Am J Cardiovasc Drugs DOI 10.1007/s40256-014-0083-2
LEADING ARTICLE
Risk Factors and Early Pharmacological Interventions to Prevent Chronic Postsurgical Pain Following Cardiac Surgery Kari Hanne Gjeilo • Roar Stenseth Pa˚l Klepstad
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Ó Springer International Publishing Switzerland 2014
Abstract Chronic postsurgical pain (CPSP) after cardiac surgery represents a significant clinical problem. The prevalence of CPSP varies widely between studies, but severe CPSP is present in less than 10 % of the patients. Important differential diagnoses for CPSP after cardiac surgery are myocardial ischemia, sternal instability and mediastinitis. CPSP after cardiac surgery may be thoracic pain present at the site of the sternotomy or leg pain due to vein-graft harvesting. The CPSP can be neuropathic pain, visceral pain, somatic pain or mixed pain. Potential risk factors for CPSP are young age, female gender, overweight, psychological factors, preoperative pain,
K. H. Gjeilo (&) Department of Cardiothoracic Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway e-mail: [email protected] K. H. Gjeilo Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway K. H. Gjeilo National Competence Centre for Complex Symptom Disorders, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway K. H. Gjeilo R. Stenseth P. Klepstad Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
surgery-related factors and severe postoperative pain. In addition to standard postoperative analgesics, the use of Nmethyl-D-aspartate (NMDA) antagonists, alpha-2 agonists, local anesthetics, gabapentinoids, and corticosteroids are all proposed to reduce the risk for CPSP after cardiac surgery. Still, no specific pharmacological therapy, cognitive therapy or physical therapy is established to protect against CPSP. The only convincing prevention of CSPS is adequate treatment of acute postoperative pain irrespective of method. Hence, interventions against acute pain, preferably in a step-wise approach titrating the interventions for each patient’s individual needs, are essential concerning prevention of CPSP after cardiac surgery. It is also important that surgeons consider the risk for CPSP as a part of the basis for decisionmaking around performing a surgical procedure and that patients are informed of this risk.
Key Points Up to one tenth of cardiac surgery patients develop severe chronic postsurgical pain. No specific therapy is established to protect against chronic postsurgical pain. Adequate treatment of acute postoperative pain may minimize the risk for chronic postsurgical pain.
R. Stenseth Department of Cardiothoracic Anaesthesiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
1 Introduction P. Klepstad Department of Anaesthesiology and Intensive Care Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
Chronic postsurgical pain (CPSP) is a common complication after most surgical procedures [1, 2], cardiac surgery
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included [1, 3]. CPSP after cardiac surgery disturbs daily life and interferes with sleep, mood and health-related quality of life (HRQOL) [4–8]. Thus, pain that persists after the surgical wound has healed is a major clinical problem [1]. Despite this, CPSP, both in general and after cardiac surgery, is often not diagnosed or treated [9, 10]. Given the large number of patients who undergo cardiac surgery, even a 10 % risk of persistent pain has a major epidemiological significance. Therefore, identifying risk factors for and potential treatment of CPSP is important [10]. The aim of the current paper was to review risk factors and prevention of CPSP after cardiac surgery through sternotomy.
2 Prevalence, Mechanisms and Risk Factors 2.1 Prevalence The prevalence of CPSP after cardiac surgery varies widely in different populations, with observed numbers from 11 to 56 % [5, 7, 11–13]. However, the number of patients reporting severe, disabling pain is quite consistently about 2–10 % [4–6, 12]. The prevalence of CPSP has generally been reported to decrease over time after surgery [14–17]. This is also exemplified in a study by Choinie`re et al. [13], who found CPSP prevalence to be 40.1 % at 3 months, 22.1 % at 6 months, 16.5 % at 12 months and 9.5 % at 24 months after cardiac surgery. The prevalence depends on the patient population, the assessment method, retrospective or prospective design, and the definition of CPSP. The following criteria, originally proposed by Macrae [3], are widely used to define CPSP [6, 11, 18, 19]: (1) the pain developed after a surgical procedure; (2) other causes for pain have been excluded; (3) the possibility that pain is continuing from a pre-existing problem has been explored and excluded; and (4) the pain is of at least 2 months duration. However, most studies follow the established definition of chronic pain by the International Association for the Study of Pain (IASP), which includes a duration of 3 months or more [5, 20, 21]. The prevalence may also depend on the location of pain. Studies on CPSP after cardiac surgery have often focused on pain related to the sternotomy [7, 11, 22, 23]. However, CPSP may also be related to leg pain due to vein-graft harvesting for coronary artery bypass grafting (CABG) [4, 5, 12]. Some studies have found that patients with pain both at the leg and sternum site have more intense pain [4, 6]. Pain from other sites such as the head, neck, back and upper extremities is also reported to appear frequently after cardiac surgery [6, 24].
