Pain constitutes a universally relatable yet highly subjective experience. While all people encounter pain throughout their lifetimes, the intensity, duration, location and quality of pain vary widely in accordance with an individual’s unique physiology at a given point in time. Defined by the International Association for the Study of Pain as an ‘unpleasant’ sensation ‘associated with actual or potential tissue damage,’ pain is a sensory experience and therefore necessarily involves not only physical but also emotional dimensions.64 Put simply, we feel a physical sensation of pain and we create an emotional interpretation of that pain. To that end, both the sensation and perception of pain play important roles in influencing an individual’s experience of the world, collectively impacting mood, motivation, functional capacity and perhaps to an extent, receptivity to treatment.
Though it manifests differently across conditions, pain is a common feature of autoimmunity. Rheumatoid Arthritis, for example, is well recognized for its characteristic joint pain, while Crohn’s Disease and Ulcerative Colitis commonly involve abdominal pain, Multiple Sclerosis often presents with neuropathic pain, and Sjogren’s Syndrome features diffuse pain.20,65 Nineteen of the twenty-four autoimmune conditions documented by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) indicate pain as a clinical feature, and other autoimmune conditions such as Crohn’s Disease and Celiac Disease not included in the inventory have well documented associations with pain.20
Because autoimmune diseases are by their nature chronic conditions, they are susceptible to the negative adaptations that accompany the shift from acute to chronic pain. Before diving into the chronification of pain and its implications for autoimmunity, however, let’s first review how pain is processed by the body under normal physiologic conditions.
When the body encounters a noxious input, whether from internal or external sources, a cascade of events is set in motion: information from this encounter is relayed from the affected area by the peripheral nervous system to the central and autonomic nervous systems, where it is parsed by the thalamus to various brain regions involved with pain processing – namely the amygdala, hypothalamus, periaqueductal grey, basal ganglia, and regions of the cerebral cortex.66 Now activated, the affected brain regions send out neural impulses, creating our subjective sensory experience of pain. This process is called nociception, and it is carried out by specialized receptors called nociceptors which may be activated by mechanical, thermal or chemical stimulation. The propensity for nociceptors to become active is also influenced by their surrounding environment, including inflammatory cytokines and other immune mediators, suggesting a link between the nociceptive and immune systems.66 Nociceptive information is propagated along myelinated Aδ and unmyelinated C fibers; myelination allows for faster transmission of the nociceptive signal, explaining why stubbing one’s toe results in an immediate, moderate pain (Aδ fibers), followed by a delayed, intense and slow-to-dissipate ‘second’ pain (C fibers).66 Importantly, the descending pain modulatory system, comprised of the prefrontal cortex, anterior cingulate cortex, insula, amygdala, hypothalamus, periaqueductal grey, rostral ventromedial medulla, and dorsolateral pons/tegmentum, serves as a gateway for the transmission of nociceptive input, as its modulation of nociceptive signals allows for inhibition or propagation of information between the periphery and the brain.66 Increased responsiveness to normal nociceptive input is termed sensitization; when it affects the central nervous system, it is called central sensitization, and when it affects the periphery, it is called peripheral sensitization.64 Aberrant activity of the descending modulatory system and ensuing central and peripheral sensitization are contributing factors in the transition from acute to chronic pain, defined as pain that persists beyond the normal healing period, typically designated to be three months.20,67 As chronic pain has significant implications for the autoimmune population, much of our discussion will be focused on the pathologic adaptations that occur in the chronification of pain, as well as the specific features of pain unique to autoimmunity.
