1 INTRODUCTION

Neurofibromatosis Type 1 (NF1) is an autosomal dominant and rare genetic condition affecting one in 3000 individuals globally (Anderson & Gutmann, 2015; Gutmann et al., 2017; Legius et al., 2021). This condition can impact numerous regions of the body (e.g., brain, spine, nerves) and is often characterized by café-au-lait macules, dermal neurofibromas, skeletal abnormalities, tumors, as well as cognitive, social, and behavioral deficits that can negatively impact quality of life (Gutmann et al., 2017; Ly & Blakeley, 2019). In accordance with such symptomology, the majority of individuals with NF1 report experiencing significant chronic pain and discomfort (Allen et al., 2018; Buono et al., 2019; Fjermestad, 2019; Wolters et al., 2016). Approximately 70% of adults report using prescription medication to treat their pain (Buono et al., 2019; Créange et al., 1999). Yet there is a lack of efficacy and even a reported exacerbation of pain (Struemph et al., 2017) with prescription medication usage for this population. Despite the high prevalence of chronic pain within the NF1 population, the topic remains understudied, giving way to suboptimal treatment (Bellampalli & Khanna, 2019).

Chronic pain exposes those with NF1 to significant physical suffering as well as psychological distress (Bellampalli & Khanna, 2019; Wolters et al., 2015). Physically, individuals with NF1 report pain in the form of headaches/migraines, scoliosis/orthopedic problems (Kongkriangkai et al., 2019), and plexiform neurofibromas and other NF1-related tumors. Psychologically, research has documented increased rates of depression and anxiety among the NF1 population (Cohen et al., 2015; Doorley et al., 2021; Doser et al., 2020; Kongkriangkai et al., 2019), negative body image, less self-confidence (Granstrom et al., 2012), and reduced self-esteem (Rosnau et al., 2017). In order to provide patients with the highest quality of care, providers must understand that their patients' pain extends beyond physical symptoms.

Healthcare providers commonly use numerical scales to obtain a self-reported rating of their patients' current level of pain (Collins et al., 2022; Karcioglu et al., 2018). Experience of pain is unique, multifaceted, and subjective (Cohen et al., 2021; Gatchel et al., 2007), and while numerical scales may offer healthcare providers information about patients' perceived severity of their pain, in order to obtain a comprehensive understanding of experience with pain there is a clear need for additional qualitative and contextual information. However, the etiology, subsequent symptomology, and impact on functioning of chronic pain remains understudied, measured, and considered in routine treatment of NF1. In an effort to address this gap, the current cross-sectional survey study sought to understand more fully the impact of chronic pain on adults with NF1 by using the novel Neurofibromatosis Pain Module (NFPM).

2 METHODS

2.3 Neurofibromatosis Pain Module

The NFPM (Buono in preparation) is a 39 question patient-reported clinical assessment that evaluates chronic pain from four different domains (i.e., interference, severity, tolerance, and symptomology). The NFPM was developed through a mixed-methods approach that included input from both NF1 patients and providers. It asks the person to self-select up to three of their most prevalent pain regions (primary, secondary, and tertiary) that are affecting their body. Additionally, participants are asked to describe their pain across all three regions from a list of descriptors (e.g., burning, stabbing, tingling). For each region, the individual completes 13 total questions (5 multiple choice, 2 short answer, and 6 Likert-based rating) concerning the perceived severity, interference, tolerance, antecedent of pain (if applicable), impact of their pain. The measure also includes two anatomically neutral silhouettes where the respondent can identify the pain location and where the pain radiates (see Figures 1 and 2). Within the NFPM, there are two open-ended questions (see Table 5) to understand more about the causes of pain and factors that exacerbate pain. Participants were allowed to answer in a multi-line textbox. Evaluating each pain region takes approximately 5 min, with the total assessment taking, on average, 15 min. Preliminary evidence indicates the NFPM displays good psychometric properties (Cronbach's alpha = 0.82).

3 RESULTS

4 DISCUSSION

The current study aimed to extend the knowledge base in the current literature by providing further clarification on the impact of chronic pain in adults with NF1. By evaluating the participants' chronic pain across three different pain regions (primary, secondary, and tertiary) and letting participants self-assign their regions of predominant pain, we were able to gather a wealth of information regarding their experience of pain. Results indicated that all participants had at least one area of moderate chronic pain, and a majority of the participants had a second area of moderate level pain. Whereas previous chronic pain measures only ask about one pain area when, in fact, people with NF1 have commonly multiple pain areas. The current findings suggest that assessing only one pain region may not yield an adequate understanding of the nature and extent of chronic pain in the NF1 population, something that has not been heretofore reported.

