Left to themselves: Time to target chronic pain in childhood rare diseases

Abstract

Background:

Chronic pain is prevalent among patients with rare diseases (RDs). However, little is understood about how biopsychosocial mechanisms may be integrated in the unique set of clinical features and therapeutic challenges inherent in their pain conditions.

Methods:

This review presents examples of major categories of RDs with particular pain conditions. In addition, we provide translational evidence on clinical and scientific rationale for psychosocially- and neurodevelopmentally-informed treatment of pain in RD patients.

Results:

Neurobiological and functional overlap between various RD syndromes and pain states suggests amalgamation and mutual modulation of the respective conditions. Emotional sequelae could be construed as an emotional homologue of physical pain mediated via overlapping brain circuitry. Given their clearly defined genetic and molecular etiologies, RDs may serve as heuristic models for unraveling pathophysiological processes inherent in chronic pain.

Conclusions:

Systematic evaluation of chronic pain in patients with RD contributes to sophisticated insight into both pain and their psychosocial correlates, which could transform treatment.

1. The problem and potential

Numbering approximately 7000 titles, rare diseases (RDs) are defined by the European Union as a life-threatening and/or debilitating chronic condition with the prevalence of less than 1 per 2,000 (Baldovino et al., 2016). Per the US definition, a rare disease affects fewer than 200,000 people (Danese and Lippi, 2018) with the available databases (https://rarediseases.org/for-patients-and-families/information-resources/rare-disease-information/, or https://rarediseases.info.nih.gov) providing information for patients and caregivers. Additional definitions related to pain can be found in Table 1.

Table 1.

Types of Pain in Rare Disease (RD - defined in GARD; https://rarediseases.info.nih.gov).

Disease	Pain Pathogenesis	Type of Pain	Location	Onset	Sex	Disease Development	Reference
Autoimmune-Inflammatory
JIA	Inflammation. Activated T & B cells;Cytokine mediators, (IL1, IL6, TNFa, IL21, IL23), Activated macrophages, Bone, Cartilage destruction	N	Joints	<16 yrs.	M/F	6 weeks – lifelong	Giancane et al., 2016. Hahn and Kim, 2010
Connective Tissue Disease
Gaucher Disease	Glucosylceramide accumulation. Nerve cell damage, Peripheral neuropathy	N, Ne, V	Spleen, liver, skeleton	10–20 yrs.	M/F	Lifelong	Stirnemann et al., 2017. Devigili et al., 2017
EDS	Collagen defects. Subluxations, dislocations, Soft-tissue injury, Myalgia	N, Ne, H	Spine, major joints	Early childhood-young adulthood	M/F	Lifelong	Chopra et al., 2017. Rodgers et al., 2017. Demmler et al., 2019
Endocrine Disease
Acromegaly	GH excess affecting skeleton, Arthralgia, Neuropathies	N, Ne, H	Large joints, carpal tunnel, vertebral	Any age	M/F	Delayed diagnosis, lower life expectancy	Adelman et al., 2013. Chanson and Salenave, 2008. Ben-Shlomo and Melmed, 2008
Metabolic Diseases
Fabry Disease	Globotriaosylceramide accumulation in organs, small fiber disfunction	Ne	Hands, Feet	6–9 yrs.	M > F	Lifelong, progressive	Ellaway, 2016. Nagueh, 2003. Gibas et al., 2006. Schiffmann and Scott, 2002. Dütsch & Hilz, 2010
Musculoskeletal
OI	Collagen type 1 synthesis mutation affecting connective tissue, decreased bone density, fractures (brittle bones)	N	Vertebral, upper/lower extremities	Birth - early childhood	M/F	Lifelong	Sam and Dharmalingam, 2017. Zack et al., 2005. Martin and Shapiro, 2007
FOP	Heterotopic ossification. Joint ankylosis	Ne	Spine, hip, knee, head, shoulders	At birth	M/F	Lifelong, Spont. Resolution, Delayed symptoms	Kaplan et al., 2008. Peng et al., 2019
Nervous System
CMT 1α	Protein mutations affecting motor & sensory nerves	Ne	Extremities	1st-2nd decade	F > M	Lifelong, progressive	National Institute of Neurological Disorders and Stroke (NINDS, 2020. Wozniak et al., 2015. Bjelica et al., 2020. Szigeti and Lupski, 2009
NF1	Neurofibromas affecting nervous tissue, Plexiform neurofibromas, Bony dysplasia	Ne, H	Nervous system, skin, skeletal	At birth	M/F	Lifelong	Boyd et al., 2009. Bellampalli and Khanna, 2019

Key: Type of Pain – N = nociceptive, Ne = Neuroppathic; V = Visceral; H = Headache.

Many RDs are characterized by chronic pain; some start in childhood, and, in others pain is more notable in adulthood. About 30 million Americans are afflicted with chronic pain associated with RD, and their quality of life may be more limited compared to other common chronic diseases (Bogart and Irvin, 2017). Therefore, it is vital to understand the neurobiology of pain in these populations as well as utilize symptomatic or curative therapies; an opportunity that has not yet been vigorously pursued in part due to relatively small numbers of those affected in comparison to other more visible and well organized groups with political influence and funding (e.g., AIDS) (Piot et al., 2007).

The paucity of effective treatments for chronic pain in RDs is derived in part from: (1) inadequate mechanistic insights into RDs’-specific components impacting acute and/or chronic manifestations (Bogart and Irvin, 2017); (2) RD patients’ exclusion from clinical trials participation given the low prevalence of the index disorder; (3) clinical focus on the genetic etiological factors that may obscure the rationale for a serious inquiry into co-occurring specific pain conditions; (4) failure to perform proper diagnostic work up; and (5) clinical emphasis on the condition per se rather than on the pain sequalae. This latter issue is particularly problematic during childhood when pain is often poorly recognized and may eventually escalate to severe conditions in adulthood (Brattberg, 2004). Accordingly, the recent Lancet commission on pediatric pain focused on delivering transformative action and recommended trials for children with complex needs in order to prevent long-term pain and to also target comorbidities, which are often common in RDs (Eccleston et al., 2020).

It is of upmost importance to provide clinical and scientific rationale for psychosocially- and neuro-developmentally-enriched care of RD patients with regard to their pain as well as for raising the awareness and sensitivity of clinicians, scientists, and policy makers alike to this important yet unmet medical and public health need. This review focuses on three lines of translational evidence, excerpted from a thorough literature review, in support of disseminating knowledge about RD and pain, as well as highlight research gaps and propose key future directions. Specifically, the following are addressed: (1) overview of RDs and pain; with specific examples provided for autoimmune- inflammatory, connective tissue, endocrine, metabolic, musculoskeletal, and nervous system; (2) the role of psychological factors in RDs and pain; and (3) other salient considerations and issues such as economic, pharmaceutical and brain measures.

