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Systems medicine, neuropathic oral diseases, and orofacial pain
14 Systems medicine, neuropathic oral diseases, and orofacial pain Edward Russell Vickers 1, 2, Rachel Shparberg 1, 3 2
1 Clinical Stem Cells Pty Ltd, Sydney, NSW, Australia University of Sydney, Department of Anaesthesia & Pain Management, Sydney, NSW, Australia 3 University of Sydney, School of Medical Sciences, Discipline of Physiology, Sydney, NSW, Australia
Abstract Neuropathic pain and disease involves multiple connected dimensions through molecular and neurological pathways. There can be a rapid vertical progression from acute injury and classical inflammation to neurogenic inflammation and progressing to the development of persistent neuropathic pain. In addition, concurrent pain states can exist in the orofacial region, for example, chronic oral mucosal inflammation from lichen planus coupled with recurrent myofascial pain from bruxism and neuropathic post herpetic neuralgia in an individual. Widespread trigeminal neurological activation from pain-initiating neuropeptides occurs in both the peripheral and central nervous systems, in turn systematically coactivating and dysregulating sympathetic nerves and thalamic and spinal trigeminal nuclei. Resulting medical complaints of motor incoordination, dysfunctional thermoregulation, disturbed sleep pattern, and poor memory are observed. Moreover, the psychosocial dimension of severe pain can show rapid deterioration of the patient involving anxiety, depression, despair, and suicide. This form of pain is prevalent in society (6%e10%) and particularly targets the trigeminal nerve in the form of persistent postendodontic pain. Pain is an invisible phenomenon and, consequently, misdiagnosis and inappropriate treatments are frequently seen. Treatments are based on the knowledge of the systems medical approach at molecular, cellular, and clinical levels. Pharmacotherapeutic interventions, psychological treatments, and evolving cellbased therapies of stem cells and pain inhibitory peptides show great promise in effectively treating persistent orofacial disease and pain.
Translational Systems Medicine and Oral Disease. https://doi.org/10.1016/B978-0-12-813762-8.00014-1 Copyright © 2020 Elsevier Inc. All rights reserved.
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Introduction Pain is a complex physiological and neurobiological phenomenon with an emotional experience that is unique to the individual. Under normal circumstances, pain is an evolutionary response that acts to remove the body from noxious and/or tissue harming environments. As such, humans have developed incredibly complex physiological mechanisms and neuronal circuitry to signal and respond to danger (“flight, fight, or freeze”) and to heal damage accordingly. The oral cavity and face is an area of multiple sensory information acquisition required for survival. Sensation and pain from the orofacial region is enervated by the trigeminal nerve and has a high priority as demonstrated by its dominant territory in the map of the homunculus. Orofacial pain encompasses pain of odontogenic origin and may occur in periodontal tissues, oral mucosa, and other regional structures of the head that are mainly enervated by the sensory divisions of the trigeminal nerve. Dental caries and periodontal disease are the most prevalent diseases in humans. In other circumstances, the psychological state of the individual can initiate bruxism and regional myofascial pain, which, in turn, may also provoke odontogenic pain by tooth cracks and pulpal inflammation. However, when the sensation of pain goes beyond a “normal” physiological response and becomes persistent with no detectable source of nociception, a neuropathic disease state has been reached.1 Understanding how one part of the pain cascade triggers other parts in a systems-based approach is necessary for successful patient outcomes. A convenient but disputed definition of chronic pain is applied when it has been present for more than 3 months.2 Epidemiological research requires subjects to have this duration of pain yet molecular changes of chronic neuropathy disease can be observed rapidly after tissue damage such as complex regional pain syndrome type 2 and measured through altered inflammatory cytokines, i.e., an acute inflammatory to chronic inflammatory response. Persistent orofacial pain can be broadly classified into chronic inflammatory nociceptive pain, neuropathic pain (NP), or mixed pain states where both are concurrent.3 This makes pain a difficult entity to define, measure, and treat effectively and predictably. For the purposes of this chapter, the authors will focus on the dimensions occurring using the systems approach to these pain states. From a timeline phase perspective ongoing classical inflammation can lead to neurogenic inflammation and reach the disease state of NP. The changes in inflammation can occur within hours of the inciting trauma. Particular areas of chronic pain that will be discussed are the molecular changes, neuroscience aspects, and psychosocial dimensions of systems pain medicine.
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Neurobiology of inflammatory pain phases The perception of acute pain, known as nociception, is detected by peripherally located nociceptors and is perceived and acted on by the peripheral and central nervous systems (PNS, CNS). Unlike somatosensory receptors, nociceptors are free nerve endings that detect noxious stimuli and have the potential to damage and/or injure tissue. Three main classes of nociceptors exist: thermal (to detect extreme temperatures that are <5 C and >45 C), mechanical (to detect intense pressure), and polymodal (to detect mechanical, thermal, and chemical stimuli) (Table 14.1).4 At their terminal nerve endings, small diameter sensory neurons express several types of voltagegated sodium channels (Nav), responsible for depolarization on stimulus detection. Nav1.7, Nav1.8, and Nav1.9 are expressed on A-delta and C fibers associated with mechanical and intense pressure pains, whereas transient receptor potential (TRP) ion channels such as TRPV1 and TRPA1 are involved in the depolarization of fibers that transmit signals from temperature stimuli. Pain sensation due to tissue damage is also often accompanied by redness, swelling, and an increase in temperature at the site of injury. Together, these are referred to as the cardinal signs of inflammation and constitute the body’s immune response. Damaged cells secrete multiple cytokines in a paracrine manner initiating the recruitment of leukocytes to the area, that when activated release a cocktail of cytokines, neuropeptides, and painmediators including bradykinin, serotonin, nerve growth factor, interleukin (IL) 1-b, IL-6, IL-5, prostaglandin-E2 (PGE2), and tumor necrosis factor-alpha
Table 14.1 Nociception and somatosensory receptors. Receptor Nociceptor
Somatosensory
Stimulus
Sensory fiber
Myelinated
Diameter size
Speed of conduction
Thermal
Extreme temperatures (<5 C or >45 C)
A-d
Thin
Small
5e30 m/s
Mechanical
Intense pressure
A-d
Thin
Small
5e30 m/s
Polymodal
Extreme temperatures Intense pressures Chemicals
C
Unmyelinated
Small
1 m/s
Proprioception Stretch Mechanical
A-a
Myelinated
Large
70e120 m/s
