Chronic Musculoskeletal Pain is a Nervous System Disorder… Now What?

In 2011, the Institute of Medicine (now the National Academy of Medicine) published Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.¹ This landmark report heralded a new era for pain relief, one in which the public health impact of limitations in providing effective pain relief would be pushed to society's forefront. The timing of the Relieving Pain in America report seems especially prescient given the fallout from the ongoing opioid crisis.

Although the public health implications of Relieving Pain in America clearly resonates, another important part of the report is the call for a “transformed understanding of pain.” A quote from the preface nicely summarizes what a transformed understanding may entail:

Our committee recognizes the need for a transformed understanding of pain. We believe pain arises in the nervous system but represents a complex and evolving interplay of biological, behavioral, environmental, and societal factors that go beyond simple explanation”¹

The purpose of this Point of View is to review foundational evidence that supports pain as a nervous system condition. The goal is to increase awareness among musculoskeletal-focused physical therapists that making meaningful progress in improving pain management is likely to involve integration of nervous system–related factors. We highlight plasticity and automaticity as specific examples with high potential to change entrenched education, practice, and research approaches in such a way that our understanding of musculoskeletal pain continues to improve.

Chronic Pain as a Nervous System Disorder

Relieving Pain in America’s assertion that “pain arises in the nervous system” is not surprising. There has always been a strong central nervous system (CNS) component for pain perception (eg, the Gate and Neuromatrix theories). However, what has substantially changed is that the development of chronic pain, which was once thought to be contingent on peripherally driven input into the nervous system, is now believed to be mitigated by changes inherent to the nervous system.¹ This shift in emphasis has resulted in a more complex model in which CNS parameters dominate the clinical phenotype of chronic pain, but the phenotype still has relevant peripheral components.

There is sufficient evidence to support this assertion, and it is beyond the scope of this Point of View to provide a comprehensive review. Suffice to say that, given our current knowledge base, it is clear that functional and structural changes in the CNS are associated with many chronic pain syndromes of different etiologies, such as chronic low back pain (LBP), fibromyalgia, pelvic pain syndrome, spinal cord injury, and phantom limb pain. As proof of concept, consider further the many different ways that CNS involvement has been implicated in individuals with chronic LBP²:

• Increased sensitivity to stimulation of lumbar tissues^3,4 and tissues distant from the site of pain (ie, the leg or the thumb).^5,6

• Decreased 2-point discrimination⁷ and mislocalization of sensory information in people with pain compared with people who are free of pain.⁸

• Shifting of cortical function when measured with magnetoencephalographic (MEG); more medial representation of the lumbar spine, for example, and posterior and lateral shifts in cortical representation of the transverse abdominis muscle within the motor cortex.⁹

• Improvements in brain structure when the pain experience is adequately treated.^10,11

Rehabilitation Considerations

Plasticity as Prognosis and Prognosis as Plasticity

Nervous system plasticity is important in the development of chronic musculoskeletal pain, and, therefore, it is likely to be equally as important in rehabilitation. An individual's potential to recover from chronic pain may be driven by factors affecting nervous system plasticity. How these specific factors shape patient prognosis has been of interest in motor recovery following stroke, spinal cord injury, and traumatic brain injury, but only recently have they been explored for relevance in patient populations with chronic musculoskeletal pain.

One example is the protein called brain-derived neurotrophic factor (BDNF), which regulates neural growth, maintenance, and repair. Several common interventions, such as aerobic exercise,^12,13 and emerging therapies such as transcranial magnetic stimulation¹⁴ and acute intermittent bouts of hypoxia,¹⁵ modulate BDNF levels (see Nijs et al¹⁶ for a more detailed review). What do all these therapies have in common? They activate BDNF signaling pathways and have been shown to enhance motor output in neurological populations.^15,17 These therapies, however, have not been studied extensively for their sensory implications and potential to provide pain relief. It is a reasonable hypothesis that using interventions shown to impact BDNF signaling in combination with established approaches may enhance the potential for plasticity in the nervous system such that chronic pain is less likely to develop. These types of approaches could be an important area of research to enhance current therapies.

