Pain Phenotypes in Rare Musculoskeletal and Neuromuscular Diseases

Abstract

For patients diagnosed with a rare musculoskeletal or neuromuscular disease, pain may transition from acute to chronic; the latter yielding additional challenges for both patients and care providers. We assessed the present understanding of pain across a set of ten rare, noninfectious, noncancerous disorders; Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Achondroplasia, Fibrodysplasia Ossificans Progressiva, Fibrous Dysplasia/McCune-Albright Syndrome, Complex Regional Pain Syndrome, Duchenne Muscular Dystrophy, Infantile- and Late-Onset Pompe disease, Charcot-Marie-Tooth Disease, and Amyotrophic Lateral Sclerosis. Through the integration of natural history, cross-sectional, retrospective, clinical trials, & case studies we described pathologic and genetic factors, pain sources, phenotypes, and lastly, existing therapeutic approaches. We highlight that while rare diseases possess distinct core pathologic features, there are a number of shared pain phenotypes and mechanisms that may be prospectively examined and therapeutically targeted in a parallel manner. Finally, we describe clinical and research approaches that may facilitate more accurate diagnosis, monitoring, and treatment of pain as well as elucidation of the evolving nature of pain phenotypes in rare musculoskeletal or neuromuscular illnesses.

1. Introduction

Patients diagnosed with rare musculoskeletal and neuromuscular conditions often present with objective clinical features. For example, in pediatric and adult fibrous dysplasia/McCune-Albright Syndrome (FD/MAS) or osteogenesis imperfecta (OI), aberrant skeletal structure and non-traumatic, bone fractures frequently occur (Rauch and Glorieux, 2004; Robinson et al., 2016), while in infantile- or late-onset Pompe disease (IOPD or LOPD), individuals may demonstrate muscle weakness, feeding problems, or respiratory difficulties (McCall et al., 2018). Such robust clinical occurrences rightfully dictate clinical care, yet other debilitating features experienced by patients, which are more subjective and vary in severity over time, such as pain, may go underdiagnosed and undertreated (Henry and Matthias, 2018; Tait et al., 2009). Importantly, for many rare musculoskeletal and neuromuscular disease patients, pain can develop into a chronic, co-morbid illness. Additionally, some disorders may present with atypical pain symptomology instead of the cardinal features of the condition and potentially should be considered as differential diagnosis within this spectrum of disorders, mimicking each other.

Rare musculoskeletal disorders; characterized by dysfunction of muscles, tendons, ligaments, joints, and skeletal tissue; and rare neuromuscular disorders, which involve direct injury or damage to peripheral nerves and surrounding soft tissues (Morrison, 2016); together account for significant disease with a broad range of etiologies. We hypothesize that while there is significant genetic and pathogenic heterogeneity across rare conditions, there are common pain phenotypes present across diseases suggesting the potential of shared pain mechanisms that may be investigated and therapeutically targeted. For many rare conditions as well as during distinct stages of a disease, there can be clear indications of physical trauma (e.g., soft-tissue edema or nerve compression) that can act as primary and peripheral sources of pain (Kim et al., 2013). However, there are also occurrences where the magnitude of self-reported pain is disproportionate to the severity of detectable pathology, or that pain is present during a ‘dormant’ stage of the disease (Marinus et al., 2011). In these cases, we project that pain may be derived or amplified by central factors; a feature seldomly investigated or treated in rare conditions.

Here, a series of rare diseases with musculoskeletal and neuromuscular pain characteristics (e.g., location, severity, onset and offset conditions, quality, triggers, analgesics strategies, etc.) are described. Pain in musculoskeletal conditions can be derived from a range of pathological features including recurrent bone fractures, skeletal lesions, heterotopic ossification, defective connective tissue or an aberrant response to limb injury. From a neuromuscular, but also musculoskeletal standpoint, pain may occur from muscular pathology/lesions such as myositis, lysosomal storage dysfunction, as well as direct damage to muscle or nerve fibers. Considering mainly these and other clinical events, the following ten rare musculoskeletal and neuromuscular conditions are reviewed; OI, Ehlers-Danlos Syndrome (EDS), Achondroplasia (AP), Fibrodysplasia Ossificans Progressiva (FOP), FD/MAS, Complex Regional Pain Syndrome (CRPS), Duchenne Muscular Dystrophy (DMD), IOPD/LOPD, Charcot-Marie-Tooth Disease (CMT), and amyotrophic lateral sclerosis (ALS). Each condition is reviewed in terms of disease overview, pain phenotype, and treatment approaches. We project that what is learned from studying the shared pain mechanisms in these distinct conditions may further our understanding and treatment of pain in both rare and common diseases.

2. Methods

2.1. Criteria for considering diseases for this review

All diseases evaluated in this review were listed in the National Organization for Rare Disorders (NORD) database. Each condition met the prevalence criteria for a rare disease; affects fewer than 200,000 United States citizens, or in the European Union, a disease occurring in fewer than 1 in 2000 individuals (2010; Nguengang Wakap et al., 2020). From the NORD database, six musculoskeletal disorders (e.g., OI, EDS. AP, FOP, FD/MAS, CRPS), and four neuromuscular disorders (e.g., DMD, IOPD/LOPD, CMT, ALS) were selected for this review. Disorders were chosen based on the availability of robust literature on disease pathogenesis, pain phenotype, and treatment approaches. Infectious or cancerous disorders were excluded from this review.

2.2. Design of this review

Each condition has been individually reviewed with the following framework; i.) disease overview, which includes data related to etiology, epidemiology, diagnostic criteria, and the clinical manifestations of the condition, ii.) pain phenotype, which includes the primary driver of pain, clinical pain manifestations, alleviating and aggravating factors, as well as associated conditions that influence the manifestation of pain and iii.) treatment approaches which includes pharmacologic and surgical, acute and chronic, as well as symptomatic and disease modifying therapies. The salient pain mechanisms and treatment modalities of each condition are then discussed comparatively across the ten conditions.

2.3. Information strategy and search terms

The literature review was conducted using published literature, clinical trials, cohort studies, case reports, and systematic reviews. Studies selected for inclusion in this review were accessed through a search of MEDLINE, PUBMED, Google Scholar, & CENTRAL from 1942 to 2020. The search terms included subject headings, text words, and keywords with the following terms: “pain mechanisms in rare diseases”, “nociceptive signaling”, “nociplastic signaling”, “neuropathic signaling”, “centralized pain”, “central sensitization”, “pain chronification”, “peripheral sensitization”, “osteogenesis imperfecta pain in adolescents/adults”, “acute fracture pain”, “chronic non-fracture pain”, “extraskeletal symptoms in osteogenesis imperfecta”, “musculoskeletal manifestations of osteogenesis imperfecta”, “bisphosphonates in osteogenesis imperfecta”, “brittle bone disease”, “analgesics in osteogenesis imperfecta”, “neuropathic pain in osteogenesis imperfecta”, “Ehlers-Danlos clinical features”, “Ehlers-Danlos pain phenotypes”, “Ehlers-Danlos”, “pain mechanisms in Ehlers-Danlos”, “Ehlers-Danlos therapies”, “achondroplasia”, “achondroplasia clinical features”, “achondroplasia genetic features”, “achondroplasia pain phenotypes”, “pain mechanisms in achondroplasia”, “achondroplasia therapies”, “fibrodysplasia ossificans progressiva”, “heterotopic ossification”, “pain in fibrodysplasia ossificans progressiva”, fibrodysplasia ossificans progressiva flares”, “fibrodysplasia ossificans progressiva quiescent pain”, “myositis ossificans progressiva”, “fibrodysplasia ossificans progressiva analgesics”, “fibrous dysplasia clinical features”, “fibrous dysplasia genetic changes”, “fibrous dysplasia/McCune Albright syndrome”, “pain mechanisms in FD”, “extraskeletal manifestations of FD”, “therapies in fibrous dysplasia”, “CRPS genetic changes”, “complex regional pain syndrome”, “CRPS pathogenesis”, “pain mechanisms in CRPS”, “CRPS biomarkers”, “CRPS treatment”, “DMD clinical features”, “DMD genetic changes”, “Duchenne muscular dystrophy”, “Duchenne muscular dystrophy genetic mutations”, “dystrophin gene”, “Duchenne muscular dystrophy and pain”, “therapies in DMD”, ““Pompe genetic mutations”, “Pompe clinical features”, “Pompe disease and pain”, “IOPD”, “LOPD”, “glycogen storage disease type II and pain”, “pain with inborn errors of metabolism”, “therapies in Pompe disease”, “CMT clinical features”, “CMT genetic mutations”, “pain in CMT”, “therapies in CMT”, “Charcot-Marie-Tooth disease”, “CMT therapies”, “hereditary motor sensory neuropathy”, “ALS clinical features”, “ALS genetic mutations”, “amyotrophic lateral sclerosis”, “ALS”, “ALS pain phenotypes”, “pain mechanisms in ALS“, “Lou Gehrig’s Disease”, “opioids therapies in rare disorders”, “bisphosphonates in rare disorders”, “therapies in rare disorders”, “psychotherapy in rare disorders”, “pain and quality of life in rare disorders”, “analgesic efficacy in rare disorders”, “enzyme replacement therapy in Pompe disease”, “surgical management of pain in rare disorders”.

3. Brief overview of pain mechanisms

3.1. Introduction to pain terminology

Pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” according to new guidelines from the International Association for the Study of Pain (IASP) . Historically, pain was dichotomized into nociceptive or neuropathic types, the former arising from actual tissue damage that leads to the activation of tissue nociceptors, and the latter arising from a disease or direct lesion to the somatosensory system. The IASP has recently adopted the term “nociplastic pain” to describe “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain”) (Raja, 2020). “Nociplastic pain” appears to replace the older term “centralized pain” which describes a similar phenomenon. Given the recency of this terminology change, much of the literature still utilizes the term “centralized pain” and thus we will use this term when it is referred to as such in the respective literature. It is important to note that neuropathic, nociceptive, or nociplastic pain may exist independently or together in a single disease state such as low back pain in which cases providers are encouraged to identify the predominant type and treat accordingly (Nijs, 2015). Inflammation may contribute to pain across pain states and therefore individual disease or disorders. Furthermore, in accordance with IASP terminology, we note the occurrence of “Central sensitization - increased responsiveness in the central nervous system to their normal or sub-threshold afferent input” and “Peripheral sensitization – increased responsiveness and reduced threshold of nociceptive neurons in periphery to the stimulation of their receptive fields” (IASP Terminology).

3.2. Pathophysiology of pain

The perception of pain often serves as a distressing sensation and emotional experience that is associated with potential or actual tissue damage. Pain sensation is divided into three main stages: 1) transduction - activation of the nociceptor, 2) transmission - signal transmission via primary afferent fibers to the dorsal horn (DH) in the spinal cord, and 3) modulation - signal transmission from the DH to higher brain centers using the spinothalamic tract (Yam et al., 2018). Pain perception results from nociceptive, neuropathic, nociplastic mechanisms (Yam et al., 2018). Varying mechanisms of pain can transition into chronic pain from untreated persistent activation of neurons that lead to changes in peripheral and central nervous system neuroplasticity (Sarzi-Puttini et al., 2011) (Fig. 1). In disease states, perception of pain may no longer follow normal pain sensation mechanisms (Ji et al., 2018), and in pathological states of chronic pain, centralized pain can emerge (Ji et al., 2018). In centralized or nociplastic pain, the perception of pain can develop in the absence of detectable peripheral pathological factors that are known to induce pain (Phillips and Clauw, 2011). Psychoneuroimmunology has described how individual subjective experiences, emotions, cognitive functions, and physiological stress reactions all interact to restore balance and resolve pain by means of complex signaling systems (Sarzi-Puttini et al., 2011). Chronic dysfunction in any of these factors, in a standalone manner or in concert, can increase the likelihood of a patient transitioning from an acute to chronic state of pain (Sarzi-Puttini et al., 2011).

Fig. 1. Pain Mechanism Overview:

The three major divisions of pain according to the International Association for the Study of Pain (IASP). Inflammation may contribute to pain across pain states and therefore individual disease or disorders. SSRI, serotonin-norepinephrine reuptake inhibitor, TCA, tricyclic antidepressant, HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome, NSAIDS, nonsteroidal anti-inflammatory drugs, CGRP, calcitonin gene-related peptide.

3.3. Nociceptive pain

Nociceptive pain is an alarm mediated response to tissue injury and serves a protective function by triggering the removal of potentially harmful stimuli from the organism (Costigan et al., 2009). Once the noxious stimuli are removed, the nociceptive pain is terminated (Costigan et al., 2009). Nociceptors are found in the skin, muscle, joint, and visceral organs and express specialized receptors that respond to intense thermal, mechanical as well as endogenous or exogenous chemical mediators (Dhaka et al., 2006; Yam et al., 2018). Localized pain is determined by the site of the injury and diffused pain is usually a pain from deeper tissues.

