Neuropathic pain in individuals with sickle cell disease

Journal Pre-proof Neuropathic pain in individuals with sickle cell disease Deva Sharma, Amanda M. Brandow

PII:

S0304-3940(19)30548-8

DOI:

https://doi.org/10.1016/j.neulet.2019.134445

Article Number:

134445

Reference:

NSL 134445

To appear in:

Neuroscience Letters

Received Date:

26 November 2018

Revised Date:

6 June 2019

Accepted Date:

20 August 2019

Please cite this article as: Sharma D, Brandow AM, Neuropathic pain in individuals with sickle cell disease, Neuroscience Letters (2019), doi: https://doi.org/10.1016/j.neulet.2019.134445

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

Neuropathic pain in individuals with sickle cell disease Deva Sharma, MD, MS1,2 and Amanda M. Brandow, DO, MS3,4,5 1

Division of Transfusion Medicine, 2Vanderbilt University Medical Center, Nashville, TN United States Section of Pediatric Hematology/Oncology, 4Medical College of Wisconsin, Milwaukee, WI, United States, 5Children's Research Institute of the Children’s Hospital of Wisconsin, Milwaukee, WI, United States 3

re

lP

Counts Text pages (including figures and tables): Figures: 0 Tables: 5

-p

ro

of

Corresponding Author: Deva Sharma, MD, MS 1161 21st Ave. South CC-3322 Medical Center North Nashville, TN 37232-256 Email: [email protected] Phone: (615) 936-8422 Fax: 615-343-7023

Jo

ur na

Abstract Pain is the most frequently occurring complication of sickle cell disease (SCD) and the leading cause of hospitalizations for affected individuals. Acute pain episodes are also an independent predictor of mortality in individuals with SCD. The pathophysiology of pain in SCD is complex and has been attributed to several biologic factors, including oxidative stress, vaso-occlusion, ischemia-reperfusion injury and inflammation. In spite of this complex biology, painful events requiring hospitalization are simplistically referred to as “acute vaso-occlusive pain episodes” by the hematology community, and subgroups of pain in SCD have not been formally classified. Neuropathic pain is an emerging unique SCD pain phenotype that could be a result of these biologic drivers in SCD. Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and has been estimated to occur in approximately 25-40% of adolescents and adults with SCD. Diagnostic modalities for neuropathic pain, including validated questionnaires incorporating pain descriptors, quantitative sensory testing and functional neuroimaging, have been evaluated in small to medium-sized crosssectional studies of adolescents and adults with SCD. However, these diagnostic tests are not currently used in the routine care of individuals with SCD. Age, female gender and hydroxyurea use have been reported to be positively associated with neuropathic pain in SCD, although modifiable risk factors for the prevention of neuropathic pain in this population have not been identified. A few early phase studies have begun to investigate neuropathic pain-specific medications in individuals with SCD. However, evidence-based strategies to target neuropathic pain in SCD are lacking, and the existing literature suggests that neuropathic painspecific medications are highly underutilized in individuals with SCD. We will review the epidemiology, underlying biology and therapeutic interventions for diagnosis and treatment of neuropathic pain in SCD. We will also highlight opportunities to address critical gaps in knowledge that remain for this under-recognized cause of SCD morbidity.

Keywords: sickle cell disease, neuropathic pain

of

Overview of sickle cell disease pain Sickle cell disease (SCD) is an inherited hemoglobinopathy that affects approximately 100,000 individuals in the United States and over 3 million individuals across the world.[1, 2] The autosomal recessive mutation (HbS) in the beta globin chain of hemoglobin leads to polymerization and erythrocyte sickling.[3] SCD is a multi-organ system disease. However, severe intermittent acute pain events and chronic daily pain are the most common complications. Acute vaso-occlusive pain episodes, or pain crises, are abrupt in onset, unpredictable and drive individuals to seek care in the emergency department and inpatient unit, with estimated health care costs of almost $2 billion per year.[4-6] The frequency and severity of SCD pain increases with age, and a subset of children develop a chronic pain syndrome in adolescence and adulthood, in addition to continued acute pain episodes. Chronic daily pain is reported in 30-40% of adolescents and adults with SCD[7, 8] and continued episodes of acute pain are superimposed on chronic pain, all of which severely impact individuals’ health-related quality of life.[9, 10] Hydroxyurea and glutamine are FDA approved disease-modifying drugs for prevention of acute pain events.[11, 12] Despite the significant morbidity that pain causes for individuals with SCD, the underlying biology of sickle cell pain is not fully understood.

re

-p

ro

Classically, SCD pain has been attributed to nociceptive or inflammatory pain resulting from sickled red blood cell-induced repeated vascular occlusion, chronic ischemia-reperfusion injury and subsequent inflammation.[13, 14] However, sickle cell pain is now understood to be highly complex, multifaceted and mechanistically varied resulting in nociceptive, inflammatory and neuropathic pain. Individuals with SCD often report significant chronic pain[7, 8] in multiple body locations[15] that is not attributable to an identifiable cause or tissue injury such as avascular necrosis or leg ulcers.[16] In addition, despite opioids and nonsteroidal antiinflammatory drugs being the backbone of SCD pain treatment, they often provide ineffective or partial pain relief. This pattern of pain and challenges of treatment have led to investigations of alternative pathways for the etiology of sickle cell pain that are outside of the red blood cell abnormality. Importantly, many of these investigations have focused on the contribution of abnormalities in the peripheral and central nervous system to SCD pain. Because of these investigations, neuropathic pain has emerged as one of the underlying components of the sickle cell pain experience.

Jo

ur na

lP

Overview of neuropathic pain Neuropathic pain is defined by the International Association for the Study of Pain as “pain caused by a lesion or disease of the somatosensory nervous system.”[17] Neuropathic pain differs from nociceptive pain with respect to underlying biological mechanisms, response to analgesic therapies and prognosis. Neuropathic pain is rooted in abnormalities of the somatosensory nervous system resulting from altered structure and/or function. Affected individuals experience spontaneous pain and pathologically amplified responses to painful and nonpainful stimuli.[18] The underlying biology leading to neuropathic pain is complex and occurs at both the central and peripheral nervous system level. Proposed mechanisms for neuropathic pain include action potentials that are generated ectopically, loss of endogenous pain control (i.e., loss of inhibitory pain mechanisms), development of new synaptic circuits, facilitation of the transmission of synaptic impulses and facilitation of neuroimmune interactions leading to nervous system sensitization.[18-21] Prognosis is often worse in individuals with neuropathic pain, as injury to major nerves is more likely to occur than injury to nonnervous tissue, resulting in the perception of pain with minimal or no noxious stimuli.[18] This review will focus on data supporting the existence of neuropathic pain in individuals with SCD. The clinical diagnosis of neuropathic pain is based on history, where qualitative aspects of pain are elicited using unique pain descriptors, and physical examination, where patterns of sensory disturbance are evaluated.[22] Examples of unique pain descriptors that have been associated with neuropathic pain include burning, hot, electric shocks, shooting, pricking, pins and needles, numbness and tingling.[23-25] On physical examination, individuals with neuropathic pain can have positive sensory signs that include spontaneous pain, allodynia (i.e., pain produced by a stimulus that is not normally painful) and hyperalgesia (i.e., exaggerated pain to a stimulus.[26, 27] Individuals with neuropathic pain can also have negative sensory signs with partial or complete sensory loss.[27] Notably, these descriptors and clinical phenomenon are not pathognomonic for neuropathic pain and have also been used to describe other pain states.[28-31] Beyond these assessments, other investigational methodologies supporting the diagnosis of neuropathic pain include quantitative sensory testing, fMRI and other neuroimaging techniques, skin biopsies and nerve conduction studies.[32-36] Results

from these assessments provide supporting data for neuropathic pain and form the basis for many of the investigations and diagnosis of neuropathic pain in individuals.

-p

ro

of

Neuropathy has been rarely reported in individuals with SCD Neuropathic pain is also phenotypically and mechanistically distinct from neuropathy. Individuals with peripheral neuropathy present with a wide variety of clinical manifestations, including altered sensation, pain, weakness or autonomic symptoms.[37] Importantly, neuropathy can exist without pain. In contrast, neuropathic pain often occurs in parts of the body that otherwise appear normal[22], without associated weakness or autonomic findings. In summary, neuropathic pain is not synonymous with neuropathy, and not all individuals with peripheral neuropathy develop neuropathic pain.[38] For example, in a large cohort study of individuals with diabetes mellitus, the prevalence of neuropathic pain symptoms was only 21% in those with neuropathy.[39] Questionnaires that are specific to neuropathy and neuropathic pain in SCD have not been established, leading to diagnostic challenges. Ballas et al. suggest that individuals with SCD with complaints of burning, tingling, numbness, pins, needles and itching may have neuropathy, whereas those with these symptoms in addition to allodynia, hyperalgesia, and sensitivity to cold and heat may have neuropathic pain.[40] Case reports suggest that neuropathy occurs in SCD. Ischemic mononmeric neuropathy, presenting as acute onset of flaccid paralysis and sensory loss of the left lower extremity, was reported in a woman with SCD presenting with acute vaso-occlusive pain, and resolved rapidly with an exchange blood transfusion.[41] In a study of asymptomatic individuals with sickle cell anemia, electromyographic studies demonstrated peripheral nervous system abnormalities in 19.6% of individuals, with findings of demyelination and axonopathy.[42] However, the risk factors for neuropathy in individuals with SCD are unknown, and the evidence for its occurrence is largely limited to case reports. Limited case reports have described peripheral neuropathy in individuals with sickle cell disease.[43, 44] At this time, the prevalence and optimal management of neuropathy in individuals with SCD is unknown. Table 1 provides an overview of the definitions of neuropathy, neuropathic pain and other chronic pain terminology that will be referenced in this review.

