REVIEW ARTICLE

Current views on acute to chronic pain transition in post-traumatic patients: Risk factors and potential for pre-emptive treatments Olivier Radresa, PhD, Jean-Marc Chauny, MD, MSc, Gilles Lavigne, DMD, PhD, Eric Piette, MD, MSc, Jean Paquet, PhD, and Raoul Daoust, MD, MSc, Montreal, Quebec, Canada

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very year in the United States, 2.6 million hospital admissions and 36 million emergency department visits are accounted for by trauma patients.1 Proportionally similar ratios are reported in Canada.2 In many cases, acute pain from tissue damage subsides normally with wound healing. Yet, in many patients, maladaptive sensitization of the nervous system may trigger chronic pain syndromes that eventually persist for years after that healing has taken place. While the definition of chronic pain may vary, it is generally considered as an ongoing pain state experienced on most days and persisting for at least 3 months.3 Patients presenting with chronic pain experience persistent manifestations of allodynia, hyperalgesia, and spontaneous pain, making it a major cause of disability. Allodynia is characterized by a painful sensation triggered by normally nonpainful stimuli such as light brushes of the skin or the simple touch of clothes.4 Hyperalgesia is an exaggerated pain intensity perception for a painful stimuli.4 ‘‘Spontaneous’’ pain would occur in the absence of identified stimuli and is often considered a major clinical issue in the manifestation of a neuropathic pain state. Underlying inflammation or the physiologic consequences of the summation of allodynic and hyperalgesic stimuli during the course of time may contribute to the physiologic background of apparent ‘‘spontaneous’’ experiences.5 In Canada, the costs associated with chronic pain total more than those of cancer, heart disease, and human immunodeficiency virus combined, with direct health care costs reaching more than $6 billion per year.6 Overall, 60% of active people living with chronic pain will eventually lose their job, incur an income loss, or see their professional responsibilities decrease, depending on the level of disability incurred.6 The total cost to society amounts to $37 billion per year when global productivity loss and sick leaves are included.6Y8 This figure compares well with a recent evaluation

Submitted: September 24, 2013, Revised: January 2, 2014, Accepted: January 2, 2014. From the Department of Emergency Medicine, Research Centre (O.R., J.-M.C., E.P., J.P., R.D.), Centre for Advanced Research in Sleep Medicine, (J.P., G.L.), Hoˆpital du Sacre´-Coeur de Montre´al; Faculties of Medicine (J.-M.C., E.P., R.D.), and Dental Medicine and Medicine (G.L.), Universite´ de Montre´al, Montreal, Quebec, Canada. Address for reprints: Raoul Daoust, MD, MSc, De´partement de me´decine d’urgence, Hoˆpital du Sacre´-Coeur de Montre´al, 5400, boul. Gouin Ouest Montre´al (Que´bec) Canada H4J 1C5; email: [email protected]. DOI: 10.1097/TA.0000000000000188

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in the United States where the global financial cost was estimated to be $560 to $635 billion annually.9 We sought to explore the acute to chronic pain transition in posttraumatic patients and the potential of preemptive treatments in at-risk patients. To identify the prevalence, risk factors, and preemptive treatments of chronic pain in the trauma population, we queried the MEDLINE and EMBASE databases with Ovid. Boolean operators were used to create combinations of the following keywords: chronic pain, posttraumatic pain, risk factors, post-surgical pain, post-operative pain, spinal cord injury, traumatic brain injury, orthopedic- or limb trauma, burns, burn trauma, thoracic trauma, torso/chest trauma. We limited our search to humans and English or French languages. Relevant articles were identified by the authors from the abstract and the bibliography; disagreements were resolved by discussion. Studies on chronic pain in posttraumatic patients are relatively scarce, although chronic pain develops with significantly high prevalence in various types of posttraumatic patients (Table 1). Globally, chronic pain occurrence across all categories of trauma patients lies between 11% and 96%, depending on the nature of the traumas (as detailed below). A specialized workgroup from the International Association for the Study of Pain has subdivided the general diagnostic of ‘‘chronic pain’’ into more specific taxonomic groups in an effort to refine the current model of the clinical manifestations of chronic pain.10 Some of these detailed diagnostics refer to generalized pain syndromes, and others refer to specific locations in the neck, head, limbs, thorax, or internal organs and indicate their eventual link to musculoskeletal, neurologic or psychological components (e.g., spinal and radicular pain syndromes, stump pain, complex regional pain syndromes).10 Up to now, although chronic pain prevalence were reported for several trauma categories, only a few studies were designed to identify which were the factors that could be associated with a transition from acute to chronic pain. Psychosocial and medical aspects, such as lasting anxiety or depressive states, sleep disorders, acute pain intensity, sex, or age, are among the commonly proposed predisposing factors (discussed below). However, recent analyses generally conclude that methodological improvements in the design of clinical studies are first needed before robust risk profiles can be drawn for trauma patients.11Y13 The prevention of the closely related postsurgical chronic pain, which occurs after iatrogenic tissue injury, is documented more substantially and may constitute a practical source of information for trauma specialists. J Trauma Acute Care Surg Volume 76, Number 4

