolescents
J Pediatr Hematol Oncol
2002
11
24
8
643
647
5
Dampier
C
Ely
B
Brodecki
D
O'Neal
P
Characteristics of pain managed at home in children and adolescents with sickle cell disease by using diary self-reports
J Pain
2002
12
3
6
461
470
6
Dampier
C
Setty
BN
Eggleston
B
Brodecki
D
O'Neal
P
Stuart
M
Vaso-occlusion in children with sickle cell disease: clinical characteristics and biologic correlates
J Pediatr Hematol Oncol
2004
12
26
12
785
790
7
Ballas
SK
Smith
ED
Red blood cell changes during the evolution of the sickle cell painful crisis
Blood
1992
79
2154
2163
8
Brandow
AM
Brousseau
DC
Panepinto
JA
Postdischarge pain, functional limitations and impact on caregivers of children with sickle cell disease treated for painful events
Br J Haematol
2009
3
144
5
782
788
9
Ballas
SK
Lusardi
M
Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance
Am J Hematol
2005
79
17
25
10
US Department of Health and Human Services, Agency for Healthcare Research and Quality
Healthcare Cost and Utilization Project (HCUP) website
Accessed October 2, 2010
11
McClish
DK
Smith
WR
Dahman
BA
et al
Pain site frequency and location in sickle cell disease: the PiSCES project
Pain
2009
9
145
1–2
246
251
12
Naets
JP
Wittek
M
The mechanism of action of androgens on erythropoiesis
Ann N Y Acad Sci
1968
149
366
376
13
Shapiro
BS
Dinges
DF
Orne
EC
et al
Home management of sickle cell-related pain in children and adolescents: natural history and impact on school attendance
Pain
1995
4
61
1
139
144
14
Carroll
CP
Haywood
C
Jr
Fagan
P
Lanzkron
S
The course and correlates of high hospital utilization in sickle cell disease: Evidence from a large, urban Medicaid managed care organization
Am J Hematol
2009
10
84
10
666
670
15
Aisiku
IP
Smith
WR
McClish
DK
et al
Comparisons of high versus low emergency department utilizers in sickle cell disease
Ann Emerg Med
2009
5
53
5
587
593
16
Grosse
SD
Boulet
SL
Amendah
DD
Oyeku
SO
Administrative data sets and health services research on hemoglobinopathies: a review of the literature
Am J Prev Med
2010
4
38
4 Suppl
S557
S567
17
Brousseau
DC
Owens
PL
Mosso
AL
Panepinto
JA
Steiner
CA
Acute care utilization and rehospitalizations for sickle cell disease
JAMA
2010
4
7
303
13
1288
1294
18
Panepinto
JA
Brousseau
DC
Hillery
CA
Scott
JP
Variation in hospitalizations and hospital length of stay in children with vaso-occlusive crises in sickle cell disease
Pediatr Blood Cancer
2005
2
44
2
182
186
19
Zempsky
WT
Loiselle
KA
McKay
K
et al
Retrospective evaluation of pain assessment and treatment for acute vasoocclusive episodes in children with sickle cell disease
Pediatr Blood Cancer
2008
8
51
2
265
268
20
Yusuf
HR
Atrash
HK
Grosse
SD
Parker
CS
Grant
AM
Emergency department visits made by patients with sickle cell disease: a descriptive study, 1999–2007
Am J Prev Med
2010
4
38
4 Suppl
S536
S541
21
Boulet
SL
Yanni
EA
Creary
MS
Olney
RS
Health status and healthcare use in a national sample of children with sickle cell disease
Am J Prev Med
2010
4
38
4 Suppl
S528
S535
22
Dampier
C
Ely
E
Eggleston
B
Brodecki
D
O'Neal
P
Physical and cognitive-behavioral activities used in the home management of sickle pain: a daily diary study in children and adolescents
Pediatr Blood Cancer
2004
11
43
6
674
678
23
Laurence
B
George
D
Woods
D
Association between elevated depressive symptoms and clinical disease severity in African-American adults with sickle cell disease
J Natl Med Assoc
2006
98
365
369
24
Jensen
MP
A neuropsychological model of pain: research and clinical implications
J Pain
2010
1
11
1
2
12
25
Brandow
AM
Brousseau
DC
Pajewski
NM
Panepinto
JA
Vaso-occlusive painful events in sickle cell disease: impact on child well-being
Pediatr Blood Cancer
2010
1
54
1
92
97
26
McClish
DK
Penberthy
LT
Bovbjerg
VE
et al
Health related quality of life in sickle cell patients: the PiSCES project
Health Qual Life Outcomes
2005
3
50
27
Johnson
MC
Kirkham
FJ
Redline
S
et al
Left ventricular hypertrophy and diastolic dysfunction in children with sickle cell disease are related to asleep and waking oxygen desaturation
Blood
2010
7
8
116
1
16
21
28
Palermo
TM
Kiska
R
Subjective sleep disturbances in adolescents with chronic pain: relationship to daily functioning and quality of life
J Pain
2005
3
6
3
201
207
29
