From OT Europe

Expert interview: Treatment approaches for chronic pain in patients with visible brain changes

EFORT

Prof. Enric Cáceres is the chair of orthopaedics at Autonomous University of Barcelona, the head of the spine unit at Institut Universitari Dexeus and part of the spine research unit at Hospital Universitari Vall d’Hebron. As main investigator in the Spine Unit, Cáceres has ongoing practical experience with spine disease. Treatments, both conservative and surgical, cover pathologies where ongoing research informs Cáceres and the teams with whom he works, including special projects in deformity, tumor conditions, cellular therapy and pain control.

This article is part of our continuing series to raise awareness of the unmet needs in postoperative pain management (POPM) and to develop solutions that improve POPM across Europe. The opinions expressed in this interview are meant as an informal conversation to facilitate dialogue. To further discuss the opinions expressed in this article, engage on Twitter, Facebook and LinkedIn at #painmanagement, #changepain and #POPM.

Diagnostic imaging

Chronic pain is complex, with poorly understood neural mechanisms underlying that pain; however, the evolution of various neuroimaging techniques has opened new windows into the brain. This provides new avenues in pain research that hold real promise for developing more effective treatments. Neuroimaging has shown us that chronic pain is different from acute pain, and that it can become a separate disease entity, in part, following changes in the entire central nervous system (CNS). These changes cause chronicity and the development of comorbid symptoms.

To study how the brain perceives and processes chronic pain, neuroimaging has become increasingly important and popular. Various neuroimaging modalities have been used, including PET, electroencephalogram (EEG), magnetoencephalography (MEG), single-photon-emission CT (SPECT/CT) and MRI. In some cases, neuroimaging provides a means of noninvasively studying altered activity levels in the CNS. Specifically, neuroimaging can be used to study the brain, brainstem and spinal cord. Much of neuroimaging research has focused on identifying the brain regions that demonstrate altered structure and activity in chronic pain states. A major goal of this research is to identify specific brain regions as future targets for chronic pain therapy.

Differences in brain structure have been widely assessed in individuals with chronic pain, typically using voxel-based morphology and cortical thickness analysis. These have been observed across several types of chronic pain. Specific to chronic low back pain (CLBP), a work assessing MRI results shows the total grey matter volume in healthy controls was significantly reduced in patients with CLBP. The same effect was observed in the total white matter volume. For both measures, it is possible to observe an age-dependent decrease in the controls, as well as in the patient group.

Gray matter reduction

Gray matter reduction contributes to chronic pain or vice-versa? It is difficult to answer this question. Likely, in specific situations like osteoarthritis of the hip with chronic pain, the decrease of grey matter could be reversible. A work comparing the grey matter situation before and after a total hip arthroplasty for patients with chronic hip pain shows that 4 months after the surgical procedure, there was grey matter increase in all structural parts that previously showed a deficit. This suggests grey matter abnormalities found in chronic pain do not reflect brain damage, but rather are a reversible consequence of chronic nociceptive transmission, which normalizes when the pain is adequately treated. The clinical implications of an altered brain state on the chronic pain experience are far from being fully understood; however, it is already possible to make observations that are of particular importance to physicians managing patients with CLBP.

Treatment options

Brain-based therapies use real-time MRI neurofeedback and neurostimulation. Neuroimaging continues to advance our understanding of how the CNS is affected by and involved in chronic pain, and neuroimaging interventions are gaining momentum as an alternative or supplement to pharmaceutical therapy. The efficacy and benefits of real-time neurofeedback for an individual may be better harnessed in the future by combining real-time neurofeedback fMRI and machine-learning classifiers (Multi-Voxel Pattern Analysis) to identify spatiotemporal brain maps ideal for individualized, real-time manipulation for each patient.

Although neurostimulation is invasive and is only implicated for use in the most severe, intractable cases of chronic pain, novel tools are being developed to better select patients who are most likely to benefit from this intervention. Implantation of neurostimulators is still an option for targeted manipulation of brain activity within specific brain regions, and there have been great advances in this technology since its inception. Current techniques use adaptive models and target brain regions, such as the motor cortex, that have the potential to activate multiple downstream effects.

