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Special Communication  |   September 2018
Does Osteopathic Manipulative Treatment Make a Neuropsychological Difference in Adults With Pain? A Rationale for a New Approach
Author Notes
  • From the Departments of Clinical Integration (Drs Rizkalla and Huntington-Alfano), Osteopathic Manipulative Medicine (Drs Henderson, Huntington-Alfano, and Heinking), and Physiology (Dr Henderson) at the Midwestern University/Chicago College of Osteopathic Medicine (Student Doctors Koronkiewicz, Knees, Hoffman, and Elahi and Dr Impens) in Downers Grove, Illinois, and from the Institute for Healthcare Innovation at Midwestern University in Downers Grove, Illinois (Dr Impens). 
  • Financial Disclosures: None reported. 
  • Support: This study was supported by grants from Midwestern University and the Chicago College of Osteopathic Medicine. 
  •  *Address correspondence to Mireille N. Rizkalla, MSc, PhD, Department of Clinical Integration, Midwestern University, 555 31st St, Downers Grove, IL 60515-1235. Email: mrizka@midwestern.edu
     
Article Information
Osteopathic Manipulative Treatment / Pain Management/Palliative Care
Special Communication   |   September 2018
Does Osteopathic Manipulative Treatment Make a Neuropsychological Difference in Adults With Pain? A Rationale for a New Approach
The Journal of the American Osteopathic Association, September 2018, Vol. 118, 617-622. doi:https://doi.org/10.7556/jaoa.2018.136
The Journal of the American Osteopathic Association, September 2018, Vol. 118, 617-622. doi:https://doi.org/10.7556/jaoa.2018.136
Web of Science® Times Cited: 2
Abstract

Cognitive impairment is common in patients with pain. While symptoms of pain are effectively treated with osteopathic manipulative treatment (OMT), the cognitive complaint is vastly ignored. Pain-induced cognitive dysfunction can be severe and is particularly apparent in working memory and attention. There is good reason to expect cognitive responsiveness to OMT. Previous research has reported the effects of OMT on related psychiatric outcomes, including relief from depression and anxiety, suggesting that OMT may produce more cortical benefits than is currently thought. The rationale to link OMT to cognition comes from the tenets of osteopathic medicine: body unity, homeostasis, and the structure-function relationship. The present article provides background evidence to support the hypothetical link between OMT and cognitive benefits and proposes a physiological mechanism of how OMT could exert its effect on cognition. Research strategies are discussed to test the hypotheses that are generated from the proposed theoretical framework.

The biopsychosocial approach considers biological, psychological, and social factors, as well as their interactions in the understanding of illness, treatment, and maintenance of health. Similar to the osteopathic tenets, an intervention on any of these components could have an effect on the others. Therefore, psychological treatments are not the only gateway to the psyche; manipulation can affect the psyche too. Our specific concept, that osteopathic manipulative treatment (OMT) and its resulting pain reduction helps cognition, falls within the range of ideas covered by these osteopathic concepts. 
The idea of a bi-directional, reciprocal interaction of systems is not a new concept in osteopathic medicine. The reciprocal interaction of systems explains why OMT can improve diverse conditions that are seemingly unrelated to the musculoskeletal system, such as otitis media, asthma, infantile colic, irritable bowel syndrome, and chronic obstructive pulmonary disease.1 System interrelatedness also provides an explanation as to why OMT has multiple neurophysiological effects. For example, neurochemically, OMT can stimulate cannabinoid receptors in the brain by increasing serum levels of anandamide.2 Neurofunctionally, OMT can affect functional connectivity between brain regions involved in modulating pain experience.3 Collectively, these effects create the emergence of neuronal outcomes that are greater than what would be expected from a biomedical perspective. 
One systematic review4 of the psychological response to spinal manipulation reported improvement in psychiatric outcomes such as depression and anxiety, suggesting that OMT may produce a wider scope of benefits to cortical functioning than is currently thought. To our knowledge, there is no research that reports the cognitive outcomes of OMT. This article is intended to provide the rationale for research to investigate the mechanisms that link the cognitive components of pain, cognitive function, and OMT. 
