Category Archives: Clinical

President’s Message: Thoughts on Addressing Disparity in the Midst of the “Opioid Crisis”

Harry J. Gould, III, MD, PhD

Pain occurs in both acute and chronic forms. In its acute form, pain is a modality that is essential for survival and is the signal that most frequently brings people to the attention of the healthcare professional.  Many cases of simple acute pain are readily treated without difficulty by physicians, practitioners in paramedical fields, and in many instances, by the lay public. Unfortunately, all too frequently problems that present as simple complaints of acute pain are the result of more a significant problem that if not accurately diagnosed and effectively treated can become a chronic condition that destroys the fabric of existence, not only for the individuals suffering the pain, but for families, loved ones, and society as a whole. In spite of its prevalence, there is a general lack of recognition that unassessed or poorly managed pain in and of itself is a problem about which we should be concerned and because of its prevalence the problem is also accompanied by substantial disparity for patient access to adequately trained providers, early evaluation and proper treatment.

For proper pain control and rationale management, society relies heavily on trained physicians and healthcare professionals for guidance. Unfortunately, the number of patients needing relief from intractable pain far exceeds the number of healthcare providers who are adequately trained to meet that need. The management of complex pain problems, thus, all too frequently falls to those with limited training in assessment and treatment strategies and little familiarity with modalities used for pain control.

In the early part of this century, the predominant treatment offered for pain control was largely a pharmacologic modalities. Unfortunately, a significant portion of the pharmacologic options included agents used by a section of society for unintended reasons e.g., affecting changes in sensory and emotional perception and cognition for recreation, which led to inconsistent, often inadequate, management of pain for those in need and the current “opioid crisis.” Because of concern for legal reprisal and the recognition that the additional time required to comply with important monitoring regulations is not accompanied by a comparable increase in compensation, fewer practitioners have been willing to treat pain or they have shifted focus and limited the offered treatment modalities to more lucrative, unidimensional approaches, thereby further exacerbating the already significant disparity between practitioners and patients for access to comprehensive evaluation and care.  The problem is further exacerbated by social limitations related to direct cost of physician visits, necessary absences from employment responsibilities to make and keep appointments, potentially additional need for care of children and transportation to care. These limitations result in delays in obtaining expert assessment, in the timely implementation of appropriate treatment and the increased likelihood of establishing chronicity of the problem with its inherent increase in co-morbid health conditions, higher costs for prolonged treatment and the development of maladaptive behaviors associated with the recognition of secondary gains.

Oddly enough, the COVID-19 pandemic and its requisite need to adapt in order to provide “social distanced” care for patients, may have enabled more physicians and healthcare administrators to recognize a possible next step in the reduction of healthcare disparity in that that when appropriately applied, telemedicine platforms can be very effective in organizing and implementing routine care in their practice and provide more uniformity of care in the communities they serve. Clearly, in person visits will always be essential in patient care and remains the preferred option for many patients and physicians alike, but it is also recognized that the virtual-visit can provide a viable option when offered for practices where access to care is limited and widespread disparities prevail.

Practitioners have noted that with the virtual-visit platforms, patients seem to be more compliant with their follow-up visits. They have also found that the virtual-visit platforms can make it possible to more easily manage schedules in the event of patient tardiness or failure to show. The primary weakness of virtual platforms is the lack of a physical exam and a significant reduction in the practitioner’s ability to assess patient affect and body language, making it more difficult to recognize undisclosed problems that should be addressed. 

Patients also have found virtual-visits satisfying. Although many continue to prefer in person visits, many have noticed improved convenience and a significant reduction in associated costs related to needs to take time off from work (visits can be done on a break at the office), to arrange for daycare, to lost time related to traveling significant distances and dealing with heavier than accustomed to traffic often found in urban centers where the specialists tend to locate their practices. There is also less downtime spent in waiting rooms especially when times are greater than normal when the doctor is delayed or other patients have arrived late or have extra needs.    

From the specialist’s perspective, especially for specialists in pain medicine, a limitation to broader utilization of virtual technology to improve the patient to specialist ratio is that frequently referrals for specialist evaluation and recommendations are assumed, even for routine pain problems, to be a complete transfer of care accompanied by assumption of responsibility for the patient’s primary care, implementation of pain care and routine follow up. Because referrals for pain issues can come from virtually all medical specialties, this approach rapidly fills the specialist’s available appointment slots thus limiting the ability to accept new referrals because of the requisite need for maintaining routine follow-up visits to monitor response to care and patient compliance.

A more effective approach might be to gather a team of specialists that could work with primary providers to evaluate a patient, develop an appropriate treatment plan and in the process impart many of the basic skills of assessment and treatment thus empowering the physician to be able to care for his/her own patient. Potentially, the patient could be exposed to a broader range of treatment options, experience less long-term morbidity related to frequent and extended trials of an ineffective “hammer and nail” approach to care and would benefit from the earlier implementation and response to appropriate management options provided closer to home by a physician with whom they have developed a relationship. Because of the collaborative relationship that is established between the primary physician and the team of specialists, the patient would have access to a network of additional treatment resources, if needed, and the specialist would benefit from having more time to be available to collaborate with other primary providers and to work on more complicated, less routine, pain problems.

Coincidentally, just such a program, Project ECHO, has been developed, trialed and was successfully launched in 2003 at the University of New Mexico Health Sciences Center in Albuquerque. For those who are interested in learning more about Project ECHO and how it might help your practice while contributing to a reduction in the disparity of pain care for many in our community, we will have the good fortune to hear Joanna Katzman, M.D. speak on “Pain Management in 2021: Exploring the Benefits of ECHO Pain Telementoring and Direct Telehealth for Your Practice” at the upcoming annual meeting of the Southern Pain Society. The meeting will be held in person in New Orleans, from September 10-12, at the Astor Crowne Plaza. I encourage you to register for the meeting on our website, www.southernpainsociety.org, and join me in the ‘Big Easy’ to hear more. I look forward to seeing you there.

Adverse Effects and Clinical Trials: The System is Broken

The CGRP Monoclonal Antibodies for Migraine Are a Prime Example

Lawrence Robbins, M.D.

This letter is in response to an excellent July, 2020 article “Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile” (Boldig and Butala) in the International Journal of Neurology and Neurotherapy. (1) There are a plethora of adverse effects (AEs) from the CGRP monoclonals (mAbs) that were not identified in the Phase 3 trials. Unfortunately we frequently encounter this with new drugs. It often takes several years to identify an accurate picture of the adverse effect profile.

The package insert (PI) for the CGRP mAbs, as with many of the new drugs, identifies few AEs. The reasons for this include:  1. trial investigators did not use a checklist of AEs (a checklist is almost never utilized during drug trials) 2. as with most drug trials, the studies were powered for efficacy but would need many more patients to accurately assess AEs 3. the studies do not extend long enough in order to identify the true adverse effect profile and 4. adverse effects become “disaggregated”.  For instance, one person may say they have malaise while another may state they suffer from fatigue. This adverse effect is disaggregated and subsequently not included in the PI. After the study is completed these effects may be reaggregated, but that method is not accurate.

To accurately assess AEs post-approval, we must examine multiple lines of evidence. The FDA/FAERS website is an important source of information. Unfortunately, the side effects listed are adverse events, not necessarily adverse effects. As of January 2021, (2.5 years post-launch) there were 40,378 adverse events catalogued from the four CGRP mAbs.  On the FDA website, serious adverse events include those that are life threatening, or that resulted in hospitalization. 5,562 serious adverse events were listed. These numbers are staggering, particularly considering that the vast majority of adverse effects, even serious ones, go unreported.  Erenumab resulted in the bulk of the adverse events. This is most likely because erenumab was the first to market and has been the CGRP mAb most widely utilized. Save for constipation, I do not believe that erenumab is necessarily more likely to produce adverse effects than are the other 3 mAbs. 

After the launch of the drug, another line of evidence is the available post-approval studies and case reports.  One of the observational studies concluded that adverse effects resulted in 33% of erenumab discontinuations (2). Another study described 63.3% of patients as having reported an adverse effect, but they concluded that the CGRP monoclonal antibodies were well tolerated. (3)

We published a study of 119 chronic migraine patients who had utilized one of the CGRP monoclonals. (4) We incorporated a checklist of 19 possible adverse effects. The patients were initially asked about adverse effects by posing the question, “Have you experienced any issues, problems, or side effects from the injection?” Subsequently the patients were interviewed regarding each possible adverse effect, utilizing the checklist. A determination was made, between the patient and researcher, as to whether the adverse effect was truly due to the use of the monoclonal. 66% of the patients identified at least one additional adverse effect via the use of a carefully chosen checklist. 18 patients had one additional adverse effect. 56 patients identified 2 to 8 additional adverse effects.

An additional line of evidence is the opinion of high prescribers of the drug. This is gleaned from chat boards of headache providers, private correspondence, and discussions during conferences. Some headache providers feel that the CGRP monoclonals are safe and adverse effects are infrequently encountered. Others believe, as I do, that the mAbs result in a number of deleterious effects.  There is no consensus at this time.

In addition to headache provider comments, the CGRP patient chat boards provide valuable insight into adverse effects. We assessed 2,800 patient comments regarding adverse effects. We judged 490 to be highly believable. The list of common adverse effects, as identified by the highly believable comments, aligns well with our other lines of evidence.