Jo

ur na

lP

re

Evidence for neuropathic pain in SCD Overview A body of translational evidence that has significantly expanded in the past decade supports the existence of neuropathic pain in SCD. This evidence encompasses patient-reported outcomes, imaging, psychophysical testing and work in animal models. Cross-sectional patient-reported neuropathic pain screening questionnaires have estimated that neuropathic pain occurs in 25-40% of individuals with SCD.[45-47] Further, animal and human data show hypersensitivity to evoked and non-evoked stimuli suggesting peripheral and/or central nervous system abnormalities exist, thus providing supporting evidence for neuropathic pain in SCD.[48-53] Functional MRI data show distinct patterns in SCD supporting centralized etiologies of pain.[54-56] However, impaired central sensitization is not pathognomonic for neuropathic pain and can be detected in other chronic disease states that are characterized by pain. Biomarker assays in mice and individuals with SCD show evidence of neuroinflammation[13, 51] and nervous system sensitization.[57] Skin biopsies of SCD mice also support evidence of neuroinflammation.[51] The objective of this review is to summarize the existing evidence supporting the presence, diagnosis and treatment of neuropathic pain in individuals with SCD. Notably, there is a growing body of evidence in the sickle cell murine model supporting altered pain mechanisms suggestive of neuropathic pain [13, 58, 59]. However, this review is focused on human studies of neuropathic pain in children and adults with SCD. Diagnosis of neuropathic pain is facilitated by clinical pain descriptors Assessment of neuropathic pain requires recognition and neuroanatomical localization of the pain lesion to the central or peripheral nervous system. The intensity of pain can be characterized numerically (on a scale of 1 to 10), verbally (from mild to moderate or severe), or visually, using an analog scale. Various descriptors of neuropathic pain are used clinically for diagnostic purposes, and commonly include burning, hot, electric shocks, shooting, pricking, pins and needles and tingling.[23, 60] However, no single descriptor is pathognomonic for neuropathic pain.[61] The International Association for the Study of Pain recommends the use of screening questionnaires for the diagnosis of neuropathic pain, which can be completed either by the patient or clinician in combination with careful clinical examination.[61] Questionnaires incorporating neuropathic pain descriptors can be used to characterize an individual pain phenotype and estimate its prevalence in a population. The presence of allodynia and hypersensitivity on examination, which test the function of sensory fibers, in combination with classic descriptors of neuropathic pain elicited from the history,

are helpful for clinical diagnosis.[23] Examples of validated questionnaires for neuropathic pain include the Leeds assessment of neuropathic symptoms and signs (LANSS)[62], Douleur neuropathique 4 questions (DN4)[63], the Neuropathic Pain Questionnaire (NPQ)[64], painDETECT[65] and ID Pain.[66] In spite of the fact that pain is the most frequent reason for hospitalization in SCD and associated with early mortality[67, 68], the use of screening questionnaires for neuropathic pain[60] and other pain subtypes is not part of routine standard clinical care for this patient population.[67] Table 2 summarizes validated screening questionnaires for neuropathic pain.

ur na

lP

re

-p

ro

of

The prevalence of neuropathic pain reported by screening questionnaire in individuals with SCD is variable and limited to research studies Prior data suggest that neuropathic pain occurs in individuals with SCD. In a cross-sectional study of 56 adolescents and young adults with SCD, 14 individuals (25%) experienced neuropathic pain defined by a LANSS (Leeds assessment of neuropathic symptoms and signs scale) score greater than 11.[62] In this study, neuropathic pain was predominately located in the lower back and positively associated with hydroxyurea use and age greater than 19 years.[69] Another cross-sectional study of 56 adolescent and adult individuals with SCD found a prevalence of neuropathic pain in 37% of participants[46] using the validated painDETECT questionnaire.[65] Age, female gender, and hydroxyurea use positively correlated with the presence of neuropathic pain.[46] In this study, only 5% of participants were taking a neuropathic pain drug, suggesting that neuropathic pain is significantly underdiagnosed and untreated in this population.[46] One potential explanation for the observed association between hydroxyurea use and neuropathic pain could be attributed to increased prescription of hydroxyurea to individuals with frequent pain episodes at baseline, although further studies are warranted to investigate the etiology of this association. A computerized self-assessment pain reporting tool based on the McGill Pain Questionnaire PAINReportIt®[70], was administered to 49 adolescents and adults with SCD at least 14 years of age in a single-center cross-sectional study. This study asked individuals with SCD to visually localize the sites of their pain and select associated sensory descriptors to distinguish nociceptive pain from neuropathic pain.[71] The majority of participants were found to experience neuropathic and nociceptive pain simultaneously, with the upper legs and back being the most frequently reported sites of pain. In the study participants, 76-100% of anatomical sties of pain were reported to have a neuropathic component based on the computerized assessment of neuropathic descriptors, including “aching, burning, cold, drilling, flickering, numb, penetrating, radiating, shooting, spreading, tight, tingling.”[45] Another crosssectional study of 25 adults with SCD between the ages of 20 to 58 years reported a 40% prevalence of neuropathic pain based on LANSS scores greater than or equal to 12, with evidence of central, peripheral or mixed sensitization on quantitative sensory testing.[47]

Jo

Quantitative sensory testing demonstrates nervous system sensitization Quantitative sensory testing (QST) involves functional assessment of sensory nerve fibers at the painful site and/or in a contralateral or non-painful site. Evaluation of a non-painful site allows for assessment of the generalized pain sensitivity of an individual. QST encompasses a variety of psychophysical testing modalities that evaluate the sensitivity of the somatosensory system to heat, cold, deep pressure, light touch and punctuate (pin prick) stimuli. QST can detect hyposensitivity (sensory loss) and hypersensitivity (sensory gain) to the applied physical stimuli to pinpoint specific pathways that are injured in an individual and support a diagnosis of neuropathic pain.[72] QST outcomes include detection of pain and tolerance thresholds of the various sensory stimuli.[73] Different biological pain pathways that correlate with these stimuli involve unique peripheral sensory receptors that detect and transmit signals to pain pathways of the central nervous system. Thus, hypersensitivity or hyposensitivity to specific noxious and non-noxious stimuli can provide evidence of pain processing abnormalities involving the peripheral and/or central nervous system.[74, 75] Further, QST can determine alterations, differences or variations in pain sensitivity between individuals with the same disease, within a patient over time or between disease states (i.e., baseline vs. acute pain). QST has been used in children and adults with SCD[47, 48, 76-78], pain conditions such as migraine and headaches, rheumatoid pain and recurrent abdominal pain.[79-81] The strength of QST lies in the ability to interrogate central and/or peripheral nervous system abnormalities that may alter, sensitize or drive pain, thus allowing for a more objective assessment of pain biology in humans. Since individuals with neuropathic pain may experience allodynia and hyperalgesia evoked by these thermal and mechanical stimuli, QST can support a diagnosis of neuropathic pain.[34] Although QST can be affected by psychosocial factors, the testing assesses individuals’ dynamic response to painful and non-painful stimuli which allows for the incorporation of patient report, thereby

encompassing all aspects of the pain experience. This psychophysical nature of QST makes it a powerful pain assessment tool. Quantitative sensory testing can identify somatosensory characteristics associated with neuropathic pain QST has been used in clinical studies to define sensory abnormalities in individuals with neuropathic pain. In a cross-sectional study of 1236 individuals with neuropathic pain, 92% were found to have hyperalgesia to nociceptive stimuli, hypoesthesia to non-nociceptive stimuli or both on quantitative sensory testing.[82] The frequency of sensory abnormalities varied depending on the type of chronic pain syndrome, with thermal and mechanical hyperalgesia more frequently found in complex regional pain syndrome and peripheral nerve injury, and allodynia more frequently detected in postherpetic neuralgia. These results suggest that neuropathic pain syndromes may be characterized by unique somatosensory pain phenotypes. However, to date, QST has not been incorporated into routine practice for the diagnosis of neuropathic pain.

Jo

ur na

lP

re

-p

ro

of

Quantitative sensory testing provides preliminary evidence of neuropathic pain in individuals with SCD QST has suggested a profile of somatosensory abnormalities in individuals with SCD in multiple small to medium-sized cross-sectional studies. A single-center cross-sectional study of a convenience sample of 25 adults with SCD showed that QST is safe and does not stimulate acute vaso-occlusive pain. Of the 25 participants who underwent QST to cold, heat and mechanical stimuli, 24 had evidence of central sensitization, peripheral sensitization, or both, which is suggestive of neuropathic pain.[47] In another single-center crosssectional study of 55 children and adults with SCD and 57 race-matched controls, 81.8% (n=45) of individuals were found to have impaired pain sensitivity to at least one sensory threshold tested (cold, heat and mechanical pain).[50] Of the patients with SCD tested, 22% had impaired pain sensitivity to all 3 thresholds, and impaired cold sensitivity was the most common finding (63.6% of patients with SCD). There was no difference in age, gender, or median number of pain episodes in those with impaired pain sensitivity to cold, heat and mechanical stimuli when compared to those without any impaired pain sensitivity.[50] Another singlecenter cross-sectional study of 83 adults (≥ 18 years of age) with SCD and 27 healthy age, race and gendermatched controls, showed that heat pain tolerance and pressure pain thresholds were lower among adults with SCD compared to healthy controls. Thermal temporal summation at a fixed temperature of 45°C was higher in the SCD group. An unexpected finding was that conditioned pain modulation and pain ratings to hot water hand immersion were higher in the control group. Conditioned pain modulation describes a phenomenon in which an individual experiences reduced pain in response to a noxious stimulus after exposure to a conditioning stimulus.[83] This phenomenon is thought to reflect endogenous opiate function[84] and may be altered in individuals with chronic opiate use.[85] The etiology of reduced conditioned pain modulation in individuals with SCD compared to controls is not entirely clear, and warrants further investigation in future studies. Inflammatory and pain biomarkers were measured in a subset of individuals with SCD and controls, with evidence of elevated baseline anti-inflammatory interleukin-10 and pro-inflammatory tumor necrosis factor alpha in the SCD group. Both groups showed changes in inflammatory markers in response to pain testing.[86] The significance of inflammatory biomarker fluctuation relative to QST remains unclear at this time. However, these studies represent a first step toward linking potentially targetable biomarkers with QST abnormalities in inidividuals with sickle cell disease. A more recent study demonstrated that QST is feasible and well-tolerated in children with SCD when performed within a week of an emergency room visit or hospitalization for acute vaso-occlusive pain.[77] Table 3 displays a detailed summary of published data from QST studies completed in individuals with SCD to date, including additional studies that have not been discussed above. Cross-sectional studies comparing QST results of individuals with SCD and controls do not consistently show differences between both groups While cross-sectional studies represent an important first-step to estimate the prevalence of neuropathic pain in individuals with SCD, the development of a standardized approach to identify subtypes of pain in this population is warranted. Importantly, not all studies have suggested a clearly detectable difference in nervous system processing between individuals with and without SCD. For example, a single center cross-sectional study of 22 individuals with SCD and 52 healthy controls did not show differences in pain ratings or temporal summation in response to noxious pressure stimulation[87]. Other single-center cross-sectional studies of QST have shown no difference in heat pain thresholds in children with SCD (n=27) when compared to controls (n=28) [76] and no difference in thermal pain thresholds between children and young adults with SCD (n=57)

when compared to controls without SCD (n=60).[88]. Table 3 provides additional information about the findings of these studies. Numerous factors related to study design and participant characteristics may account for varying findings of neuropathic pain in individuals with SCD when compared to controls A number of factors may contribute to the differences in findings between groups studying somatosensory abnormalities in individuals with SCD summarized in this review. These factors include, but are not limited to, study participant characteristics which may influence pain frequency and perception (age, gender, sickle cell phenotype and baseline mental health disorders), permission to use outpatient analgesic medications prior to application of noxious stimuli, absence of SCD-specific reference standards for QST[76], use of therapies which may affect QST results (hydroxyurea use, which may decrease thermal sensitivity shortly after initiation[88] and chronic opiate therapy, which has been associated with higher central sensitization index scores),[89] and variations in the screening modalities for neuropathic pain in this population, which have not been standardized. Additional studies are required to fully understand the variability in these findings.