The Impact of Chronic Pain
The impact of chronic pain is undeniably devastating; not only does chronic pain affect patients’ quality of life, mood, and functional capacity, but it also exerts a ripple effect that reaches family members, friends, the workplace, and society as a whole.20,21,69 Persistent pain has been estimated to impact 100 million American adults and to account for 40% of adult primary care visits.67,68 The economic burden of chronic pain, owing to medical expenses and decreased work productivity, is astounding; research funded by the Institute of Medicine Committee on Advancing Pain Research, Care, and Education estimated that chronic pain costs between $560 and $635 billion annually, surpassing costs associated with the six most costly medical diagnoses.68
Consistent with the other common features of autoimmunity we have reviewed – inflammation, HPA axis dysregulation and gut dysbiosis/intestinal permeability – pain, in particular the chronification of pain, is influenced by both endogenous and exogenous factors. The biopsychosocial model of pain holds that chronic pain cannot be purely viewed as a physiological phenomenon, but rather the manifestation of a confluence of physical, emotional, psychological and social factors.70 Accordingly, it comes as no surprise that the neuroplasticity that contributes to maladaptive nociceptive processing at the level of the central nervous system has significant implications on not only the persistence of pain but also the development of enduring mood shifts and other co-morbidities such as insomnia, immunosuppression, eating disorders, cognitive deficits, and impaired stress responses.69
Chronification of Pain
With regard to neuroplasticity, or changes in the structural and functional integrity of key regions of the brain, chronic pain has been shown to induce shifts in a number of areas involved in pain processing, pain memory, and pain behavior, as well as areas responsible for mediating reward and motivation, including the nucleus acumbens (NAc), ventral tegmental area (VTA), the prefrontal cortex (PFC), the periaquaductal gray area (PAG) and the amygdala.69,71 Such shifts are associated with impaired mood and cognition as well as poor analgesic efficacy, pointing to yet another feedback loop in which persistent pathologic inputs trigger maladaptive changes that favor their continued harmful effects and prohibit a break in the cycle. The activation of microglia, the inflammatory components of the central nervous system, has also been implicated in chronic pain, having demonstrated roles in mediating altered dopamine transmission and release of pro-inflammatory cytokines, contributing to central sensitization and its attendant chronic pain.20
Autoimmune patients who suffer from chronic pain are not exempt from these unsavory neuroadaptations, and the pain they experience may be additionally influenced by mechanisms specific to autoimmunity.
T Cells and Pain
An imbalance of helper T cell populations has long been thought to be a contributing factor in the pathogenesis of autoimmunity; while we know now that a simple imbalance between pathogenic and pro-inflammatory T cells and anti-inflammatory T cells and Tregs does not sufficiently account for the onset of autoimmunity, it is evident that there are manifold ways in which T cell function, or dysfunction, promotes autoimmunity and even pain in autoimmunity.
Infiltration of T cells into the CNS has been linked to chronic pain, having been shown to induce thermal hyperalgesia and mechanical allodynia (a pain response to non painful stimulus) in rat models of pain as well as mouse models of MS and Guillain-Barrée syndrome, an autoimmune disease that affects peripheral nerves, causing muscle weakness and pain.20 In a rat model of peripheral nerve injury, passive transfer of Th1 cytokines induced pain hypersensitivity, while passive transfer of Th2 cytokines attenuated pain hypersensitivity – another testament to the cross talk between nociceptive and immune processes.20 The pro-inflammatory Th17 subset of T cells has been shown to interact with glial cells in the spinal cord, further stimulating inflammatory responses that contribute to the onset of central sensitization and perpetuation of chronic pain.20 Th17 cells have demonstrated involvement a number of autoimmune diseases, including RA, MS, uveitis, Crohn’s, psoriatic arthritis and psoriasis and antibody therapies targeted against them have indicated beneficial effects for RA, MS, and plaque psoriasis patients. Influx of CD8+ (cytotoxic) T cells in peripheral nerves was associated with enhanced nociceptive behavior in a mouse model of spontaneous polyneuropathy, while a mouse model of chronic prostatitis demonstrated enhanced nociceptive behavior among mice subject to CD4+ and CD8+ T cells.20
Microglia and Pain
Activation of certain receptors on microglia, implicated in RA, MS, and Guillain-Barrée Syndrome, is thought to contribute to pain by increasing the excitability of nociceptive neurons, leading to central sensitization. A genetic polymorphism of the P2X7 receptor has been shown to determine susceptibility to chronic pain, while P2X7 receptor inhibitors have demonstrated the capacity to reduce pain; alterations in P2Y12 receptor activity have been linked to neuropathic pain20 – though these findings comprise only a minor insight into the relationship between genetics, microglia and pain in autoimmune conditions, they represent a potentially promising opportunity to better understand and treat pain in autoimmune conditions.