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Increased risk* Increased risk* Not associated*

Increased risk* V V V

Increased risk* V Increased risk*

V V V V

Increased risk*

Increased risk* OR, 2.3 (95% CI, 1.4Y3.6)

Increased risk*

OR, 1.5 (95% CI, 1.1Y1.9)

OR, 2.1 (95% CI, 1.6Y2.8) Inconsistent association*

11Y48% (77% in severe traumas)

Sex (women)

Education (lower)

Economic status (lower) Alcohol consumption

Chronic pain prevalence in patients

59%

V Increased risk*

V

V

V V

V

V Increased risk*

OR, 1.8 (95% CI, 1.4Y2.5)**

Thoracic Trauma

V OR, 2.3 (p G 0.05) 30%

Increased risk*

V

Increased risk* Increased risk*

Increased risk*

V Increased risk*

Increased risk*

Burns

10Y50%

Increased risk* V

Inconsistent association* Increased risk*

V Decreased risk*

Increased risk*

Increased risk* Increased risk*

Increased risk*

Postsurgical Chronic Pain

*Different authors have used different statistical models for the calculation of the associations; ORs cannot been reported. **The ‘‘prolonged pain’’ outcome was measured at 2 months. Em dashes mean that no data were identified in our search. The risk factors associated with chronic pain development are reported for the five major trauma categories and compared with those of postsurgical patients. CI, confidence interval; OR, odd ratio.

40Y75%

V Increased risk*

V Increased risk*

Presence of preinjury pain Severity or level of disability Psychological factors (e.g., depression, PTSD) Sleep dysfunction Age (older)

26Y96% (mean, 86%)

Increased risk*

TBI

Posttraumatic Chronic Pain SCI Increased risk*

Orthopedic Trauma

OR, 2.4 (95% CI, 1.8Y3.1); OR, 11.2 (95% CI, 2.0Y61.2) OR, 1.8 (95% CI, 1.3Y2.5) Increased risk*

Acute pain intensity

Potential Risk Factors 12

References Clay et al., Smith et al.,25 Fabricant et al.,26 Margot-Duclot et al.,34 Browne et al.,40 Macrae,50 VanDenKerkhof et al.53 Clay et al.,12 Macrae50 Clay et al.,12 Kerr-Valentic et al.,28 Hoffman et al.,41 VanDenKerkhof et al.53 Clay et al.,12 Smith et al.,25 Hoffman et al.,41 Macrae,50 VanDenKerkhof et al.53 Clay et al.,12 Smith et al.,25 Hoffman et al.41 Clay et al.,12 Smith et al.,25 Werhagen et al.,33 Macrae50 Clay et al.,12 Margot-Duclot et al.,34 Hoffman et al.41 Clay et al.,12 Smith et al.,25 Hoffman et al.,41 VanDenKerkhof et al.53 Clay et al.,12 VanDenKerkhof et al.53 Clay et al.,12 Kowalske et al.,21 Daoust et al.,27 Browne et al.40 Dijkers et al.,13 Castillo et al.,17 Williamson et al.,19 Moore and Leonardi-Bee,20 Schneider et al.,23 Fabricant et al.,26 Nampiaparampil36