 After assessing the various post-approval lines of evidence, there are signals that the following adverse effects may result from the use of CGRP monoclonals: constipation, anxiety, injection site reactions, weight gain or loss, worsening hypertension, increased headache, insomnia, depression, hair loss, joint pain, fatigue, irritability, muscle pain or cramps, nausea, rash, sexual dysfunction, and tachycardia (or other heart irregularities).  Most likely there are others as well.  In addition, there have been cases of reversible cerebral vasoconstriction syndrome and stroke. Angina and myocardial infarction have also been reported. Thomas Moore, a leading expert in the acquisition of adverse effects of drugs, published a review of the CGRP monoclonals in the online journal QuarterWatch. QuarterWatch utilizes various resources, including FDA reports and published post-approval studies. (5) The report cites the “sheer number of case reports,” and concludes that “…it is likely that adverse effects of this migraine preventive were underestimated in the clinical trials.”

This discussion has revolved around short-term adverse effects. Long-term effects, which are unknown at this time, remain a serious concern. CGRP has been important in various species for 400 million years. We ignore evolution at our peril. There are a multitude of beneficial effects partially mediated by CGRP. These include protecting our cardiac and cerebrovascular systems through vasodilatory effects(particularly during stressful conditions), resisting the onset of hypertension, decreasing oxidative stress in the aorta, improving circulation in the face of heart disease (including heart failure), aiding with wound healing, burns, and tissue repair, minimizing the effects of sepsis, aiding in the healing of GI ulcers, protecting the GI mucosa, affecting GI motility, contributing to flushing and thermoregulation, aiding with cold hypersensitivity, regulating bone metabolism, protecting the kidneys in certain pathologic conditions, playing a role in regulating insulin release, affecting metabolism and body weight, and helping to mediate the adrenal glucocorticoid response to acute stress in the mature fetus. (6) The hypothalamic-pituitary-adrenal axis may be affected by CGRP, and this has not been adequately studied. If these mAbs are to be used in adolescents, we must first study the hormonal effects.

 The package inserts often do not reflect the reality of the AE profile. I believe that the FDA should overhaul the guidelines as to how adverse events are acquired in formal studies. This situation has been harmful to patients. This is not unique to the mAbs. We should work towards improving the early identification of an accurate adverse effect profile. Certain adverse effects, such as sexual adverse effects, or depression, are missed in formal studies.

The CGRP monoclonal antibodies have been beneficial for many migraineurs. The efficacy of these mAbs rivals that of onabotulinumtoxinA. However, CGRP plays a crucial role in many physiological processes. There is evidence for a multitude of deleterious effects that result from blocking CGRP. Long-term effects are completely unknown. We should be cautious and judicious in our use of the CGRP monoclonal antibodies.

Disclosure: L. Robbins is a speaker for Abbott Labs, Teva, and Amgen.

 

References

 

  1. Boldis K, Butala, N (2020) Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile. International Journal of Neurology and Neurotherapy 7:101: DOI:10.23937/2378-3001/1410101
  2. Robblee J, Devick K, et al. (2020) Real-World Patient Experience with Erenumab for the Preventive Treatment of Migraine.  Headache 60:9, p. 2014-2025. https://doi.org/10.1111/head.13951
  3. Alex A, Vaugh C., Rayhill M (2020) Safety and Tolerability of 3 CGRP Monoclonal Antibodies in Practice: A Retrospective Cohort Study. Headache 60:10, p. 2454-2462. https://doi.org/10.1111/head13956
  4. Robbins L, Phenicie B, (2020) CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using a Checklist. Practical Pain Management 20:2, p. 48-52.  (online at practicalpainmanagement.com, March/April, 2020)
  5. Moore T. (2019) Aimovig, Ajovy, and Emgality. QuarterWatch Reports 24:16, p. 2-4.
  6. Robbins L (2018) CGRP Antagonists: Physiologic Effects and Serious Side Effects (Letter). Headache 58:9, p. 1469-1471.

Laser Treatment Offers a 5 day Treatment for COVID19

Bert Ray, MD

Laser therapy has been utilized for multiple medical problems, as the light energy improves mitochondrial function in cells that are involved with medical illnesses, has an anti-inflammatory effect, boosts the immune response, and restores oxidative redox balance. Thus, the laser energy helps rebalance the oxidative redox system that underlies the inflammation involved in almost all current medical issues, including cardiovascular diseases, diabetes mellitus, Parkinson’s, dementia, chronic pain, and even cancer.

Photodynamic therapy consists of utilizing a “photo-sensitizer”, of which there are many, and they will vary depending on the wavelength of laser light to be used. For example, methylene blue or curcumin can be used to “sensitize” target tissue for red and infrared laser wavelengths. The sensitizer draws the light energy to the intended source and thus, the combination of the laser energy and the photosensitizer amount to what is known as photodynamic therapy.

At our clinic, we use a Weber Medical laser which can utilize red, infrared, yellow, blue, green, and ultraviolet light wavelengths. It is also the only laser that we have found that can allow for dermal, intra-articular, and intravenous applications. We have found this treatment to be extremely helpful in doing either trigger point injections or regenerative injections, because we can use laser light through the needle and place it directly at the site of injection, thus giving us a synergistic effect on the applied treatment.

COVID19 has presented an opportunity to evaluate the effects of photodynamic therapy on the coronavirus. We know from previous work that methylene blue intra-nasal and intra-orally combined with red and infrared laser can kill viruses and bacteria in the oral cavities. In the unique study attached to this note, photodynamic therapy was tested against COVID 19 in patients who tested positive and were in Stage 1 or 2 symptomatically, utilizing riboflavin as the photosensitizer and blue and ultraviolet wavelengths. The results showed excellent improvement in 5 days, indicating that here is an effective, non-invasive treatment for COVID 19. Further studies are now ongoing to test this treatment for hospitalized COVID 19 patients, and also to see if this non-invasive treatment can prevent COVID 19.

Please review this recently published article on a new and effective treatment available for non-hospitalized COVID Stage 1 or 2 patients. Keep in mind that even though these patients didn’t require hospitalized care, they were all very sick people, who made rapid recovery. The implication of a rapid recovery indicate that a shorter quarantine time could allow people to resume normal function in a shorter time, creating less drain on the economy, both directly by avoiding hospitalizations and indirectly by early return to work, home functions, schools, etc.

I would refer our readers to Google ISLA (Intl Soc for Medical Laser Application) for further articles on photodynamic therapies.

In addition, Weber Medical now has kits available for HOME treatment using  the same protocol as in their published study.  The whole family can use these kits if anyone gets COVID.  You  don’t have to go to a doctor for this treatment. 

References:

Reduction of the Viral Load by Non-Invasive Photodynamic Therapy in Early
Stages of COVID-19 infection. Am J of Viro and Dis. 2020; 2(1): 01-05

Successful Reduction of SARS-CoV-2Viral Load by Photodynamic Therapy (PDT) Verified by QPCR – A Novel Approach in Treating Patients in Early Infection Stages

Chaos, Migraine, and Evolution

Lawrence Robbins, MD

 INTRODUCTION

Migraine often results in disability and diminished quality of life. Despite this, our species remains particularly vulnerable to migraine. Why is this so?  Evolution may provide answers. The study of evolution and disease is not simply an academic exercise. In studying the history of our species, and those that preceded us, we may be able to develop safer and more effective treatments. We ignore evolution at our peril.

Chaos theory is a subset of nonlinear dynamics. Nature has been able to utilize chaotic dynamics in the brain, heart, and elsewhere (Korn, & Faure, 2003). Chaotic dynamics provide advantages over stochastic (random) or reductive (simple, linear) systems. Neurons and neuron clusters effectively utilize chaos. One hallmark of chaos is the extreme sensitivity to initial conditions (Bird, 2003). This leads to the classic butterfly effect, where a tiny perturbation in the beginning results in enormous changes down the line. Initial conditions played a significant role in the development of Homo sapiens (Bird, 2003). If we travelled back in time, and changed even the tiniest initial traits, today’s human would appear significantly different. 

Chaotic dynamics may play several roles in migraine pathophysiology. For instance, a tiny initial change in blood flow, such as occurs due to a patent foramen ovale (PFO), could eventually lead to the initiation of a migraine. The complex electrical wiring of the brain involves chaotic dynamics (Korn et al., 2003).  Chaos, migraine, and evolution are intimately interwoven. This paper outlines some of their connections. 

CHAOS AND THE NERVOUS SYSTEM

Chaos is a math-based subset of non-linear dynamics. Chaos improves the adaptability, efficiency, and versatility of neuronal systems.  A number of biological systems are governed somewhat by chaotic dynamics.  These systems include the ion flow and electrical activity of the brain, the beating of the heart, blood glucose levels, and glycolysis. Several studies have demonstrated chaos at the cellular level in the brain (Schweighofer, Doya, et al., 2004). By evaluating the flow of ions through the energy barriers of the channel protein, maps reveal the chaotic controls. Algorithms and numerical solutions have been constructed revealing when the transition to chaotic dynamics occurs (Landau, Sompolinsky, 2018). Characteristics of chaotic systems include, most importantly, an exquisite sensitivity to initial conditions.  Chaos is deterministic and predictable solely from one point to the next, but not beyond that point. The initial conditions are then reset after each point.