re

-p

ro

of

Neuroimaging studies show alterations in central pain processing in individuals with SCD Neuroimaging studies are not routinely used to diagnose neuropathic pain but may be helpful as adjunctive studies to define altered pain processing mechanisms in affected individuals. Three main groups of neuroimaging studies are used to characterize central pain processing: metabolic, functional and anatomical.[90] Metabolic neuroimaging studies in individuals with chronic pain can be used to correlate chemical and metabolic changes in the brain with excitatory and inhibitory neurotransmitters.[90] Anatomical neuroimaging studies allow chronic pain to be followed with structural changes in the brain. Functional magnetic resonance imaging (fMRI) can be used to localize sensory activation to distinct anatomical sites and measure functional connectivity of different brain regions.[90, 91] Positron emission tomography (PET) scans have also been used to define metabolic changes in relation to neuropathic pain, with one clinical study suggesting that spontaneous neuropathic pain is associated with alterations in normal thalamic activity on PET scan.[92]

ur na

lP

Pathognomonic neuroimaging patterns have not been identified specifically for neuropathic pain A common emerging theme in the study of central pain processing is the identification of pain signatures unique to subgroups of pain syndromes. Prior studies have suggested that a “pain matrix” consisting of cortical and subcortical networks play a role in pain perception.[34, 93] At this time, however, no unique "pain matrix" has been identified that is pathognomonic of neuropathic pain.[34] Detection of differences between resting and activated states of the brain in response to pain can help define a chronic pain signature.[94] However, one of the challenges associated with the study of neuropathic pain using functional neuroimaging studies is the spontaneous nature of pain in the absence of physical stimuli. Therefore, comparison of imaging patterns in pain and pain-free states is often not feasible. The interpretation of changes on fMRI of the brain in response to noxious stimuli is further complicated due to variations in experimental protocols.[95]

Jo

Few studies suggest that individuals with SCD and chronic pain may have altered neural connectivity that is detectable by functional MRI The use of neuroimaging studies in individuals with SCD for the study of pain processing mechanisms has been shown to be safe and feasible. In a single-center cross-sectional study of 15 adolescents and adults with SCD and 15 controls, electroencephalogram (EEG) and functional MRI (fMRI) studies were completed to test the hypothesis that neural connectivity is altered in individuals with SCD as a result of chronic pain. The EEG and fMRI data revealed increased activity in pain processing regions in the SCD group relative to controls. In the SCD group, the cerebellum showed stronger connectivity to the periaqueductal gray matter, which is involved in pain inhibition, as well as negative connections to pain processing areas when compared to the control group. These results raise the possibility that individuals with SCD have reduced activity of the default mode network and a compensatory increase in connectivity to regions of the brain that are involved in pain inhibition.[56] In a subsequent single-center cross-sectional study, 13 adults with SCD and 14 age-matched controls underwent fMRI in the resting state. The adults with SCD had decreased functional connectivity strength when compared to controls among networks involved in salience, emotion, learning, and memory. When these inter-network functional connectivity strength differences were examined within adults with SCD, significant associations were found with age, SCD genotype and number of pain days.[96] These data provide additional evidence of unique central pain processing mechanisms in individuals with SCD and raise the

possibility that altered connectivity in the brain of adults with SCD contributes to the development of a chronic pain syndrome. These studies also support the prior findings of Darbari et al., who conducted a single-center cross-sectional study of 25 adolescents and adults with SCD who underwent fMRI evaluation.[54] Participants were stratified into high or low pain groups based on the number of hospitalizations for pain in the preceding 12 months. Individuals in the high pain group displayed an excess of pro-nociceptive connectivity, including anterior cingulate to default-mode-network structures such as the precuneus. In contrast, individuals who were stratified to the low pain group showed more connectivity to anti-nociceptive structures, such as the peri- and sub-genual cingulate. Fetal hemoglobin levels were significantly higher in the low pain group and were associated with greater connectivity to anti-nociceptive structures.[54] These results suggest that evaluation of intrinsic brain connectivity may provide objective functional outcomes that can be correlated with pain measures and elucidate pathologic central processing mechanisms in SCD. While there are multiple published studies detailing the role of neuroimaging for the diagnosis and surveillance of neurovascular and cognitive outcomes in SCD, there few published studies that correlate neuroimaging specifically with pain outcome measures in this population. Table 4 displays a summary of the data from neuroimaging studies that have been completed in individuals with SCD to date.

lP

re

-p

ro

of

There is a paucity of literature defining risk factors for neuropathic pain in individuals with SCD The study of risk factors associated with neuropathic pain in SCD has been largely derived from small to moderate-sized cross-sectional studies. In a convenience sample of 56 individuals with SCD who completed the painDETECT questionnaire, older age, hydroxyurea use and female gender were associated with neuropathic pain.[46] Deva- can you add any more data here from other studies to ensure that we are quoting other people’s work? Any other studies look at risk factors? I think one of the other questionnaire studies looked at this? The risk factors for neuropathic pain have been defined more clearly in other disease states. In diabetes mellitus, for example, risk factors for neuropathy include age[97], body mass index[44], hypertension[98], smoking, elevated triglyceride levels[99] and waist circumference.[100, 101] An observational study of 449 pain-free individuals with HIV demonstrated that the presence of at least one abnormal neuropathic exam finding and history of opiate dependence or abuse was predictive of developing neuropathic pain.[102] There is overall a paucity of literature elucidating risk factors for neuropathic pain in individuals with SCD. The impact of hydroxyurea, regular blood transfusion therapy and disease-specific factors, such as excessive iron stores and vascular end-organ damage, on the development and progression of neuropathic pain in SCD is unknown.

Jo

ur na

Underlying pain mechanisms in SCD are poorly understood The etiology of acute pain episodes in SCD is complex and hypothesized to occur due to multiple diseasespecific factors, including oxidative stress, ischemia-reperfusion injury, vaso-occlusion and neuro-inflammation. In clinical practice, however, acute pain episodes in SCD are labeled as "acute vaso-occlusive pain episodes," without consideration of diagnostic studies to identify the presence of neuropathic pain and other pain phenotypes. As a result, patients are treated non-specifically with acetaminophen, non-steroidal antiinflammatory drugs and opioids for "acute vaso-occlusive pain episodes," which may not necessarily target the underlying mechanisms causing acute pain. Further studies are warranted to elucidate the complex biology of acute pain in SCD, with the ultimate goal of developing a "sickle cell pain lexicon" that effectively links pain sub-phenotypes and their underlying pathophysiology with targeted interventions. Treatment of neuropathic pain in individuals with SCD Despite data supporting the existence of neuropathic pain in SCD, systematic strategies for management and prevention of neuropathic pain in these individuals are lacking. The treatment of neuropathic pain can be challenging. Individuals suffering from neuropathic pain do not usually respond to conventional analgesics such as opioids, acetaminophen or non-steroidal anti-inflammatory drugs.[103, 104] Drugs commonly considered as first line for neuropathic pain treatments include gabapentinoids, serotonin-noradrenaline reuptake inhibitors (SNRIs), and tricyclic antidepressants.[105-108] In contrast to other neuropathic pain conditions, systematic investigations of these drugs have not been done in individuals with SCD. Thus, data for the use of neuropathic pain drugs in individuals with SCD are limited. Table 5 displays data from only three trials that investigate neuropathic pain-focused treatments in individuals with SCD; a phase I open label study, a pilot safety and feasibility randomized controlled trial and a phase II single-arm study. In addition, since acute SCD pain is often superimposed on the background of chronic pain, acute pain exacerbations could also be driven by a neuropathic pain component. Opioids are the backbone of acute SCD pain treatment but are often

ineffective at fully relieving individuals’ pain. This suggests other pain mechanisms may also be driving acute SCD pain. Ketamine, a drug shown to effectively treat some neuropathic pain conditions[109, 110], is emerging as a potential treatment for SCD pain. Limited data using ketamine for acute SCD pain treatment suggest the drug may be effective[111-114] but additional studies are needed. Further, patient inclusion for these studies was not delineated based on neuropathic pain phenotype.

ro

of

Limited epidemiological data suggest neuropathic pain drugs are used infrequently in individuals with SCD. It is unknown whether this is due to lack of efficacy data or underdiagnosis of neuropathic pain in this population. Two studies that elicited a neuropathic pain phenotype in individuals with SCD using patient-reported screening tools found infrequent use of neuropathic pain drugs in these individuals. Using the PAINReportIt® tool, Wilkie et al. found 90% of individuals described their pain using words classically associated with neuropathic pain, however only 5% were taking a neuropathic pain drug.[45] Further, Brandow et al. found 37% of individuals had evidence of neuropathic pain using the painDETECT neuropathic screening tool and only 5% were taking a neuropathic pain drug.[46] A single study investigated the use of neuropathic pain drugs in the real world setting in children and adolescents with SCD. Secondary data analysis of the Pediatric Health Information System data from 53,557 SCD inpatient visits was done to determine the prevalence and associated demographics of those prescribed neuropathic pain drugs (antiepileptics, selective serotonin reuptake inhibitors, tricyclic antidepressants).[115] Data show only 2.9% of individuals received a neuropathic pain drug.[115] The odds of receiving a neuropathic pain drug significantly increased with older age and female sex.[115]

lP

re

-p

Data addressing neuropathic pain in young children and elderly individuals with SCD are lacking The majority of studies assessing neuropathic pain in SCD have focused on adolescents and adults with, as the availability of validated screening tools for neuropathic pain in individuals under the age of 14 years is limited. Therefore, the prevalence of neuropathic pain in younger children with SCD has not been systematically evaluated. As the life expectancy of individuals with SCD continues to increase[68], inclusion of older adults into these studies and understanding how non-hematologic comorbidities contribute to the development and progression of neuropathic pain will help to guide therapeutic and preventative interventions. The mean age of adults with SCD in prior cross-sectional studies was under 33 years.[46, 69, 71, 87] Finally, prospective observational studies may help to identify targetable risk factors for neuropathic pain in individuals with SCD and provide a better understanding of how neuropathic pain develops and progresses from adolescence to adulthood.