A list of chronic pain and RD in a search of the NORD data base results in 844 titles (https://rarediseases.org/?s=pain&submit=). The domains reflect underlying disease categories (e.g., neurological, rheumatological) changes that result in chronic pain.

2. Rare disease and pain

Examples of RDs with associated with chronic pain states are displayed in Table 2; more detailed information can be found at the Genetic and RDs’ Information Center (GARD https://rarediseases.info.nih.gov/diseases). Below we consider some examples within each category noted in the table with an emphasis on the co-occurring pain and psychiatric disorders as well as on prevalence (as available). For clarity, we attempted to present each category of conditions with opposite (e.g., hypo- vs. hyperactive state) or common pathophysiological processes (e. g., fractures or hypermobility). In each, we provide a brief overview of the etiology of the condition, the types of pain experienced, potential predictors of pain (if known) and emerging pharmacotherapies based on the mechanistic insights. Additionally, in the following section (Section 3: Dysmorphia, Rare Disease and Chronic Pain – Effects on Psychosocial Measures), we discuss emotional responses arising in the context of RDs that may contribute to chronic pain and how various entities may interact to alter coping with stress along with activities of daily living (see Figure 1). In addition to disease type, pain and pain treatment, we also evaluate studies on psychological co-morbidities and brain changes in these conditions since the former is a significant contributor to the pain state and the latter may contribute to evaluation of the pain state as well as be a potential biomarker for pharmacotherapies (see below). The information we have carefully chosen to include applies the biopsychosocial model of pain to rare disease, in that the physiological, psychological, and social factors all influence each other and contribute to furthering our understanding of pain profiles in these patient populations (Figure 2).

Table 2.

Examples of Support Societies for Patients with RD.

Disease Entity	Website
Autoinflammatory Allianc	autoinflammatory.org
The Myositis Association	https://www.myositis.org
Sjögren’s Foundation	sjogrens.org
Juvenile Arthritis Association	www.juvenilearthritis.org
Stiff Person Syndrome Support Group & Therapy	http://www.smssupportgroup.co.uk/
National Gaucher Foundation	gaucherdisease.org
Ehlers-Danlos Society	https://www.ehlers-danlos.com
The Marfan Foundation	www.marfan.org
Mixed Connective Tissue Disease Foundation	mctdfoundation.org
Acromegaly Community	acromegalycommunity.org
National Fabry Disease Foundation	fabrydisease.org
Lesch-Nyhan Disease International Study Group	lesch.nyhan.org
American Porphyria Foundation	poprphyriafoundation.org
United Mitochondrial Disease Foundation	umdf.org
International Fibrodysplasia Ossificans Progressiva Ass.	ifopa.org
Osteogenesis Imperfecta Foundation	oif.org
Batten Disease Support and Research Association	bdsra.org
Charcot-Marie-Tooth Association	cmtausa.org
The Erethromelalgia Association	erythromelalgia.org
National Organization for Rare Disorders	rarediseases.org
Children’s Tumor Foundation: Ending NF Through Research	ctf.org

Fig. 1. Pain-Disease Interactions in RD.

While pain may involve musculoskeletal or neuropathic conditions for the most part, in some RD, patients are subjected to multiple acute episodes (e.g., bone fracture), or treatment related processes that may exacerbate their pain condition (e.g., fibrodysplasia ossificans progressiva). Whatever the nature of the etiology of the pain, it too may be exacerbated and exacerbate psychological processes that include anxiety, depression, ostracization (with dysmorphic RD), together contributing to diminished quality of life (QoL). Such processes contribute to centralization of pain – where nociceptive processes that may induce central sensitization, progressively recruit circuits that have altered structure, chemistry and function – so called centralization of pain.

Fig. 2. Dynamic Field of RD and Opportunities for development of Novel Analgesics.

Because RD may be the result of single gene mutations, targeting disease modifying therapies may be more effective than ‘broad spectrum diseases”. As such, some of these approaches have provided pain relief. However, for the most part this is not the case, particularly in diseases that have a neuropathic pain component (e.g., NF1, Fabry Disease).

2.1. Autoimmune/Autoinflammatory

Chronic pain has a significant inflammatory component, which is an endogenous process, so patients who also have autoimmune conditions in which antibodies produce self-harm, in addition to their chronic pain, are at particular risk (Ahmad and Tagoe, 2014). Some chronic pain conditions, such as Complex Regional Pain Syndrome (CRPS), have been implicated as an autoimmune painful condition (David Clark et al., 2018. Here we have chosen one example of an autoimmune RD, Juvenile Idiopathic Arthritis (JIA) as an exemplar of an autoimmune process that produce a painful condition.

2.1.1. Juvenile Idiopathic Arthritis (JIA)

JIA is a chronic rheumatic condition affecting children prior to the age of 16 that usually presents with arthritis with a number of subtypes (Barut et al., 2017). It is the result of an increased inflammatory response to endogenous (e.g., GI bacteria) and exogenous (e.g., infections, stress, physical trauma) antigens. The acute phase of the disease lasts no more than 6 weeks with specific diagnostic criteria (see Giancane et al., 2016). As a result of the inflammatory response, proinflammatory cytokines such as IL1, IL6 and TNF-alpha act as mediators in the synovial fluid that produce joint destruction.

Pain in JIA:

Pain is commonly present in the extremities - in hands, elbows, wrists, knees and ankles. Following the onset of the acute inflammatory response, both the synovial membranes and the joints are targets for the inflammatory response. In addition, patients are at increased risk of fractures because of osteoporosis (Thornton et al., 2008). In addition to pain, stiffness and fatigue are common (Bromberg et al., 2014). Persistent pain due to JIA results in significant problems with physical, emotional, social, and school functioning. Pain hypersensitivity to pressure, touch and heat has been observed in patients with JIA even in the presence of low pain scores (Cornelissen et al., 2014) representing either peripheral or central sensitization. A neuropathy (e.g., carpal tunnel syndrome (Unal et al., 2003) is also present in some patients with JIA. Rarely, atlanto-axial subluxation may lead to spinal cord compression (Laiho et al., 2002). Pain ranges from low (approx. 52 %) to high (approx. 30 %) levels and some even recovered (approx. 18 %) (Bowen, 2017). There are a number of predictors of increased pain in JIA patients (Stinson et al., 2012) including: (1) early onset (Arnstad et al., 2019); (2) family history of chronic pain; and (3) negative affective states. For example, pain exacerbates catastrophizing (I.e., pain-related worry) and diminishes coping abilities including substantial functional limitations (Anthony and Schanberg, 2003).