When compared to reductive or stochastic systems, chaotic systems save energy and are more adaptable.  Chaotic dynamics are involved in governing cortical spreading depression (CSD) (Pietrobon, Moskowitz, 2014). Chaos has been demonstrated to play a role in K+, Ca+, and Na+ movements. The flow of ions about the cell has been determined to be a combination of randomness, reductive(linear) movements, and chaotic processes. A small initial change in K+ efflux, or Ca+ influx, will result in a large effect downstream. Clusters of neurons, as well as single neurons, fire in a variety of patterns. These range from regular oscillating patterns to bursts, and everything in between. Neuronal systems undergo transitions that carry them between diverse states (Vreeswijk, Sompolinsky, 1998). Chaotic dynamics partially govern both individual neurons, as well as groups of neurons.

CHAOS AND MIGRAINE

Tiny CNS perturbations may be brought about by the usual migraine triggers such as weather, stress, or hormonal changes. Through chaotic dynamics this may result in plasma protein extravasation (PPE) and cortical spreading depression, both of which are vital processes in the pathophysiology of migraine (Kernick, 2005). Medications affecting CSD may influence the neuronal membrane through chaotic controls. A small number of patients with patent foramen ovale (PFO) have experienced resolution of their migraines after PFO closure. The usual explanation for the PFO induction of migraine is via microemboli. It is also possible that chaotic dynamics play a role.  A small change in blood flow downstream (the heart) may induce a significant change in CNS dynamics upstream.

Chronic migraine pathophysiology involves wind-up and central sensitization(CS) . These are possibly controlled by chaotic dynamics. Thalamic recruitment involved in expansion of the pain area is likely governed by chaotic dynamics. Thalamic-cortical circuits involve chaotic dynamics. The pathological shift of homeostasis observed in chronic CS, with a loss of brainstem inhibition, may actually reflect a loss of chaotic control (Vreeswijk,et al.,1998). This is similar to the loss of control in the heart, resulting in arrhythmia.  The brainstem periaqueductal grey (PAG)—important in migraine—has been shown to be under chaotic control thru P/Q- type Ca+ channels. Migraine physiology incorporates a combination of genetic and environmental factors.  Trigger factors that affect migraine include stress, weather, and hormonal   changes.   These may affect the delicate balance between interneuronal nonlinear, reductive, and stochastic dynamics.  This may lead to chronic migraine. When a system is forced or stressed, nonlinear dynamics may be affected. 

New onset daily persistent headache (NDPH) may result from a perturbation of neuronal dynamics. Emotional, infectious, or other stresses may influence the delicate balance between nonlinear dynamics and stochastic or reductive dynamics. This could lead to chronic head pain.

Calcium and sodium efflux occur with CSD. Potassium and P/Q calcium channels are also involved. This complex system is unlikely to be governed primarily by random or linear kinetics. Chaotic controls have been demonstrated to be involved with these ionic movements (Pietrobon, et al., 2014). Chaotic dynamics could explain some of the properties of CSD. The initiation of CSD may be brought about by a miniscule change in potassium levels. This tiny effect may activate receptors and result in a large change downstream. The result is CSD and oligemia. With the potassium efflux partially under chaotic control, the chaos probably helps to regulate the increased cortical hyperactivity inherent in the brain of some migraineurs.

The trigeminal nucleus caudalis, vital in migraine pathophysiology, may be activated by a tiny initial stimulus. Through chaotic dynamics, this may result in the release of pro-inflammatory peptides and a release of glutamate. CSD leads to increased plasma protein extravasation. Only chaotic dynamics may explain how this may be possible. The medications that affect CSD (amitriptyline, topiramate, sodium valproate) may influence chaotic dynamics via membrane effects. When nonlinear dynamics are involved, it possibly takes less drug to produce an effect. The periaqueductal gray matter is involved in a number of CNS processes, including migraine. There is evidence that the periaqueductal gray is partially controlled by chaotic dynamics (Schweighofer, et al., 2004).

The loss of chaotic dynamics may lead to a pathological shift of homeostasis. The loss of brainstem inhibitory activity may actually reflect a lessening of chaotic control, eventually leading to a migraine. Similar loss of chaotic dynamics may explain certain arrhythmias and epileptic seizures.

The primary excitatory neurotransmitter in the brain is glutamate.  Along with calcium, glutamate is crucial in the feedback process. Glutamate is directly involved in bi-directional communications between neurons and astrocytes. It is likely that glutamate feedback processes are critical in the generation of complex bursting oscillations in astrocytes. These glutamate-mediated events are involved in migraine, epilepsy, and memory storage. The control of this feedback process may be partially enacted through chaotic dynamics. The cascade of magnesium binding to N-methyl-D-aspartate (NMDA) in the periphery about the brain, with subsequent calcium influx, is very sensitive to minute initial changes (Kernick, 2005).  This cascade is important in peripheral sensitization, which leads to migraine attacks. These magnesium and NMDA effects may be under chaotic control.

Brain-derived neurotrophic factor (BDNF) is a neurotropin that modulates neuronal membrane excitability. BDNF was used in one study to affect hippocampal neurons (Fujisawa, Yamada, Nishiyama, Ikegaya, 2004). Chaotic dynamics partially govern patterns of electrical activity in hippocampal neurons. The hippocampal electrical system is a deterministic one with a few degrees of freedom. Neuronal chaos may be sensitive to change by the application of small amounts of materials, such as BDNF, that influence temporal spiking. The application of BDNF to cultured hippocampal neurons enhanced spike timing and resulted in stereotyped firing patterns. It was felt that BDNF influenced chaos through effects on membrane levels of sodium (Fujisawa, et al., 2004).  BDNF enhanced membrane conductance and thus stabilized the membrane. The application of BDNF affected the switching between periodic and aperiodic neuronal oscillations. BDNF has been linked to modulation of neuroplasticity. The BDNF application decreased irregularity of firing patterns by modulating neuronal outputs as well as inputs. The result was a BDNF-induced chaos stabilization. This was the first experiment to demonstrate a pharmacological stabilization of chaos at the neuronal level (Fujisawa, et al., 2004).

CHAOS AND EVOLUTION

Chaos and evolution are intimately interconnected. There is a chaotic (non-linear) connection between phenotype and genotype. This complex relationship is constantly in flux. A single mutation may be inconsequential, or it may result in enormous changes that are unpredictable. This is typical for a non-linear system. With these unpredictable mutations, iterations over thousands of generations will usually result in evolutionary changes (McKee, 2000). It is debatable as to how much the environment plays a role, versus genetic changes that are generated internally.

The unpredictability of evolution is typical of non-linear systems. Most discussions of evolution predictors focus on random, stochastic processes (mutations, genetic drift, random environmental changes). A reductive system would behave in a much more orderly, predictable manner. However, these fixed reductive systems are limited, and non-linear dynamics allows for enhanced evolutionary adaptability. The behavior of evolutionary systems is extremely sensitive to initial conditions. This was demonstrated during the quaternary period. At the beginning of each interglacial, the initial circumstances determined the outcome of that period. Between interglacials there were differences that were unpredictable, due to the non-linear nature of the system (Bird, 2003).

Non-linear dynamics lead to a system that is not scaled. The tree of life is fractal, and follows non-linear dynamics. The branches of the tree are continuously being split, resulting in evolutionary changes.  If we travelled back 5 million years, and re-started the human evolutionary process, the result would be dramatically different. This is the nature of a non-linear system. A simpler stochastic reductive system would be predictable but limited. It has been demonstrated that, when many traits interact, chaotic dynamics may govern phenotypic evolution.   Ancient species in human evolution, such as Australopithecus and Homo habilis, may have diverged due to chaotic dynamics (McCann, Yodzis, 1994).

Natural selection utilizes chaotic dynamics, chance, and coincidence (McKee, 2000). Natural selection does not invent, it tends to mosey along and tinker. The chance mutation must be coincidentally beneficial because of some environmental change.  For instance, if our ancestors needed robust teeth due to changing climactic conditions, those who happened to have larger teeth would have prevailed. Chaotic dynamics oversees chance and coincidence in the evolutionary process.

 EVOLUTION AND MIGRAINE

 Examining evolutionary systems in relation to disease is much more than an academic exercise. The evolutionary history will give us a complete picture of a disease. Understanding the evolutionary foundation may help us in developing safe and effective treatments.

Illness can be considered through two frameworks: 1. a proximate view, and 2. an evolutionary lens. The proximate view considers the nuts and bolts of a disease: pathophysiology, treatment, biochemistry, etc. It’s vitally important to also consider the disease process using an evolutionary viewpoint (Perlman, 2013). One essential question is: “why have migraines persisted, and why are humans still so susceptible to migraine?” The proximate lens says that migraine is a physical trait that involves multiple physiologic systems. The evolutionary framework begs the question: “why does our DNA code for migraine?”

There are physiological trade-offs that permeate evolution. While sickle cell disease is devastating, the sickle cell gene does also protect against malaria. Cystic fibrosis also involves serious trade-offs. Heterozygotes for cystic fibrosis were less likely to suffer dehydration from illnesses such as cholera. Genes exist to propagate themselves, sometimes to the detriment of the organism (the “selfish gene”)(Dawkins, 2013). This is also the story of migraine. Evolutionary benefits from migraine are possible (Loder, 2002).  It is also possible that our species simply continues to be vulnerable to migraine, and the evolutionary benefits are few. There are multiple genes involved in migraine, and evolution does not easily remove “bad genes”(Loder, 2002).

