Prevalence of Neuropathic Pain and Associated Factors in Nigerian Sickle Cell Disease Patients – A Cross Sectional Study

doi:10.21203/rs.3.rs-8223904/v1

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Prevalence of Neuropathic Pain and Associated Factors in Nigerian Sickle Cell Disease Patients – A Cross Sectional Study

https://doi.org/10.21203/rs.3.rs-8223904/v1

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Background

Sickle cell disease (SCD) is the most common hemoglobinopathy. Nigeria has the highest burden of disease worldwide. Despite the great burden, very little is known about neuropathic pain (NP) in SCD patients in Nigeria. The prevalence of NP in SCD patients in Nigeria is unknown.

Method

This cross-sectional study was conducted at two tertiary facilities in Nigeria: University of Ilorin Teaching Hospital (UITH), Ilorin and Ladoke Akintola University of technology (LAUTECH) Teaching Hospital, Ogbomoso. A total of 145 patients (85 from UITH, 60 from LAUTECH) were enrolled in the study. The painDETECT questionnaire was used to determine the presence of neuropathic pain in patients with SCD. Scores ≥ 13 were taken as evidence of NP.

Results

The mean age was 29.14 ± 12.53. The study showed that 29.7% of the patients have evidence of neuropathic pain. Age was significantly associated with NP among the patients. Performance Status (ECOG) was a predictor of NP.

Conclusion

Neuropathic pain is present among Nigerian SCD patients. Age and a number of factors were associated with NP in Nigerian SCD patients. The use of screening tools can help identify those that are at risk of NP and have them placed on neuropathic pain therapies.

Anesthesiology & Pain Medicine

sickle cell disease

neuropathic pain

painDETECT

chronic pain

Sickle cell disease (SCD) is a genetic disorder of haemoglobin that results from mutation in the beta globin chain of haemoglobin and is characterized by various complications including haemolytic anaemia and vaso-occlusive pain crisis. The prevalence of SCD varies worldwide. In Nigeria, it is reported to vary between 1% and 3% with an estimated annual birth of 150,000 affected children and a carrier frequency that affects 20–25% of its population of over 200 million people, making it a critical public health issue [1]. The pathophysiology of SCD involves the point mutation and the substitution of the amino acid glutamic acid for valine at the sixth position of the beta-globin chain. This mutation during the de-oxygenated state of the red cell causes it to lose its normal biconcave shape and become ‘sickled’ leading to a number of complications which include different forms of pain.

Pain, most especially recurrent painful episodes otherwise known as pain crises is the leading cause of morbidity in SCD; the most dominant and debilitating feature of SCD, representing the primary reason for emergency department visits, hospital admissions, and impaired quality of life [2]. These painful events are multifaceted and historically can be classified as either acute recurrent painful crisis or chronic pain syndromes. Acute painful crisis is the distinguishing characteristic of the disease which causes most presentation at the emergency room. Akinola et al described 2 phases of painful crisis, later on Ballas refined it into four phases which are: the prodromal, initial, established and resolving phases [3, 4]. These painful episodes are accompanied by inflammation and can be fraught with complications such as multi-organ tissue damage and sometimes death. Chronic pain on the other hand – consistent pain for 3 or more months, behaves differently from acute pain. It can be with or without an identifiable cause or without obvious pathology. These pains, especially the acute pains are largely nociceptive in nature and are most often driven by ischaemia, chronic inflammation and tissue damage. These pains normally arise from the afferent nerves when there is a stimulus from the aforementioned causes. This pain response is a normal physiologic mechanism. However, pain can also arise from responses generated within nerves despite a lack of stimulation from the peripheral nerves. This type of pain also seen in SCD is known as neuropathic pain (NP). Unlike nociceptive pain in which tissue damage and other inflammatory factors are responsible for the pain, neuropathic pain happens as a result of damage to the somatosensory system [5]. NP can occur without a deleterious stimulus. It can also occur spontaneously or when evoked by a stimulus.

