caregiver

Sickle cell disease (SCD) can cause episodes of severe pain that lead to patient hospitalization. These episodes are usually referred to in the hematology community as “acute vaso-occlusive pain episodes” which are classically nociceptive in nature, although no subgroups of pain have been officially described yet.

Nonetheless, the recognition of chronic pain and neuropathic pain (NP) in SCD patients has been changing the way healthcare providers (HCPs) address difficult-to-treat pain episodes. As discussed by Alexander Glaros, MD, and Amanda M. Brandow, DO, in the journal Hematology, American Society of Hematology (ASH) Education Program, the taxonomy of pain in SCD was modified in the last decade to better reflect its complexity.

“The current model includes the chronic pain that most patients with SCD are now known to experience, with potential contributions from multiple etiologies to varying degrees.” Among the no identifiable causes are NP, chronic inflammatory pain, and chronic nociceptive.

A Common Occurrence

NP is an understudied, less recognized, and clinically undertreated subcategory of pain in SCD. However, it is estimated to occur in more than a quarter (25%-40%) of adults with SCD, based on studies using patient-reported outcome (PRO) questionnaires.

Moreover, a recent study published in the journal Children showed that NP is common in children with SCD during painful vaso-occlusive crises (VOCs). The study enrolled 54 children with SCD aged 6 to 18 years who were hospitalized due to an acute painful VOC. Of those, 22 experienced NP, particularly at an early stage of the episode (day 2). “This neuropathic component would have gone completely unrecognized and, therefore, underestimated and undertreated if it had not been researched with adapted tools,” the authors acknowledged.

NP represents a unique phenotype of pain in SCD caused by a lesion or disease of the somatosensory nervous system. However, the identification of such a lesion in SCD is not always obvious, which delays the recognition of SCD as an etiologic factor for NP. “The lack of discrete nerve injury or lesion (eg, compression, degeneration, infarction) in the case of SCD does not necessarily preclude a diagnosis of NP, however, as much as it suggests a broader interpretation of which neurologic changes represent a ‘lesion or disease’,” Glaros and Brandow explained.

One possible explanation for NP in SCD is the potentially harmful effects of chronic inflammatory and oxidative stress on peripheral nerves that are exacerbated during VOCs. As a result, recurrent stimulation of nociceptive neurons increases the sensitivity and density of various membrane channels that initiate signaling cascades. However, these molecular mechanisms are far from being completely understood.

Since NP is often overlooked in SCD patients, no modifiable risk factors are currently identified. However, some studies suggest that age, female gender, and hydroxyurea use are positively associated with NP in SCD.

Assessing NP in SCD

Several methodologies to aid the diagnosis of NP in SCD have been evaluated in small- to medium-sized cross-sectional studies. These include validated questionnaires incorporating pain descriptors, quantitative sensory testing (QST), and functional magnetic resonance imaging (fMRI). However, none has been clinically adopted as gold-standard practice.

Hence, the identification of NP in SCD patients relies on active investigation. A patient’s history and physical examination might provide the first diagnostic clues, but even those can be difficult to mine. “Because of this gradual transition in phenotype from nociceptive to neuropathic/mixed-type pain, [SCD] patients may have a harder time recognizing and describing unique NP symptoms,” Glaros and Brandow said. Therefore, HCPs should be attentive to descriptions such as burning, electric shocks, pins and needles, pricking, shooting, radiating, allodynia, and pain exacerbated by temperature changes. These should trigger an investigation for NP in SCD patients.

In an attempt to improve SCD pain assessment, the US National Institutes of Health has funded the development of three PROs: the Patient-Reported Outcome Measurement Information System (the only specifically geared for NP), the Adult Sickle Cell Quality of Life Measurement Information System, and the Pediatric Quality of Life Inventory Sickle Cell Disease Module. These tools evaluate and track changes in pain, function, and quality of life of patients. However, their application in evaluating NP in SCD patients is still limited and requires further validation. The same applies to other PROs that have been explored in the context of NP in SCD.

“Given all of these unknowns, a specific recommendation regarding a universally “best” tool for assessing SCD-related NP cannot be made,” Glaros and Brandow said. “For clinicians choosing from among those PROs previously studied in SCD, however, consideration should be given to the intent of the assessment, cost, test length, comprehensive vs “quick” screen, sensitivity/specificity, and the age of study participants.”

Recent investigation suggests that QST and neuroimaging could also be useful in assessing NP in SCD patients. In particular, the use of a multilevel approach, combining QST with both PROs and neuroimaging, seems to add value, but additional studies are required. In the case of neuroimaging, for instance, the current lack of knowledge of specific neural networks underlying NP and, consequently, the absence of a pathognomonic imaging pattern to guide its identification are major challenges.

“The abnormalities typical of chronic pain have been identified in patients with SCD, but although these studies support the existence of altered central pain-processing mechanisms, similarly to QST, they cannot currently replace patient reports of NP symptoms in the diagnostic process,” Glaros and Brandow advised.

Treating NP in SCD

A few NP-specific pain medications are undergoing early phase trials to assess their safety and efficacy in patients with SCD. However, according to an article by Sharma and Brandow, “Evidence-based strategies to target NP in SCD are lacking, and the existing literature suggests that NP-specific medications are highly underutilized in individuals with SCD.”

The pain-management regimen used in SCD patients experiencing NP and nociceptive chronic pain includes opioids. However, the general recommendation is downgrading them to second- or third-line treatment of NP due to the likelihood of being ineffective, together with the risks of tolerance and significant side effects.

Additional medications include gabapentinoids, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, topical patches, tramadol, ketamine, and trifluoperazine, as advised by Glaros and Brandow. Nonetheless, pharmacological treatment decisions should always consider side effect profiles in relation to SCD-related comorbidities. Moreover, patients suffering from chronic pain and NP should be referred to psychology/psychiatry consultation.

Reference

Glaros A, Brandow AM. Neuropathic pain in sickle cell disease: measurement and management. Hematol Am Soc Hematol Educ Progr. 2020(1):553-561. doi:10.1182/hematology.2020000142

Sharma D, Brandow AM. Neuropathic pain in individuals with sickle cell disease. Neurosci Lett. 2020;714:134445. doi:10.1016/j.neulet.2019.134445

Sigalla J, Duparc Alegria N, Le Roux E, et al. Neuropathic pain in children with sickle cell disease: the hidden side of the vaso-occlusive crisis. Children. 2021;8(2). doi:10.3390/children8020084