 It’s likely that migraines in humans increased as a result of our migration to more northern latitudes (Vigano, Manica, Di Piero, Leonardi, 2019).  Low vitamin D levels may help explain the increase in prevalence of migraine farther north (Prakash, 2010). The TRPM8 gene involves a receptor that plays a part in cold sensation and thermoregulation. TRPM8 (the “T” variation) is also linked to an increased risk for migraine (Dussor, Cao, 2016).  People who carry the “T” variation are better adapted to cold environments, and this adaptation likely improved their survival and reproductive success. Migraine may have been a negative consequence from this cold adaptation: another trade-off. The TRPM8 and latitudinal studies were the first to link migraine, evolution, natural selection, and geography (Vigano, et al., 2019).

The reasons why migraine persists are varied. While there is no epidemiological data from past millenia, the prevalence of migraine may be increasing. An increased sensitivity to light, smells, and sound could be beneficial under certain conditions. Migraine may be advantageous in combating certain infections (Loder, 2002). This may occur through an enhanced immune response, or by an increase in blood flow. Only a small percentage of people never experience headache (7% of men, and 1% of women), signaling that there may be some evolutionary advantage of headache.

Certain genes that result in harmless “quirks” in one environment can have deadly outcomes in other venues. Our modern environment certainly contributes to migraine frequency. The environment has radically changed, after millions of years of evolution (Cochran, Harpending, 2009).  For the vast majority of human history, we were primarily hunting and gathering. Recently, only 10 to 12 thousand years ago, societies in Southwest Asia (the fertile crescent) began to cultivate plants and domesticate animals. Many factors may contribute to increased migraine frequency: changes in culture, living circumstances, agriculture and diet, environmental toxins, densely packed populations, infections (particularly viral), harsh indoor lighting, loud speakers, poor sleep, and increased stress (Loder, 2002).  When modern hunter-gatherer societies switch to our “western diet,” they suffer from heart disease and an increase in cancer (Milton, 2000).  One of many examples where a changing environment has an impact on disease involves the genes for heart disease. These genes may not have been particularly detrimental for Stone Age humans, due to short lifespans. But as lifespans have been significantly lengthened, these genes have become threatening. Phenotypic and adaptive plasticity are significant factors in humans adapting to the changing environment (Perlman, 2013).

While migraine is three times more common in women than in men, the evolutionary explanation for this is unclear. Men generally did most of the hunting and gathering, for which migraine could pose disadvantages. For child care, food preparation, and homekeeping, migraine may possibly offer small evolutionary advantages. Migraine commonly decreases during pregnancy, providing an evolutionary incentive for more pregnancies.

It’s likely that migraine only afflicts the human species. Our ancient human brainstem has obstacles in coping with a cortex that is recently enlarged. With excessive afferent input, our brainstem may be overwhelmed. Having higher cortical functions not found in other primates may contribute to our continued vulnerability to migraine.   

Migraine may function as a defense mechanism against excessive stress, noise, or light (Loder, 2002).  The elevated sense of smell may serve as a defense from toxins or viruses entering the CNS. Vomiting may help to remove toxins. Women migraineurs probably have a lower prevalence of type 2 diabetes, compared to those without migraine (Fagherazzi, El Fatouhi, Fournier, et al., 2019).  An activation of the trigeminal nuclear complex could be protective (Loder, 2002).  If migraine offers protections for an individual, then that individual’s genes may be propagated more successfully. If an ancestral human experienced 100 migraines during a year, and just one of those migraines protected the person from harm, the trade-off would have been worthwhile. In an evolutionary framework, the cost of migraine may be inexpensive.

There is a difference between a defense and a defect. Coughing is a defense, but becoming blue from hypoxia is not. We want to retain our natural defenses. The calcitonin gene-related peptide (CGRP) associated with migraine may be advantageous under stress (Kee, 2018). CGRP has existed in a variety of species for hundreds of millions of years. CGRP plays various roles in the body, some positive, some harmful (Kee, Kodji, Brain, 2018). Under stress, CGRP is beneficial for our cerebrovascular and cardiovascular systems. Disrupting this natural defense, as happens with our CGRP monoclonal antibodies that prevent migraine, may be harmful.  The CGRP story is one example of the danger in ignoring the evolutionary importance of a compound.       

Natural selection is dependent on reproduction. After the reproductive years, a particular trait could very well become detrimental, but that does not affect gene propagation. In order to understand a trait (or disease) such as migraine, we must consider all of the evolutionary processes. These include genetic drift, mutations, migration, non-random mating, and natural selection (Perlman, 2013). Sometimes, natural selection produces opposing effects, resulting in a heightened vulnerability to disease.

 It’s imperative to not only view individuals through an evolutionary lens, but to also consider the phylogeny of the species (Perlman, 2013). The relationships between humans have morphed in the past 12,000 years (Cochran, et al., 2009).  One primary factor driving phylogenetic changes is the increase in population density, resulting in most humans living in significantly smaller spaces. Culture, which influences our state of disease or health, may also contribute to an increase in headache prevalence.

Headache and pain are adaptive responses. Being still, or in bed, may help repair damaged tissues. Incomplete or inadequate natural selection is often cited as the cause for our flaws or disease, but it is more likely that many illnesses are the result of compromises and/or design flaws (Nesse, Williams, 2012).  For example, our esophagus crosses our trachea. Because of this, our airway must inconveniently be closed every time that we swallow, to prevent choking. Allergies, atherosclerosis, nearsightedness, and nausea in pregnancy are similar examples stemming from evolutionary compromises and design flaws (Nesse, 2005, 2012).

Another important evolutionary concept to consider is intrinsic vulnerability (Nesse, 2011). Different species have various levels of vulnerability to certain diseases. Humans mature rather slowly, with infrequent reproduction. This is a factor regarding enhanced vulnerability of our species to certain diseases. It’s difficult for us to rid ourselves of genes that cause harm. Migraine involves a multitude of factors and genes, and it’s not likely that natural selection would be capable of eliminating migraine.

To more wholly understand migraine, we should venture beyond the proximate and physiologic processes. The evolutionary foundations of migraine are vitally important to study. Examining migraine under an evolutionary lens may help us in evaluating the safety of new treatments, such as the CGRP monoclonal antibodies. We must pay attention to evolution.

CONCLUSION

Chaos, migraine, and evolution are intertwined. Chaotic dynamics are vital within the central nervous system. Chaos is important at the ionic, neuronal, and neuronal cluster levels. Chaos may be involved in the generation of CSD. Sensitization and wind-up, crucial components of migraine, probably incorporate chaotic dynamics.

Evolution and natural selection involve chaos, chance, and coincidence. The evolutionary result of thousands of generations depends exquisitely upon initial conditions, characteristic of chaotic dynamics.

For myriad reasons, our species remains remarkably vulnerable to migraine. To understand migraine, we have to look farther than simple physiologic and proximate processes. We cannot truly understand migraine without examining the evolutionary underpinnings. The safety of new migraine treatments should be evaluated under an evolutionary lens.

                                                               REFERENCES

Bird, R. (2003). Chaos and Life: complexity and order in evolution and thought. NY,NY: Columbia University Press.

Cochran G, Harpending H (2009). The 10,000 Year Explosion: How civilization accelerated human evolution. NY,NY: Basic Books.

Dawkins,R.  (2016). The Selfish Gene. Oxford, UK: Oxford University Press.

Dussor G, Cao,Y-Q. (2016). TRPM8 and migraine. Headache, 56, 1406-1417.

Fagherazzi G, El Fatouhi D, Fournier A. (2019). Associations between migraine and type 2 diabetes in women: findings from the E3N cohort study. JAMA, 76, 257-263.

Fujisawa S, Yamada M, Nishiyama N, Ikegaya N. (2004). BDNF boosts spike fidelity in chaotic neural oscillations. Biophysics J, 86, 1820-1828.

Kee Z, Kodji X, Brain SD. (2018). The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Frontiers in Physiology, 9, 1249.

Kernick D. (2005). Migraine—new perspectives from chaos theory. Cephalalgia, 25, 561-566.

Korn H, Faure P. (2003). Is there chaos in the brain? C.R. Biologies, 326, 787-840.

Landau ID, Sompolinsky H. (2018). Coherent chaos in a recurrent neural network with structured connectivity. Computational Biology, Retrieved May 20, 2020 from https://doi.org/10.1371/journal.pcbi.1006309

Loder E. (2002). What is the evolutionary advantage of migraine? Cephalalgia, 22, 624-632.

McCann K, Yodzis P. (1994). Non-linear dynamics and population disappearances. The American Naturalist, 144, 873-879.

McKee, J (2000). The Riddled Chain: chance, coincidence, and chaos in human evolution. Piscataway,NJ: Rutgers University Press.

Milton K. (2000). Hunter-gatherer diets: a different perspective. The American Journal of Clinical Nutrition, 71, 665-667.

Nesse,RM. (2005). Maladaptation and natural selection. The Quarterly Review of Biology, 80, 62-70.

Nesse,RM. (2011). Ten questions for evolutionary studies of disease vulnerability. Evolution Applications, 4, 264-277.

Nesse,RM, Williams GC. (2012). Why We Get Sick: the new science of Darwinian medicine. New York, New York: Vintage Books.

Perlman R. (2013). Evolution and Medicine. Oxford, UK: Oxford University Press.

Pietrobon D, Moskowitz MA. (2014). Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nature Review Neuroscience, 15, 379-393.

