Chronic Pain in Neuromuscular Disease

The importance of pain extent (ie, number of body areas with pain) and pain site as factors contributing to dysfunction in persons with chronic, slowly progressive neuromuscular disease (NMD), remains poorly understood. This article discusses the importance of assessing pain site in addition to global pain intensity in patients with chronic, slowly progressive NMD. The importance of addressing pain at multiple sites will have a major impact on future studies assessing interventions to treat pain in this patient population.

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Most patients with slowly progressive neuromuscular disease have chronic pain, to some degree. The studies done to date have typically assessed average pain intensity rather than occurrence and severity of pain in specific body locations. This assessment limits the usefulness of the data with respect to formulating treatment plans that address both physical and psychological aspects of pain.
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The available data suggest that pain extent and intensity at specific sites are associated with pain interference and negatively affect both physical and psychological functioning in patients with slowly progressive neuromuscular disease.
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Future studies assessing pain in persons with slowly progressive neuromuscular disease should address pain site in addition to global pain intensity. Investigating pain at multiple sites in future studies will enable clinicians to design more effective therapeutic interventions to treat pain in this patient population.

Key Points

Introduction

A growing body of research indicates that chronic pain is a significant problem for many persons with chronic, slowly progressive neuromuscular disease (NMD). However, it is still not clear how much pain intensity factors in to the negative biopsychosocial and physical consequences of chronic pain in the setting of slowly progressive NMD. Pain intensity is one of the most common dimensions assessed by clinicians and researchers who treat and study pain. Reduction in global pain intensity is also the standard by which most pain treatments are judged. However, although average pain intensity is an important pain domain, other pain domains are also potentially important (eg, pain frequency, duration, location, and quality) as factors that could contribute to patient dysfunction, especially in individuals with chronic pain. Unfortunately, research is lacking regarding the relative importance of these additional domains for understanding adjustment to pain.

The research that has been conducted on this topic in other pain populations suggests that pain site may contribute to adjustment to chronic pain over and above the effects of global pain intensity. For example, Marshall and colleagues found that the intensity of back pain in patients with amputation explained a significant amount of variance in interference in daily activities beyond the pain associated with limb amputation. Similarly, there is some preliminary evidence that pain in the low back and arms is more strongly associated with patient functioning than pain in other body locations in a sample of patients with a variety of chronic pain problems (Tan G, Jensen MP, unpublished data, 2011). Nonetheless, research in this area is sparse, and it is not known whether these preliminary findings replicate in other samples of patients with chronic pain, including those with NMD. If these findings do replicate across different chronic pain populations, then clinicians should assess both pain intensity and its location(s) to better understand the potential impact that the pain might have on a specific patient. Moreover, if low back pain or pain in the extremities is more closely linked to a patient’s quality of life than pain at other sites, then treatments that address pain at these sites may be more important to patients with chronic pain than treatments that address pain at other sites (eg, the head or torso). Thus, research in this area could help inform the work of clinicians and scientists who are developing new pain treatments for individuals with specific pain conditions. However, the authors are not aware of any research that has studied the relative importance of pain site to patient functioning in individuals with slowly progressive NMD.

Pain extent is a separate and distinct domain from intensity and refers to the overall number of body areas with pain. Research suggests that this pain domain may also be important to patient functioning. For example, Tait and colleagues found a significant association between pain extent and the tendency of patients to report greater complaints of weakness, fatigue, and depression. Similarly, Toomey and colleagues reported that patients with more pain sites were more likely to report pain as having a greater negative impact in their functioning. Türp and colleagues found that pain extent, along with pain intensity, was a significant predictor of pain-related disability in a sample of female patients with chronic facial pain. Patients with pain at multiple sites have shown a reduced level of health-related functioning, are more likely to have difficulties with mobility regardless of physical impairments than those with no pain or localized pain, and have worse prognosis for future work ability. In a series of studies, Kamaleri and colleagues reported significant associations between pain extent and functioning in patients with musculoskeletal pain. They found a strong and linear association between increasing number of pain sites and decreasing functional ability; a strong relationship with decreasing psychological health, sleep quality, and overall health; and future work disability after a 14-year period.

As with research on the importance of specific pain sites to patient functioning, it is unclear if these findings regarding pain extent replicate in other populations of individuals with chronic pain, including persons with slowly progressive NMD. Most published studies on these issues have been conducted with low back patients receiving treatment at secondary and tertiary care facilities. Thus, these findings may not generalize to other populations of patients with pain.

Further delineating the relative importance of pain site and extent in relation to patient functioning is particularly important in patients with NMD, because research indicates they typically experience pain in more than one location. Given what previous studies have found in other pain populations, the authors hypothesize that pain extent would be negatively associated with psychological functioning and positively associated with pain interference, whereas pain intensity in specific pain sites would show stronger associations with measures of patient functioning than pain at other sites. More specifically, one would expect that pain in the low back and arms might evidence stronger associations with pain interference and psychological functioning than pain at other sites.