NP have been characterized using various descriptors such as aching, heat, stabbing etc. and their precipitating factors can with time induce sensory alterations. Thus, neuropathic pain is a clinical description and not a diagnosis [6]. The neurobiological mechanism of NP is not well understood; however, its complex pathophysiology is seen to involve some changes in peripheral nociceptive fibers, increased neuronal hyperexcitability, ectopic activity, altered signal transmission, central sensitization, and imbalances between excitatory and inhibitory signals [5, 7]. In terms of overall prevalence, between 7–10% of the general population experience neuropathic pain [6, 8]. Epidemiological studies has also shown that the prevalence of neuropathic pain to between 3–17% in the chronic pain population, and in some cases much more [9–11].

Neuropathy has been insinuated to occur in SCD patients. However, neuropathic pain is less often reported [12]. Kehinde et al reported a significantly higher percentage of neurological complications in SCD patients than controls, but neuropathic pain was not mentioned [13]. Lagunju and Brown also reported neurological complications in SCD patients; likewise neuropathic pain was not mentioned [14]. In their separate reviews, Noubiap et al and Farooq noted that neurological complications like silent brain infarcts, peripheral neuropathies, or moyamoya disease, have been rarely or not studied at all in the African setting [15, 16]. Although it has been somehow challenging proving NP in SCD patients. In non-SCD patient populations, NP screening tools have been used to great effect in identifying patients with neuropathic pain or at risk. The screening tools have been used to determine the prevalence of NP in different population settings, and this can apply to SCD patients too. Few studies have been done on the evaluation of NP in SCD patients. Ramsay et al reported an NP prevalence of 17.9% in an SCD population in Jamaica; Cregan et al had a prevalence of 19.3% in adolescent SCD patients [17–18]. In previous studies, the prevalence of NP has been estimated at 25–40% [19]. All the aforementioned studies used the painDETECT questionnaire, a validated questionnaire to differentiate neuropathic pain from non-neuropathic pain [20].

From these studies, it can be inferred that some form of neuropathic pain components can be found in SCD patients. Nigeria is the most populous black nation in the world with an estimated population of over 200 million people. It also has the highest burden of SCD in the world [1]. However, a review of the literature showed that no study has been done on neuropathic pain in SCD patients in Nigeria despite the high burden. This research gap is particularly concerning given that unmanaged NP is notoriously refractory to conventional opioid therapy and is strongly associated with worse quality of life, greater psychological distress, and higher healthcare utilization. The number of SCD patients with neuropathic pain in Nigeria is therefore not known. Therefore, this study was designed to address this significant knowledge gap. The primary objective was to determine the prevalence of neuropathic pain among adult Nigerian SCD patients using a validated screening tool. The secondary objectives were to evaluate the relationship between NP and specific clinico-demographic variables and to identify independent predictors of NP in this population. Based on previous published studies in SCD patients from other countries, we propose that the prevalence of NP in Nigerian SCD patients should be between 20–40%. Also, we propose that age would be positively associated with NP.

This cross-sectional study was conducted between January 2023 and December 2023 in two separate cities, Ilorin and Ogbomoso. All patients were recruited from the haematology outpatient clinics of the University of Ilorin Teaching Hospital (UITH) and the Ladoke Akintola University of Technology (LAUTECH) Teaching Hospital and some from the surgical clinics. The study population comprised consecutively recruited adult SCD patients (aged 17 years and above) attending routine follow-up appointments. To be eligible, patients had to be in a "steady state," defined as the absence of an acute painful crisis, blood transfusion, or hospitalization for any SCD-related complication for at least four weeks prior to recruitment. This criterion was essential to ensure that reported pain symptoms reflected a chronic or baseline state rather than an acute illness. All the SCD patients confirmed by hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) were eligible for this study. Causes of pain like VOC, arthritis, bony infarcts, diabetic neuropathy, vitamin deficiency were excluded through a clinical history and examination. Documented history of traumatic nerve injury, spinal cord compression, or radiculopathy from causes unrelated to SCD, inability to comprehend the questionnaire or provide informed consent due to cognitive impairment or severe psychiatric illness, patients who had undergone surgical procedures within the last three months

