Neuropathic and Nociplastic Pain Profiles are Common in Adult Chronic Nonbacterial Osteitis (CNO)

Chronic nonbacterial osteitis (CNO) is a rare bone disease with a heterogeneous clinical presentation, occurring in children and adults [1‐3]. CNO has historically been indicated by various terms, including synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO)-syndrome and chronic recurrent multifocal osteomyelitis (CRMO). The disease spectrum is centrally characterized by relapsing–remitting sterile bone inflammation, causing bone pain, stiffness, compromised joint mobility and bone deformation [3, 4]. Despite ongoing efforts for timely diagnosis, patients with CNO still face an average diagnostic delay of 5 years during which they may be exposed to chronic pain [5, 6]. After diagnosis, chronic pain remains the main contributor to overall disease burden, reflected in frequent work absence and decreased quality of life [6‐8]. Clinical management of CNO therefore focuses on alleviating pain through targeting the osteitis with various anti-inflammatory and anti-resorptive treatments, all of which are off-label due to lack of supportive evidence [1, 2, 9].

While controlling inflammation is the primary focus of treatment, studies in related musculoskeletal diseases, such as axial spondylarthritis and psoriatic arthritis, have shown that patients may continue to report pain in the absence of active inflammation [10, 11]. This implies that non-inflammatory factors also contribute significantly to overall pain and associated disease burden [12, 13]. Physiologically, (musculoskeletal) pain can be categorized into nociceptive, neuropathic or nociplastic pain [14]. Nociceptive pain arises from damage to non-neural tissue and includes pain caused by inflammation or injury. Neuropathic pain arises from peripheral or central nervous system damage and is often described as shooting, burning, or tingling and may be associated with dysesthesia or allodynia. Nociplastic pain is a relatively recently proposed pain profile thought to arise from alterations in central sensory processing and pain modulatory mechanisms. Phenotypically, nociplastic pain is more widespread and intense than would be expected from the amount of identifiable tissue damage, and is often accompanied by central nervous system symptoms such as fatigue, sleep problems, memory and mood disorders [15]. A well-known example where nociplastic pain is believed to be the main pain profile is fibromyalgia [14, 16, 17].

Both neuropathic and nociplastic pain have proven common in axial spondylarthritis, psoriatic arthritis and rheumatoid arthritis alongside nociceptive pain caused by inflammation. Their co-existence is associated with higher patient reported disease activity, poorer treatment outcomes, and lower quality of life [11, 18‐20]. For adult CNO, the co-existence of these pain profiles is currently unknown, but suspected based on the notable number of patients that do not experience pain improvement despite receiving anti-inflammatory treatments [21]. This study therefore aimed to investigate the prevalence of neuropathic pain and nociplastic pain in adult CNO, to identify patients characteristics associated with these pain profiles, and to assess their influence on patient reported outcomes before and after treatment.

In this study, we found that the co-existence of neuropathic and nociplastic pain alongside nociceptive bone pain is common in adult CNO. Only 29% of participating patients had nociceptive pain exclusively. By contrast, the majority of patients reported mixed pain, which included combinations of nociceptive and neuropathic pain (3%), nociceptive and nociplastic pain (40%), or all three pain profiles (29%). These findings suggest that disease burden in CNO–largely dictated by pain–involves more than just nociceptive pain signals resulting from inflammation. Therefore, multi-angled rather than just anti-inflammatory treatments may offer opportunity to reduce the high burden of disease [6]. This notion is gaining recognition in other musculoskeletal diseases too [10, 17, 31‐34], with growing understanding that nociceptive pain can intermingle with both neuropathic pain and nociplastic pain and integrated management can significantly improve patient outcomes [35].

Our study revealed that 32% of adult CNO patients exhibited neuropathic pain in addition to their nociceptive bone pain, as evaluated by PAIN-detect. This proportion is similar to what has been reported for axial spondylarthritis, which shares clinical overlap with CNO, where PAIN-detect scores range between 28% and 34% [18, 36, 37]. Although our data cannot reveal the exact source of neuropathic pain in CNO, it is known from other bone pathologies that neuropathic pain may arise due to damage to small nerve fiber in the bone and periosteum [38]. In CNO, this damage may arise from progressive sclerosis and hyperostosis, both of which characterize prolonged disease. Also, soft tissue ossification forms a key disease process and may cause small nerve fiber damage in the affected areas [39‐41].