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(TNF-a). These mediators play a critical role in peripheral sensitization, whereby a neuron experiences decreased thresholds for depolarization, often leading to allodynia (painful sensation from a normally nonpainful stimulus) and hyperalgesia (increased sensitivity to pain).2 Afferent neurons have also been shown to release excitatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) that, with other inflammatory cytokines, recruit immune cells to the area to initiate the immune response. SP is a parent 11 amino acid neuropeptide encoded by the Tac1 gene and is expressed in a variety of cell types including neural, glial, epithelial, and endothelial cells, some cells of the immune system5 and is extensively investigated by endodontic researchers. SP is synthesized by small diameter afferent neurons which synapse in laminae I and II of the spinal cord, i.e., pain transmitting neurons as well as within the trigeminal nerve. SP is peripherally released at the site of damage, as well as centrally into the cerebrospinal fluid where it is able to bind to NK1 receptors on afferent nerve fibers and induce a variety of responses involved in neurogenic inflammation including peripheral vasodilation, increased vascular permeability, mast cell activation, and cytokine production.6 NK1 receptors have also been shown to be located in brain regions associated with emotional responses to pain including the hippocampus, amygdala, hypothalamus, and the periaqueductal gray zone. CGRP is an important mediator of pain sensation and is colocalized with SP in the trigeminal nerve but with different anatomical population densities where SP is higher in the dental pulp. Following depolarization, CGRP is released from vesicles via exocytosis in sensory neurons where it has been shown to both directly activate nociceptors and increase their firing rate, resulting in peripheral sensitization. This is accompanied by a decrease in the thresholds for depolarization of the affected fibers leading to hyperalgesia. Changes in the ion channel expression and thus neuronal hyperexcitability can often occur. Increased expression of CGRP and SP from sensory neurons stimulates adjacent fibers and perpetuates the neurogenic inflammatory response.7 Mast cells in particular have been shown to be directly involved in the neurogenic inflammatory response and release histamine on activation. Histamine is a key algogen (pain-producing agent) responsible for the activation of C and A-d fibers and the histamine receptor H3 colocalizes with the CRGP receptor on A-d fibers. During a normal healing phase, the neuropeptides undergo enzymic degradation and are metabolized. Interestingly, the parent SP is degraded to SP(1e7) that has analgesic properties to NP.8
Chronic inflammatory orofacial pain Several orofacial diagnostic conditions manifest a progressive inflammatory disease state and include autoimmune conditions such as oral lichen planus
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(OLP) and arthritic destruction of the temporomandibular joints (TMJs). Autoimmune disease is prevalent in the oral cavity with conditions such as OLP occurring in 1.7% of the population with associated symptomatic pain in two-thirds of afflicted patients.9 This is a further example of the complexity of systems medicine where patients with OLP may progress to oral cancer,10 although the incidence of malignant transformation is low at 2.45% over 6.8 years (average 0.36% per year).11 Molecular changes in malignancy then, over time and with the spread of the disease, involve structural tissue problems and the major psychological impact of the cancer diagnosis and treatment. In contrast to NP with neurogenic inflammation, OLP is characterized by persistent classical tissue inflammation. Nevertheless, the vertical involvement of the psychosocial dimension of the patient’s personal “system of response” is shown with a decline in social activity due to pain on eating, metabolic imbalance from reduced nutritional intake, and typically an overuse of topical steroids leading to local and systemic complications. A similar situation is identified in advanced cases of TMJ problems where persistent pain leads to psychosocial problems involved in restricted eating, talking, and inappropriate use of analgesics.
Neuropathic pain NP is defined by the International Association for the Study of Pain as “Pain caused by a lesion or disease of the somatosensory nervous system.”2 While NP has distinguishable pain qualities and features, its anatomical characteristics reveal its targeted distribution to bodily regions rich in sensory nerve density such as the trigeminal region. NP is prevalent in the human population with various studies showing a rate from 6.9% to 10%.12 It exists in animals, and laboratory research uses well-validated animal models,13 particularly the rat model of trigeminal and tail NP.14 NP medical diagnostic states include postherpetic neuralgia (PHN), phantom limb pain, post thoracotomy pain, complex regional pain syndromes, and central pain states such as thalamic and ictal (poststroke) pain, and spinal cord injury pain. Trigeminal NP states include first division trigeminal PHN, burning tongue/ mouth syndrome, and numerous competing terms in taxonomies such as phantom tooth pain, persistent idiopathic facial pain, neurovascular odontalgia, persistent dento-alveolar pain disorder, neuropathic trigeminal pain, and neuropathic orofacial pain.14e16 Emerging evidence indicates that endodontic treatment is a major contributor to the prevalence of this form of trigeminal pain and is reported in the literature in 12% of patients after treatment.17 The underlying mechanism, in part, is thought to be nociceptor presensitization from bacterial toxins combined with repetitive mechanical microtrauma and exposure to chemical irrigating solutions.
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More recently, other potential trigeminal neuropathic nondental conditions are being recognized including “empty nose syndrome” characterized by altered sensory phenomena after maxillary turbinectomy18 and dry painful eyes following corrective refractive (LASIK) surgery.19,20 The prevalence of these first and second trigeminal division conditions are alarming from a chronic pain perspective, particularly dry eye disease after refractive surgery with an estimated prevalence rate of 62%.21 Improvements in the diagnostic testing, validation, and treatment of dental NTP would help other medical specialists in the early diagnosis and therapy of persistent pain after surgical otolaryngology and ophthalmology.
Molecular basis of neuropathy in systems medicine Genetic and epigenetic research are a crucial element to connecting the neural, vascular, and endocrine systems of pain modeling.22 Pain genetics is an emerging field for identifying these components of persistent orofacial pain.23 Genetic testing has advanced considerably over the last decade with commercial companies providing rapid screening for neuropathy genes, for example, 83 gene neuropathy assays (Invitae Corp. San Francisco, USA) that can be tested within several days. Epigenetic profiling of NP is still in the developmental phase due to cost and the enormous range of candidate compounds that are involved. For example, excitatory and inhibitory neuropeptides and neurotransmitters are intensively investigated for their respective roles in pain intensity, and the territorial expansion and temporal/ circadian effects of pain. Moreover, the influence of anti-NP medication pharmacodynamics and pharmacokinetics on ligands and receptors constitute an enormous number of variables on maladaptive pain neuroplasticity. Multipanel ELISA/magnetic bead assays are becoming more accessible to establish real-time measurements for epigenetic analysis of NP. This will complement the system-based medical approach to molecular diagnoses and individualized treatments particularly identifying imbalances in pain excitatory and inhibitory neuropeptides (Table 14.2).