This study was approved by the Ethics Review Committee of both institutions (LTH/OGB/EC/2021/259; UITH/CAT/189/21/1119). The study's purpose, procedures, risks, and benefits were thoroughly explained to each potential participant in their preferred language. Written informed consent was obtained from all enrolled individuals. Anonymity and confidentiality were maintained throughout the research process by using unique identification numbers instead of personal identifiers.

The tool used in this study for NP detection was the painDETECT questionnaire. The painDETECT questionnaire is a NP screening tool that has been validated to detect NP in patients as young as 14 years. The sensitivity, specificity, and positive predictive value are 85%, 80% and 83% respectively. The one-page questionnaire comprises of 12 questions, 7 of which are specifically about NP symptoms put on a scale of 0 (never) to 5 (very strongly). In addition, the questionnaire grade pain based on intensity (0–10) in three settings: the present pain, worst pain experienced over the past 4 week and the average over the past four weeks. The remaining two are pictorial description of the pain course and location/ site of pain along with a question on the presence/ absence of radiating pain. The final total score range between 0–38. A score between 19–38 indicates a definite NP, while a score of between 0–12 show a lack of NP; however, a score between 13–18 suggests a probable NP. In this study, those that had a score ≥ 13 was taken as evidence of neuropathic pain just like studies done in previously published literature17.

Clinical data were obtained from patients’ case files, and from interview. These data included demographics (age and sex), SCD phenotype, number of blood transfusions, body composition (weight and height), lifestyle (drinking and smoking history), hydroxyurea therapy etc.

Descriptive statistics were done. The Chi-square or Fisher’s exact test was used to compare the groups with NP (total score ≥ 13) and without NP (total score ≤ 12) as a function of the different variables with values of p < 0.05 being considered significant. Spearman’s correlation coefficient was used to compare the neuropathic pain evaluation score with the variables. The rho-values were obtained to observe the strength and direction of the correlation. Parameters that were significantly associated with neuropathic pain were analyzed by binary logistic regression. We calculated the odds ratio (OR) with the respective 95% confidence intervals. The criterion for inclusion of a variable in the multivariate model was a P-value < 0.05 in the univariate analysis. Statistical analysis was performed using SPSS version 23.0.

A total of 145 patients were included in this research. There were 85 patients from the UITH and 60 patients from the LAUTECH Teaching Hospital. All 145 patients consented to participate and answered all the questions appropriately. The mean (± SD) age among the SCD patients was 29.14 ± 12.53. There were more females than males (65.5 vs 34.5%); most of the patients had a tertiary education (69.7%). The remainder of the baseline characteristics and clinical events are shown in Table 1. The analysis of pain intensity revealed the mean (± SD) score for pain at presentation was 1.7 ± 1.5 (11.7% had moderate/severe pain); the mean score of the average pain over the past 4 weeks was 3.4 ± 1.7(57.2% had moderate/severe pain) and the mean score of the strongest pain experienced during the past 4 weeks was 5.3 ± 2.4(73.8% had moderate/severe pain). In the pictorial depiction of pain, more than a quarter of the patients (26.2%) chose a picture that represented chronic pain (Fig. 1). The majority of the SCD patients had pain in more than one area of the body; the highest, 46.2% complained of pain two areas of their body, while about 2.8% complain of pain in about 5 areas of their body. Approximately 40% of the SCD patients mentioned that their pain does radiate (41.4%). The mean score of the painDETECT score was 8.9 ± 5.0. The pain characteristics are shown in Table 2.

