Advertisement

Postoperative Pain Management in Adult Cardiac Surgery

  • Ali Dabbagh
Chapter

Abstract

Postoperative pain management is not only a medical concern but also among the human rights; this challenging issue would be much more difficult in postoperative period of cardiac surgery patients in whom the burden of the cardiac disease and the complex perioperative events impose their heavy shadow on the decision-making process for selection of analgesic remedies for acute pain suppression.

In this chapter, a brief discussion about the pathologic mechanisms of pain and their possible risk factors and potential mechanisms is presented first, and then, analgesia methods are discussed in two main categories: pharmacologic methods (including opioids, alpha 2 agonists, nonsteroidal anti-inflammatory drugs “NSAIDs,” paracetamol, ketamine, MgSO4, gabapentin, pregabalin, multimodal analgesia, and patient-controlled analgesia) and non-pharmacologic interventions (mainly infiltration of local anesthetics, intercostal nerve block, intrapleural infiltration of local anesthetics, and neuraxial blocks, “paravertebral, intrathecal, thoracic epidural”).

Keywords

Postoperative pain Acute pain management Patient satisfaction and patients’ expectations Anticipated pain and experienced pain Etiologic factors aggravating pain “Chronic thoracic chest pain” or “chronic leg pain” Analgesic methods Pharmacologic alternatives Opioids Fentanyl Sufentanil Alfentanil Remifentanil Alpha 2 agonists Nonsteroidal anti-inflammatory drugs (NSAIDs) Paracetamol Ketamine Gabapentin Pregabalin Magnesium sulfate Patient-controlled analgesia Regional anesthetic techniques Intrapleural infiltration of local anesthetics Neuraxial block Paravertebral block Spinal Epidural Intrathecal 

17.1 Introduction: The Effects of Acute Postoperative Pain and the Benefits of Acute Pain Management in Postoperative Period

Today, a considerable number of patients experience acute postoperative pain, and it has been demonstrated that between 30 and 80% of patients complain of acute “moderate to severe postsurgical pain”; so, the health-care team still have to consider postoperative pain as a challenge of care. Still acute postoperative pain management is among the highest priorities, both for the patients and the health-care team. According to the NIH report, the annual pain-related health-care costs in the United States were more than one hundred billion dollars ($100,000,000,000) in 1998, estimated to be more than doubled now. According to the 13th World Congress on Pain in Montreal, Quebec, Canada, “Access to Pain Management is a Fundamental Human Right”; it has been mentioned in Article 3: “The right of all people with pain to have access to appropriate assessment and treatment of the pain by adequately trained health care professionals,” while there are millions of patients who tolerate pain and experience the unpleasant sensation of acute pain, due to acute, chronic, or cancer pain. Improper or incomplete treatment of acute pain potentially leads to chronic pain in a considerable number of patients; the ultimate outcome would be “irreversible changes in the nervous system” ending in “progressive biopsychosocial epiphenomena” with further impairments, incapacities, and chronic health (Dolin et al. 2002; Popping et al. 2008a, b; International Pain Summit of the International Association for the Study of Pain 2011; Chou et al. 2016).

Besides, the quality of “acute postoperative pain management” is an important and considerable index in patient outcome; proper management of acute postoperative pain could potentially prevent a number of unwanted hemodynamic, neuroendocrine, hemostatic, and immunologic side effects, possibly decreasing the prevalence of postoperative morbidities (Peters et al. 2007; Caputo et al. 2011; Zheng et al. 2017).

In 2012, the American Society of Anesthesiologists has published the updated version of “the American Society of Anesthesiologists’ Practice Guideline for Acute Pain Management in the Perioperative Setting.” According to this guideline, “Anesthesiologists and other healthcare providers should use standardized, validated instruments to facilitate the regular evaluation and documentation of pain intensity, the effects of pain therapy, and side effects caused by the therapy.” Also, the guideline emphasizes that “Anesthesiologists responsible for perioperative analgesia should be available at all times to consult with ward nurses, surgeons, or other involved physicians” (2012). Also, the guideline released by American Society of Pain’s expert panel declares that “Safe and effective postoperative pain management should be on the basis of a plan of care tailored to the individual and the surgical procedure involved, and multimodal regimens are recommended in many situations” (Chou et al. 2016).

In this chapter, a brief explanation of the pathophysiologic pain mechanisms is described first. Then, different pharmacologic and non-pharmacologic approaches of acute pain management are discussed with an explanation about the methods of use, their potential risks, and benefits.

17.2 The Effects of Acute Postoperative Pain and the Benefits of Acute Pain Management in Postoperative Period

Acute postoperative pain imposes undesirable perioperative surgical stress response; the effects of perioperative insults to the body cause modifications in a number of body systems including the immune system and its inflammatory components and, also, the metabolic and neurohormonal systems; the collective response is called “the stress response,” which would directly and indirectly affect many of the body organs. The sympathetic system is affected by the effects of acute pain, though age and sex could significantly influence the sympathetic response, although other studies suggest a much more important role for factors such as the severity of surgical lesion and “surgical trauma” than the amount of sympathetic tone severity (Liu and Wu 2007; Ledowski et al. 2011, 2012; Wolf 2012; Bigeleisen and Goehner 2015).

Suppressing acute postoperative pain would alter patient satisfaction, prevent unnecessary patient discomfort, and decrease the duration of postoperative hospital length of stay, patient costs, overall morbidity, and even mortality; most are alleviated after adequate postoperative pain management. Hence, postoperative analgesia is a major indicator of postoperative care needing “early aggressive perioperative care” (Bigeleisen and Goehner 2015; Stephens and Whitman Stephens and Whitman 2015a, b).

Acute postoperative pain in adult cardiac surgery has some special features compared with the other patients, both regarding the patient factors and the analgesic methods, while often severe and undertreated which might cause severe and prolonged chronic pain; hence, the pain management strategy should be “tailored” to each patient in order to have satisfactory results. However, the newly adopted fast-track anesthesia approach in cardiac surgeries necessitates more aggressive postoperative pain management in these patients. Multimodal analgesic methods are highly effective and possibly the best technique in the management of acute postoperative pain. However, this approach has very important considerations due to the specific type of cardiac procedures. For example, neuraxial analgesia has its own considerations due to the coagulation disturbances after administration of anticoagulation and antiplatelet agents, to be discussed later in this chapter (Schwann and Chaney 2003; Bigeleisen and Goehner 2015; Stephens and Whitman 2015a, b; Guimaraes-Pereira et al. 2016a; Alzahrani 2017; Correll 2017; Guimaraes-Pereira et al. 2017; Liu et al. 2017a; Sangesland et al. 2017; Monico and Quiñónez 2017; Dabbagh 2014).

17.3 Patient Satisfaction and Patients’ Expectations

When dealing with pain in cardiac surgery patients, it should be considered that cardiac surgery patients usually expect a greater amount of postoperative pain than the real pain. So, when they make a comparison between anticipated pain and experienced pain (which is the actual pain), the patients usually express an acceptable and high level of satisfaction, although they really experience severe pain. So, there is a good level of patient satisfaction in such patients in the postoperative period. However, the health-care team should describe all aspects of postoperative pain with each patient, especially the potential for occurrence of chronic pain syndromes and its risk factors before the surgery. Of course, the different activities of the patients have different pain thresholds. One study demonstrated the following decreasing order of postoperative pain in cardiac surgical patients: “coughing, moving or turning in bed, getting up, deep breathing or using the incentive spirometer, and resting,” while the pain intensity was decreased after removal of chest tubes. Also, the patients expect the health-care team to help them improve the tolerance of acute pain in order to gain their normal life (Azzopardi and Lee 2009; Ravven et al. 2013; Stenman et al. 2016).

17.4 The Pathophysiology of Acute Pain in Cardiac Surgery Patients

It should be always considered as an alerting note that in patients undergoing cardiac surgery, the acute postoperative pain could be due to residual ischemia and/or incomplete revascularization; so, acute postoperative pain in these patients should always lead the health-care team to a very important differential diagnosis: residual ischemia. This differentiation is so much important. After ruling out the above condition, we would focus on the most common source of acute postoperative pain in these patients which is mainly with a myofascial origin and originates from many sources, most commonly originates from the chest wall (including the muscles, bony structures, tendons, and ligaments) (Guimaraes-Pereira et al. 2016a; Guimaraes-Pereira et al. 2017).