Transcranial magnetic stimulation is also gaining popularity as an interventional and alternative method for reducing the symptoms of chronic pain. Preliminary clinical trials of transcranial magnetic stimulation have demonstrated effective pain reduction that persists days to weeks after treatment.

Additional exciting advancements for the future use of neuroimaging in chronic pain-related therapy include the development of brain–computer interfaces using electrocorticography and visual feedback, which has been tested as a potential therapy for phantom limb pain. Advancements in the use of PET imaging are making it possible to use this technique to predict the efficacy of motor cortex stimulation, in particular, using opioid binding and receptor density to predict the efficacy of motor cortex stimulation.

Damaged or abnormal pain systems

Chronic neuropathic pain alters neuronal structure and function along the neural axis, from the peripheral nerve to the spinal cord and higher brain centers (cortical and subcortical regions). The ability to replace neurons through cytotherapeutic technologies, such as embryonic stem cells (currently in animal models) or gene therapy, offers exciting new opportunities to the research community.

Neuroinflammation

Some non-neuronal inflammatory systems play an important role in conditions such as chronic neuropathic pain, which can produce persistent neuroinflammatory changes in the CNS. Evaluating ongoing pain in the context of low-grade neuroinflammatory processes in the brain could further define exciting targets for potential therapies. Some drugs, such as ketamine, may be beneficial thanks to anti-inflammatory effects.

Neurorehabilitation

Several neurorehabilitative approaches may allow for the reversal of maladaptive changes in the brain. From mirror therapy and immersive virtual reality to brain stimulation techniques, such as transcranial magnetic stimulation (TMS), researchers have developed new approaches with potentially useful applications in the treatment of chronic pain. The way in which motor activity or motor cortex stimulation (through TMS or direct stimulation) helps pain is unclear, but it may relate to forced interactions between the brain circuits involved in motor control and those involved in sensory processing. The notion of resetting disrupted or abnormal pain networks is clearly part of disease modification. There is a limited understanding of how these and other treatments may modify and improve neural circuits involved in pain, so more randomized clinical trials are warranted.

Overall brain grey matter reduction

Why, in your opinion, are these the options to be considered? How do they relate to overall brain grey matter reduction? We hypothesize the transition to chronic pain is dependent on activity-induced plasticity of the corticostriatal circuit, leading to reorganization of the network such that aversive cues lead to aberrantly elevated and prolonged network activity. Given that we have identified the main components of this same circuitry in pain chronification, we assume close parallels between mechanisms leading to addiction and those leading to pain chronification.

Within this framework, chronic pain and addictive behavior are viewed as distinct yet mechanistically related manifestations of reorganization of the brain’s motivational learning circuitry. Thus, similar to addiction, chronic pain may be viewed as a brain disease state, and we presume that the sequelae of the transition to chronic pain within the corticostriatal system should exhibit strong parallels to the reorganization observed for addiction. A corollary to this hypothesis is the idea that chronic pain may be prevented either by blunting the aversive drive impinging on the corticostriatal circuit or by blocking the reorganization of the latter circuit, or by combining both approaches.

As recent evidence shows the striatum can modulate nociception by direct or indirect descending pathways the corticostriatal circuit may also be involved in spinal cord sensitization. Given this conceptualization, clinicians and scientists face the challenge of managing, reversing and ideally preventing the dysfunction of pain or addiction.

Future understanding, treatment options

Chronic pain is an enormous public health challenge that deserves immediate focus and attention. The strategies discussed could form a cornerstone for integrated planning to conquer this pervasive problem.

Neuroimaging of chronic pain has largely focused on identifying individual regions of the brain implicated in chronic pain and determining what these regions contribute to the development and persistence of chronic pain and its comorbid symptoms. Neuroimaging has demonstrated that we need a more network-based approach to the study of chronic pain, with a particular focus on how the various regions in the brain interact with each other and with other regions of the CNS, such as the cervical spinal cord. Neuroimaging has shown us that no specific pain center exists in the brain, and the quest to find this conceptual, single pain center responsible for chronic pain may have ended. However, all the regions that have been found to play specific roles in chronic pain will continue to be useful targets for brain-based therapies.

