McLean, Samuel A. MD; Clauw, Daniel J. MD; Abelson, James L. MD, PhD; Liberzon, Israel MD
Among survivors of motor vehicle collision (MVC), persistent symptoms are common even after “minor” collisions and result in tremendous patient suffering and societal costs (1–4). These symptoms often present as psychological disorders, such as posttraumatic stress disorder (PTSD) (2,3). However, a substantial portion of post-MVC morbidity also involves chronic pain syndromes. Whiplash-associated disorders (WAD) are the prototypical MVC-related pain disorders, but fibromyalgia, with its more widespread pain, can also be triggered by MVC (5). For each of these disorders, the transition from acute injury to chronic illness remains poorly understood.
During the past 2 decades, considerable advances have been made in developing biopsychosocial models to describe the transition from acute injury to chronic pain. These advances utilized novel conceptualizations of cognitive-behavioral factors, such as pain-related fear and avoidance (6), which appear to influence the development of chronic pain in many individuals. The cyclical process whereby pain produces fear, which leads to behavioral avoidance, inactivity, disability, and increased focus on pain avoidance, is well-described in the Vlaeyen’s model of chronic pain pathogenesis (6) (Figure 1). In a recent amendment of this model, Norton and Asmundson (7) emphasized the importance of physiologic activities that increase pain (eg, via increased muscle tension) and augment normal physiologic processes (eg, cause increased heart rate), which are then interpreted catastrophically. This later concept is rooted in an extensive literature on a cognitive etiology for panic disorder (catastrophic misinterpretation of bodily sensations) (8).
The ability of psychological factors to influence the development of chronic pain by shaping behavior and amplifying peripheral sensations, as highlighted in these models, is well supported by considerable research (6,7). However, there is increasing evidence that specific neurobiological mechanisms within central stress systems may participate in this process, derailing recovery and mediating progression to chronicity. These mechanisms have been most thoroughly examined in studies of PTSD but may be equally relevant to the development of chronic pain syndromes. Indeed, evidence suggests that PTSD and chronic pain disorders after trauma have many common links. The objective of this review is to examine available evidence that centrally controlled stress response systems can influence the development of all three conditions—WAD, fibromyalgia, and PTSD—after MVC and to suggest that insights from the PTSD literature may enhance our understanding of the development of WAD and fibromyalgia after MVC. An expanded biopsychosocial model for the development of posttraumatic pain syndromes is proposed that emphasizes the importance of interactions between central neurobiological processes and identified cognitive-behavioral factors during their development.
WAD, FIBROMYALGIA, AND PTSD AFTER MVC
WAD are common after MVC, with symptoms that include pain in the neck, shoulder, or arm; headache; jaw pain; dizziness; tinnitus; and cognitive difficulties (9). Although some consider whiplash to be biomechanical in etiology (10), there is ample evidence that in many individuals WAD is not caused by biomechanical mechanisms alone. First, there is great variation in the prevalence of WAD among different populations (eg, high in North America (1) but very low in Greece (11)). Second, decreasing the financial benefit of developing whiplash syndrome improves WAD outcomes. The incidence of WAD decreased as much as 40% in Saskatchewan, Canada, when the providence changed from a tort-compensation system to a no-fault system (1). Third, collisions that occur in other settings (eg, in bumper cars) exert the same biomechanical stress as a low-speed MVC (12), yet prolonged WAD after bumper car collisions are rare (13). Fourth, there is no clear “dose effect” between trauma intensity and the likelihood of developing WAD (14,15). Although the severity of initial symptoms is an important predictor of chronic pain (15–17), the assumption that initial symptoms are proportional to initial tissue injury has not been validated. In an interesting experimental approach to this issue, Castro et al. (18) exposed patients to a “sham” rear-end collision. Twenty percent of subjects reported whiplash symptoms 3 days later, despite no actual collision.
Fibromyalgia is a common clinical syndrome defined by the presence of chronic widespread pain and tenderness (19) Fibromyalgia also occurs as a sequela of MVC, although its MVC-related incidence rate is less well defined. An anecdotal association between MVC and fibromyalgia symptom onset has long been reported: between 24% and 47% of fibromyalgia patients report that an MVC triggered the onset of their illness (20,21). A recent prospective, multisite study of fibromyalgia development after MVC found that among 224 subjects reporting neck pain after MVC, 3% developed fibromyalgia, as opposed to only 0.4% of 643 patients presenting to the emergency department for treatment of (non–MVC- related) minor laceration (5). The unadjusted relative risk of developing fibromyalgia among those initially presenting with neck pain after MVC versus those with laceration was 8.4. The cumulative direct and indirect evidence for a causal relationship between MVC and fibromyalgia exceeds that of other rheumatologic conditions for which an environmental trigger has been accepted (22).