TABLE 1. Summary Table of the Risk Factors Associated With Chronic Posttraumatic and Chronic Postsurgical Pain Developments

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Chronic Pain Prevalence and Associated Risk Factors in Different Trauma Types A 2011 Canadian national study indicated that the leading cause of hospitalization after major traumas was unintentional falls, accounting for approximately 40% of the cases, while motor vehicle collisions were responsible for a similar percentage.14 Falls are also the leading cause of trauma-related admissions in the United States.15 A recent study of blunt polytrauma survivors indicated that chronic pain prevalence affected between 46% and 85% of the patients 2 years after the initial injury.16 As highlighted below, large variations in chronic pain prevalence appear commonly across epidemiologic studies interested in specific trauma categories. Data on prevalence are summarized later with some major predisposing factors; they also appear in Table 1.

Orthopedic Traumas Only 23% of trauma patients reported a complete absence of pain 7 years after severe trauma of the lower limbs.17 A few early predictors of chronic pain were identified in orthopedic trauma patients; they included psychosocial and medical factors such as level of school education, disability in usual daily activities, and baseline alcohol consumption, with the latter being inconsistently related to an increased or a decreased chronic pain development.12 In addition, sleep dysfunction, depression, and anxiety at 3 months after discharge seemed strong predictors of chronic pain several years later.17,18 An epidemiologic study on orthopedic traumas reported a prevalence of chronic pain reaching 48% of trauma patients on average and identified a combination of social and medical risk factors. These included self-reported preinjury pain states, disability levels, the school education, the eligibility for compensation, and pain at discharge after treatment of the initial trauma.19 Considering only the simple distal fractures of the radius, chronic pain prevalence reached 11% and chronic pain at 1 year after injury was associated to the increasing need for pain medication during the time of fracture resolution (i.e., the acute pain phase).20 A more recent systematic review of the literature on orthopedic traumas highlighted that the strongest levels of association were obtained for age, sex, level of education, initial pain intensities, and presence of an underlying depression or anxiety state.12

Burn Patients Persistent neuropathic pain following burn injuries has been studied for sometime.21,22 The prevalence of chronic pain at 1 year after injury amounts to 30% in burn patients,23 and it seems to correlate with some of the risk factors already identified earlier. Namely, several types of psychiatric diagnoses were significantly associated with chronic pain. These were detailed in terms of posttraumatic stress disorder (PTSD) (22%), substance abuse (14%), and, to a lesser extent, depression and psychiatric medical history.23 Additional risk factors may also include a history of alcohol abuse and the patient’s age, which were both associated with the development of peripheral neuropathies.21 The severity of burn seems a major risk factor for subsequent neuropathic pain development;24 1144

this was equally true for the presence of hypertrophic scarring and pruritis.23 Finally, results from a prospective multisite study on major burn traumas indicated that insomnia at discharge was associated to an increase pain severity over the long term (6, 12, and 24 months).25 Here too, significant independent associations were noted and included the intensity of acute pain at discharge, the lack of college education, and an older age.25

Thoracic Traumas Considering the thoracic (chest) trauma population, a prospective pain study on 187 patients with severe thoracic traumas concluded that prolonged pain was a common morbidity and that its presence may be predicted from the level of acute pain in the first few days that followed the trauma.26 Although prolonged pain was only defined as pain lasting for 2 months, its prevalence was common among thoracic trauma patients and reached 59%.26 The data indicate that the chain of painful complications can be connected to the original intensity of the acute posttraumatic pain.26 Rib fractures are notoriously painful namely because of the difficulty to limit respiratory movements in the chest that inevitably affect the broken ribs. A prospective multisite study positively correlated the number of rib fractures, smoking habit, alcohol consumption, presence of dyspnea and asthma, and an initial oxygen saturation of less than 95% to the persistent pain level at 90 days.27 An independent study also correlated the number of fractured ribs to persistent pain at 120 days following the trauma;28 the authors concluded on the importance of a better control of acute pain in the first place, to prevent persistent pain on the long term.