Eventually, neuroimaging of chronic pain will evolve into a therapy-driven field. We are building a large knowledge-base about regional alterations seen in chronic pain states, and we are redirecting research efforts to examine networks and combinations of regions that are altered in the presence of chronic pain. Additional integration of pain medicine with other fields, such as psychology, physical and occupational therapy, immunology and other chronic pain–related fields will continue to increase the potential for us to develop interventions that modulate response of the CNS to chronic pain. The ultimate goal is to prevent and reverse the maladaptive processes that take place in the CNS in the presence of chronic pain.

Determining differences in patients who respond and patients who do not respond even to current treatments would seem to be a pragmatic approach to research. More complex clinical research requiring larger cohorts, such as to evaluate the genetics of pain, reconstitute neural systems with embryonic stem cells and modify brain circuits, may require longer-term processes before direct patient applications become possible.

All treatments, including so-called alternative or homeopathic medications, need to be evaluated in clinical trials to filter out what does and does not work. Patients should not be exposed to practices that do not show benefit. Currently, there are no objective measures for chronic pain or analgesic effects, and subjective responses are notoriously variable. Evaluation of treatments (in the clinic or in clinical trials) is fraught with difficulties because of subjective measures. Researchers need to determine measures that can be used as biomarkers for pain; their development would be a huge boost to clinical treatment and therapeutic trials. In addition, physicians must be trained to have a better understanding of chronic pain as a disease that affects the brain, using clinical insights to drive treatment plans. Integrating basic scientists into the clinic, so that researchers work with clinicians, would be a major step forward in having our brightest minds in pain neurobiology understand a patient and his or her pain-related problem.

Collaborative and team initiatives are essential to this effort. Each of these centers should have an integrated pain research clinic that encourages interaction among basic scientists and research clinicians. We need to start with patients and integrate molecular, genetic, and other processes around them. To do this, we need to set up processes for consortia to work effectively and efficiently. Approaching chronic pain as a national emergency would allow for a better future in terms of treatments for chronic pain, costs to society and individual well-being.

EFORT

Prof. Enric Cáceres is the chair of orthopaedics at Autonomous University of Barcelona, the head of the spine unit at Institut Universitari Dexeus and part of the spine research unit at Hospital Universitari Vall d’Hebron. As main investigator in the Spine Unit, Cáceres has ongoing practical experience with spine disease. Treatments, both conservative and surgical, cover pathologies where ongoing research informs Cáceres and the teams with whom he works, including special projects in deformity, tumor conditions, cellular therapy and pain control.

This article is part of our continuing series to raise awareness of the unmet needs in postoperative pain management (POPM) and to develop solutions that improve POPM across Europe. The opinions expressed in this interview are meant as an informal conversation to facilitate dialogue. To further discuss the opinions expressed in this article, engage on Twitter, Facebook and LinkedIn at #painmanagement, #changepain and #POPM.

Diagnostic imaging

Chronic pain is complex, with poorly understood neural mechanisms underlying that pain; however, the evolution of various neuroimaging techniques has opened new windows into the brain. This provides new avenues in pain research that hold real promise for developing more effective treatments. Neuroimaging has shown us that chronic pain is different from acute pain, and that it can become a separate disease entity, in part, following changes in the entire central nervous system (CNS). These changes cause chronicity and the development of comorbid symptoms.

To study how the brain perceives and processes chronic pain, neuroimaging has become increasingly important and popular. Various neuroimaging modalities have been used, including PET, electroencephalogram (EEG), magnetoencephalography (MEG), single-photon-emission CT (SPECT/CT) and MRI. In some cases, neuroimaging provides a means of noninvasively studying altered activity levels in the CNS. Specifically, neuroimaging can be used to study the brain, brainstem and spinal cord. Much of neuroimaging research has focused on identifying the brain regions that demonstrate altered structure and activity in chronic pain states. A major goal of this research is to identify specific brain regions as future targets for chronic pain therapy.