PTSD, the prototypical stress-related disorder, is also common after MVC. To meet criteria for the diagnosis of PTSD, an individual must have 3 distinct types of symptoms related to the MVC event for at least 1 month: reexperiencing the event (eg, psychological distress on exposure to reminders), avoidance of reminders of the event, and hyperarousal (23). Multiple studies suggest that 10% to 16% of patients presenting to the emergency department after MVC will have PTSD 1 year later (2–4). As described below, there is increasing evidence that dysregulation within central stress response systems may play a critical role in the development of PTSD.
THE STRESS RESPONSE SYSTEM AND ITS PUTATIVE ROLE IN THE DEVELOPMENT OF PTSD AFTER MVC
Multiple mechanisms have been proposed by which abnormal stress system function during or after a stressor might increase the risk of PTSD development by disrupting the neurobiological processes which orchestrate an adaptive stress response. Acute stressors trigger the release of corticotrophin-releasing factor, which initiates the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis and is a modulatory neurotransmitter within the locus ceruleus/norepinephrine-sympathetic (LC/NE) system, shaping the release of cortisol and epinephrine (24). These and other factors both help optimize one’s ability to respond to the stressor and, importantly, modulate remembering of the event (“memory consolidation”) (25). Pitman hypothesized that an exaggerated stress response (increased catecholamines and other neuropeptides) might lead to “overconsolidated memories” contributing to the development of PTSD (26). Consistent with this theory, increased heart rate after MVC (reflecting increased sympathomimetic response) has been found to predict the later development of PTSD (27–29). In addition, 2 recent preliminary studies have found that a pharmacologic intervention (propranolol) provided in the emergency department to attenuate the sympathomimetic response decreases the development of PTSD symptoms (30,31). Randomized controlled trials of this intervention are currently ongoing.
Cortisol enhances memory consolidation for emotionally adverse experiences (32), and thus increased cortisol levels after a stressor might be expected to increase the risk of PTSD development. Consistent with this, increased cortisol levels have been found to increase the risk of PTSD in children experiencing MVC (33). However, cortisol also inhibits memory retrieval (32,34), which may help prevent recurrent recollections of the traumatic event (memory reinforcement) during the postevent period, limiting memory formation and stress system activation (26). In addition, cortisol helps contain the acute stress response by down-regulating adrenergic hormone release (35), which might also indirectly contribute to PTSD prevention (36). Three studies of cortisol response in adults after MVC have found that low cortisol levels increase PTSD risk (37–39). In addition, 2 randomized controlled trials have found that hydrocortisone administration in the intensive care unit during stressful events (cardiac surgery and sepsis) decreases subsequent PTSD development (40,41). In summary, although there are conflicting data and disagreements within the field about the precise role of cortisol as a risk factor for PTSD, it does seem clear that HPA axis function, like LC/NE system function, is an important factor in creating or identifying vulnerability and/or in shaping the progression of this stress disorder.
THE POSSIBLE ROLE OF STRESS RESPONSE SYSTEMS IN THE DEVELOPMENT OF PERSISTENT PAIN AFTER MVC
As described above, the possible role of stress response systems in the development of PTSD after stressful events continues to be extensively examined. However, the possible role of stress systems in the development of persistent pain after MVC has not been considered, and the possible mechanisms by which stress systems may interact with cognitive-behavioral factors and provide a common substrate for the production of both persistent pain and psychological sequelae have not been explored.
Multiple lines of evidence support the hypothesis that stress response systems are involved in the pathogenesis of chronic pain, as well as psychological sequelae after MVC: (1) WAD, PTSD, and fibromyalgia have overlapping epidemiologic and clinical features (see below); (2) there is a close association between PTSD symptoms and pain symptoms after MVC, beginning soon after the collision, in those developing WAD (42,43); (3) like PTSD, chronic pain syndromes (such as fibromyalgia (44,45)) developing after MVC are characterized by stress system dysregulation; and (4) stress systems are capable of influencing pain processing (see below). Stress systems may contribute to pain development through multiple mechanisms, including via the initial stress response to the collision and associated injuries and via behavioral changes that occur after the collision.