3.4. Neuropathic pain

Neuropathic pain begins with a lesion or disease resulting in mal-function of the somatosensory system (Costigan et al., 2009) and can be subdivided into central and peripheral neuropathic pain (Ji et al., 2018; Rosenberger et al., 2020). Central neuropathic pain may specifically emanate from central nervous system (CNS) tissue injury to the brain or spinal cord, such as in multiple sclerosis for example (Ducreux et al., 2006; Kaku and Siao, 2019). Peripheral neuropathic pain develops from injury to the peripheral nervous system, such as in Guillain-Barre syndrome (Walling and Dickson, 2013). Neuropathic pain can be caused by hereditary conditions, mechanical trauma, metabolic diseases, neurotoxic chemicals, infections, or tumor invasion (de Greef et al., 2019d; Dworkin et al., 2003; Ji et al., 2018; Woolf and Mannion, 1999). The damaged axons lead to changes in gene expression patterns and ion channel properties resulting in hyper-excitability and ectopic firing of the neurons (Rosenberger et al., 2020; Yam et al., 2018). Enhanced synaptic transmission in the CNS and a decrease in descending inhibition at the spinal, thalamic, and cortical level results in an amplified central processing of the pain signal (Rosenberger et al., 2020). Neuropathic pain is considered maladaptive as it neither protects nor supports the healing process (Costigan et al., 2009). With specific regard to pharmacotherapy of neuropathic pain, most conditions in this review likely have some neuropathic component and may benefit from commonly used agents for neuropathic pain (Finnerup et al., 2015). Conducting randomized clinical trial (RCTs) of pharmacotherapies for each disease would be optimal and are greatly necessary for elucidating treatment efficacy, optimal dosing regimens and determining clinical and biological variables driving therapeutic response or resistance. Given the serious risks of developing opioid use disorder, opioid-induced hyperalgesia, physical dependence on opioids, GI upset (e.g., constipation, vomiting, abdominal pain, etc.), hormonal imbalances (e.g., decreased testosterone, estrogen, progesterone, etc.), immunologic reactions (e.g., immunosuppression), opioids should be limited to the acute setting and avoided in the treatment of chronic pain (Khademi et al., 2016; Webster, 2017).

3.5. Nociplastic pain

Nociplastic pain arises as a result of alterations in nociceptive signaling. The term was introduced in 2005 but recently adjusted by the IASP in 2017 to categorize painful conditions that neither had evidence of nociceptive stimulation (nociceptive pain) nor lesions in the nervous system (neuropathic pain) (Trouvin and Perrot, 2019). While this exact term remains controversial (Aydede and Shriver, 2018) and is not yet widely reflected in the literature, it categorizes disorders such as fibromyalgia, nonspecific back pain, or irritable bowel syndrome, which do not strictly demonstrate nociceptive or neuropathic mechanisms (Kosek et al., 2016). Of note, nociplastic pain is not a catch all category nor a diagnosis of exclusion. There must be evidence of “altered nociception” at least in the form of pain with hypersensitivity (Kosek et al., 2017).

3.6. Inflammation in pain

Inflammation or inflammatory pain, which also occurs in response to tissue damage (Costigan et al., 2009) is a natural biological response (Yam et al., 2018) that results in changes to local sensory nervous system responsiveness to stimuli (Juhl et al., 2008). The communication between immune cells and nociceptors is bidirectional and can mediate the immune response to inflammation (Basbaum et al., 2009; Liu and Ji, 2013). Nociceptors can be sensitized by inflammatory mediators such as prostaglandins, nerve growth factors, and bradykinin, along with pro-inflammatory cytokines TNF-alpha, chemokines and interleukins (Basbaum et al., 2009; Dawes et al., 2011; Hucho and Levine, 2007; Ji et al., 2018). Like immune cells, nociceptors can release cytokines and chemokines to regulate local inflammation. Activation of nociceptors can cause neurogenic inflammation, releasing substance P and calcitonin gene - related peptide (CGRP)or prostanoids (Liu et al., 2016; Zhang et al., 2013). Neurogenic inflammation results in plasma extravasation and edema even before infiltration of immune cells (Ji et al., 2018). The inflammatory response leads to states of hyperalgesia and allodynia, which prevent the already damaged tissue from being reinjured and allow the body to initiate the healing process and restore integrity without further damage (Ji et al., 2018).

3.7. Chronification of pain

In certain diseases, an ongoing or recurrent noxious stimulus can produce chronic pain (Costigan et al., 2009). Central sensitization can facilitate and occur in such chronic pain states. Central sensitization is a result of synaptic neuroplasticity and increase in neuronal hyperexcitability within central pain pathways (Ji et al., 2018). The central pain pathway consists of an ascending branch projecting between the dorsal horn to the thalamus and somatosensory cortices via the spinothalamic tract (Yam et al., 2018). Other CNS pathways involving the basal ganglia, amygdala, cingulate, insula, and prefrontal cortex; CNS regions contributing more so to the affective pain experience (Yam et al., 2018). The descending pain pathway enables top-down control of pain and entails not only cortical structures, but also the midbrain (e.g., periaqueductal gray), medulla (e.g., rostral ventromedial medulla), and dorsal horn. Equilibrium in terms of pain processing is maintained via a balance between the ascending and descending arms of the CNS pain system. In chronic pain conditions, maladaptive mechanisms such as a state of persistent neurogenic inflammations and increased release of neurotransmitters (glutamate, substance P, CGRP, brain-derived growth factor) may offset this inherent balance. Furthermore, neuroinflammation in either the central or peripheral nervous system may exist and at least in part drive central sensitization. Some key characteristics of neuroinflammation are increased vascular permeability, infiltration of leukocytes, activation of glial cells, and production of inflammatory mediators (Yam et al., 2018).

4. Rare musculoskeletal diseases

4.1. Osteogenesis imperfecta (OI)

4.1.1. Disease overview

Osteogenesis imperfecta (OI) is a rare inherited disorder of connective tissue characterized by high susceptibility to bone fractures, discoloration of sclera, joint laxity, skeletal deformities, and hearing loss (Binh et al., 2017; Brizola et al., 2017; Denholm and Cole, 1983; Greeley et al., 2013). The prevalence of OI is ~1:15,000 births (Stoll et al., 1989). At least 17 genetically determined subtypes of OI have been identified (Van Dijk and Sillence, 2014). The majority of cases (~85–90 %) are characterized by autosomal dominant mutations in the COLIA1 and COLIA2 genes, which encode alpha 1 and alpha 2 chains of type I collagen; a fundamental component of bone (Forlino and Marini, 2016; Marini et al., 2007). In clinical practice, patients with OI can be classified into 5 subtypes based on clinical features; (Type I.) classic non-deforming OI with blue sclerae and most common, (Type II.) perinatally lethal OI, (Type III.) progressively deforming OI, (Type IV.) OI with normal sclerae, (Type V.) OI with calcification in interosseous membranes (Marom et al., 2016) (Table 1). The severe phenotypes of OI lead to progressive bone deformity, poor bone healing and growth delays, yet pain in OI is common and complex across genotypes or subtypes (Dahan-Oliel et al., 2016).

Table 1.

Categorization of Disease Subtypes:

Disease	Phenotypic subtypes
OI	Type I – classic non-deforming OI with blue sclerae Type II – perinatally lethal Type III – progressively deforming Type IV – OI with normal sclerae Type V – OI with calcification in interosseous membranes
EDS	Classical EDS – hyperextensible and fragile skin Hypermobile EDS – joint hypermobility leading to frequent dislocations Vascular EDS – vascular fragility Rare or unclassified EDS
CRPS	Type I – patients without evidence of peripheral nerve injury Type II – patients with evidence of peripheral nerve injury
PD	Infantile-onset PD Late-onset PD
CMT	CMT1 – demyelination and marked reduction of nerve conduction velocities (less than 38 m/s at the upper extremity) CMT2 – axonal loss with normal or mildly reduced nerve conduction velocities

OI, Osteogenesis Imperfecta, EDS, Ehlers-Danlos Syndrome, CRPS, Complex Regional Pain Syndrome, PD, Pompe Disease, CMT, Charcot-Marie-Tooth Disease.

4.1.2. Pain phenotype

Acute pain related to pathological bone fractures is a common issue in even mild cases of OI. When bone fractures, the damage tissue triggers the release of inflammatory mediators (e.g., prostaglandins, bradykinin, endothelin, and nerve growth factor) which activate nociceptors (Mitchell et al., 2018). One study showed that fractures occurred most commonly in the lower extremities (57 %), upper extremities (27 %), and in the bones of the torso (16 %) (Zack et al., 2005). The likelihood of experiencing a fracture initially increases with age due to increased physical activity and greater potential for musculoskeletal injury (Nghiem et al., 2017). However, there is evidence that patients with OI experience chronic pain in the absence of an acute pathological fracture. In a survey, 86 % of patients reported experiencing non-fracture pain most commonly in the shins (42 %), thighs (40 %), and lower back (37 %) (Zack et al., 2005). Of note, lower back pain as well as scoliosis may be a result of undiagnosed vertebral fractures which are frequent in severe OI subtypes (Frater et al., 1995; Rao et al., 1993; Sepulveda et al., 2017). In addition, chronic pain may arise due to cumulative micro-fractures with mechanical stress (Gomez-Alonso, 2020) and skeletal deformities (Kim et al., 2013). Patients with OI also suffer from skeletal deformities such as scoliosis (Arponen et al., 2014), spondylolisthesis (Ivo et al., 2007), and transient osteoporosis of the hip (Karagkevrekis and Ainscow, 1998). In a separate study, patients with OI reported experiencing chronic pain, stiffness and instability most often in the ankles, hips, knees, and lower back (McKiernan, 2005). In addition, the most severe form of OI, Type III, is associated with abdominal pain. In a review of OI patients receiving orthopedic care, 28 % reported abdominal pain, 67 % of whom had acetabular protrusion on radiographs (Lee et al., 1995). Unexpectedly, acetabular protrusion, the displacement of the femoral head medial from the ilio-ischial line (Ajlouni et al., 2020; Violas et al., 2002), has been suggested to contribute to recurrent abdominal pain in OI (Lee et al., 1995). While pain in OI is mainly nociceptive, trigeminal neuralgia is a frequent source of neuropathic pain (Iwai et al., 2018; Ruschel et al., 2017) and arises due to basilar skull displacement (Hayes et al., 1999; Ray, 1942). In OI, higher pain scores are associated with worse quality of life (Nghiem et al., 2017). In a study comparing acute fracture and chronic non-fracture pain, all children reported that fracture pain affected at least 2 activities of daily living (ADLs) (Zack et al., 2005). 86 % of children who reported non-fracture pain reported pain on at least 1 day in the study week. 47 % reported that non-fracture chronic pain affected at least 1 ADL. 38 % of children reported analgesia use for non-fracture pain and this group was associated with higher pain scores.

4.1.3. Treatment approaches

In OI, patients experience better outcomes from a comprehensive multimodal pain therapy approach, combining pharmacotherapy, physical therapy, occupational therapy and rehabilitation therapy, as well as corrective surgery (Marom et al., 2016). To date, there is no FDA-approved disease modifying therapy for OI. Bisphosphonates are currently widely used in OI due to evidence of increased bone mass and reduction of fracture risk with therapy (Dwan et al., 2014; Ierardo et al., 2017). In a prospective investigation, patients with OI reported decreased pain scores and improved function after infusion of pamidronate or zoledronate (Garganta et al., 2018). Although, the use of bisphosphonates is common in OI, this practice remains controversial. Based on a comprehensive review of 14 trials, bisphosphonates did not conclusively reduce pain or improve growth and functional mobility in OI (Dwan et al., 2016). While there have been clinical trials that assess the effect of bisphosphonates on bone density and fractures risk as described above, they seldom if ever correlate these metrics to pain outcomes. Furthermore, RCTs of pharmacotherapies that assessed pain as a primary outcome in OI have been absent. Thus, the current body of evidence for pain pharmacotherapy in OI comes from retrospective studies or surveys. Importantly, corrective surgery is the mainstay of treatment in OI patients with acute fractures or chronic skeletal deformities (Ralston and Gaston, 2019). However, there is evidence that surgery may lead to further orthopedic complications and pain (Karbowski et al., 2000; Pogorelic et al., 2017; Ring et al., 1996). Nevertheless, corrective surgery may alleviate symptoms of trigeminal neuralgia (Iwai et al., 2018; Ruschel et al., 2017). In some cases, epidural nerve blockade may be beneficial for neuropathic back pain (Kim et al., 2013).