The exploration of factors that influence CNS plasticity will ensure that progress is made on a foundational (and, to the best of our knowledge, still unanswered) question: in which patients is chronic pain completely reversible? Certainly, innovative treatment approaches (eg, constraint-induced movement therapy^18,19) following CNS injury have resulted in improvements in motor function outcomes, but fully recovered movement for all individuals with stroke remains a holy grail. Similarly, favorable pain reduction has been reported for patients with persistent chronic pain conditions (eg, complex regional pain syndrome and phantom limb pain) in response to cognitive behavioral therapy, guided imagery, and sensory discrimination.²⁰ However, the complete resolution of these pain conditions—that is, reestablishment of a pain-free state—remains an unrealistic goal for any one treatment paradigm.

Would investigating the factors that influence nervous system plasticity better guide treatment application for resolution of pain? The fact that one patient responds favorably to exercise whereas another responds best to repeated transcranial magnetic stimulation could have less to do with the intervention and more to do with characteristics of the patient's CNS. For example, specific BDNF subtypes have been shown to mediate the response to transcranial magnetic stimulation.²¹ This assertion is speculative, but identification of biologically based subgroups would directly address the subgrouping controversy that has puzzled our generation for the past few decades.²² Prognostic approaches that consider plasticity directly might constitute “personalized medicine” for pain relief through the identification of the unique CNS profile that maximizes potential for a favorable treatment response.

Automatic for Pain Relief

There is vested interest in the CNS’s ability in balancing the demands of a given task, and the capability of the individual to meet those demands. In tasks that involve cognitive processing, the balance of interest is between automatic and executive control, and rehabilitation research tends to focus on how this balance is impacted by CNS damage or injury.²³ Following stroke, for example, a strong indicator of healthy walking is the dominance of automaticity during steady state walking.²³ Automaticity can be identified in many different ways, but definitions typically contain 2 themes: 1) processing that is fast and done in parallel and 2) processing that requires little effort even with increasing workload.²³ Following a stroke, walking initially involves higher executive control, and recovery could be defined as the ability to regain automaticity during steady state walking.

The balance between automaticity and executive control is not typically considered for those with chronic musculoskeletal pain conditions, but perhaps it should be. The hypothesized change in balance that occurs from a normal state to a damaged state for stroke and chronic pain is described in the Figure. Obviously, mechanisms of injury and what is impaired differ (ie, gait vs pain inhibition), but, through this lens, some interesting parallels can be seen:

• In a normal state, the balance for pain relief is toward automaticity. That is, in most instances, pain inhibition occurs quickly and does not require conscious effort.

• When pain persists, either there is a loss of automaticity, or automaticity alone is not sufficient to provide pain relief. The balance moves toward executive control, and effort is needed for pain relief to occur (ie, change in behavior or development of coping skills).

Figure.

The normal state of the nervous system is a balance between automaticity (brainstem and spinal cord, represented in yellow) and executive control (cortex, represented in red). Efficient and effective performance of both gait and pain modulation is dominated by automaticity (indicated by the larger area of yellow shading)–processing that is fast, in parallel, and requires little effort even with increasing workload. After insult and changes to the nervous system (ie, damaged state), control of both gait and endogenous pain modulation becomes dominated by executive control (indicated by the larger area of red shading). Then, the contrast between intervention target strategies used is stark (indicated by differences in shading between stroke and chronic pain). The majority of the focus in gait rehabilitation is on regaining automaticity. Rehabilitation in chronic pain often emphasizes executive control and includes exogenous inhibitory agents rather than building endogenous capacity. Despite the differences in intervention target and management strategies, the ideal outcome remains the same: the resumption of dominance in automaticity, demonstrated by efficient and effective gait and pain modulation (indicated by the similarities in shading between stroke and chronic pain).

Assuming the reader accepts these parallels, there are future implications to consider for improving pain management. The first implication is that existing therapies may provide pain relief through restoring automaticity for pain inhibition. Consider muscle- or joint-based manual therapy, as they have an established inhibitory effect on nervous system processing of nociceptive input.^24,25 The primary way manual therapy was hypothesized to provide pain relief was through inhibition of facilitatory input.²⁶ Evidence supporting the importance of endogenous pain modulation, however, was observed in patients who were healthy receiving spinal manipulation²⁷ and patients with knee osteoarthritis receiving joint mobilization.²⁸ For therapies such as manual therapy, a mechanistic shift of action from inhibition to enhanced modulation of nociception will not directly impact efficacy, but it could be a theoretical foundation for creating next-generation delivery approaches.