Overlapping Clinical and Epidemiologic Features of WAD, PTSD, and Fibromyalgia
Fibromyalgia, PTSD, and WAD have overlapping clinical and epidemiologic characteristics. Female gender (1,15–17, 46,47), lower socioeconomic status (1,48,49), and a preexisting history of mood disorders (18,46,47,50) increase the risk of developing all 3 conditions. All are characterized by multisystem complaints, such as headache, axial pain, fatigue, cognitive dysfunction, and sleep disturbances (46,51,52).
PTSD commonly co-occurs with fibromyalgia and WAD. Clinically significant PTSD-like symptoms have been found in more than 50% of fibromyalgia patients (21,53) and in more than 50% of patients receiving treatment for chronic pain after MVC (54,55). At least 15% to 25% of patients with persistent whiplash symptoms meet diagnostic criteria for PTSD (56,57). Also, just as PTSD is common in patients with chronic pain, chronic pain is also common in patients with PTSD. Twenty percent to 30% of outpatient samples with PTSD (58–60) and 80% of combat veterans with PTSD (59) also have chronic pain. Recent epidemiologic studies have also established genetic linkage between fibromyalgia, PTSD, and other “affective spectrum” disorders (61).
Sexual abuse is the most common cause of PTSD in women (62), and a history of previous trauma or child abuse increases the risk of developing PTSD after a traumatic event (38,63). Fibromyalgia populations report an increased prevalence of child abuse; 50% or more of tertiary care clinic populations report such a history (64–66). Child abuse can cause permanent stress system dysregulation (67), and such dysregulation may render abuse victims more vulnerable to subsequently developing fibromyalgia or WAD after MVC or other stressors. Recent animal studies have confirmed that early life stress can permanently alter nociceptive circuitry (68,69). The prevalence of self-reported child abuse among community-based samples of fibromyalgia patients who report the onset of chronic pain after MVC is unknown, as is the prevalence of child abuse among patients with WAD. The above data suggest the testable hypothesis that such prevalence rates are higher than those of the general population.
Association Between PTSD Symptoms and WAD Symptoms During WAD Development
Most studies examining the relationship between chronic pain and PTSD are cross-sectional and thus cannot provide information on the relative timing of pain and PTSD symptoms after MVC. Available evidence suggests that pain and PTSD symptoms are closely associated, beginning soon after MVC (42,43,70). In addition, PTSD symptoms after MVC have been shown to predict the development of chronic WAD. Drottning (43) found that increased PTSD symptoms within 1 to 2 days of the MVC were found in 70% of patients with significant neck pain 4 weeks after MVC as opposed to only 26% of those in the low pain group. Sterling et al. (42) found that elevated Impact of Event Scale scores (which reflect PTSD symptomatology) within 1 month of MVC were unique to those with moderate or severe WAD at 6 months. A recent study by Sterling et al. (71) also found that PTSD symptoms after MVC predicted whiplash severity at 6 months. These data suggest that evidence of vulnerability to PTSD in the immediate aftermath of a MVC predicts subsequent development of chronic WAD. Evidence that a subset of those with neck pain after MVC progresses to develop fibromyalgia (72) suggests that WAD and FM may be linked and that vulnerability to develop PTSD after MVC may also predict the development of fibromyalgia. These data suggest the testable hypothesis that factors which predict vulnerability to PTSD in prospective studies will also predict vulnerability to WAD and fibromyalgia.
Like PTSD, Fibromyalgia Developing After MVC Is Characterized by Stress System Dysregulation
A comprehensive review of the complex and heterogeneous literature regarding stress system findings in PTSD and fibromyalgia is beyond the scope of this review. However, abnormal stress system function is an important feature of both disorders (44,73). Though specifics have varied across studies and there have been conflicting findings, the preponderance of evidence suggests that the HPA axis is dysregulated in patients with PTSD (73,74). Both excessive and reduced HPA axis activity has been seen (74). Increased cerebrospinal fluid corticotrophin-releasing hormone (CRH), blunted ACTH responses to CRH, low baseline cortisol levels, and altered cortisol responses to acute stressors have all been reported (73,74) in PTSD. LC/NE system dysregulation is also present in PTSD, with a heightened catecholamine and autonomic response to stressors (75). Like PTSD, HPA axis findings in fibromyalgia have also been inconsistent, with both hyper- and hypoactivity noted (76). Also like PTSD, heightened autonomic reactivity (reflected in both heart rate variability and plasma catecholamine levels) has been observed in fibromyalgia and suggests a central hypernoradrenergic state (77,78).