Autoantibodies and Pain
Previously we’ve touched on the well-established role of autoantibodies as mediators of autoimmune disease development; recently, however, research has elucidated a relationship between autoantibodies and autoimmune-associated pain. Autoantibodies may cause pain in multiple ways, namely by inducing inflammatory responses in which the involved inflammatory mediators excite nearby nociceptors, causing pain, or by binding to nociceptors directly, inducing nerve cell damage or changes in nerve cell function, leading to neuropathic pain.21
Furthermore, autoantibodies can modulate nociceptor expression and function in ways that render it more sensitive to both painful and non painful stimulation; that autoantibodies can exert similar effects on receptors of other cells such as keratinocytes and sympathetic nerve cells further contributes to nociceptor activation and sensitization, which may be even further augmented when they induce nociceptor damage. Chronic pain triggered by trauma, whether physical or emotional, can stimulate the activation of dormant autoantibodies, as the inflammatory cascade following trauma effectively switches them on.21 Lastly, autoantibodies can cause alterations in voltage gated ion channels that lead to neuronal excitation and ensuing pain. Aberrant activity of voltage gated potassium channel complexes (VGKCC’s) has been implicated in autoimmune pain; through their actions on neurons in the CNS, VGKCC’s are able to influence neuronal firing patterns and neurotransmitter release, leading to pain.20 Notably, these activities of autoantibodies can occur in the absence of inflammation,21,65 as was demonstrated in a mouse model of RA in which the injection of autoantibodies specific to RA induced long lasting pain behavior in mice despite not having triggered inflammatory activity.65
At present, autoantibodies have been associated with pain in the autoimmune conditions RA, Guillain-Barré Syndrome, Complex Regional Pain Syndrome (CRPS), and Morvan’s Syndrome, as well as Chronic Fatigue Syndrome.20,21,65
As we have seen, chronic pain represents a burgeoning and burdensome problem for patients and society; from a clinical perspective, identifying and treating chronic pain can be a particularly onerous challenge for a number of reasons: 1) known risk factors for chronic pain tend to be poor predictors of chronic pain in an individual, 2) differences intrinsic to animals limit the generalizability of animal model findings to the human population, 3) certain individuals can develop spontaneous chronic pain in the absence of tissue damage, creating an obstacle for taxonomy-driven diagnosis and treatment and 4) pharmacological interventions have poor efficacy, significant side effects and carry the risk of dependence and addiction.21 These insights call to attention the need for pain treatment modalities that are both based on an individual’s unique symptomatic presentation and history and have low side effect profiles. The following discussion will highlight some of the ways in which acupuncture can yield not only symptomatic relief, but also address the maladaptive mechanisms that encourage the persistence of pain and co-morbid pain behavior among sufferers of chronic pain conditions.
Acupuncture’s analgesic effects comprise a topic on which the clinical and research communities tend to part ways; while clinically, pain is very often one of if not the most frequent driver of patient visits (and pain relief, a primary reason for patient satisfaction), the research paints a somewhat murkier picture. For reasons discussed previously, namely methodological flaws owing to the inherent disconnect between Chinese medicine and the western biomedical research construct which attempts to evaluate it, acupuncture research has yielded conflicting results; whereas some research points to significant reductions in pain and equally valuable improvements in quality of life, often systematic reviews and meta-analyses are reticent to recommend acupuncture owing to limited effect sizes relative to sham control, inadequate blinding, lack of methodological uniformity across studies, and other factors. Though a substantial number of systematic reviews and meta-analyses have demonstrated the benefits of acupuncture for the treatment various chronic pain and autoimmune conditions,72,73,74,75 others have concluded that acupuncture cannot be recommended on the grounds of inconsistent methodology across the trials analyzed, owing in large part to variant sham techniques, which may include needling of non acupuncture points (‘off channel’ points), non-insertive needling of true acupuncture points, non-insertive needling of non acupuncture points, and needling of true points deemed irrelevant to the condition being treated. With all of these options serving as sham controls to true, or verum, acupuncture, it is easy to see how they might lead to confusing and conflicting results. At the heart of this issue lies an inadequate understanding of the physiological similarities and differences between verum and sham acupuncture; because sham acupuncture is not physiologically inert, it often demonstrates some measure of efficacy in benefiting the patient population being studied, which creates an obstacle to isolating and validating the effects of verum acupuncture. While a sham should be predicated on the knowledge of how sham controls are both physiologically similar to and disparate from the verum intervention, in reality acupuncture studies tend to utilize shams focused on what to mimic based on known similarities with verum acupuncture, essentially sidestepping a major potential confounding element.109 While our knowledge of acupuncture – and by extension, sham acupuncture – mechanisms has grown exponentially in recent years, the tendency towards using shams that mimic acupuncture with no regard for what should be avoided indicates a significant gap in our understanding of sham acupuncture and therefore, the ability to construct a viable one.
