PainChampions October 16, 2016 WHAT HAPPENS WHEN PAIN GOES UNTREATED? Not only is it “inhumane to tell people with impossible pain to just suck it up” as I said in the previous article: untreated or under-treated pain is more than uncomfortable. There are profound effects on someone who lives with pain. Many of us living with pain would respond sarcastically, “No. Really?!” Yes, many of those changes seem like common sense, but it helps us know the details. A 1999 Chinese study of cancer patients showed that, after taking into account the effects of cancer, the more pain someone had, the worse the effects on their health and how they functioned. Understandably, the relationship between the severity of pain and impairment was nonlinear: patients with no pain or only mild pain were significantly better functioning than those with moderate and severe pain.1 Dr. Forest Tennant has written, “Persistent pain, which is also often characterized as chronic or intractable, has all the ramifications of a disease in that it may have pre-clinical and overt phases. It may be intermittent or constant, as well as, mild, moderate, or severe. The most unappreciated clinical feature of persistent pain, however, is the plethora of complications that may result — particularly if the pain is constant and unremitting.”2 Our doctors are more likely to listen to us and treat our pain if they can see evidence — and as people with pain, the more we know about what the consequences are, the better we can work to prevent them and search out more appropriate tools for our pain toolbox. Pain steals the resources we need to get through our days. Let’s define some of these losses by looking at three general areas: • Neural and brain changes; • Physical damage (cardiovascular, respiratory, immune system); and • Social and psychological effects.
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NEURAL AND BRAIN CHANGES Pain is serves as a warning; the feeling of pain triggers a fight-or-flight response, telling us that we’re in danger and that we need to fix whatever is causing us injury. If the pain continues, our body and brain don’t understand why, and the sensation of pain is increased to get our attention and make us fix the problem. This is the neural change with which most doctors are probably familiar, the adaptation our nervous systems make when pain persists. The Society’s Pain Management Medical Resource Guide describes it this way: “A cardinal feature of EDS is pain. At first there are just small pains; but acute pains may accumulate, then become continual and chronic. There may be a major dislocation of injury to start the cycle; but without adequate treatment, persistent pain can change the nervous system in a process that is difficult to reverse. By lowering the threshold for pain signals, chronic pain becomes harder to treat.”3 Reduced to one statement: acute pain that is inappropriately managed can result in neural changes which can progress to chronic pain.4 This is particularly crucial to remember with EDS, because it’s nearly impossible for us to prevent acute pain. The connective tissue weaknesses we’re born with affect the molecular structures that protect our body tissue from stretching too far. Not only do our joints dislocate fully or partially which may hurt in themselves; all the tissues around our joints (and on into the muscles, tendons, and fascia that are connected to those joints) are stretched beyond the ability of the tissue to hold itself together, so those tissues are injured in a myriad of microscopic tears. Over and over and over. Even nerve pathways and neurons can be disrupted when tissue stretches too far, something else our brains will likely interpret as pain. We are subject to chronic pain in two forms, not only the normal, burned-into-nerve pathways type of pain commonly called chronic pain, but also chronic acute pain: we don’t injure the tissue around our joints once, but continually, every time a joint slips, day in, day out. It’s not just our neural net that changes. It turns out our brains adapt, too, but in ways not directly associated with pain. In a healthy brain, the various regions maintain a balance; when one region becomes active, the others calm down. In people with
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chronic pain, a front region of the cortex that is mostly associated with emotion never calms down, staying fully active all the time. This wears out neurons and alters the connections between neurons; when neurons fire constantly, they can even die out from such intense activity, causing permanent damage. Dante Chialvo, the lead investigator in an 2008 study5 From Northwestern University: documenting that activity, said, “If you are a chronic pain These images show the brain from the left side, demonstrating patient, you have pain 24 hours a day, seven days a week, striking differences between every minute of your life. That permanent perception of pain healthy subjects and chronic pain patients. They illustrate with color in your brain makes these areas in your brain continuously how much activation (red/yellow) or deactivation (dark/light blue) active. This continuous dysfunction in the equilibrium of the was found at each location. brain can change the wiring forever and could hurt the brain. [The changes] may make it harder for you to make a decision or be in a good mood to get up in the morning. It could be that pain produces depression and the other reported abnormalities because it disturbs the balance of the brain as a whole.”6 Other studies have seen lower numbers of grey matter nerve cells in the brains of people with chronic pain.7 Another noted significantly less neocortical grey matter volume, after correcting for intracranial volume, age, and sex, compared to matched controls; 1.3 cubic centimeters of grey matter (the part of the brain that processes information and memory) are lost for every year of chronic pain.8 White matter has also shown to be decreased, which falls in line with neuronal loss but also suggests the brain is reorganizing connections.9 These changes result from the constant sensation of pain; they reflect the suffering of perceiving pain and the ways our bodies try to cope with that suffering. Peripheral and spinal cord nerve systems reorganize their interactions because they’re constantly in use. Those systems then affect the cortex itself, and all of them continue to try to negotiate daily life under the barrage of continual pain.10 By the way, the reorganization of information processing in the brain appears to have other unexpected effects. One that’s been documented is a decreased threshold (increased sensitivity) to taste.11