Usually in patients undergoing surgical procedures, the perioperative surgical stress response will increase to its uppermost levels just in the immediate postoperative period when it produces its many major pathophysiologic effects (including postoperative pain). This is the same after cardiac surgery with even more severe degrees of stress response due to the nature of cardiac surgery patients; most of them often tolerate the imposed inflammatory response due to cardiopulmonary bypass.

In patients undergoing cardiac surgery, there are great homeostatic disturbances which could lead to a number of great pathophysiologic changes in many of the major organ systems, including (but not limited to) the cardiovascular system, the lungs, the gastrointestinal system, the urinary system, the endocrine system, improved oxygen consumption, the immunologic system, and, finally, the central nervous system; these unwanted effects of cardiac surgery may lead to substantial postoperative morbidity and possibly to increased mortality. On the other hand, there are many studies that have clearly demonstrated potentially improved clinical benefits after adequate postoperative analgesia, which is due to increased level of stability in hemodynamic, metabolic, immunologic, and homeostatic factors and also more levels of stress response attenuation (Guimaraes-Pereira et al. 2016a, 2017; Correll 2017).

17.5 The Etiologic Factors Aggravating Pain After Cardiac Surgery

The following are the possible etiologic risk factors for acute pain in this patient population and their pain sources:
  • Incision site pain after sternotomy or thoracotomy

  • Intraoperative tissue retraction and surgical dissection

  • The arterial and venous vascular cannulation sites

  • The site of vein harvesting

  • The chest and abdominal sites for chest tubes

  • A few other factors

Usually the pain location varies being a function of time; in other words, during the early postoperative days (usually the 3 postoperative days), the pain is mainly in the thoracic area, while afterward, it immigrates to the legs (i.e., the location of vein harvesting in CABG patients) and would be dominant there up to the end of the first postoperative week. During this transition, the type of pain will often change from a radicular chest pain to osteoarticular type leg pain at the end of the 1st week.

The etiology for thoracic pain is usually the injuries of the rib cage, which is a very common source of postoperative pain in cardiac surgery. It will produce an unexplained postoperative non-incisional pain which is the physical result of sternal retraction. In clinical evaluation, the patients often have normal routine CXR, and the potential rib fracture (usually the posterior or lateral parts of the lower ribs) could be mainly detected in bone scans. These fractures are due to sternal retraction during the surgical procedure, which causes posterior or lateral rib fracture; also, there is the possibility for brachial plexus injury leg pain: leg pain due to vein-graft harvesting could be also problematic in cardiac surgery patients. This phenomenon, limited to patients with conventional saphenous vein harvesting, usually occurs in the late postoperative days; the possible explanation for this delayed presentation of pain could be patient mobilization in the 3rd or 4th postoperative days, while there is a decrease in sternotomy-related pain which would unmask the leg pain. There is current evidence that demonstrates the minimally invasive vein-graft harvesting method (endoscopic harvesting) “reduces” the intensity and duration of postoperative leg pain.

There are a number of underlying factors including gender, age, and some ethnic groups; young age, prolonged surgical duration, and anatomical surgery location increase the chance of acute postoperative pain. Acute postoperative pain has been demonstrated to be much more severe in patients below 60 years (compared with those above 60). Also, it is experienced much more severely in women compared with men, though chronic discomfort after discharge is seen more frequently in men (Gallagher et al. 2004; Peters et al. 2007; Ferasatkish et al. 2008; van Gulik et al. 2011; Papadopoulos et al. 2013; Chou et al. 2016; Guimaraes-Pereira et al. 2016a, 2017; Correll 2017; Zheng et al. 2017).

17.6 Chronic Pain in Cardiac Surgery Patients

Chronic pain is a relatively frequent finding after cardiac surgery; its incidence has been reported to be about 20–55%; and some other recent studies have demonstrated even higher prevalence rates for chronic pain. Chronic pain and its related depressive states could affect the clinical outcome of cardiac surgical patients. Even patient sleep pattern, physical and emotional status, and daily activities might be affected by chronic postoperative pain; neuropathic pain is a very common finding in most patients with chronic postoperative pain after cardiac surgery. Chronic pain after cardiac surgery is mainly due to “chronic thoracic chest pain” or “chronic leg pain ”; so, in one way, sternotomy could induce chronic pain in a number of patients with many referrals to pain clinics for managing chronic post-sternotomy pain mainly in the thoracic area; on the other hand, a number of patients undergoing CABG would refer for relief of chronic leg pain due to cardiac harvesting. These painful events should be differentiated from residual cardiac pain. Many studies have assessed post-cardiac surgery chronic pain to elucidate the related mechanisms, risk factors, and their treatment; a summary is presented here (Peters et al. 2007; Chou et al. 2016; Guimaraes-Pereira 2016; Guimaraes-Pereira et al. 2016a, b, 2017; Correll 2017).

The following are among the most possible risk factors for occurrence of postoperative chronic pain:
  • Patients undergoing extensive surgical procedures (e.g., CABG plus valve surgery is associated with increased incidence of postoperative chronic pain than CABG alone)

  • Prolonged time of the procedure (especially surgeries more than 3 h)

  • Severe acute postoperative pain (with numeric rating scale3 ≥ 4)

  • Patients with ASA classifications> III

  • Any underlying history of preoperative or postoperative depression

  • Any underlying history for psychological vulnerability: preoperative or postoperative

  • Non-elective operations

  • Redo operations needing sternotomy

  • Increased needs for analgesic use during the first few postoperative days

  • Female patients

Chronic chest pain: although may be rare, this type of chronic pain could be problematic; it is usually manifested as prolonged and severe chest wall pain, which presents as a persistent pain after cardiac surgery. It is often localized to the arms, shoulders, or legs. The clinician should differentiate this type of pain from residual cardiac diseases which cause cardiac pain, due to possible residual ischemia or graft failure. This syndrome is neuropathic in origin, would cause significant morbidity and discomfort for the patients, and occurs occasionally; but it is really difficult to treat. It is more frequent in the thoracic area after CABG, due to its etiologic factors discussed in the next paragraph. The patients who have severe acute pain in the first 10 days after surgery or who have “negative beliefs” about treatment of acute pain with opioids are at increased risk for chronic pain.

There are a great number of possible factors mentioned as etiologies for chronic pain in cardiac surgery patients, which might contribute to the appearance of chronic postoperative pain and postoperative neuropathies including:
  • Physical effects of sternotomy

  • Surgical dissection and harvesting of the IMA, either skeletonized or pedicled

  • Direct damage to the trauma to the thoracic nerve branches including the anterior rami of intercostal nerve branch nerves

  • Pressure of the retractor

  • Surgical tissue destruction, fractures of the ribs

  • Separation of the costochondral junction

  • The surgical scar formation

  • Postoperative infection of the sternum

  • Sternal stainless steel wire sutures

  • Inappropriate positioning of the body organs or suboptimal positioning of the arms before start of the surgical procedure

  • Intraoperative or postoperative injury to the brachial plexus

  • The pressure effects of rib fracture fragments

  • Placement of central venous catheter

Among the above etiologies, IMA harvesting (either skeletonized or not) has been reported to cause neuropathic pain with a burning and sharp feature, which aggravates at night and would increase in severity by stretching, since it is due to neuritis of IMA harvest. Harvesting of IMA (thermal or mechanical injury) causes a number of dysesthesia areas presented as numbness and/or hypersensitivity located on the anterior chest region. It may even become so much worse that it would be aggravated by usual daily activities like putting on the clothes or showering. The patients would usually complain of the following words for describing the pain: “annoying, persistently recurring, dull, cutting and sharp, exhausting, tender, and tight.” The temporal nature of pain is almost reported as brief, transient, and intermittent (Bruce et al. 2003; Dick et al. 2011; Hakim and Narouze 2015).

Chronic leg pain: chronic pain may also occur in the leg, primarily due to postoperative neuralgia of the saphenous nerve which happens after saphenous vein harvesting for CABG. It is more prevalent in the younger patients, while the correlation of severity of acute post-op pain and development of chronic pain syndromes is still vague (Bruce et al. 2003; Dick et al. 2011; Hakim and Narouze 2015).

17.7 Different Analgesic Methods

The American Society of Anesthesiologists’ Practice Guideline for Acute Pain Management in the perioperative setting defines acute pain as “pain that is present in a surgical patient after a procedure. Such pain may be the result of trauma from the procedure or procedure related complications” and “pain management in the perioperative setting refers to actions before, during, and after a procedure that are intended to reduce or eliminate postoperative pain before discharge” (2012).