Schweighofer N, Doya K, et al. (2004). Chaos may enhance transmission in the inferior olive. Proceedings of the National Academy of Science, 101, 4655-4660.

Vigano A, Manica A, Di Piero V, Leonardi M. (2019). Did going north give us migraine? An evolutionary approach on understanding latitudinal differences in migraine epidemiology. Headache, 59, 632-634.

Vreeswijk C, Sompolinsky H. (1998). Chaos in neuronal networks with balanced excitatory and inhibitory activity. Science, 274, 1724-1726.

Update on Gepants: New Abortives for Migraine

Lawrence Robbins,M.D.

Gepants are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. The preventive CGRP monoclonal antibodies(Aimovig, Emgality, Ajovy) are large molecules, delivered once per month as a SQ injection. Seven gepants have been developed since 2004. (1) Telcagepant was extensively studied, but withdrawn due to hepatotoxicity concerns. CGRP has many effects throughout the body. CGRP triggers a cascade of inflammatory mediators that feed into the trigeminovascular system. By blocking CGRP, the gepants stop the process prior to inflammation.

Regarding migraine, CGRP is an inflammatory compound. They will initially be utilized as migraine abortives, but eventually they will also be used to prevent migraine. The gepants may be helpful for 3 groups of migraineurs. They will be prescribed for a number of patients who found triptans (sumatriptan, rizatriptan, zolmitriptan, etc.) to be ineffective. In addition, gepants will be used for certain patients who cannot tolerate triptans. Finally, for those patients with significant cardiac or cerebrovascular risk factors, the gepants may be relatively safe, since they do not constrict cardiac or cranial arteries. While efficacy is modest, these are well tolerated medications.

The first gepant to come to market will be ubrogepant. Almost 2,700 patients participated in the ubrogepant ACHIEVE studies. (2,3) The doses have ranged from 25mg to 100mg. The t-max is 0.7 to 1.5 hours. Approximately 20% of patients who used the 50mg dose were pain free after 2 hours. While 25mg and 100mg tablets of ubrogepant were evaluated, it is likely that 50mg will be the primary dose. Ubrogepant was well tolerated, with 2% to 5% of patients reporting nausea, somnolence, dry mouth, dizziness, or upper respiratory tract infections. No serious adverse events were reported. The safety and tolerability were also explored in a 52 week extension study. Few adverse events, and no hepatotoxicity was reported. The effect of ubrogepant on the patient’s most bothersome migraine symptom was evaluated 2 hours post-dose. 39% of those treated with ubrogepant reported that their worst migraine symptom was resolved. The therapeutic gain for ubrogegepant (active drug vs. placebo) is relatively low, 6.4%-9.4%. In comparison, the therapeutic gain for sumatriptan is 16%-21%.

Rimegepant is another gepant, in development for abortive and preventive use. The dose is 75mg, with a t-max of 2 hours. In the 2 main trials, 19.4% of patients achieved pain freedom at 2 hours. (4) 37% of patients reported freedom from their most bothersome symptom. As with ubrogepant, no significant liver toxicity was reported. Adverse events were low, with nausea being reported by 1.4% of patients. The therapeutic gain for rimegepant is 5% to 7.6%.

A third gepant, atogepant, is currently being studied.

The gepants will be a useful alternative to triptans. Many patients find triptans to be ineffective. Some migraineurs cannot tolerate the adverse effects of the triptans. For certain patients with cardiovascular risk factors, triptans may not be completely safe. Gepants will be considered in these clinical settings. The initial (2 hour) efficacy rates are fairly low, but it appears that gepants may become more effective over 2 to 8 hours. During the trials, these were fairly well tolerated medications. It will take at least several years before we are able to accurately assess the true adverse effect profile of the gepants.

References

1. Olesen J, Diener H-C, Husstedt IW et al Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. 2004. N Eng J Med 350:1104-1110.

2. Allergan Announces Positive Top Line Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at http://www.allergan.com/news/news/thomson-reuters/allergan-announces-positive-phase-3-resul.

3. Allergan Announces Second Positive Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at http://www.allergan.com/News/News/Thomson-Reuters/Allergan-Announces-Second-Positive-Phase-3-Clinica.

4. Biohaven Announces Successful Achievement of Both Co-Primary regulatory Endpoints in Two Pivotal Phase 3 Trials of Rimegepant an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine Available at https://biohavenpharma.com/wp-content/uploads/2018/03/CONFIDENTIAL-BIOHAVEN-PRESS-RELEASE-FINAL-v2.pdf.

Reducing Harm from Opioids – Lessons Learned

Lisa Edgerton, PharmD, BCPS, CPP, Olivia Herndon, MA, and Joseph Pino, MD, MHA

Wilmington is a community in southeastern North Carolina known for its beautiful beaches, historic river-walk district, and the largest domestic television and movie production facility outside of California. In April of 2016, this city also became recognized for something else.

In 2016, Castlight Health released a report titled “The Opioid Crisis in America’s Workforce.” The study noted those who abused opioids are more likely to live in the rural south with 22 of the top 25 cities in Southern states. Furthermore, it named Wilmington, NC as the city with the highest abuse rate in the United States. In response, our medical community mobilized and recruited partners from disciplines outside of healthcare to reduce harm from opioids in our region.

Through a “call to action” where more than 100 regional stakeholders and leaders, the Community Partners Coalition (CPC) was born. This CPC aims to improve collaboration and coordination between those who provide care to individuals seeking access to mental health and substance use services by aligning efforts in the region. A primary focus of the CPC was to improve safe medication disposal options in our region by expanding medication take-back events and permanent drop boxes.

The first medication take-back event was held at New Hanover Regional Medical Center (NHRMC) in March 2009. This event was held at one location on our hospital’s main campus in New Hanover county. NHRMC partnered with the Wilmington Sheriffs office and collected 140 pounds of medication at that event. This solo event continued biannually however, dates were chosen based upon availability of volunteer coordinators and coinciding community events. NHRMC continued to host this single site medication take-back event biannually through the Spring of 2017.

Through the support of the CPC, in the Fall of 2017, this event was expanded to 9 locations within 4 counties and collected 3,680 pounds of medication and 29,675 needles or sharps. This biannual medication take-back event has continued to grow now hosting 19 locations spanning 6 counties in our region.

In October 2019, we collected almost 6,000 pounds of medication, 43,000 needles or sharps and 178 medications, valued at $55,000, that were donated to a local clinic serving those without resources for re-dispensing. Expanding our medication take-back event to 19 locations did present some challenges along the way.

To expand our reach, leaders of the takeback event needed to engage in detailed planning and consider logistical challenges. We aligned our event dates to the Drug Enforcement Administrations (DEA) National Prescription Drug Take Back Day. Aligning with the DEA allowed us to plan for future events as these dates are standardized on the last Saturdays in April and October. Alignment also enabled law enforcement to register event locations in their national website. This site is searchable and provides a map of locations nearest to search area. Alignment with the DEA also connected us to our regional State Bureau of Investigation (SBI). This partnership enabled us to receive support including standard boxes used to collect medications at each take-back location. The SBI supplied NHRMC with 250 evidence boxes that were distributed to site leaders at each take-back location.

When planning to staff each of our sites, federal rules indicate that law enforcement must be present at each medication take-back location. When planning for our Fall 2017 expansion, we discovered that our hospital law enforcement officers could staff all NHRMC and affiliate locations. At the Fall 2017 event, we were able to utilize NHRMC police for 5 of the 9 locations. This allowed us to extend our partnership with local sheriff’s offices and expand to additional sites. We continue to collaborate with our regional county sheriff departments who provide an additional 1-2 law enforcement officers for each location.
NHRMC company police have been instrumental in not only staffing these events but also coordinating with regional law enforcement agencies. They collect and store the medication until the “burn day”. This often occurs 2-3 days after the takeback event. Our event has become so large that NHRMC law enforcement transports over 100 boxes of medication. As a result of our success, we have outgrown the transport capacity of our standard vehicles. We now either have to rent commercial trucks or borrow large box trucks from another department in our hospital.

In addition to organizing law enforcement to be present at each site, we decided we would accept needles or sharps at each of the 19 drop off locations. This became an issue for sites that were not affiliated with a health system because they did not have sharps containers at their locations. Prior to each event, NHRMC now donates sharps containers to each of these sites. Following the event, we now also coordinate with either law enforcement or a volunteer at the site to collect the sharps bins.

To raise awareness of this multi-county, multi-site drug takeback event, we approached our hospital’s marketing department to help us by advertising this event. They created a universal flyer listing each drop off location by county. This flyer is printed in a variety of sizes and is posted across our health system and to each of our drop-off location partners. We also advertise in advance of this event on social media, radio stations and local newspapers as well as media outlets on the day of the event. We also created a NHRMC webpage dedicated to medication disposal where we post our upcoming flyer and list locations of all area permanent drop boxes. Through this effort, we also learned that funeral homes, hospice care centers, veterinarian offices and churches are effective locations to advertise these events and added these sites to our marketing locations for future events. We also realized that we needed to create a Spanish-version of our flyer to appeal to other segments of our community and plan to do so for our next event.

We also discovered that we needed to develop a standard process to enable us to repurpose unused medication. Medication take-back locations staffed with NHRMC volunteers may collect any unused medications and can donate them to a charitable clinic. These medications must meet North Carolina repository rules and regulations to qualify for donation. Following the event, each unused medication collected is visually inspected by a pharmacist to ensure it meets all applicable federal guidelines for donated medications. By following this process, we could donate $ 55,000 of medication to one of our local, charitable clinics.

