Anatomy and pathophysiology

Anatomically speaking, interaction between orofacial pain and PTSD is related to the trigeminal nerve. Unpleasant trigeminal sensations are important as a warning for injuries and potentially dangerous substances and for initiating protective reflexes and behavior. The neurons essential for the transmission of stimuli and the formation of neurogenic inflammation are the C and A-delta fibers, and to a lesser extent A-beta fibers. The signal is transmitted to the second order neurons located in the nucleus caudalis of the trigeminal ganglion, onward to the ventroposterior thalamic nucleus and then to the cerebral cortex. There are a number of common neuroimmunological pathways between the trigeminal sensory pathways and pathophysiological processes in PTSD (5). The most important pathways are mediated by the CGRP (Calcitonin Gene Related Peptide), substance P, nitric oxide and TRPV1 (transient receptor potential vanilloid receptor) receptors (6).

PTSD is caused by a stressogenic event, with hypercortisolemia as an early metabolic response produced by plastic changes in glucocorticoid and mineralocorticoid receptors of the hippocampus, directly affecting the hypothalamic pituitary adrenal (HPA) axis, with the consequent reduction of dendritic branching, reduced neurogenesis and the death of neurons of the hippocampus. The processes in the amygdalae, hippocampus, hypothalamus, periaqueductal grey matter and the thalamus are responsible for a series of adaptable psychological reactions to stress which sync with physical physiological responses (7, 8).

Peripheral cells and central nervous system cells share the neurotransmitter receptors, neuropeptides and hormones. This enables feedback communication between the periphery of the organism and the CNS, including the interaction between the autonomic nervous system and emotions and cognitive functions. Information about the processes at the periphery of the body is transmitted to the CNS and triggers reactions that are manifested in adaptive and metabolic changes. Conversely, psychological and cognitive reactions cause changes in the periphery, which can manifest themselves as psychosomatic diseases (9).

Experimental models of facial pain

Interaction of stress and peripheral inflammation can be illustrated with a model of temporomandibular dysfunction, pain and stress in rats. Masseter inflammation will not express pain if the inflammatory cytokine interleukin-6 (IL-6) is only locally pronounced, by locally induced inflammation of the muscle, but if the stress induces an increased concentration of IL-6 in the serum originating from the CNS, pain occurs (10).

Central mechanisms of trigeminal pathways can cause inflammation and pain outside of the inflamed area. The reduction in concentration of CGRP in the dorsal horn of the medulla oblongata of the trigeminal pathway reduces the increased sensitivity to inflammatory and neuropathic pain. Further the central pathways of the CGRP neurons go in the amygdalae where the pain gets the associative component, which is essential for learning processes and fear. Projections in the thalamic tract nucleus and insular complex encourage autonomous, motor and emotional responses related to pain. Blockade of the CGRP receptors in these areas also blocks the reactions related to the emotional upgrade of pain (11). TRPV1 (transient receptor potential vanilloid receptor) receptors are neurons that release the CGRP and as such play a key role in inflammatory and non-inflammatory pain conditions. Unilateral induced inflammation and hyperalgesia of the masseter muscle increase the number of TRPV1 receptors and CGRP mRNA in the inflamed area. Hyperalgesia without inflammation and without increasing the concentration of TRPV1 and CGRP mRNA occurs in a symmetrical contralateral area, and this contralateral pain can be prevented by blocking the function of the TRPV1 in hippocampus indicating a role of the hippocampal TRPV1 receptors in the etiopathogenesis of the inflammation-induced facial pain outside of the inflammatory area (12). Trigeminal CGRP is involved both in the pathophysiology of pain at all levels from the periphery to the center in the brain, and back to the periphery via the descending inhibitory mechanisms. Thus, amygdalae, hypothalamus and insular complex are integrated in processing emotional pain structure that includes a reaction to fear and stress. Further conscious processing in cortical centers fully processes the pain stimulus (13).

PTSD and facial pain as clinical entities

Psychoneuroimmunology is the basis of very complicated evolutionary and interpersonal relationships. Pain and psychological traumas are an integral part of human evolution. Pain is the primary sensation that is hard to forget and its manipulation creates new conscious or unconscious cognitive patterns. For the understanding of pain and PTSD it is necessary to realize that influenced by culture pain can interfere with biological processes (14, 15).