Psychological Comorbidities in JIA:

Depression and anxiety are common comorbidities in JIA for those affected (ranging from 7 to 36 percent) as well as their families (Fair et al., 2019). In a population cohort, 72 % had significant depression that was associated with mild to moderate disability (Bano et al., 2020). Additionally, it has been found that patients with JIA who also have orofacial pain have high rates of stress, depression, pain catastrophizing and pain related disability (Dimitrijevic Carlsson et al., 2019). Brain Changes in JIA: Few studies have been performed on evaluating brain processes of chronic pain in JIA – although given its status as a neuroinflammatory process, opportunities for brain measures or response as markers for disease state may be useful. Other targets such as the joints are routinely imaged to define the disease state and treatment responsivity (Hemke et al., 2018).

Analgesic Treatments JIA:

Advances in JIA treatment (e.g., biologics) have improved remission rates (Shoop-Worrall et al., 2017) that have reduced pain and functional disability. However, many patients do not remain in remission without regular treatment, for example using modifying anti-rheumatic drugs (DMARD’s) (Glerup et al., 2020). These relatively new treatments target cytokines and other inflammatory molecules and together with older standard analgesic treatments (Non-steroidal anti-inflammatory drugs – NSAIDS, and methotrexate) have provided significant benefits to these patients. Biologics directed at inflammatory molecules/cytokines (e.g., IL-6 – tocilizumab (Hoffmann-La Roche, Chugai); CD-20 receptor – rituximab (Biogen, Genentech); cytotoxic T cell Lymphocyte antigen - abatacept (Bristol-Myers Squibb)), based on our understanding of pain neurobiology not only affect the main issue in JIA (i.e., arthritis) but also secondary pain conditions including generalized hypersensitivity to external stimuli (Ren and Torres, 2009; Hess et al., 2011; Enteshari-Moghaddam et al., 2019). Novel therapeutics for JIA range from improvements to existing drug and biological therapies to clinical trials on yoga and aerobic dance. The clinical trial on yoga and aerobic dance (NCT03833609) is the first randomized control trial of its kind to use these two popular exercise methods to manage pain in female adolescent JIA patients. Management of pain through movement is an emerging perspective as the motor system has diverse connectivity with pain centers in the brain and significant analgesic potential (Holmes et al., 2020; Neurobiology of Disease). The classes, consultations, and surveys are administered virtually, which is a promising remote alternative to traditional treatments with the potential to widen access to pain management services in this population.

2.2. Connective tissue diseases (CTD)

Pain is common in CTD (Di Franco et al., 2015). In the two examples provided below, one (Gaucher Disease) has a condition of infiltration of a lysosomal product due to an enzyme deficiency resulting in bone and, to a lesser extent, nerve problems, and the other (Osteogenesis Imperfecta) results from brittle bones.

2.2.1. Gaucher disease (GD)(https://rarediseases.org/rare-diseases/gaucher-disease/)

GD is a RD with an autosomal recessive genetic background that is an inborn error of metabolism – due to deficiency of glucocerebrosidase. As a result, there is an accumulation of glucosylceramide (Stirnemann et al., 2017). There are three subtypes (see Stirnemann et al., 2017).

Pain in GD:

Pain in GD is due to skeletal (Baris et al., 2016) or nerve (large and subclinical small fiber) involvement (Andréasson et al., 2019). In GD Type 1, neuropathic pain may present as paroxysmal or as hypoesthesia, with some patients having increased cold thresholds to quantitative sensory testing (Devigili et al., 2017).Pain from the skeletal origin may be due to avascular necrosis and arthritis or osteoporosis (Linari and Castaman, 2015).

Psychological comorbidities in GD:

As with many RDs, psychological comorbidities in GD are common (Packman et al., 2010) and elevated in GD with chronic pain (Packman et al., 2006). For example, patients with GD often endorse emotional distress such as feelings of isolation as well as illness uncertainty and have difficulty being future oriented (e.g., getting married; having children) (Packman et al., 2010) Additionally, patients with GD also often have decreased quality of life, most notably around physical well-being (Damiano et al., 1998).

Brain changes in GD:

altered brain measures have been reported in GD Type I, with resting state measures found to be abnormal with changes in the motor and sensory regions being prominent (Zhang et al., 2019). Such sensory-motor alterations might be a focus for pain treatment including transcranial magnetic stimulation (TMS) that usually targets the motor cortex for pain treatment (Hamid et al., 2019) as well as other extracranial (e.g., direct current stimulation) and intracranial (e.g., motor imagery) methods of targeting the motor system (Holmes et al., 2020).

Analgesic Treatment in GD:

Enzyme Replacement therapy (ERT) is associated with a reduction in bone crisis and bone pain in patients with GD type 1 (Charrow et al., 2007). Analgesic treatments are divided into primary enzyme replacement treatment for the underlying pathophysiology, but this may not have any effect on pain in the short or long term. Ongoing episodes of bone crisis may require temporary immobilization with adjunct analgesics. While acute crises may respond to analgesic, ongoing chronic pain in GD may be resistant to analgesics (Cohen et al., 1996). Alternative methods for pain management in patients living with GD are currently being explored in a therapeutic exercise clinical trial (NCT04050137). Through a series of in-person group workshops led by a physiotherapist and accompanying at-home exercise assignments, the trial aims to improve quality of life and target neuropathic pain in those with consistently elevated pain scores and stable disease evolution.

2.2.2. Ehlers-Danlos Syndromes (EDS) (https://rarediseases.org/rare-diseases/ehlers-danlos-syndrome/)

Ehlers-Danlos Syndromes are a group of several heterogenous diseases, characterized by collagen defects that damage the integrity of the body’s connective tissues. Symptoms vary between the classical, vascular, and hypermobile subtypes, but often include velvety, delicate skin, vascular fragility, joint hypermobility, and widespread body pain (Syx et al., 2017).

Pain in EDS:

Pain is a common and severe symptom across all subtypes of EDS. Pain in EDS is most frequently reported in the major joints, and can be caused by their frequent dislocations, soft-tissue injury, and peripheral nerve injury in surgery (Voermans et al., 2010). Pain is more frequently reported in female than male EDS patients, and more common in patients diagnosed with the hypermobile type than both the classic and vascular types (Voermans et al., 2010). The pain often begins as nociceptive but progresses to include neuropathic qualities and central sensitization. 90 % of EDS patients say their pain is chronic, and worsens throughout their lives (Zhou et al., 2018).