The prevalence of CP among individuals with NF1 is evidenced by the self-description of “constant” and or “frequent” related to participants' primary pain which constituted 83% of total responses. Aggregate pain severity scores for the three regions above were 6.0 on a 1–10 scale, indicating moderate to moderate/high pain severity. Moreover, CP was not limited to a single region of the body. In fact, as noted in Figures 1 and 2, each region was selected. Chronic pain affected individuals' quality of life and their ability to sleep, exercise, regulate their mood, and pay attention to tasks. The findings from this study also support previous research stating that the available treatment options are relatively ineffective (Burns et al., 2011; Struemph et al., 2017). The current study indicates that individuals with NF1 often struggle to reduce their pain symptoms by reportedly attempting 2 or 3 more strategies to relieve pain (e.g., heat, sleeping, or physical activity). These findings support previous research concerning the ineffectiveness of current strategies to mitigate or reduce chronic pain (Buono et al., 2019). Thus, requiring multiple strategies (e.g., more than two strategies) to lower pain symptoms.

The open-ended questions in which participants noted what they felt triggered or worsened their pain provided context on the impact of chronic pain for individuals with NF1. In both cases (causing or worsening pain), movement activities or the sensitive nature of the tumor when physically bumped or rubbed initiated symptoms. Interestingly, what caused the pain to occur was unknown for 20% of the respondents, potentially indicating that their pain could be triggered by a combination of different stimuli. This lack of understanding about the underlying cause of the pain may increase the potential for generalized anxiety, hopelessness, and reduced quality of life. These findings emphasize the complexity of chronic pain within NF1 patients.

As noted, 92% of participants indicated two or more descriptors related to their primary pain region, potentially indicating that participants may not understand the difference between the sensorial pain descriptors or that their pain is multi-sensorial (e.g., burning, throbbing, and tingling). Given that pain is a subjective experience, differences among seemingly identical pain conditions can occur, thus leading to a variety of descriptors being affixed to those identical pain conditions (Boureau et al., 1990). Previous research has indicated that pain descriptors should be classified by pain disorders (Fernandez et al., 2011); however, research in adults with NF1 has yet to derive classifications for this specific disease. Moreover, research with NF1 adults has yet to establish how pain types (e.g., burning, throbbing, stabbing) can be discriminated. In addition, given the multitude of NF1-related symptoms that cause pain and discomfort (e.g., plexiform and cutaneous tumors, scoliosis, and bone abnormalities), the heterogeneity of pain descriptors is not unexpected.

Only 45% participants had a medical expert that specialized in NF. The rarity of the disease, in combination with the lack of medical experts trained in NF1 and the complexity of chronic pain, creates a need for multidisciplinary care for these patients. Findings from this study highlight the need for a thorough evaluation of chronic pain in individuals with NF1 that goes beyond Likert-based responses. Scales such as the visual analogue scale are predominantly severity-based (e.g., no pain to worst pain imaginable) and limited to a specific range of time; therefore, they neither provide a sufficiently thorough understanding to the medical provider about pain over time nor validate the experience of the individual suffering from the pain. Thus, given the limited knowledge that can be gained through existing measures used by NF1 providers, it is critical that evaluations encompass a more complete understanding of the patient to ensure that the patient can be provided the best care.

The current study is not without limitations. As noted in Figures 1 and 2, pain among this patient population was not limited to a single anatomic region and instead they identified multiple regions. In other words, we could not distinguish where their primary, secondary, and tertiary pain originated. Furthermore, the presentations of Figures 1 and 2 indicate that chronic pain in NF1 is diffuse and not necessarily constrained to the exact location of the tumor. A second limitation of the current study is the relatively small sample size and the lack of a random sampling strategy; the findings may therefore be of limited generalizability. Yet, given the rarity of the condition, the presentation provides an initial understanding. A third limitation is the current study is a cross-sectional design and completing only one time-point limits on the understanding of the duration of the chronic pain. A final limitation of the study is that participants having severe psychiatric symptoms and/or other co-occurring diagnoses that could artificially inflate chronic pain scores. Given the parameters of the study, we attempted to exclude severe psychiatric patients and in so doing, the current study may also limit the generalizability of the findings. However, in the instructions of the NFPM, we only asked the participant to describe their NF-related pain.

5 CONCLUSION

Chronic pain has substantial effects on individuals living with NF1. The current study demonstrates that chronic pain can affect individuals with NF1 across all areas of life and multiple regions of their body. Clinical tools such as the NFPM will be useful in providing a more comprehensive description of NF1-related pain to inform treatment plans of providers to facilitate patient care.

AUTHOR CONTRIBUTIONS

FDB: Conceptualization; funding acquisition; methodology; formal analysis; original draft writing, reviewing, and editing. KL: Data curation; methodology; original draft writing, reviewing, and editing. WTZ: Conceptualization; supervision; reviewing, and editing. LEG: Supervision; reviewing, and editing. SM: Conceptualization; supervision; reviewing, and editing.

FUNDING INFORMATION

Funding from this project came from Children's Tumor Foundation, Clinical Research Award (#2021-10-001, PI: Buono, Frank).

CONFLICT OF INTEREST STATEMENT

No conflicts of interest to declare.