Preoperative pain management techniques: according to the guideline text, it is very important to start the analgesic approaches from the preoperative period. Also, preoperative expectations of the patients would influence postoperative patient satisfaction level. The preoperative patient preparation steps include (but are not limited to) the following (Aslan et al. 2009; Guo et al. 2012; Chou et al. 2016):
  • Reducing underlying pain and anxiety by effective treatments.

  • Restoring or adjusting those medications which are used by the patients and their abrupt discontinuation could provoke signs or symptoms of withdrawal.

  • Administration of multimodal analgesic pain management program as preoperative medications before the operating room.

  • Application of patient and family education programs, which could be as pain control techniques and behavioral adaptations.

Perioperative pain management techniques: among all the pain management techniques used during the perioperative period, the following are the most common; however, these are not the only options:
  • Neuraxial administration of opioid analgesics (including epidural and intrathecal administration of analgesics and local anesthetics).

  • Peripheral regional analgesic techniques (including intercostal blocks, intrapleural, plexus blocks, paravertebral block, local anesthetic infiltration into the incisions).

  • Patient-controlled analgesia (PCA ) with systemic opioids and NSAIDs .

  • Traditional intravenous administration of analgesics (especially opioid analgesics, with their prototype being morphine); however, intravenous opioids have their well-known side effects, including nausea, vomiting, pruritus, urinary retention, respiratory depression, and delayed tracheal extubation; other agents like NSAIDs and α-adrenergic agents could also be added.

17.8 Pharmacologic Alternatives Used for Treatment of Acute Cardiac Surgery Patients

17.8.1 Opioids

Morphine was detected by Friedrich Sertürner in 1803–1806, and its analgesic activity was used afterward (Klockgether-Radke 2002; Rachinger-Adam et al. 2011). However, the routine clinical administration of opioids for acute pain suppression began in the 1960s, when administration of very high doses of intravenous opioids (especially morphine) was a standard care for cardiac anesthesia. However, in the following years, it was elucidated that even administration of very large intravenous doses of opioids could not induce complete anesthesia (including full unconscious state and amnesia); so, other inhalational or intravenous anesthetics were added to the anesthetic regimens for surgical anesthesia.

17.8.1.1 Opioid Receptors

The clinical effects and side effects of the opioid agents are classified – like many other drugs – based on their receptors; the opioids interact with many different body systems through these receptors. The current opioid receptors are classified as three distinct ones, μ, κ, and δ, and the analgesic effects of opioids in the central nervous system (both at the spinal and supraspinal level) are exerted through these receptors. Primarily, the μ receptor is classified as μ1 and μ2; however, μ1 is a high-affinity receptor mainly with supraspinal analgesia, while μ2 is a low-affinity receptor predominantly with spinal anesthesia. The μ agonists cause a dose-related respiratory depression which would mainly act via μ2 receptor activities. However, kappa (κ) receptors have potential analgesic role both at the spinal and supraspinal level with possibly lower drug side effects and complications related to μ receptors, though pure κ agonists have little effect on respiration. The third type of opioid receptors known as delta (δ) receptors presents modulatory role than analgesic role, both at the spinal level δ1 and supraspinal level δ2. Peripheral terminals for opioid receptors have been also demonstrated with their special role in some clinical findings like pruritus, also cardioprotection, and wound healing. However, it seems that the greatest advantage of peripheral terminals of opioid receptors would possibly be used as a common practice in near future, in such a way that we would be able to administer opioids peripherally without the fear of their risks on the CNS; the latter clinical use of peripheral opioid receptors has now appeared practically in some tissues like joints, bone, and teeth for postoperative pain relief; possibly other surgical operations (like cardiovascular) would be able to use these new molecules of analgesics; the peripheral role of opioid receptors seems to be a result of peripheral interaction/counteraction between opioid receptors and different ingredients of the immune system including but not limited to dendritic cells and toll-like receptors (Leung Leung 2004a, b; Rachinger-Adam et al. 2011; Xu et al. 2015b; Floettmann et al. 2017; Hong et al. 2017; Oehler et al. 2017; Tejada et al. 2017; Zhang et al. 2017).

17.8.1.2 Opioid Effects on the Body Systems

Analgesics and sedatives (especially opioids ) have many important interactions with body homeostasis including the body stress modulating systems like “hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain stress system”; so, opioids could have many beneficial effects in counteracting the unwanted effects of surgical stress response after cardiac surgery, which would help the body in maintenance of homeostasis; however, opioid-related adverse drug events affect the postoperative recovery (Rachinger-Adam et al. 2011; Barletta 2012; Camilleri et al. 2017).

Opioids are used extensively for suppression of acute postoperative pain in cardiac surgery and are known as the “gold standard” of pharmacologic acute pain suppression, mainly as intravenous and/or neuraxial routes. Morphine has more effective analgesic properties than the other opioids. Pharmacologically speaking, opioids have two distinct locations for their analgesic effects, supraspinal and spinal, i.e., neuraxial. Neuraxial administration of hydrophilic opioids (e.g., morphine sulfate) could create excellent postoperative analgesia, lasting at least 24 h for intrathecal and 48 h for epidural route with a number of clinical benefits; however, a very high degree of vigilance is needed to prevent possible side effects, mainly respiratory complications, hypoventilation and apnea being the most lethal ones. A maximum dose of 300 μg intrathecal morphine sulfate is considered the safety margin for prevention of postoperative respiratory depression. Morphine, used in different modes, has many potential benefits compared with other analgesic drugs (Whiteside et al. 2005; Vosoughian et al. 2007; Dabbagh et al. 2011; Mugabure Bujedo 2012; Walker and Yaksh 2012; Mahler 2013; Yamanaka and Sadikot 2013).

Respiratory system: opioids cause respiratory depression which could be known as the most important side effect of these very potent analgesics. The main mechanism is decreased sensitivity of the brain respiratory center to arterial pressure of CO2, in which its mechanism is through decreased sensitivity of both medullary and peripheral chemoreceptors. Rostral ventromedial medulla is the region implicated in pain modulation and homeostatic regulation. Opioids could inhibit the chemoreceptors through the μ receptors especially μ2 receptor, while their respiratory depressant effect in medulla is exerted through μ and δ receptors. It has been demonstrated that among the many CNS neurotransmitters involved in respiratory depression, the major neuroexcitatory and neuroinhibitory transmitters are glutamate and GABA, respectively. A third mechanism of obstructive apnea due to airway obstruction of opioids has been mentioned as the mechanism of opioid-induced apnea. The clinical steps in this process as follows are the steps of the effect of opioids on respirations:
  1. 1.

    Decreased respiratory rate.

     
  2. 2.

    Decreased tidal volume would happen after respiratory rate decrease.

     
  3. 3.

    Disturbed rhythmic function and generation of the respiration.

     
  4. 4.

    Change in the pattern of respiration from normal regular breath to irregular gasping pattern of spontaneous ventilation; this pattern is the characteristic pattern for the patients with diagnosis of opioid overdose.

     
  5. 5.

    Decreased sensitivity to hypoxia leading to decreased ventilator drive to hypoxia.

     
  6. 6.

    Finally, apnea.

     

The opioid compound with active metabolites (e.g., morphine-6-β-glucuronide) has increased respiratory depressant effects. Also, elderly patients are at higher risk of respiratory depression after opioid administration, since their central respiratory center is more sensitive to the respiratory depressant effects of opioids than the younger patients. Besides, when other anesthetics (like benzodiazepines, barbiturates, or inhalation anesthetics) are used simultaneously, the respiratory depressant effects of opioids would be more severe. And finally, genetic, environmental, and demographic factors may play a role in the severity of opioid-induced respiratory depression (Ozaki et al. 2001; Yamanaka and Sadikot 2013; Chen et al. 2017a; Pergolizzi et al. 2017; Xie et al. 2017).

Cardiovascular system : the opioids and their metabolites, including morphine, improve the analgesic effects of opioids in treatment of acute pain in patients with a history of ischemic heart disease undergoing major surgical operations. In patients undergoing cardiac surgery with extracorporeal circulation, due to increased volume of drug distribution, the required dose is increased. There are also studies that demonstrate the cardioprotective effects of opioids (Bodnar 2012; Tanaka et al. 2014; Geng et al. 2017; Gunther et al. 2017; Owusu Obeng et al. 2017; Phillips et al. 2017).