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PHYSICAL DAMAGE The stress of pain also affects physical systems. It’s been documented that acute untreated pain after operations increases the risk of lung collapse, respiratory infection, myocardial ischemia, infarct or cardiac failure, and thromboembolic disease.12 And persistent pain profoundly affects our endocrine, cardiovascular, immune, and musculoskeletal systems.2,13 When pain is unending, there is an increase in the level of cortisol, the primary stress-induced hormone. Some cortisol is necessary for the immune system, but when the level is raised for long periods, cell function in the immune system and kidney is compromised and the immune system doesn’t work well, operating at less than capacity. This affects overall quality of life, as well as the ability to fight infections and heal. There is evidence that these immune system effects of chronic pain may speed up growth of cancer cells.14
Pain Hypothalamus Corticotropin-Releasing Hormone Pituitary Adrenocorticotropin Hormone Adrenal Gland Glucocorticoid Excess
In fact, chronic pain may even reprogram the way genes work in the Adrenal Exhaustion immune system. A study at McGill University found that chronic pain Glucocorticoid Deficiency changes the way DNA is marked in the Forest Tennant, MD DrPH brain and in T-cells, a type of white “Complications of Uncontrolled, Persistent Pain” www.practicalpainmanagement.com/pain/other/co-morbidities/ blood cell essential for immunity. DNA complications-uncontrolled-persistent-pain from brains and white blood cells of rats was examined using a method that mapped DNA marking by a chemical called a methyl group. Methyl marks are important for regulating how those genes function. (Chemical marking like this is part of epigenetics, the study of changes caused by modification of gene expression rather than alteration of the genetic code itself.)
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Moshe Szyf, a professor in the Faculty of Medicine at McGill, said, “We were surprised by the sheer number of genes that were marked by the chronic pain — hundreds to thousands of different genes were changed. We can now consider the implications that chronic pain might have on other systems in the body that we don’t normally associate with pain.”15 Compromised homeostatic function of prefrontal cortical-limbic circuitry in major depressive disorder and chronic pain disrupts autonomic, neuroendrocrine, and neuroimmune regulation, shown here. 1. Stress, pain, and depression lead to excessive, untimely release of corticotropinreleasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids. 2. Sympathetic overactivity, combined with diminished parasympathetic tone, contributes to immune activation and release of proinflammatory cytokines (e.g., tumor necrosis factor-alpha [TNF-alpha], interleukin-1 [IL-1], and interleukin-6 [IL-6]) from macrophages and other immune cells. 3. Inflammatory cytokines further interfere with monoaminergic and neurotrophic signaling. Proinflammatory cytokines also can reduce central glucocorticoid receptor sensitivity, leading to further disruptions of (1) the hypothalamic-pituitary-adrenal (HPA) axis and (2) immune system regulation. 4. Disturbances of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) signaling in major depressive disorder and chronic pain impair the function of descending pain modulatory pathways. Elevated mediators of the inflammatory response, combined with excessive sympathetic tone, can further affect dorsal column processing of pain signals by contributing to activation of microglia and astroglia. 5. Activated microglia exchange chemical signals with astrocytes and nociceptive neurons, thus amplifying pain-related transmission of glutamate (Glu), substance P (SP), adenosine triphosphate (ATP), brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines (IL-1, IL-6, interleukin-8, TNF-alpha, nitrogen oxide (NO), and prostaglandins (PGs). Ach: acetylcholine; ATP: adenosine triphosphate; CRF: corticotropin releasing factor; PVN: paraventricular nucleus of hypothalamus Illustration from Maletic V, Raison CL (2009). Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci (Landmark Ed). 2009;14:5291-5338
SOCIAL AND PSYCHOLOGICAL EFFECTS The fight-or-flight response to pain was a useful evolutionary aid for selfpreservation. But fight-or-flight isn’t very useful in the modern world, and next to useless for chronic pain. Common consequences of untreated chronic pain can include decreased mobility, impaired immunity as already discussed, decreased concentration, sleep disturbances, and anorexia.16,17 As a result, those of us with chronic pain — with or without the contributions of EhlersDanlos — face social isolation, dependence on care givers, and impaired relationships
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with friends and family.18 We’re four times more likely than those without pain to have depression or anxiety.17 Absenteeism, loss of income loss, healthcare costs, and workers compensation due to chronic pain place the same strain on countries as cancer and cardiovascular disease do.16 The annual cost of untreated pain in the United States alone is reported to be between US$560–$635 billion, and in a larger view, many of the greatest disease burdens globally, such as depression, trauma from vehicle collisions, and falls, are caused by acute or chronic pain.18 The following are some of the disorders directly related to pain, and more particularly pain in Ehlers-Danlos. Please note this does not in any possible way suggests that Ehlers-Danlos or our pain is psychiatric in nature: instead, it adds to the possible symptom list for EDS a variety of psychiatric associations — and indirectly suggests that if our pain were treated adequately, these effects would be at least minimized. Hershenfeld SA, Wasim S, McNiven V, Parikh M, Majewski P, Faghfoury H and So J (2016). Psychiatric disorders in Ehlers–Danlos syndrome are frequent, diverse and strongly associated with pain. Rheumatol Int 36: 341. doi:10.1007/s00296-0153375-1 Abstract Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings.