4.2. Ehlers-Danlos syndrome (EDS)

4.2.1. Disease overview

Ehlers-Danlos syndrome (EDS) is an inherited, heterogeneous group of connective tissue disorders characterized by defects in skin, ligaments, joints, and blood vessels (Cortini and Villa, 2018) leading to joint hypermobility, skin hyperextensibility, and tissue fragility (Malfait et al., 2017). There are at least 13 genetically distinct subtypes of EDS all resulting from autosomal dominant or autosomal recessive defects in various collagen related genes including, but not limited to, COL1A1, TNXB, ADAMTS2, and PLOD1 (Cortini and Villa, 2018). The most widely accepted clinical classification is the Villefranche Nosology (Beighton et al., 1998). According to this classification four subtypes can be defined: i) classical, ii) hypermobile, iii) vascular, iv) rare or unclassified (Bascom et al., 2019) (Table 1). Of those, hypermobile EDS (hEDS, also known as EDS Type III), the most common and least severe subtype (Gazit et al., 2016), is inherited in an autosomal dominant fashion and accounts for 80–90 % of cases with a prevalence of ~1:5,000. The female to male ratio in hEDS ranges from ~2:1 to 9:1 (Tinkle et al., 2017). Unlike the other subtypes of EDS, hEDS has no known consistent genetic cause. Patients with hEDS tend to transition through 3 distinct phases of the disease; i) hypermobile phase, ii) pain phase, iii) stiffness phase (Castori et al., 2010). The hypermobile phase dominates the first several years of life and is characterized by dislocations, pain, and contortionism which is the voluntary bending and flexing of the joints, often for performance (Castori et al., 2010) (Fig. 2). The pain phase begins in the second to fourth decade of life and is characterized by generalized and progressive paresthesiae, GI disorders, and orthostatic hypotension. The stiffness phase is usually confined to adulthood and is characterized by weakness, reduced muscle mass, arthritis, and defective proprioception. In classical (cEDS), a diagnosis can be made on the basis of joint laxity (Beighton score ≥ 5/9), extremely hyperextensible skin, fragility of the skin with evidence of easy bruising, and the presence of thin atrophic scars, plus other criteria including family history and prolonged history of joint pain (Bascom et al., 2019). EDS is often difficult to distinguish from other connective tissue conditions (Tofts et al., 2009), yet widespread pain, painful and/or unstable joints and fatigue are common underestimated symptoms (Tinkle et al., 2017).

Fig. 2.

Joint Hypermobility in Ehlers-Danlos Syndrome (EDS): EDS patients are characterized by hypermobile and unstable joints causing joint dislocations, joint pain and early onset arthritis. Both upper (A.) and lower body (B.) joints are affected in EDS. Adapted from (Yen et al., 2006).

4.2.2. Pain phenotype

The natural history of pain in EDS tends to begin in childhood or young adulthood as acute and local pain that is triggered by relatively mild injuries, surgery, sports activities, psychological distress or various comorbidities (Castori et al., 2010). The most commonly affected regions are the spine (neck and lower back), shoulders, forearms, fingers, hips, knees and feet (Voermans et al., 2010). A recent study showed that pain was most severe in the lower limbs, upper limbs, and spine (Benistan and Martinez, 2019). In later life, pain may become widespread and chronic with arthralgias and myalgias being the most common manifestations (Rombaut et al., 2010). However, as pain persists and spreads, patients often lose the ability to localize their symptoms (Syx et al., 2017). Chronic pain is one of the major symptoms presented by patients with hEDS (Syx et al., 2017). Patients experience a wide variety of pain including generalized body pain, soft tissue pain, dislocations, joint pain (Fig. 7), fatigue, bone loss, headaches, gastrointestinal pain, temporo-mandibular joint pain, menorrhagia, dysmenorrhea and vulvodynia/-dyspareunia (Chopra et al., 2017). One study revealed that up to 90 % of patients with EDS experience generalized pain, most often in the hEDS subtype (Voermans et al., 2010). In addition, pain in EDS was more often chronic with 92 % reporting a pain duration of at least one year. Multiple studies corroborate the findings that pain in EDS is usually chronic, severe (Benistan and Martinez, 2019; Voermans et al., 2009) and often requires analgesic use and a comprehensive multimodal treatment approach (Voermans et al., 2010). Sustained neuropathic or nociceptive injury, separately or in concert, may promote central sensitization and chronic pain over time (Syx et al., 2017). Central sensitization tends to lead to widespread pain that may resemble fibromyalgia (Di Stefano et al., 2016). In separate study, 68 % of patients with EDS described burning, pressing, and paresthesia sensations consistent with neuropathic pain (Voermans et al., 2009). Nociceptive pain may arise from tissue injury related to hypermobility, dislocations, and previous surgeries (Benistan and Martinez, 2019).

Fig. 7. Sources of Pain in Rare Musculoskeletal Conditions:

(*) Vertebral deformities include vertebral arthritis, scoliosis, kyphosis, lordosis, spondylolisthesis, degenerative spondylosis, spinal stenosis, and rigid spine syndrome. (**) Arthritis commonly occurs in the knees but may also occur in the hips. Coxa vara is the reduced angle between the femoral neck and shaft to <120 degrees. Genu varum is the pathological outward bowing of the legs. OI, Osteogenesis Imperfecta, EDS, Ehlers-Danlos Syndrome, AP, Achondroplasia, FOP, Fibrodysplasia Ossificans Progressiva, FD/MAS, Fibrous Dysplasia/McCune Albright syndrome, CRPS, Complex Regional Pain Syndrome.

Pain and disability in EDS are significantly associated with fatigue (Blitshteyn and Chopra, 2018; Hakim et al., 2017), and potentially exacerbated by, psychiatric conditions (Muriello et al., 2018) and poor quality of sleep (Voermans et al., 2010). A retrospective study of patients with the hypermobile and classic EDS subtypes revealed 42 % with comorbid psychiatric conditions, most commonly anxiety and depression (Hershenfeld et al., 2016). In a separate prospective cohort study, patients with hEDS had an increased risk for developing panic disorder or simple phobia (Bulbena et al., 2011). In addition, the eventually development of pain EDS may be associated with non-disease factors. For example, an analysis showed that delays in diagnosis and thoughts of helplessness may increase the risk of severe pain (Kalisch et al., 2019) which highlights the important of a multidisciplinary comprehensive treatment approach when managing pain in EDS.

4.2.3. Treatment approaches

Pain control is the primary goal in managing patients with EDS, while the hypermobility and joint instability are often addressed secondarily (Benistan and Gillas, 2020). In general, it is recommended that medications be combined with mindfulness meditation and psychotherapy such as cognitive behavioral therapy (Benistan and Gillas, 2020). Unfortunately, pain control in EDS remains difficult and refractory to non-opiate measures such as NSAIDS, psychotherapy, and behavioral therapy (Baeza-Velasco et al., 2019; Benistan and Gillas, 2020). This is partly due to a lack of controlled trials that assess pharmacotherapies and pain as an outcome measure in EDS. A few potentially effective non-opiate analgesics include acetaminophen where NSAIDS are ineffective or poorly tolerated, topical lidocaine for joint subluxation, and topical estrogen for dyspareunia (Chopra et al., 2017). A patient survey revealed that the most effective treatment for acute and chronic pain were opioids (Benistan and Gillas, 2020), heat therapy, splints, braces, surgical interventions and avoidance of aggravating activities (Baeza-Velasco et al., 2019). Given the serious risk of dependence and harm, therapy with opioids should be carefully monitored. Preferential use of medium potency opioids such as tramadol, tilidine and tapentadol may be discussed and only recommended in the short term and for acute pain. Vitamin C, up to 500 mg daily, may strengthen collagen and has thus been speculated to be helpful in osteoarthritis, although this has not been thoroughly studied (Levy, 1993). While the anti-inflammatory effects of fish oil have been speculated to improve osteoarthritis (Boe and Vangsness, 2015), this has not been tested in RCTs (Hill et al., 2016).

4.3. Achondroplasia (AP)

4.3.1. Disease overview

Achondroplasia (AP) is the most common genetic bone dysplasia with a prevalence of 1:20,000 live births (Stratbucker, 2009). AP is an inherited autosomal dominant condition with 100 % penetrance (Ornitz and Legeai-Mallet, 2017). However, up to 80 % of newborns diagnosed with achondroplasia have a sporadic de novo mutation (Pauli, 2019). A gain-of-function point mutation in fibroblast growth factor receptor 3 (FGFR3) underlies the condition with two specific mutations in the FGRF3 gene occurring in 99 % of cases (Pauli, 2019). Both mutations result in a glycine-to-arginine amino acid (380) substitution, which permanently activates FGFR3 and results in downstream inhibition of chondrocyte proliferation (Ornitz and Legeai-Mallet, 2017). This leads to impaired endochondral bone formation, clinically presenting as distinctive craniofacial features and bone shortening starting at birth (Sahni et al., 1999). Newborns typically have a slowed motor development, which typically resolves by 2–3 years of age (Brust et al., 1976). As the infant grows, kyphoscoliosis disappears, yet lumbar lordosis becomes more prominent at time of ambulation (~1.5 years old) (Brust et al., 1976). Other clinical phenotypes in AP include a disproportionate short stature with rhizomelic shortening of the arms and legs, brachydactyly, kyphoscoliosis, and accentuated lumbar lordosis (Brust et al., 1976).

4.3.2. Pain phenotype

As patients with AP age, chronic pain develops often from orthopedic or neurologic complications (Ain et al., 2010; Alade et al., 2013). Up to two-thirds of adults diagnosed with AP report chronic pain (Alade et al., 2013). Pain is often secondary to coxa vara, leg bowing, spinal stenosis, and cervical medullary compression, where symptoms of the latter include ataxia, incontinence, occipito-cervical pain, and respiratory arrest (Gordon, 2000) (Fig. 7). Such dysplastic bone features may also lead to or exacerbate joint pain. Knee pain presents in children around 5–6 years of age due to joint laxity and leg bowing (Pauli, 2019; Shirley and Ain, 2009). The majority of the bones that make up the vertebral bodies and the base of the skull are formed by means of endochondral ossification (Kubota et al., 2020). The combination of hypertrophy from ligamentum flavum and degenerative spondylosis leads to aggravation of underlying spinal stenosis (O’Brien and Mehdian, 1988). Patients in their 3rd to 4th decade of life present with symptoms from spinal stenosis (Ain et al., 2010), which often starts as back pain and progresses to proximal and distal leg pain as spinal stenosis worsens. The spinal stenosis-related pain may occur in combination with tingling, numbness and muscle weakness.

Ain and colleagues investigated the progression of low back and lower extremity pain in a cohort of 181 AP patients (mean age of ~43 years) across two time points separated by 17 months (Ain et al., 2010). At baseline, 35 % of AP patients reported having previous decompressive surgical treatment for pain. At follow-up, a significant progression in low back pain and greater involvement of the lower extremities pain was noted. Moreover, approximately 25 % of participants at follow-up had stopped working or changed their type of work due to pain. In a larger investigation of 353 AP patients (mean age of ~36 years), 70 % of the study population reported chronic pain which increased with age (Alade et al., 2013).

4.3.3. Treatment approaches

Pain in AP is underdiagnosed and undertreated. A key focus should be to better understandthe optimization and implementation of treatment (e.g., surgery, physical therapy, and use of adaptive equipment) with the goal of improved pain management and improving physical function (Alade et al., 2013). Currently, there are no FDA-approved treatments for AP, yet several pharmacological therapies are under clinical development (Klag and Horton, 2016). A major challenge in developing treatments that modulate FGFR3 activity specifically stems from the global presence of this receptor class. One therapeutic investigation involves C-type natriuretic peptide (CNP) (Pauli, 2019), which acts to counterbalance the effects of FGFR3 on the growth plate (Pauli, 2019). CNP analogue, Vosoritide, has been shown to increase the rate of bone growth for at least 3.5 years (Savarirayan et al., 2019). Several studies have analyzed growth hormone replacement to enhance growth in children (Hertel et al., 2005; Kanazawa et al., 2003; Seino et al., 2000), however this is not considered an effective treatment. Currently, pain management in AP is accomplished using a variety of methods (Pauli, 2019). For example, spinal stenosis in AP is often initially managed using nonsurgical approaches (e.g., utilizing analgesics, NSAIDs, epidural steroid injections, and physical therapy) (Ammendolia et al., 2012). Many patients in the 4^th to 5^th decade of life will progress to needing a surgical laminectomy to alleviate symptoms (Hunter et al., 1998; Lonstein, 1988). Pain prevention is aided with bracing, massage, physical therapy, and assistance equipment (Pauli, 2019). As is the case in most diseases included in this review, there is a dearth of RCTs that assess pain as a primary endpoint in AP.