Spinal Cord Injuries Spinal cord injury (SCI) patients typically manifest the highest prevalence of chronic pain with a reported prevalence ranging from 26% to 96% and an average at 86%. The calculation resulted from a systematic review of 42 high-quality clinical studies of SCI patients.13 Persistent pain after SCI is referred to as central pain because it derives from a central lesion to the spine. Pain sensation itself in SCI patients can be of visceral, musculoskeletal, or neuropathic origin, with the latter being the most debilitating form that often results in spontaneous, excruciating pain.29 Despite the high prevalence, the pathophysiologic mechanisms of chronic pain in SCI are poorly known. Physiologic investigations conducted to date refer to the loss of inhibitory inputs and to the increased hyperexcitability along the spinothalamic tract and somatosensory cortices. Neural and microglial (or astrocytic) cells also contribute to the pathophysiologic mechanisms in SCI (see Hulsebosch et al.30 for detailed review). Pain in SCI patients is commonly described as ‘‘at level,’’ ‘‘below level,’’ or ‘‘above level’’ according to the position of the referred painful dermatome with respect to the location of the spinal injury. Chronic pain was reported to occur at multiple sites in 40% of SCI patients.31 In an independent survey, it seemed that 81% of patients recounted chronic pain at 5 years after the original trauma and 58% reported severe-to-excruciating pain.32 At least for neuropathic pains, their intensities could be predicted * 2014 Lippincott Williams & Wilkins

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from the early acute pain ratings,32 although sex was not significantly associated to chronic pain development.33 Given the high prevalence of chronic pain in SCI patients (26Y91%), risk factors are rarely identified in this group, although an older age seems to be associated with an increased risk for chronic pain.33,34 Especially for SCI patients, with most patients presenting a high-risk profile of developing chronic pain following spinal injuries, any preventive strategies would potentially benefit a vast number of patients. The completeness of SCI (measured on an impairment scale) or the lesion location seem to constitute associated risk factors for the development of chronic pain.13,29 Persistent pain was coupled with a trend toward lower levels of psychological functioning and social integration that may constitute risk factors in SCI patients.35

Traumatic Brain Injuries In addition to SCI and orthopedic trauma, the traumatic brain injury (TBI) is another major trauma type triggering the development of posttraumatic chronic pain. A systematic review of civilians and war veterans with TBI identified that up to 75% of civilians with mild TBI and more than 40% of war veterans developed chronic pain.36 In both groups, PTSD seemed to correlate with the development of chronic pain states. In this regard, the chronic pain prevalence among Iraqi and Afghanistan war veterans who incurred TBI reached 70%, while PTSD alone affected 73%; 54% of war veterans presented both.37 These findings indicate a high prevalence and a significant cooccurrence of PTSD in TBI patients experiencing chronic pain.37 Sleep disorders are comorbidities commonly associated with TBI patients.38,39 Chronic pain development in TBI patients has been associated with acute pain intensity,40 states of depression, and lower overall functioning.41 It was also associated to cognitive deficits,11 impairment of sleep and sex (female at higher risk),41 but not with age.41 Moreover, these comorbidities seem to be interrelated in TBI patients who complain about the quality of their sleep.42 As in SCI patients, because of the high prevalence of chronic pain observed among TBI patients, the simple occurrence of TBI may be regarded as a significant predictor of a future transition toward a chronic pain state in the months or years after trauma injury. In summary, the prevalence of chronic pain in the major trauma categories is both high and variable. The difficulties are considerable in recognizing associated risk factors of robust predictive value. Nonetheless, the data raise the possibility of generating future predictive models that could be of general applicability and including descriptors of trauma characteristics and identifiable medical and psychosocial factors. At present although, among a few large-scale analyses,11Y13 only few studies were designed with that prognostic objective in mind. One largescale, multicenter study encompassing all categories of trauma patients (including orthopedic trauma, SCI, and TBI) indicated an overall chronic pain prevalence of 63% at 1 year after trauma. Pain scores at 3 months, sex, untreated underlying depression, and education seemed to constitute additional risk factors of general applicability.18 Posttraumatic chronic pain pertains to a large portion of the North American trauma population and a limited set of predictive factors reported to date indicates just how complex it is to identify which may be the leading risk

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factors of predictive values that will help us understand chronic pain development in trauma patients.