Neuroscience of neuropathic pain Trigeminal nerve anatomy The trigeminal nerve (cranial nerve V, CNV) is the primary nerve responsible for the sensory and motor functions of the face and head and has three major divisions: V1, V2, and V3. V1 is the ophthalmic division and is responsible for enervating the superior-most structures of the face and head including the orbit, nose, forehead, and scalp. V2 is the maxillary division and is responsible
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Table 14.2 Major excitatory and inhibitory neuropeptides involved in neuropathic pain in the peripheral and central nervous system (PNS, CNS). Neuropeptide/compound
Receptor location CNS/PNS
Key pharmacological action (excitatory/inhibitory on pain)
Substance P
CNS, PNS, dental pulp
Neuropathic pain þþþ
Calcitonin gene-related peptide
CNS, PNS, dental pulp, CNV first division
Headache þþþ
Vasoactive intestinal peptide
CNS, PNS
Pain inhibition in the somatosensory cortex
Bradykinin
Blood circulation
Inflammatory pain þþþ
Oxytocin
CNS, PNS
Potential antimigraine therapy
Neuropeptide Y
CNS, PNS, macrophages
Potentially prevents posttraumatic stress disorder
Neurokinin-1
CNS, body tissues
Promotes hyperalgesia, pain
Met-enkephalin
CNS, PNS
Opioid peptide, reduces pain
Beta-endorphin
CNS, PNS
Opioid peptide, reduces pain
Endomorphins-1,-2
CNS, PNS
Opioid peptides, reduces pain
for the sensation of the maxillary teeth and bone, oral mucosa and palate, and maxillary sinuses and midface tissues. V3 is the mandibular division and enervates mandibular teeth, mandible, tongue, and floor of the mouth. CNV is a mixed population nerve consisting of both sensory and motor neurons. At the level of the sensory input, there are three major nuclei, the spinal trigeminal nucleus (STN), the principal sensory trigeminal nucleus (PSTN), and the mesencephalic trigeminal nucleus (MTN). The STN is located in the medulla and is responsible for touch, pain, and temperature sensations of the face, head and neck, and oral cavity. The PSTN is located in the mid-pons and receives information regarding light cutaneous sensations of the face, as well as proprioception of the jaw. These two nuclei together are known as trigeminal sensory nuclear complex. The MTN is primarily responsible for receiving proprioceptive information about the periodontium and jaw muscles and its role is to sense and assess masticatory forces of biting and chewing. The motor nucleus of the trigeminal nerve is located medial to the PSTN and enervates the muscles involved in mastication such as the masseter, temporalis, medial, and lateral pterygoids, and other muscles of
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tensor tympani (contracts to dampen the sound of chewing), tensor veli palatini (tenses the palate), mylohyoid (floor of the oral cavity), and digastric muscles (involved in movement of the jaw when speaking, chewing, and swallowing).
Normal CNS pain modulation The thalamus has critical significance for integrating motor and sensory information from the body and head regions and relays this information to brain centers for higher order processing. On stimulation, peripheral nociceptors send information to the CNS via first-order neurons (A-d and C fibers) that synapse in the dorsal ganglion of the spinal cord (laminae I and II) or in the case of the head and oral cavity via CNV. Sensory fibers from body sites synapse onto second-order neurons which cross the midline via laminae IVeVI (collectively known as the nucleus proprius), before ascending toward the brain via the spinothalamic tract. These projections from the body are sent to a region of the thalamus known as the ventral posterior lateral nuclei (VPLN), whereas the ventral posterior medial nuclei receive input from the head and neck region via the trigeminal nerve. Thalamocortical, third-order neurons, then project to various regions of the cortex for higher order processing. Both the primary and the secondary somatosensory cortices receive input from the thalamus. The primary somatosensory cortex processes intensity information received from the VPLN and is involved in the sensory discriminative component of pain. The secondary somatosensory cortex, along with the cingulate cortex, is involved in the recognition, learning, and memory of pain. The ventral anterior cingulate cortex has direct projections to the amygdala (associated with emotional learning and fear), as well as the hippocampus (associated with memory), hypothalamus (associated with activation of the sympathetic and autonomic nervous system), and the nucleus accumbens (associated with pain recognition). The thalamus also projects to the insula cortex of which the posterior cortex is involved in auditory, visual, and somatosensory perception, whereas the anterior cortex is involved in olfactory, gustatory, and visceral autonomic perception, providing the contextual information about pain. Together these brain regions, which collectively form part of the limbic system, produce physiological pain sensation, contextual information, and the emotional responses to pain (Fig. 14.1).24
Trigeminal neuropathic pain induces CNS degeneration Recent evidence has shown that trigeminal neuropathic pain (TNP) originating from the PNS in humans has dramatic negative effects on the thalamus.25 Consistent fMRI study results show a decrease in thalamic volume from markers of glial inflammation from TNP but not patients with trigeminal neuralgia or temporomandibular disorder diagnoses.26 Specifically, TNP
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Figure 14.1 Role of the thalamus in normal nociceptive processing and its systems dysfunction in neuropathic pain. The thalamus receives information from the body to the ventral posterior lateral nuclei (VPL), and from the head to the ventral posterior medial nuclei (VPM). Thalamic neuronal inflammation from high intensity trigeminal neuropathic pain causes widespread disruption to multiple parts of the brain involved in memory, sleep, coordination, visual and auditory information, mental health dimensions, and pain memory.
showed significant decreases in various parts of the CNS including the thalamus, primary somatosensory cortex, anterior insula, putamen, and nucleus accumbens.27e29 Further research is needed to identity if the CNS degenerative effects from peripheral origin TNP is similar to CNS neuropathies such as stroke to the spinothalamic tract or thalamic ventroposterior nucleus. From a clinical systems approach, there are potential thalamic consequences of muscle incoordination, dysfunctional changes in other cranial nerve functioning (auditory and visual, but not olfactory nerve), sleep, memory, spatial memory (clumsiness), and, as previously mentioned, the somatic, visceral, and gustatory systems. Moreover, TNP is often characterized on pain maps by a spreading phenomenon as revealed from the original CNV site that extends over time to other sites of the body and demonstrates marked maladaptive neuroplasticity (Fig. 14.2).30
Psychosocial dimensions of neuropathic pain NP has a disturbing medical and dental past. It was only a generation back that health clinicians generally showed a complete lack of medical knowledge of NP that resulted in the dismissal and contempt of afflicted patients.
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Mark all areas where you experience pain (write left or right side of the body as necessary) R ×
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PAIN MEDICATION
Figure 14.2 Pain map of a 28-year-old female with undiagnosed neuropathic trigeminal pain of 2 years duration. The original site of pain was a left maxillary premolar tooth that began after endodontic treatment. The undiagnosed and untreated condition reveals a marked increase in the pain territory to encompass the whole body.