Neuroanatomical work in PTSD suggests dysregulation in limbic, paralimbic, and prefrontal regions, many of which are involved in the stress response and emotional processing (79). Considerable interest has focused on prefrontal circuitry, which is responsible for the modulation of emotional responses, and amygdaloid regions, which are important in processing fear and emotional salience (79). An emerging hypothesis suggests that decreased prefrontal inhibition of amygdaloid and/or hypothalamic activity may contribute to altered HPA function, autonomic/adrenergic hyperactivity, and the generation of some PTSD symptoms (80). Intriguingly, abnormal prefrontal function has also been associated with pain catastrophization (81), which is associated with the development of chronic musculoskeletal pain (82). Future research is warranted to explore the possibility that prefrontal dysregulation, in some cases rooted in early life stress, may contribute to vulnerability to and manifestations of both PTSD and poststress pain syndromes by permissively contributing to the dysregulation of subcortical neuroendocrine, autonomic, emotional, and pain processing centers.
Stress Systems Are Capable of Influencing Pain Processing
In animal studies, prefrontal cortical regions are capable of influencing widespread pain sensitivity via their influence on descending pain modulatory pathways (83). These pathways can either inhibit or facilitate the spinal transmission of both noxious and nonnoxious stimuli (84) via opioid and nonopioid mechanisms (85). In addition, the laterocapsular division of the central nucleus of the amygdala also appears to play an important role in pain modulation (86). This area, which has been described as the “nociceptive amygdala,” is capable of either enhancing or suppressing painful stimuli (86) and may be critical to the development of chronic pain after MVC in some patients.
The possible dysregulation of descending pain modulating pathways in poststress pain states is suggested by the early onset and widespread nature of the hyperalgesia, which develops soon after MVC (70,87) in some patients who develop chronic WAD (31). Patients with WAD have been found to have the same widespread hypersensitivity to sensory stimulation as patients with fibromyalgia (88), and considerable data in fibromyalgia suggest that antinociceptive pathways are hypoactive in this condition (89–93). Recently, evidence of abnormal function of antinociceptive pain pathways has been identified in individuals developing chronic WAD, beginning soon after the MVC (94).
Although contemporary evidence most strongly suggests that stress systems influence post-MVC pain development via descending pain modulatory pathways, stress systems are also capable of modulating pain via other mechanisms, such as via spinal cord dorsal horn glucocorticoid receptors. Such receptors respond to peripheral nociceptive stimulation (95,96) and are capable of inducing antinociception (97–99). Cortisol variation may also influence the balance of peripheral proinflammatory cytokines, which might contribute to pain symptoms via peripheral or central mechanisms (100).
CANDIDATE NEUROBIOLOGICAL PROCESSES INVOLVED IN THE RESOLUTION OR PERSISTENCE OF SYMPTOMS AFTER MVC
Given the linkages described above between trauma, stress, PTSD, fibromyalgia, and WAD, it seems logical to wonder whether the acute stress response factors that mark or create vulnerability to PTSD may also contribute to vulnerability to develop chronic pain. No studies have examined the importance of stress response systems and their acute reactivity in the development of chronic pain after MVC. We might hypothesize that heightened acute autonomic activity and variations in HPA axis activity after MVC would predict an increased likelihood of subsequently developing WAD and fibromyalgia.
Stress response system dysregulation after MVC would then interact with cognitive-behavioral factors, such as avoidance learning, to further modulate neurobiological systems related to pain processing and stress. Consistent with this hypothesis, recent studies indicate that cognitive-behavioral factors alter pain perception and other symptoms via central neurobiological pathways (81,101). Such evidence supports a model of chronic symptom development that incorporates the potential for interactions between past experience, acute stress responses to trauma, post-MVC behavior, and cognitive/psychosocial consequences to alter activity within pain-sensitive brain regions and affect pain, as well as other psychological experiences (Figure 2). This model also suggests that, in many individuals, the dysregulation of neurobiological processes related to stress systems in the early aftermath of trauma may be a critical step in chronic pain development. If posttraumatic pain syndromes are similar to PTSD in this regard, there may be value in testing the ability of agents like propranolol or hydrocortisone, delivered in the immediate aftermath of trauma, to prevent the development of chronic pain.