Other systems are also affected by the effects of opioids:

Immune system: opioid as demonstrated induces immunomodulation, both acquired and innate immunity, which can even affect the surgical outcome of the patients. The role of the immune system changes in creation of acute and chronic pain is negligible. Among many cellular structures and receptors, the role of toll-like receptor subtypes in many fields, including their interactions with opioids and their role in myocardial ischemia and acute coronary syndrome, has gained a great importance during the last years (Saadat et al. 2012; Chen et al. 2017a; Oehler et al. 2017; Plein and Rittner 2017; Tejada et al. 2017; Xie et al. 2017).

Gastrointestinal tract: opioids, especially morphine, decrease the mobility of the GI tract ending not only in constipation but also at times aggravate the centrally mediated nausea and vomiting, which are well-recognized unwanted side effect of opioids in all patients especially in the old age. The treatment of opioid-induced bowel dysfunction is not yet satisfactory, though a number of traditional laxatives (bulking laxatives, stimulant agents, etc.) or newer prokinetic agents like “prucalopride and lubiprostone” have been tested with different clinical results. Prucalopride is a selective, high-affinity agonist of 5-HT(4) receptor used for treatment of chronic constipation, and lubiprostone is a prostaglandin E1 derivative which could increase the activity of chloride channels in the apical aspect of epithelial cells to produce a very high chloride content fluid secretion inside the bowel lumen, leading to softened stool and increased motility and defecation. On the other hand, opioids have a wide range of interactions with the “super active” immune system of the bowels, at times leading to aggravation of colon diseases (Cuthbert 2011; Smith et al. 2012; Dabbagh and Rajaei 2013; Valdez-Morales et al. 2013; Anselmi et al. 2015; Talebi and Dabbagh 2017).

Urinary retention: the opioid agents, especially morphine, could induce urinary retention which is accompanied with increased bladder pressure and urinary bladder sphincter pressure; also, histological damage of bladder and the sphincter of bladder are possible. There are some clinical risk factors for increased risk of urinary retention like male sex and intrathecal morphine use; possibly the use of continuous peripheral nerve block could decrease the chance of this complication (Griesdale et al. 2011; Holzer 2012; Pergolizzi et al. 2017).

Cell growth and cell death: the opioid agents have some effects in suppressing the cell growth. This might be at times against the tumor cells; however, in the recent years, there is an increasing concern regarding the apoptotic effects of anesthetics including opioids (Djafarzadeh et al. 2012; Dabbagh and Rajaei 2013; Eftekhar-Vaghefi et al. 2015; Chen et al. 2017a, b; Pergolizzi et al. 2017; Xie et al. 2017).

Other effects: there are a number of other side effects of opioids, namely, nausea and vomiting, pruritus, and urinary retention, which could be decreased by concomitant use of adjuvant analgesic agents, leading to decreased side effects of opioids while maintaining adequate postoperative analgesia. Opioids also affect appetite, thermoregulation, and mental features of the patients (Chen et al. 2017a; Pergolizzi et al. 2017; Xie et al. 2017).

17.8.1.3 Opioid Compounds

Currently, opioids are classified as two main groups: natural agents and synthetic agents; morphine is the prototype of opioid agents and known as the gold standard (i.e., the benchmark of opioid analgesics). More detailed description of these agents is presented in the “Cardiovascular Pharmacology” chapter.

Morphine is the prototype opioid agonist and the most popular analgesic used in patients after cardiac surgery. Also, many synthetic and semisynthetic opioid compounds are made by simple modifications of morphine. Morphine is a lipid-soluble agent and for therapeutic purposes has been changed to some compounds like morphine sulfate which are more water-soluble. Morphine has 30–40% plasma protein binding and has primarily hepatic metabolism being conjugated to water-soluble glucuronides like morphine-3-glucuronide and morphine-6-glucuronide. Elimination half-life of morphine is 2–3 h but would be increased in liver diseases like liver cirrhosis, though the half-life of morphine is normal in renal disease. Morphine has also extrahepatic clearance through the gut, brain, and kidneys, which comprises about 30% of the total clearance of the drug (Bosilkovska et al. 2012; Hughes et al. 2012; Ishii et al. 2012; Swartjes et al. 2012; et al. 2012).

Synthetic opioid agents: currently, we have four main synthetic opioid agonists used in clinic for acute pain management in anesthesia and/or analgesia: fentanyl, sufentanil, alfentanil, and remifentanil. These compounds are synthetic chemical derivatives of phenylpiperidine, which are chemical derivatives of meperidine.

Fentanyl, sufentanil, alfentanil, and remifentanil are very fast-equilibrating agents; alfentanil and remifentanil equilibrate “very fast” having an equilibrium half-life of just 1 min in order to equilibrate between plasma and CNS; fentanyl and sufentanil have a half-life of about 6 min for such an equilibration followed by methadone’s half-life being 8 min; however, the equilibration half-life of morphine is very much longer, 2 to 3 h, and morphine-6-glucuronide (an active metabolite of morphine) near 7 h; it means that alfentanil, remifentanil, fentanyl, and sufentanil have a higher speed for reaching from plasma to their effect site (mainly CNS) compared with morphine and its metabolites (Ing Lorenzini et al. 2012; Scott 2016; Ziesenitz et al. 2018).

Another concept considered important for opioid infusions used as acute pain management is the context-sensitive half-life (CSHL) considered as the time interval from discontinuation of the infusion until gaining a plasma level of the drug half as much of the time of infusion discontinuation; of course the infusion should be discontinued after gaining a steady-state plasma level of the drug; among some other indicators of pharmacokinetic and pharmacodynamics, “time to equilibrate after start of infusion” and “CSHL” are two very important factors that could help us choose a more appropriate analgesic in acute postoperative pain management. In this regard, remifentanil and alfentanil have both short “plasma-CNS equilibration time” and short CSHL; the lowest CSHL among all the opioids belongs to remifentanil; also, due to their metabolism, none of these four compounds would impose much considerable problem due to drug overdosage in patients with renal impairment; studies have shown that administering infusion of short-acting opioids could decrease the time necessary for postoperative mechanical ventilation and help earlier ventilator weaning, so they could decrease the “ICU length of stay” (Servin 2003, 2008; Servin and Billard 2008; Ziesenitz et al. 2018).

Fentanyl is a very potent opioid being about 80–120 times more potent than morphine, though its receptor affinity is three times more than morphine. Since fentanyl is highly lipid-soluble (about 150 times more lipid-soluble than morphine), it can bypass the blood-brain barrier (BBB) so much faster than the water-soluble morphine, hence, creating its analgesic effects more rapidly than morphine (either administered as IV, IM, intrathecal, or other routes).

Fentanyl is metabolized by the liver and does not have an active metabolite. This is why its clearance is not impaired in renal diseases, but prolonged effects of the drug are well anticipated in liver diseases. Another interesting issue regarding fentanyl is that the drug undergoes active storage in the lungs; so, nearly two-thirds of fentanyl is inactivated in the first pass of the lung. CYP3A4 inhibitors and inducers have considerable interaction of fentanyl metabolism (Kuip et al. 2017; Ziesenitz et al. 2018).

Bolus doses of fentanyl create their analgesic effect so soon without much residual effects. On the other hand, the effects of infusion doses of fentanyl are not much similar. In other words, due to its high lipophilicity, fentanyl infusion leads to accumulated amounts of drug in adipose tissues, and when the infusion is disconnected, the infused amounts of fentanyl are released into plasma. This is why the effects of prolonged fentanyl infusion are not offset immediately after discontinuation of the infusion; this is especially very important after prolonged infusion of the drug, which could lead to very prolonged drug effects after long-time infusion. Pharmacologically speaking, context-sensitive half-time of fentanyl increases along with the saturation of inactive sites.

However, it is recommended to use fentanyl infusion as the following dosage for having adequate sedation while preventing prolonged residual effects (George et al. 2010; Scott 2016; Ziesenitz et al. 2018).
  • Start fentanyl administration drug with a primary bolus dose of 1–2 μg/Kg of the drug.

  • At the same time, start an IV infusion of 1–3 μg/Kg/h.

  • Depending on patient needs, adjust the infusion dose, especially if the patient has a history of preoperative drug use.