Clinical Models of Acute to Chronic Pain Transition in Adult Patients Clinical studies on the transition from acute to chronic pain usually derive from three types of acute pain origins: (1) postsurgical pain, (2) posttherapeutic neuralgia, and (3) posttraumatic pain.43 Perhaps, the most studied model of acute to chronic pain transition is the postsurgical model. Development of persistent postsurgical pain is akin to persistent posttraumatic pain in terms of underlying factors and physiologic changes that occur after tissue injuries.44 The prevalence of persistent postsurgical pain is also quite comparable with that observed in posttraumatic patients, with chronic pain affecting 10% to 50% of all individuals undergoing common surgeries.44 A recent systematic review of 11 different types of surgeries determined that thoracic and breast surgeries, followed closely by total hip and knee arthroplasties, were accountable for the highest prevalence of persistent postsurgical pain (Q3 months after the initial surgery).45 Here too, predictive factors, including psychological and social aspects, were identified in addition to the intensity of acute postsurgical pain level46Y50 (Table 1). Yet, both postsurgical and posttraumatic pain etiologies are complex, and the risk factors for a transition toward chronic pain states are still incompletely understood. As detailed later, in a large part, the risk factors of chronic pain development after surgery are similar to those observed in posttraumatic patients and include surgery procedures, underlying medical conditions, and psychosocial or sex variables. Based on these elements, a predictive model composing of a data set of six factors has recently been built to assess the risk of potential transition toward postsurgical chronic pain, specifically in women undergoing breast cancer surgery.51 Among the factors bearing the highest weight were age, preexisting pain state (acute or chronic), postsurgical medical complications, depressive or anxiety states, as well as alcohol and tobacco consumption. Here however, only factors of nonpsychosocial origin were included in the six-variable model, making it a tool of direct applicability by practitioners. Another study on women undergoing hysterectomy identified predictive factors of persistent postsurgical pain that included anxiety, pain catastrophizing, emotional distress, and pain control efficacy around or during surgery.52 In addition to the physiologic determinants related to tissue injury, other psychological factors are recognized as being common to postsurgical and posttraumatic chronic pain development. The authors of a systematic analysis on postsurgical persistent pain have proposed that a few identified core factors should be included by default in clinical studies aiming at a better understanding of the development of postsurgical chronic pain. These factors include demographic factors, pain levels, clinical aspects, as well as factors specific to the surgery and to the patient’s psychological state.53 As discussed earlier, similar approaches have been taken for posttraumatic chronic pain. Although usually focusing on specific trauma types, they resulted in the identification of a set of associated factors that were very similar in nature11,12,54 (Table 1). Naturally, as traumas care often involves surgical procedures, the exact boundaries

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between posttraumatic and postsurgical chronic pain are not clearly delineated in trauma patients. Therefore, information on predictive models and preventive treatments for postsurgical chronic pain development holds potential benefit also for posttraumatic pain patients. Finally, several reports indicate a prevalence of chronic pain higher than average among opiates drug abusers. Approximately 37% to 55.3% of drug users followed for methadone treatments met the criteria for chronic pain.55,56 Yet, to this date, the population of drug abusers has not been specifically looked at in clinical studies on the development of postsurgical or posttraumatic chronic pain. As such, the quantitative associations of drug abuse factors, although possibly bearing important effects, have not yet been assessed specifically in populations of postsurgical or posttraumatic patients.