During our medication take-back expansion in 2017, NHRMC also installed three permanent medication drop boxes across several sites within our health system. Medication drop boxes were installed on the main campus within our Outpatient Pharmacy, at our free-standing emergency department located off campus, and at our critical access hospital located in a neighboring county. It was anticipated that the drop boxes would need to be emptied once a month. When first installed, the permanent drop box in our main hospital, which holds roughly 55 pounds of medication, needed to be emptied every 9-10 days. This was not anticipated. We now collect 1,600 pounds of medication in our 3 permanent medication boxes annually.

Like other communities across the country, Wilmington and our surrounding area have been significantly impacted by the opioid crisis. Through the development of the CPC and the leadership of NHRMC, we expanded our drug takeback events to multiple sites in multiple counties in our region. As a consequence of our success, we also discovered we needed to coordinate law enforcement at each location, establish safe storage, rent large trucks to transport thousands of pounds of medication collected at each event, develop a process to reclaim medication and manage high volume disposal of medication in permanently installed drop boxes across our health system. We are fortunate to have such an engaged community to collectively work to reduce harm from medication. Hopefully, these lessons learned will help you do the same.

Personality and Pain: Which Came First?

James N. Weisberg, PhD

This article is adapted from a chapter in a soon to be published text:
Weisberg, J.N., Paul, C. & Twyner, C. Personality and Personality Disorders in Chronic Pain.  In Incayawar, M., Clark, M. & Maldonado-Bouchard, S. (Eds.). Overlapping Pain and Psychiatric Syndromes-Global Perspectives. New York, NY: Oxford University Press

Chronic pain is a significant health care issue at epidemic proportions in the United States1 and there is a high incidence of both clinical psychiatric disorders2,3 and personality disorders (PD) in the chronic pain population.4 This article will briefly summarize some of the important points pertaining to the prevalence and interplay between personality disorders and chronic pain.

Personality and Pain

The relationship between personality and pain can easily be traced to ancient Greece. More recently, in the late 19th century psychodynamic theorists discussed the connection between emotional factors and the experience of chronic pain.5 George Engel maintained that, while physical pain may result from underlying pathophysiology, the interpretation of pain is a psychological phenomenon and also noted that certain diagnoses, including Depression, Hysteria and Hypochondriasis were relatively common in people experiencing chronic pain.6 In an attempt to further characterize personality characteristics, the use of Minnesota Multiphasic Personality Inventory (MMPI)7 and its successors (MMPI-2, MMPI-2-RF) led to a plethora of research seeking to use psychometric tests quantify these early theorists, help predict treatment outcome from multidisciplinary treatment8, spine surgery9, spinal cord  stimulators10as well as  and pain-related disability11.  However, despite the hundreds of studies using the MMPI and its successors, there continues to be controversy regarding the applicability and appropriateness of in the chronic pain population.12,13

A number of other psychological inventories have been used in an attempt to describe and characterize individuals with chronic pain and to predict treatment outcomes. Some, but not all of these measures include the NEO Personality Inventory (Neuroticism-Extroversion-Openness Personality Inventory-NEO-PI) and its revisions,14-16 the Millon Clinical Multiaxial Inventory and subsequent revisions (MCMI; MCMI-IV)17,18 and the Temperament and Character Inventory (TCI).19

While psychological inventories have investigated different personality characteristics as they relate to pain, relatively few studies have investigated personality disorders in chronic pain. 

Personality Disorders and Chronic Pain

Whereas personality refers to the constellation of non-pathological characteristics in an individual’s patterns of thought, emotion, and behavior the DSM defines a personality disorder as “an enduring pattern of inner experience and behavior that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adolescence or early adulthood, is stable over time, and leads to distress or impairment.”20 Thus, the essential difference between a trait and disorder is the degree of distress and disruption caused.

Personality and personality disorders are likely the combination of biological, developmental, and environmental factors that become impacted by state-dependent variables such as mood and anxiety. The Diathesis-Stress model purports that individuals have underlying genetic vulnerabilities and possibly early life experiences that interact with stressors the individual encounters later in life.21  Depending on the nature of the stressors and the individual’s ability to cope with such stressors, the underlying vulnerability may or may not become expressed as a disease process. The diathesis-stress model was first applied to explain schizophrenia21 and depression.22  It has also been applied to the development of chronic back pain23 and the development of depression in chronic pain patients.2 Similarly, this model has been proposed to apply to personality disorders in chronic pain patients.24 Thus, combined with underlying traits and situational stressors brought on by chronic pain, an individual’s underlying personality traits and characteristics may become magnified to the extent the individual meets criteria for a personality disorder.

Epidemiology of Personality Disorders:

In its most recent edition, the American Psychiatric Association cites data from a national epidemiologic survey suggesting approximately 15% of US adults meet criteria for at least one personality disorder.25 A large epidemiological study found prevalence estimates for the different clusters suggest 5.7% for disorders in Cluster A (Paranoid, Schizotypal and Schizoid Personality Disorder), 1.5% for disorders in Cluster B (Histrionic, Narcissistic and Borderline Personality disorders),  6.0% for disorders in Cluster C (Avoidant, Dependent, Obsessive-Compulsive Personality Disorders), and 9.1% for any personality disorder, indicating frequent co-occurrence of disorders from different clusters.26

To date, approximately 15 studies have investigated the prevalence of personality disorders in chronic pain.  Some of the more seminal studies are highlighted here.  The first published study using a semi-structured interview to diagnose DSM-III personality disorders in chronic pain found 37% of their sample met criteria for at least one personality disorder with the most common diagnoses being histrionic PD (14%), dependent PD (12%) and borderline PD  (7%).27  Fishbain et al,28 using a semi-structured interview to diagnosis both DSM-III axis I and Axis II disorders, found 59% of their chronic pain sample met criteria for a personality disorder with most common diagnoses being dependent PD (17%), Passive-Aggressive PD (15%) and histrionic PD (12%).   Weisberg et al29 used a combination of clinical interview, treatment notes and both patient and family self-report measures to assess personality disorders in 55 chronic pain patients who were evaluated and treated at a comprehensive outpatient pain management program. They found that 31% met criteria for at least one PD and an additional 27% met criteria for PD-NOS which is used when an individual meets incomplete criteria for two or more personality disorders.  Similar to other studies, the most common diagnoses were borderline PD (13%) and dependent PD (11%).  These researchers suggest that obtaining longitudinal information from both the patient and an individual with a longstanding relationship with the patient might provide a more thorough assessment of the impact of state factors such as mood, anxiety, and stress on the presentation of personality.29 More recently, Conrad et al30 found that 41% of their chronic pain sample met criteria for a personality disorder diagnoses compared to 7% of their control group.  Most common were Borderline PD (11%) and paranoid PD (12%). The authors found clinical disorders, such as depression at a equally high rate, lending more credence to the importance of assessing personality in context of state factors.

In summary, the relatively few studies that have investigated personality disorders in various samples of patiens with  chronic pain have found prevalence rates from 31% to over 80%. However, as has been noted by previous researchers, due to a variety of factors including state-dependent variables, stressors unique to chronic pain, genetic and developmental influences and other known and unknown factors, significant caution must be used when making a personality disorder diagnosis in the individuals with chronic pain.  In addition, knowing premorbid functioning is crucial in understanding the multifactorial nature of the observed behavior.  Nontheless, the presence of a personality disorder increases the liklihood of co-morbid conditions, such as substance misuse and abuse and makes treatment of chronic pain that much more challenging to the pain clinician.

The Nexus of Personality Disorders in Chronic Pain and Substance Use Disorders:

There has also been a paucity of research on the interaction between personality disorders and substance use disorders in chronic pain.  One study investigated psychological comorbidities, including personality disorders, in chronic pain sufferers presenting to either a university emergency department or an urgent care clinic requesting opioids.31 Pertinent results demonstrated 18% likely had a personality disorder diagnosis and found that personality disorder was significantly related to opioid abuse.31 A recent study found the incidence of personality disorders to be 52% in those with co-occurring chronic pain and substance use disorders.32 The most common personality disorder was antisocial PD (22%) followed by avoidant PD (19%) and paranoid PD (16%). Although there is little literature on this topic, both of these studies suggest that personality disorders may be a moderating variable in the incidence of substance use disorders in persons with chronic pain.                                                                                                                                         

Treatment of Personality Disorders in Chronic Pain

While working with people living with either chronic pain or personality disorders can prove to be daunting to the clinician separately, working with those with the co-morbid diagnoses of both personality disorders and chronic pain can pose unique challenges and opportunities in regard to treatment. Although maladaptive behaviors are, by definition, problematic in a variety of settings, legitimate concerns may be disregarded as secondary to the manifestations of personality disorders or simply attributed to being “difficult.”

The need for the pain clinician to screen for personality disorders is rooted in the understanding that the manifestations of a personality disorder in a person living with chronic pain can be exacerbated or unmasked by the individual’s pain condition according to the diathesis-stress model.24  In addition, the need for vigilance and awareness with these conditions is considerable as these patients are at higher risk for various adverse outcomes, including substance use disorders. 31 Attempting to detangle the personality disorder from the chronic pain state with the goal of treating one or the other may be difficult at best.