Sherman et al.31 reported that among the majority of US veterans with NP 2% were told nothing could be done, 5% were told it would go away (regardless of number of years since onset), 24% found their questions avoided, and the remainder were told it was imaginary and were considered “insane” if they felt pain from the amputated limb. Furthermore, of the range of treatments that were performed only 1% of the veterans reported pain relief from treatment. A similar scenario of dental injustice occurred with the term “persistent idiopathic facial pain” that was a popular but wastebasket diagnostic condition in the 1980e1990s.32 Persistent idiopathic facial pain had an emphasis on psychogenic causes to the pain. Pain, being an invisible symptom, can trigger high levels of anxiety, depression, and stress leading to an antagonistic dentist who could find no odontogenic pathology on visual examination or radiographs. Consequently, the dentist without taking a detailed pain history dismissed the genuine complaints of the patient and routinely amputated sound teeth in an attempt to remove the pain. Moreover, the accepted term among dentists of persistent idiopathic facial pain implies there were common conditions called “typical facial pain,” and medical entities of “typical and atypical headaches” and “typical and atypical
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backache”dthese do not exist. Clearly, a lack of understanding and patient empathy has resulted in unnecessary and prolonged pain and suffering, and multiple endodontic treated and extracted teeth. The systems approach of NTP is crucial to apply for successful diagnosis and treatment (Fig. 14.3). NP is a complex multidimensional disease involving alterations of molecular and cellular functioning causing integrative but maladaptive mechanisms in the mind and body. There are horizontal and vertical systems associated with NTP. The vertical system comprises of the biopsychosocial construct of pain where persistent inflammation of the biological system, i.e., neuroinflammation of the PNS and then CNS, produces throbbing, burning, aching, and sharp pain qualities. This activates cortical awareness and the psychological construct of emotional pain (“the pain is punishing and cruel, it is hurting me”) that in turn triggers the social upheaval of pain (“the pain is bad, I cannot go to work today”). For each vertical dimension, there is a corresponding lateral involvement. The biological dimension of NP initiates sympathetic nervous system changes of swelling, redness, and increased pain from catecholamine release. In addition, there are first-order neuron reflex connections to the regional muscles causing muscle spasm and secondary myofascial temporomandibular pain. Further changes occur in the CNS, particularly thalamic dysregulation with other cranial nerve dysfunction and corresponding hypothalamic issues that will impact on the patient. The psychological dimension can show rapid and dramatic changes with the emergence of comorbidities of anxiety, stress, and depression. The social dimension involves further lateral spread of social upheaval leading to inappropriate use of analgesic medication,
SYSTEMS DETERIORATION
SYSTEMS REHABILITATION Identify molecular diagnosis Use genetic & epigenetic tests Early treatment with analgesic peptides & stem cell therapy
Maladaptive PNS changes Maladaptive CNS changes Thalamic degeneration • Unknowledgeable doctor & wrong medication, side effects • Unknowledgeable specialist & more unnecessary surgery • No further referral • “you are imagining the pain”
Depression, anxiety, stress Loss of employment & family issues Frustration & anger Hopelessness & despair Suicide
Nociception & tissue injury
Identify clinical diagnosis • Knowledgeable doctor • Knowledgeable specialist • Pain clinic team • Treat with appropriate medication & allied health
Identify psychosocial diagnosis Psychologist & Psychiatrist Treat with medication, relaxation, cognitive behavioral therapy, meditation, mindfulness
Figure 14.3 Systems medicine approach to pain shows an integrative multilevel deterioration or rehabilitation following tissue injury and nociception.
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addiction, anger, and frustration toward the treating doctor/dentist, inability to work, family upheaval, hopelessness and despair, and unfortunately terminal aspects involving suicide to end his/her pain (Tables 14.3 and 14.4). Taken together, the multidisciplinary systems-based assessment to an integrative diagnosis is crucial for multilevel diagnosis.
Conclusion and future directions The systems-based approach is applicable to health personnel engaged in the diagnosis and treatment of NTP. A single dental practitioner does not have the knowledge or training to effectively treat a patient with NTP. A team approach is needed and should include a dentist (or dental specialist), medical practitioners (family doctor, pain specialist, psychiatrist), psychologist and
Table 14.3 Peripheral and central nervous system (PNS, CNS) cascade of the changes occurring from persistent trigeminal neuropathy. PNS changes of increased Naþ ion channels on neuron (inadequate analgesia from standard local anesthetic) and Mg2þ plus loss of Ca2þ channels, i.e., entire peripheral branch of the trigeminal nerve division can become sensitized through substance P expression.
This produces CNS changes of NMDA (pain receptor) upregulation, but GABA receptor downregulation (pain reduction).
Trigeminal brain and brain stem connections and spinal cord projections leads to activation of interneurons back to the further PNS changes to sympathetic nervous system (termed secondary sympathetically maintained pain) and reflexes to regional muscles (tertiary myofascial pain, i.e., muscle-related pain in temporomandibular disorder).
Maladaptive neuroplasticity: spontaneous neuronal discharge, recruitment of silent nociceptors, further increased PNS and CNS changes of sensitization, CNS centralization, cold hyperalgesia, mechanical allodynia, nerve deficit of pins and needles, and numbness, expansion of receptive fields and neuronal sprouting via nerve growth factor.
CNS degeneration of the thalamus and consequent systems deterioration involving brain, cranial nerves, sleep, muscle coordination, and memory.
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Table 14.4 Narratives of pain.
The pain I have is inhumane (28-yr-old female)
I will kill myself (80-yr-old grandmother)
I will kill myself (38-yr old mother with 2 young children)
The pain reminds me of when I was tortured and mutilated by a Chilean death squad
I rigged up a pulley and electric drill and tried to extract my teeth at midnight (professional soldier)
comment from a dental postgraduate student: Thank you Dr. Vickers for allowing me to sit in with the morning pain patients, I noted that three of the six patients this morning wanted to commit suicide.
allied health, and the clinical scientist for stem cell therapy. The systems-based approach to diagnosis is crucial and the corresponding systems approach for treatment is equally imperative to achieve a positive and meaningful outcome of reduced pain, less suffering, anxiety, and depression, and a return to normal behavior, family engagement, and work. Treatments for the biological dimension use medications such as oral systemic anticonvulsants and antidepressants (typically gabapentin, pregabalin, amitriptyline),33 judicious use of topical local anesthetics34 and benzodiazepines (clonazepam), natural compounds such as the oral systemic endocannabinoid called palmitoylethanolamide35 and topical natural antineuropathics (capsaicin, gingerol),36 and preliminary evidence of autologous stem cell therapy for NTP.37 Other psychological techniques include cognitive behavioral therapy, meditation, mindfulness, and stress reduction strategies. The consequence of thalamic dysregulation and degeneration attributed to TNP is an alarming finding considering the prevalence of this oral disease from routine dental procedures such as endodontic treatment. A greater awareness of this neuropathology is needed through professional education. A systems-based approach to diagnosis and treatment is necessary to reduce pain in all of its dimensions and to acknowledge a founding principle of the World Health Organization that “pain relief is a basic human right.”38
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21. Son DY, Hwang S, Hyun J, Lim DH, Chung ES, Chung TY. Prevalence and risk factors of dry eye disease after refractive surgery. J Korean Ophthalmol Soc. July 1, 2017;58(7):782e787. 22. Sexton JE, Cox JJ, Zhao J, Wood JN. The genetics of pain: implications for therapeutics. Annu Rev Pharmacol Toxicol. 2018;(0). 23. Seltzer ZE, Diehl SR. Genetic biomarkers of orofacial pain disorders. In: Orofacial Pain Biomarkers. Berlin, Heidelberg: Springer; 2017:107e118. 24. Yen C-T, Lu P-L. Thalamus and pain. Acta Anaesthesiol Taiwanica. June 2013;51(2):73e80. https://doi.org/10.1016/j.aat.2013.06.011. 25. Alshelh E, Di Pietro F, Youssef A, et al. Chronic neuropathic pain: it’s about the rhythm. J Neurosci. January 20 , 2016;36(3):1008e1018. https://doi.org/10.1523/JNEUROSCI.276815.2016. 26. Youssef AM, Gustin SM, Nash PG, et al. Differential brain activity in subjects with painful trigeminal neuropathy and painful temporomandibular disorder. PAINÒ. March 1, 2014;155(3):467e475. 27. Mills EP, Di Pietro F, Alshelh Z, et al. Brainstem pain control circuitry connectivity in chronic neuropathic pain. J Neurosci. November 2017;24, 1647-17 https://doi.org/10. 1523/JNEUROSCI.1647-17.2017. 28. Di Pietro F, Macey P, Rae C, et al. The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain. Hum Brain Mapp. 2018;39(5):1945e1956. 29. Alshelh Z, Di Pietro F, Mills EP, et al. Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain. Neuroimage: Clin. January 1, 2018;19:167e173. 30. Vickers ER. The molecular and clinical progression of pain. In: Orofacial Pain: Problem Based Learning. Sydney University Press; 2005. 31. Sherman RA, Sherman CJ, Parker L. Chronic phantom and stump pain among American veterans: results of a survey. Pain. January 1984;18(1):83e95. https://doi.org/10.1016/ 0304-3959(84)90128-3. 32. Vickers ER, Cousins M. Management of chronic oro-facial pain. Aust Fam Physician. 1994;20:2315e2321. 33. Dworkin RH, O’connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. March 1, 2010;85(3):S3eS14. Elsevier. 34. Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev. January 1, 2014:7. 35. Skaper SD, Facci L, Fusco M, et al. Palmitoylethanolamide, a naturally occurring diseasemodifying agent in neuropathic pain. Inflammopharmacology. April 1, 2014;22(2):79e94. 36. Vickers ER, Cousins MJ, Walker S, Chisholm K. Analysis of 50 patients with atypical odontalgia: a preliminary report on pharmacological procedures for diagnosis and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. January 1, 1998;85(1):24e32. 37. Vickers ER, Karsten E, Flood J, Lilischkis R. A preliminary report on stem cell therapy for neuropathic pain in humans. J Pain Res. 2014;7:255e263. 38. Cousins M, Lynch M. The Declaration Montreal: access to pain management is a fundamental human right. Pain. 2011;152(2):2673e2674. https://doi.org/10.1016/j.pain. 2011.09.012.
