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The chronicity of pain is the feature of pain that is least understood and most directly linked with our inability to effectively manage pain. Acute pain is relatively responsive to our current pharmacologic and interventional armamentarium. However, as pain persists, our ability to treat effectively diminishes and the patient's frustration and resource utilization increases. This article explores our current understanding of the factors linked to pain duration and the transition from acute to chronic pain in both human and animal models, and across a spectrum of human chronic pain conditions.
Advances in pain research have elucidated a great deal about the factors that may lead to chronic pain. Peripheral injury leads to increased excitability in peripheral nociceptors (peripheral sensitization) that manifests as primary hyperalgesia. Subsequent barrage of the central nervous system (CNS) leads to increased and prolonged excitability of CNS nociceptors (central sensitization), leading to increased sensitivity to painful stimuli in areas of normal tissue removed from the site of injury (secondary hyperalgesia). Furthermore, peripheral nerve injury is accompanied by a variety of changes, including the new expression of sodium channels, adrenergic receptors, and cholinergic receptors that contribute to depolarization of injured nociceptors. This depolarization of injured nociceptors can result in adequate sodium and calcium flux to endow the injured nociceptor with a pacemaker function in which the cell reaches action potentials spontaneously and regularly without outside stimulation. All of these elements make the occurrence of chronic pain following injury (especially nerve injury) seem rather predictable. However, these factors do not explain why most people have no persistent pain following injury (or even nerve injury).
Every surgery cuts cutaneous nerves. It is well documented that even these small cutaneous nerves can lead to chronic neuropathic pain (scar neuromas). However, most patients do not experience persistent pain following surgery. Similarly, many patients continue to show evidence of nerve damage following acute herpes zoster but most do not progress to the chronically painful state of postherpetic neuralgia. The mystery is not why some develop chronic pain in the face of this biology but rather why most do not.
A great many studies have focused on predictors and causes of pain severity, pain thresholds, treatments for reducing acute and chronic pain severity, and even incidence. However, the number of studies specifically studying the duration of pain across the spectrum from acute to chronic pain has been limited. As a result, our understanding of the specific variables influencing pain duration has been poorly elucidated. The factors controlling the duration of pain following an injury are highly important because chronic pain may be nothing more than the extended duration of acute pain. In other words, the same factors that lead to delayed pain resolution following injury may also lead to unresolving pain when carried to the extreme. Alternatively, chronic pain may arise from fundamentally different biology and factors than those leading to delayed pain resolution. This article highlights animal and human research explicitly examining pain duration and the shift from acute to chronic pain.
Animal studies suggest a crucial role for the CNS in general and the brain in particular in determining the persistence of pain. Rat data suggest that the duration of pain is controlled by supraspinal systems projecting from the rostral ventromedial medulla (RVM) of the brain to the spinal cord [1,2]. Our understanding of these descending projections has evolved to encompass the presence of “on” cells that functionally facilitate the transmission of pain in the dorsal horn of the spinal cord. Colocalized with these “on” cells are “off” cells that project to similar locations but have the opposite effect—inhibiting pain transmission at the first synapse in the dorsal horn of the spinal cord. Within this context, the perception of pain or its extinguishment can be understood as specifically under control of supraspinal CNS systems that may be more determinant in the persistence of pain following injury than the nature of the peripheral nerve injury. Furthermore, the experience of pain can be conceived as an active supraspinally modulated behavior rather than a passive sensory experience.
The relative importance of these supraspinal systems in the RVM and the nature of the peripheral injury in determining the duration of pain and its eventual perpetuation or cessation is illustrated by a series of elegant experiments in the rat. Selective block, physical lesion, or immunologic reduction of opioid receptor–positive “on” cells of the rat RVM creates a rat in which nerve injury pain can be initiated but not maintained [3–6]. In other words, injuries that reliably produce chronic pain in intact rats produce acute, but not chronic, pain in the absence of descending signals from the brain. These findings suggest that the lesions in the RVM do not create analgesia per se, but rather regulate the duration of pain and its transition from acute to chronic. These signals appear to be dependent at least in part on central cholecystokinin release, and are elicited by the presence of the peripheral nerve injury.
Other studies point to the importance of microglial activation in the CNS in perpetuating acute pain. Intrathecal minocycline (a known microglial inhibitor), but not saline control, has been shown to prevent the development of persistent mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation [7•]. Minocycline also inhibits the generation of persistent mechanical allodynia in both acute and persistent pain models induced by sciatic nerve inflammation (sciatic inflammatory neuropathy [SIN]). Moreover, minocycline was able to attenuate established SIN-induced allodynia 1 day but not 1 week after sciatic nerve injury . These findings suggest an early and crucial role for microglial cells in initiating, but not necessarily maintaining, enhanced pain responses. Furthermore, similar to the role of the RVM, early reactive changes in microglial activation in the CNS appear to be more determinant than the mode or severity of injury in determining the persistence of pain following nerve injury. Together, these animal experiments suggest that a significant part of the variance in whether an acute injury will cause prolonged pain is likely determined by activity in the CNS rather than in the peripheral nervous system or the mode of injury.