2.2 Mechanisms and Risk Factors CPSP develops through complex mechanisms. The development of chronic pain may be due to both peripheral and central sensitization caused by the acute pain and by changes caused by direct neuronal damage during surgery [25, 26]. The resulting pain may both be somatic, visceral or neuropathic [27, 28]. Whether the biological changes are a result of the surgical trauma, neuroplastic changes induced by the operation, a lack of adequate analgesia, or preoperative predisposing factors has not been clarified [1]. Even if the role of acute pain in the development of chronic pain is unknown, acute pain may be viewed as an initial phase of pain responses that has the potential to progress to chronic pain [1, 29]. The multiple biological systems with a potential to be involved in the pathophysiology of CPSP have been recently reviewed by Deumens et al. [30]. Despite the fact that the mechanisms of CPSP are not clear, a number of risk factors for CPSP in general have been identified [1–3, 31]. Preoperative pain, psychological vulnerability, repeat surgery, nerve damage and acute postoperative pain are all factors suggested to contribute to CPSP. Psychological factors that heighten pain sensitivity are also predictors of chronic pain. Furthermore, genetic predisposition is in some studies shown to be associated with an increased frequency or intensity of chronic pain [1, 31–33]. The most studied genes involved are the catecholO-methyltransferase (COMT) gene and the GTP cyclohydrolase 1 gene [34]. However, no studies have assessed if such genetic risk factors also are relevant specifically for CPSP after cardiac surgery. Risk factors for CPSP after cardiac surgery are not well established. However, potential risk factors are illustrated in Fig. 1. Studies have found patient-related factors such as younger age [4, 6, 8, 12], increased body mass index [4] and female gender [8, 13, 24] predict CPSP. Furthermore, psychological factors are believed to be important. High levels of preoperative anxiety, depression and catastrophizing, which is a tendency to magnify the threat value of pain and to feel helpless in the context of pain, are associated with higher rates of CPSP [35–37]. Presence of preoperative pain is also found to be a risk factor for the development of CPSP after cardiac surgery [8]. Studies on CABG patients have found that patients who developed CPSP had more presurgery coronary-related pain than those without [27]. In a prospective study of CPSP, we found that patients with CPSP reported higher pain scores and also lower HRQOL before surgery, suggesting that patients likely to develop CPSP after cardiac surgery are a subset of a vulnerable group of patients [6]. Furthermore, Choinie`re et al. [13] found that patients with nonanginal pain before surgery were at significantly increased risk of CPSP.
Risk Factors and Prevention of Chronic Pain Following Cardiac Surgery Fig. 1 Potential risk factors for chronic postsurgical pain (CPSP) following cardiac surgery. REDO Repeat Cardiac Surgery
Preoperative pain Younger age
Female gender
Acute postoperative pain
CPSP
REDO surgery
Over weight
Psychological vulnerability
Surgery-related factors such as emergency surgery, type of cardiac surgery (e.g., CABG, heart valve surgery or combined surgery), re-sternotomy during hospital admission, surgical technique and duration of surgery [8], and previous cardiac surgery are all suggested as risk factors for the development of CPSP after cardiac surgery. However, the present evidence related to the role of these factors remains inconclusive [13]. The immediate postoperative course may also have implications for the development of chronic pain. More pain and higher requirements for analgesics during the first postoperative days after cardiac surgery have been associated with increased risk of CPSP [5, 8] as well as pain in the first weeks after surgery [12, 23]. Whether this observation simply reflects that more complex surgery results in both more postoperative pain and a higher risk for CPSP, or whether inadequately treated postoperative pain in itself increases the risk for CPSP, is not known. Thus, whether the relationships between acute pain and CPSP are associative or causal is unclear and part of an ongoing debate [13, 31]. Intraoperative use of remifentanil has been associated with acute hyperalgesia, but conflicting results have been
Surgical factors
Genetic predisposition
reported [38–40]. Higher intraoperative doses of remifentanil were associated with CPSP 1 year after cardiac surgery [41]. However, the role of remifentanil as a trigger of CPSP is still under debate.