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1 Clinical Stem Cells Pty Ltd, Sydney, NSW, Australia University of Sydney, Department of Anaesthesia & Pain Management, Sydney, NSW, Australia 3 University of Sydney, School of Medical Sciences, Discipline of Physiology, Sydney, NSW, Australia
Abstract Neuropathic pain and disease involves multiple connected dimensions through molecular and neurological pathways. There can be a rapid vertical progression from acute injury and classical inflammation to neurogenic inflammation and progressing to the development of persistent neuropathic pain. In addition, concurrent pain states can exist in the orofacial region, for example, chronic oral mucosal inflammation from lichen planus coupled with recurrent myofascial pain from bruxism and neuropathic post herpetic neuralgia in an individual. Widespread trigeminal neurological activation from pain-initiating neuropeptides occurs in both the peripheral and central nervous systems, in turn systematically coactivating and dysregulating sympathetic nerves and thalamic and spinal trigeminal nuclei. Resulting medical complaints of motor incoordination, dysfunctional thermoregulation, disturbed sleep pattern, and poor memory are observed. Moreover, the psychosocial dimension of severe pain can show rapid deterioration of the patient involving anxiety, depression, despair, and suicide. This form of pain is prevalent in society (6%e10%) and particularly targets the trigeminal nerve in the form of persistent postendodontic pain. Pain is an invisible phenomenon and, consequently, misdiagnosis and inappropriate treatments are frequently seen. Treatments are based on the knowledge of the systems medical approach at molecular, cellular, and clinical levels. Pharmacotherapeutic interventions, psychological treatments, and evolving cellbased therapies of stem cells and pain inhibitory peptides show great promise in effectively treating persistent orofacial disease and pain.
Translational Systems Medicine and Oral Disease. https://doi.org/10.1016/B978-0-12-813762-8.00014-1 Copyright © 2020 Elsevier Inc. All rights reserved.
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Introduction Pain is a complex physiological and neurobiological phenomenon with an emotional experience that is unique to the individual. Under normal circumstances, pain is an evolutionary response that acts to remove the body from noxious and/or tissue harming environments. As such, humans have developed incredibly complex physiological mechanisms and neuronal circuitry to signal and respond to danger (“flight, fight, or freeze”) and to heal damage accordingly. The oral cavity and face is an area of multiple sensory information acquisition required for survival. Sensation and pain from the orofacial region is enervated by the trigeminal nerve and has a high priority as demonstrated by its dominant territory in the map of the homunculus. Orofacial pain encompasses pain of odontogenic origin and may occur in periodontal tissues, oral mucosa, and other regional structures of the head that are mainly enervated by the sensory divisions of the trigeminal nerve. Dental caries and periodontal disease are the most prevalent diseases in humans. In other circumstances, the psychological state of the individual can initiate bruxism and regional myofascial pain, which, in turn, may also provoke odontogenic pain by tooth cracks and pulpal inflammation. However, when the sensation of pain goes beyond a “normal” physiological response and becomes persistent with no detectable source of nociception, a neuropathic disease state has been reached.1 Understanding how one part of the pain cascade triggers other parts in a systems-based approach is necessary for successful patient outcomes. A convenient but disputed definition of chronic pain is applied when it has been present for more than 3 months.2 Epidemiological research requires subjects to have this duration of pain yet molecular changes of chronic neuropathy disease can be observed rapidly after tissue damage such as complex regional pain syndrome type 2 and measured through altered inflammatory cytokines, i.e., an acute inflammatory to chronic inflammatory response. Persistent orofacial pain can be broadly classified into chronic inflammatory nociceptive pain, neuropathic pain (NP), or mixed pain states where both are concurrent.3 This makes pain a difficult entity to define, measure, and treat effectively and predictably. For the purposes of this chapter, the authors will focus on the dimensions occurring using the systems approach to these pain states. From a timeline phase perspective ongoing classical inflammation can lead to neurogenic inflammation and reach the disease state of NP. The changes in inflammation can occur within hours of the inciting trauma. Particular areas of chronic pain that will be discussed are the molecular changes, neuroscience aspects, and psychosocial dimensions of systems pain medicine.