4.4. Fibrodysplasia ossificans progressiva (FOP)

4.4.1. Disease overview

Fibrodysplasia ossificans progressiva (FOP), also known as myositis ossificans progressiva, is a severe, ultra-rare (1:800,000–1:3,000,000 prevalence worldwide (Baujat et al., 2017)) condition characterized by heterotopic bone growth in soft-tissue structures such as skeletal muscles, tendons, ligaments, and fascia (Huning and Gillessen-Kaesbach, 2014; Pignolo et al., 2011). Most FOP cases arise due to a gain-of-function mutation in the Activin A receptor type I/Activin-like kinase 2 gene (ACVR1/ALK2), which leads to heterotopic bone growth or ossification (Bouvard et al., 2016; Kaplan et al., 2009; Shore et al., 2006; Upadhyay et al., 2017). FOP patients also suffer from repetitive & progressive flare-up episodes, which are often severely painful and may precede heterotopic ossification induction or expansion (Gomez-Alonso, 2020; Pignolo et al., 2016). Flare-ups may be elicited by minor soft tissue injury, muscle perturbations, over-exertion and fatigue, intramuscular injections, or falls (Pignolo et al., 2016), the latter of which may lead to permanent immobility (Glaser et al., 1998). Heterotopic ossification induction and growth may be observed during infancy in conjunction with a malformation of the of great toe (Huning and Gillessen-Kaesbach, 2014), which in combination often points to a FOP diagnosis. The progression of FOP tends to follow a predictable pattern. Heterotopic ossification first appears in the dorsal, axial, cranial, and proximal regions of the body and later in the ventral, appendicular, caudal, and distal regions. For many patients, the accumulation of heterotopic ossification occurs throughout the body, leading to ankylosis of joints, progressive loss of range-of-motion, worsening musculoskeletal deformity (e.g. kyphoscoliosis, osteochondromas, and degenerative joint disease) (Kaplan et al., 2018; Morales-Piga et al., 2012) and thoracic insufficiency (Kaplan et al., 2017).

4.4.2. Pain phenotype

Early clinical observations and investigations revealed that flare-ups are a key source of pain in FOP patients (Gencer-Atalay et al., 2019; Gomez-Alonso, 2020; Peng et al., 2019). Flare-ups as well as severe pain may last for weeks or even months. In a recent study, 86 % of patients with FOP reported pain during a flare-up (Pignolo et al., 2016). In FOP, pain tends to occur at the location of heterotopic ossification and can lead to acute unilateral hip pain (Kaplan et al., 2018) or pain in the neck, back, chest, abdomen, elbows, wrists, fingers, and feet (Pignolo et al., 2016; Rogers and Geho, 1979) (Fig. 7). Although flare-ups are a major source of pain in FOP, subsequent studies have revealed that patients also experience pain during non-flare up, or quiescent periods (Peng et al., 2019). In a recent analysis of the approximately 100 FOP patients across a 30-month period, 55 % of patients who were not experiencing a flare-up reported similar pain levels to those experiencing a flare-up (Fig. 3) (Peng et al., 2019). This observation is in line with prior investigations that have noted recurrent severe headache (e.g., migraine, cluster, or tension-type headache), neurologic manifestations, neuropathic pain, allodynia, and hyperalgesia (Kitterman et al., 2012). A source of pain and dysfunction in FOP patients that should be investigated in future studies is the presence of degenerative joint disease caused by skeletal dysplasia. Furthermore, entities such as emotional functioning and cognitive health in FOP may be important to explore as insight may be gained as to why pain is not commensurate with severity of disease or why pain occurs during ‘dormant’ stages of FOP.

Fig. 3. Pain in Fibrodysplasia Ossificans Progressiva:

A. Across time points, FOP patients (N~100) with and without flare-up status reported moderate to severe pain (Pain ≥ 4). This indicates that pain may be present in FOP patients during ‘quiescent’ periods. FOP patients reporting pain ≥ 4 experienced more emotional problems (B.) and poorer physical health (C.) compared to patients reporting little to no pain. Adapted from (Peng et al., 2019).

4.4.3. Treatment approaches

There are currently no FDA-approved disease modifying treatments available in FOP; however, multiple novel therapies are under evaluation (Kaplan et al., 2013; Wentworth et al., 2019). Case studies alone have shown that corticosteroids, NSAIDs, COX-2 inhibitors, and bisphosphonates are often beneficial for treating pain (Kitterman et al., 2012; Pignolo et al., 2016; Rogoveanu et al., 2013). Attempts to surgically remove regions of heterotopic ossification often leads to the growth of new lesions, therefore surgery, and in general, other invasive medical procedures are contraindicated in FOP patient (Rogers and Geho, 1979). Nonetheless, case reports have described patients who have elected to undergo surgical removal of heterotopic ossification in order to regain function (Eekhoff et al., 2018b; Seok et al., 2012). The clinical utility of prescription opioids and gabapentinoids (pregabalin/gabapentin) remains largely unknown, yet these classes of analgesic drugs are utilized by patients (Gencer-Atalay et al., 2019; Gomez-Alonso, 2020).

4.5. Fibrous dysplasia/McCune Albright syndrome (FD/MAS)

4.5.1. Disease overview

Fibrous dysplasia (FD) is a rare {MAS prevalence of ~1:100,000 – 1:1,000,000 (Dumitrescu and Collins, 2008)}, non-inherited bone disease occurring from a R201 missense mutation of the GNAS gene (Boyce et al., 1993; Robinson et al., 2016). The Gα_s protein, which is encoded by GNAS gene, acts as an ‘on-off switch’ for many cells, including those critical for healthy bone formation and maintenance. Moreover, Gα_s, a subunit of heterotrimeric G proteins, activates downstream signaling through cyclic adenosine monophosphate (cAMP), and has a key function in controlling osteoblast and osteoclast differentiation during skeletal tissue (re-)modeling (Ramaswamy et al., 2017; Zhao et al., 2018). FD may affect one bone (monostotic FD) or multiple (polyostotic FD), and may occur in isolation or in association with skin hyperpigmentation and hyperfunctioning endocrinopathies (precocious puberty, hyperthyroidism, acromegaly, neonatal hypercortisolism, FGF23-mediated hypophosphatemia). The combination of FD and one or more extraskeletal feature is termed McCune-Albright syndrome (MAS). FD/MAS is a complex and variable condition due to the mosaic nature of the tissues involved.

In FD, the GNAS mutation impairs differentiation of skeletal stem cells, leading to replacement of healthy bone tissue and marrow with pre-osteoblastic, fibrous tissue (Riminucci et al., 1999). The resulting bone forms expansile, lytic-appearing lesions that are structurally unsound, resulting in fractures, deformity pain, and functional impairment (Boyce et al., 1993; Robinson et al., 2016) (Fig. 4). The clinical presentation in FD follows an age-related pattern: skeletal development appears to occur relatively normally in utero, and FD lesions become apparent during childhood and expand during skeletal growth, before reaching final disease burden in early adulthood. Fracture incidence and metabolic activity of FD lesions then decreases in adulthood (Florenzano et al., 2019; Hart et al., 2007; Isobe et al., 2018).

Fig. 4. Representative Radiographic Images in Fibrous Dysplasia:

A. ¹⁸F-NaF-PET/CT scan in a patient with polyostotic disease shows multiples areas of tracer uptake in areas of fibrous dysplasia involving the bilateral lower extremities, spine, left-sided ribs, and skull (arrows). B. Head computed tomography scan shows an expansile fibrous dysplasia lesion involving the right maxilla (arrow), which has occluded the maxillary sinus. Note the homogeneous, “ground glass” appearance. C. Radiograph of the proximal femur shows extensive fibrous dysplasia involvement and the development of a typical coxa valga “shepherd’s crook” deformity. Note the lucent, “ground glass” appearance of lesion and cortical thinning, which is particularly notable on the lateral portion (arrow). D. MRI performed in a patient with monostotic disease with fibrous dysplasia of the right proximal femur. Coronal T2 MRI with fat suppression show heterogenous hyperintensity within the femur. F. In the same patient, post-contrast axial T1 MRI shows periosteal elevation and enhancement.

4.5.2. Pain phenotype

The manifestation of pain in FD is of particular importance as pain may be the presenting symptom that facilitates early FD diagnosis, but also, substantially diminishes the quality-of-life for many FD/MAS patients (Chapurlat et al., 2012; Kelly et al., 2008; Majoor et al., 2017). To date, what is understood about pain in FD is primarily garnered from subjective measures such as the Brief Pain Inventory (BPI), patient interviews, and clinician observations. These reports indicate that the intensity and frequency of pain is greater in adults compared to children and adolescents, while a correlation between disease burden (determined by clinical findings, radiographs or non-physiologic uptake of ⁹⁹Tc-MDP or ¹⁸F-NaF), bone turnover markers, and pain levels do not exist (Florenzano et al., 2019; Kelly et al., 2008; Majoor et al., 2019). This lack of a consistent association between skeletal abnormalities and patients’ self-reported pain levels may be suggestive of mechanisms outside of the skeletal system that contribute to the FD/MAS pain phenotype. Moderate to severe pain is frequently experienced by patients, where the pain quality can initially present itself as a ‘deep ache’ that often transitions into or co-occurs with a burning or shooting pain. This quality may indicate a neuropathic-like pain phenotype in some FD/MAS patients. Pain may be complicated by co-existing MAS-related endocrinopathies, such as FGF23-mediated hypophosphatemia, which leads to rickets and osteomalacia (Florenzano et al., 2019). Deformation of lower-body long bones in particular may lead to subsequent development of osteoarthritic pain (Kim et al., 2015), while craniofacial skeletal dysplasias commonly observed in FD/MAS are likely sources of headaches, migraine, or trigeminal neuralgia (Couturier et al., 2017; Frisch et al., 2015; Kim, 2016) (Fig. 7). Additionally, orthopedic or craniomaxillofacial surgery is performed in FD/MAS and in some cases, may ameliorate some forms of pain (e.g., pain emanating from soft-tissue compression) (Javaid et al., 2019); however, the occurrence of acute or chronic post-surgical pain has not been investigated to date in this population. Surgery also has the potential to exacerbate pain, and surgeons should exercise caution and avoid performing procedures without first establishing a clear causative relationship between a skeletal deformity and pain.

4.5.3. Treatment approaches

In any patient with FD/MAS reporting pain, it is important to first evaluate for orthopedic causes and uncontrolled endocrinopathies. For patients without a clear etiology for pain, first-line medical treatments include bisphosphonates (e.g., pamidronate, zoledronate, or alendronate). The principal mechanism of bisphosphonates is to suppress bone resorption, which may yield a concurrent analgesic effect, yet a reoccurrence of bone pain during the course of bisphosphonate treatment is not uncommon³. Moreover, a double-blind placebo-controlled study of the oral bisphosphonate, alendronate, in patients with FD did not reveal an effect on pain (Boyce et al., 2014).

At the time of writing this publication, investigational trials involving, for example, tocilizumab (NCT01791842) and denosumab (NCT03571191) are ongoing in FD/MAS patients; however, the therapeutic efficacy of these treatments is currently unknown. Prior case studies have indicated the ability of denosumab to provide pain relief to FD/MAS patients (Boyce et al., 2012; Polyzos et al., 2019), however safety concerns exist in this population, including the potential for life-threatening post-discontinuation hypercalcemia. At present denosumab treatment in FD should be limited to clinical trials and on a compassionate basis for patients with severely impaired quality of life. Analgesics, including, NSAIDs and prescription opioids, in particular, are currently less often used by FD/MAS patients, and while high quality, controlled studies are lacking, intravenous bisphosphates appear to have the highest level of efficacy in retrospective studies (Kelly et al., 2008). Despite the use of these pharmacological therapies in conjunction with non-pharmacological analgesic approaches, acute and chronic pain remains prevalent across many individuals diagnosed with FD/MAS.

4.6. Complex regional pain syndrome (CRPS)

4.6.1. Disease overview

Complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy, causalgia, Sudeck atrophy, and algodystrophy, is a debilitating pain condition characterized by persistent pain in one or more limbs following an initial injury (Goebel et al., 2010; Harden et al., 2010; Kaplan et al., 2017). The incidence of CRPS is ~1:3,800 in the U.S. and is more common among women (de Mos et al., 2007d). The pathophysiology of CRPS is multifactorial, mainly an aberrant host immune response (Schinkel and Kirschner, 2008) to tissue injury leading to pain, hyperalgesia and loss of limb function. Clinically, patients are categorized with either CRPS 1 (no identifiable nerve injury) or CRPS 2 (identifiable nerve injury) (Kaplan et al., 2017) (Table 1). CRPS is diagnosed with clinical criteria when ongoing pain can no longer be explained by the degree of initial injury, however accurate diagnosis of CRPS is a challenge, partly due to lack of consensus upon a single diagnostic criterion.