In humans, fear in particular appears to play a central role in the duration of pain. Catastrophizing thoughts lead to pain-related fear [9,10], and in prospective longitudinal studies, catastrophizing and fear have been specifically associated with an increased risk of chronic back pain 1 year after acute low back injury [11,12•]. Catastrophizing was more than 7 times more powerful a predictor than any other predictor or clinical variable among acute back pain patients in determining the risk of subsequent chronic pain . These findings are bolstered by the findings of a prospective population-based study linking fear in pain-free individuals with the risk of subsequently developing chronic pain complaints . Pain-related fear causes patients with pain to overpredict the severity of pain they will experience. This results in subsequent overproduction of avoidance behavior, which conceptually may delay pain resolution . Fear and anxiety may exert pain-modulating effects through brain activity in the medial prefrontal region, ventral lateral frontal region, and cingulate regions associated with monitoring and evaluation of affective responses . Links between these regions and the RVM remain to be demonstrated.
Anxiety and depression may also be markers for CNS physiology that play a significant role in the durability of pain. Between 30% and 65% of patients with chronic pain have comorbid depression . Longitudinal epidemiologic studies evaluating depression and anxiety together [17,18] or depression alone [19–23] indicate that patients with depression and anxiety are between 2 to 5 times more likely to have a new chronic pain problem at follow-up from 1 to 8 years later. This occurs despite the robust findings reviewed and expanded on by Dworkin et al.  that patients with depression appear to be less sensitive to pain in response to experimental noxious stimuli compared with healthy controls. These studies suggest that depression and possibly anxiety may exert elevated risk of chronic pain by either altering pain durability or altering new pain incidence rather than by altering pain thresholds or pain severity. Together, these findings argue for future emphasis on studying pain duration rather than pain severity or pain thresholds.
There remains a great need to define if the elevated prevalence seen at follow-up among those with elevated baseline fear, anxiety, and depression are related to increased onset of new pain complaints or decreased resolution (ie, increased duration) of new pain complaints. Furthermore, there is a need to characterize the mechanisms by which these psychological factors either increase the risk of new pain complaints or lengthen the duration of these new pain complaints. It is tempting to speculate, based on the animal data previously cited, that the supraspinal physiology manifesting as fear, anxiety, or depression may be a marker of global CNS processes that simultaneously modulate either descending signals from the RVM or mark elevated levels of microglial activation in response to injury, thereby enhancing both pain duration and the probability that new injuries will result in chronic pain.
The occurrence of chronic postsurgical pain has provided an opportunity to examine the predictive nature of psychologic distress on the subsequent occurrence of chronic pain. Unlike the epidemiologic studies previously described, postsurgical studies look among a group in whom all have an injury. In other words, there is equal incidence in the cohort of a new acute pain condition. Therefore, elevated levels of persistent pain and the factors predicting persistent postsurgical pain more directly implicate these psychologic factors in affecting pain resolution and duration (rather than incidence rates).
State-Trait Anxiety Index and Beck Depression Inventory scores have been reported to be significantly correlated with pain 12 months after knee surgery . Preoperative pain was also found to be a significant long-term predictor of chronic postsurgical knee pain .
Following thoracotomy, greater continuous pain in the acute postoperative setting was also significantly correlated with chronic postoperative pain . Advanced age has been found to predict greater duration of residual post-thoracotomy pain in some studies , but reduced risk in other studies . The role of gender has been similarly uncertain. The female gender has been found to predict increased risk for prolonged pain by a study in a Japanese cohort of 85 patients  and a study of 120 patients . However, another study of 149 post-thoracotomy patients failed to show a significant correlation . It has been proposed that women experience greater sensitivity to pain, with some work suggesting a neurophysiologic basis in the brain for gender differences . It is imperative, however, that cultural effects are investigated instead of ignored. In stark contrast with these studies of Japanese and Brazilian women, a study of more than 2000 patients in China found that women experienced less pain and used fewer analgesics . Although many studies have documented the risks associated with the occurrence of chronic postsurgical pain, to our knowledge only one small study has specifically measured pain duration following surgery . Unfortunately, notwithstanding undergoing a thoracotomy, patients in this study received no opioids, limiting the generalizability to the more common experience seen in hospitals where practically all postoperative patients receive opioids. Nonetheless, the study concluded that anxiety and aggressivity were correlated with prolonged postsurgical pain.