3 Pharmacological Approaches to Prevent CPSP 3.1 Acute Pain The most common source of acute postoperative pain, in addition to pain from the surgical incision, is pain from the chest wall. Sternal retraction results in a trauma to muscles, bones, tendons and ligaments. A local inflammatory component will usually follow a surgical insult, in addition to a general inflammatory response due to cardiopulmonary bypass (CPB) [1]. If nerves are injured during surgery, a neuropathic component of the pain might develop immediately and then persist in the absence of any peripheral noxious stimulus or ongoing peripheral inflammation [1]. Opioids have been the cornerstone in the treatment of acute pain after cardiac surgery for decades. There are several alternative opioid agents, each with unique
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pharmacological characteristics, which give differences in time of onset and duration of action. Among the most commonly used opioids for postoperative pain relief are morphine, fentanyl, and oxycodone [42]. In addition, a number of other opioids with specific indications (i.e., alfentanil and remifentanil, which are mainly used during surgery) and those only used in some countries (i.e., ketobemidone in Scandinavia) are available. There is no convincing evidence that one opioid is universally better than another [43], but for an individual patient, one opioid can have a better effect versus adverse effect profile than others. The opioids can be given by several routes. Usually intravenous administration is used in the acute care setting and for unstable pain, while oral opioids are preferred for more stable long-standing pain. In addition to opioids, non-opioid analgesia with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) is frequently used. Paracetamol reduces the dose of opioid required [44]. Reduction in the overall dose of opioid can reduce opioid-induced adverse effects. Absorption of paracetamol after oral or rectal administration is unpredictable, and intravenous administration may be preferred for the first 24 h after surgery [45]. NSAIDs, with a documented opioid sparing effect, are popular after non-cardiac surgery, as part of a multimodal analgesic regimen, but are less frequently used in cardiac surgery [46, 47]. Cardiac surgery patients regularly receive platelet inhibitors until the day of surgery. An increased risk for postoperative bleeding in such patients after CPB can cause some reluctance to administer NSAIDs [48]. These drugs may also increase the risk for renal insufficiency in susceptible cardiac surgery patients [48]. However, NSAIDs are potent analgesics, in particular with regard to myofascial pain and pain from mediastinal drains. Therefore, NSAIDs may be used for short periods in selected patients who have a normal preoperative renal function and are not bleeding after surgery [49]. In addition to standard therapy with opioid and nonopioid treatment, a number of other medications have been added either to improve postoperative analgesia or to reduce sensitization and the risk of chronic pain. These medications include drugs from several classes. 1.
The N-methyl-D-aspartate (NMDA) blocker ketamine, a noncompetitive NMDA receptor antagonist, may prevent opioid-induced analgesic tolerance and hyperalgesia [50]. In some studies, it has also been shown to reduce acute postoperative pain and opioid requirements [51]. Because of its psychotomimetic side effects, the use of ketamine in large doses is generally restricted to the intraoperative period, or, alternatively, it may be given in sub-anesthetic doses postoperatively.
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The alpha-2 agonists clonidine and dexmedetomidin will provide both analgesia and sedation in addition to sympatholysis, which may be beneficial in cardiac surgery. However, sedation is less favorable, as modern fast-track cardiac surgery will include early mobilization and activation [30, 52]. Intravenous infusion of local anesthetics, most often lidocaine, has in numerous clinical studies been shown to reduce postoperative pain and morphine requirements [30, 53–55]. This reduction of pain may be caused by an antihyperalgesic action [30]. The gabapentinoids gabapentin and pregabalin may prevent the establishment of surgery-induced central sensitization and have in some studies been shown to be effective in the treatment of acute postoperative pain [56, 57]. Pre-incisional use of methylprednisolone has been used to reduce postoperative pain after surgery [58]. Corticosteroid therapy, whether used in high or low doses, attenuates the inflammatory responses to cardiac surgery and CPB. One smaller study suggests a beneficial effect of reduced doses of steroids on pain after cardiac surgery [59]. However, the use of steroids in cardiac surgery patients remains controversial [59– 61]. Corticosteroids have multiple potential adverse effects, and the cost–benefit analyses of corticosteroid must be assessed for each particular group of patients. Regional techniques like intercostal, paravertebral and spinal or epidural local anesthetic blocks have been recommended as useful analgesic techniques after cardiac surgery [62–64]. However, cardiac surgery patients regularly receive antithrombotic and antiplatelet drugs before surgery, during surgery they are on CPB with full heparinization, and they receive antithrombotic and antiplatelet drugs after surgery. Therefore, because of the risk of bleeding, regional techniques are used sparingly [65, 66].