According to the criteria utilized by the International Association for the Study of Pain (IASP), the diagnosis requires a history of symptoms in at least three out of four categories with at least two out of four being present at time of evaluation (Birklein et al., 2018; Harden et al., 2010). The clinical categories are 1) sensory symptoms, 2) vasomotor differences between affected and unaffected limbs, 3) sudomotor differences, 4) the presence of limb edema, and a trauma related motor disorder that includes weakness, tremor or dystonia and/or characteristic trophic changes of skin, hair, and nail (Birklein et al., 2018). This guideline is imperfect due to high sensitivity at the expense of low specificity.

4.6.2. Pain phenotype

CRPS typically develops after limb injury (Kaplan et al., 2017). In the initial phase following an injury, patients develop predictable swelling, redness, warm, and pain common to all forms of trauma. This physiologic response, however, is overexaggerated and persists well beyond the window of normal. Research on how the physiologic response to injury is replaced by pathologic and persistent inflammation focuses on dysregulation in nociceptive signaling. There is also evidence that the persistent pain in CRPS is due to inappropriate or persistent nociceptor sensitization by immune cells (e.g., B-cells) (Goebel et al., 2010; Totsch and Sorge, 2017). Specific inflammatory cytokines (IL-8 & TNF) (Schinkel et al., 2006) and neuropeptides (substance P, neuropeptide Y, CGRP & nerve growth factor) (Kingery, 2010; Schinkel et al., 2006) are elevated in human serum and animal models of CRPS. These inflammatory mediators appear to sensitize peripheral pain receptors (Sommer and Kress, 2004) and lead to hyperalgesia (an overexaggerated perception of painful stimuli), persistent edema, vasodilation, and temperature changes (Birklein et al., 2001; Holzer, 1998; Weber et al., 2001) in the affected limb (Fig. 7). In addition, very recent research highlighted an autoimmune component of CRPS pain. Purified IgM from acute CRPS patients can magnify pain and hyperalgesia in tibia fracture mice when injected systemically, intradermally or intrathecally, but normal subject serum had no effect (Guo et al., 2020). Chronic CRPS IgM was mainly not pronociceptive (Guo et al., 2020). However, purified serum IgG from patients with chronic CRPS significantly increased and prolonged swelling and induced stable hyperalgesia in the paw incision mouse model compared with IgG from healthy controls (Guo et al., 2020). CRPS IgG-injected mice displayed sustained microglia and astrocyte activation in the dorsal horn of the spinal cord indicating central sensitization (Guo et al., 2020). Genetic deletion of interleukin-1 (IL-1) prevented these changes (Helyes et al., 2019). Furthermore, chronic CRPS IgG increased evoked impulse activity in A and C nociceptors, and an increased spontaneous impulse rate in the skin nerve preparation of the saphenous nerve (Cuhadar et al., 2019).

Acute inflammation in CRPS is usually confined to the limb which suffered the initial trauma (Birklein et al., 2018). Within weeks to months of the injury, patients may develop allodynia (the perception of pain from non-painful stimuli) and hyperalgesia (Marinus et al., 2011). Movement of the limb tends to exacerbate pain which leads to further immobilization (Birklein and Schlereth, 2015). As the disease progresses the affected limb may exhibit sensory loss, decreased voluntary motor control, dystonia, tremor, myoclonus and temperature changes (Kaplan et al., 2017) (Fig. 5). In particular, the affected limb may transition from a ‘warm’ edematous phenotype to a ‘cold’ phenotype in cases where acute CRPS (<3 months in duration) becomes chronic (>3 months in duration) (Bruehl, 2015). Of note, pain levels and disease progression appear worse in patients who initially present with a cold limb compared with a warm limb (Vaneker et al., 2005). While patients with acute CRPS may initially have more severe pathology including increased keratinocyte proliferation, inflammatory markers, & mast cell activation (Birklein et al., 2014), most patients report significant improvement of symptoms within 1 year (Zyluk, 1998). CRPS that lasts for >1 year, however, is more likely to be refractory to treatment and persist for several years (de Mos et al., 2009). Patients who are female, have higher pain levels, or psychological or emotional comorbidities may be at greater risk of developing chronic CRPS (Bean et al., 2014; Zyluk, 1998), although more research is warranted.

Fig. 5.

Musculoskeletal Abnormalities in Complex Regional Pain Syndrome (CRPS): A. Acute CRPS with characteristic erythema, edema. B. Chronic CRPS with trophic skin changes. C. Left ankle dystonia related to CRPS. Adapted from (Marinus et al., 2011).

The risk of developing CRPS is highly correlated with the location of injury, although there is no consensus as to which region causes the greatest risk. Historically, in CRPS literature distal radius fractures (DRF) have been considered the most likely inciting event with upwards of 32 % (Jellad et al., 2014) of arising from DRF and more often in women (McGee et al., 2018). Of note, however, DRF independently occur more frequently in women which may account for the female gender predilection seen in CRPS. Moreover, in a separate study tibial fractures appeared to confer the greatest risk for the development of CRPS (Beerthuizen et al., 2012; Sarangi et al., 1993), while other reports suggest knee surgery is a significant risk factor (Harden et al., 2003). This variability of risk factors is likely related to the variability in diagnostic criteria utilized.

4.6.3. Treatment approaches

The current consensus for treating CRPS is to use a multidisciplinary approach including a combination of physical rehabilitation, psychosocial behavioral therapy, and pharmacotherapy. Physical and occupational therapy are the first line treatment for CRPS (Harden et al., 2013). An exercise program with a gradual increase of strength and flexibility through weight-bearing has been shown to improve pain (Watson and Carlson, 1987). Regarding pharmacotherapy, bisphosphonates appear to be most effective in reducing pain that has been present for less than 12 months. However, their use remains controversial due to the small sample size of the conducted studies (O’Connell et al., 2013; Wertli et al., 2014). A prior reivew indicated that the evidence for using bisphosphonates to effectively treat pain in patients with CRPS was of low quality and insufficient (O’Connell et al., 2013). Additionally, side effects from bisphosphonate, usually GI adverse effects, such as heartburn, abdominal pain, nausea, and diarrhea, limit their use (Brunner et al., 2009; Liberman et al., 1995). Calcitonin shows some efficacy for treating pain that persists beyond 12 months according to a meta-analysis of RCTs (Wertli et al., 2014). In the same analysis, NMDA antagonists (e.g., memantine, ketamine), vasodilators (e.g., tadalafil), radical scavengers, (e.g., mannitol), anticonvulsants (e.g., gabapentin), also effective, but to a lesser extent. Steroids (e.g., methylprednisolone, prednisone) seem to have a better effect as previously assumed in the acute stage, but the optimal dose is undetermined (Birklein et al., 2015). NSAIDS, tricyclic antidepressants, and corticosteroids have been widely tested (Christensen et al., 1982) with corticosteroids being the anti-inflammatory drug most strongly supported by evidence. One trial showed no improvement in pain with opioids when compared to placebo (Harke et al., 2001).

5. Rare neuromuscular diseases

5.1. Duchenne Muscular Dystrophy (DMD)

5.1.1. Disease overview

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder caused by a frameshift mutation in the dystrophin gene which renders the protein product non-functional (Verhaart and Aartsma-Rus, 2019). Approximately 33 % of cases arise from de novo mutations (Cai and Kong, 2019). The prevalence of DMD in Europe and North America is shown to be as high as 1:4,700 live male births (Moat et al., 2013; Romitti et al., 2015; Ryder et al., 2017). The dystrophin gene is one of the largest protein-coding human genes and is responsible for anchoring muscle fibers, primarily in skeletal and cardiac muscles. The dystrophin protein connects the intracellular cytoskeleton to the transmembrane proteins, which connect to the extracellular matrix. The resulting defect in the dystrophin protein leads to progressive myofiber damage with weakness usually seen first in pelvic girdle muscles (Bello and Pegoraro, 2019). DMD is characterized by proximal limb weakness, elevated serum creatine kinase, transaminases, delayed growth velocity in the first years of life, cardiomyopathy and orthopedic complications. Pseudohypertrophy of calf muscles can be seen in most cases which is due to fibrofatty replacement within the gastrocnemius muscle. Children usually present with clinical symptoms by age four or five years, with difficulty running or rising from the floor (Yiu and Kornberg, 2015). Many DMD patients are usually full-time wheelchair users by the age of twelve and by late teens or early 20 s, and most affected individuals ultimately respiratory difficulty from severe progressive scoliosis (Smith et al., 1989). Even with excellent supportive care, most people affected by this disease die before the age of 30 years as the pulmonary complications and an associated cardiomyopathy become robust (Yiu and Kornberg, 2015).

5.1.2. Pain phenotype

Historically, pain has not been considered a major clinical symptom of DMD, an outcome likely stemming in part from the dominant focus on loss of ambulation in DMD. However, a recent report indicated that chronic pain is a frequent reported symptom in studies of DMD (Verhaart et al., 2019). A study by Lager et al., found 69 % of adolescents with DMD reported pain during the last 3 months and 50 % reported chronic pain (Lager and Kroksmark, 2015). In a separate study, DMD patients reported pain between two and seven days/week (Zebracki and Drotar, 2008). Pain episodes were often described as having an achy feeling. In a study of fifteen patients, pain was most often reported in the lower back (47 %) and the hips (87 %) (Hamel et al., 2019). Researchers speculated that full-time wheelchair use contributed to such high rates of pain frequencies in these patients, while a high rate of fracture is likely a common cause of pain in DMD.

DMD patients frequently report pain in the posterior aspect of the shoulders (20 %), posterior distal back (47 %), medial (33 %) and lateral (87 %) regions in hips, and anterior proximal (47 %) and posterior distal legs (67 %) (Jacques et al., 2019). Chronic pain in DMD patients is multifactorial, including severe contractures, muscular overuse, and fractures (Fig. 8). Fracture rates are understudied in DMD, yet one study showed that the incidence is at least 20 % and was most often precipitated by falls (McDonald et al., 2002). Vertebral fractures, in particular, occur frequently in DMD (Bothwell et al., 2003) and may contribute to the high rates of back pain. The nature and mechanism of pain potentially differs depending on ambulatory status (Lager and Kroksmark, 2015). Pain in DMD has high across patient variability, as an example, some patients report muscle stretching increases pain and others report relief (Lager and Kroksmark, 2015). Nociceptive, inflammatory, and neuropathic pain all contribute to chronic pain seen in DMD. The predominant pain involvement in the shoulders, back, and legs suggest a musculoskeletal origin.

Fig. 8. Sources of Pain in Rare Neuromuscular Conditions:

(*) Vertebral deformities include vertebral arthritis, scoliosis, kyphosis, lordosis, spondylolisthesis, degenerative spondylosis, spinal stenosis, and rigid spine syndrome. (**) Peripheral neuropathy commonly occurs in the feet but may also occur in the hands. (***) Arthritis commonly occurs in the knees but may also occur in the hips. (****) Foot malformations include pes cavus, & hammer toe. DMD, Duchenne Muscular Dystrophy, PD, Pompe Disease, CMT, Charcot-Marie-Tooth disease, ALS, Amyotrophic Lateral Sclerosis.

5.1.3. Treatment approaches

Multimodal treatment plans for pain in DMD patients is necessary and involves pharmaceutical, surgical, physical rehabilitation, and psychosocial interventions (Jacques et al., 2019). To date, there is no curative treatment for DMD, however disease-modifying synthetic antisense oligonucleotides (e.g., eteplirsen and golodirsen) have recently become available (Frank et al., 2020; Grages et al., 2020; Shawi et al., 2016) and can be used in a subset of patients with certain mutations to slow progression. Treatment also includes corticosteroid therapy that has been shown to improve strength and pulmonary function, although chronic corticosteroid therapy predisposed boys with DMD to osteoporosis and painful vertebral fractures (Pangalila et al., 2015; Sbrocchi et al., 2012). Intravenous bisphosphonates used to treat symptomatic vertebral fractures have shown to decrease back pain in DMD (Sbrocchi et al., 2012). Other pharmacological interventions, commonly, NSAIDs and acetaminophen were reported to reduce pain symptomology in DM in retrospective studies (Engel et al., 2009). Our search did not reveal any RCTs assessing pharmacotherapies and pain outcomes in DMD. Cognitive- behavioral therapy aimed at improving the patient’s ability to cope and manage pain may help improve the quality of life in patients with DMD (Jacques et al., 2019; Zebracki and Drotar, 2008). Physical rehabilitation that includes regular stretching of the joints and muscles may prevent the development of contractures (Birnkrant et al., 2018).