Psychological Comorbidities in EDS:

Almost half of EDS patients also carry comorbid diagnoses of psychiatric disorders, most commonly anxiety and depression. The prevalence of psychiatric disorders in this patient population is significantly higher in patients who reported any pain symptom, including abdominal pain, neuropathic pain, migraines, joint pain, and fatigue (Hershenfeld et al., 2016).

Brain Changes in EDS:

Little is known about brain changes in this group of diseases.

Analgesic Treatment in EDS:

Most EDS patients reported using one or more analgesic for daily and peak pain management, with 67 % using NSAIDs, 57 % using acetaminophen, 23 % using opioids, and 11 % using antineuropathic pain drugs (Voermans et al., 2010). Clinical trials for alternatives to drug therapies for chronic pain in EDS are in progress, with compression garments appearing in multiple trials. A compression garment in the form of a short-sleeved vest was used in one clinical trial to stabilize the shoulder joint, both alleviating pain and preventing further injury at the joint (NCT02144532).

2.3. Endocrine disease

While pain may produce changes in endocrine function, endocrine disorders, aside from muscle pain, are not usually associated with significant pain. Two rare diseases including acromegaly and chordoma are endocrine rare disease phenotypes that have associated pain de-novo but also especially in the case of chordoma’s, chronic neuropathic pain.

2.3.1. Acromegaly (https://rarediseases.org/rare-diseases/acromegaly/)

Acromegaly Is a progressive disease characterized by excess growth hormone and insulin-like growth factor (Dineen et al., 2017). It is a disease affecting heart, brain and lung and usually associated with a decrease in life span (Melmed, 2009).

Pain in Acromegaly:

A few pain related processes occur in patients with Acromegaly including wrist pain (carpal tunnel syndrome); headache (Musolino et al., 1990); and joint pain (Chanson and Salenave, 2008). In patients with pituitary tumors, most of the headaches are migrainous or stabbing in nature (Levy et al., 2005).

Psychological Comorbidities in Acromegaly:

Acromegaly may negatively impact cognitive factors including learning and attention (Alibas et al., 2017). As most patients with acromegaly experience physical disfigurement including bony overgrowth and soft tissue swelling, they also report self-esteem impairments and body image distortion that may contribute to social withdrawal anxiety and disruptions to relationships (Pantanetti et al., 2002). Although depression may not be different in these patients vs. healthy controls (Alibas et al., 2017), overall quality of life in acromegaly is affected by depression and anxiety that should be evaluated to improve overall treatment (Geraedts et al., 2014), including pain control.

Brain Changes in Acromegaly:

A number of MRI-related studies have evaluated acromegaly including the use of DTI, noting changes that had no relation to disease duration or treatment, suggesting subclinical processes are present prior to symptom onset (Kilicarslan et al., 2014). No reports of brain fMRI changes in patients with pain conditions including headache have been noted.

Analgesic Treatments for Acromegaly:

Drugs that block GH such as those targeting the somatostatin receptor are often used (Chin et al., 2019) Mindfulness and compassion techniques were utilized by one clinical trial to manage chronic pain, sleep problems, mood, and blood pressure in adult patients carrying a diagnosis of Acromegaly. The weekly therapist-led group sessions and daily assigned meditations were paired with assessments and surveys, and aimed to explore the effects of mindfulness on quality of life (NCT04420000)

2.3.2. Chordoma (https://rarediseases.org/rare-diseases/chordoma/)

Chordomas are slow growing tumors found along the spinal cord (George et al., 2015)) – from the base of the skull or in the sacrococcygeal region (Jeys et al., 2008; Pillai and Govender, 2018). They develop from the residual embryonic notochord. For many patients, the condition presents in adulthood.

Pain in Chordoma:

Chronic pain is reported in 35 % of patients (Song et al., 2017). Pain is usually related to the location of the chordoma – for example sacrococcygeal or lumbar chordomas are associated with low back pain and neuropathic pain from nerve root involvement (Heery, 2016) or in other regions of the spinal cord that may result in spinal cord compression and pain (Liu et al., 2019) The prevalence of neuropathic pain after surgical resection of sacral chordomas is over 50 % (Phimolsarnti and Waikakul, 2015).

Psychological Comorbidities in Chordoma:

Depression and anxiety are reported in 32 percent of chordoma patients (Song et al., 2017).

Brain Changes in Chordoma:

We are unaware of any fMRI related measures in patients with Chordoma.

Analgesic Treatments in Chordoma:

Treatment usually involves surgical resection and radiation therapy (Atalar et al., 2006; Pendharkar et al., 2015). A clinical trial looking to compare surgical resection and radiation therapy outcomes in primary localized sacral chordomas is still ongoing but will examine differences in relapse-free survival rate and pain reporting between the two treatment methods (NCT02986516).

2.4. Metabolic disease

2.4.1. Fabry disease (FD) (https://rarediseases.org/rare-diseases/fabry-disease/)

FD is an X-linked disorder of glycosphingolipid metabolism as a result of a deficiency within lysosomes of alpha-galactosidase A activity affecting 1 in 100,000 individuals (Germain, 2010). It is a multisystem disease and produces pain, the most frequent symptom, in most patients within the first decade of life (Ries et al., 2005).

Pain in FD:

Damage occurs in small fibers (C and A-delta) affecting sensory (Dütsch et al., 2002) and autonomic (Cable et al., 1982) systems. Pain is frequently severe in the first three decades of life (Schiffmann and Scott, 2002). The damage to the nerves is length dependent and affects cold and warm perception in a manner that exposure to cold may worsen pain (Schiffmann and Scott, 2002). Pain is observed in around 60 % of males, occurring at a slightly younger age than females (median age of male onset is 7 yrs.) (Hopkin et al., 2008).

Psychological Comorbidities in FD:

Depression and anxiety levels in FD are high (Laney et al., 2010) and may be present in over 50 % of patients with FD (Lelieveld et al., 2015). Males are more likely to report symptoms of depression and/or anxiety (Sigmundsdottir et al., 2014). Additionally, these patients often present with decreased quality of life (Bugescu et al., 2016).

Brain Changes in FD:

A number of fMRI studies have been conducted in FD including gray mater volume in hippocampi and thalami (Pontillo et al., 2018; Fellgiebel et al., 2012). The hippocampal volume loss worsens over time (Lelieveld et al., 2015). Both structures are part of the pain connectome and similar changes observed in chronic pain, but their specific involvement in pain is not yet defined in this disease. Functional connectivity changes relate mostly to motor circuits (Cocozza et al., 2017) and cognitive performance (Cocozza et al., 2018).