Quantitative sensory testing (QST) has yielded varying results when used to quantify peripheral and CNS function that may predict persistent pain. One study comparing 46 patients reporting moderate to severe postherniorrhaphy pain 1 year following surgery was compared with a control group of pain-free postherniorrhaphy patients. Overall, the significant peripheral sensory dysfunction found was hypoesthesia to various sensory modalities when comparing pain with pain-free patients. Equally robust, however, was the evidence of CNS functional change manifested in patients with persistent pain as a higher incidence and intensity of temporal summation to repetitive pinprick stimulation around the scar compared with the contralateral side. In contrast, temporal summation was absent in the pain-free controls. Other QST changes, such as warmth detection thresholds, were abnormal in both those with and without chronic pain . In a similar study of 72 patients 6 to 12 months after open herniorrhaphy, QST showed that mechanical hypoesthesia and tactile allodynia were common findings in the surgical area. However, these sensory disturbances did not occur more often in patients with pain than those without pain. Also, no difference was observed in thermal detection thresholds and heat pain thresholds between pain and nonpain patients . The study concluded that QST had a low specificity for chronic pain after inguinal herniorrhaphy. These results highlight the common occurrence of sustained peripheral nervous system dysfunction following surgery as well as the unclear relationship that this dysfunction has with pain duration and the incidence of chronic pain. In contrast, peripherally manifested signs of altered CNS function, such as temporal summation, may have better predictive value.
The role that opioids play in pain duration following surgery specifically or acute injury in general has received little attention. Many animal studies have documented that opioids generate a state of pain hypersensitivity to noxious mechanical, chemical, and thermal stimuli termed opioid-induced hyperalgesia (OIH). OIH may arise rapidly in humans in both the experimental  and perioperative setting . However, the role of this hyperalgesia in the persistence of pain over time is uncertain. Recently, Webster et al. [38•] demonstrated a dose-response relationship between the early use of prescription opioids for acute low back pain and both increased pain duration and elevated risk of chronic opioid use. However, this intriguing finding may simply reflect that early use of opioids is a marker of disease severity. There is a great need to examine how pain affects opioid use duration and conversely how opioids affect pain resolution rates. The work cited above suggests that opioid use may exert a prolonging effect on the duration of pain even when controlled for pain severity.
Only a handful of human studies in other areas have longitudinally studied the factors related to pain duration and directly measured the rate of pain resolution. These studies have used the model of acute herpes zoster (AHZ) and have been largely focused on the specific use of antiviral medications to speed pain resolution. Models of acute to chronic pain persistence, including AHZ and acute back pain, have proven to be intrinsically limited by the fact that patients already have pain when they become available for study, and such patients are only sporadically available to study. However, one intriguing finding from these studies is that factors associated with increased rates of pain resolution in AHZ (initial pain severity, younger age, use of antiviral medication, and use of continuous local anesthetic epidural blockade) [39–44] have also been associated with reduced prevalence of chronic pain (postherpetic neuralgia) in other studies [45–47]. Within this context, the rate of pain resolution may be both a clinically important end point in itself and an equally important early measurable indicator of the risk of chronic pain across a wide range of acute injuries. There is a significant need to further assess in other models if factors that influence the rate of pain resolution produce corresponding changes in the rate of chronic postsurgical pain.
Important studies have identified intrathecal clonidine , intraoperative ketamine , and epidural analgesia  as modalities that may reduce the likelihood of chronic postsurgical pain. However, these studies have not investigated the link between this long-term outcome for a minority of patients with their effects of pain duration more generally among all comers. In other words, is the reduction in chronic pain seen with these agents a manifestation of altering the physiology that controls pain duration more generally? Future work should explore the link between reductions in pain duration and the incidence of chronic pain in postsurgical patients. Finally, there is a tremendous gap in the literature on postsurgical pain duration, with a great need for studies to test whether we can intervene therapeutically to reduce the duration of acute and subacute pain for the 34 million Americans undergoing surgery every year. The perioperative setting provides a robust research environment to carefully characterize variables that may confer risk of delayed pain resolution before the first onset of pain, in a setting that reliably produces a steady stream of subjects of all ages, races, and genders. Furthermore, the perioperative setting is an ideal setting for future interventions aimed at prophylaxis or early intervention for those at greatest risk of reduced pain resolution. This model should be useful to investigators interested in pain duration and the crucial transition from acute to chronic pain.
Disclosures: No potential conflicts of interest relevant to this article have been reported.
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