5.2. Pompe disease (IOPD/LOPD)

5.2.1. Disease overview

Pompe disease (PD), also known as acid maltase deficiency (Chan et al., 2017), is a lysosomal (Tarnopolsky et al., 2016) and glycogen storage disorder (type II) that results from an autosomal recessive mutation in the acid alpha glucosidase (GAA) gene (De Filippi et al., 2014). Variants of the GAA gene may yield deficient or absent GAA leading to accumulation of glycogen in skeletal, cardiac, and smooth muscle (De Filippi et al., 2014; Kohler et al., 2018). Clinically, PD is categorized as infantile-onset Pompe disease (IOPD) or late-onset Pompe disease (LOPD) (Table 1) depending on the age at which symptoms first manifest. IOPD is quite rare (prevalence of ~1:138,000) and more aggressive with symptoms of hypotonia, generalized muscle weakness, muscle edema, feeding difficulties, respiratory failure developing within the first few months of life (Pichiecchio et al., 2017; Tarnopolsky et al., 2016) and the cardinal sign of cardiomyopathy manifesting by 12 months of age (Winkel et al., 2005). Scoliosis is also a common manifestation in PD that is more common in children and adolescents than in adults (Roberts et al., 2011). LOPD is more common (prevalence of ~1 in 57,000) and refers to symptom development after infancy (Tarnopolsky et al., 2016). These patients typically present with weakness in the limb-girdle, lower extremity, and trunk muscles (Tarnopolsky et al., 2016) with hypertrophic cardiomyopathy occurring in IOPD (Burton et al., 2017). Of note, the duration of disease is closely linked to disease severity (Hagemans et al., 2005a). The initial constellation of symptoms in LOPD is highly variable making diagnosis often difficult. Patients may present with nonspecific gastrointestinal symptoms including abdominal pain, diarrhea and constipation (Gesquiere-Dando et al., 2015) or with difficulty ambulating. In a recent study of LOPD, 67 % reported problems with running, 28 % reported issues with climbing stairs, and 24 % endorsed fatigue as their first symptom (Hagemans et al., 2005b).

Past reports have shown that IOPD and LOPD patients demonstrate hearing loss due to neuronal abnormalities (Chan et al., 2017), small fiber neuropathy (SFN) (Hobson-Webb et al., 2015; Lacomis, 2002), motor dysfunction (Schuller et al., 2012), neurodegeneration (Dasouki et al., 2014), pain (Gungor et al., 2013), and fatigue (Chaudhuri and Behan, 2004; Hagemans et al., 2007). From a neuropsychological or cognitive standpoint, IOPD and LOPD patients have faced a number of challenges including learning disabilities, loss of executive processing or cognitive decline (Schoser et al., 2017; Spiridigliozzi et al., 2017). Investigations involving IOPD or LOPD patients have further described T2-magnetic resonance imaging (MRI) hyperintensities in white matter (Schneider et al., 2019). Moreover, central nervous system (CNS) glycogen deposition, particularly in spinal motor neurons or pathways may also contribute to impaired respiratory function present in PD (Turner et al., 2016). These clinical findings collectively indicate that core clinical deficits in PD may not only emanate from peripheral abnormalities (Fidzianska et al., 2011) but also, pathological mechanisms embedded within the CNS. Moreover, with the advent of enzyme replacement therapy (ERT), the IOPD phenotype has evolved. IOPD is now considered a multisystemic disorder with neurocognitive, auditory, speech, swallowing, musculoskeletal, cardiac, and respiratory symptoms now observed (Kishnani et al., 2012).

5.2.2. Pain phenotype

While often absent on initial evaluation, pain is a common symptom in the disease course of LOPD. In one study (Hagemans et al., 2005b), 46 % reported frequent pain in at least one area of the body. The mechanisms of pain and disability are multifactorial including muscle and nerve inflammation, fatigue, and musculoskeletal deformities. In several landmark reports, glycogen deposits were identified on muscle and nerve biopsy of children diagnosed with PD (Fidzianska et al., 2011; Origuchi et al., 1986) suggesting SFN due to accumulation of glycogen in peripheral nerve Schwann cells (Chan et al., 2017) (Fig. 6). SFN is form of neuropathic pain and typically manifests clinically as paresthesia such as burning, tingling or aching (Lacomis, 2002). In separate study, 50 % of patients with IOPD and LOPD reported pain that met the neuropathic criteria (Hobson-Webb et al., 2015). In addition, most patients with PD demonstrate pathologic EMG studies (Muller-Felber et al., 2007). Pain in LOPD is usually chronic and widespread. In a recent study, 45 % of patients with LOPD reported having pain within the last 24 h that affected the back (50 %), shoulders (48 %), and upper legs/thighs (46 %) (Gungor et al., 2013). In a separate study with similar patient demographics, 88 % of patients reported pain in the last week and in similar body regions (Karabul et al., 2014). Scoliosis is a common feature of PD and may contribute to the high prevalence of back pain in PD. In a recent review of PD, 33 % of patients had scoliosis with a higher risk in IOPD than in LOPD (Roberts et al., 2011) (Fig. 8). In addition, scoliosis may lead to a gradual, painless stiffening of the cervical and thoracic spine known as rigid spine syndrome (Dubowitz, 1973; Gesquiere-Dando et al., 2015). Such structural changes may limit mobility and contribute to a profound sense of fatigue. Chronic fatigue is often comorbid with pain and may even be more debilitating for patients. In a recent patient survey, 78 % reported experiencing chronic pain that interfered with work, family, social life, physical functioning and was among the top three most debilitating symptoms (Gungor et al., 2013). It is no surprise, therefore, that the presence of fatigue and pain are associated with reduced quality of life (Schoser et al., 2017). Thus, to effectively treat patients with PD, close attention must be given to the management of pain, fatigue, and other quality of life metrics.

Fig. 6. Nervous System Glycogen Deposition in Pompe Disease:

A. Glycogen deposition observed within peripheral nerves innervating skeletal muscle using electron microscopy. Adapted from (Fidzianska et al., 2011). Glycogen may also occur in other peripheral nerves causing small fiber neuropathy. Adapted from (Hobson-Webb et al., 2015). B. Periodic acid-Schiff (PAS) and hematoxylin and eosin (H&E) staining of the spinal cord revealing glycogen deposition in an LOPD patient who suffered from neurological and respiratory deficits. Adapted from (Byrne et al., 2019).

5.2.3. Treatment approaches

ERT with recombinant human alglucosidase alfa (rhGAA, Myo-zyme^™/Lumizyme^™) is the standard of care in PD and the only approved disease modifying treatment (Tarnopolsky et al., 2016). Current guidelines for IOPD recommend initiation of treatment within the first days after birth (Kohler et al., 2018). In IOPD, ERT started before 6 months of age has been shown to improve cardiomyopathy, cardiac function and reduce the risk of death (Kohler et al., 2018; Schiffmann and Brady, 2002). In IOPD and LOPD, clinical trials have shown the ability of rhGAA to mitigate the rate of decline in terms of lung function, muscle strength, and mobility (Case et al., 2015; Orngreen and Vissing, 2017; van der Ploeg et al., 2010v). To date, there are no RCTs of ERT or other pharmacotherapies assessing pain as a primary outcome in PD, yet prior reviews demonstrate improvement in factors that may influence pain perception such as depression, fatigue, and quality of life (Tarnopolsky et al., 2016; Toscano and Schoser, 2013). The efficacy of ERT is influenced by a patient’s cross-reactive immunologic material (CRIM) status. CRIM positive patients have some functional copy of native GAA enzyme while CRIM negative (only observed in IOPD) have no functional enzyme and thus develop neutralizing antibodies to rhGAA leading to poorer response to ERT in IOPD and LOPD (Banugaria et al., 2011). Thus, establishing CRIM status is an important step in disease management. In CRIM negative patients, prophylactic immune tolerance reduction (ITI) with IVG, methotrexate and rituximab may prevent the development of rhGAA cross-reactive antibodies and prolong the efficacy of rhGAA (Banugaria et al., 2013; Mendelsohn et al., 2009; Messinger et al., 2012). Regarding analgesics, NSAIDs and acetaminophen are the most frequently used (Gungor et al., 2013). The individual efficacy of these or other analgesics in PD is undetermined. In general, patients with metabolic myopathies are encouraged to avoid situations that lead to muscle exertion, dehydration or extremes in body temperature (Olpin et al., 2015). However, physical therapy has been shown to improve fatigue and pain scores without worsening functional status (Favejee et al., 2015; Santalla et al., 2014).

5.3. Charcot-Marie-Tooth disease (CMT)

5.3.1. Disease overview

Charcot-Marie Tooth (CMT) disease, also known as peroneal muscular atrophyand hereditary motor and sensory neuropathy is the most common inherited neuromuscular condition (prevalence of ~1:2,800) (Skre, 1974) and is characterized by peripheral nervous system dysfunction (Pareyson and Marchesi, 2009). CMT was originally classified into two subtypes; i) CMT1, characterized by demyelination and marked reduction of nerve conduction velocities on electromyography, and ii) CMT2, characterized by axonal loss and normal or mildly reduced nerve conduction velocities (Dyck and Lambert, 1968) (Table 1). Subsequently, it was not only revealed that these subtypes are heterogeneous but that intermediate phenotypes exist (Braathen, 2012). To date, at least 90 causal genetic mutations have been identified in CMT (Pisciotta and Shy, 2018) with ~80 % of cases arising due to an autosomal duplication of the PMP22gene leading to neuronal demyelination and the classic CMT1a subtype (Braathen, 2012; Morena et al., 2019; Scherer and Wrabetz, 2008; Tazir et al., 2014). Among the first symptoms to manifest in CMT are muscle atrophy and weakness in the extremities with a lower limb predominance (Jani-Acsadi et al., 2015). Symptoms usually manifest by early adulthood as symmetric distal limb weakness, hyporeflexia or areflexia, and gait instability (Karakis et al., 2013; Pareyson and Marchesi, 2009). In addition, musculoskeletal deformities such as scoliosis, pes cavus, and hammer toes often develop (Pareyson and Marchesi, 2009). The diagnosis is usually established with a combination of characteristic clinical symptoms, family history, and abnormal electromyographic studies, while genetic testing may be beneficial if the clinical presentation is atypical (Jani-Acsadi et al., 2008; Pareyson and Marchesi, 2009).

5.3.2. Pain phenotype

Although the genetics and pathogenesis of nerve dysfunction in CMT is well-understood, the pain phenotype is underappreciated. In CMT, pain is typically chronic, widespread (Azevedo et al., 2018), and potentially more severe in women (Laura et al., 2014). In a recent study, 88 % individuals with CMT1A experienced pain, a majority of whom reported pain in multiple locations (Laura et al., 2014). The most common locations included the feet (61 %), distal lower limbs (27 %), and hands (22 %) (Fig. 8). In a separate study, 66 % reported chronic pain that lasted an average of 12 years (Ribiere et al., 2012), pain was again mainly peripheral, with 74 % reporting pain in the distal upper or lower extremities (Ribiere et al., 2012). Participants most often described pain as crawling (82 %), burning (75 %), and tingling (61 %) consistent with a neuropathic mechanism. In a separate survey of CMT1a patients, ~63 % met the criteria for neuropathic pain and the presence of such pain was correlated with diminished laser evoked potentials (LEP) (Pazzaglia et al., 2010). The latter is in line with prior studies showing that increased latency and diminished amplitude of LEP may correlate with diminished Aδ afferent signaling in neuropathies (Treede et al., 2003; Valeriani et al., 2012). In addition, fMRI may reveal changes in the somatosensory cortex corresponding to the affected body region (De Salvo et al., 2018).

Yet, it is unclear if neuropathy is the predominant pain mechanism in CMT. Laura et al. showed that while pain was a frequent symptom in CMT1a specifically, only 18 % of reported pain was neuropathic (Laura et al., 2014). In addition, ~85 % of patients with CMT may complain of muscle cramping (Johnson et al., 2015), a symptom not characteristic of neuropathic pain (Bouhassira et al., 2005). Independently, Gemignani et al. demonstrated that nociceptive pain was more frequent in CMT1a and that these patients tended to manifest such symptoms earlier than those with CMT2 (Gemignani et al., 2004). The frequent occurrence of musculoskeletal pain in the hips, back and knees (Gemignani et al., 2004; Laura et al., 2014) in CMT suggests that nociceptive mechanisms (e.g., joint ankylosis, osteoarthritis) are also at play. While longer disease duration may not correlate with more severe neuropathy, musculoskeletal pain may worsen with age and lead to further disability, adverse effects on mood, work, sleep and other quality of life metrics (Laura et al., 2014; Ramchandren et al., 2014).