Analgesic Treatments in FD:

Enzyme replacement therapy improves the pain symptoms (Schiffmann and Scott, 2002) aside from standard analgesic for neuropathic pain (Politei et al., 2016). Lucerastat is a novel therapeutic for FD that aims to reduce the accumulation of glycosphingolipids that cause pain in these patients. The clinical trial is examining the safety and efficacy of lucerastat to relieve neuropathic pain in all patients and abdominal pain in patients with GI symptoms (NCT03425539)

2.5. Musculoskeletal

2.5.1. Fibrodysplasia ossificans progressiva (https://rarediseases.info.nih.gov/diseases/6445/fibrodysplasia-ossificans-progressiva/)

FOP is a very rare (1:2,000,000) connective tissue disease that transitions (heterotopic) various connective tissues to bone (heterotopic ossification), with ~800 documented cases worldwide (Peng et al., 2019). It is the result of a mutation of the activin receptor IA/activin-like kinase 2 (Kaplan et al., 2008).

Pain in FOP:

We have previously reported pain related symptoms in FOP (Peng et al., 2019). Episodic flareups are a result of soft tissue injury and the progressive ossification may lead to immobility as bone replaces muscle (Kaplan et al., 2008). Minor trauma may precipitate inflammation and bone deposition with similar flareup pain (Peng et al., 2019). Moderate to severe pain is associated with flare ups – occurring in over 50 % of patients, but patients also may have significant pain during non-flare up states. Surgical removal or other invasive treatments may exacerbate the condition. Spinal abnormalities may result from fusion of facet joints leading to stiffness. Patients with FOP also tend to present with recurrent and severe headaches, neuropathic pain of the lower extremities, and somatosensory abnormalities (Pignolo et al., 2016; Kitterman et al., 2012).

Psychological Comorbidities in FOP:

A strong correlation of emotional problems is observed in 36–48 % of patients with FOP (Peng et al., 2019) and our group found that anxiety, depression and irritability were prevalent in patients even when not experiencing a flare-up (Peng et al., 2019).

Brain Changes in FOP:

Little is known about brain changes in FOP.

Analgesic Treatments for FOP:

There is no definitive treatment for FOP (Qi et al., 2017) and many treatments (e.g., surgery) make the condition worse (see above). Novel drug therapy REGN2477 (garetosmab) is a blocking antibody infusion that keeps the mutant receptor in FOP from turning on, which should stop the abnormal bone growth. REGN2477 is in its clinical trial phase to determine its safety and tolerability, as well as assess any changes from baseline in pain scores and heterotopic ossification lesions in FOP patients who receive the drug versus a placebo (NCT03188666).

2.5.2. Osteogenesis Imperfecta (OI (https://rarediseases.org/rare-diseases/osteogenesis-imperfecta/))

OI, also known as brittle bone disease, results from a defect in collagen type 1 biosynthesis and has a number of subtypes (Van Dijk et al., 2010; Tournis and Dede, 2018). It is a disease found in pediatric and adult patients.

Pain in OI:

Acute and chronic pain is common in OI and may result from fractures and other causes such as articular pain and back pain, often including scoliosis (McKiernan, 2005). Pain may thus include fracture and non-fracture pain (Zack et al., 2005).

Psychological Comorbidities in OI:

OI is a challenging disease for patients and parents (Dogba et al., 2013; Dung et al., 2013). Of note, parents of children with higher levels of pain and diminished physical functioning are themselves at risk for increased stress and diminished quality of life (Lazow et al., 2019). Interestingly, it has been found that children with OI often minimize their pain in order to protect their parents from their illness (Tsimicalis et al., 2016).

Brain Changes in OI:

We are unaware of any fMRI related studies in the disease.

Analgesic Treatments in OI:

Intravenous bisphosphonates are used to enhance bone density. Other therapies include denosumab, teriparatide, sclerostin inhibition, combination therapy with antiresorptive and anabolic drugs and TGF-β inhibition (Tournis and Dede, 2018). Pain control for surgical patients is a particular challenge. Further bone loss from post-operative immobilization or non-weightbearing instruction was addressed in a clinical trial for single dose pamidronate to reduce risk of future lower extremity fractures (NCT00655681). Another clinical trial examined the combination effect of parathyroid hormone and zoledronic acid on adult OI patients on reducing incident fractures and reported pain scores (NCT03735537).

2.6. Nervous system

2.6.1. Charcot marie tooth (CMT) (https://rarediseases.org/rare-diseases/charcot-marie-tooth-disease/CMT)

CMT includes a group of genetic (autosomal dominant, recessive or X-linked) disorders with progressive sensory-motor neuropathy (Claussen, 1988). The prevalence is 1:2500 (McCorquodale et al., 2016). The long fibers are first affected, and patients have difficulty with use of hands and feet. Sensory changes include diminished sensation to heat, pain or touch. The disease is slowly progressive. Although there are multiple subtypes of CMT, we will discuss type 1A as it is more relevant to our discussion of chronic pain.

Pain in CMT:

Pain is frequently present in this condition (Ribiere et al., 2012). In the studies listed, approximately 60–70 percent of patients reported pain, often in the moderate range. Pain is most commonly spine, knees, ankles and feet (Legorreta et al., 1988; Carter et al., 1998). In a study utilizing laser evoked potentials (LEP), the authors indicate that A-delta fibers may be the major contributor to the neuropathic pain state (Pazzaglia et al., 2010). Regarding this data, a study utilizing thermal threshold supported the LEP findings of small fiber dysfunction in A delta fibers (Laurà et al., 2014). Confocal corneal microscopy in patients with CMT disease a number of changes are observed including decreased corneal sensitivity and alteration in the morphology of corneal nerves (decreased corneal fiber density, fiber branch density, fiber length), all indicators of alteration in C-fibers (Tavakoli et al., 2012). Combining data from these reports, the condition is most likely a mixed small fiber neuropathy.

Psychological Comorbidities in CMT:

Patients with CMT trend more towards depressive symptoms than the general population (Cordeiro et al., 2014) and Pediatric patients with CMT report higher psychological distress and social impairment compared to their healthy classmates. The severity of their psychological problems varies by type of CMT and tends to get worse with age (Burns et al., 2010).