Pain Causes Cognitive Impairment
The increasing prevalence of pain-related illnesses has resulted in a heightened interest in the effects of pain on cognitive function.5 Jorge et al6 showed that nearly 80% of patients with chronic pain complain of cognitive impairment, and Weiner et al7 found that greater pain intensity was associated with lower neuropsychological performance. That chronic pain could significantly impede cognitive function has long been shown in the literature. The cognitive profiles of patients with pain appear to mimic those of patients with cortical dementia, presumably because chronic pain impinges on the fronto-parietal networks.8 Deficits are particularly apparent in working memory9 and attention,10 with several imaging models of how this impedance occurs.8 A 2013 meta-analysis9 showed that compared with healthy controls, patients with pain are expected to have a decline in working memory and attention by an effect of 0.47 and 0.52 (Cohen d), respectively, representing clinically relevant implications. 
Most of the literature on pain and attention has been derived by the limited-capacity model11 of human cognition. This neurocognitive model proposes that pain is an active consumer of attention; it highjacks attention because of its salience, thereby diverting cognitive resources away from other cognitive processes.11 Vlaeyen et al12 argue that pain should be defined as an enduring cognitive interruption, which is hard to disengage from and results in impaired cognitive performance. In other words, the cognitive impairments seen in patients may be the result of unequal allocation of attention favoring pain and antagonizing higher-order cognitive processes. This limited-capacity model implies that effective pain relief should liberate the brain's attentional resources and reverse cognitive impairment, and this implication is consistent with a study by Seminowicz et al,13 who found that structural and functional brain changes can be reverted by pain management. 
Role of Cytokines
It is well recognized that chronic pain is associated with an inflammatory response characterized by an upregulation of pro-inflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α).14 The relationship between pain severity and cytokines is so close that there appears to be a dose-related relationship.15 Cytokines provoke pain in several ways. For example, they promote matrix degeneration by enhancing the production of metalloproteinases.16 They also infiltrate the medulla–spinal cord pathway to release neuromodulators that signal pain.17 The direct and well-defined immune-to-brain pathway provides an explanation as to why cytokines can subjugate the brain and antagonize memory, neural plasticity, and neurogenesis.18 Accordingly, pain may be linked to cognitive impairment through a neuroinflammatory mediator model. 
Elevated cytokines pose a great risk to the aging brain and have been the subject of extensive cross-sectional and longitudinal dementia studies.19 Specifically, elevated IL-6,20 IL-1β,21 and TNF-α22 have each been associated with cognitive impairment, as well as a greater cognitive decline over longitudinal follow-ups.23 Preclinical trials on the effect of cytokines on the brain have demonstrated their role in suppressing hippocampal long-term potentiation,24 impeding hippocampal neurogenesis,25 reducing acetylcholine and nerve growth factors,26 and sustaining neuroinflammation.27 Consequently, there are degenerative changes in hippocampal-dependent processes, such as memory consolidation.28 The identification of inflammatory mechanisms involved in pain-related cognitive impairment makes cytokines ideal targets for examination. In the past decade, both human and in vitro studies29,30 have established that OMT can affect cytokine levels for musculoskeletal conditions. 
Remove the Pain, Improve the Brain
Patients with pain and those with cognitive impairment frequently exhibit common clinical features, suggesting that they may share some pathophysiologic aspects. For example, from a neurologic perspective, pain involves the activation of the prefrontal cortex, the anterior cingulate cortex, and the thalamus,31 which are brain regions that are also critical to selective attention, working memory, and error awareness.8,32 Furthermore, pharmacologic inhibition of the “pain matrix”33 restores normal cognitive task performance.34 Second, from an inflammatory perspective, pro-inflammatory cytokines—IL-1β, IL-6, and TNF-α—are central to the clinical manifestations of both somatic dysfunction30 and cognitive impairment.18 Thus, analgesic interventions that attenuate these cytokines are ideal targets for managing pain-induced cognitive impairment. However, prescribing opioids for pain management is under scrutiny, as resultant deaths and addictions are reaching epidemic proportions.35,36 Osteopathic manipulative treatment offers another therapeutic option that is safe and capable of modifying inflammatory parameters in as little as 6 sessions.30 Therefore, nonpharmacologic multidisciplinary pain management is not only consistent with recent federal guidelines,37,38 but it is integral to the mind-body connection. 
Current Research and Clinical Applications
The existing gaps in knowledge can help generate testable hypotheses that can be empirically tested with a variety of research strategies that include descriptive, experimental, and mechanistic approaches. Careful consideration of common methodologic issues within pain research will be vital for well-designed clinical trials to test the proposed framework. 
Descriptive Research: To what extent are neuropsychological functions impaired in pain clinic populations?