Jo

ur na

Ongoing research focused on neuropathic pain in individuals with SCD A recent review of ClinicalTrials.gov was done to determine ongoing or completed studies (not yet published) targeted at neuropathic pain in individuals with SCD. Search terms “sickle” and “neuropathic” revealed one study targeted at the treatment of neuropathic pain in individuals with SCD. This study, “Pain Management in children and Young Adults with SCD”, is completed but not yet published. This is a “phase II double-blind placebo-controlled clinical trial evaluating the effect of gabapentin when added to standard pain management for patients with SCD experiencing acute pain crisis in the ambulatory care setting.”[4] The search was then expanded to terms “sickle” and “pain” and studies were reviewed to identify trials that likely target neuropathic pain mechanisms. Two additional studies were found. One study entitled “tDCS Associated With Peripheral Electrical Stimulation for Pain Control in Individuals With Sickle Cell Disease (tDCS/PES_SCD)” aims to “assess the effect of a single session of transcranial direct current stimulation (tDCS) associated to peripheral electrical stimulation (PES) on safety and efficacy analgesic in individuals with sickle cell disease (SCD).”[116] Transcranial direct current stimulation (tDCS) has been used to treat neuropathic pain in other pain populations.[117] The second study, entitled “Vaporized Cannabis for Chronic Pain Associated With Sickle Cell Disease(Cannabis-SCD)”, is completed but not yet published and sought to “assess whether inhaling vaporized cannabis ameliorates chronic pain in patients with sickle cell disease (SCD)”.[118] This study was included since cannabinoids are thought to have properties that could ameliorate neuropathic pain.[119] The results of these studies will contribute to the growing body of literature addressing neuropathic pain treatment in individuals with SCD. Research gaps and future directions Several research gaps remain regarding the mechanisms, diagnosis and treatment of neuropathic pain in individuals with SCD. First, the assessment of neuropathic pain in younger children is a challenge. Most crosssectional patient-reported outcomes developed for neuropathic pain assessment are not indicated or validated

ro

of

for use in children. The development of newer pediatric tools by the PROMIS / HealthMeasures [120] initiative may provide a framework for assessment of younger children, however additional validation is needed for these measures for neuropathic pain diagnosis. Additional randomized controlled trials that test the efficacy of drugs and devices used to treat neuropathic pain are needed that incorporate appropriate pain phenotype selection into these trials. Further somatosensory pain phenotyping will help to assess various pain profiles and their clinical significance. QST and fMRI scans of the brain have been used in research studies to identify somatosensory and central pain processing abnormalities, respectively, in individuals with SCD. However, there are currently no evidence-based guidelines for their incorporation into routine clinical practice for the management of neuropathic pain in individuals with SCD. Additionally, no evidence-based strategies to prevent the onset of neuropathic pain in this population have been established. The study of additional pain biomarkers and neuropathic pain genetics will provide clues to other potential neuropathic pain mechanisms that could be targeted.[121] Additional brain imaging studies are needed to further understand the biology and impact of central nervous system abnormalities on SCD pain. Nerve conduction studies and microneurography have also not been explored in SCD. Ultimately, the continued study of the combination of peripheral and central nervous system abnormalities and the cross-talk between the entire nervous system is needed to fully unravel the complex mechanisms underlying neuropathic pain in individuals with SCD. This will optimally be accomplished through translational work that bridges human and basic animal research and interdisciplinary collaboration between hematologists, neuroscientists with expertise in pain biology, pain medicine specialists, immunologists, among others.

lP

**The authors declare no conflicts of interest

re

-p

Conclusions Data herein reviewed show evidence of neuropathic pain in individuals with SCD. However, investigations into the mechanisms, diagnosis and treatment of neuropathic pain in individuals with SCD continue to evolve. The growing body of data show the etiology of pain in SCD is beyond the red blood cell, and pathologic changes in the nervous system likely perpetuate the acute and chronic pain endured by individuals with SCD. Continued study of these mechanisms is imperative to advance the understanding of SCD pain and ultimately generate novel targeted treatments that will decrease patient suffering.

References

Jo

ur na

1. Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013;381(9861):142-51. doi: 10.1016/S0140-6736(12)61229-X. PubMed PMID: 23103089; PubMed Central PMCID: PMCPMC3547249. 2. Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell disease in the United States: national and state estimates. Am J Hematol. 2010;85(1):77-8. Epub 2009/12/24. doi: 10.1002/ajh.21570. PubMed PMID: 20029951. 3. Fitzsimmons R, Amin N, Uversky VN. Understanding the roles of intrinsic disorder in subunits of hemoglobin and the disease process of sickle cell anemia. Intrinsically Disord Proteins. 2016;4(1):e1248273. doi: 10.1080/21690707.2016.1248273. PubMed PMID: 28232898; PubMed Central PMCID: PMCPMC5314875. 4. Lanzkron S, Carroll CP, Haywood C, Jr. The burden of emergency department use for sickle-cell disease: an analysis of the national emergency department sample database. Am J Hematol. 2010;85(10):7979. doi: 10.1002/ajh.21807. PubMed PMID: 20730795; PubMed Central PMCID: PMCPMC3431910. 5. Kauf TL, Coates TD, Huazhi L, Mody-Patel N, Hartzema AG. The cost of health care for children and adults with sickle cell disease. Am J Hematol. 2009;84(6):323-7. doi: 10.1002/ajh.21408. PubMed PMID: 19358302. 6. Brousseau DC, Owens PL, Mosso AL, Panepinto JA, Steiner CA. Acute care utilization and rehospitalizations for sickle cell disease. JAMA. 2010;303(13):1288-94. Epub 2010/04/08. doi: 303/13/1288 [pii] 10.1001/jama.2010.378. PubMed PMID: 20371788. 7. Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148(2):94-101. Epub 2008/01/16. doi: 148/2/94 [pii]. PubMed PMID: 18195334.

Jo

ur na

lP

re

-p

ro

of

8. Sil S, Cohen LL, Dampier C. Psychosocial and Functional Outcomes in Youth With Chronic Sickle Cell Pain. Clin J Pain. 2016;32(6):527-33. Epub 2015/09/18. doi: 10.1097/AJP.0000000000000289. PubMed PMID: 26379074. 9. Bakshi N, Ross D, Krishnamurti L. Presence of pain on three or more days of the week is associated with worse patient reported outcomes in adults with sickle cell disease. J Pain Res. 2018;11:313-8. Epub 2018/02/16. doi: 10.2147/JPR.S150065. PubMed PMID: 29445298; PubMed Central PMCID: PMCPMC5810514. 10. 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;54(1):92-7. PubMed PMID: 19653296. 11. Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood. 2014;124(26):3850-7; quiz 4004. Epub 2014/10/08. doi: 10.1182/blood-2014-08-435768. PubMed PMID: 25287707; PubMed Central PMCID: PMC4271176. 12. FDA Approved L-glutamine powder for the treatment of sickle cell disease [cited 2017 October 1]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm566097.htm . 13. Tran H, Gupta M, Gupta K. Targeting novel mechanisms of pain in sickle cell disease. Blood. 2017;130(22):2377-85. doi: 10.1182/blood-2017-05-782003. PubMed PMID: 29187376; PubMed Central PMCID: PMCPMC5709786. 14. Brandow AM, Zappia KJ, Stucky CL. Sickle cell disease: a natural model of acute and chronic pain. Pain. 2017;158 Suppl 1:S79-S84. doi: 10.1097/j.pain.0000000000000824. PubMed PMID: 28221286; PubMed Central PMCID: PMCPMC5350013. 15. Ezenwa MO, Molokie RE, Wang ZJ, Yao Y, Suarez ML, Dyal B, et al. Differences in Sensory Pain, Expectation, and Satisfaction Reported by Outpatients with Cancer or Sickle Cell Disease. Pain Manag Nurs. 2018;19(4):322-32. Epub 2018/03/05. doi: 10.1016/j.pmn.2017.11.010. PubMed PMID: 29501359; PubMed Central PMCID: PMCPMC6078788. 16. Dampier C, Palermo TM, Darbari DS, Hassell K, Smith W, Zempsky W. AAPT Diagnostic Criteria for Chronic Sickle Cell Disease Pain. J Pain. 2017;18(5):490-8. doi: 10.1016/j.jpain.2016.12.016. PubMed PMID: 28065813. 17. IASP Taxonomy: Neuropathic Pain [October 1, 2017]. Available from: http://www.iasppain.org/Education/Content.aspx?ItemNumber=1698 - Neuropathicpain. 18. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32. doi: 10.1146/annurev.neuro.051508.135531. PubMed PMID: 19400724; PubMed Central PMCID: PMCPMC2768555. 19. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006;52(1):77-92. doi: 10.1016/j.neuron.2006.09.021. PubMed PMID: 17015228; PubMed Central PMCID: PMCPMC1810425. 20. Bridges D, Thompson SW, Rice AS. Mechanisms of neuropathic pain. Br J Anaesth. 2001;87(1):12-26. PubMed PMID: 11460801. 21. Nickel FT, Seifert F, Lanz S, Maihofner C. Mechanisms of neuropathic pain. Eur Neuropsychopharmacol. 2012;22(2):81-91. doi: 10.1016/j.euroneuro.2011.05.005. PubMed PMID: 21672666. 22. Gilron I, Watson CP, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ. 2006;175(3):265-75. doi: 10.1503/cmaj.060146. PubMed PMID: 16880448; PubMed Central PMCID: PMCPMC1513412. 23. Bennett MI, Attal N, Backonja MM, Baron R, Bouhassira D, Freynhagen R, et al. Using screening tools to identify neuropathic pain. Pain. 2007;127(3):199-203. Epub 2006/12/22. doi: 10.1016/j.pain.2006.10.034. PubMed PMID: 17182186. 24. Cruccu G, Truini A. Tools for assessing neuropathic pain. PLoS Med. 2009;6(4):e1000045. doi: 10.1371/journal.pmed.1000045. PubMed PMID: 19360134; PubMed Central PMCID: PMCPMC2661248. 25. Dubuisson D, Melzack R. Classification of clinical pain descriptions by multiple group discriminant analysis. Exp Neurol. 1976;51(2):480-7. PubMed PMID: 1269574. 26. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630-5. Epub 2007/11/16. doi: 10.1212/01.wnl.0000282763.29778.59. PubMed PMID: 18003941. 27. Finnerup NB, Haroutounian S, Kamerman P, Baron R, Bennett DL, Bouhassira D, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain. 2016;157(8):1599-606. doi: 10.1097/j.pain.0000000000000492. PubMed PMID: 27115670; PubMed Central PMCID: PMCPMC4949003.