Brain Changes in CMT:

Resting state functional connectivity measures have indicated significant alterations in the brains of these patients that are partially correlated with peripheral nerve damage (Pontillo et al., 2020a, 2020b). Gray matter volumes indicated increase volumes in cerebellum and hippocampus (Pontillo et al., 2020a, 2020b). The cerebellum is of interest since it seems to be involved in a number of autonomic functions including the sensory system (including pain) as well as emotional functioning (Moulton et al., 2011). Measures of the sciatic nerve using Diffusion Tensor Imaging (DTI) indicate decreased volumes suggestive of loss or damage to nerve fibers (Dortch et al., 2014).

Analgesic Treatments for CMT:

No evidence supports specific medications for CMT, although combination treatments have been tried for neuropathic pain (Attarian et al., 2014; Chumakov et al., 2014). Selected trials have focused on ascorbic acid as a known promoter of myelination for motor dysfunction (Passage et al., 2004). Based on current understanding of motor-sensory integration for pain, improvement of sensory function may also influence motoric activity (Geneen et al., 2017). Coenzyme Q10, an essential electron carrier within the Mitochondria, is being investigated in clinical trials for its cytoprotective and neuroprotective qualities. CoQ10 in the form of daily 300 milligram wafers is being tested for its ability to reduce pain and weakness while improving overall quality of life in CMT patients (NCT00541164).

2.6.2. Neurofibromatosis type 1 (https://rarediseases.org/rare-diseases/neurofibromatosis-type-1-nf1/)

NF1 is a genetic (autosomal dominant) multisystem disease affecting 1:3500 individuals that include plexiform neurofibromas affecting peripheral nerves and plexuses (Boyd et al., 2009; Packer et al., 2002).

Pain in NF1:

Pain is common in most NF1 patients originating from malignant peripheral nerve sheath tumors (Bellampalli and Khanna, 2019). Chronic pain is common in pediatric and adolescent patients (Wolters et al., 2015).

Psychological Comorbidities in NF1:

As in many neuropathic pain conditions there is a high level of depression and anxiety in patients with NF1 (Wang et al., 2012). In addition, patients have increased perceived stress (Wang et al., 2012) and cognitive deficits may occur in children (Hyman et al., 2005). Such issues may contribute to overall functional ability relating to their overall QoL that includes pain interference (Hamoy-Jimenez et al., 2020).

Brain Changes in NF1:

Using diffusion imaging techniques, alterations in white matter microstructure (increased radial diffusivity) is reported to be present that corresponds with increase white matter volume suggestive of looser packing of axons (Karlsgodt et al., 2012). In addition, cerebellar abnormalities have been reported (focal abnormal signal intensities) (Salman et al., 2018) indicative of potential anatomical alterations that may alter brain functional connectivity. Resting state fMRI has indicated an abnormal functional connectivity (reduced anterior-posterior) in NF1 patients (Tomson et al., 2015). Segregation of such changes have not been evaluated in patients with and without pain. Interestingly, lovastatin (a drug used for hypercholesterolemia) may regulate low frequency brain activity as measured by modulation of anterior-posterior and local in resting state functional connectivity in NF-1 (Chabernaud et al., 2012). Other reports of frequency evaluation, including our own (Hodkinson et al., 2019) have also reported changes in low frequency patterns correlating with pain processing (Ploner et al., 2017; Lin et al., 2016).

Analgesic Treatments for NF1:

Treatments include analgesics for underlying neuropathic symptoms and surgical treatment (Buono et al., 2019). Other treatments have generally been empiric until recently, with the use of biological based drugs that target tumor growth are being used. Trials in children are complicated by age, toxicity and the nature of cancer treatment trials (Kim et al., 2009). An alternative to traditional analgesic therapies for NF1 in younger populations is Acceptance and Commitment Therapy (ACT), a behavioral intervention aimed at addressing avoidance behaviors by increasing openness to difficult experiences, such as pain, and to develop awareness of behavioral options that will aid to facilitate behavior change processes that are in accord with living a values-based life (Hayes, 2016). A clinical trial is leading patients with NF1 through ACT workshops and goal setting exercises to shift the focus from how to avoid their pain to how to manage pain and anticipates reductions in pain-related anxiety and depression (NCT01633008).

2.7. General comments on RD and pain

As noted in the examples above, while pain in RDs share some characteristics of more common pain disorders, such as centralized pain, there are also key differences in the pain presentation of patients with RDs including later onset degeneration (e.g., arthritis, including back pain), traumatic nerve damage (e.g., post-surgical neuropathic pain), and complications secondary to infection (e.g., post herpetic neuralgia). Additionally, unlike many syndromes that have a more delayed onset with aging, RDs may be expressed earlier across the age spectrum. Furthermore, while the subdivisions noted in Table 2 are based on www.rd.gov, some of these conditions may produce an overlapping pain syndrome, such as those that directly affect pain fibers (e.g., Fabry Disease) or resulting in an acute on chronic condition from repeated injuries (e.g., Ehlers-Danlos) or repeated fractures (e.g., Osteogenesis Imperfecta). Finally, in some but not all, replacement therapies may be useful in disease modifying as well as in producing analgesic effects. However, in most conditions, pain persists despite these targeted therapies as well as the inherent resistance to pain treatment, common to many chronic pain conditions. Given the complexities of how pain modifies our brain connectome, a number of contributing factors may exacerbate pain including anxiety, depression, physical disabilities, difficulties in daily activities including school attendance, as well as self-esteem, especially in patients with a dysmorphic state. Changes within the motor-cortex, which affects sensory-motor function, are known to be related to chronic pain, but it is unknown which causes the other (Mercier and Léonard, 2011). Altered brain systems due to fear of pain and anxiety may exacerbate the underlying pain condition (Turk and Wilson, 2010; Martin et al., 2007; Martinez-Calderon et al., 2019; Simons, 2016). These issues are discussed in Section 3: below.

2.8. Pain, stress, and anxiety in RD

The pain type, location for the examples noted above are summarized in Table 2. In addition to pain comorbid changes may exacerbate their condition. Both acute pain and acute stress are important challenges that allow us to adapt to our changing environment but become maladaptive, however, when either wears on the body for too long. It is important to keep in mind that the interaction between pain and stress/anxiety is bidirectional. For example, chronic pain patients may develop an abnormal stress response, which in turn exacerbates their chronic pain (Vachon-Presseau, 2018). Stress and pain are continuously remodeling the learning and emotional circuitry within the corticolimbic system of the brain, both physiologically and structurally, in conditions like chronic pain and depression (Abdallah and Geha, 2017). Psychological processes (fear of pain, avoidance, anhedonia) in patients with anxiety are known to be both predictors and exacerbators of pain. Pain with comorbid psychiatric disorders like anxiety see lowered efficacy of treatment, increased pain reporting, and chronification of pain (Borsook et al., 2018).