Hebbel
RP
Vercellotti
G
Nath
KA
A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis
Cardiovasc Hematol Disord Drug Targets
2009
12
9
4
271
292
30
Conran
N
Franco-Penteado
CF
Costa
FF
Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion
Hemoglobin
2009
33
1
1
16
31
Kato
GJ
Hebbel
RP
Steinberg
MH
Gladwin
MT
Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions
Am J Hematol
2009
9
84
9
618
625
32
Woolf
CJ
American College of Physicians; American Physiological Society
Pain: moving from symptom control toward mechanism-specific pharmacologic management
Ann Intern Med
2004
3
16
140
6
441
451
33
Ballas
SK
Current issues in sickle cell pain and its management
Hematology Am Soc Hematol Educ Program
2007
97
105
34
Merskey
H
Bogduk
N
Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms
2nd ed
Seattle
IASP Press
1994
35
Fischer
TZ
Waxman
SG
Neuropathic pain in diabetes–evidence for a central mechanism
Nat Rev Neurol
2010
8
6
8
462
466
36
Gracely
RH
Petzke
F
Wolf
JM
Clauw
DJ
Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia
Arthritis Rheum
2002
46
1333
1343
37
Giesecke
T
Gracely
RH
Grant
MA
et al
Evidence of augmented central pain processing in idiopathic chronic low back pain
Arthritis Rheum
2004
50
613
623
38
Flor
H
Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies
Expert Rev Neurother
2008
5
8
5
809
818
39
Lembo
T
Naliboff
BD
Matin
K
et al
Irritable bowel syndrome patients show altered sensitivity to exogenous opioids
Pain
2000
8
87
2
137
147
40
Bennett
MI
Attal
N
Backonja
MM
et al
Using screening tools to identify neuropathic pain
Pain
2007
2
127
3
199
203
41
Hansson
P
Backonja
M
Bouhassira
D
Usefulness and limitations of quantitative sensory testing: clinical and research application in neuropathic pain states
Pain
1007
129
256
259
42
Hsieh
MM
Kang
EM
Fitzhugh
CD
et al
Allogeneic hematopoietic stem-cell transplantation for sickle cell disease
N Engl J Med
2009
12
10
361
24
2309
2317
43
Ballas
SK
Lieff
S
Benjamin
LJ
et al
Investigators, Comprehensive Sickle Cell Centers
Definitions of the phenotypic manifestations of sickle cell disease
Am J Hematol
2010
1
85
1
6
13
44
Ballas
SK
Reyes
PF
Peripheral neuropathy in adults with sickle cell disease
Am J Pain Management
1997
7
53
58
45
Wilkie
DJ
Molokie
R
Boyd-Seal
D
et al
Patient-reported outcomes: descriptors of nociceptive and neuropathic pain and barriers to effective pain management in adult outpatients with sickle cell disease
J Natl Med Assoc
2010
1
102
1
18
27
46
Hay
JL
White
JM
Bochner
F
Somogyi
AA
Semple
TJ
Rounsefell
B
Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients
J Pain
2009
3
10
3
316
322
47
Nolan
VG
Zhang
Y
Lash
T
Sebastiani
P
Steinberg
MH
Association between wind speed and the occurrence of sickle cell acute painful episodes: results of a case-crossover study
Br J Haematology
2008
143
433
438
48
Smith
WR
Bauserman
RL
Ballas
SK
et al
The Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
Climatic and geographic temporal patterns of pain in the Multicenter Study of Hydroxyurea
Pain
2009
11
146
1–2
91
98
49
Hankins
J
Aygun
B
Pharmacotherapy in sickle cell disease–state of the art and future prospects
Br J Haematol
2009
5
145
3
296
308
50
Steinberg
MH
Genetic etiologies for phenotypic diversity in sickle cell anemia
ScientificWorldJournal
2009
1
18
9
46
67
51
Gracely
RH
Geisser
ME
Giesecke
T
et al
Pain catastrophizing and neural responses to pain among persons with fibromyalgia
Brain
2004
4
127
Pt 4
835
843
52
Citero
VA
Levenson
JL
McClish
DK
et al
The role of catastrophizing in sickle cell disease–the PiSCES project
Pain
2007
12
15
133
1–3
39
46
53
Laurence
B
George
D
Woods
D
Association between elevated depressive symptoms and clinical disease severity in African-American adults with sickle cell disease
J Natl Med Assoc
2006
98
365
369
54
Levenson
JL
McClish
DK
Dahman
BA
et al
Depression and anxiety in adults with sickle cell disease: the PiSCES project
Psychosom Med
2008
2
70
2
192
196
55
Gil
KM
Abrams
MR
Phillips
G
Keefe
FJ
Sickle cell disease pain: relation of coping strategies to adjustment
J Consult Clin Psychol
1989
12
57
6
725
731
56
Anie
KA
Steptoe
A
Bevan
D
Sickle cell disease: Pain, coping and quality of life in a study of adults in the UK
Br J Health Psychol
2002
7
331
344