Jo

ur na

lP

re

-p

ro

of

28. Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol. 2014;13(9):924-35. Epub 2014/08/22. doi: 10.1016/S1474-4422(14)70102-4. PubMed PMID: 25142459. 29. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-15. doi: 10.1016/j.pain.2010.09.030. PubMed PMID: 20961685; PubMed Central PMCID: PMCPMC3268359. 30. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-84. Epub 2009/10/20. doi: 10.1016/j.cell.2009.09.028. PubMed PMID: 19837031; PubMed Central PMCID: PMCPMC2852643. 31. Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol. 2001;429(1-3):23-37. Epub 2001/11/08. PubMed PMID: 11698024. 32. Haanpaa M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152(1):14-27. Epub 2010/09/21. doi: 10.1016/j.pain.2010.07.031. PubMed PMID: 20851519. 33. Serra J, Bostock H, Sola R, Aleu J, Garcia E, Cokic B, et al. Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats. Pain. 2012;153(1):42-55. doi: 10.1016/j.pain.2011.08.015. PubMed PMID: 21993185. 34. Moisset X, Bouhassira D. Brain imaging of neuropathic pain. Neuroimage. 2007;37 Suppl 1:S80-8. doi: 10.1016/j.neuroimage.2007.03.054. PubMed PMID: 17512757. 35. Walk D. Role of skin biopsy in the diagnosis of peripheral neuropathic pain. Curr Pain Headache Rep. 2009;13(3):191-6. PubMed PMID: 19457279. 36. Sarah Callin MIBAonp, Continuing Education in Anaesthesia Critical Care & Pain, Volume 8, Issue 6, 1 December 2008, Pages 210–213. 37. Hughes RA. Peripheral neuropathy. BMJ. 2002;324(7335):466-9. PubMed PMID: 11859051; PubMed Central PMCID: PMCPMC1122393. 38. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002. doi: 10.1038/nrdp.2017.2. PubMed PMID: 28205574; PubMed Central PMCID: PMCPMC5371025. 39. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011;34(10):2220-4. doi: 10.2337/dc11-1108. PubMed PMID: 21852677; PubMed Central PMCID: PMCPMC3177727. 40. Ballas SK, Darbari DS. Neuropathy, neuropathic pain, and sickle cell disease. Am J Hematol. 2013;88(11):927-9. doi: 10.1002/ajh.23575. PubMed PMID: 23963922. 41. Agapidou A, Aiken L, Linpower L, Tsitsikas DA. Ischemic Monomeric Neuropathy in a Woman with Sickle Cell Anaemia. Case Rep Hematol. 2016;2016:8628425. doi: 10.1155/2016/8628425. PubMed PMID: 27994894; PubMed Central PMCID: PMCPMC5138463 publication of this paper. 42. Okuyucu EE, Turhanoglu A, Duman T, Kaya H, Melek IM, Yilmazer S. Peripheral nervous system involvement in patients with sickle cell disease. Eur J Neurol. 2009;16(7):814-8. doi: 10.1111/j.14681331.2009.02592.x. PubMed PMID: 19473371. 43. Giabicani M, Compere V, Fourdrinier V, Dureuil B. Is sickle cell disease a possible risk factor for peripheral neuropathy after popliteal sciatic nerve block? Br J Anaesth. 2013;111(3):508-10. doi: 10.1093/bja/aet269. PubMed PMID: 23946362. 44. Meisinger C, Doring A, Thorand B, Heier M, Lowel H. Body fat distribution and risk of type 2 diabetes in the general population: are there differences between men and women? The MONICA/KORA Augsburg cohort study. Am J Clin Nutr. 2006;84(3):483-9. doi: 10.1093/ajcn/84.3.483. PubMed PMID: 16960160. 45. Wilkie DJ, Molokie R, Boyd-Seal D, Suarez ML, Kim YO, Zong S, 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;102(1):18-27. PubMed PMID: 20158132; PubMed Central PMCID: PMCPMC3641147. 46. Brandow AM, Farley RA, Panepinto JA. Neuropathic pain in patients with sickle cell disease. Pediatr Blood Cancer. 2014;61(3):512-7. Epub 2013/10/30. doi: 10.1002/pbc.24838. PubMed PMID: 24167104; PubMed Central PMCID: PMC4357477. 47. Ezenwa MO, Molokie RE, Wang ZJ, Yao Y, Suarez ML, Pullum C, et al. Safety and Utility of Quantitative Sensory Testing among Adults with Sickle Cell Disease: Indicators of Neuropathic Pain? Pain

Jo

ur na

lP

re

-p

ro

of

practice : the official journal of World Institute of Pain. 2016;16(3):282-93. Epub 2015/01/13. doi: 10.1111/papr.12279. PubMed PMID: 25581383; PubMed Central PMCID: PMC4499503. 48. Brandow AM, Stucky CL, Hillery CA, Hoffmann RG, Panepinto JA. Patients with sickle cell disease have increased sensitivity to cold and heat. Am J Hematol. 2013;88(1):37-43. doi: 10.1002/ajh.23341. PubMed PMID: 23115062; PubMed Central PMCID: PMCPMC3552380. 49. Brandow AM, Farley RA, Panepinto JA. Early insights into the neurobiology of pain in sickle cell disease: A systematic review of the literature. Pediatr Blood Cancer. 2015;62(9):1501-11. Epub 2015/05/16. doi: 10.1002/pbc.25574. PubMed PMID: 25976161; PubMed Central PMCID: PMCPMC4515148. 50. Brandow AM, Panepinto JA. Clinical Interpretation of Quantitative Sensory Testing as a Measure of Pain Sensitivity in Patients With Sickle Cell Disease. J Pediatr Hematol Oncol. 2016;38(4):288-93. doi: 10.1097/MPH.0000000000000532. PubMed PMID: 26907660; PubMed Central PMCID: PMCPMC4856159. 51. Kohli DR, Li Y, Khasabov SG, Gupta P, Kehl LJ, Ericson ME, et al. Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids. Blood. 2010;116(3):456-65. doi: 10.1182/blood-2010-01-260372. PubMed PMID: 20304807; PubMed Central PMCID: PMCPMC2913454. 52. Hillery CA, Kerstein PC, Vilceanu D, Barabas ME, Retherford D, Brandow AM, et al. Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease. Blood. 2011;118(12):3376-83. Epub 2011/06/29. doi: 10.1182/blood-2010-12-327429. PubMed PMID: 21708890; PubMed Central PMCID: PMC3179403. 53. Uhelski ML, Gupta K, Simone DA. Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis. Pain. 2017;158(9):1711-22. Epub 2017/06/02. doi: 10.1097/j.pain.0000000000000966. PubMed PMID: 28570479; PubMed Central PMCID: PMCPMC5561456. 54. Darbari DS, Hampson JP, Ichesco E, Kadom N, Vezina G, Evangelou I, et al. Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease. J Pain. 2015;16(11):1077-86. doi: 10.1016/j.jpain.2015.07.005. PubMed PMID: 26291276; PubMed Central PMCID: PMCPMC4986827. 55. Wang Y, Wang X, Chen W, Gupta K, Zhu XH. Functional MRI BOLD response in sickle mice with hyperalgesia. Blood Cells Mol Dis. 2017;65:81-5. Epub 2017/06/06. doi: 10.1016/j.bcmd.2017.03.005. PubMed PMID: 28579187; PubMed Central PMCID: PMCPMC5521217. 56. Case M, Zhang H, Mundahl J, Datta Y, Nelson S, Gupta K, et al. Characterization of functional brain activity and connectivity using EEG and fMRI in patients with sickle cell disease. Neuroimage Clin. 2017;14:1 17. doi: 10.1016/j.nicl.2016.12.024. PubMed PMID: 28116239; PubMed Central PMCID: PMCPMC5226854. 57. Brandow AM, Wandersee NJ, Dasgupta M, Hoffmann RG, Hillery CA, Stucky CL, et al. Substance P is increased in patients with sickle cell disease and associated with haemolysis and hydroxycarbamide use. Br J Haematol. 2016;175(2):237-45. doi: 10.1111/bjh.14300. PubMed PMID: 27539682; PubMed Central PMCID: PMCPMC5063705. 58. Wang ZJ, Wilkie DJ, Molokie R. Neurobiological mechanisms of pain in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2010;2010:403-8. Epub 2011/01/18. doi: 10.1182/asheducation-2010.1.403. PubMed PMID: 21239826; PubMed Central PMCID: PMCPMC3650026. 59. Gupta K, Jahagirdar O, Gupta K. Targeting pain at its source in sickle cell disease. Am J Physiol Regul Integr Comp Physiol. 2018;315(1):R104-R12. Epub 2018/03/29. doi: 10.1152/ajpregu.00021.2018. PubMed PMID: 29590553; PubMed Central PMCID: PMCPMC6087885. 60. Attal N, Bouhassira D, Baron R. Diagnosis and assessment of neuropathic pain through questionnaires. Lancet Neurol. 2018;17(5):456-66. Epub 2018/03/31. doi: 10.1016/S1474-4422(18)30071-1. PubMed PMID: 29598922. 61. Ballantyne JC, Cousins, Michael J., Adele Giamberardino, Maria, Jamison, Robert N., McGrath, Patricia A., Rajagopal, M.R., Smith, Maree T., Sommer, Claudia, Wittink, Harriet M. . Diagnosis and Classification of Neuropathic Pain. International Association for the Study of Pain. September 2010;Vol. XVIII, Issue 7 62. Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain. 2001;92(1-2):147-57. PubMed PMID: 11323136. 63. Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005;114(1-2):29-36. doi: 10.1016/j.pain.2004.12.010. PubMed PMID: 15733628.