3.2 Effect of Treatment of Acute Pain on Development of CPSP There is no substantial evidence that the use of specific drug agents, opioid or non-opioid analgesics, co-analgesics or regional anesthesia reduces the risk of CPSP [30, 31, 67]. However, some promising results are reported, for example, for gabapentin and pregabalin in non-cardiac surgery [57, 68]. More likely it is the reduction of acute pain that may reduce the risk for CPSP. Therefore, the current advice is to use the analgesics needed to provide optimal postoperative pain relief. The choice of analgesics may be based upon individual considerations and local hospital routines. Irrespective of the choice of medications,
Risk Factors and Prevention of Chronic Pain Following Cardiac Surgery
pain should be adequately monitored in all patients and a step-wise approach with increasing doses or additional medications used to decrease severe postoperative pain. Evidence to support the protective effect of an analgesic regimen in cardiac surgery is either lacking or limited [13, 69]. The few studies suggesting some effect on the risk for developing CPSP include the use of epidural analgesia [70], pregabalin [71] and gabapentin [56]. The evidence from these studies is not sufficient to change clinical practice. The lack of convincing evidence related to the effect of specific drugs on the development of CPSP after cardiac surgery may be due to small study samples and the relatively low prevalence of severe CPSP. In addition, the underlying mechanisms are complex, and to believe that one single treatment is effective may be an unrealistic oversimplification.
4.1 Evaluation and Treatment of Chronic Pain Myocardial ischemia, sternal instability and mediastinitis should be ruled out in every cardiac surgery patient presenting with chest pain, and the appropriate non-surgical or surgical therapy should be initiated. Also, sternal wire removal may be considered, as it is an effective treatment for pain in a subgroup of cardiac surgery patients [76, 77]. If these specific causes of pain are not present, referral to a chronic pain management specialist is recommended. A pain clinic will evaluate the pain through an interdisciplinary approach and initiate physical, cognitive and pharmacological treatment. The principles for evaluation and treatment of CPSP are similar to those used for other chronic pain diagnoses.
5 Conclusion 4 Non-pharmacological Approaches to Prevent CPSP Studies of non-pharmacological approaches to prevent CPSP after cardiac surgery are scarce. As CPSP may be related to the nerve injury and tissue trauma, nerve-sparing techniques and less extensive surgery may prevent both acute pain and CPSP. Studies on the impact of performing surgery through ‘‘mini’’ sternotomy have mixed results concerning postoperative pain, and are inconclusive. Still, alternative minimally invasive surgically techniques may also provide a pain benefit for cardiac patients [69]. Patient education may play an important role in the prevention of CPSP. Patients undergoing cardiac surgery might not be aware of the risk of chronic pain and its potential detrimental effects on their well-being. Several barriers to adequate pain management after cardiac surgery have been identified [72]. Patients may not use adequate analgesics for postoperative pain, because of fear of addiction and adverse effects. They may also hold beliefs about being a ‘‘good’’ patient and therefore not complain about pain. Some patients also believe that pain medication should be saved in case the pain worsens [67, 72]. Lee at el. [73] found that patients with a negative belief in opioid use had more CPSP 3 months after cardiac surgery. The development of fast-track cardiac surgery has reduced the duration of the hospital stay. Shorter in-hospital stay obviously gives a shorter period where analgesics are administered by health care workers and less time for patient education [74, 75]. This may reduce patient adherence to pain medication regimens after discharge [75]. The subsequent subacute period, when the patient is responsible for pain management, may be more important than previously thought in preventing CPSP.
The potential development of CPSP after cardiac surgery is an important clinical challenge and should be discussed in preoperative counseling of patients as a part of the decision-making and informed consent for surgery [78]. Patient education and decision-making must be reliable and up to date. Hence, older and retrospective studies should not be the foundation for decision-making. A prevalence of about 50–60 % in these older studies may be an overestimation of the problem [1]. Current prospective studies report an overall prevalence from 9.5 to 35 % and numbers below 10 % for severe pain [6, 8, 11, 13]. The lower prevalence of CPSP in current studies may, in addition to better methodology, reflect an improvement in treatment and care along the pain trajectory of cardiac surgery patients. Pharmacological studies of specific interventions to protect against the development of CPSP have been disappointing. However, there is an association between the intensity of acute postoperative pain and CPSP. Hence, interventions to decrease acute pain should be considered important in the prevention of CPSP after cardiac surgery. Acute postoperative pain after cardiac surgery is usually treated with a combination of opioids and paracetamol, but a number of other agents may be used. Irrespective of the choices made regarding opioids, route and co-analgesics, the patient should receive the medications needed to provide optimal pain relief. CPSP is a serious and important complication after cardiac surgery that may interfere with daily activities and HRQOL. Therefore, not only treatment, but also prevention of CPSP is essential. Acknowledgments K.H. Gjeilo, R. Stenseth and P. Klepstad have no conflicts of interest to declare related to the content of this article. No funding was received for the preparation of the manuscript.