5.3.3. Treatment approaches

Treatment should be multidisciplinary and focused on improving quality of life (Carter et al., 2008). There is currently no FDA approved disease modifying therapy for CMT. In animal models, progesterone has been shown to increase expression of PMP22 and worsen symptoms (Sereda et al., 2003). This model was recapitulated in pregnant women who displayed an exacerbation of CMT symptoms. In animal studies, the progesterone antagonist onapristone has been shown to reduce the overexpression of PMP22, improve muscle mass and muscle strength (Meyer zu Horste et al., 2007; Sereda et al., 2003). Unfortunately, however, this compound is toxic in humans and the future of other anti-progesterone therapies is bleak. One RCT of 8 patients with CMT neurotrophin-3 showed improvements in the Mayo Clinic Neuropathy Impairment Score (NIS) compared to placebo, with a potential decrease in the perception of prickling pain (Sahenk et al., 2005). In a Cochrane review, the use of creatinine monohydrate, purified bovine brain ganglioside injections, physical therapy, or foot orthoses showed no benefit (Young et al., 2008). Despite promising data in mouse models that ascorbic acid may correct the CMT phenotype (Passage et al., 2004), multiple RCTs spanning adults and children have failed to show any disease modifying benefit or improvements in neuropathy (Burns et al., 2009; Micallef et al., 2009; Pareyson et al., 2011; Verhamme et al., 2009). Theoretically, general agents for neuropathic pain such as capsaicin patch, TCAs, & anticonvulsants (e.g., gabapentinoids, carbamazepine) (Bril et al., 2011; Shy, 2006) may also be effective in CMT neuropathy. For musculoskeletal pain, NSAIDs/acetaminophen are safe and frequently used (Chou et al., 2007). Physical therapy and rehabilitation are essential treatments in CMT and may improve balance, mobility, and decrease the risk of falls especially if initiated early (Sautreuil et al., 2017). Unfortunately, clinical trials of physical therapy and rehabilitation show only modest or no improvements in ambulatory distance (Sackley et al., 2009). Ankle-foot orthoses are often prescribed to treat foot drop and improve ambulation, yet compliance is poor (Vinci and Gargiulo, 2008), and they do not appear to provide any benefit with regard to pain (Young et al., 2008). Corrective surgery is often performed for pes cavus and other foot deformities (Beals and Nickisch, 2008; Ward et al., 2008), however the benefit is unclear, and recurrence is possible. Despite concerns that regional anesthesia in CMT may be risky due to the diminished or absent myelin sheaths in peripheral neurons, it does not appear to result in more adverse events (Bui and Marco, 2008; Dhir et al., 2008; Hebl et al., 2006).

5.4. Amyotrophic lateral sclerosis (ALS)

5.4.1. Disease overview

Amyotrophic lateral sclerosis (ALS), is a motor neuron disease (Brettschneider et al., 2013), and is also known in the United States as Lou-Gehrig Disease. ALS is rare neuromuscular condition characterized by the loss of motor neurons in the cerebral cortex, brainstem, and spinal cord leading to progressive muscle weakness (de Tommaso et al., 2017). The incidence of ALS in Europe is ~1:46,000 each year and is more common among men and in those of European ancestry (Logroscino et al., 2010). Approximately 5–10 % of ALS cases are familial (FALS) (Byrne et al., 2011) and are inherited in an autosomal dominant fashion (Rosen et al., 1993), while the remaining ~90 % are sporadic (SALS) and are due to a combination of genetic and environmental factors(Al-Chalabi and Hardiman, 2013; Kiernan et al., 2011). In both FALS and SALS, the most commonly mutated genes are SOD1, TARDB, C9orf72, and FUS (Zou et al., 2017), which contribute to progressive motor neuronal cell death. Patients with ALS transition from a susceptibility phase, with minimal to no symptoms, to a clinical phase (Chio et al., 2017), marked by the rapid development hyperreflexia, bulbar symptoms (e.g. dysphagia, dysarthria, facial weakness, etc.) (Donaghy, 1999), pseudobulbar affect (e.g. uncontrollable laughter or tearfulness) (Gallagher, 1989), extremity weakness (Brooks, 1996), and respiratory distress (Morelot-Panzini et al., 2018). Weakened skeletal and respiratory muscles eventually lead to confinement to a wheelchair, with additional complications arising from a lack of mobility and respiratory failure (Kimura et al., 2006; Leone et al., 1987). ALS is universally fatal with a median survival of 2–4 years from the time of diagnosis (Kiernan et al., 2011), yet recent studies show that patients with ALS are living longer (Qureshi et al., 2009), which highlights the need to improve quality of life in these patients.

5.4.2. Pain phenotype

Despite ongoing evidence that pain is a prominent and debilitating symptom for patients with ALS (Hanisch et al., 2015), it remains a commonly ignored symptom in ALS. In ALS, pain often interferes with areas of daily functioning including general activity, mood, sleep, and relations with other people (Chio et al., 2012) and is associated with higher rates of depression (Hanisch et al., 2015). Patients may present with painless progressive motor weakness or muscle cramping (Caress et al., 2016) and pain (Hanisch et al., 2015). Pain may worsen after ALS symptoms manifests (Wallace et al., 2014). The prevalence of pain in ALS ranges between 15–85 % and can be neuropathic or nociceptive (Chio et al., 2017).

In ALS, neuropathic pain is reported as burning, tingling, shooting pain with allodynia and hyperalgesia (Chio et al., 2017) and separate studies have demonstrated evidence of sensory nerve fiber dysfunction including SFN (Weis et al., 2011). However, in a cross-sectional study only 9 % of ALS patients with pain presented with neuropathic pain (Moisset et al., 2016). Nociceptive pain is more prevalent and occurs as a result of muscle atrophy and weakness, prolonged immobility, and degenerative changes in bones and joints (Chio et al., 2017). A retrospective study, for example, showed that shoulder pain was present in 23 % of patients with ALS and the presence of shoulder pain was associated with proximal arm weakness (Ho et al., 2011). Pain in ALS is usually chronic and widespread. In a recent study, 53 % of ALS patients reported pain in more than one site including the back (50 %), the extremities (47 %), and the joints (42 %) (Hanisch et al., 2015). Patients use a variety of terms to describe discomfort in ALS including “tender”, “dull/pressing”, “exhausting” (Hanisch et al., 2015) or “cramping”, the last of which can be present in up to 95 % of patients (Caress et al., 2016). In ALS, the majority of patients who report pain will rate a mild severity (Delves et al., 1989), while the majority of patients who report muscle cramping will rate a moderate severity (Chio et al., 2017; Hanisch et al., 2015). The variability in terms used by patients to describe their discomfort highlights the complexity of pain in ALS and suggests the need for careful questioning on the part of providers when investigating symptoms in these patients.

5.4.3. Treatment approaches

FDA-approved treatments for ALS include riluzole, dextromethorphan/quinidine, and recently edaravone (Hardiman and van den Berg, 2017; Writing and Edaravone, 2017), which have been shown to improve survival (Miller et al., 2012), provide relief from pseudobulbar symptoms (Brooks et al., 2004), and improve functioning (Hardiman and van den Berg, 2017; Writing and Edaravone, 2017). To date, there are no RCTs of pain management in ALS (Brettschneider et al., 2013). Retrospective studies show that for neuropathic pain the most commonly used drugs were gabapentenoids and TCAs (Borasio et al., 2001; Chio et al., 2001) and for nociceptive pain NSAIDs and paracetamol were the most commonly used (Brettschneider et al., 2013). Opioids may be used for both neuropathic and nociceptive pain in advanced disease states or when pain is poorly controlled yet there is a scarcity of reliable data (Brettschneider et al., 2013). Studies have shown that cannabis might be effective in reducing both neuropathic and nociceptive pain and may act synergistically with opioids (Amtmann et al., 2004; Carter et al., 2010). Mexiletine may effectively reduce the frequency of muscle cramps (Weiss et al., 2016) while quinine may reduce muscle cramp intensity (El-Tawil et al., 2010). For patients with evidence of respiratory decline, respiratory support with non-invasive or invasive ventilation may be beneficial. Non-invasive ventilation has been shown to improve quality of life (Bourke et al., 2006), while invasive mechanical ventilation is associated with pressure ulcers, painful ventilation and pain from suctioning of phlegm and saliva (Hirano et al., 2006). The use of mechanical ventilation is a controversial clinical issue and may need thorough assessment of the overall functional level and the psychosocial environment of the patient.

6. Discussion

6.1. Pain phenotypes: from acute and protective to chronic and complexic

In rare musculoskeletal and neuromuscular diseases, pain often serves as an early and critical warning signal of active pathological mechanisms at play or occurrence of a specific clinical event. This review demonstrates that while etiologies across rare conditions are heterogeneous, there is often considerable overlap from a pain phenotype or symptomology perspective. Thus, distinct musculoskeletal and neuromuscular diseases may benefit from parallel analgesic treatment approaches, which we believe can be achieved within a comprehensive, multimodal pain therapy setting.

The presence of pain has been shown to precede key disease hallmarks, such as motor weakness in ALS (de Castro-Costa et al., 1999d). This review exemplifies that on one hand, acute or episodic pain can commonly emanate from skeletal fractures in FD/MAS, OI or DMD or soft tissue edema in FOP and CRPS (Table 2, Figs. 7 and 8). In such cases, the presence of pain can be viewed as a necessary protective process and equally important, a leading factor for why patients seek clinical care. On the other hand, recurrent clinical events, whether they are frequent fractures or disease flare-ups with local inflammation, over time can yield nervous system sensitization and substantial emotional and physical distress, which all contribute to an amplification or exacerbation of pain independent of the disease. In a more chronic setting, the primary disease pathology whilst varying greatly across conditions can ultimately lead to parallel pain-related outcomes. For example, glycogen deposition in peripheral nerves in IOPD and LOPD and neuronal death caused by C9orf72 gene mutations in ALS have been similarly associated with neuropathy, neuropathic pain state and muscle cramps. Moreover, from our analyses of rare musculoskeletal and neuromuscular diseases, skeletal deformities (e.g., scoliosis, kyphosis or coxa vara deformity), musculoskeletal joint instability, progressive immobilization, or contractures can all result in pain, particularly back pain, or painful degenerative joint diseases such as osteoarthritis. Patients with OI, EDS, FD, DMD, and CMT may present with back pain as a result of primary pathology in the back such as recurrent fractures, joint laxity or heterotopic ossification in the vertebrae. Furthermore, as disease progression occurs, the pain phenotype or severity may evolve, but perhaps less appreciated in other rare conditions such as FOP. In FOP pain may be perceived during severely painful flare-up; however, as the HO induction and expansion occurs (Upadhyay et al., 2017), the integrity and functionality of peripheral nerves is likely compromised, which may in some patients yield neuropathy. Thus, this review illustrates that pain is not only highly prevalent in rare musculoskeletal and neuromuscular disorders but that there are commonalities and complexities across conditions with regards to pain pathogenesis, regional involvement, timing and trajectories.

Table 2.