Though an extensive review of factors that prohibit a more comprehensive research-born understanding of acupuncture is tangential to the focus of our acupuncture analgesia discussion, because these factors influence the outcomes that inform the sometimes-puzzling evidence base, our conversation cannot be readily carried out without referencing these variables. To that end, the following section aims to focus on the most salient and well established data regarding acupuncture analgesia, while providing context to account for the heterogeneity of results both across and within various pain conditions, autoimmune or otherwise.
Acupuncture Analgesia Research: Reconciling Inconsistencies
Worth mentioning at the outset of this discussion on acupuncture analgesia is that there exists a dichotomy between research acupuncture and clinical acupuncture which may be sufficient to account for some of the differences in results observed in these two settings. While research acupuncture needling aims to elicit a strong sensation from the patient and is often administered in a short-term fashion, clinical acupuncture typically seeks to evoke a milder stimulation and a relaxation response; further, the duration of clinical acupuncture may extend beyond that seen in a research setting, guided by the principles that treatment effects are cumulative, augmented over time and successive treatments, and that a patient’s prognosis and recommended treatment duration is largely individually-based and to that end, variable.
Mechanisms of Acupuncture Analgesia
Many of the mechanisms responsible for acupuncture’s pain relieving effects have been previously described, but will be briefly reviewed here. Locally, acupuncture needling stimulates the release of vasodilatory peptides such as CGRP, causing enhanced circulation, and encephalin, which potentiates analgesic responses by inhibiting nociceptive pathways.13,14 Additionally, acupuncture-induced release of endorphin may cause an accumulation of endorphins and their receptors over a period of one to several days, leading to peripheral opioid analgesia.14 Acupuncture’s actions at the spinal-segmental level account for its modulation of the autonomic nervous system, resulting in visceral effects such as regulation of heart rate, blood pressure, and gastric motility. At this level, acupuncture’s stimulation of A-delta fibers may work to reverse the long term potentiation (LTP) characteristic of many chronic pain conditions to long term depression (LTD), effectively attenuating central sensitization. The central effects of acupuncture have been observed in fMRI studies indicating acupuncture-induced activation of a number of regions in the brain, including the PAG, hypothalamus, pituitary, prefrontal cortex, insula and amygdala, among others. Acupuncture-induced sympathetic activation stimulates the descending pain modulatory system starting in the PAG, triggering the release of endorphins, serotonin, and norepinephrine.53,14 The question of needle stimulation comes into play here, as more aggressive stimulation, typical of research acupuncture, has demonstrated a more stimulatory effect on the sympathetic nervous system, resulting in increased levels of stress hormones and activation of the descending modulatory system, whereas the milder stimulation that characterizes clinical acupuncture tends to reduce sympathetic outflow, leading to a reduction in stress hormones and subsequent anti-stress effects.14,76 Electroacupuncture is commonly used in research settings as a means of amplifying its effects and ensuring reliable quantification of the stimulation it delivers; while it is used clinically, the extent of its use varies by practitioner, and may constitute all, part or none of a given treatment. That different frequencies yield variant effects further illustrates the potential for heterogeneity of responses among both research and clinical patient populations, low frequency electroacupuncture has been shown to affect activation of wider range of brain regions involved with pain, stimulating mu and delta opioid receptors to release endorphin, enkephalin and endomorphin, while high frequency electroacupuncture has been shown to stimulate kappa opioid receptors to affect dynorphin release, activating a narrower range of brain regions.77,78
Physiological Individuality Influences Response
If the effects of acupuncture are dependent on the elements that comprise the treatment – needle depth and gauge, stimulation intensity, needle retention time, point selection, etc – then it follows that physiological differences among patients may also contribute to heterogeneity of results. It is generally accepted that an undefined subset of patients may be non responders to acupuncture therapy,14 whether owing to physiological factors, belief and expectation factors, or a combination of the two. Of particular relevance to autoimmunity, a significant physiological factor that may impact a patient’s response to acupuncture is the presence of inflammation, as a rat model of acupuncture analgesia indicated that a group of rats without inflammation included both responders and non responders to acupuncture, while all rats with inflammation were deemed responders, hinting once again at the potential for acupuncture to exert an adaptogenic effect according to an individual’s unique physiological circumstances.76 The hormone cholecystokinin (CCK), known for its role in gastrointestinal function but also implicated in neuropathic pain, may also shed some light on individual variances in analgesic response to acupuncture. Acupuncture has been shown to modulate the CCK receptor and enhance CCK mRNA expression77 with effects varying based on patients’ levels of CCK, as a study indicated that administration of CCK-8 decreased the analgesic effect of acupuncture, while administration of CCK-8 receptor antagonists augmented its pain-relieving effects.76 Another study lent further support to the implications of individual variances on acupuncture analgesia, as rats that had weak analgesic responses to acupuncture demonstrated significant increases in CCK release, while rats with strong analgesic responses had minimal CCK release in the spinal cord.76 Alterations in CCK activity have been reported in a number of gastrointestinal disorders, as well as autoimmune polyglandular syndrome type 1.79