Therapeutic Strategies for the Control of Acute Pain May Help Prevent the Transition From Acute to Chronic Pain States in the Long Term Preventive treatments for postinjury chronic pain (of surgical or traumatic origin) are typically based on behavioral, cognitive, and drug approaches. Strategies for chronic pain prevention follow two routes.43 ‘‘Primary prevention’’ is the prevention of acute pain in the first place and relies on preemptive analgesia. It is applicable preoperatively to avoid future postsurgical chronic pain development. In a context of scheduled surgeries, inevitable iatrogenic tissue injuries are anticipated and can be prepared for to limit the nociceptive load already at its very onset. However, primary prevention strategies cannot be applied in the context of unpredictable traumatic events. ‘‘Secondary prevention’’ partially relies on the control of acute pain after initial injury, as a way of preventing the transition from normal peripheral acute pain to maladaptive neural sensitization. For primary or secondary prevention, multimodal analgesic strategies can prove beneficial when any combination of the analgesic treatments exerts additive or synergistic effects. Once the chronic condition is diagnosed, possible drug treatments for chronic pain may involve combinations or individual treatment lines based on the use of cyclo-oxygenase blockers (COX),57 gabapentin,58 pregabalin,59 local analgesics (lidocaine, bupivacaine), ketamine (a N-methyl-D-aspartate receptor antagonist),60 antidepressants (duloxetine, venlafaxine), >-adrenergics adjuvants (clonidine, dexmedetomidine),61 or opioids.62 Despite some success for chronic pain treatment, their clinical efficacy in primary or secondary prevention strategies is still poorly documented. A few studies were specifically designed to characterize their therapeutic efficacy as preventive treatments and involved long-term patient follow-up (as detailed later). Additional efficacy data on the control of acute postinjury pain are presented as indicative of their potential application in primary or secondary prevention strategies.

COX-2 Blockers Systematic studies have established the efficacy of COX blockers in reducing postsurgical pain.48,63 Studies on the efficacy of perioperative or intraoperative COX blockers and their combinations with opioids indicated significant opioidsparing effects in orthopedic and thoracic surgeries as well as a reduced incidence of pain in the first days following surgery.64Y66 Concerns arose, however, about an eventual impairment of 1146

fracture healing caused by COX treatments that were reported in a few human and animal studies.67 Systematic reviews indicate that the evidence is still controverted,68,69 and the weak risks on short-term use of nonsteroidal anti-inflammatory drugs for bone healing should be weighed by their generally safe and good analgesic profile in trauma patients.70 Studies on the efficacy of nonsteroidal anti-inflammatory drugs in preventive strategies for cardiovascular diseases or cancer are ongoing, yet to date, no data were reported on their efficacy for the prevention of chronic pain.

Pregabalin and Gabapentin In an 18-week, placebo-controlled, double-blinded study on 20 paraplegic pain patients with complete SCI, gabapentin treatment improved significantly all measures of chronic pain.71 The observed improvements in anxiety and poor sleep constituted potentially helpful side effects for the control of associated comorbidities. In a placebo-controlled, multicenter study of 150 patients with posttraumatic SCI, daily pregabalin treatment (a gabapentin analog) was significantly more effective than placebo in reducing pain scores from Week 1 to Week 12 after treatment start.72 In another randomized, double-blind, placebocontrolled study of 40 patients experiencing central neuropathic painVhalf of them after SCIVpregabalin was moderately effective at 4 weeks after treatment start.73 Follow-up studies revealed that the overall gain in health measures persisted in the treatment group (assessed by the EQ-5D questionnaire), yet no differences in the Pain Disability Index were seen in the long term. A meta-analysis by the Cochrane group concluded that perioperative administrations of pregabalin and gabapentin were effective in preventing postsurgical chronic pain development.63 It is reasonable to assume that pregabalin may be useful in prevention strategies as well, where its broad spectrum of effects and side effects on pain, sleep, and anxiety would provide additional value. In this regard, perioperative treatment with pregabalin was shown to reduce chronic pain occurrence at 3 months and 6 months in the treatment group (0%) compared with placebo (8.7% and 5.2%) in a randomized, controlled study on 240 arthroplasty patients.74 These two drugs seem to be important components in effective prevention strategies.