From the survey done, it was discovered that approximately 30% (29.7%) of the SCD patients had evidence of neuropathic pain; out of which 5 of them has definite neuropathic pain. A total of fifty-four of the SCD patient were on hydroxyurea (37.2%). The SCD patients at both centres showed evidence of neuropathic pain symptoms. More than 60% of the patients had some form of numbness (64.1%), the highest mentioned, while 12.4% of them had some form of mechanical allodynia, the lowest mentioned. A detailed breakdown of symptom prevalence is provided in Fig. 2. The number of blood units transfused, performance status (ECOG), level of education and alcohol use were all significantly associated with the presence of neuropathic pain (p < 0.05). This is represented in Table 3. Interestingly, age, level of education, Hb phenotype, smoking, alcohol use, diastolic blood pressure, pain radiating, pain at presentation, and average pain recorded in the past 4 weeks were also significantly associated with numbness (p < 0.05). Likewise, age, level of education, smoking, BMI, and systolic blood pressure were significantly associated with mechanical allodynia, the least mentioned neuropathic pain component.

The age (rho = 0.347, p < 0.001), the number of blood units transfused (rho = 0.213, p = 0.01), performance status (rho = 0.604, p < 0.001), systolic blood pressure (rho = 0.181, p = 0.029), level of pain at presentation (rho = 0.517, p < 0.001), and the average pain in the past 4 weeks (rho = 0.691, p < 0.001) were significantly positively correlated with the presence of neuropathic pain suggesting the higher the values of these variables, the more the neuropathic pain. Table 4.

In the multivariate analysis, factors were independently evaluated with the presence of neuropathic pain. Performance status (p < 0.001), level of pain at presentation (p < 0.001) and the average pain in the past 4 weeks (p < 0.001) were significant independent predictors of the presence of neuropathic pain in SCD patients. Table 5.

The findings in this study are the first to determine the prevalence and other associated factors of neuropathic pain in Nigeria sickle cell disease patients. This is also the first study to use a validated screening tool for neuropathic pain in SCD patients in Nigeria.

Previous studies from other climes have shown that neuropathic pain is present in SCD patients. Data from our study show that neuropathic pain exists in Nigerian SCD patients. In this present study, the PDQ questionnaire was used to evaluate for neuropathic pain in SCD and about 30% of the SCD population had evidence of neuropathic pain. This value falls within the range of the hypothetical figures we initially proposed, and it is surprisingly higher than values obtained from epidemiologic studies in chronic pain population [20–23]. However, it is similar to some chronic conditions and even lower in some others [24–28]; this however, unequivocally positions SCD as a high-risk condition for the development of neuropathic pain. The prevalence of NP in our study is equally slightly higher than the 17.9% reported by Ramsay et al. in Jamaica and the 19.3% found by Cregan et al. in adolescents, but comparable to the 25–40% estimates from studies focusing on SCD patients with chronic pain [17–19]. When viewed through an African perspective, this prevalence figure carries profound implications. For decades, the narrative of SCD pain in Africa has been dominated by the acute, nociceptive vaso-occlusive crisis. Our findings disrupt this monolithic view. The high prevalence suggests that a significant proportion of what is often dismissed as "background" or "unexplained" chronic pain in African SCD patients may, in fact, have a neuropathic basis. This aligns with the observations of Noubiap et al. and Farooq et al [15, 16]., who lamented the near-total absence of research on neurological complications like NP in African SCD populations. The high prevalence in our study could also be as a result of the cumulative effect of a lifetime of undertreated painful episodes in a resource-constrained setting, or a lack of access to disease-modifying therapies that might mitigate neuronal damage.