Differences in brain structure have been widely assessed in individuals with chronic pain, typically using voxel-based morphology and cortical thickness analysis. These have been observed across several types of chronic pain. Specific to chronic low back pain (CLBP), a work assessing MRI results shows the total grey matter volume in healthy controls was significantly reduced in patients with CLBP. The same effect was observed in the total white matter volume. For both measures, it is possible to observe an age-dependent decrease in the controls, as well as in the patient group.

PAGE BREAK

Gray matter reduction

Gray matter reduction contributes to chronic pain or vice-versa? It is difficult to answer this question. Likely, in specific situations like osteoarthritis of the hip with chronic pain, the decrease of grey matter could be reversible. A work comparing the grey matter situation before and after a total hip arthroplasty for patients with chronic hip pain shows that 4 months after the surgical procedure, there was grey matter increase in all structural parts that previously showed a deficit. This suggests grey matter abnormalities found in chronic pain do not reflect brain damage, but rather are a reversible consequence of chronic nociceptive transmission, which normalizes when the pain is adequately treated. The clinical implications of an altered brain state on the chronic pain experience are far from being fully understood; however, it is already possible to make observations that are of particular importance to physicians managing patients with CLBP.

Treatment options

Brain-based therapies use real-time MRI neurofeedback and neurostimulation. Neuroimaging continues to advance our understanding of how the CNS is affected by and involved in chronic pain, and neuroimaging interventions are gaining momentum as an alternative or supplement to pharmaceutical therapy. The efficacy and benefits of real-time neurofeedback for an individual may be better harnessed in the future by combining real-time neurofeedback fMRI and machine-learning classifiers (Multi-Voxel Pattern Analysis) to identify spatiotemporal brain maps ideal for individualized, real-time manipulation for each patient.

Although neurostimulation is invasive and is only implicated for use in the most severe, intractable cases of chronic pain, novel tools are being developed to better select patients who are most likely to benefit from this intervention. Implantation of neurostimulators is still an option for targeted manipulation of brain activity within specific brain regions, and there have been great advances in this technology since its inception. Current techniques use adaptive models and target brain regions, such as the motor cortex, that have the potential to activate multiple downstream effects.

Transcranial magnetic stimulation is also gaining popularity as an interventional and alternative method for reducing the symptoms of chronic pain. Preliminary clinical trials of transcranial magnetic stimulation have demonstrated effective pain reduction that persists days to weeks after treatment.

Additional exciting advancements for the future use of neuroimaging in chronic pain-related therapy include the development of brain–computer interfaces using electrocorticography and visual feedback, which has been tested as a potential therapy for phantom limb pain. Advancements in the use of PET imaging are making it possible to use this technique to predict the efficacy of motor cortex stimulation, in particular, using opioid binding and receptor density to predict the efficacy of motor cortex stimulation.

PAGE BREAK

Damaged or abnormal pain systems

Chronic neuropathic pain alters neuronal structure and function along the neural axis, from the peripheral nerve to the spinal cord and higher brain centers (cortical and subcortical regions). The ability to replace neurons through cytotherapeutic technologies, such as embryonic stem cells (currently in animal models) or gene therapy, offers exciting new opportunities to the research community.

Neuroinflammation

Some non-neuronal inflammatory systems play an important role in conditions such as chronic neuropathic pain, which can produce persistent neuroinflammatory changes in the CNS. Evaluating ongoing pain in the context of low-grade neuroinflammatory processes in the brain could further define exciting targets for potential therapies. Some drugs, such as ketamine, may be beneficial thanks to anti-inflammatory effects.

Neurorehabilitation

Several neurorehabilitative approaches may allow for the reversal of maladaptive changes in the brain. From mirror therapy and immersive virtual reality to brain stimulation techniques, such as transcranial magnetic stimulation (TMS), researchers have developed new approaches with potentially useful applications in the treatment of chronic pain. The way in which motor activity or motor cortex stimulation (through TMS or direct stimulation) helps pain is unclear, but it may relate to forced interactions between the brain circuits involved in motor control and those involved in sensory processing. The notion of resetting disrupted or abnormal pain networks is clearly part of disease modification. There is a limited understanding of how these and other treatments may modify and improve neural circuits involved in pain, so more randomized clinical trials are warranted.