The second implication is whether there is value in training automaticity in pain relief by intentionally having an individual experience pain without harm. Training automaticity via locomotor training has shown equivalent benefit to physical therapist–supervised home exercise for walking recovery,²⁹ but similar paradigms testing the efficacy of automaticity for treating pain through the experience of pain have not been developed. Instead, most pain management approaches rely on pharmacological or nonpharmacological agents to inhibit pain. Paradoxically, training automaticity for pain relief would provoke pain, under the assumption that this provocation would build psychological and biological resilience over time. This may sound counter to a “do no harm” approach to patient care, but precedent exists from a systematic review outlining the short-term advantage of experiencing pain with exercise³⁰ for reducing pain intensity. Much more research must be completed in this area before it is established when experiencing pain may be beneficial by developing resiliency.

The third implication is to avoid solely relying on executive control for providing pain relief. In routine care episodes, there appears to be some advantage to incorporating approaches that increase cognitive load (eg, neuroscience education, cognitive behavioral therapy, and psychologically informed approaches). These interventions all involve a level of executive control necessary in developing adaptive pain beliefs and behaviors; however, their use comes at a cost of limiting the potential for automaticity. The overall balance between executive control and automaticity in a treatment plan may be especially important to consider if full recovery is still a feasible treatment goal. Think again of enhancing motor recovery following stroke. These treatment paradigms involve training that emphasizes automaticity by performing the task directly, with repetition and variation.^18,29 Executive control is used as an adjunct to the automaticity-focused approach by providing feedback that allows for motor learning. As best we can tell, there are very few programs that are focused entirely on education and cognitive behavioral therapies to enhance walking; instead, patients are given the opportunity to enhance recovery by performing the task. Perhaps it is time to take a similar stance in promoting automaticity for pain relief when developing the next generation of nonpharmacological treatments for musculoskeletal conditions.

Conclusions

This Point of View focused on the roles that plasticity and automaticity could play when chronic musculoskeletal pain is conceptualized as a nervous system disorder. The assertions we make are speculative and represent an attempt at generating hypotheses and providing direction for integrating research in areas not typically integrated (ie, it is rare to have a combination of nociceptive, motor control, and movement sciences³¹).

A shift from focusing on peripheral input to acknowledging the importance of the CNS is not meant to encourage mutual exclusiveness. Both systems are relevant to the development of chronic pain syndromes, with special interest in how the peripheral and central systems interact to perpetuate or extinguish nociceptive signals. The inherent complexity of these interactions has yet to be captured in a way that enhances clinical decision making. The available research suggests that conditions characterized as central sensitization syndromes also exhibit signs of peripheral sensitization (and vice versa). For example, in our own work involving patients with unilateral shoulder pain scheduled for arthroscopic surgery, we found evidence for local and remote pain sensitivity to exist in all 4 possible combinations of proxy measures (ie, peripheral sensitivity only, peripheral and central sensitivity, central sensitivity only, or no evidence of sensitivity).³²

The temporal association of peripheral and central systems is another layer of complexity to consider. It is often assumed that the ongoing peripheral input leads to the development of central sensitization. However, in our aforementioned study in shoulder pain, there was evidence of elevated remote pain sensitivity with and without elevated local pain sensitivity.³² These examples indicate that more work is needed before we fully understand the spatial and temporal interplay between peripheral and central systems involved with chronic pain development. There are likely to be both peripheral and central treatment targets, along with optimal times for their application, for providing effective pain relief; however, we haven’t identified these windows of opportunity yet.

The assertions in this Point of View may spur physical therapists to explore management models that go beyond only providing pain relief (eg, movement as a way to alter the relevance of pain to the individual beyond only a reduction in pain intensity³³). We fully acknowledge that more scientific work is to be done before speculations such as these are actualized into gains in patient care; however, we also acknowledge there is a good chance that paradigm-shifting improvements in patient care may emerge through better integration of what we know about providing pain relief and what we know about the nervous system.

Look for PTJ’s Special Issue on the Nonpharmacological Management of Pain in May

Author Contributions

Concept/idea/research design: Steven Z. George, Mark D. Bishop

Writing: Steven Z. George, Mark D. Bishop

Consultation (including review of manuscript before submitting): Steven Z. George

Funding

S.Z. George's and M.D. Bishop's writing time was supported through a grant from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (ref. no. AR055899).

Disclosures

The authors completed the ICJME Form for Disclosure of Potential Conflicts of Interest and reported no conflicts of interest.