In one of their research works, Ballas and Darbari argued that though neuropathy was present in SCD, neuropathic pain was rarely reported [28]. Symptoms outside allodynia, hyperalgesia and sensitivity to cold and heat were mere neuropathy and not neuropathic pain [29]. However, our data showed that SCD patients do exhibit neuropathic pain symptoms including allodynia and hyperalgesia. Previous studies showed that SCD patients exhibit symptoms of neuropathic pain which may alter pain and sensory processing with evidence of central and peripheral sensitization [30–34]. Experiments performed in SCD mice also support the findings of altered pain and sensory processing [35–37]. A recent study reported that the brain network in SCD underlies the hypersensitivity in them during pain crisis [38]. In another review, Ballas and Darbari acknowledged the existence of neuropathic pain in SCD [39].

Our findings show that age is significantly associated with neuropathic pain. This is consistent with previously published works [19, 40]. In the general population, neuropathic pain is known to increase with age [41, 42]. This may be a result of increased co-morbidities encountered in the aged. However, gender was not associated with neuropathic pain in our study. Though a slightly higher number of females had neuropathic pain compared to males, it was not significant. This may appear to be different from what is reported in literature [43], or perhaps those females have more health-seeking attitudes. Blood transfusion is one of the common treatments administered to SCD patients, especially in the prevention of neurological deficits like stroke.

Blood transfusion is also known to be used for the prevention of frequent painful crises [44]. However, its role in chronic pain is less well-known. In our study, there was a significant association between the units of blood transfused and neuropathic pain. Our findings show that approximately 80% of the SCD patients have had at least one unit of blood transfusion. A study by Curtis et al reported an increased neuropathic and nociceptive pain quality among SCD patients on chronic transfusion indicating worse pain [45]. Similarly, there was also a significant positive correlation between the units of blood transfused and neuropathic pain. Thus, it may mean that chronic blood transfusion may also play a role in neuropathic pain in SCD patients. The univariate association between a higher number of blood transfusions and NP is a critical finding that warrants further research. Chronic transfusion therapy is a standard intervention for primary and secondary stroke prevention and, in some cases, for intractable pain. However, in our cohort, a high transfusion burden may likely mean proxy marker for a more severe disease phenotype, which translate to more frequent and severe vaso-occlusive insults, leading to cumulative ischaemic damage to peripheral nerves and the central nervous system, thereby predisposing them to NP.

On hydroxyurea use, our data did not show any significant association between its use and neuropathic pain. Hydroxyurea is known to reduce painful episodes in SCD [46]. Previous studies have been reported to be positively associated with neuropathic pain in SCD [19]. The reason for this may not be fully known, but in our case, many of the patients were not on hydroxyurea, only about 37% were on hydroxyurea. Thus, analyzing its relationship with neuropathic pain is somewhat tricky. A review of the literature does not reveal any data supporting the use of hydroxyurea as a treatment for neuropathic pain. While pain in SCD is rather complex, the use of pain relievers is rather inadequate. The majority of the patients have not used morphine before to manage their pain. Also, while pregabalin and gabapentin are the mainstay of treatment for neuropathic pain, approximately 2% of SCD patients are on the drugs in this study. This low use of neuropathic pain drugs was also reported by Brandow et al [19]. The use of neuropathic pain drugs has been reported to be beneficial in SCD [47–49]. The American Society of Hematology 2020 guidelines for sickle cell disease recommend the use of gabapentinoids, SSRIs, and TCAs for the management of neuropathic pain (SCD-related chronic pain with no identifiable cause beyond SCD) albeit for adults only [50]. The almost non-existent use of gabapentinoids in our study is a major therapeutic gap that may reflect systemic barriers including cost, concerns about monitoring, limited availability etc. It also underscores a critical disconnect between international best practices and the realities in many African healthcare systems, where pain management remains heavily reliant on NSAIDs and often scarce opioids, which are largely ineffective for neuropathic pain. It is hoped that the use of neuropathic pain drugs will be adopted alongside conventional pain therapies for the management of pain in SCD patients.

Neuropathic pain in SCD can have some significant clinical implications. These include a worsening quality of life [51], negative psychological impact [52] and with association to some inflammation markers. It was associated with worse sleep and greater stiffness in another study [53]. This invariably can have adverse effect on social functioning, increasing psychological distress. Thus, identifying SCD patients with neuropathic pain is important in order to improve their quality of life.