POSSIBLE NEUROBIOLOGICAL MECHANISMS MEDIATING KNOWN ENVIRONMENTAL RISK FACTORS FOR CHRONIC PAIN DEVELOPMENT
The utility of an interactive model incorporating neurobiological and cognitive-behavioral factors can be further illustrated by considering one post-event factor known to influence individual outcomes: decreased activity level. Decreased activity after MVC increases the risk of WAD (102), but the mechanisms by which decreased activity influences nociceptive processing are unknown. Results from a recent study suggest that depriving normally exercising individuals of routine exercise (as may occur if an individual reduces activity after MVC) may lead to symptoms such as pain, fatigue, and mood disturbances and that stress response system function may identify those individuals particularly vulnerable to the development of such symptoms (103). After 1 week of exercise cessation, 8 of 18 subjects developed worsening pain, tenderness, fatigue, or mood symptoms. These 8 subjects had significantly reduced baseline HPA axis activity (mean AM cortisol 27.42 μg/dl versus 37.97 μg/dl) and autonomic nervous system function (heart rate variability assessed using total power 7662 m/s2 versus 13,929 m/s2) relative to subjects who did not develop such symptoms.
These data support the hypothesis that stress system activity, shaped by genetic or experiential factors, predicts vulnerabilities to develop altered mood and pain experiences in the setting of reduced activity. This has relevance to the potential contribution of reduced activity following MVC to the development of chronic pain and suggests that reduced activity may also increase the risk of developing psychological sequelae. In addition, these data indicate that a full explanation of the link between decreased activity and chronic pain development may require a model that incorporates meaningful interactions between stress response systems, behavior, and central pain processing pathways.
These data also suggest a mechanism whereby interactions between central neurobiological pain processing systems and stress response systems may contribute to cultural variations in WAD prevalence via both MVC-related and post-MVC-related factors. There are cultural differences in the expected consequences of whiplash injury (104), and in those cultures in which more chronic sequelae are expected, the MCV event itself may be more likely to result in an exaggerated and/or poorly modulated stress response, which in vulnerable individuals may lead to persistent pain and/or psychological symptoms. In addition, individuals in countries where the perceived threat of MVC is high may also be more likely to decrease their activity level after an MVC (eg, “rest up” after the injury), which also may contribute to symptom development in vulnerable individuals via central neurobiological processes. These mechanisms are not mutually exclusive and in fact may often occur together and be synergistic.
In summary, a number of lines of evidence suggest that central neurobiological processes, such as those related to stress response systems and central pain processing, may be important to the development of persistent pain and psychological sequelae after MVC. We propose a model in which the acute physical and emotional effects of MVC involve an interaction between the direct effects of tissue injury and the emotional responses to the experienced threat. This emotional response to threat includes the response to the MVC itself, as well as the response to associated injuries and symptoms after the MVC. These physical and emotional effects interact with an acute stress response that has been shaped by genetics and prior traumatic experience. Together, these influences in turn interact with central processing pathways, including those related to pain, that are highly sensitive to cognitive and emotional modulatory input. Amplified pain signaling may result, which may then interact with post-MVC behaviors to produce further amplification and reverberating activity that becomes self-sustaining.
This model incorporates all of the relevant factors identified in prior biopsychosocial theories of chronic pain development after injury and places them in the landscape of our rapidly developing understanding of stress systems and CNS pain-modulating pathways. It should be useful in shaping further studies of chronic symptom development after MVC, as it generates numerous specific, testable hypotheses. Longitudinal studies will be needed to test some of these hypotheses and to examine the influence of central factors in the development of chronic WAD, fibromyalgia, and PTSD among unselected patient cohorts. Examining these factors longitudinally will allow evaluation of the mechanisms that are likely to directly mediate chronic symptom development. Such studies should simultaneously examine a range of outcomes after MVC, including both regional and widespread pain and psychological sequelae. These studies will allow us to learn more about the rich and complex interactions between central neurobiological processes and psychosocial factors which occur during the transition from acute injury to chronic disorder, whether the outcome is a chronic pain disorder like WAD or fibromyalgia or a psychiatric disorder like PTSD. They may also lead us to acute, posttrauma interventions that may be able to prevent development of both PTSD and chronic pain syndromes.
The authors gratefully acknowledge the assistance of Richard H. Gracely, PhD, and the reviewers for helping us to improve the paper.
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