Interest in the effect of pain management on cognition creates a need for accurate cognitive profiling for both osteopathic and allopathic settings. A comprehensive battery of neuropsychological tests should be selected to measure basic cognitive functions, such as executive function, attention, language, visuospatial ability, and memory, in addition to self-reported measures of depression, anxiety, and stress. All tests should possess strong psychometric properties, be widely used in standard clinical neuropsychological assessment procedures, and have a well-established normative standard of comparison. Clinically, if a substantial number of patients perform below normative cut-off, recommendations for routine cognitive screening measures as part of intake procedures would be generated. From a research perspective, it is possible to create an archive of normative data on the population of interest, creating a benchmark for future investigations to compare or define effect of change. 
Experimental: To what extent does pain management reverse cognitive dysfunction?
Imperfect research designs are common in pain trials. When trying to apply a double-blind, randomized controlled trial, it quickly becomes apparent that this biomedical model does not lend itself well to manual interventions.39 For example, randomly assigning a nonmedicated control group raises ethical issues in studies involving pain patients.5 Furthermore, it may be useless to use sham manipulation, as these conditions are not perceived by patients to be as credible as OMT, thereby introducing bias and compromising the internal validity of the study.39 Although randomized controlled trials can afford a high degree of experimental control, studies based on such controlled settings are often less efficacious than expected because they are unrealistic in “real-world” practices and can create interventions that may be too complex or costly to integrate with existing activities.40 
The literature11-13 suggests that pain management may improve cognition. Future osteopathic research should examine how pain amelioration with OMT compares with that of allopathic treatment and whether unique benefits of osteopathic care exist. Using an allopathic group as a point of comparison is a novel extension to osteopathic research and would be intended to control for nonspecific or confounding treatment effects while determining whether there is an extended benefit to osteopathic care above and beyond standard allopathic care. That is, because both osteopathic and allopathic physicians treat patients who have pain using conventional approaches, any differences observed can be reasonably attributed to the practice of osteopathic medicine. Assuming such a design reveals group differences, the question remains: “What is the active ingredient of osteopathic medicine?” Therefore, an allopathic-osteopathic comparison would initially expose a proof of principle, whereas further dismantling would be required to isolate the precise curative osteopathic ingredient. A third comparison group composed of osteopathic physicians who do not practice OMT could be used to further delineate general osteopathic principles and practice, as described in Kuchera's algorithm.41 Experimental precision is challenged by standardizing OMT to permit comparative analysis yet tolerate the considerable variability that characterizes pain and the idiosyncrasies of individual physicians. These factors might be controlled by letting them vary unsystematically across groups and by creating a comprehensive high-yield protocol, akin to the “dirty half dozen” approach formulated by Greenman.42 The ability to isolate the curative osteopathic ingredients is of central importance to increase empirical support of this long-embraced approach to patient care. 
Mechanistic: Understanding the OMT phenomenon at deeper levels
Discovering an association between OMT and cognitive recovery serves as the impetus for further investigation about what factors predict the strength of their relationship (moderators) and what factors account for the therapeutic mechanism (mediators). For example, the degree of somatic dysfunction can be examined as a potential moderating factor influencing the relationship between OMT and cognitive functioning. In previous OMT trials, the number of key osteopathic lesions (a proxy for somatic dysfunction severity) reliably accounted for individual variation in back-specific disability and general health outcomes.43 This conceptualization predicts that intervention gains are not created equal; that is, not all patients with pain benefit from treatment uniformly. Knowing how the effectiveness of OMT varies as a function of somatic characteristics will not only have theoretical implications, but, clinically speaking, will help to identify patients who would likely benefit from such treatment. 
Likewise, cytokines can be examined as a potential mediating factor underpinning the relationship between OMT and cognitive recovery. This hypothesis could be assessed by evaluating the extent to which treatment reduces inflammation and produces concomitant improvement in cognitive function. Elucidating the process by which OMT imparts its benefits is an important advancement in understanding, and it continues to be identified as a priority area for research by the American Osteopathic Association.44,45 
Conclusion
Pain has unrecognized effects on cognitive function that may be amenable to OMT. The premise that OMT could improve pain-induced cognitive dysfunction is not only consistent with the tenets of osteopathic medicine, but is also empirically supported by research showing that inflammatory and neurologic responses are reversible by pain management. A wide range of research strategies are available to study this uncharted field, potentially broadening OMT practice parameters beyond the body and into the brain. 
Author Contributions
All authors contributed to the conception and oversight; Dr Rizkalla drafted the article; all authors revised it critically for important intellectual content; all authors gave final approval of the version of the article to be published; and all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy and integrity of any part of the work are appropriately investigated and resolved. 
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