  • Adding patient-controlled analgesia (PCA ) route with a dose of 0.1–1 μg/Kg for each bolus (depending on patient needs) and a lock time interval about 15 min to the background IV infusion for the relatively awake patient leads to excellent analgesia with good satisfaction and cooperation with limited side effects.

  • This method mandates extreme cautious and close monitoring regarding respiratory depression, including respiratory rate, pulse oximeter, end-tidal CO2, etc.

  • Fentanyl is accumulated in patients with hepatic impairment due to drug accumulation, though this is not a major problem in patients with renal impairment.

Sufentanil is another opioid synthetic compound which is about five to ten times more potent than fentanyl. Being extremely lipid-soluble with a very high plasma protein-binding capacity, sufentanil is metabolized mainly in the liver. So, sufentanil pharmacokinetics (like fentanyl and alfentanil) is not very much affected in patients with renal disease; however, its effects are significantly prolonged in patients with hepatic disease due to impaired hepatic metabolism and the resulting drug accumulation. Prolonged infusions of sufentanil are offset much sooner than comparable analgesic doses of fentanyl or alfentanil. This is why IV sufentanil infusions do not demonstrate as much long sedation effects as fentanyl. Of course, the clinical effects of alfentanil are presented sooner than sufentanil and fentanyl; i.e., the time lag between plasma levels and effect site (CNS) is shorter in alfentanil (about 1 min) compared with sufentanil (about 6 min) and fentanyl (about 7 min); however, CSHL of sufentanil is shorter than alfentanil and of course fentanyl; the CSHL order after 3 h of IV infusion is sufentanil (30 min), alfentanil (50–60 min), and fentanyl (250 min) in increasing order; in other words, after discontinuation of equivalent doses of IV infusion, the drug effects would disappear first in sufentanil, then alfentanil, and, finally, fentanyl; this effect is mainly due to larger sufentanil volume of distribution. Of course, as discussed later, the effects of remifentanil would disappear very much sooner than all the other three compounds; vide infra (Bosilkovska et al. 2012; Jeleazcov et al. 2012; Zhang et al. 2015a).

Alfentanil is another opioid compound similar to fentanyl but five to ten times less potent than fentanyl. Its clinical effects are presented very shortly, 1 min after IV administration, mainly due to its very high lipid solubility which could bypass the BBB very fast; its lipid solubility is even more than fentanyl. So, alfentanil pharmacokinetics (like fentanyl and sufentanil) is not very much affected in patients with renal disease; however, its effects are significantly prolonged in patients with hepatic disease due to impaired hepatic metabolism and the resulting drug accumulation. As mentioned in the previous paragraph, its CSHL is shorter than fentanyl and longer than sufentanil (Jeleazcov et al. 2012; Ziesenitz et al. 2018).

Remifentanil is the newest version of synthetic opioids, being a potent mu agonist, having an analgesic potency “equal to fentanyl and 20–30 times more potent than alfentanil.” However, remifentanil has a very short start time lag (1 min); more importantly, it has the shortest possible time (among all the opioids) for its effects to be offset after discontinuation of drug infusion. The following are among the most important pharmacological and clinical features of remifentanil (Servin 2003, 2008; Komatsu et al. 2007; Servin and Billard 2008; Olofsen et al. 2010; Ing Lorenzini et al. 2012; Hoshijima et al. 2016):
  • Time interval from start of drug administration until presentation of its clinical effects is about 1 min (i.e., very fast onset).

  • Its CSHL being as short as 3–5 min irrespective of the duration of IV infusion (the shortest CSHL among all the opioid compounds).

  • The drug must be used as a continuous infusion as long as the patient has pain.

  • The opioid effects of the drug, including respiratory depression, are offset in just 3–5 min after discontinuation of infusion irrespective of the duration of the infusion.

  • Acute postoperative pain management in patients under anesthesia using remifentanil as the main opioid mandates considering an appropriate agent as soon as the remifentanil infusion is set off, or remifentanil infusion with its analgesic dose (and not the anesthetic dose) should be continued postoperatively.

  • The main mechanism of remifentanil metabolism is rapid hydrolysis by nonspecific esterase found both in tissue and plasma, which takes a very short time for drug disappearance and leaves inactive drug metabolites.

  • The drug metabolism mandates infusion of the drug as the main effective mechanism of action; its bolus administration should be done very cautiously since bolus dose has the possibility for severe bradycardia, hypotension, decreased cardiac output, and cardiac arrest.

  • Its analgesic dose is 0.05–1 μg/Kg/min, based on ideal body mass.

  • Only IV route is recommended; never use intrathecal or epidural routes for its administration due to glycine added to drug combination.

  • Remifentanil is the only opioid with no special consideration in patients with either renal or hepatic disease regarding its metabolism.

  • A meta-analysis demonstrated that “remifentanil is associated with increased incidence of postoperative shivering compared with alfentanil or fentanyl” (Hoshijima et al. 2016).

17.8.2 Alpha 2 Agonists

α2 Adrenergic agonists can cause analgesia, sedation, and sympatholysis. These agents are primarily known in practice as clonidine (natural) and its synthetic analog, dexmedetomidine which is a pure α2 adrenergic agonist and has a half-life of 2–3 h. They could be administered orally, intrathecally, or intravenously. The mechanism of action in these agents is creation of sedation through stimulation of α2 receptors in the locus coeruleus and creation of analgesia through stimulation of α2 receptors within the locus coeruleus and the spinal cord; also, these agents could enhance the analgesic effects of the opioids via an unknown mechanism of action. Their clinical effects could be classified after systemic administration (antinociception and sedation) and intrathecal administration (only antinociception). There are reports that have mentioned tolerance to these agents after their prolonged administration. When used as sedative for post-CABG patients, their perioperative superior effects may include:
  • Increased stability of the hemodynamic parameters and attenuated hemodynamic responses.

  • Decreased perioperative myocardial ischemia and cardioprotective effects.

  • Decreased need for analgesic agents.

  • Treatment of delirium.

  • Antiarrhythmic effects.

  • Decreased postoperative opioid consumption, pain intensity, and nausea, accompanied with decreased use of analgesics, beta-blockers, antiemetics, epinephrine, and diuretics.

  • There might be some protective effects in a number of organs.

However, overdose of these agents could induce excessive postoperative sedation accompanied with postoperative hemodynamic instability, bradycardia, and/or hypotension with bradycardia, at times mandating pharmacologic treatment (Dabbagh 2011; Blaudszun et al. 2012; Moghadam et al. 2012; Jabbary Moghaddam et al. 2013; Zhang et al. 2015b; Cruickshank et al. 2016; Liu et al. 2017a, b).

17.8.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Having analgesic and anti-inflammatory properties, a number of agents are categorized in this class of analgesics. Their main mechanism of action is blockade of cyclooxygenase (COX) enzyme leading to prostaglandin synthesis inhibition described by Vane in 1971 for the first time. Their analgesic mechanism is theoretically classified as two main groups: traditional NSAIDs inhibiting COX in a nonselective manner and relatively newer class of NSAIDs which inhibit COX-2 in a selective manner. Selective COX-2 inhibitors were produced in order to decrease the unwanted effects of nonselective inhibition of COX-1 by traditional NSAIDs, especially regarding the GI mucosa; however, their merit was not completely fulfilled because of the deep concern of potential unwanted cardiac effects of COX-2 inhibitors. NSAIDs are used frequently in the perioperative period; however, they are used usually in combination with other analgesic methods (mainly in combination with opioids, local anesthetics, or regional techniques) as a multimodal analgesic technique. NSAIDs are clinically effective in suppressing acute postoperative pain; in decreasing the need for postoperative opioid use, an effect named as opioid-sparing effect; and, also, in improving the clinical outcome. If contraindications of NSAIDs are considered logically, accompanied with close observation of their potential side effects, these agents could be used cautiously and safely. Potential contraindications of NSAIDs are elderly people, heart failure, hypovolemic states, cirrhotic patients, renal failure, history of active GI tract disease and peptic ulcer disease, active bleeding diathesis, and pregnant patients (Bell et al. 2006; Langford and Mehta 2006; Derry and Moore 2012; Khan and Fraser 2012; Jalkut 2014; Huang and Sakata 2016):

The most important adverse effects of NSAIDs are as follows:
  1. 1.

    Gastrointestinal complications which could lead to serious and life-threatening hemorrhage, especially in postoperative period of cardiac surgery due to concomitant administration of anticoagulants.