3. Dysmorphia, rare disease and chronic pain – effects on psychosocial measures

3.1. Ongoing pain

While most conditions start in childhood, some express in adulthood (e.g., spinocerebellar ataxia (Bogart and Dermody, 2020) and chronic pain is present in both populations and has been found to have a detrimental impact of quality of life. Living with a RD has been associated with decreased health-related quality of life (HRQL) with one study finding that patients with RDs, when compared to patients with common chronic diseases (Bogart and Irvin, 2017). Risk factors for poor HRQL among patients with RDs include those with rare systemic and rheumatologic, neurological and immune diseases as well as being older, female or from a lower socioeconomic status (Bogart and Irvin, 2017). Interestingly having a formal diagnosis for a longer duration is also associated with better HRQL (Bogart and Irvin, 2017) perhaps tapping into disease acceptance.

3.2. Conditions with disability

There is little information on the impact of physical disabilities and RD (de Chalendar et al., 2014). There have been efforts to improve knowledge through programs such as Orphanet (https://www.orpha.net), which has significant potential if motor-based therapies are engaged with as a non-pharmacological tool for pain treatment (Holmes et al., 2020; Neurobiology of Pain). Additionally, there does not seem to be any research on the impact of having a co-morbid cognitive impairment or intellectual disability and an RD with chronic pain. This should be further explored as the pain in this population (RD + cognitive impairment or intellectual disability) may be under-recognized and under-treated, especially in patients with communication impairments who may be unable to verbally express pain (McGuire et al., 2010).

3.3. Psychological impact – RD and pain

While pain is common in many RDs – for example in Marfan Syndrome- with nearly 90 percent reporting pain and almost 30 % as a presenting symptom stress is also a persistent component of the disease (Speed et al., 2017), A number of issues may contribute to increased stress in RD that leads to anxiety and diminished mood (Uhlenbusch et al., 2019). Stress may also be exacerbated by delayed and incorrect diagnosis (see below). Pain is not a unitary sensation evoked by a local injury, inflammation or other tissue pathology but is also a complex state modulated by (to name a few) emotional and cognitive factors. In addition to the epidemiological association between pain and negative affective states (IsHak et al., 2018), clinical and even diagnostic features of pain syndromes point to their neuropsychiatric etiology (Elman and Borsook, 2018). The International Association for the Study of Pain defines pain by as "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" (https://www.iasp-pain.org). Such blurring of sensory/emotional boundaries is evident in the lay language where the “pain” term is used interchangeably in both contexts (Takahashi et al., 2009). Negative affective states enhance pain, whereas pain evokes depression, anxiety, anger, catastrophizing and demoralization (i.e., feedforward interaction) leading to further pain (Elman and Borsook, 2018) that may eventually produce chronicity along with a transition from an occasional analgesic use to opioid addiction (Elman and Borsook, 2016).

A comprehensive set of emotional, motivational and cognitive processes are applicable for evaluating an RD patient, in weighing the prospects of pain relapse or deterioration and in evaluating the outcomes of the ongoing therapy. Impairments in the functioning of these mechanisms may determine whether a patient achieves control over pain or whether pain attains control over a patient. As with many other life experiences, pain is subjectively evaluated according to distinct mental operations including “editing” (Kahneman and Tversky, 1979) that readjusts the experience of continues pain or of successful analgesia with respect to a tolerable amount of pain. Patients with earlier onset of pain and resultant developmental delays may (re)formulate coping strategies to allow a greater tolerance of pain (Gilbert-Macleod et al., 2000) that up to the limit of this new ‘neutral state’ is not perceived as an aversive experience (Kahneman and Miller, 1986). This strategy follows the model of allostasis, in that the patients adapted to and coped with a consistently heightened pain state by changing the defended levels of regulated parameters to adjust to their new normal (Ramsay and Woods, 2014). Importantly, this sort of pain hyposensitivity in RDs patients (Letts and Hobson, 1975) may be apparent in the context of real-life situations, for example, tissue damage following surgical treatment to grave medical outcomes as silent myocardial infarction or delays in management of abdominal emergencies that could be followed by perforated bowel and ruptured appendix (Elman et al., 2006).

As another consideration, beauty is a ubiquitously recognized esthetic characteristic, valued by most people while disfigurements associated with RDs can evoke a sense of shame, disappointment and ostracism. Indeed, studies of children who have suffered abuse consistently link disfigurements to maltreatment by the caregivers (Barden et al., 1989; Hibbard et al., 2007). This may be to some extent because adults are unconsciously motivated to care for infants with healthy facial features indicating fitness for survival and to exclude the least fit (Glocker et al., 2009; Wang et al., 2018). Prospective research is needed to examine implication of esthetic defects on pain and on potential for abuse and neglect of children. Further research is also needed to determine the neural substrate underlying emotional responses to esthetic problems and how it may be involved in the psychopathologies of pain conditions.

3.4. Socioeconomic costs

Economic burden in RD is significant. The most extensive review of socioeconomic burden and cost of illness in rare disease is a study by the BURQOL-RD project ("Social Economic Burden and Health-Related Quality of Life in patients with Rare Diseases in Europe" (see Angelis et al., 2015). Other non-financial burdens, including schooling, may be a challenge because, in part, due to low numbers of children affected and the specific requirements that some RD may require (Paz-Lourido et al., 2020). Couple this with the significant costs of chronic pain (an estimated $635 billion is spent annually in the United States due to pain related disability (Gaskin and Richard, 2012)), having a co-morbid RD and chronic pain is a significant socio-economic burden,

3.5. Medical knowledge

While specialists may be well versed in specific rare disease, primary care physicians may have limited exposure to patients with RD (Domaradzki and Walkowiak, 2019) as well as limited expertise in treating associated pain a number of websites have been established to encourage understanding in this domain (e.g., see Table 3) and often patients have to become experts on their own disease in order to educate physicians about their condition (Budych et al., 2012). Additionally, it has been reported that parents may wait more than 10 years before receiving a diagnosis, often made worse by incorrect diagnoses (Anderson et al., 2013), thus delaying specialist evaluation. For patients with co-morbid RD and pain, these diagnostic delays can be detrimental by resulting in unchecked disease progression and increased risk and severity of morbidity later in life, especially as it relates to the maintenance and exacerbation of chronic pain. The longer a patient has untreated and or poorly understood pain, the increased chance that the pain will become centralized. Independent of pain treatment, treatment of RD is challenging and as noted from the different etiologies, complexity of underlying pathophysiologies, and different regions of the body being affected, numerous other specialties (e.g., neurology, psychiatry, immunology, pharmacy, physical therapy etc.) are frequently needed (Wolyniak et al., 2015).