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Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5%, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain (odds ratio [OR] 7.38), neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS. Chronic pain changes our behavior. When part of the cortex is firing constantly, not only our emotions are affected. The cortex also plays a role in memory, attention, and consciousness, so it’s as though we are multi-tasking all the time, which can make concentration difficult. Simple decisions and human interaction become more complicated. Chronic pain affects our sleep, not just because we hurt; pain interrupts our usual wake/sleep cycle. And not getting enough sleep makes pain worse, pain and sleep cycling around each other.19 Ehlers-Danlos sleep is also disturbed by adrenaline rushes that result from the physical threats of dysautonomia as well as from shifting pain. When we don’t have control over our pain, our brains become hyper-vigilant and anticipate future pain. Chronic pain sets up a continual level of anxiety.20 Studies have identified that 30–60 percent of chronic pain patients develop depression.21 The reduced pain control and the complex rewiring in the brain also contribute to a sense of hopelessness, making treatment of depression more
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difficult.20 Functional and structural changes in the amygdala and hippocampus have been described in major depressive disorder, fibromyalgia, and neuropathic pain.22 Those changes disrupt neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms — relaying us back to physical changes resulting from pain.22,23 CONCLUSIONS While it comes as no surprise to so many of us with Ehlers-Danlos, pain clearly reduces the quality of our lives both physically and mentally. Chronic pain becomes disabling as the brain changes, trying to manage first the pain, then its own interactions with peripheral nerves and the spinal cord as they become sensitized. But these attempts to cope actually further erode our ability to live with pain. Chronic pain cannot be seen anymore as only being the perception of pain. The simple pleasures of everyday life are lost to suffering, as well as learning, memory, and concentration. Even our emotions are influenced, increasing levels of anxiety and depression in a cycle that makes pain less bearable. Changes in our cortex also impinge on the limbic system, increasing our suffering by reshaping our basic emotions and drives.10 Chronic pain causes brain damage, a reorganization of our neural circuitry, affecting our emotions, decisions, and behavior. While it would be easy to read all this loss I’ve described and feel hopeless, there is good news. The brain damage doesn’t appear to be permanent. Researchers at McGill University found that chronic pain patients who were eventually treated for their pain were able to recover. Their brain mass began to increase, the area of the brain that controls pain repaired itself (cortical thickness increased, and gray matter cells grew — and the ability to perform tasks requiring mental focus returned to normal.24 Pain management in all available forms is crucial for our health. The more we can manage our pain and suffering, the more able we’ll be to deal with everything else life and Ehlers-Danlos throw our way. Mark Martino, The Ehlers-Danlos Society
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SOURCES For an in-depth look at how depression and chronic pain are interlinked, consider a review paper in Current Psychiatry from February 2016, “Chronic pain and depression: Understanding two culprits in common,” authored by Malefic and DeMuri. It’s available in full on http://www.mdedge.com/ currentpsychiatry/article/106087/depression/chronic-pain-and-depression-understanding-2culprits. Wang XS, Cleeland CS, Mendoza TR, Engstrom MC, Liu S, Xu G, Hao X, Wang Y and Ren XS (1999). The effects of pain severity on health-related quality of life. Cancer, 86: 1848–1855. http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19991101)86:9%3C1848::AIDCNCR29%3E3.0.CO;2-M/full 1
Tennant F. Complications of Uncontrolled, Persistent Pain. www.practicalpainmanagement.com/ pain/other/co-morbidities/complications-uncontrolled-persistent-pain 2