Local Anesthetics In amputees at risk of developing chronic pain from their phantom limbs, mixed pain prevention efficacies were noted following spinal nerve blockade, with perioperative local anesthetics given epidurally or infused topically close to the peripheral nerves.75Y77 However, in a randomized study of 21 amputees, no differences in the prevalence of chronic pain at 12 months could be observed after local postsurgical nerve blockade for a short period (72 hours) with bupivacaine.76 Here however, patient-controlled intravenous administration of morphine was authorized for both groups, and it was significantly reduced in the bupivacaine group. In an open-label study, bupivacaine was used in postsurgical local anesthetic treatment for more than 30 days and showed its efficacy in decreasing chronic pain at 3, 6, and 12 months, but definitive confirmation will have to await double-blinded, randomized trial.78 A systematic analysis of 23 double-blind, randomized * 2014 Lippincott Williams & Wilkins

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trials including various local anesthetics concluded that their perioperative administration proved beneficial in the control of persistent postsurgical pain at 6 months and 1 year after surgery.79

Ketamine Complementary epidural ketamine treatment during surgery was shown to diminish postsurgical acute pain intensity but not its prevalence at 12 months following limb amputation.80 Similar conclusions were drawn on the short-term efficacy of systemic ketamine in SCI patients: pain sensation was decreased at 2 weeks with respect to controls but then stabilized at 3 weeks and 4 weeks after trauma.60 However, a randomized, double-blind study on disc herniation patients presenting with lumbar radiculopathy indicated that a single dosing of epidural ketamine in combination with steroid infusion produced significant analgesia starting at 1 week after injection and persisting at 12 months; the analgesic effects correlated with the doses of the ketamine treatment.81

Antidepressants Antidepressants of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, such as duloxetine and venlafaxine, are considered first-line treatments for neuropathic pain conditions.82 They are also recommended by the Neuropathic Pain Panel of the European Federation of Neurological Societies.83 Although SNRIs have been validated as neuropathic pain treatments, these conditions are usually not of posttraumatic origin (diabetic peripheral neuropathies, fibromyalgia, arthritis and low back pain); however, musculoskeletal injuries were also included in some studies.84 Clinical data suggest that antidepressants with dual inhibitory effects at serotonin and norepinephrine levels (duloxetine, maprotiline) constitute effective analgesics and opioid-sparing agents in acute pain conditions,60 making them potential adjuvants in secondary prevention strategies for posttraumatic chronic pain. Their primary indication as antidepressant may also provide an edge in controlling the associated risk factors and comorbidities associated with chronic pain. Yet, to date, no data were reported on their long-term efficacy for chronic pain prevention.

>2-Adrenergic Agonists (Clonidine, Dexmedetomidine)

The potential of >-adrenergic receptor agonists, especially those of the >2 type, as adjunct analgesics is well documented. The benefits of clonidine combinations with opioids for the prolongation of general anesthesia or for the peripheral nerve blockade when combined to local anesthetics have been reviewed extensively.85,86 The clinical use of dexmedetomidine, an >2-adrenergic agonist distinct from clonidine is not approved in the United States. Several meta-analyses have concluded that clonidine, administered intraoperatively as adjuvant to systemic local anesthetics or to intrathecal opioids, proved beneficial for the reduction of postsurgical pain episodes and for the duration of analgesia.87Y89 Given their efficacy in the control of perioperative acute pain, clonidine adjuvants may prove useful in secondary prevention strategies also after trauma

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surgery.90 Although their performance as adjuvant analgesics has been demonstrated for the short term, long-term studies on the prevention of chronic pain were not yet reported. Nonetheless, preliminary data from a pilot study on the epidural administration of clonidine, steroid, and lidocaine combination concluded on the potential benefits of clonidine addition in decreasing postsurgical chronic pain at 6 months following treatments.91

Opioids There is a large body of information on short-acting and long-acting opioids efficacy in established chronic pain conditions. In all cases, with prolonged opioid use, treatment strategies have to take into account known opioid adverse effects. An updated meta-analysis of prolonged opioid treatment in chronic pain states of noncancer origin confirmed a significant pain relief with long-term opioid treatments.92 Yet here, many patients had to discontinue their treatment because of insufficient pain relief or insufficient tolerance to the adverse effects. The overall modest level of pain relief experienced by a subgroup of opioid responders led to a reappraisal of guidelines on opioid’s use for noncancer chronic pain and to an invitation to consider multimodal pharmacologic treatments as replacement strategies for opioid-based monotherapies whenever possible.93