Disease-specific pain traits

There are intriguing differences among degrees of pain in the slowly progressive forms of NMD. It is not unexpected that neuropathic diseases like Charcot Marie Tooth would rank high in pain intensity, given the pathogenesis of the disease, particularly the demyelinating forms. However, it is clear that 2 of the most common forms muscular dystrophy, myotonic type 1 (DM1), and facioscapulohumeral (FSHD), are also high on the list of painful NMDs. Worldwide, DM1 and FSHD are the first and third most common forms of dystrophic myopathies, respectively, with the dystrophinopathies coming in second. Both DM1 and FSHD are autosomal dominant, slowly progressive neuromuscular disorders (NMDs). DM1 is caused by a polynucleotide (CTG) triplet expansion located on the 3′ untranslated region of chromosome 19q13.3. This location results in a toxic gain of function of abnormally stored RNA in the nuclei of affected cells, leading to deregulation of RNA binding protein levels and mRNA splicing processes of multiple genes. This action is presumed responsible for the multisystem features typical of DM1, with involvement of skeletal, cardiac, and smooth muscles, and the central nervous, endocrine, ocular, respiratory, and gastrointestinal systems to varying degrees.

In FSHD, most patients possess a large deletion in the polymorphic D4Z4 macrosatellite repeat array at 4q35, presenting with up to 10 repeats, as opposed to 11–150 repeats in unaffected individuals. This situation is complicated by a nearly identical repeat array present at 10q26. The remarkably similar sequence identity between these 2 arrays can cause difficulties in molecular diagnosis. Each 3.3-kb D4Z4 unit contains a DUX4 (double homeobox 4) gene that is activated on contraction of the 4q35 repeat array via induction of chromatin remodeling. Myofiber synthesis of both DUX4 transcripts and protein causes significant cell toxicity. As a transcription factor, DUX4 may target several genes, resulting in cellular deregulation with inhibition of myogenesis, muscle degradation, and oxidative stress.

Prior studies indicate that as many as nearly 90% and 70% of patients with FSHD and DM1 report pain, respectively. In addition to indentifying pain as a major problem for patients with either of these NDMs, these studies also indicate that pain is more common in patients with FSHD versus DM1. The average severity of pain in patients with FSHD (approximately 4.4 of 10 on an ordinal pain scale) is less than that reported by patients with DM1 (6.28 of 10). The reasons these disease in particular have more pain are not clear but they involve membrane-related pathology, and both disorders have underlying genetic expansion-type mutations and are multisystem disorders.

As already mentioned, almost all previously published studies on the effects of pain extent have been conducted on patients with musculoskeletal problems. Results from these reports seem to support that simply counting the number of pain sites might be important when assessing a patient’s pain problem. This approach does not seem adequate, however, for people with an NMD. At least, for this specific population, our data suggest that overlooking the pain intensity of the specific sites may result in a failure to capture the true meaning and implications of the pain experience of these patients. Reasons for this failure include the fact that NMDs involve pathophysiology in the peripheral nerves or muscles as part of the underlying disease process, which is distinctly different from a musculoskeletal disorder. Thus, a variety of abnormal processes may generate and maintain the symptom of pain in NMDs, and conceptually, it is likely that no one mechanism may be disease specific, although this topic remains to be studied. It is more likely that any given NMD would have several mechanisms associated with it. Thus, accounting for the pain in any single patient may require hypothesizing one or more mechanisms at work simultaneously. Once neuropathic pain is present, all levels of the nervous system, peripheral, central, and autonomic, may play a role in the generation and maintenance of pain. Therefore, independent of actual clinical diagnosis, several different pathophysiologic processes may be present simultaneously. Further, some patients with neuropathic pain may also develop secondary myofascial pain. Myofascial pain may mimic neuropathic pain and result in referred pain distant from the actual soft tissue source and is a logical explanation for the chain of events occurring in a hereditary neuropathy like Charcot Marie Tooth disease. However, these myofascial pain generators are likely further accentuated in diseased, dystrophic muscle such as seen in DM1 or FSHD.

It is probable that, to some extent, skeletal muscle pathophysiology plays a significant role in pain generation in this setting. Because of active, ongoing muscle degeneration, there is significant risk for overwork weakness and exercise-induced muscle injury, even with simply doing activities of daily living. Dystrophic muscle is susceptible to exercise-induced muscle injury, particularly eccentric (lengthening) muscle contractions. Patients with NMD are susceptible to overwork weakness and muscle injury, resulting in excessive delayed-onset muscle soreness. This soreness usually occurs 24–48 hours after exercise. Other symptoms might include muscle cramping, heaviness in the extremities, prolonged dyspnea, and fatigue. Fatigue in this setting is likely multifactorial because of deconditioning and impaired muscular activation, but likely contributes to pain.