Jo

ur na

lP

re

-p

ro

of

64. Haussleiter IS, Richter H, Scherens A, Schwenkreis P, Tegenthoff M, Maier C. NeuroQuick--a novel bedside test for small fiber neuropathy? Eur J Pain. 2008;12(8):1000-7. doi: 10.1016/j.ejpain.2008.01.005. PubMed PMID: 18325802. 65. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911-20. doi: 10.1185/030079906X132488. PubMed PMID: 17022849. 66. Portenoy R. Development and testing of a neuropathic pain screening questionnaire: ID Pain. Curr Med Res Opin. 2006;22(8):1555-65. doi: 10.1185/030079906X115702. PubMed PMID: 16870080. 67. Matthie N, Jenerette C. Sickle cell disease in adults: developing an appropriate care plan. Clin J Oncol Nurs. 2015;19(5):562-7. doi: 10.1188/15.CJON.562-567. PubMed PMID: 26688919; PubMed Central PMCID: PMCPMC5565201. 68. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-44. Epub 1994/06/09. PubMed PMID: 7993409. 69. Antunes FD, Propheta VGS, Vasconcelos HA, Cipolotti R. Neuropathic pain in patients with sickle cell disease: a cross-sectional study assessing teens and young adults. Ann Hematol. 2017;96(7):1121-5. doi: 10.1007/s00277-017-2984-z. PubMed PMID: 28361297. 70. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975;1(3):27799. PubMed PMID: 1235985. 71. Richard J. Labotka REM, A. Kyle Mack, Alexis A Thompson, Young Ok Kim and Diana J Wilkie. Neuropathic Vs. Nociceptive Pain in Adolescent Sickle Cell Disease (SCD) Evaluated by a Computer-Based Self-Assessment Pain Tool. Blood 2009 114:2576;. 72. McGrath PA, Brown SC. Quantitative Sensory Testing in children: practical considerations for research and clinical practice. Pain. 2006;123(1-2):1-2. Epub 2006/05/16. doi: S0304-3959(06)00190-4 [pii] 10.1016/j.pain.2006.03.024. PubMed PMID: 16697112. 73. Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;60(6):898-904. PubMed PMID: 12654951. 74. Arendt-Nielsen L, Curatolo M, Drewes A. Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs. 2007;8(1):41-53. PubMed PMID: 17263184. 75. Backonja MM, Walk D, Edwards RR, Sehgal N, Moeller-Bertram T, Wasan A, et al. Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities. Clin J Pain. 2009;25(7):641-7. doi: 10.1097/AJP.0b013e3181a68c7e. PubMed PMID: 19692807. 76. O'Leary JD, Crawford MW, Odame I, Shorten GD, McGrath PA. Thermal pain and sensory processing in children with sickle cell disease. Clin J Pain. 2014;30(3):244-50. doi: 10.1097/AJP.0b013e318292a38e. PubMed PMID: 23629596. 77. Bakshi N, Lukombo I, Belfer I, Krishnamurti L. Quantitative sensory testing is feasible and is welltolerated in patients with sickle cell disease following a vaso-occlusive episode. J Pain Res. 2018;11:435-43. doi: 10.2147/JPR.S150066. PubMed PMID: 29503580; PubMed Central PMCID: PMCPMC5827673. 78. Campbell CM, Moscou-Jackson G, Carroll CP, Kiley K, Haywood C, Jr., Lanzkron S, et al. An Evaluation of Central Sensitization in Patients With Sickle Cell Disease. J Pain. 2016;17(5):617-27. doi: 10.1016/j.jpain.2016.01.475. PubMed PMID: 26892240; PubMed Central PMCID: PMCPMC4851873. 79. Hogeweg JA, Kuis W, Huygen AC, de Jong-de vos van Steenwijk C, Bernards AT, Oostendorp RA, et al. The pain threshold in juvenile chronic arthritis. Br J Rheumatol. 1995;34(1):61-7. Epub 1995/01/01. PubMed PMID: 7881842. 80. Zohsel K, Hohmeister J, Oelkers-Ax R, Flor H, Hermann C. Quantitative sensory testing in children with migraine: preliminary evidence for enhanced sensitivity to painful stimuli especially in girls. Pain. 2006;123(12):10-8. Epub 2006/02/24. doi: S0304-3959(05)00637-8 [pii] 10.1016/j.pain.2005.12.015. PubMed PMID: 16495010. 81. Zohsel K, Hohmeister J, Flor H, Hermann C. Somatic pain sensitivity in children with recurrent abdominal pain. Am J Gastroenterol. 2008;103(6):1517-23. Epub 2008/05/31. doi: AJG1911 [pii] 10.1111/j.1572-0241.2008.01911.x. PubMed PMID: 18510619. 82. Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010;150(3):439-50. doi: 10.1016/j.pain.2010.05.002. PubMed PMID: 20627413.

Jo

ur na

lP

re

-p

ro

of

83. Kennedy DL, Kemp HI, Ridout D, Yarnitsky D, Rice AS. Reliability of conditioned pain modulation: a systematic review. Pain. 2016;157(11):2410-9. doi: 10.1097/j.pain.0000000000000689. PubMed PMID: 27559835; PubMed Central PMCID: PMCPMC5228613 at the end of this article. 84. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain. 2012;13(10):936-44. doi: 10.1016/j.jpain.2012.07.005. PubMed PMID: 22981090. 85. Ram KC, Eisenberg E, Haddad M, Pud D. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid-induced hyperalgesia. Pain. 2008;139(2):431-8. doi: 10.1016/j.pain.2008.05.015. PubMed PMID: 18583047. 86. Campbell CM, Carroll CP, Kiley K, Han D, Haywood C, Jr., Lanzkron S, et al. Quantitative sensory testing and pain-evoked cytokine reactivity: comparison of patients with sickle cell disease to healthy matched controls. Pain. 2016;157(4):949-56. doi: 10.1097/j.pain.0000000000000473. PubMed PMID: 26713424; PubMed Central PMCID: PMCPMC4932897. 87. Hollins M, Stonerock GL, Kisaalita NR, Jones S, Orringer E, Gil KM. Detecting the emergence of chronic pain in sickle cell disease. J Pain Symptom Manage. 2012;43(6):1082-93. doi: 10.1016/j.jpainsymman.2011.06.020. PubMed PMID: 22579409; PubMed Central PMCID: PMCPMC3366027. 88. Miller RE, Brown DS, Keith SW, Hegarty SE, Setty Y, Campbell CM, et al. Quantitative sensory testing in children with sickle cell disease: additional insights and future possibilities. Br J Haematol. 2019. doi: 10.1111/bjh.15876. PubMed PMID: 30924134. 89. Carroll CP, Lanzkron S, Haywood C, Jr., Kiley K, Pejsa M, Moscou-Jackson G, et al. Chronic Opioid Therapy and Central Sensitization in Sickle Cell Disease. Am J Prev Med. 2016;51(1 Suppl 1):S69-77. doi: 10.1016/j.amepre.2016.02.012. PubMed PMID: 27320469; PubMed Central PMCID: PMCPMC5379857. 90. Alomar S, Bakhaidar M. Neuroimaging of neuropathic pain: review of current status and future directions. Neurosurg Rev. 2018;41(3):771-7. doi: 10.1007/s10143-016-0807-7. PubMed PMID: 27975115. 91. Fomberstein K, Qadri S, Ramani R. Functional MRI and pain. Curr Opin Anaesthesiol. 2013;26(5):58893. doi: 10.1097/01.aco.0000433060.59939.fe. PubMed PMID: 23995063. 92. Chen FY, Tao W, Li YJ. Advances in brain imaging of neuropathic pain. Chin Med J (Engl). 2008;121(7):653-7. PubMed PMID: 18466688. 93. Iannetti GD, Mouraux A. From the neuromatrix to the pain matrix (and back). Exp Brain Res. 2010;205(1):1-12. doi: 10.1007/s00221-010-2340-1. PubMed PMID: 20607220. 94. Borsook D, Becerra L. How close are we in utilizing functional neuroimaging in routine clinical diagnosis of neuropathic pain? Curr Pain Headache Rep. 2011;15(3):223-9. doi: 10.1007/s11916-011-0187-1. PubMed PMID: 21369853. 95. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9(4):463-84. doi: 10.1016/j.ejpain.2004.11.001. PubMed PMID: 15979027. 96. Arun Singavi GC, Nancy Wandersee, Collin Hubler, Amanda M Brandow, Pippa Simpson, Shi-Jiang Li and Joshua J Field. Daily Pain Is Associated with Alterations in Functional Connectivity of the Brain on fMRI in Adults with Sickle Cell Disease. Volume: 128 Issue: 22 Pages: 3656 DOI: https://doiorg/. Blood 2016 128:3656;. 97. Erbas T, Ertas M, Yucel A, Keskinaslan A, Senocak M, Group TS. Prevalence of peripheral neuropathy and painful peripheral neuropathy in Turkish diabetic patients. J Clin Neurophysiol. 2011;28(1):51-5. doi: 10.1097/WNP.0b013e3182051334. PubMed PMID: 21221008. 98. Forrest KY, Maser RE, Pambianco G, Becker DJ, Orchard TJ. Hypertension as a risk factor for diabetic neuropathy: a prospective study. Diabetes. 1997;46(4):665-70. PubMed PMID: 9075809. 99. Sone H, Mizuno S, Yamada N. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352(18):1925-7; author reply -7. PubMed PMID: 15877321. 100. Miralles-Garcia JM, de Pablos-Velasco P, Cabrerizo L, Perez M, Lopez-Gomez V, Sociedad Espanola de Endocrinologia y N. Prevalence of distal diabetic polyneuropathy using quantitative sensory methods in a population with diabetes of more than 10 years' disease duration. Endocrinol Nutr. 2010;57(9):414-20. doi: 10.1016/j.endonu.2010.05.006. PubMed PMID: 20638348. 101. Hebert HL, Veluchamy A, Torrance N, Smith BH. Risk factors for neuropathic pain in diabetes mellitus. Pain. 2017;158(4):560-8. doi: 10.1097/j.pain.0000000000000785. PubMed PMID: 27941499; PubMed Central PMCID: PMCPMC5359789.

