Neuroimaging: Applications in Chronic Pain Management

Pain is a complex emotion with a wide spectrum of sensations spanning from extreme acute physical pain to emotional psychological pain. Chronic pain, in particular, is a significant global burden; misuse and abuse of opioid analgesics have made headlines, and continue to plague America and its healthcare system at astronomical cost.^1-3

Less publicized are the individuals who cannot express or feel pain, but also need effective management of pain. These include infants, patients in coma, those with dementia, and those with rare genetic mutations that prevent pain sensation.

Several factors contribute to the challenges of optimal pain management, including poor understanding of pain pathology, and the adoption of a ‘one size fits all’ treatment strategy. Also poorly understood are the psychological factors that can impact coping skills, and pre-existing personality traits such as impulsivity and catastrophizing, which may increase risky behavior such as opioid misuse and abuse.^4,5

Furthermore, the subjective nature of the pain experience suggests that a universal treatment strategy using current pharmacological options is extremely challenging to achieve optimal results. Alternative approaches to pain management that can better differentiate pain stimuli (ie,  acute, chronic, and psychological) across all patient populations are needed.

Seminal work investigating mechanisms of placebo analgesia showed the central role of the brain in pain processing.

The literature suggests that multiple brain regions play a pivotal role in pain processing. Blood flow measurements using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have revealed that analgesia is related to a reduction in neural activities in brain regions involved in the modulation of pain signals (ie, rostral anterior cingulate cortex, insula, thalamus, and brainstem including the periaqueductal gray and the ventromedial medulla).^6,7

The endogenous opioid system and its activation of µ-opioid receptors are thought to mediate the observed placebo effects.^6,7 Studies provide evidence to show that empathy for pain activates brain areas partially overlapping with those underpinning response to the first-hand experience of pain.⁸

Functional magnetic resonance imaging and PET studies have identified a distributed neural network in the brain involved in the sensory-discriminative aspect of pain, as well as its cognitive and affective/emotional factors.⁹

The pain matrix region -which includes the somatosensory cortices, and the anterior cingulate cortex and insula- is activated not only by a specific physical pain stimulus, but also by sensory stimuli such as flashes of light or sudden loud noise, as well as emotional experience such as social rejection and empathy for or memory of pain.¹⁰

From a neurobiological standpoint, the mechanisms contributing to the transition from acute to subacute and chronic pain are heterogeneous. Distinguishing the different patterns of brain signals in response to pain can potentially differentiate physical from emotional pain, as well as acute from chronic pain.

An algorithm based on machine-learning techniques has been used to develop a neurological signature of pain that is sensitive enough to distinguish painful heat from non-painful heat; actual pain from anticipation or recall of pain, and physical from emotional pain.¹¹

Indeed, advanced neuroimaging techniques have revolutionized our knowledge of chronic migraine; identifying specific cortical substrates can help explain different forms of chronic migraine and perhaps the predisposition of patients to different therapeutics and to possible relapse in drug abuse.¹²

In fact, the brainstem region that processes pain when an individual is distracted has been identified; this knowledge may help distinguish acute pain from chronic pain or one’s vulnerability to transition from acute to chronic pain.^13,14

Neuroimaging studies have been used to show functional and anatomical differences between the brains of individuals with chronic pain and those with acute pain, and this has led to the first longitudinal brain imaging study of chronic pain.^15,16

Although this study involved a relatively small number of individuals, the findings clearly show a reduction in gray matter density in the insula and nucleus accumbens of individuals who developed chronic pain, and as pain transitioned from acute to chronic, brain activity shifted to regions associated with emotion and reward.¹⁷ The study was also able to predict, to approximately 80% accuracy, individuals who were likely to progress to chronic pain.¹⁷

More recent studies document cellular changes in gross brain anatomy in individuals with neuropathic and chronic pain.

Determining the basis of these changes may provide a platform for development of targeted, personalized and ultimately more effective treatment regimens.^18,19 Blocking transition from acute to chronic pain has been demonstrated in animal model,²⁰ and a human proof of concept study in which nucleus accumbens neurons are inhibited, has been initiated.¹⁰

Based on the current advances, is it then possible to apply neuroimaging techniques clinically to more accurately treat different pain sensations, and thus provide an alternative approach to targeted chronic pain management? In theory, yes, but with caution, according to Karen Davis, PhD, Neuroscientist at the University of Toronto.

“Using a vascular-based technology has issues that people haven’t been considering. Getting this right will be crucial if brain imaging is going to play a part in evaluating pain. The use of the technology is getting ahead of itself, and there are enormous legal and neuroethical implications.”¹⁰

Although independent groups, nationally and internationally are making significant advances with neuroimaging to better characterize the role of the brain in processing different pain sensations, at present, the techniques are not standardized or validated as a pain management tool.

Therefore, emerging data are inconsistent, especially given the fact that some drugs can change the vascular architecture and function, and thus the fMRI signal without changing brain activity. 

Despite these limitations, the value of neuroimaging as a potential treatment modality, especially to improve the management of chronic pain is well recognized. This is reflected in the task force initiated in December 2015 by the International Association for the Study of Pain, to develop guidelines on neuroimaging, determine it accuracy and reliability, and the ethical considerations surrounding its use.¹⁰

Summary and Clinical Applicability

In the past decade, brain imaging studies have shed light on the neural correlates of pain perception and pain modulation, and recently have also begun to clarify the neural mechanisms that underlie different pain sensations. New developments in functional, structural and neurochemical imaging have advanced understanding of chronic pain, and may help predict individuals with acute pain who are likely to progress to chronic pain.  

These advances with neuroimaging are clinically valuable, particularly for personalizing the management of chronic pain, reducing the risk of misuse and abuse and managing pain in individuals who cannot feel or express their pain.

However, clinical integration of neuroimaging techniques in pain management must wait for the development of standardized techniques with proof of accuracy and reliability, guidelines, and the clarification of the ethical considerations surrounding its use.

Limitations and Disclosures

Few human studies have been conducted, investigating the application of neuroimaging in chronic pain management.

No emerging conflict of interest.

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References

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19. Henderson LA, Di Pietro F.  How do neuroanatomical changes in individuals with chronic pain result in the constant perception of pain? Pain Manag. 2016;6(2):147-159.

20. Ren W, Centeno MV, Berger S, et al. The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain. Nat Neurosci. 2016;19(2):220-222.