Disease-specific pain traits

There are intriguing differences among degrees of pain in the slowly progressive forms of NMD. It is not unexpected that neuropathic diseases like Charcot Marie Tooth would rank high in pain intensity, given the pathogenesis of the disease, particularly the demyelinating forms. However, it is clear that 2 of the most common forms muscular dystrophy, myotonic type 1 (DM1), and facioscapulohumeral (FSHD), are also high on the list of painful NMDs. Worldwide, DM1 and FSHD are the first and third most common forms of dystrophic myopathies, respectively, with the dystrophinopathies coming in second. Both DM1 and FSHD are autosomal dominant, slowly progressive neuromuscular disorders (NMDs). DM1 is caused by a polynucleotide (CTG) triplet expansion located on the 3′ untranslated region of chromosome 19q13.3. This location results in a toxic gain of function of abnormally stored RNA in the nuclei of affected cells, leading to deregulation of RNA binding protein levels and mRNA splicing processes of multiple genes. This action is presumed responsible for the multisystem features typical of DM1, with involvement of skeletal, cardiac, and smooth muscles, and the central nervous, endocrine, ocular, respiratory, and gastrointestinal systems to varying degrees.

In FSHD, most patients possess a large deletion in the polymorphic D4Z4 macrosatellite repeat array at 4q35, presenting with up to 10 repeats, as opposed to 11–150 repeats in unaffected individuals. This situation is complicated by a nearly identical repeat array present at 10q26. The remarkably similar sequence identity between these 2 arrays can cause difficulties in molecular diagnosis. Each 3.3-kb D4Z4 unit contains a DUX4 (double homeobox 4) gene that is activated on contraction of the 4q35 repeat array via induction of chromatin remodeling. Myofiber synthesis of both DUX4 transcripts and protein causes significant cell toxicity. As a transcription factor, DUX4 may target several genes, resulting in cellular deregulation with inhibition of myogenesis, muscle degradation, and oxidative stress.

Prior studies indicate that as many as nearly 90% and 70% of patients with FSHD and DM1 report pain, respectively. In addition to indentifying pain as a major problem for patients with either of these NDMs, these studies also indicate that pain is more common in patients with FSHD versus DM1. The average severity of pain in patients with FSHD (approximately 4.4 of 10 on an ordinal pain scale) is less than that reported by patients with DM1 (6.28 of 10). The reasons these disease in particular have more pain are not clear but they involve membrane-related pathology, and both disorders have underlying genetic expansion-type mutations and are multisystem disorders.

As already mentioned, almost all previously published studies on the effects of pain extent have been conducted on patients with musculoskeletal problems. Results from these reports seem to support that simply counting the number of pain sites might be important when assessing a patient’s pain problem. This approach does not seem adequate, however, for people with an NMD. At least, for this specific population, our data suggest that overlooking the pain intensity of the specific sites may result in a failure to capture the true meaning and implications of the pain experience of these patients. Reasons for this failure include the fact that NMDs involve pathophysiology in the peripheral nerves or muscles as part of the underlying disease process, which is distinctly different from a musculoskeletal disorder. Thus, a variety of abnormal processes may generate and maintain the symptom of pain in NMDs, and conceptually, it is likely that no one mechanism may be disease specific, although this topic remains to be studied. It is more likely that any given NMD would have several mechanisms associated with it. Thus, accounting for the pain in any single patient may require hypothesizing one or more mechanisms at work simultaneously. Once neuropathic pain is present, all levels of the nervous system, peripheral, central, and autonomic, may play a role in the generation and maintenance of pain. Therefore, independent of actual clinical diagnosis, several different pathophysiologic processes may be present simultaneously. Further, some patients with neuropathic pain may also develop secondary myofascial pain. Myofascial pain may mimic neuropathic pain and result in referred pain distant from the actual soft tissue source and is a logical explanation for the chain of events occurring in a hereditary neuropathy like Charcot Marie Tooth disease. However, these myofascial pain generators are likely further accentuated in diseased, dystrophic muscle such as seen in DM1 or FSHD.

It is probable that, to some extent, skeletal muscle pathophysiology plays a significant role in pain generation in this setting. Because of active, ongoing muscle degeneration, there is significant risk for overwork weakness and exercise-induced muscle injury, even with simply doing activities of daily living. Dystrophic muscle is susceptible to exercise-induced muscle injury, particularly eccentric (lengthening) muscle contractions. Patients with NMD are susceptible to overwork weakness and muscle injury, resulting in excessive delayed-onset muscle soreness. This soreness usually occurs 24–48 hours after exercise. Other symptoms might include muscle cramping, heaviness in the extremities, prolonged dyspnea, and fatigue. Fatigue in this setting is likely multifactorial because of deconditioning and impaired muscular activation, but likely contributes to pain.

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