     
  2. 2.

    Increased risk of bleeding which could be a potential complication in patients receiving neuraxial block for postoperative pain suppression.

     
  3. 3.

    Acute renal ischemia, especially if administered concomitantly with diuretics, angiotensin-converting enzyme inhibitors “ACE inhibitors,” and/or angiotensin receptor antagonists “ARA”; this drug combination is known as the “triple whammy” (Loboz and Shenfield 2005).

     

NSAIDs as adjuvant analgesics could reduce the dose of opioids needed for acute pain suppression in postoperative period; the concomitant administration of NSAIDs with opioids helps us to administer them while this method of NSAID use does not create clinically important renal impairments, though they might be able to decrease renal function during the early postoperative period in a transient and insignificant mode; meanwhile, these agents do not boost the risk of postoperative renal failure in cardiac surgery patients would they be prescribed within a logical dose range and avoiding their contraindications (Buvanendran and Kroin 2009; Frampton and Quinlan 2009; Acharya and Dunning 2010; Barletta 2012; Huang and Sakata 2016).

17.8.3.1 Paracetamol (N-Acetyl-P-Aminophenol)

Paracetamol (N-acetyl-p-aminophenol) is one of the most common analgesics used worldwide, mainly acting through central blockade of acute pain pathways and creating mild to moderate analgesia and mild anti-inflammatory effects. Its mechanism is not fully elucidated yet; however, some clinicians consider paracetamol as one of NSAIDs, though it does not have the same mechanism as classic drugs of this category. Its main toxicity could be after large doses to create hepatotoxicity, manifested much earlier in alcoholics. A Cochrane Database Systematic Review has provided “high quality evidence” demonstrating effective analgesia (4 h) in about 36% of patients having acute postoperative pain, after “a single dose of either IV paracetamol or IV propacetamol” (McNicol et al. 2016). However, other studies have claimed that analgesic properties of paracetamol in cardiac surgery patients are not so much considerable. In practice, the drug is recommended as part of a multimodal analgesic regimen (Lahtinen et al. 2002; Pettersson et al. 2005; McDaid et al. 2010; Maund et al. 2011; Tzortzopoulou et al. 2011).

17.8.4 Other Pharmaceutical Agents

Among the pharmaceuticals used for acute pain suppression in cardiac surgery patients, a number of other agents could be mentioned.

17.8.4.1 Ketamine

Ketamine is an intravenous anesthetic, mainly acting through “N-methyl-D-aspartate receptor” blockade; this drug could suppress acute pain effectively by a mechanism completely different from opioids: it acts mainly through dissociative anesthesia, “i.e., a combination of analgesia, hallucination, catalepsy, and some degrees of amnesia”; so, ketamine does not cause respiratory depression as much as opioids and also does not perturb the hemodynamic status as much. However, due to unwanted clinical experience of the patients (known as emergence reactions), it is strongly recommended that ketamine should not be used solely unless preceded by an amnestic agent (like one of the benzodiazepine family); otherwise, the patients would have a very bad experience from the effects of the drug; however, a number of studies have demonstrated fewer unwanted effects of ketamine when administered as the S(+)-ketamine isomer. Currently, smaller doses of the drug are used as a part of a multimodal analgesic regimen, especially for thoracic incisions, in such a way that the needed amount of other analgesic drugs, especially opioids, are decreased, possibly improving the respiratory function. Ketamine could be used through many different routes including intravenous or intravenous patient-controlled analgesia (IV or IV-PCA ). Some studies have claimed an anti-inflammatory effect for ketamine in patients undergoing CPB, possibly through its mechanism of action: NMDA antagonism (Lahtinen et al. 2004; Michelet et al. 2007; Buvanendran and Kroin 2009; Suzuki 2009; Carstensen and Moller 2010; Mathews et al. 2012; Liu et al. 2017a).

17.8.4.2 Magnesium Sulfate (MgSO4)

This ionic compound has gained frequent attention during recent years; its analgesic mechanism is mainly through calcium channel antagonism and NMDA antagonism; however, bolus doses of the drug could lead to asystole, and accumulation of the drug in the blood, “i.e., overdose,” could lead to severe afterload reduction and, hence, hypotension. Anti-inflammatory effects of magnesium sulfate in patients undergoing CPB have been observed in a number of studies (Ferasatkish et al. 2008; Buvanendran and Kroin 2009; Dabbagh et al. 2009, 2010, 2013; Aryana et al. 2014; Duan et al. 2015; Pearce et al. 2015; Fairley et al. 2017).

17.8.4.3 Gabapentin and Pregabalin

This is mainly an anticonvulsant agent belonging to a class of drugs known as “alpha-2-delta receptor modulators,” also used for management of chronic pain; its mechanism of action is inhibition of glutamate release through NMDA antagonism. Gabapentin has been used for treatment of acute pain as an adjuvant in the multimodal analgesia regimen, with opioid-sparing effect goal; however, results are still inconclusive (Ucak et al.2011; Ho et al. 2006; Fabritius et al. 2016). Pregabalin is also an anticonvulsant agent inhibiting the voltage-dependent calcium channel in CNS leading to inhibition of release of a number of agents including glutamate. Its use as an analgesic for acute pain suppression is off-label; though it is one of the agents used in multimodal analgesia regimen (Buvanendran and Kroin 2009; Dauri et al. 2009; Graterol and Linter 2012; Chang et al. 2014; Liu et al. 2017a).

17.8.5 Multimodal Analgesia

Multimodal or “balanced” analgesia is a method of analgesia which considers the multistep nature of pain. In acute pain management, this method involves administration of analgesics throughout the perioperative period; so pain management is performed through administration of more than one single drug (opioids plus non-opioids), or even we can add non-pharmacologic analgesia methods to our list of pharmacologic analgesics. Adjuvant analgesics (i.e., drugs in which their primary effect is not necessarily analgesia) and non-pharmacologic analgesia methods are mainly added to our battery of opioid compounds and the wide range of opioid administration. The main goals of multimodal analgesia are summarized as follows:
  • Create additive analgesia from administration of different classes of analgesic methods.

  • Decrease the dose of each analgesic modality.

  • Experience less unwanted side effects of each drug or non-drug method.

  • Counteract pain at different levels, i.e., at the level of CNS, spinal cord, peripheral nerves, wound site, etc.

  • Decrease time duration of recovery from surgery (Kehlet and Dahl 1993; Kehlet et al. 2006; Buvanendran and Kroin 2009; Gandhi et al. 2011; Rafiq et al. 2014; Correll 2017; Liu et al. 2017a).

17.8.6 Patient-Controlled Analgesia

During the last decades, patient-controlled analgesia (PCA ) has been proposed to replace the conventional method of analgesia prescription, in order to increase the efficacy of analgesic methods. Among its benefits, the following have been proposed:
  • Increased patient autonomy

  • Decreased time from pain sensation until the first dose of analgesics

  • Increased concordance between analgesics and patient demands

  • Decreased frequency of opioid complications including nausea and vomiting

There are a vast number of pro and con studies regarding the efficacy of the method. Compared with intramuscular analgesics, PCA is more effective; however, compared with nurse-administered intravenous (IV) analgesia or epidural PCA , it is not yet determined which method is more effective (Boldt et al. 1998; Dolin et al. 2002; Bainbridge et al. 2006; Hansdottir et al. 2006; Hudcova et al. 2006; Mota et al. 2010; McNicol et al. 2015).

In order to have a successful PCA , it is suggested to follow these considerations (Bainbridge et al. 2006; McNicol et al. 2015):
  • As a standard, use a baseline analgesic infusion which should be added to PCA in order to prevent unwanted effects of delayed analgesia administration, meanwhile benefiting concomitant effective analgesia.

  • Always consider baseline opioid dose; this baseline opioid, added to other analgesics, could increase the efficacy of pain management.

  • Beware of respiratory depression which should be always considered as a potential risk.

  • Apply a baseline-appropriate PCA dose accompanied with lockout interval, and adjust it for each patient.

  • Try to increase patient cooperation as much as possible; insufficient patient cooperation leads to ineffectiveness of PCA ; in case of impaired patient cooperation, PCA use should be discouraged.