Summary of disease etiology, pain syndrome, and therapies:

Disease	Disease Etiology (Genotype)	Pain Characteristics	Therapies
OI	COL1A1, COL1A2 mutation (*)	Bone pain Arthralgias Back pain Abdominal pain Neuropathic pain	Bisphosphonates Epidural nerve blockade Physical therapy Corrective surgery Adaptive equipment
EDS	COL1A, COL1A2, COL3A1, COL5A1, COL5A2, TNXB mutation (**)	Arthralgias Myalgias Back pain Abdominal pain Headache/migraine Vulvodynia/dyspareunia Dysmenorrhea Neuropathic pain Centralized pain Postsurgical pain	NSAIDs Acetaminophen Topical lidocaine Topical estrogen Opioids Vitamin C Fish oils Corrective surgery Psychotherapy
AP	FGFR3 mutation (***)	Bone pain Arthralgias Back pain Occipito-cervical pain	Human growth hormone Epidural steroid injections NSAIDs Physical therapy Corrective surgery Adaptive equipment
FOP	ACVR1/ALK2 mutation	Flare-up related pain Bone pain Arthralgias Headaches/migraines Back pain Neuropathic pain (nerve entrapment)	Corticosteroids Bisphosphonates NSAIDS COX-2 inhibitors Opioids Gabapentinoids Adaptive equipment
FD/MAS	GNAS mutation Non-inherited	Bone pain Arthralgias Headache/migraine Neuropathic pain (nerve entrapment)	Bisphosphonates Denosumab NSAIDs Acetaminophen Calcium Vitamin D Corrective surgery
CRPS	Immune system dysregulation Non-inherited	Inflammatory pain Bone pain Limb dystonia Neuropathic pain Centralized pain	Bisphosphonates # Calcitonin # Corticosteroids # NMDA-R antagonists # Vasodilators # Radical scavengers TCAs Gabapentinoids NSAIDs Opioids Physical therapy Occupational therapy Psychotherapy
DMD	Dystrophin gene mutation X-linked recessive	Arthralgias Myalgias Inflammatory pain Back pain Bone pain Neuropathic pain	Eteplirsen Golodirsen Bisphosphonates Corticosteroids NSAIDs Acetaminophen Physical therapy Psychotherapy
PD	GAA gene mutation	Arthralgias Myalgias Back pain Headaches Neuropathic pain	rhGAA (recombinant human GAA) IVIG Methotrexate Rituximab NSAIDs Acetaminophen
CMT	PMP22 gene mutation (****)	Arthralgias Myalgias Back pain Neuropathic pain Centralized pain	SNRIs Opioids Gabapentinoids TCAs Foot orthoses Physical therapy Corrective surgery
ALS	SOD1, TARDBP, C9orf72, FUS mutations (*****)	Arthralgias Myalgias Back pain Neuropathic pain	Riluzole Edaravone Dextromethorphan/Quinidine Mexiletine Quinine Gabapentinoids TCAs Opioids

^(*)Listed genes are the most frequently mutated however approximately 17 distinct genetic mutations have identified in OI (Van Dijk and Sillence, 2014).

^(**)Listed genes are the most frequently mutated however approximately 13 distinct genetic mutations have identified in EDS (Cortini and Villa, 2018).

^(***)While autosomal dominance is the most common mode of inheritance in AP, ~80 % of cases are sporadic.

^(****)Listed gene is the most common, however approximately 90 distinct genetic mutations have identified in CMT (Pisciotta and Shy, 2018).

^(*****)Most cases of ALS are sporadic. Underlined therapies represent potential long-term pharmacological treatments.

^(#)Indicates drugs that have demonstrated efficacy in treating pain in clinical trials (O’Connell et al., 2013; Wertli et al., 2014).

NMDA-R (partial) antagonists include ketamine and memantine. Vasodilators include tadalafil. Radical scavengers include mannitol. FD/MAS, fibrous dysplasia/McCune Albright syndrome, OI, osteogenesis imperfecta, FOP, fibrodysplasia ossificans progressiva, AP, achondroplasia, CRPS, complex regional pain syndrome, EDS, Ehlers-Danlos syndrome, CMT, Charcot-Marie-Tooth disease, DMD, Duchenne muscular dystrophy, PD, Pompe disease, ALS, amyotrophic lateral sclerosis, GNAS, G-nucleotide binding protein alpha subunit, COL1A1, collagen type 1 alpha 1 chain, COL1A2, collagen type 1 alpha 2 chain, COL3A1, collagen type 3 alpha 1, COL5A1, collagen type 5 alpha 1, COL5A2, collagen type 5 alpha 2, TNXB, ACVR1/ALK2, activin A receptor/activin-like kinase 2, FGFR3, fibroblast growth factor receptor 3, TNXB, tenascin XB, PMP22, peripheral myelin protein 2, GAA, acid alpha-glucosidase or acid maltase, C9orf72, chromosome 9 open reading frame 72, SOD1, superoxide dismutase 1, TARDBP, TAR DNA binding protein, FUS, FUS RNA binding protein, COX-2, cyclooxygenase 2, NSAIDs, nonsteroidal anti-inflammatory drugs, TCA, tricyclic antidepressants, rhGAA, recombinant human GAA, IVIG, intravenous immunoglobulin.

6.2. Diagnosis and monitoring of pain

The onset of pathological mechanisms for the conditions described herein, but also for other rare diseases may present as early as infancy and last across a patient’s lifespan. While the emergence of pain may occur in lockstep with disease onset, its detection and characterization are often difficult considering the lack of objective biomarkers of pain, intra-patient fluctuations in pain, and difficultly pediatric as well as many adult patients have in communicating or describing their pain (Tracey et al., 2019). Moreover, pain may be overlooked in the clinic as there is often more focus on other issues that are the most characteristic features of the disease such as weakness in ALS. There is a critical need to recognize that for many rare disease patients (pediatric and adult populations), the presence of pain substantially reduces quality of life.

Presently, pain is often evaluated using several pain rating scales (PRS) that measure pain intensity such as the visual analogue, numerical rating, verbal rating, or faces pain scale (Karcioglu et al., 2018; Thong et al., 2018). While these scales and measures are highly important and validated clinical tools, they are often implemented cross-sectionally, for instance, during a clinical visit. Additionally, unidimensional rating scales do not provide an account of pain behaviors, pain phenotypes (e.g., nociceptive, neuropathic, centralized, or mixed pain), or how pain impacts or is interrelated with mental and physical health (Gordon, 2015). Collectively, the cross-sectional use of unidimensional pain scales may not always provide physicians or care providers an accurate account of pain dynamics, evolution of pain or pain phenotypes, or response or resistance to analgesic treatment(s).

In the case with pediatric populations suffering from chronic illnesses, as is the cases of many rare diseases, effective management of pain alongside core pathology is highly critical. As shown in other conditions such as juvenile idiopathic arthritis, the presence of pain may not only negatively impact the overall health-related quality-of-life in during childhood years, but pain and its influence can carryover and interfere with adulthood (Rebane et al., 2019). Thus, there is a great importance of diagnosing and mitigating pain early in its presentation and prior to its chronification.

The use of multidimensional pain scales (e.g., painDETECT – for neuropathic pain (Verhamme et al., 2009), Brief Pain Inventory – for pain intensity and effects across multiple areas (Poquet and Lin, 2016), McGill Pain Questionnaire – for sensory, affective, and evaluative aspects of pain (Main, 2016), or PROMIS-pain questionnaires – for quality of life (Hays et al., 2018) in rare musculoskeletal and neuromuscular diseases is likely more informative in clinical and research settings relative to more simple pain rating scales (Gordon, 2015; Taylor et al., 2016). We hypothesize that structured assessments of pain and pain-related symptomology, as recently performed in CRPS patients and the use of comprehensive patient-reported outcomes will identify sub-types of patients for specific rare diseases (Dimova et al., 2020). The identification of distinct pain phenotypes for a condition may refine implementation of analgesic strategies (pharmacological or non-pharmacological).

Pain often emanates from aberrant or pathological activity within multiple biological systems (e.g., musculoskeletal, immunological, or neurological), and therefore, implementing clinical tools or methods that allow for accurate monitoring of these systems is critical. Such methods may offer more precise insights into local and systemic sources of pain, whole-body disease burden, or onset of new musculoskeletal lesions. For many rare musculoskeletal conditions with variable clinical presentations and extent of disease, MRI, with its excellent soft tissue contrast and lack of ionizing radiation, plays a crucial role in initial diagnosis, quantification of disease burden, and assessment of complications (Javaid et al., 2019). MRI examination consisting of T1-weighted, Short Tau Inversion Recovery (STIR), and T2-weighted images with and without fat suppression in multiple imaging planes of the area of interest is suggested. Contrast enhanced examination can be of added value to evaluate for enhancing components for targeted tissue diagnosis, and to identify potential complications such as cystic or malignant degeneration in FD/MAS patients (Bousson et al., 2014).

Standard and advanced MRI techniques assist in evaluation of patients presenting with new acute onset pain or change in chronic pain. MRI is useful for assessing complications such as fracture with resulting bone marrow edema, periosteal edema and soft tissue edema in patients presenting with acute onset pain. A rare but serious complication of malignant sarcomatous transformation in FD/MAS patients should also be suspected with new onset of pain and MRI findings of cortical breakthrough and adjacent soft tissue extension of disease. Specialized MR neurography sequences are helpful in assessment of peripheral nerve involvement by adjacent osseous and soft tissue disease, and is demonstrated as compression of the involved nerves, swelling and enlargement of the fascicles, and denervation changes in the affected muscle groups (Holzgrefe et al., 2019). Quantitative MRI is used to measure the amount of fat replacement of skeletal muscle such as fat fraction muscle volume assessment and is useful in assessing disease burden and progression in neuromuscular conditions such as DMD/MD (Burakiewicz et al., 2017). For rare conditions with robust skeletal involvement, for example, FD/MAS (Papadakis et al., 2019), OI (Drubach et al., 2011), and FOP (Eekhoff et al., 2018a), ¹⁸F-NaF PET/CT has shown utility in defining skeletal disease burden, onset of new skeletal lesions, and to a lesser extent, treatment response (Botman et al., 2020). By incorporating a multidisciplinary or multimodal approach, it is possible to determine the interaction of biological systems and how the interface among systems may yield a pain state. For example, ¹⁸F-NaF PET/CT and T2- or short-TI inversion recovery MRI, have been used to identify induction plus expansion of skeletal lesions and soft tissue edema, respectively; both of which can cause pain. Moreover, musculoskeletal MRI in combination with quantification of c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) together can help determine the presence of local or systemic inflammatory states.

In multiple rare diseases reviewed herein, peripheral neuropathy was a common occurrence. Neuropathy can not only yield paresthesia or a neuropathic pain phenotype, but also autonomic dysfunction, and potentially, muscle cramping (Abraham et al., 2018; Lacomis, 2002). While quantification of epidermal nerve fiber density with skin biopsy can be informative towards characterizing neuropathy, other tools such as the Small-Fiber Neuropathy Screening List, quantitative sensory testing or electrochemical skin conductance test might be considered (Dickenson and Patel, 2020; Fabry et al., 2020; Hoitsma et al., 2011).

Independent of the condition, it is often the case that pain is not commensurate with the extent of detectable peripheral pathology. The presence of this pain-peripheral pathology disconnect can be frustrating, challenging and daunting for patients, their families, and physicians alike. In these circumstances, aberrant central mechanisms embedded within CNS circuitry mediating somatosensory processing, negative emotionality, salience or executive function may be active particularly in chronic pain states (Upadhyay et al., 2018; van der Miesen et al., 2019v). Methods such as functional MRI may be implemented to interrogate such circuitry, yet their current utility is limited to population level investigations. Nonetheless, characterization of CNS properties within a specific rare disease and across a spectrum of clinical pain levels may provide novel insights into neurobiological underpinnings of centralized or amplified pain states.

6.3. Treatment of primary disease pathology and pain

Disease modifying treatments are lacking for many rare musculoskeletal and neuromuscular conditions and first-line treatments may only slow the rate of disease progression (Field and Boat, 2010). Achieving therapeutic exposure levels within certain biological systems harboring pathology, mainly the CNS, may be difficult if not all together impossible. Considering these factors, it is perhaps less surprising that pain phenotypes emerge in the conditions discussed here, but also others. Relatedly, for many rare conditions, disease diagnosis occurs as early as infancy; however, late- or adult-onset of the condition is also common. Considering the first, it is likely that the causes of pain may change from pediatric to late adulthood across a patient’s lifespan or the pain phenotype may evolve as the patient matures. In some cases, such as FD/MAS and AP, patients may not complain of pain until late teenage or early adulthood stages, while diagnosis of the condition occurred early in childhood. These factors should be taken into consideration as optimal analgesic treatment strategies, from both a safety and efficacy perspective, may vary based on developmental or disease stage. To date, very few clinical investigations involving rare diseases have evaluated pain as a primary or secondary endpoint within RCTs. Therefore, the rationale for prescribing analgesics largely stems from observations made in other conditions affecting larger populations, open-label use of a therapy or observational studies. This current situation provides an opportunity to more rigorously evaluate the analgesic effects of novel therapeutic be their purpose to treat core pathological elements of the condition or are novel analgesics. Evaluating the impact of novel treatments on clinical pain endpoints, imaging and other markers of disease activity will be equally important.

7. Conclusion

Herein, we demonstrate that pain frequently emerges in rare musculoskeletal and neuromuscular conditions and that there is significant overlap regarding pain mechanisms, phenotypes, and treatment modalities. Of note, there is a scarcity of controlled clinical trials assessing pain as a primary or secondary outcome in rare disorders which leads to inappropriate or ineffective management of pain in the clinical setting. Future research should investigate the efficacy of disease specific or disease modifying agents on the treatment of pain, which, as we have shown significantly reduces quality of life and, in some cases functional status, for patients with musculoskeletal and neuromuscular conditions.