Table 3.

Definitions related to pain.

Term	Definition	Reference
Acute Pain	Awareness of noxious signaling from recently damaged tissue, within the central nervous system (CNS). Has been present for less than 3 months.	King, 2013
Chronic Pain	Chronic primary pain represents chronic pain as a disease in itself, and chronic secondary pain is chronic pain where the pain is a symptom of an underlying condition. Both must be present for more than 3 months.	King, 2013. IASP, 2012
Neuropathic Pain	Pain caused by a lesion or disease of the somatosensory nervous system.	IASP, 2012
Nociceptive Pain	Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors.	IASP, 2012
Visceral Pain	Pain that is diffuse and poorly localized, caused by inflammation, damage or disease to internal organ.	Collett, 2013
Hyperalgesia	Increased pain from a stimulus that normally provokes pain.	IASP, 2012
Pain Chronification	The process of transient pain progressing into persistent pain.	Morlion et al.,2018
Pain Connectome	Pain variability encoded in brain communication.	Kucyi and Davis, 2015
Resting State Networks	Discernable functional communities within the brain.	Fricchione and Beach, 2019
Allodynia	Pain due to a stimulus that does not normally provoke pain.	IASP, 2012

4. Other considerations- economics, drugs and brain state

4.1. Economics of rare disease treatment – opportunities

The average annual cost of medications for rare disease rose from around $7000 in 2007 to over $187,000 in 2017 (https://www.ahip.org/drug-prices-for-rare-diseases-skyrocket-while-big-pharma-makes-record-profits/). Treatment costs for RD are very high: for example, the lifetime costs of treating GD1 with ERT is over 5 million Euros (Van Dussen et al., 2014) and for Fabry’s disease is over $13 million (Rombach et al., 2013). These costs do not incorporate the overall costs at a societal level (Angelis et al., 2015; Cannizzo et al., 2018).

4.2. Pharmaceutical strategies

Because RDs usually have relatively few patients, it is more difficult to perform randomized controlled trials particularly in the pediatric populations, and retro use on biologic targets. The strategy is enhanced by the notion of a specific defect that can be targeted, and the potential “off label” benefits such as analgesia as is seen with some current therapies for the disease condition that may ameliorate pain symptoms. Because RD usually cannot do randomized controlled trials in pediatric and retro use on biologic targets, a number of countries have embraced the notion of RD to enhance the development of orphan drugs (see Ekins, 2017).

4.3. Drug trials in rare disease

Drug discovery and development for RD by both large pharmaceuticals and biotech startups (www.medicalstartups.org > top > rare) has been enhanced by precision medicine (e.g., target based and phenotypic screens) and also advocacy groups including disease foundations and patients themselves (Slade et al., 2018). Many RD conditions have support groups that monitor developments in the field (including new treatments), provide financial help to research enterprises (see Table 3). As such, acceleration of drug discovery and development in the RD domain has increased (Sun et al., 2017). In addition, drug repurposing and Biologics, including stem cell approaches, are all being used. As noted by others for challenges in the condition of neuronal ceroid lipofuscinosis, there are disease specific barriers to therapeutic success, including an incomplete understanding of diseases pathophysiology and medications that are unable to cross the blood-brain barrier in order to access the central nervous system (Augustine et al., 2013). As well, recruiting for clinical trials of rare disease is challenging, as exemplified for the condition of trigeminal neuralgia (Zakrzewska et al., 2018).

4.4. Brain biomarkers for disease state and analgesic responses – from fMRI to fNIRS

As noted above, given the relative rarity of these disease entities, performing RTC type trials is challenging for neuroimaging evaluations that typically require moderate group sizes (approximately 20–30) to perform. With the increased sensitivity of modern scanners and integration of machine learning techniques (Holmes et al., 2019; Pain Reports), a viable approach towards understanding RD is the use of N-of-1 trials (Borsook et al., 2020). The application of an N-of-1 method implemented for drug vs. placebo or drug vs. current standard alongside structural and/or functional neuroimaging can provide a robust evaluation of the disease and pain connectome and a viable approach for studying paradigms with orphan drugs. Notably, such approaches require particular research methods and their applicability towards a general populus may be marginal; however, knowledge gained can be applied towards improving treatment of the respective RD, its related comorbidities, and our understanding of the distributed nature of pain processing in the brain (see Coghill, 2020). While the standard imaging method fMRI (functional magnetic resonance imaging) allows one to capture structural and functional images of the brain, a relatively new approach for evaluation of brain function in pain and analgesia uses near infrared spectroscopy – fNIRS (Karunakaran et al., 2020). FNIR imaging detects ongoing neural activity and connectivity, effectively testing cognitive functionality and neural communication. A major advantage of this approach in RD is that the fNIR cap is portable and can be used in any space, including homes, when patients are at RD meetings or in physician offices, thus not requiring patients to be in the fMRI scanner, which for some, for example, FOP or OI may be challenging.

5. Conclusions

The impact of living with an RD can be devastating for patients, their families and society as a whole, including the ongoing need for surgical interventions, disability, disfigurement, rejection, and chronic pain that may arise due to pathophysiological or iatrogenic (i.e., induced by various treatments) causes. RDs are frequently affected by acute, acute on chronic (i.e. joint dislocations in EDS, flare-ups in FOP), as well as chronic pain. In this review, we underscored the importance of providing clinical and scientific rationale for psychosocially- and neuro-developmentally-enriched care of patients with RDs with regard to their pain as well as for raising the awareness and sensitivity of clinicians, scientists, and policy makers alike to this important yet unmet medical and public health need.

As with many difficult clinical conditions, the initial focus is on the disease state and not associated symptom management such as chronic pain. Systematic evaluation of chronic pain in patients with RDs contributes to a deeper and more sophisticated insight into both pain conditions and their psychosocial correlates. Furthermore, it underscores the necessity of a multi/inter- disciplinary team-based approach drawing upon complementary strengths in the domains of pain medicine, mental health, surgery, anesthesiology, endocrinology, social services and community outreach specialists appreciating each member’s strengths and the synergistic nature of their contribution. Additionally, the development of novel therapeutics for a specific RD is likely to contribute to the alleviation of pain through disease modification and may be improved through greater integration of neuroimaging studies and n-of-1 trials, methodologies, which hold promise for transforming the lives of those living with RDs.