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Neurobiology of inflammatory pain phases The perception of acute pain, known as nociception, is detected by peripherally located nociceptors and is perceived and acted on by the peripheral and central nervous systems (PNS, CNS). Unlike somatosensory receptors, nociceptors are free nerve endings that detect noxious stimuli and have the potential to damage and/or injure tissue. Three main classes of nociceptors exist: thermal (to detect extreme temperatures that are <5 C and >45 C), mechanical (to detect intense pressure), and polymodal (to detect mechanical, thermal, and chemical stimuli) (Table 14.1).4 At their terminal nerve endings, small diameter sensory neurons express several types of voltagegated sodium channels (Nav), responsible for depolarization on stimulus detection. Nav1.7, Nav1.8, and Nav1.9 are expressed on A-delta and C fibers associated with mechanical and intense pressure pains, whereas transient receptor potential (TRP) ion channels such as TRPV1 and TRPA1 are involved in the depolarization of fibers that transmit signals from temperature stimuli. Pain sensation due to tissue damage is also often accompanied by redness, swelling, and an increase in temperature at the site of injury. Together, these are referred to as the cardinal signs of inflammation and constitute the body’s immune response. Damaged cells secrete multiple cytokines in a paracrine manner initiating the recruitment of leukocytes to the area, that when activated release a cocktail of cytokines, neuropeptides, and painmediators including bradykinin, serotonin, nerve growth factor, interleukin (IL) 1-b, IL-6, IL-5, prostaglandin-E2 (PGE2), and tumor necrosis factor-alpha
Table 14.1 Nociception and somatosensory receptors. Receptor Nociceptor
Somatosensory
Stimulus
Sensory fiber
Myelinated
Diameter size
Speed of conduction
Thermal
Extreme temperatures (<5 C or >45 C)
A-d
Thin
Small
5e30 m/s
Mechanical
Intense pressure
A-d
Thin
Small
5e30 m/s
Polymodal
Extreme temperatures Intense pressures Chemicals
C
Unmyelinated
Small
1 m/s
Proprioception Stretch Mechanical
A-a
Myelinated
Large
70e120 m/s
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(TNF-a). These mediators play a critical role in peripheral sensitization, whereby a neuron experiences decreased thresholds for depolarization, often leading to allodynia (painful sensation from a normally nonpainful stimulus) and hyperalgesia (increased sensitivity to pain).2 Afferent neurons have also been shown to release excitatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) that, with other inflammatory cytokines, recruit immune cells to the area to initiate the immune response. SP is a parent 11 amino acid neuropeptide encoded by the Tac1 gene and is expressed in a variety of cell types including neural, glial, epithelial, and endothelial cells, some cells of the immune system5 and is extensively investigated by endodontic researchers. SP is synthesized by small diameter afferent neurons which synapse in laminae I and II of the spinal cord, i.e., pain transmitting neurons as well as within the trigeminal nerve. SP is peripherally released at the site of damage, as well as centrally into the cerebrospinal fluid where it is able to bind to NK1 receptors on afferent nerve fibers and induce a variety of responses involved in neurogenic inflammation including peripheral vasodilation, increased vascular permeability, mast cell activation, and cytokine production.6 NK1 receptors have also been shown to be located in brain regions associated with emotional responses to pain including the hippocampus, amygdala, hypothalamus, and the periaqueductal gray zone. CGRP is an important mediator of pain sensation and is colocalized with SP in the trigeminal nerve but with different anatomical population densities where SP is higher in the dental pulp. Following depolarization, CGRP is released from vesicles via exocytosis in sensory neurons where it has been shown to both directly activate nociceptors and increase their firing rate, resulting in peripheral sensitization. This is accompanied by a decrease in the thresholds for depolarization of the affected fibers leading to hyperalgesia. Changes in the ion channel expression and thus neuronal hyperexcitability can often occur. Increased expression of CGRP and SP from sensory neurons stimulates adjacent fibers and perpetuates the neurogenic inflammatory response.7 Mast cells in particular have been shown to be directly involved in the neurogenic inflammatory response and release histamine on activation. Histamine is a key algogen (pain-producing agent) responsible for the activation of C and A-d fibers and the histamine receptor H3 colocalizes with the CRGP receptor on A-d fibers. During a normal healing phase, the neuropeptides undergo enzymic degradation and are metabolized. Interestingly, the parent SP is degraded to SP(1e7) that has analgesic properties to NP.8
Chronic inflammatory orofacial pain Several orofacial diagnostic conditions manifest a progressive inflammatory disease state and include autoimmune conditions such as oral lichen planus
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(OLP) and arthritic destruction of the temporomandibular joints (TMJs). Autoimmune disease is prevalent in the oral cavity with conditions such as OLP occurring in 1.7% of the population with associated symptomatic pain in two-thirds of afflicted patients.9 This is a further example of the complexity of systems medicine where patients with OLP may progress to oral cancer,10 although the incidence of malignant transformation is low at 2.45% over 6.8 years (average 0.36% per year).11 Molecular changes in malignancy then, over time and with the spread of the disease, involve structural tissue problems and the major psychological impact of the cancer diagnosis and treatment. In contrast to NP with neurogenic inflammation, OLP is characterized by persistent classical tissue inflammation. Nevertheless, the vertical involvement of the psychosocial dimension of the patient’s personal “system of response” is shown with a decline in social activity due to pain on eating, metabolic imbalance from reduced nutritional intake, and typically an overuse of topical steroids leading to local and systemic complications. A similar situation is identified in advanced cases of TMJ problems where persistent pain leads to psychosocial problems involved in restricted eating, talking, and inappropriate use of analgesics.
Neuropathic pain NP is defined by the International Association for the Study of Pain as “Pain caused by a lesion or disease of the somatosensory nervous system.”2 While NP has distinguishable pain qualities and features, its anatomical characteristics reveal its targeted distribution to bodily regions rich in sensory nerve density such as the trigeminal region. NP is prevalent in the human population with various studies showing a rate from 6.9% to 10%.12 It exists in animals, and laboratory research uses well-validated animal models,13 particularly the rat model of trigeminal and tail NP.14 NP medical diagnostic states include postherpetic neuralgia (PHN), phantom limb pain, post thoracotomy pain, complex regional pain syndromes, and central pain states such as thalamic and ictal (poststroke) pain, and spinal cord injury pain. Trigeminal NP states include first division trigeminal PHN, burning tongue/ mouth syndrome, and numerous competing terms in taxonomies such as phantom tooth pain, persistent idiopathic facial pain, neurovascular odontalgia, persistent dento-alveolar pain disorder, neuropathic trigeminal pain, and neuropathic orofacial pain.14e16 Emerging evidence indicates that endodontic treatment is a major contributor to the prevalence of this form of trigeminal pain and is reported in the literature in 12% of patients after treatment.17 The underlying mechanism, in part, is thought to be nociceptor presensitization from bacterial toxins combined with repetitive mechanical microtrauma and exposure to chemical irrigating solutions.
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More recently, other potential trigeminal neuropathic nondental conditions are being recognized including “empty nose syndrome” characterized by altered sensory phenomena after maxillary turbinectomy18 and dry painful eyes following corrective refractive (LASIK) surgery.19,20 The prevalence of these first and second trigeminal division conditions are alarming from a chronic pain perspective, particularly dry eye disease after refractive surgery with an estimated prevalence rate of 62%.21 Improvements in the diagnostic testing, validation, and treatment of dental NTP would help other medical specialists in the early diagnosis and therapy of persistent pain after surgical otolaryngology and ophthalmology.
Molecular basis of neuropathy in systems medicine Genetic and epigenetic research are a crucial element to connecting the neural, vascular, and endocrine systems of pain modeling.22 Pain genetics is an emerging field for identifying these components of persistent orofacial pain.23 Genetic testing has advanced considerably over the last decade with commercial companies providing rapid screening for neuropathy genes, for example, 83 gene neuropathy assays (Invitae Corp. San Francisco, USA) that can be tested within several days. Epigenetic profiling of NP is still in the developmental phase due to cost and the enormous range of candidate compounds that are involved. For example, excitatory and inhibitory neuropeptides and neurotransmitters are intensively investigated for their respective roles in pain intensity, and the territorial expansion and temporal/ circadian effects of pain. Moreover, the influence of anti-NP medication pharmacodynamics and pharmacokinetics on ligands and receptors constitute an enormous number of variables on maladaptive pain neuroplasticity. Multipanel ELISA/magnetic bead assays are becoming more accessible to establish real-time measurements for epigenetic analysis of NP. This will complement the system-based medical approach to molecular diagnoses and individualized treatments particularly identifying imbalances in pain excitatory and inhibitory neuropeptides (Table 14.2).