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LEADING ARTICLE
Risk Factors and Early Pharmacological Interventions to Prevent Chronic Postsurgical Pain Following Cardiac Surgery Kari Hanne Gjeilo • Roar Stenseth Pa˚l Klepstad
•
Ó Springer International Publishing Switzerland 2014
Abstract Chronic postsurgical pain (CPSP) after cardiac surgery represents a significant clinical problem. The prevalence of CPSP varies widely between studies, but severe CPSP is present in less than 10 % of the patients. Important differential diagnoses for CPSP after cardiac surgery are myocardial ischemia, sternal instability and mediastinitis. CPSP after cardiac surgery may be thoracic pain present at the site of the sternotomy or leg pain due to vein-graft harvesting. The CPSP can be neuropathic pain, visceral pain, somatic pain or mixed pain. Potential risk factors for CPSP are young age, female gender, overweight, psychological factors, preoperative pain,
K. H. Gjeilo (&) Department of Cardiothoracic Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway e-mail: [email protected] K. H. Gjeilo Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway K. H. Gjeilo National Competence Centre for Complex Symptom Disorders, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway K. H. Gjeilo R. Stenseth P. Klepstad Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
surgery-related factors and severe postoperative pain. In addition to standard postoperative analgesics, the use of Nmethyl-D-aspartate (NMDA) antagonists, alpha-2 agonists, local anesthetics, gabapentinoids, and corticosteroids are all proposed to reduce the risk for CPSP after cardiac surgery. Still, no specific pharmacological therapy, cognitive therapy or physical therapy is established to protect against CPSP. The only convincing prevention of CSPS is adequate treatment of acute postoperative pain irrespective of method. Hence, interventions against acute pain, preferably in a step-wise approach titrating the interventions for each patient’s individual needs, are essential concerning prevention of CPSP after cardiac surgery. It is also important that surgeons consider the risk for CPSP as a part of the basis for decisionmaking around performing a surgical procedure and that patients are informed of this risk.
Key Points Up to one tenth of cardiac surgery patients develop severe chronic postsurgical pain. No specific therapy is established to protect against chronic postsurgical pain. Adequate treatment of acute postoperative pain may minimize the risk for chronic postsurgical pain.
R. Stenseth Department of Cardiothoracic Anaesthesiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
1 Introduction P. Klepstad Department of Anaesthesiology and Intensive Care Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
Chronic postsurgical pain (CPSP) is a common complication after most surgical procedures [1, 2], cardiac surgery
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included [1, 3]. CPSP after cardiac surgery disturbs daily life and interferes with sleep, mood and health-related quality of life (HRQOL) [4–8]. Thus, pain that persists after the surgical wound has healed is a major clinical problem [1]. Despite this, CPSP, both in general and after cardiac surgery, is often not diagnosed or treated [9, 10]. Given the large number of patients who undergo cardiac surgery, even a 10 % risk of persistent pain has a major epidemiological significance. Therefore, identifying risk factors for and potential treatment of CPSP is important [10]. The aim of the current paper was to review risk factors and prevention of CPSP after cardiac surgery through sternotomy.
2 Prevalence, Mechanisms and Risk Factors 2.1 Prevalence The prevalence of CPSP after cardiac surgery varies widely in different populations, with observed numbers from 11 to 56 % [5, 7, 11–13]. However, the number of patients reporting severe, disabling pain is quite consistently about 2–10 % [4–6, 12]. The prevalence of CPSP has generally been reported to decrease over time after surgery [14–17]. This is also exemplified in a study by Choinie`re et al. [13], who found CPSP prevalence to be 40.1 % at 3 months, 22.1 % at 6 months, 16.5 % at 12 months and 9.5 % at 24 months after cardiac surgery. The prevalence depends on the patient population, the assessment method, retrospective or prospective design, and the definition of CPSP. The following criteria, originally proposed by Macrae [3], are widely used to define CPSP [6, 11, 18, 19]: (1) the pain developed after a surgical procedure; (2) other causes for pain have been excluded; (3) the possibility that pain is continuing from a pre-existing problem has been explored and excluded; and (4) the pain is of at least 2 months duration. However, most studies follow the established definition of chronic pain by the International Association for the Study of Pain (IASP), which includes a duration of 3 months or more [5, 20, 21]. The prevalence may also depend on the location of pain. Studies on CPSP after cardiac surgery have often focused on pain related to the sternotomy [7, 11, 22, 23]. However, CPSP may also be related to leg pain due to vein-graft harvesting for coronary artery bypass grafting (CABG) [4, 5, 12]. Some studies have found that patients with pain both at the leg and sternum site have more intense pain [4, 6]. Pain from other sites such as the head, neck, back and upper extremities is also reported to appear frequently after cardiac surgery [6, 24].