Limitations

This study has some limitations. Firstly, being a cross-sectional study limits our ability to understand the course of the pain. Secondly, the painDETECT questionnaire was the only screening tool used and it is not validated in SCD patients under 14 years of age, hence, that population of patients are unaccounted for in the prevalence. In addition, a neurological examination was not done to help further understand the aetiopathology of the pain. In addition, a nerve conduction study was also not done. As a result of the subjective nature of pain, recall bias could be an issue; the patient could also have received some form of management before a presentation.

In conclusion, our study shows that neuropathic pain exists in Nigerian SCD patients and approximately one-third of them have evidence of neuropathic pain. This is also the first study in Nigeria to evaluate the prevalence of neuropathic pain in SCD patients. We found that the presence of neuropathic pain was significantly associated with several socio-demographic factors. Performance status (ECOG), units of blood transfusion, level of education and alcohol use were significantly associated with neuropathic pain. Age was significantly positively correlated with neuropathic pain implying older patients may experience more neuropathic pain. While hydroxyurea has no significant role in neuropathic pain in our SCD patients, the gabapentinoids which are used in neuropathic pain management were rarely used in our study.

In addition, the prevalence of NP in our study is commensurate with global figures, but its occurrence within a healthcare landscape marked by limited diagnostics, low uptake of disease-modifying therapy, and negligible access to neuropathic pain medications transforms this clinical finding into an urgent public health mandate.

Our recommendations to bridge this identified care gap include i) the integration of NP Screening into routine SCD assessments in Nigerian and similar African clinics to facilitate early identification. ii) A development of local guidelines for the dissemination of context-appropriate national or regional guidelines for the management of SCD pain, including specific pathways for NP, incorporating the rational use of gabapentinoids and other adjuvant therapies where available. iii) the scale-up of Disease-Modifying Therapies through making and implementing policies that try to overcome barriers to hydroxyurea access, and potentially preventing the development of chronic pain states. Setting up targeted education and research for healthcare workers to recognize and manage NP in SCD, as well as promoting longitudinal studies and qualitative work to understand the patient experience, which is important to guide effective, culturally sensitive interventions.

By acknowledging and addressing the neuropathic component of SCD pain, we can catalyze a shift from a reactive, palliative model of care towards a proactive, precision-based approach that has the potential to improve the quality of life many SCD patients in Nigeria and Africa.

Finally, the use of screening tools for neuropathic pain like the painDETECT can be a powerful tool to quickly identify SCD patients with neuropathic pain so they can benefit from the right therapies.

Acknowledgement

We would like to thank the haematology nurses in both institutions for their assistance in patient recruitment. We also want to thank the patients for being part of this study.

Authors’ contribution

Ogochukwu Izuegbuna, Israel Kolawole, Musa A. Sani and Olawale Olakunlehin designed the research study. Ogochukwu Izuegbuna and Musa A. Sani were involved with data collection. Ogochukwu Izuegbuna wrote the original draft. Ogochukwu Izuegbuna, Israel Kolawole and Olawale Olakunlehin were involved in corrections and rewriting. All authors read and approved the final manuscript.

Conflict of interest statement

The authors declare no conflicts of interest.

Funding information

The authors declare that no funds, grants, or other support were received for this work.

Ethics statement

This study was conducted following the approval by the Ethical review committee of both institutions. Consent was obtained from all participants.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Patient consent statement

Each patient provided a written informed consent to participate.

Permission to reproduce material from other sources

N/A

Clinical trial registration (including trial number)

N/A

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Tables 1 to 5 are available in the Supplementary Files section.

The authors declare no competing interests.

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Prevalence of Neuropathic Pain and Associated Factors in Nigerian Sickle Cell Disease Patients – A Cross Sectional Study

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