Cognitive-Behavioral Therapy for chronic pain (CBT-CP) has been well documented in the literature to be one of the most effective treatments for chronic pain.33-35 Acceptance and Commitment Therapy (ACT)36, has been shown to benefit patients with personality disorders that had failed in previous treatment with significant improvements in personality pathology and quality of life.37 ACT for chronic pain has also been effective at decreasing pain intensity, anxiety, and disability38 The use of CBT-CP and ACT may be a potential avenue for treatment, but research designed to investigate these interventions among people with coexisting chronic pain and personality disorders is lacking.

Dialectical Behavior Therapy (DBT), a current mainstay of treatment of borderline personality disorder, focuses on the development of coping skills with the ultimate goal of improving emotional regulation and control.39 However, as with other therapeutic modalities, there is minimal evidence for treatment for DBT in those with chronic pain and comorbid personality disorders.

Given the common elements between Cognitive-Behavioral Therapy and Dialectical Behavior Therapy, it stands to reason that a hybrid model combining elements of both CBT-CP with DBT might be a highly successful approach to maximizing treatment potential in patients with co-morbid chronic pain and personality disorders, especially borderline personality disorder.

Summary: 

In summary, it is important to assess patients not just for depression, anxiety and other clinical psychiatric disorders, but for personality traits and disorders in order to better understand the impact personality may have on the expression of their pain perception, medication use and coping styles.  Understanding the role personality disorders may play in the complexities of chronic pain should result in the tailoring of multimodal treatments for chronic pain that emphasize non-opioid medical management, cognitive-behavioral and physical therapies.

References

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Hypnotically Enhanced Addictions Treatment

Joseph Tramontana, Ph.D.

As a member of the Board of Directors of the Southern Pain Society, I want to share with the membership a recent workshop I presented to the Canadian Federation of Clinical Hypnosis in Banff, Canada.  The workshop was titled “Hypnotically Enhanced Addictions Treatment: Drug Abuse, Alcoholism and Alcohol Abuse, Gambling Addiction, Smoking Cessation, and Obesity, with a Focus on Drug Dependence during this Opioid Crisis.”

The 2-day workshop was presented by invitation to a group of 19 advanced hypnosis practitioners, including MDs, Psychologists, Licensed Clinical Social Workers, and Licensed Counselors.

While the title was lengthy, a number of problem behaviors were addressed. Dealing with pain patients, was a major focus. For example, if a patient came in experiencing pain at a “7,” (on a 10-point scale)  and after the first hypnosis session he/she reported it was down to a “3,” the change was not only significant, but interpreted to them as “probably as much relief as you get from a pain pill, but it’s natural.” More importantly, the patient is taught self-hypnotic techniques to use at home as a coping skill. The goal is to use hypnotic relaxation when hurting instead of instinctively reaching for the pill bottle. 

Another technique is having the patient, while in trance, imagine the sensation of pain medication, but replicating the relief without the actual medicine.

These techniques fit well with psychoeducation interpretations to patients about the “Mind-body connection.”

Cognitive Behavioral Therapy for Chronic Pain

James L. McAbee, Ph.D.

Individuals living with chronic pain often present with myriad complaints and a decrease in quality of life driven, in many cases, by a lack of adaptive coping skills. Frequently, patients apply conventional wisdom, opting to reduce their activity levels and “resting” as a response to their pain and, in doing so, further reduce their functional capacity and involvement in daily life. These changes in behavior increase the likelihood of time spent ruminating over and brooding about their pain- “will this ever get better?”, “this might get worse”, “nothing seems to help me or my pain”, “I can’t do anything anymore”. Such thought patterns are known in the psychological literature as “Pain Catastrophizing” (Gatchel, 2017; Leung, 2012; Quartana, 2009), and are driven by fears associated with pain and a sense of helplessness/hopelessness when faced with demands to manage pain. This form of thinking leads to increased negative emotions such as anxiety and depression, which can also be influenced by decreased socialization and increased isolation. Patients can then experience physical deconditioning from inactivity and once they engage in some form of activity again they often misinterpret an increase in pain, any experience of new pain, or activity-related soreness as confirmation that that activity is “dangerous”, thus reinforcing the cycle of negative thinking and behaviors. Over time, if left untreated, this cycle leads to less time spent tending to the important territories of life, the boundaries of life shrink inward, and pain overshadows the land.

Cognitive Behavioral Therapy (CBT) is the most efficacious therapeutic intervention utilized by clinical psychologists and has been researched and validated across a multitude of diagnostic categories. CBT is a collaborative, problem-focused intervention that is intended to be delivered in a time-limited format, and which challenges the problematic thoughts/beliefs and behaviors which contribute to and/or maintain the patient’s presenting concern and negative emotions. A therapy session in this approach is more active than traditional psychotherapies and challenges the patient to make changes in both behavioral and cognitive patterns. In CBT the focus is on ‘doing’ things, not just ‘talking’ about things. CBT for Chronic Pain (CBT-CP) can help patients to break free from the chronic pain cycle, and evidence suggests that this modality of psychological intervention improves patients’ functioning and quality of life (Hoffman, Papas, Chatkoff, &Kerns, 2007; Morley, Williams, & Eccleston, 1999; Turner, Mancl, & Aaron, 2006).

As one can see in the cycle of chronic pain described above there are various entry points for intervention from a psychological perspective. In my clinical practice, the initial meeting with a patient is focused on normalizing the patient’s experience, reassuring them that they are not “crazy” nor are they meeting with a psychologist because their pain is “all in their head”, common concerns of patients referred to a pain psychologist. The information gathered via the clinical interview and the patient’s responses to screening instruments and questionnaires, their self-report of current difficulties and observations of their behavior permit more comprehensive feedback regarding the conceptualization of their situation and the opportunity to educate them about the rationale for how CBT-CP can be helpful. I find that when I reflect back to the patient my understanding of their condition (in their own words) paired with printed materials depicting the relationships of how chronic pain impacts their thoughts, feelings, and behaviors, and the cycle of chronic pain, patients are able to relate to the information, understand these connections and “see” problem areas in their lives, thus demystifying the process of treatment.

The overarching goals of CBT-CP are to promote adaptive coping by increasing self-efficacy in the management of pain, reduce avoidant behaviors, reduce “catastrophizing”, reduce negative or unhelpful beliefs about their pain, reduce negative mood symptoms, increase physical activity, to shift the perspective from pain to improved functioning, and to increase general quality of life despite having chronic pain. The intervention itself works toward achieving these goals through liberal use of psychoeducation about factors that perpetuate chronic pain and those which reduce the experience of chronic pain through the acquisition and development of adaptive coping skills. In essence, the goal of CBT-CP is to help patients reclaim the lost territories in their lives, and to have a life worth living despite chronic pain.

CBT-CP sessions are highly structured with the provider setting an agenda of important topics and specific skills to be introduced and developed during a session; however, assisting patients in the development of their own behavioral goals is equally, if not more, important. After all, the goal of CBT is to promote self-efficacy. Printed materials are always given in my practice to allow visual integration of the topics covered in session. Doing so allows patients to leave with information in hand which they can review between sessions. I find that this approach allows patients to remain connected to the material in their everyday environment and to return to the next session with any questions to be clarified. CBT-CP sessions are initially focused on increasing general activities to promote behavioral activation and increase functioning. The use of psychoeducation about how to properly pace activities without overexerting oneself (and possibly a few gentle reminders of the perils of inactivity) allow for development of specific, measurable, achievable, relevant, and time-limited goals (SMART Goals). Integration of scheduling pleasurable activities is also conducted in these early phases of treatment. In addition to increasing general activity, these “new” behaviors begin to inconspicuously challenge patients’ assumptions of “I can’t do anything”, and also begin to improve negative mood symptoms. As one patient eloquently stated, “I’m learning that I can do nothing and hurt, or I can hurt and do some things I enjoy”.

Of course, CBT would simply not be CBT without the “C”. Assisting patients to identify problematic, maladaptive, and unhelpful cognitive patterns is a critical component of the intervention. Providing patients with psychoeducation about the powerful influence thinking has on their behaviors and emotions helps to ground them in their own internal experiences and in their everyday lives. Normalizing problematic thinking can be a validating experience for patients. I always tell patients when reviewing a list of the 12 most common cognitive errors, “If you identify with these, congratulations, you have a normal brain!”. As we review the list together many patients will say, “oh yeah, I do that” and will frequently provide a recent example from their lives. However, simply identifying problematic thoughts is not enough for change to occur, it is essential to “do” something about it. The use of thought logs allows patients to identify their thoughts and beliefs about their pain in relation to a triggering event and their emotional, physical, and behavioral reactions. Once we have a “map” of this process, together the patient and provider can begin to collaboratively examine how thoughts and behaviors influence emotions and outcomes of the situation in question, and to decide what to “do” about it. Cognitive restructuring is the process of developing more balanced, adaptive, and helpful thought patterns which lead to more adaptive behaviors, reduction in negative emotions, and greater desired outcomes. Patients are then encouraged to experiment with these new patterns of thinking and behaviors to determine whether this change was effective. CBT-CP trains patients to become behavioral scientists in their own right- continuously positing hypotheses and testing new behaviors to (dis)confirm the null hypothesis.