2.2 Mechanisms and Risk Factors CPSP develops through complex mechanisms. The development of chronic pain may be due to both peripheral and central sensitization caused by the acute pain and by changes caused by direct neuronal damage during surgery [25, 26]. The resulting pain may both be somatic, visceral or neuropathic [27, 28]. Whether the biological changes are a result of the surgical trauma, neuroplastic changes induced by the operation, a lack of adequate analgesia, or preoperative predisposing factors has not been clarified [1]. Even if the role of acute pain in the development of chronic pain is unknown, acute pain may be viewed as an initial phase of pain responses that has the potential to progress to chronic pain [1, 29]. The multiple biological systems with a potential to be involved in the pathophysiology of CPSP have been recently reviewed by Deumens et al. [30]. Despite the fact that the mechanisms of CPSP are not clear, a number of risk factors for CPSP in general have been identified [1–3, 31]. Preoperative pain, psychological vulnerability, repeat surgery, nerve damage and acute postoperative pain are all factors suggested to contribute to CPSP. Psychological factors that heighten pain sensitivity are also predictors of chronic pain. Furthermore, genetic predisposition is in some studies shown to be associated with an increased frequency or intensity of chronic pain [1, 31–33]. The most studied genes involved are the catecholO-methyltransferase (COMT) gene and the GTP cyclohydrolase 1 gene [34]. However, no studies have assessed if such genetic risk factors also are relevant specifically for CPSP after cardiac surgery. Risk factors for CPSP after cardiac surgery are not well established. However, potential risk factors are illustrated in Fig. 1. Studies have found patient-related factors such as younger age [4, 6, 8, 12], increased body mass index [4] and female gender [8, 13, 24] predict CPSP. Furthermore, psychological factors are believed to be important. High levels of preoperative anxiety, depression and catastrophizing, which is a tendency to magnify the threat value of pain and to feel helpless in the context of pain, are associated with higher rates of CPSP [35–37]. Presence of preoperative pain is also found to be a risk factor for the development of CPSP after cardiac surgery [8]. Studies on CABG patients have found that patients who developed CPSP had more presurgery coronary-related pain than those without [27]. In a prospective study of CPSP, we found that patients with CPSP reported higher pain scores and also lower HRQOL before surgery, suggesting that patients likely to develop CPSP after cardiac surgery are a subset of a vulnerable group of patients [6]. Furthermore, Choinie`re et al. [13] found that patients with nonanginal pain before surgery were at significantly increased risk of CPSP.
Risk Factors and Prevention of Chronic Pain Following Cardiac Surgery Fig. 1 Potential risk factors for chronic postsurgical pain (CPSP) following cardiac surgery. REDO Repeat Cardiac Surgery
Preoperative pain Younger age
Female gender
Acute postoperative pain
CPSP
REDO surgery
Over weight
Psychological vulnerability
Surgery-related factors such as emergency surgery, type of cardiac surgery (e.g., CABG, heart valve surgery or combined surgery), re-sternotomy during hospital admission, surgical technique and duration of surgery [8], and previous cardiac surgery are all suggested as risk factors for the development of CPSP after cardiac surgery. However, the present evidence related to the role of these factors remains inconclusive [13]. The immediate postoperative course may also have implications for the development of chronic pain. More pain and higher requirements for analgesics during the first postoperative days after cardiac surgery have been associated with increased risk of CPSP [5, 8] as well as pain in the first weeks after surgery [12, 23]. Whether this observation simply reflects that more complex surgery results in both more postoperative pain and a higher risk for CPSP, or whether inadequately treated postoperative pain in itself increases the risk for CPSP, is not known. Thus, whether the relationships between acute pain and CPSP are associative or causal is unclear and part of an ongoing debate [13, 31]. Intraoperative use of remifentanil has been associated with acute hyperalgesia, but conflicting results have been
Surgical factors
Genetic predisposition
reported [38–40]. Higher intraoperative doses of remifentanil were associated with CPSP 1 year after cardiac surgery [41]. However, the role of remifentanil as a trigger of CPSP is still under debate.