Overall brain grey matter reduction

Why, in your opinion, are these the options to be considered? How do they relate to overall brain grey matter reduction? We hypothesize the transition to chronic pain is dependent on activity-induced plasticity of the corticostriatal circuit, leading to reorganization of the network such that aversive cues lead to aberrantly elevated and prolonged network activity. Given that we have identified the main components of this same circuitry in pain chronification, we assume close parallels between mechanisms leading to addiction and those leading to pain chronification.

Within this framework, chronic pain and addictive behavior are viewed as distinct yet mechanistically related manifestations of reorganization of the brain’s motivational learning circuitry. Thus, similar to addiction, chronic pain may be viewed as a brain disease state, and we presume that the sequelae of the transition to chronic pain within the corticostriatal system should exhibit strong parallels to the reorganization observed for addiction. A corollary to this hypothesis is the idea that chronic pain may be prevented either by blunting the aversive drive impinging on the corticostriatal circuit or by blocking the reorganization of the latter circuit, or by combining both approaches.

PAGE BREAK

As recent evidence shows the striatum can modulate nociception by direct or indirect descending pathways the corticostriatal circuit may also be involved in spinal cord sensitization. Given this conceptualization, clinicians and scientists face the challenge of managing, reversing and ideally preventing the dysfunction of pain or addiction.

Future understanding, treatment options

Chronic pain is an enormous public health challenge that deserves immediate focus and attention. The strategies discussed could form a cornerstone for integrated planning to conquer this pervasive problem.

Neuroimaging of chronic pain has largely focused on identifying individual regions of the brain implicated in chronic pain and determining what these regions contribute to the development and persistence of chronic pain and its comorbid symptoms. Neuroimaging has demonstrated that we need a more network-based approach to the study of chronic pain, with a particular focus on how the various regions in the brain interact with each other and with other regions of the CNS, such as the cervical spinal cord. Neuroimaging has shown us that no specific pain center exists in the brain, and the quest to find this conceptual, single pain center responsible for chronic pain may have ended. However, all the regions that have been found to play specific roles in chronic pain will continue to be useful targets for brain-based therapies.

Eventually, neuroimaging of chronic pain will evolve into a therapy-driven field. We are building a large knowledge-base about regional alterations seen in chronic pain states, and we are redirecting research efforts to examine networks and combinations of regions that are altered in the presence of chronic pain. Additional integration of pain medicine with other fields, such as psychology, physical and occupational therapy, immunology and other chronic pain–related fields will continue to increase the potential for us to develop interventions that modulate response of the CNS to chronic pain. The ultimate goal is to prevent and reverse the maladaptive processes that take place in the CNS in the presence of chronic pain.

Determining differences in patients who respond and patients who do not respond even to current treatments would seem to be a pragmatic approach to research. More complex clinical research requiring larger cohorts, such as to evaluate the genetics of pain, reconstitute neural systems with embryonic stem cells and modify brain circuits, may require longer-term processes before direct patient applications become possible.

All treatments, including so-called alternative or homeopathic medications, need to be evaluated in clinical trials to filter out what does and does not work. Patients should not be exposed to practices that do not show benefit. Currently, there are no objective measures for chronic pain or analgesic effects, and subjective responses are notoriously variable. Evaluation of treatments (in the clinic or in clinical trials) is fraught with difficulties because of subjective measures. Researchers need to determine measures that can be used as biomarkers for pain; their development would be a huge boost to clinical treatment and therapeutic trials. In addition, physicians must be trained to have a better understanding of chronic pain as a disease that affects the brain, using clinical insights to drive treatment plans. Integrating basic scientists into the clinic, so that researchers work with clinicians, would be a major step forward in having our brightest minds in pain neurobiology understand a patient and his or her pain-related problem.

PAGE BREAK

Collaborative and team initiatives are essential to this effort. Each of these centers should have an integrated pain research clinic that encourages interaction among basic scientists and research clinicians. We need to start with patients and integrate molecular, genetic, and other processes around them. To do this, we need to set up processes for consortia to work effectively and efficiently. Approaching chronic pain as a national emergency would allow for a better future in terms of treatments for chronic pain, costs to society and individual well-being.