17.9 Regional Anesthetic Techniques for Acute Pain Suppression in Cardiac Surgeries

There are a number of regional anesthetic techniques used for acute pain suppression in cardiac surgery patients, each having their benefits and drawbacks. These techniques include the following; however, they are not limited just to the following list:
  • Infiltration of local anesthetic in wound

  • Intercostal nerve block

  • Intrapleural infiltration of local anesthetics

  • Neuraxial analgesia (paravertebral, intrathecal, thoracic epidural)

17.9.1 Infiltration of Local Anesthetics in Wound

This is an effective method in cardiac surgery patients especially when used as an adjunct to other analgesic methods for controlling acute postoperative pain and administered as parasternal approach or, possibly, directly into the surgical wound; we could control sternotomy-related acute pain and also pain related to chest tubes and thoracic pain. This method has two characteristics in order to be effective for pain control:
  • It is better to use this technique as “post-incision infiltration method” of local anesthetic; however, pre-incision local anesthetic infiltration is “equivocal,” since acute postoperative pain in cardiac surgery patients is originated mainly from sternotomy.

  • It should be used primarily in patients after sternotomy.

Infusion of local anesthetic directly into the surgical wound is another possible method, with tissue necrosis being the most common potential complication; however, cellulitis, infection, and tissue necrosis of the wound are very rare after cardiac surgery. In cardiac surgery patients, it is possible that the use of bilateral catheters for continuous infusion of local anesthetics could be even more effective, when used as a part of multimodal analgesia technique (Dowling et al. 2003; White et al. 2003; Chaney 2005a; McDonald et al. 2005; Kocabas et al. 2008; Buvanendran and Kroin 2009; Eljezi et al. 2012; Kossowsky et al. 2015; Ozturk et al. 2016).

17.9.2 Intercostal Nerve Block

Intercostal nerve block is a simple and efficient method for administration of local anesthetic agents into the intercostal neurovascular bundle(s), which could be an effective adjuvant analgesic method for acute postoperative pain suppression, causing pain temporal blockade; however, it would last between 6 and 12 h unless an indwelling catheter is placed adjacent to the intercostal nerves or repeated injections are needed. The block is better to be performed under direct vision, i.e., before chest closure by the surgeon or after the operation, by injecting the local anesthetics into intercostal nerves through the subcostal approach for each of the nerves. However, prophylactic administration (i.e., before surgical incision) is equivocal. Ropivacaine (0.5–0.75%) or bupivacaine (0.25–0.5%) is often used for this purpose (Barr et al. 2007; Chaudhary et al. 2012; Kossowsky et al. 2015).

17.9.3 Intrapleural Infiltration of Local Anesthetics

This method involves administration of local anesthetics between the visceral and parietal pleura. The main origin of pain is parietal pleura; however, the proposed mechanism of analgesia in this method is diffusion of local anesthetics in the potential space between the two pleural layers leading to diffusion of a very thin layer of local anesthetics distributed between the two pleura layers and, finally, blocking pain, though some studies are controversial regarding its clinical outcome. Local anesthetics may be administered as a single shot or continuous infusion through a catheter. The method has a number of limitations (Chaney 2005a, b; May and Bartram 2007; Ogus et al. 2007; Mansouri et al. 2011; Esme et al. 2012; Ziyaeifard et al. 2014; Yousefshahi et al. 2016):
  • Intact anatomy and physiology of the pleural layers.

  • If the patient has chest tubes, it may lead to leakage of local anesthetics into chest bottle.

  • The lung is not damaged (e.g., after lung surgery).

  • There is the possibility for systemic absorption of local anesthetics.

17.9.4 Neuraxial Blocks (Paravertebral, Intrathecal, Thoracic Epidural)

17.9.4.1 Thoracic Paravertebral Block

Thoracic paravertebral block is considered as one of the neuraxial analgesia techniques by some authors; being considered an old technique, it was reappraised just in the last two to three decades used for local anesthetic blockade though the paravertebral spaces, so, to some clinicians, it is not as much familiar as intrathecal and epidural techniques. Paravertebral spaces are located bilaterally, in each side; they are anatomically located lateral to the spine, where the nerve endings pass through them to go from spine to end in their related nerve fibers. Thoracic epidural analgesia is usually considered as the gold standard of care for acute postoperative pain management, namely, in some procedures like thoracic and cardiac surgeries, especially regarding cardiovascular and pulmonary outcomes; however, thoracic paravertebral block could be a good potential alternative when performed appropriately. The interested reader is referred to study the related referenced for the classic approach of Eason and Wyatt in performing thoracic paravertebral block; however, a summary of the technique is described and includes a step-by-step process:
  • Placing the patient in sitting position with the spine being curved as a “C” letter or in lateral decubitus position, i.e., “fetal position”

  • Using strict aseptic technique

  • Finding and localizing the 6th cervical vertebra (C6)

  • Localizing the spinous process at the level of 4th thoracic vertebra (T4)

  • Going 3–6 cm laterally in horizontal direction

  • Creating a local wheal by local anesthetics in awake patients

  • Inserting the needle in a perpendicular direction

  • Reaching the transverse process

  • Walking downward and lateral until a sense of “loss of resistance” is reached

  • Finally, injecting local anesthetic slowly

The main benefits of thoracic paravertebral block compared with thoracic epidural could be considered as:
  • Being less invasive.

  • Very lower risk for epidural hematoma formation.

  • Less hemodynamic derangement (albeit some degrees of sympathetic block exists).

  • Fewer contraindications.

  • Easier technique.

  • Lower incidence of complications (especially neurologic complications).

  • Fewer reports of postoperative complications like nausea, vomiting, and urinary retention.

  • Rare reports of systemic toxicity due to local anesthetics, though very high doses are used in this technique.

  • Improved patient outcome especially regarding pulmonary function.

  • Nowadays, application of ultrasound leads to increased safety and efficacy features of the block.

Some clinicians believe that bilateral thoracic paravertebral block is not as effective as thoracic epidural analgesia in suppressing acute pain-induced stress response, especially in major procedures like cardiac surgery, while there are others who believe exactly vice versa and consider thoracic paravertebral block as effective as, and even at times more effective than, thoracic epidural analgesia improving clinical outcomes with reduced rate of complications (Eason and Wyatt 1979; Richardson and Sabanathan 1995; Davies et al. 2006; Daly and Myles 2009; Scarci et al. 2010; Thavaneswaran et al. 2010; Richardson et al. 2011; Rawal 2012; Ding et al. 2014; Li and Halaszynski 2015; Okitsu et al. 2016; Yeung et al. 2016; Monico and Quiñónez 2017; Dabbagh 2014).

17.9.4.2 Spinal (Intrathecal) Analgesia

Postoperative analgesia through intrathecal (IT) administration of drugs is a very popular method among clinicians for non-cardiac surgeries of the abdominal and pelvic area and/or lower extremities used for more than 100 years. However, in cardiac surgeries, the idea of IT analgesia was first described in 1980 which included IT morphine administration (Mathews and Abrams 1980). Later, IT administration of local anesthetics was also used which was performed through lumbar interspaces accompanied with downward positioning of the patient (usually after induction of general anesthesia) to deliberately create a high level of spinal block. Theoretically , this method appeared effective, since spinal receptors of pain are located in substantia gelatinosa of Rolando, posterior horn of the spinal cord (Wu et al. 1999; Furue et al. 2004; Fujita and Kumamoto 2006; Ellenberger et al. 2017); hence the drug could attach the receptors with much easier access and higher efficacy than the intravenous route of drug administration of analgesics. Potential benefits of this method would be possibly:
  • Improved postoperative analgesia with better quality of pain control

  • Fewer postoperative respiratory problems

  • Decreased level of postoperative stress response

  • Improved clinical outcome

The first studies favored IT morphine usage for cardiac surgery, and even during the recent years, some studies approved it. These studies have usually administered a wide range of IT opioids “from 0.3 to 10 mg IT morphine as single shot” administered just before induction of general anesthesia, just after induction of anesthesia, or even during the early postoperative period; however, further studies have demonstrated that IT opioid for cardiac surgery could not suppress the level of stress response. Also, improved postoperative analgesia and decreased respiratory problems are gained at the expense of unwanted opioid effects in the postoperative period including pruritus, respiratory depression (early or delayed), urinary retention, nausea and vomiting, and delayed extubation. To the above, the fact that shorter-acting opioids are possibly less effective during the postoperative period should be added, shifting the choice for IT opioids to opioid compounds like morphine with a longer time profile in order to have adequate postoperative analgesia which at the same time would result in increased chance for postoperative opioid complications, especially delayed postoperative respiratory depression (which is usually due to delayed or cephalad migration of water-soluble opioids like morphine) and delayed extubation; also, we should add to the above items that the unwanted respiratory depression and delayed extubation are aggravated by concomitant use of other sedatives and anesthetics; besides, some other factors like underlying age could not be neglected; elderly people are at increased risk for unwanted postoperative respiratory depression of IT opioids (Chaney et al. 1997, 1999; Boulanger et al. 2002; Chaney 2005b, 2006, 2009; Dabbagh et al. 2011; Nigro Neto et al. 2014; Li and Halaszynski 2015; Tabatabaie et al. 2015; Xu et al. 2015a; Huang and Sakata 2016; Ellenberger et al. 2017; Hong et al. 2017).