Orofacial pain is one of the most common forms of head and neck pain and it accounts for 40% of all the chronic pain conditions in US and Europe (12).

Patients with PTSD, war and peacetime, are eight times more likely to suffer from some form of chronic pain, and two times more often than patients diagnosed with anxiety. The pattern of the reaction to pain in patients with PTSD is different than in the normal population, and it consists from an elevated pain threshold, increased sensitivity to pain above the pain threshold, unchanged sensitivity to summation of multiple consecutive non-painful stimuli and unchanged threshold for sensing hot/cold. This kind of pain pattern in patients with PTSD suggests preserved sensitization pathways of the second and third neuron of the spinal cord and the central nervous system and the absence of sensory polyneuropathy. This sample proves that the majority of pain perception in PTSD is conditioned by emotional patterns of pain perception (16).

In 88% of patients with PTSD headache is the leading symptom of pain, and if the causal trauma of PTSD was associated with a physical trauma, only 9% of such patients referred to chronic pain in previously injured area, which suggests that the primary injury is not crucial for the occurrence of chronic pain but it appears subsequently (4). Headache is the most common pain syndrome of marriage partners of patients with PTSD (17).

About 50% of patients with orofacial pain have a history of a traumatic event and 15-24% of them meet the criteria for PTSD (18). Research on comorbidity is more difficult due to a number of symptoms contained in PTSD clusters and because comorbidity of PTSD with other mental illnesses is up to 80% (2). When analyzing the symptoms of PTSD contained in the main groups of PTSD symptoms and connecting them with orofacial pain, it can be seen that the main symptoms of PTSD that enhance the problems associated with chronic orofacial pain are avoidance of dealing with problems, numbness and dysphoria, and that anxiety and relieving of traumatic memories have the lowest impact. Contrary to popular belief, sleep disorders do not have a direct impact on chronic orofacial pain in PTSD, instead this association was found only through anxiety as the main symptom (18).

Today, the comorbidity of PTSD and orofacial pain is described by a model of a mutual maintenance of pain and PTSD that was first defined by Sharp. The model is graphically displayed as a variety of interconnected and mutually reciprocal symptoms, diseases and patterns. Components of such a model: excessive concentration of attention, anxiety sensitivity, remembering the trauma, avoidance, depression, misperception of pain and lack of cognitive abilities for adaptive strategy are interdependent with stress, chronic pain, post-traumatic stress disorder and disability (in terms of immobilization). Each component of this model can aggravate or cause deterioration of PTSD and chronic pain (19).

Emotional interpretation of pain in PTSD is explained by two mechanisms: dissociation and anxious sensitivity. Dissociation is a psychological defense mechanism in which the identity, memories, ideas, feelings, or perceptions are separated from conscious cognition and cannot be recalled or willingly experienced. Dissociative mechanisms are associated with disorders of attention both in peaceful and in emotionally charged state. Anxiety sensitivity is the fear that the symptoms such as palpitations, sweating, derealization, muscle tension and headaches will have adverse social, physical or mental effects. The fear of anxiety or pain itself can also occur, a fear that these symptoms are a sure way to insanity. The increased intensity of pain that occurs in PTSD is part of the emotional pattern according to which the pain is perceived as an unrealistic threat and/or associated with the trauma that caused the PTSD. Therefore, painful stimulus serves as a trigger of anxiety and encourages the catastrophic attitude towards pain and thus the fear of pain. The result is a much stronger pain than in the control population (4).

Two-thirds of patients with PTSD have another psychiatric diagnosis; the most common are depressive disorders, anxiety disorders, substance abuse and somatoform disorders (2). Comorbidity greatly increases the ability to connect with other symptoms from the cluster of symptoms and these multiple mechanisms can worsen the pain and PTSD. Pain in PTSD can cause discomfort, boost stress, apathy and helplessness and may be a reminder of the trauma. PTSD patients have an attentional bias to pain that can lead to amplification of pain. All this in turn can lead to anxiety, attempt to avoid the trauma itself and all that is reminiscent of the trauma, which extends the pattern of possible disturbing situations. This has created a positive feedback loop between sensory, affective and cognitive components of psychogenic and chronic pain, where any component can induce and maintain chronic pain (18).