Neuroscience of neuropathic pain Trigeminal nerve anatomy The trigeminal nerve (cranial nerve V, CNV) is the primary nerve responsible for the sensory and motor functions of the face and head and has three major divisions: V1, V2, and V3. V1 is the ophthalmic division and is responsible for enervating the superior-most structures of the face and head including the orbit, nose, forehead, and scalp. V2 is the maxillary division and is responsible
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Table 14.2 Major excitatory and inhibitory neuropeptides involved in neuropathic pain in the peripheral and central nervous system (PNS, CNS). Neuropeptide/compound
Receptor location CNS/PNS
Key pharmacological action (excitatory/inhibitory on pain)
Substance P
CNS, PNS, dental pulp
Neuropathic pain þþþ
Calcitonin gene-related peptide
CNS, PNS, dental pulp, CNV first division
Headache þþþ
Vasoactive intestinal peptide
CNS, PNS
Pain inhibition in the somatosensory cortex
Bradykinin
Blood circulation
Inflammatory pain þþþ
Oxytocin
CNS, PNS
Potential antimigraine therapy
Neuropeptide Y
CNS, PNS, macrophages
Potentially prevents posttraumatic stress disorder
Neurokinin-1
CNS, body tissues
Promotes hyperalgesia, pain
Met-enkephalin
CNS, PNS
Opioid peptide, reduces pain
Beta-endorphin
CNS, PNS
Opioid peptide, reduces pain
Endomorphins-1,-2
CNS, PNS
Opioid peptides, reduces pain
for the sensation of the maxillary teeth and bone, oral mucosa and palate, and maxillary sinuses and midface tissues. V3 is the mandibular division and enervates mandibular teeth, mandible, tongue, and floor of the mouth. CNV is a mixed population nerve consisting of both sensory and motor neurons. At the level of the sensory input, there are three major nuclei, the spinal trigeminal nucleus (STN), the principal sensory trigeminal nucleus (PSTN), and the mesencephalic trigeminal nucleus (MTN). The STN is located in the medulla and is responsible for touch, pain, and temperature sensations of the face, head and neck, and oral cavity. The PSTN is located in the mid-pons and receives information regarding light cutaneous sensations of the face, as well as proprioception of the jaw. These two nuclei together are known as trigeminal sensory nuclear complex. The MTN is primarily responsible for receiving proprioceptive information about the periodontium and jaw muscles and its role is to sense and assess masticatory forces of biting and chewing. The motor nucleus of the trigeminal nerve is located medial to the PSTN and enervates the muscles involved in mastication such as the masseter, temporalis, medial, and lateral pterygoids, and other muscles of
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tensor tympani (contracts to dampen the sound of chewing), tensor veli palatini (tenses the palate), mylohyoid (floor of the oral cavity), and digastric muscles (involved in movement of the jaw when speaking, chewing, and swallowing).
Normal CNS pain modulation The thalamus has critical significance for integrating motor and sensory information from the body and head regions and relays this information to brain centers for higher order processing. On stimulation, peripheral nociceptors send information to the CNS via first-order neurons (A-d and C fibers) that synapse in the dorsal ganglion of the spinal cord (laminae I and II) or in the case of the head and oral cavity via CNV. Sensory fibers from body sites synapse onto second-order neurons which cross the midline via laminae IVeVI (collectively known as the nucleus proprius), before ascending toward the brain via the spinothalamic tract. These projections from the body are sent to a region of the thalamus known as the ventral posterior lateral nuclei (VPLN), whereas the ventral posterior medial nuclei receive input from the head and neck region via the trigeminal nerve. Thalamocortical, third-order neurons, then project to various regions of the cortex for higher order processing. Both the primary and the secondary somatosensory cortices receive input from the thalamus. The primary somatosensory cortex processes intensity information received from the VPLN and is involved in the sensory discriminative component of pain. The secondary somatosensory cortex, along with the cingulate cortex, is involved in the recognition, learning, and memory of pain. The ventral anterior cingulate cortex has direct projections to the amygdala (associated with emotional learning and fear), as well as the hippocampus (associated with memory), hypothalamus (associated with activation of the sympathetic and autonomic nervous system), and the nucleus accumbens (associated with pain recognition). The thalamus also projects to the insula cortex of which the posterior cortex is involved in auditory, visual, and somatosensory perception, whereas the anterior cortex is involved in olfactory, gustatory, and visceral autonomic perception, providing the contextual information about pain. Together these brain regions, which collectively form part of the limbic system, produce physiological pain sensation, contextual information, and the emotional responses to pain (Fig. 14.1).24
Trigeminal neuropathic pain induces CNS degeneration Recent evidence has shown that trigeminal neuropathic pain (TNP) originating from the PNS in humans has dramatic negative effects on the thalamus.25 Consistent fMRI study results show a decrease in thalamic volume from markers of glial inflammation from TNP but not patients with trigeminal neuralgia or temporomandibular disorder diagnoses.26 Specifically, TNP
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Figure 14.1 Role of the thalamus in normal nociceptive processing and its systems dysfunction in neuropathic pain. The thalamus receives information from the body to the ventral posterior lateral nuclei (VPL), and from the head to the ventral posterior medial nuclei (VPM). Thalamic neuronal inflammation from high intensity trigeminal neuropathic pain causes widespread disruption to multiple parts of the brain involved in memory, sleep, coordination, visual and auditory information, mental health dimensions, and pain memory.
showed significant decreases in various parts of the CNS including the thalamus, primary somatosensory cortex, anterior insula, putamen, and nucleus accumbens.27e29 Further research is needed to identity if the CNS degenerative effects from peripheral origin TNP is similar to CNS neuropathies such as stroke to the spinothalamic tract or thalamic ventroposterior nucleus. From a clinical systems approach, there are potential thalamic consequences of muscle incoordination, dysfunctional changes in other cranial nerve functioning (auditory and visual, but not olfactory nerve), sleep, memory, spatial memory (clumsiness), and, as previously mentioned, the somatic, visceral, and gustatory systems. Moreover, TNP is often characterized on pain maps by a spreading phenomenon as revealed from the original CNV site that extends over time to other sites of the body and demonstrates marked maladaptive neuroplasticity (Fig. 14.2).30
Psychosocial dimensions of neuropathic pain NP has a disturbing medical and dental past. It was only a generation back that health clinicians generally showed a complete lack of medical knowledge of NP that resulted in the dismissal and contempt of afflicted patients.
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Mark all areas where you experience pain (write left or right side of the body as necessary) R ×
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PAIN MEDICATION
Figure 14.2 Pain map of a 28-year-old female with undiagnosed neuropathic trigeminal pain of 2 years duration. The original site of pain was a left maxillary premolar tooth that began after endodontic treatment. The undiagnosed and untreated condition reveals a marked increase in the pain territory to encompass the whole body.