Like any other field of healthcare, pain psychology is also concerned with significant and reliable change. In order to determine whether or not the intervention is effective, we must have a system of objective measurement. Therefore, empirical assessments of symptoms are given on an ongoing basis to track patients’ progress and to better inform treatment. Not only is CBT-CP an evidence-based practice, we generate our own practice-based evidence! These data can be utilized for various purposes in the context of treatment. For example, data can be used to challenge patients’ maladaptive beliefs that they are “not getting any better” when subjective reports of difficulties remain high despite the evidence of lower scores compared to the baseline. Equally important, it is quite validating for patients to witness positive change in their objective measures and enhances motivation for sustained behavioral change, particularly in cases where their pain scores remain unchanged, but their function and quality of life is improved.

CBT-CP is an effective intervention to complement a comprehensive approach to pain management. If you are a non-psychologist pain provider, you might find yourself asking, “how do I know that my patients are receiving ‘good’ CBT”. Aside from witnessing a change in your patients’ behaviors (i.e. increased behavioral activities, decreased “catastrophizing” talk, increased self-efficacy, improved mood), ‘good’ CBT is informed by ongoing assessment. It is important for clinicians to ask about patients’ experiences with their pain psychologist to determine the topics discussed and skills developed and ask them directly if they are routinely completing brief assessment measures and receiving feedback in treatment. I personally welcome collaboration with pain providers and encourage patients to sign release of information forms so that I can communicate with other members of the pain management team. This open communication allows for other providers to see what the patient and I are doing, and to provide them with practice-based evidence of patients’ progress. Moreover, it is helpful to hear other potential concerns that have developed over the course of treatment outside the initial referral or the patients’ reports which ought to be addressed in treatment. Speak with the psychologists to whom you refer routinely about how patients are progressing, although we “CBTer’s” are “doers”, we also enjoy talking with other providers.

References:

Gatchel, R. J., & Neblett, R. (2017). Pain Catastrophizing: What clinicians need to know. Practical Pain Management, 15(6). Retrieved from: https://www.practicalpainmanagement.com/pain/other/co-morbidities/pain-catastrophizing-what-clinicians-need-know

Hoffman, B.M., Papas, R.K., Chatkoff, D.K., & Kerns, R.D. (2007). Meta-analysis of psychological interventions for chronic low-back pain. Health Psychology, 26(1), 1-9. doi: 10.1037/0278-6133.26.1.1

Leung, L. (2012). Pain Catastrophizing: An updated review. Indian Journal of Psychological Medicine, 34(3), 204–217. http://doi.org/10.4103/0253-7176.106012

Morley, S., Eccleston, C., & Williams, A. (1999). Systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy and behavior therapy for chronic pain in adults, excluding headache. Pain, 80(1-2), 1-13. http://dx.doi.org/10.1016/S0304-3959(98)00255-3

Quartana, P. J., Campbell, C. M., & Edwards, R. R. (2009). Pain catastrophizing: a critical review. Expert Review of Neurotherapeutics, 9(5), 745–758. http://doi.org/10.1586/ERN.09.34

Sullivan, M. J. L., Bishop, S. R., & Pivik, J. (1995). The Pain Catastrophizing Scale: Development and validation. Psychol. Assess., 7: 524–532.

Turner, J.A., Mancl, L., & Aaron, L.A. (2006). Short- and long-term efficacy of brief cognitive-behavioral therapy for patients with chronic temporomandibular disorder pain: A randomized, controlled trial. Pain, 121(3). 181-194.

Catastrophizing and the Meaning of Pain: Why It Matters

by David Gavel, PhD

Consider this situation: A 51-year-old pipe-welder and father of 3 was in your office this morning to hear the results of an MRI related to complaints of progressively worsening back pain. He sits down and anxiously awaits your feedback as he writhes in pain. You inform him that imaging showed the presence of degenerative disc disease and briefly explain that his condition is present in some form with more than 90% of men over the age of 50 [1], many of whom are asymptomatic [2]. Before he even asks, you explain a variety of non-invasive treatment options for managing the pain and recommend that he consider limiting or altering activities that may speed up the “wear and tear” of his back. He expresses his understanding and heads home to inform his wife that “the doc said my back is disintegrating and I’ll never be able to work again. I don’t know how we’ll survive if I can’t work.”

Notice how the news received by the wife seems to be drastically different than the words you expressed in the office. In this scenario, during your conversation with him there was no conversation about employment, specific worsening of symptoms, or any direct orders to cease and desist all meaningful activity. So, what happened? How did your objective diagnosis and empirically supported recommendations turn into a convoluted message to the wife as if it was a game of telephone at a 7-year-old slumber party? The answer is catastrophizing, and it is explained by the cognitive model.

The cognitive model [3] is a widely accepted and well published framework for understanding the crucial role that internal thoughts and attitudes play in the daily experience of emotion and behavior. More specifically, the model proposes that over the course of our lifetime, we all develop patterns of thought that influence our understanding of the world around us and the meaning we place on events in our lives. Unfortunately, these thought patterns do not always work in our favor and certain dysfunctional thinking patterns tend to underline many of our most undesirable experiences. Among these dysfunctional patterns is the aforementioned catastrophizing. In a nut shell, catastrophizing is the tendency to draw erroneous and often irrational conclusions about the severity of a current situation or to believe that a future situation will end in the worst possible way. For example, after a seven-week romantic relationship ends, a 15-year-old screams “I’ll be alone forever in a house full of cats for the rest of my life!”. Or a middle-aged employee recklessly speeds through rush hour traffic with the thought “If I’m late, I’ll be fired, and we’ll be out on the street for sure.” In both examples, the individual expresses emotions and behaviors that seem unreasonable given the reality of the situation. But that reality is distorted by the worst-case scenario (i.e., belief) that keeps running through their mind (i.e., thought). And the result is a series of undesirable emotions and behaviors.

In the management of chronic pain, catastrophizing is linked to a host of negative physical [4] and psychological outcomes [5] and is a common reason why patients sit in my office and describe how their depression began after a medical provider said “Your back is the worst I’ve ever seen,” “You’ll just have to learn to live with the pain,” or “You will never be able to…(work, play, walk, run, function)…again.” Now to be clear, I have no way of knowing whether quotes like these are the exact words used by the treating medical provider or not. In fact, it is quite likely they are not, and I would like to go on believing that way. But when a patient sits in my office for a psychological evaluation after 8 years of chronic pain that nearly ended with a recent suicide attempt, it is almost irrelevant whether these exact words were ever spoken or not. What matters most is that the patient carrying these burdensome thoughts interpreted that meaning from the situation: “life as I know it, is over.” And like a church bell clanging through the empty halls of a cathedral, this sentiment rings loud and clear inside the mind of the patient and influences every aspect of life for the worse.

Fortunately, there are a number of very effective forms of mental health treatment of chronic pain (e.g. cognitive behavioral therapy for pain) but one does not have to be a psychologist or other mental health provider to help offset some of this influence with patients. In a brief informational blog post entitled “What’s in a Word? The Power of Language in Chronic Pain Treatment,” [6] physiotherapist Carol Miller discusses the influence of language in the assessment and treatment of pain. Ms. Miller encourages providers to use language to explore and understand the patients’ subjective beliefs about pain, expectations for their treatment, and goals for the future. Asking open ended questions or using norm-referenced pain screeners (e.g., Pain Catastrophizing Scale) are two effective and brief methods for eliciting thoughtful information about the patient experience. Furthermore, she offers the idea that understanding our own beliefs about chronic pain and how those beliefs are reflected in our language can lead to more effective patient encounters. Regarding catastrophizing, Ms. Miller’s recommendations for intentional focus on language can lead to invaluable opportunities for providers to clarify any erroneous conclusions a patient may have drawn about the implications of their condition. George Orwell once remarked that “if thought corrupts language, language can also corrupt thought.” If we accept that our spoken words are the outward expression of internal thought, then we must also accept that our words carry weight that bears meaning for the thoughts and lives of our patients.

[1] Teraguchi M, Yoshimura N, Hashizume H, et al. Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. Osteoarthritis And Cartilage. 2014;22(1):104-110. doi:10.1016/j.joca.2013.10.019.

[2] Brinjikji W, Luetmer PH, Comstock B, et al. Systematic Literature Review of Imaging Features of Spinal Degeneration in Asymptomatic Populations. AJNR American journal of neuroradiology. 2015;36(4):811-816. doi:10.3174/ajnr.A4173.

[3] Beck, J. S. (2011). Cognitive behavior therapy: Basics and beyond (2nd ed.). New York, NY, US: Guilford Press.

[4] Talaei KM, Fischerauer SF, Lee S, Ring D, Vranceanu A. Pain Catastrophizing Mediates the Effect of Psychological Inflexibility on Pain Intensity and Upper Extremity Physical Function in Patients with Upper Extremity Illness. Pain Practice. 2017;17(1):129-140. doi:10.1111/papr.12494.

[5] Shim E, Song Y, Park S-H, Lee K-M, Go D, Hahm B-J. Examining the Relationship Between Pain Catastrophizing and Suicide Risk in Patients with Rheumatic Disease: the Mediating Role of Depression, Perceived Social Support, and Perceived Burdensomeness. International Journal of Behavioral Medicine. 2017;24(4):501-512. http://lynx.lib.usm.edu/login?url=http://search.ebscohost.com/login.aspx? direct=true&db=s3h&AN=124131574&site=ehost-live. Accessed October 10, 2018.
[6] https://ignitephysio.ca/blog/whats-in-a-word-the-power-of-language-in-chronic-pain-treatment/

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