The Ehlers-Danlos Society. Pain Management Medical Resource Guide. http://ehlers-danlos.com/ wp-content/uploads/MRGPainManagementS.pdf 3
Stephens J, Laskin B, Pashos C, Pena B, Wong J (2003). The burden of acute postoperative pain and the potential role of the COX-2-specific inhibitors. Rheumatology (Oxford) 42 Suppl 3: iii40–52. doi:10.1093/rheumatology/keg497 4
Baliki MN, Geha PY, Apkarian AV and Chialvo DR (2008). Beyond Feeling: Chronic Pain Hurts the Brain, Disrupting the Default-Mode Network Dynamics. J Neurosci 28(6): 1398-1403. doi:10.1523/ JNEUROSCI.4123-07.2008. 5
Paul M. Chronic pain harms the brain. February 5, 2008. http://www.northwestern.edu/ newscenter/stories/2008/02/chronicpain.html 6
Robinson ME, Craggs JG, Price DD, Perlstein WM and Staud R (2011). Gray Matter Volumes of Pain Related Brain Areas are Decreased in Fibromyalgia Syndrome. J Pain. 2011 Apr; 12(4): 436–443. Published online 2010 Dec 13. doi:10.1016/j.jpain.2010.10.003 and https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3070837/ 7
Apkarian AV, Sosa Y, Sonty S, Levy RE, Harden R, Parrish T, Gitelman D (2004). Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24:10410– 10415. 8
Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, Apkarian AV (2008). The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron. 2008;60:570–581. 9
Apiarian AV. Chapter 15: Human Brain Imaging Studies of Chronic Pain. Kruger L, Light AR, editors (2010), Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis. https://www.ncbi.nlm.nih.gov/books/NBK57254/ 10
Small DM, Apkarian AV. Increased taste intensity perception exhibited by patients with chronic back pain. Pain. 2006;120:124–130. 11
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Stephens J, Laskin B, Pashos C, Pena B, Wong J (2003) The burden of acute postoperative pain and the potential role of the COX-2-specific inhibitors. Rheumatology (Oxford) 42 Suppl 3: iii40–52. doi: 10.1093/rheumatology/keg497 12
Chapman RC and Gavin J (1999). Suffering: The contributions of persistent pain. Lancet. 1999. 353:2233-7. 13
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McIlwain, HH. http://www.sharecare.com/question/chronic-pain-affect-immune-system
Massart R, Dymov S, Millecamps M, Superman M, Gregoire S, Koenigs K, Alvarado S, Tajerian M, Stone L and Szyf M (2016). Overlapping signatures of chronic pain in the DNA methylation landscape of prefrontal cortex and peripheral T cells. S Rep 6:19615. doi:10.1038/srep19615. http://www.nature. com/articles/srep19615 15
Lipman AG (2005). Pain as a human right: the 2004 Global Day Against Pain. J Pain Palliat Care Pharmacother 19: 85–100. doi: 10.1080/j354v19n03_16 16
Lohman D, Schleifer R, Amon JJ (2010). Access to pain treatment as a human right. BMC Med 8: 8. doi: 10.1186/1741-7015-8-8 17
International Association for the Study of Pain (2013). Unrelieved pain is a major global healthcare problem. Washington (D.C.): International Association for the Study of Pain 18
Optum (2016). The Effect of Sleep on Chronic Pain: Enhancing Sleep Can Lead to Less Pain and Better Outcomes (2016) http://www.helioscomp.com/docs/default-source/White-Paper/insomniawhitepaper-and-chart.pdf?sfvrsn=6 19
Strigo IA, Simmons AN, Matthews SC, Craig AD and Paulus MP (2008). Association of Major Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of Heat Pain. Arch Gen Psychiatry 2008;65(11):1275-1284. doi:10.1001/archpsyc.65.11.1275 https://www. ncbi.nlm.nih.gov/pmc/articles/PMC2702160/ 20
Bair MJ, Wu J, Damush TM, et al. (2008). Association of depression and anxiety alone and in combination with chronic musculoskeletal pain in primary care patients. Psychosom Med. 2008;70(8):890-897 21
Maletic V, Raison CL (2009). Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci (Landmark Ed). 2009;14:5291-5338 22
Gracely RH, Ceko M, Bushnell MC (2011). Fibromyalgia and depression [published online November 19, 2011]. Pain Res Treat. 2012;2012:486590. doi: 10.1155/2012/486590 23
Seminowicz DA, Wideman TH, Naso L, Hatadmi-Khoroushahi Z, Fallatah S, Ware MA, Jarzem P, Bushnell MC, Shir Y, Ouellet JA and Stone LS (2011). Effective Treatment of Chronic Low Back Pain in Humans Reverses Abnormal Brain Anatomy and Function. J Neurosci 31(20): 7540-7550; doi: 10.1523/JNEUROSCI.5280-10.2011 and http://www.mcgill.ca/newsroom/channels/news/no-pain-biggain-174398 24