Sherman et al.31 reported that among the majority of US veterans with NP 2% were told nothing could be done, 5% were told it would go away (regardless of number of years since onset), 24% found their questions avoided, and the remainder were told it was imaginary and were considered “insane” if they felt pain from the amputated limb. Furthermore, of the range of treatments that were performed only 1% of the veterans reported pain relief from treatment. A similar scenario of dental injustice occurred with the term “persistent idiopathic facial pain” that was a popular but wastebasket diagnostic condition in the 1980e1990s.32 Persistent idiopathic facial pain had an emphasis on psychogenic causes to the pain. Pain, being an invisible symptom, can trigger high levels of anxiety, depression, and stress leading to an antagonistic dentist who could find no odontogenic pathology on visual examination or radiographs. Consequently, the dentist without taking a detailed pain history dismissed the genuine complaints of the patient and routinely amputated sound teeth in an attempt to remove the pain. Moreover, the accepted term among dentists of persistent idiopathic facial pain implies there were common conditions called “typical facial pain,” and medical entities of “typical and atypical headaches” and “typical and atypical
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backache”dthese do not exist. Clearly, a lack of understanding and patient empathy has resulted in unnecessary and prolonged pain and suffering, and multiple endodontic treated and extracted teeth. The systems approach of NTP is crucial to apply for successful diagnosis and treatment (Fig. 14.3). NP is a complex multidimensional disease involving alterations of molecular and cellular functioning causing integrative but maladaptive mechanisms in the mind and body. There are horizontal and vertical systems associated with NTP. The vertical system comprises of the biopsychosocial construct of pain where persistent inflammation of the biological system, i.e., neuroinflammation of the PNS and then CNS, produces throbbing, burning, aching, and sharp pain qualities. This activates cortical awareness and the psychological construct of emotional pain (“the pain is punishing and cruel, it is hurting me”) that in turn triggers the social upheaval of pain (“the pain is bad, I cannot go to work today”). For each vertical dimension, there is a corresponding lateral involvement. The biological dimension of NP initiates sympathetic nervous system changes of swelling, redness, and increased pain from catecholamine release. In addition, there are first-order neuron reflex connections to the regional muscles causing muscle spasm and secondary myofascial temporomandibular pain. Further changes occur in the CNS, particularly thalamic dysregulation with other cranial nerve dysfunction and corresponding hypothalamic issues that will impact on the patient. The psychological dimension can show rapid and dramatic changes with the emergence of comorbidities of anxiety, stress, and depression. The social dimension involves further lateral spread of social upheaval leading to inappropriate use of analgesic medication,
SYSTEMS DETERIORATION
SYSTEMS REHABILITATION Identify molecular diagnosis Use genetic & epigenetic tests Early treatment with analgesic peptides & stem cell therapy
Maladaptive PNS changes Maladaptive CNS changes Thalamic degeneration • Unknowledgeable doctor & wrong medication, side effects • Unknowledgeable specialist & more unnecessary surgery • No further referral • “you are imagining the pain”
Depression, anxiety, stress Loss of employment & family issues Frustration & anger Hopelessness & despair Suicide
Nociception & tissue injury
Identify clinical diagnosis • Knowledgeable doctor • Knowledgeable specialist • Pain clinic team • Treat with appropriate medication & allied health
Identify psychosocial diagnosis Psychologist & Psychiatrist Treat with medication, relaxation, cognitive behavioral therapy, meditation, mindfulness
Figure 14.3 Systems medicine approach to pain shows an integrative multilevel deterioration or rehabilitation following tissue injury and nociception.
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addiction, anger, and frustration toward the treating doctor/dentist, inability to work, family upheaval, hopelessness and despair, and unfortunately terminal aspects involving suicide to end his/her pain (Tables 14.3 and 14.4). Taken together, the multidisciplinary systems-based assessment to an integrative diagnosis is crucial for multilevel diagnosis.
Conclusion and future directions The systems-based approach is applicable to health personnel engaged in the diagnosis and treatment of NTP. A single dental practitioner does not have the knowledge or training to effectively treat a patient with NTP. A team approach is needed and should include a dentist (or dental specialist), medical practitioners (family doctor, pain specialist, psychiatrist), psychologist and
Table 14.3 Peripheral and central nervous system (PNS, CNS) cascade of the changes occurring from persistent trigeminal neuropathy. PNS changes of increased Naþ ion channels on neuron (inadequate analgesia from standard local anesthetic) and Mg2þ plus loss of Ca2þ channels, i.e., entire peripheral branch of the trigeminal nerve division can become sensitized through substance P expression.
This produces CNS changes of NMDA (pain receptor) upregulation, but GABA receptor downregulation (pain reduction).
Trigeminal brain and brain stem connections and spinal cord projections leads to activation of interneurons back to the further PNS changes to sympathetic nervous system (termed secondary sympathetically maintained pain) and reflexes to regional muscles (tertiary myofascial pain, i.e., muscle-related pain in temporomandibular disorder).
Maladaptive neuroplasticity: spontaneous neuronal discharge, recruitment of silent nociceptors, further increased PNS and CNS changes of sensitization, CNS centralization, cold hyperalgesia, mechanical allodynia, nerve deficit of pins and needles, and numbness, expansion of receptive fields and neuronal sprouting via nerve growth factor.
CNS degeneration of the thalamus and consequent systems deterioration involving brain, cranial nerves, sleep, muscle coordination, and memory.
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Table 14.4 Narratives of pain.
The pain I have is inhumane (28-yr-old female)
I will kill myself (80-yr-old grandmother)
I will kill myself (38-yr old mother with 2 young children)
The pain reminds me of when I was tortured and mutilated by a Chilean death squad
I rigged up a pulley and electric drill and tried to extract my teeth at midnight (professional soldier)
comment from a dental postgraduate student: Thank you Dr. Vickers for allowing me to sit in with the morning pain patients, I noted that three of the six patients this morning wanted to commit suicide.
allied health, and the clinical scientist for stem cell therapy. The systems-based approach to diagnosis is crucial and the corresponding systems approach for treatment is equally imperative to achieve a positive and meaningful outcome of reduced pain, less suffering, anxiety, and depression, and a return to normal behavior, family engagement, and work. Treatments for the biological dimension use medications such as oral systemic anticonvulsants and antidepressants (typically gabapentin, pregabalin, amitriptyline),33 judicious use of topical local anesthetics34 and benzodiazepines (clonazepam), natural compounds such as the oral systemic endocannabinoid called palmitoylethanolamide35 and topical natural antineuropathics (capsaicin, gingerol),36 and preliminary evidence of autologous stem cell therapy for NTP.37 Other psychological techniques include cognitive behavioral therapy, meditation, mindfulness, and stress reduction strategies. The consequence of thalamic dysregulation and degeneration attributed to TNP is an alarming finding considering the prevalence of this oral disease from routine dental procedures such as endodontic treatment. A greater awareness of this neuropathology is needed through professional education. A systems-based approach to diagnosis and treatment is necessary to reduce pain in all of its dimensions and to acknowledge a founding principle of the World Health Organization that “pain relief is a basic human right.”38
References 1. Siddall P, Cousins M. Persistent pain as a disease entity: implications for clinical management. Anesth Analg. 2004;99(2):510e520. 2. Merskey H, Bogduk N. Part III: pain terms, a current list with definitions and notes on usage. In: Classification of Chronic Pain. 2nd ed. Seattle: IASP Task Force on Taxonomy, IASP Press; 1994:209e214.
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