Acupuncture has been shown to modulate serotonin (5-HT) activity and expression, highlighting a potential avenue for the treatment of both chronic pain and co-morbid mood disorders.53,76,97 Though 5-HT has the potential for both excitatory and inhibitory effects, when it binds to receptors in the spinal cord, it takes part in the descending pain modulatory system, exerting the inhibitory effects that impact both pain and mood.80 In a rat model of depression, a condition marked by reduced hippocampal release of 5-HT, acupuncture significantly increased 5-HT and mRNA expression of 5-HT relative to untreated controls,53 while another rat model of depression illustrated significant behavioral change and restoration of the ratio between 5-HT and its metabolite 5-HIAA among acupuncture-treated rats relative to controls.97
Previously, we’ve touched on some of the functional and structural alterations that transpire within certain regions of the brain in chronic pain conditions, as evidenced by fMRI studies that indicate such changes in real time. Acupuncture has entered the fMRI research arena, with findings demonstrating a capacity for activating regions of the brain involved with the affective, sensory, cognitive, and inhibitory aspects of pain processing.78,81 The recruitment of cortical and subcortical networks by acupuncture lends itself to the potential for both inhibitory and stimulatory effects on the pain modulatory system, indicating a role in the modulation of both pain sensation and pain perception; these findings have significant implications for the autoimmune chronic pain population, given the close relationship between pain and attendant maladaptive pain behavior. A study examined the effects of acupuncture on regions of the brain showing impairment owing to chronic osteoarthritis of the knee: the periaqueductal gray matter (PAG), medial frontal cortex (MFC), and bilateral hippocampus (Hpc) – areas involved with attention to pain, pain memory and avoidance learning, and emotional distress.82 Study subjects (n=44) displayed higher PAG – Hpc connectivity at the outset of the study, a pattern associated with increased attention to pain, anxiety and nociceptive memory, and lower PAG – MFC connectivity, also linked to increased attention to pain, as well as low expectation for analgesia, and higher pain avoidance.82 Acupuncture restored proper connectivity between the affected brain regions, such that PAG – Hpc connectivity was lowered and PAG – MFC connectivity was strengthened relative to sham acupuncture.82 These results led to improved pain scores as measured by the KOOS sport index, an indicator of not only pain, but also functioning in daily living, functioning in sports and recreation, and knee-related quality of life. As the PAG is considered a hub for development and solidification of pain memory, learning and behavior, these findings suggest that acupuncture may play a role in updating nociceptive memory, rectifying maladaptive pain behaviors such as pain avoidance and attention to pain. Though the measurement of acupuncture’s clinical effects was related specifically to sport and function in this study, these pain behavior results may be considered a proxy for willingness and motivation to maintain functional capacity despite chronic pain, which serve as salient implications for the chronic pain community.
Expectation and Belief
As an extension of the concept of pain perception and behavior, fMRI studies have begun to tease out the role of expectation in acupuncture analgesia. In a study in which verum and sham acupuncture groups were divided according to high and low levels of expectation for analgesia, while verum and sham high expectancy groups achieved similar levels of analgesia, the verum acupuncture group indicated a significant signal decrease in regions of the brain associated with pain processing, suggesting that expectation alone may confer some benefit to the chronic pain patient with positive expectation. Furthermore, these findings hint at the possibility that high expectancy may augment acupuncture analgesia through activation of brain areas involved with emotion and perception.83
Chronic pain serves as yet another area in which what we know is evolving and updating at a rapid pace, and yet is vastly eclipsed by what we do not yet understand. In the context of pain, the research elucidating relationships between autoantibodies and pain is a prime example of how novel and newly uncovered mechanisms are just scratching the surface of the whole picture of autoimmunity. To that end, acupuncture research has not yet investigated a potential role for acupuncture in mediating the relationship between autoantibodies in pain. Given what we know about acupuncture’s effects on inflammation, coupled with what we now know about autoantibodies provoking inflammatory responses that stimulate nociceptive activity to cause pain, the potential for acupuncture to alleviate autoantibody-mediated pain is not unfounded and represents an exciting possible avenue of exploration.