A majority of 69% of CNO patients in the present study displayed a nociplastic pain profile alongside their nociceptive pain, as reflected by signs of central sensitization on CSI and/or symptoms consistent with fibromyalgia on FiRST or the AAPT criteria, both of which represent elements of nociplastic pain [15]. These findings align with those from multiple studies on axial spondylarthritis and a single study on adult CNO [19, 42‐45]. While nociplastic pain is described as pain that does not exhibit clear nociceptor activation or neuropathy [15], it is known to frequently develop within the context of chronic nociceptive pain via adaptive alterations in pain processing. Consequently, this commonly results in mixed pain including elements of both [15]. Inflammatory musculoskeletal diseases forms an illustrative example of this phenomenon, as inflammatory nociceptive pain often becomes entangled with nociplastic pain, sometimes taking the clinical shape of comorbid fibromyalgia [42]. Our data suggest that CNO is no exception to this phenomenon. Although this study does not enable us to draw causal conclusions about why CNO patients are prone to nociplastic pain, we can hypothesize about potential disease-specific risk factors. First, although this was not addressed in the study surveys, we speculate that the lack of awareness of the disease, and the absence of evidence-based treatments and clear prognostic information may be risk factors as they decrease patients’ perceived locus of control, which is known to play a role in nociplastic pain [46‐48]. Second, diagnostic delays may be another risk factor for nociplastic pain development via both physiological and psychological mechanisms. Physiologically, persistent nociceptive signaling due to untreated disease activity is known to trigger the aforementioned plastic changes in the central nervous system, resulting in a widespread, intense pain phenotype [15, 35]. Psychologically, diagnostic delay is known to represent a period of distress, uncertainty and reduced self-efficacy, all of which are risk factors for the development of nociplastic pain [46‐48]. Indeed, this study demonstrated that patients with mixed pain had longer diagnostic delays, confirming the suspected association. Although additional studies, preferably with in-depth patient interviews, are required to understand these mechanisms in more detail, it is once again evident that quick diagnosis of CNO should receive attention in both clinical practice and research.

Patients with mixed pain demonstrated higher CNO-related bone pain scores as compared to patients with exclusive nociceptive pain, even though disease severity as reflected by number of bone lesions, skeletal distribution pattern, and extra-skeletal features was similar between groups. This finding holds significance given that the current evaluation of CNO and therapeutic decision-making mainly relies on pain scores, owing to the absence of concrete biomarkers for measuring disease activity [2]. Our study therefore suggests that the presence of mixed pain complicate the interpretation of pain scores and their accuracy in reflecting the state of inflammation. Indeed, in other musculoskeletal diseases, mixed pain is increasingly recognized as an important contextual factor in the evaluation of disease activity [33, 49], associated with higher pain scores despite similar levels of inflammatory activity [50‐52].

Patients with mixed pain exhibited similar or even greater improvements in CNO-related bone pain after treatment with NSAIDs and intravenous bisphosphonates, compared to those with only nociceptive pain. Initially, this result seemed surprising since these treatments are not typically considered effective against neuropathic nor nociplastic pain. However, the greater improvement in the mixed pain group can be attributed to their higher baseline pain levels, which inherently allow for greater decrease in psychometric sense. This pattern is also observed in other musculoskeletal conditions, where patients with mixed pain present higher pain scores at baseline, but achieve similar remission rates [53, 54]. Another explanation may be that patients with mixed pain more frequently receive intravenous bisphosphonates, which may be more effective against CNO-related bone pain than NSAIDs alone, and have also been suggested partly effective against neuropathic and/or nociplastic pain [1, 55].

A significant proportion of CNO patients, mainly those with mixed pain, had engaged in myriad pain-related therapies outside the hospital setting. Non-hospital pain treatments are common in other chronic musculoskeletal diseases as well, but they might hold a special appeal for CNO patients considering the absence of evidence-based treatments available within the clinical setting. While many of these interventions were unharmful, it is worth noting that opioids were used by 30% of patients at some point during disease course for a median duration of 6 months, and their usage was associated with the presence of mixed pain. The study design cannot ascertain whether opioid use precedes or follows the development of mixed pain, but underscores the importance of actively discussing these medications during patient evaluation. This is particularly crucial given the significant adverse effects and the risk of patient tolerance and misuse. Additionally, this finding calls for clinical collaboration with specialized pain centers which can provide expert guidance to patients on safely discontinuing opioid use and are specialized in pain medication effective for neuropathic and nociplastic pain.

There are several limitations to consider in this study. Firstly, CNO-related pain scores at baseline and after treatment were obtained from a different point in time compared to survey completion, which may have introduced variability in the data. In future studies, it is essential to implement systematic data collection from baseline and throughout follow-up, incorporating standardized measurements of pain scores, the extent of neuropathic and nociplastic pain, and narrow tracking of CNO and specific pain-related treatments. Such approaches offer improved insights into causal risk factors for mixed pain in adult CNO and consequently facilitate the implementation of preventive measures. Secondly, the sample size was small. However, it was reasonably substantial considering the rarity of the condition and the final sample effectively represented the CNO population in terms of sociodemographic and disease-specific characteristics. Thirdly, some relevant data were unavailable, such as health beliefs, religious background, and current socioeconomic status, all of which are recognized as factors associated with the development of mixed pain. Finally, although validated surveys were employed to classify pain types among patients, this approach has its constraints. Future studies should aim to integrate direct clinical data gathering, encompassing findings from physical examinations and neurophysiological pain evaluation methods like quantitative sensory testing.

Our findings have important implications for the clinic and research. Clinically, they imply that management for CNO needs to encompass more than just bone inflammation control. Measuring neuropathic and nociplastic pain via validated questionnaires, and addressing their presence in a multifaceted management plan may be an important step towards improving clinical outcomes, including work participation and overall quality of life [56‐59]. Similarly, neuropathic and nociplastic pain should be considered as contextual factors in disease activity assessment and treatment decisions, as they may lead to overestimation of inflammatory activity and therefore over-treatment. Regarding research, we recommend to consider neuropathic pain and nociplastic pain in the design of treatment trials, which are anticipated in the near future to address the unmet need of evidence-based therapy in this rare disease.