Jo

ur na

lP

re

-p

ro

of

102. Ellis RJ RD, Clifford D, McArthur J, Simpson D, Alexander T, Marra C, Morgello S, Gelman BB, Dworkin RH, Vaida F, Grant I. Risk factors for incident neuropathic pain in HIV infection: the CHARTER study. 2009. 103. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006;7(4):281-9. Epub 2006/04/19. doi: 10.1016/j.jpain.2005.11.008. PubMed PMID: 16618472. 104. Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136(3):380-7. Epub 2007/09/25. doi: 10.1016/j.pain.2007.08.013. PubMed PMID: 17888574. 105. Magrinelli F, Zanette G, Tamburin S. Neuropathic pain: diagnosis and treatment. Practical neurology. 2013;13(5):292-307. Epub 2013/04/18. doi: 10.1136/practneurol-2013-000536. PubMed PMID: 23592730. 106. Vadalouca A, Raptis E, Moka E, Zis P, Sykioti P, Siafaka I. Pharmacological treatment of neuropathic cancer pain: a comprehensive review of the current literature. Pain practice : the official journal of World Institute of Pain. 2012;12(3):219-51. Epub 2011/07/30. doi: 10.1111/j.1533-2500.2011.00485.x. PubMed PMID: 21797961. 107. Piano V, Verhagen S, Schalkwijk A, Hekster Y, Kress H, Lanteri-Minet M, et al. Treatment for Neuropathic Pain in Patients with Cancer: Comparative Analysis of Recommendations in National Clinical Practice Guidelines from European Countries. Pain practice : the official journal of World Institute of Pain. 2013. Epub 2013/01/31. doi: 10.1111/papr.12036. PubMed PMID: 23360414. 108. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-73. Epub 2015/01/13. doi: 10.1016/S1474-4422(14)70251-0. PubMed PMID: 25575710; PubMed Central PMCID: PMCPMC4493167. 109. Maher DP, Chen L, Mao J. Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization. Anesthesia and analgesia. 2017;124(2):661-74. Epub 2017/01/10. doi: 10.1213/ANE.0000000000001787. PubMed PMID: 28067704. 110. Aiyer R, Mehta N, Gungor S, Gulati A. A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice. Clin J Pain. 2018;34(5):450-67. Epub 2017/09/07. doi: 10.1097/AJP.0000000000000547. PubMed PMID: 28877137. 111. Lubega FA, DeSilva MS, Munube D, Nkwine R, Tumukunde J, Agaba PK, et al. Low dose ketamine versus morphine for acute severe vaso occlusive pain in children: a randomized controlled trial. Scand J Pain. 2018;18(1):19-27. Epub 2018/05/26. doi: 10.1515/sjpain-2017-0140. PubMed PMID: 29794277. 112. Palm N, Floroff C, Hassig TB, Boylan A, Kanter J. Low-Dose Ketamine Infusion for Adjunct Management during Vaso-occlusive Episodes in Adults with Sickle Cell Disease: A Case Series. J Pain Palliat Care Pharmacother. 2018:1-7. Epub 2018/05/24. doi: 10.1080/15360288.2018.1468383. PubMed PMID: 29791238. 113. Sheehy KA, Muller EA, Lippold C, Nouraie M, Finkel JC, Quezado ZM. Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study. BMC Pediatr. 2015;15:198. Epub 2015/12/02. doi: 10.1186/s12887-015-0515-4. PubMed PMID: 26620833; PubMed Central PMCID: PMCPMC4665913. 114. Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010;26(2):163-7. Epub 2010/01/22. doi: 10.1097/AJP.0b013e3181b511ab. PubMed PMID: 20090444. 115. Brandow AM, Farley RA, Dasgupta M, Hoffmann RG, Panepinto JA. The use of neuropathic pain drugs in children with sickle cell disease is associated with older age, female sex, and longer length of hospital stay. J Pediatr Hematol Oncol. 2015;37(1):10-5. Epub 2014/09/16. doi: 10.1097/MPH.0000000000000265. PubMed PMID: 25222053; PubMed Central PMCID: PMC4270887. 116. tDCS Associated With Peripheral Electrical Stimulation for Pain Control in Individuals With Sickle Cell Disease (tDCS/PES_SCD)” ClinicalTrials.gov; [cited 2018 September 19]. Available from: https://clinicaltrials.gov/ct2/show/NCT02813629?term=tDCS&cond=sickle&rank=1 . 117. Kumru H, Soler D, Vidal J, Navarro X, Tormos JM, Pascual-Leone A, et al. The effects of transcranial direct current stimulation with visual illusion in neuropathic pain due to spinal cord injury: an evoked potentials and quantitative thermal testing study. Eur J Pain. 2013;17(1):55-66. Epub 2012/05/23. doi: 10.1002/j.15322149.2012.00167.x. PubMed PMID: 22610590.

118. Vaporized Cannabis for Chronic Pain Associated With Sickle Cell Disease (Cannabis-SCD): ClinicalTrials.gov; [cited 2018 September 19]. Available from: https://clinicaltrials.gov/ct2/show/NCT01771731?term=pain&recrs=e&cond=sickle&rank=9 . 119. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3:CD012182. Epub 2018/03/08. doi: 10.1002/14651858.CD012182.pub2. PubMed PMID: 29513392. 120. HealthMeasures: Pain Domains http://www.healthmeasures.net/search-viewmeasures?task=Search.search2017. Available from: http://www.healthmeasures.net/search-viewmeasures?task=Search.search. 121. Zorina-Lichtenwalter K, Parisien M, Diatchenko L. Genetic studies of human neuropathic pain conditions: a review. Pain. 2018;159(3):583-94. Epub 2017/12/15. doi: 10.1097/j.pain.0000000000001099. PubMed PMID: 29240606; PubMed Central PMCID: PMCPMC5828382. Table 1. Overview of pain terminology

(Tsao et al., 2013)vvv

re

-p

Conditioned pain modulation

Reference (Merskey and N. Bogduk, 1994) (Spiegel et al., 2017)

of

Central sensitization

Definition Pain due to a stimulus that does not normally provoke pain. Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input Assessment of the extent to which a noxious stimulus applied to one body site reduces the painfulness of a second stimulus applied to a remote body site. This laboratory method can be used to assess pain inhibitory function Increased pain from a stimulus that normally provokes pain Diminished pain in response to a normally painful stimulus A disturbance of function or pathological change in one or more nerves Pain caused by a lesion or disease of the somatosensory nervous system, including peripheral fibers (Aβ, Aδ and C fibers) and central neurons Pain that results from activity in neural pathways secondary to tissue damage or stimuli that have the potential to damage tissue A set of exaggerated and negative cognitive and emotional responses associated with actual or anticipated painful stimulation Decreased threshold and increased responsiveness of nociceptors to noxious stimuli due to post-translational changes in and altered trafficking of transducer receptors and ion channels A psychophysical evaluation of the somatosensory system through measurement of sensory loss (hyposensitivity) or gain (hypersensitivity) to cold, heat or mechanical stimuli that

ro

Term Allodynia

Hyperalgesia

lP

Hypoalgesia Neuropathy

Nociceptive pain

ur na

Neuropathic pain

Jo

Pain catastrophizing

Peripheral sensitization

Quantitative sensory testing (QST)

(Yi & Pryzbylkowski, 2015) (Merskey and N. Bogduk, 1994) (Merskey and N. Bogduk, 1994) (Colloca et al., 2017; Merskey and N. Bogduk, 1994)

(Nicholson, 2006)

(Quartana, Campbell, & Edwards, 2009)

(Spiegel et al., 2017)

(Arendt-Nielsen et al., 2007; Backonja et al., 2009; Brandow & Panepinto, 2016)

Somatosensory nervous system

Temporal summation

correlate with pain sensing somatic small nerve fibers Elements of the central and peripheral nervous system relating to touch, vibration, temperature, pain and kinesthesia. An increase in pain rating after repetitive stimulation at a constant intensity.

(Arezzo, Schaumburg, & Spencer, 1982) (Cathcart, Winefield, Rolan, & Lushington, 2009; Ge, Madeleine, & Arendt-Nielsen, 2005; Staud et al., 2003)

Table 2: Summary of validated questionnaires that are used to screen for neuropathic pain

ID Pain

PAINReportIt

Reference

of

(M. Bennett, 2001; Ezenwa et al., 2016)

ro

Jo

painDETECT

Screening tool for neuropathic pain that has been validated in 2 chronic pain populations

(Bouhassira et al., 2005)

Not yet validated in sickle cell disease

(Haussleiter et al., 2008)

Validated in 411 patients from 10 pain treatment centers

Brandow et al. administered painDETECT questionnaire to 56 patients with SCD 14 or more years of age. 37% had scores indicative of neuropathic pain

(Brandow et al., 2014; Freynhagen et al., 2006)

Validated questionnaire for neuropathic pain in 308 individuals

Not yet validated in individuals with sickle cell disease

(Portenoy, 2006)

Validated questionnaire for neuropathic pain in African-American adults with sickle cell disease, people with

Wilkie et al., administered the PAINReportIt to 145 adults with sickle cell disease to assess sensory

(Keesha Roach; Wilkie et al., 2003; Wilson & Keye, 1989)

Validated screening tool for neuropathic pain

-p

Neuropathic Pain Questionnaire (NPQ)

Incorporates analysis of sensory descriptions with examination findings of sensory dysfunction Incorporates sensory pain descriptors with sensory exam findings Questionnaire designed to differentiate neuropathic and non-neuropathic pain based on 12 descriptors of neuropathic pain Developed to detect neuropathic pain in individuals with low back pain; comprised of 7 questions assessing quality of neuropathic pain symptoms and completed by patient 6-item questionnaire used to distinguish neuropathic pain from nociceptive pain using verbal descriptors Computerized selfreported pain assessment tool based on the 1970 version of the McGill Pain Questionnaire,

Applicability to SCD Enezwa et al. administered LANSS to 25 adults with SCD. 40% met criteria for neuropathic pain Not yet validated in sickle cell disease

Validated screening tool for neuropathic pain

re

Douleur neuropathique 4 questions (DN4)

Validation

lP

Leeds assessment of neuropathic symptoms and signs (LANSS)

Description

ur na

Questionnaire

in which patients are prompted to choose words that best described their pain from a list of 78 verbal pain descriptors

1. No overall differences in pain ratings or temporal summation were found between SCD and control groups. 2. Experimental pain ratings in the SCD group tended to increase with age. 3. Individuals reporting a history of very painful episodes demonstrated rapid temporal summation of pain unpleasantness. 4. Individuals in the SCD group were significantly impaired at discriminating intensities of noxious stimulation, and were more hypervigilant than controls. 5. Catastrophizing was elevated only during acute pain episodes in the SCD group. 1. Children and adolescents with SCD exhibited significantly lower median cold and heat detection and pain thresholds compared to controls, suggestive of peripheral or central sensitization. 2. No differences in mechanical threshold were detected between the SCD and control groups. 3. Older age was associated with lower cold, heat, and mechanical pain

(Hollins et al., 2012)

of

Reference

ro

22 adults with SCD and 52 race-matched controls

Key findings

-p

Subjects

pain characteristics

55 children and adolescents with SCD and 57 controls (≥7 years)

Jo

Single center crosssectional study

ur na

lP

re

Study Design Single center crosssectional study

cancer pain and the general public

(Brandow et al., 2013)

of ro

48 children with SCD (ages 10-17 years)

-p

Single center crosssectional study

(O'Leary et al., 2014)

(Jacob et al., 2015)

re

27 children with SCD (ages10-18 years) and 28 race-matched controls

Jo

ur na

lP

Single center crosssectional study

thresholds in both groups. 4. No association with pain, gender, or hemolysis was found. 1. Children with SCD were less sensitive to heat and cold stimuli at the thenar eminence compared to controls. 2. Children with SCD had increased sensitivity to cold pain at the forearm, but not at the thenar eminence. 3. No differences in heat pain thresholds were detected between SCD and control groups. 4. No difference for perceptual sensitization at the thenar eminence was detected between SCD and control groups. 1. 13 children (27%) showed decreased sensitivity to heat or cold sensations (hypoesthesia), and also experienced pain in response to nonpainful stimuli (allodynia). 2. Pain ratings associated with cold and heat stimuli were significantly higher in children with abnormal QST compared to those with normal QST. 3. Pediatric quality of life measures were not different between children with normal and abnormal QST. 1. 81.8% (n=45) of individuals with SCD were found to have impaired pain sensitivity to at least one sensory threshold tested (cold, heat and mechanical pain). 2. 22% of individuals