3 Pharmacological Approaches to Prevent CPSP 3.1 Acute Pain The most common source of acute postoperative pain, in addition to pain from the surgical incision, is pain from the chest wall. Sternal retraction results in a trauma to muscles, bones, tendons and ligaments. A local inflammatory component will usually follow a surgical insult, in addition to a general inflammatory response due to cardiopulmonary bypass (CPB) [1]. If nerves are injured during surgery, a neuropathic component of the pain might develop immediately and then persist in the absence of any peripheral noxious stimulus or ongoing peripheral inflammation [1]. Opioids have been the cornerstone in the treatment of acute pain after cardiac surgery for decades. There are several alternative opioid agents, each with unique
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pharmacological characteristics, which give differences in time of onset and duration of action. Among the most commonly used opioids for postoperative pain relief are morphine, fentanyl, and oxycodone [42]. In addition, a number of other opioids with specific indications (i.e., alfentanil and remifentanil, which are mainly used during surgery) and those only used in some countries (i.e., ketobemidone in Scandinavia) are available. There is no convincing evidence that one opioid is universally better than another [43], but for an individual patient, one opioid can have a better effect versus adverse effect profile than others. The opioids can be given by several routes. Usually intravenous administration is used in the acute care setting and for unstable pain, while oral opioids are preferred for more stable long-standing pain. In addition to opioids, non-opioid analgesia with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) is frequently used. Paracetamol reduces the dose of opioid required [44]. Reduction in the overall dose of opioid can reduce opioid-induced adverse effects. Absorption of paracetamol after oral or rectal administration is unpredictable, and intravenous administration may be preferred for the first 24 h after surgery [45]. NSAIDs, with a documented opioid sparing effect, are popular after non-cardiac surgery, as part of a multimodal analgesic regimen, but are less frequently used in cardiac surgery [46, 47]. Cardiac surgery patients regularly receive platelet inhibitors until the day of surgery. An increased risk for postoperative bleeding in such patients after CPB can cause some reluctance to administer NSAIDs [48]. These drugs may also increase the risk for renal insufficiency in susceptible cardiac surgery patients [48]. However, NSAIDs are potent analgesics, in particular with regard to myofascial pain and pain from mediastinal drains. Therefore, NSAIDs may be used for short periods in selected patients who have a normal preoperative renal function and are not bleeding after surgery [49]. In addition to standard therapy with opioid and nonopioid treatment, a number of other medications have been added either to improve postoperative analgesia or to reduce sensitization and the risk of chronic pain. These medications include drugs from several classes. 1.
The N-methyl-D-aspartate (NMDA) blocker ketamine, a noncompetitive NMDA receptor antagonist, may prevent opioid-induced analgesic tolerance and hyperalgesia [50]. In some studies, it has also been shown to reduce acute postoperative pain and opioid requirements [51]. Because of its psychotomimetic side effects, the use of ketamine in large doses is generally restricted to the intraoperative period, or, alternatively, it may be given in sub-anesthetic doses postoperatively.
2.
3.
4.
5.
6.
The alpha-2 agonists clonidine and dexmedetomidin will provide both analgesia and sedation in addition to sympatholysis, which may be beneficial in cardiac surgery. However, sedation is less favorable, as modern fast-track cardiac surgery will include early mobilization and activation [30, 52]. Intravenous infusion of local anesthetics, most often lidocaine, has in numerous clinical studies been shown to reduce postoperative pain and morphine requirements [30, 53–55]. This reduction of pain may be caused by an antihyperalgesic action [30]. The gabapentinoids gabapentin and pregabalin may prevent the establishment of surgery-induced central sensitization and have in some studies been shown to be effective in the treatment of acute postoperative pain [56, 57]. Pre-incisional use of methylprednisolone has been used to reduce postoperative pain after surgery [58]. Corticosteroid therapy, whether used in high or low doses, attenuates the inflammatory responses to cardiac surgery and CPB. One smaller study suggests a beneficial effect of reduced doses of steroids on pain after cardiac surgery [59]. However, the use of steroids in cardiac surgery patients remains controversial [59– 61]. Corticosteroids have multiple potential adverse effects, and the cost–benefit analyses of corticosteroid must be assessed for each particular group of patients. Regional techniques like intercostal, paravertebral and spinal or epidural local anesthetic blocks have been recommended as useful analgesic techniques after cardiac surgery [62–64]. However, cardiac surgery patients regularly receive antithrombotic and antiplatelet drugs before surgery, during surgery they are on CPB with full heparinization, and they receive antithrombotic and antiplatelet drugs after surgery. Therefore, because of the risk of bleeding, regional techniques are used sparingly [65, 66].