Multimodal Pharmacologic and Nonpharmacologic Strategies In practice, persistent pain experiences are diverse in nature and present complex etiologies. It is maybe not surprising if multimodal drug treatments targeting different biologic mechanisms along the pain neuraxis provide analgesic benefits with eventual dose-sparing effects when compared, for instance, to opioid monotherapies.94 Several of these successful pharmacotherapies based on analgesic combinations for the prevention of postsurgical chronic pain are presented previously. Administrations of clonidine, ketamine, COX blockers, or antidepres sants (including SNRIs) combined to opiates or local anesthetics have proven their superiority in the control of established chronic pain states.65 However, in view of the limited number of studies and interindividual variability, it is not easy to identify a ‘‘one-size-fits-all’’ multimodal treatment. For instance, combinations of adjuvant antidepressants with opioids have a broader spectrum of activity and show superior analgesic efficacy against acute pain when compared with monotherapies.60,95 Drug combinations are typically administered to control clinical neuropathic pain, especially in SCI patients. Here, gabapentin, pregabalin, antidepressants (SNRIs and amitriptyline), as well as cannabinoids have been used successfully to control neuropathic pain states in SCI patients and target complementary biologic mechanisms to mitigate the risks of tolerance and habituation.59 Many new combination analgesic treatments have proven successful in preclinical SCI animal models; it is expected that a fraction of these will translate to patients in the near term and hopefully provide similar benefits of analgesic synergism and complementation. In addition to multimodal drug treatment, psychological and cognitive therapies represent common complementary treatment options; long-term cognitive and behavioral treatments of chronic spinal pain have been

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proven effective.96 Here, patients following cognitive or behavioral therapies reported not only lower pain intensities but also a better ability to cope with their ongoing pain after that they had returned to work. Other complementary therapies such as massage therapy, activity therapy, acupuncture, and transcutaneous electrical stimulation (TENS) may be of use in the nonpharmacologic control of chronic pain. Among them, TENS treatments have been the subject of a large number of studies that have been studied in subsequent meta-analysis by the Cochrane group on analgesia.97,98 Although a definitive claim on TENS efficacy at the meta-analysis level was not possible, the authors concluded that in the few controlled studies, some positive analgesic outcomes were observed following active TENS treatments. Yet, overall, the majority of studies showed no differences in terms of efficacy between high-frequency and low-frequency stimulations. Additional controlled studies are needed to better understand the clinical advantages of TENS in the context of prevention strategies.

Current Status and Perspectives on Chronic Pain Prevention in Trauma Patients To date, most of our knowledge on preventive treatments for chronic pain development after tissue injury comes from progresses made with persistent postsurgical pain prevention. With respect to the surgery itself, some surgical procedures reviewed elsewhere may prove beneficial in reducing the risks for a transition toward chronic pain states.12,44,54,99,100 As seen earlier, several factors associated with chronic postsurgical pain development can be addressed with preemptive drug treatments that target acute pain in the first place, either as primary or secondary prevention strategies. Among them, multimodal treatments have already proven beneficial in a number of cases for the prevention of postsurgical chronic pain and present with additional potential for the control of associated comorbidities. However, their general applicability and therapeutic efficacy in trauma patients remain to be assessed clinically.

CONCLUSION Posttraumatic chronic pain represents a significant portion of the financial and social burdens caused by chronic pain in North America. Postsurgical and posttraumatic chronic pain conditions share several traits of physiopathology and etiology. This parallel may also apply to several predisposing risk factors; some are directly linked to trauma types, yet many others are linked to patient’s characteristics, including the responsiveness in the original phase of acute pain. It is reasonable to think that prevention strategies useful for postsurgical chronic pain might also be beneficial in the posttraumatic setting. Further studies are needed to determine which set of risk factors may be used in trauma patients to better characterize high-risk individuals and evaluate prospectively the efficacy of preventive strategies in this population. AUTHORSHIP All coauthors have seen and agree with the article’s contents. They all reviewed the final manuscript and agreed to publication. R.D. and J-M.C. conceived the study and obtained research funding. O.R., J-M.C.

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and R.D. performed the literature search as well as the article selection and interpretation. O.R. drafted the manuscript, and all authors contributed substantially to its revision. O.R. takes responsibility for the article as a whole.

DISCLOSURE The authors declare no conflicts of interest.

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