Singlecenter crosssectional study

55 children (≥ 7 years of age) and adults with SCD and 57 race-matched controls

(Brandow & Panepinto, 2016)

lP

ur na

Jo

of

38 adults with SCD divided into high and low central sensitization groups

ro

Single center prospective cohort study

(C. M. Campbell, Carroll, et al., 2016)

-p

83 adults (≥ 18 years of age) with SCD and 27 age, race and gendermatched controls

re

Single center crosssectional study

with SCD had impaired pain sensitivity to all 3 thresholds. 3. Impaired cold sensitivity was the most common finding (63.6% of individuals with SCD). 4. When characteristics were compared between those with ≥ 1 impairments in pain sensitivity to those without any impairment in pain sensitivity, there was no difference in median age, gender or median number of pain encounters. 1. Heat pain tolerance and pressure pain thresholds were lower among adults with SCD compared to controls. 2. Thermal temporal summation at a fixed temperature of 45°C was higher in the SCD group. 3. Conditioned pain modulation and pain ratings to hot water hand immersion were higher in the control group. 4. Both groups showed changes in inflammatory biomarker levels in response to quantitative sensory testing 1. The higher central sensitization group (determined by thermal and mechanical temporal summation and aftersensations) tended to include older individuals with higher BMI, who were more likely to be taking opioids. 2. The higher central sensitization group reported more severe pain, more calls to

(C. M. Campbell, MoscouJackson, et al., 2016)

lP

ur na Jo

of

ro

-p

83 adults with SCD (≥ 18 years of age), among which 29 were on chronic opioid therapy

re

Single center prospective cohort study

providers, more sleep disturbances and a greater number of medical visits. 3. Situational catastrophizing in response to pain testing was enhanced among the high central sensitization group. 4. Significant differences between the low and high central sensitization groups were observed in several QST measures, including pressure pain threshold and hot temperature. 1. Participants on (Carroll et al., chronic opioid therapy 2016) had greater scores on the central sensitization index, which were also observed in the multivariate analysis controlling for depressive symptoms. The central sensitization index was created by averaging Zscores for thermal and mechanical temporal summation, and after sensations to temporal summation and hot water. 2. No differences between adults with SCD taking and not taking chronic opioid therapy were observed on the QST index, which was created by averaging Z-scores for heat pain threshold and tolerance, pressure pain thresholds, conditioned pain modulation, hand withdrawal time and intensity, and water temperature.

(Bakshi, Lukombo, Shnol, Belfer, & Krishnamurti, 2017)

lP

ur na Jo

Single center prospective cohort study

30 adults with SCD and 30 controls

of

29 children (ages 8-21 years) with SCD with 26 race-matched controls

(Ezenwa et al., 2016)

ro

Single center crosssectional study

1. QST is safe and feasible in adults with SCD (does not stimulate an acute pain episode). 2. 24 out of 25 individuals had evidence of central sensitization, peripheral sensitization, or both. 3. 72% of participants had abnormal cold pain sensitivity, 76% had abnormal heat pain sensitivity, and 44% had abnormal mechanical pain sensitivity. 1. Age was significantly associated with pressure and heat pain tolerance in SCD and control groups. 2. Male sex was associated with higher heat detection threshold. 3. No difference in median QST values was detected between SCD and control groups. 4. Higher PROMIS depression scores were associated with increased sensitivity to heat and cold pain in SCD but not in controls. 5. Anxiety was associated with increased sensitivity to cold pain in SCD but not in controls. 1. Static thermal testing using cold stimuli showed lower pain thresholds and tolerance in the SCD group, but not for heat stimuli. 2. Individuals with SCD reported higher pain ratings with random heat pulses and pressure pain stimuli. 3. Temporal summation

-p

25 adults (≥ 18 years of age) with SCD

re

Singlecenter crosssectional study

(Darbari et al., 2017)

of

10 children or adolescents with SCD (≥ 8 years of age)

ro

Single center crosssectional study

-p

57 children and adolescents with SCD and 60 racematched controls (8-20 years of age)

(Bakshi, Lukombo, et al., 2018)

ur na

Jo Single center prospective cohort study

lP

re

Single center cohort study

pain score changes using 2 pinprick probes were significantly greater in the SCD group. 4. Delayed recovery was associated with lower fetal hemoglobin levels. 1. No significant differences in mean thermal or pain pressure thresholds between SCD and control groups were detected at baseline or at 3 months. 2. No association between mean thermal thresholds and chronic transfusion therapy was identified. 3. Significant reductions in all thermal sensitivity and pain threshold measurements were detected following initiation of hydroxyurea in 6 individuals with SCD. 1. No statistically significant differences were found in Gracely Box scores after QST was performed within a week of an acute pain episode requiring an emergency room visit or hospitalization, when compared to QST performed in the steady-state. Gracely Box scores measure pain intensity and unpleasantness using a 21-box vertical scale, with numerical values on a scale of 0-20 for verbal descriptors of pain intensity and unpleasantness. 1. Individuals with SCD have increased cold and mechanical hypersensitivity during acute pain episodes as

24 children (≥ 7 years of age) with SCD assessed at both baseline

(Brandow et al., 2018)

compared to their baseline health. 2. No changes in heat pain hypersensitivity were detected during acute pain episodes. 3. Differences between baseline health and acute pain episodes persisted after adjusting for age, gender, opioid use, hydroxyurea use and clinical pain scores.

Abbreviations: SCD = sickle cell disease; QST = quantitative sensory testing

ro

Table 3. Studies of quantitative sensory testing in individuals with SCD

of

and during hospitalization for pain

Jo

ur na

lP

re

-p

Table 4. A summary of studies that have correlated neuroimaging and pain outcomes in children and adults with sickle cell disease

Subjects

Key findings

Reference

15 individuals with SCD and 15 controls

(Case et al., 2017)

Singlecenter crosssectional study

13 adults with SCD and 14 age-matched controls

Singlecenter crosssectional study

25 adolescents and young adults with SCD (ages 1222 years) were stratified into high and low pain rate groups

1. Functional MRI and EEG showed increased activity in pain processing regions in the SCD group relative to controls. 2. In the SCD group, the cerebellum showed stronger connectivity to the periaqueductal gray matter, which is involved in pain inhibition, as well as negative connections to pain processing areas 1. Adults with SCD had decreased functional connectivity strength when compared to controls among networks involved in salience, emotion, learning, and memory. 2. When these internetwork functional connectivity strength differences were examined within adults with SCD, significant associations were found with age, SCD genotype and number of pain days. 1. Individuals in the high pain group displayed an excess of pronociceptive connectivity 2. Individuals who were stratified to the low pain group showed more connectivity to antinociceptive structures 3. Fetal hemoglobin levels were significantly higher in the low pain group and were associated with greater connectivity to antinociceptive structures

-p

ro

of

Study Design Singlecenter crosssectional study

Jo

ur na

lP

re

(Arun Singavi, Blood 2016 128:3656;)

(Darbari et al., 2015)

Abbreviations: SCD = sickle cell disease; MRI = magnetic resonance imaging; EEG = electroencephalogram

Table 5: Summary of interventional trials for the treatment of neuropathic pain in SCD

Double-blind RCT of pregabalin (n=11) versus placebo (n=11)

1. Multidimensional Experience of Pain: Average Pain Index (API), Composite Pain Index (CPI)

Jo

2. Presence of Neuropathic Pain: Neuropathic Pain Symptom Index (NPSI), Leeds Assessment of Neuropathic Signs and Symptoms (SLANSS)

-Phase II -Single-arm Lidocaine patch study

3. Quality of Life: Short Form 36 Health Survey (SF-36) 1. Proportion of patients with a visual analog score (VAS)

 

of



Drug has good safety profile Evidence of reduction of pain intensity Preliminary evidence to support larger Phase I/II trial for patients with SCD and evidence of neuropathic pain

(Molokie et al., 2014)

Drug has good safety profile with minimal adverse effects observed Trend of pain reduction over time within pregabalin group Additional studies needed to determine efficacy of pregabalin for treatment of neuropathic pain in patients with SCD

(Schlaeger et al., 2017)

Drug provided clinically significant pain reduction scores and had a

(Rousseau et al., 2018)

ro

1. Safety: 10mg found to be minimum toxic dose (sedation, dystonia) Sedation: most common severe adverse effect, other effects were mild

Reference

-p

2. Pain intensity: visual analog scale (VAS)

Conclusions

2. Pain: 44% (n=8) of subjects had ≥50% pain reduction from baseline without other analgesics other than study drug *No statistically significant differences between groups 1. Placebo group reported more intense pain as measured by both API and CPI scores at baseline and monthly visits. 2. Placebo group reported higher NPSI scores and a higher percentage of S-LANSS scores ≥ 12 across monthly visits. These scores can be indicative of neuropathic pain. 3. Placebo and pregabalin groups had varied results per SF-36 domain.

re

-Repeated measures dose escalation

1. Safety: extrapyramidal symptom rating scale, adverse effects checklist

Results

lP

-Phase I -Open-label study of Trifluoperazine at 6 doses (n=18)

Primary Outcomes

ur na

Study Design

1. Pain: 12-hour VAS ≥ 2-point decrease over 2 consecutive days reached in 48.6% of









(n=39)

decrease of ≥ 2 points between t0 and t12, and the proportion with a VAS decrease of ≥ 2 points between t0 and t6 over at least 2 consecutive days out of 3 days of treatment 2. Tolerance

patients, 6-hour VAS ≥ 2-point decrease in 46.9% of patients, unable to conclude  efficacy due to results being below prespecified rate of 60%

good tolerance in more than half of the patients Additional studies needed to assess efficacy of lidocaine 5% patches in pediatric population

2. Tolerance: Welltolerated, 3 patients experienced sideeffects of low to moderate intensity

Jo

ur na

lP

re

-p

ro

of

Abbreviations: SCD = sickle cell disease; SD = standard deviation; RCT = randomized controlled trial; API = average pain intensity; CPI = composite pain index; NPSI = Neuropathic Pain Symptom Inventory; S-LANSS = Leeds Assessment of Neuropathic Signs and Symptoms; SF-36 = Short Form 36 Health Survey; VAS = visual analog pain scale