3.2 Effect of Treatment of Acute Pain on Development of CPSP There is no substantial evidence that the use of specific drug agents, opioid or non-opioid analgesics, co-analgesics or regional anesthesia reduces the risk of CPSP [30, 31, 67]. However, some promising results are reported, for example, for gabapentin and pregabalin in non-cardiac surgery [57, 68]. More likely it is the reduction of acute pain that may reduce the risk for CPSP. Therefore, the current advice is to use the analgesics needed to provide optimal postoperative pain relief. The choice of analgesics may be based upon individual considerations and local hospital routines. Irrespective of the choice of medications,
Risk Factors and Prevention of Chronic Pain Following Cardiac Surgery
pain should be adequately monitored in all patients and a step-wise approach with increasing doses or additional medications used to decrease severe postoperative pain. Evidence to support the protective effect of an analgesic regimen in cardiac surgery is either lacking or limited [13, 69]. The few studies suggesting some effect on the risk for developing CPSP include the use of epidural analgesia [70], pregabalin [71] and gabapentin [56]. The evidence from these studies is not sufficient to change clinical practice. The lack of convincing evidence related to the effect of specific drugs on the development of CPSP after cardiac surgery may be due to small study samples and the relatively low prevalence of severe CPSP. In addition, the underlying mechanisms are complex, and to believe that one single treatment is effective may be an unrealistic oversimplification.
4.1 Evaluation and Treatment of Chronic Pain Myocardial ischemia, sternal instability and mediastinitis should be ruled out in every cardiac surgery patient presenting with chest pain, and the appropriate non-surgical or surgical therapy should be initiated. Also, sternal wire removal may be considered, as it is an effective treatment for pain in a subgroup of cardiac surgery patients [76, 77]. If these specific causes of pain are not present, referral to a chronic pain management specialist is recommended. A pain clinic will evaluate the pain through an interdisciplinary approach and initiate physical, cognitive and pharmacological treatment. The principles for evaluation and treatment of CPSP are similar to those used for other chronic pain diagnoses.
5 Conclusion 4 Non-pharmacological Approaches to Prevent CPSP Studies of non-pharmacological approaches to prevent CPSP after cardiac surgery are scarce. As CPSP may be related to the nerve injury and tissue trauma, nerve-sparing techniques and less extensive surgery may prevent both acute pain and CPSP. Studies on the impact of performing surgery through ‘‘mini’’ sternotomy have mixed results concerning postoperative pain, and are inconclusive. Still, alternative minimally invasive surgically techniques may also provide a pain benefit for cardiac patients [69]. Patient education may play an important role in the prevention of CPSP. Patients undergoing cardiac surgery might not be aware of the risk of chronic pain and its potential detrimental effects on their well-being. Several barriers to adequate pain management after cardiac surgery have been identified [72]. Patients may not use adequate analgesics for postoperative pain, because of fear of addiction and adverse effects. They may also hold beliefs about being a ‘‘good’’ patient and therefore not complain about pain. Some patients also believe that pain medication should be saved in case the pain worsens [67, 72]. Lee at el. [73] found that patients with a negative belief in opioid use had more CPSP 3 months after cardiac surgery. The development of fast-track cardiac surgery has reduced the duration of the hospital stay. Shorter in-hospital stay obviously gives a shorter period where analgesics are administered by health care workers and less time for patient education [74, 75]. This may reduce patient adherence to pain medication regimens after discharge [75]. The subsequent subacute period, when the patient is responsible for pain management, may be more important than previously thought in preventing CPSP.
The potential development of CPSP after cardiac surgery is an important clinical challenge and should be discussed in preoperative counseling of patients as a part of the decision-making and informed consent for surgery [78]. Patient education and decision-making must be reliable and up to date. Hence, older and retrospective studies should not be the foundation for decision-making. A prevalence of about 50–60 % in these older studies may be an overestimation of the problem [1]. Current prospective studies report an overall prevalence from 9.5 to 35 % and numbers below 10 % for severe pain [6, 8, 11, 13]. The lower prevalence of CPSP in current studies may, in addition to better methodology, reflect an improvement in treatment and care along the pain trajectory of cardiac surgery patients. Pharmacological studies of specific interventions to protect against the development of CPSP have been disappointing. However, there is an association between the intensity of acute postoperative pain and CPSP. Hence, interventions to decrease acute pain should be considered important in the prevention of CPSP after cardiac surgery. Acute postoperative pain after cardiac surgery is usually treated with a combination of opioids and paracetamol, but a number of other agents may be used. Irrespective of the choices made regarding opioids, route and co-analgesics, the patient should receive the medications needed to provide optimal pain relief. CPSP is a serious and important complication after cardiac surgery that may interfere with daily activities and HRQOL. Therefore, not only treatment, but also prevention of CPSP is essential. Acknowledgments K.H. Gjeilo, R. Stenseth and P. Klepstad have no conflicts of interest to declare related to the content of this article. No funding was received for the preparation of the manuscript.
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