On the other hand, IT administration of local anesthetics in a way to create high spinal levels of block covering the spinal thoracic nerve roots could create a sufficient sensory block to decrease the level of tress response; however, simultaneous widespread sympathetic block associated with this method leads to repeated episodes of hypotension and hemodynamic instability mandating administration of vasopressors and inotropes. Finally, most studies have claimed that benefits of IT local anesthetics could not clearly outweigh its risks. Besides, the effects of IT local anesthetics usually last shorter duration and often disappear or vanish during the early postoperative hours.

Finally, though the risk of neurologic complications (including epidural hematoma) is much lower in spinal technique compared to thoracic epidural technique, it is not negligible and could be as high as 1:1500 up to 1:220.000. Detailed discussion about prevention and management of this complication is presented just in the next pages, and the reader is addressed to refer there (Horlocker et al. 2010; Horlocker 2011b; Leffert et al. 2017).

In summary, creating analgesia through administration of IT opioids or IT local anesthetics in cardiac surgery patients could not improve the clinical outcome sharply and is not usually considered as a main analgesic method in such patients.

17.9.4.3 Thoracic Epidural Analgesia

Thoracic epidural analgesia (TEA) is considered by many as the “gold standard” of care for acute postoperative pain management in adult cardiac surgery mainly for nearly two decades, because of the following features:
  • Adequate and qualitative analgesia (both intraoperative and postoperative).

  • Efficient suppression of stress response (induced by CPB and the surgery).

  • Thoracic sympathectomy which is relatively selective in TEA and does not involve total sympathetic block as seen in total spinal anesthesia.

  • Improved myocardial blood flow (mainly due to thoracic sympathetic block which covers cardiac sympathetic nerves, T1–T5) and is claimed to be associated with increased diameter of the coronary arteries (especially the stenotic epicardial coronary arteries).

  • Improved left ventricular function due to the previous item.

  • Decreased level of myocardial ischemia mainly due to cardiac sympathetic block (T1–T5).

  • Cardiac sympathetic blockade (T1–T5) would lead to decreased need for postoperative use of beta-blockers.

  • Decreased incidence of cardiac arrhythmias mainly after improved myocardial perfusion status.

  • Earlier postoperative extubation time comparable or even earlier than conventional general anesthesia mainly due to decreased need for rescue analgesia in postoperative period.

  • Improved postoperative pulmonary function possibly due to decreased level of stress response, improved postoperative analgesia, improved patient ability for deep breathing, and earlier postoperative ambulation.

  • The possibility to perform “awake” off-pump coronary bypass surgery or some other percutaneous valve replacements using TEA as the main anesthetic method (Karagoz et al. 2000; Schachner et al. 2003; Campos 2009; Royse 2009; Breivik et al. 2010; Watanabe et al. 2011; Karadeniz et al. 2013; Toda et al. 2013; Bektas and Turan 2015; Paliwal et al. 2016).

However, during the last years, some clinicians have seriously criticized TEA for cardiac surgery and questioned its validity as “gold standard of care” for cardiac surgery. Their reason is mainly the very serious associated risk of “epidural hematoma” which could heavily outweigh the above detailed list of benefits. The issue is that in patients undergoing cardiac surgery receiving very high doses of perioperative anticoagulants, and also under full systemic heparinization, TEA is potentially much more “risky” than all the other surgical patient groups. Based on a variety of studies, the risk of epidural hematoma after TEA for cardiac surgery is widely divergent, ranging from 1:1500 to 1:150,000, though in some patient groups, the risk is “increasing” as much as 1:3000 (upper). Also, during the postoperative period, when trying to normalize the coagulation profile in order to remove the catheter, there is an increased risk of thromboembolic events which should be considered as another potential complication (Chaney et al. 1997, 1999; Schwann and Chaney 2003; Chaney 2005a, b; Chaney and Labovsky 2005; Chaney 2006, 2009; Royse 2009; Breivik et al. 2010; Horlocker et al. 2010; Horlocker 2011b; Svircevic et al. 2011a, b; Rawal 2012; Li and Halaszynski 2015).

Most importantly, clinicians should have sophisticated care accompanied with vigilance and a very high degree of suspicion during early postoperative hours in order to be able to detect new onset epidural hematoma through surgical evacuation in its “golden time” of neurologic recovery. This golden time is good if less than 8 h, partial if between 8–24 h, and poor if no intervention is performed (Neal et al. 2008; Breivik et al. 2010; Horlocker 2011a). Occurrence of epidural hematoma is possible during needle introduction, bolus drug injection, catheter insertion, systemic heparinization period until restoration of coagulation profile, and finally during or after catheter removal; however, we have always to keep in mind that occurrence of epidural hematoma and its neurologic complications is a catastrophe.

Based on the 3rd version of the “American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guideline: Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy” released in 2010 and also the 2009 version of “Nordic guidelines for neuraxial blocks in disturbed haemostasis” released by “the Scandinavian Society of Anaesthesiology and Intensive Care Medicine,” the following items could help us prevent potential high-risk patients (Breivik et al. 2010; Horlocker et al. 2010; Horlocker 2011b):
  • Underlying hemostatic disorders

  • Dose and preoperative “drug-free” interval for anticoagulants

  • Any preexisting anatomical disorders and malalignments in the spine, spinal cord, vertebrae, and spinal arteries and vessels

  • Elderly

  • Technical problems when introducing the epidural needle or the catheter

  • Underlying liver or kidney disorders imposing patient to abnormal coagulation profile

Also, according to the 2010 American Society of Regional Anesthesia and Pain Medicine guideline and the 2009 the Scandinavian Society of Anaesthesiology and Intensive Care Medicine, the following recommendations should be kept in mind if there is the possibility of epidural hematoma after neuraxial block:
  1. 1.

    Do not use neuraxial blocks if the patient has a “known underlying coagulopathy” no matter what is the etiology.

     
  2. 2.

    If the epidural needle tap is traumatic, surgery should be postponed for at least 24 h.

     
  3. 3.

    Time interval from the end of the epidural technique (including needle tap, drug administration, etc.) until start of systemic heparinization should be at least more than 60 min.

     
  4. 4.

    The clinicians should adhere strictly to the administration doses of heparin and its reversal agents (try strictly to administer as low as possible doses of heparin which are adjusted for the “shortest duration” for the desired “therapeutic objective”).

     
  5. 5.

    Removing the epidural catheter is permitted only when the coagulation profile tests are resumed to normal values; besides, catheter removal should be followed by strict control of signs and symptoms for any potential epidural hematoma (Neal et al. 2008; Breivik et al. 2010; Horlocker et al. 2010; Horlocker 2011a; b; Leffert et al. 2017).

     

17.10 Summary

The readers could find a summary of the analgesia methods (pharmacological and non-pharmacological) used for acute and chronic pain management in adult cardiac surgery.

References

  1. Acharya M, Dunning J. Does the use of non-steroidal anti-inflammatory drugs after cardiac surgery increase the risk of renal failure? Interact Cardiovasc Thorac Surg. 2010;11:461–7.PubMedCrossRefGoogle Scholar
  2. Alzahrani T. Pain relief following thoracic surgical procedures: a literature review of the uncommon techniques. Saudi J Anaesth. 2017;11:327–31.PubMedPubMedCentralCrossRefGoogle Scholar
  3. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116:248–73.CrossRefGoogle Scholar
  4. Anselmi L, Huynh J, Duraffourd C, Jaramillo I, Vegezzi G, Saccani F, Boschetti E, Brecha NC, De Giorgio R, Sternini C. Activation of mu opioid receptors modulates inflammation in acute experimental colitis. Neurogastroenterol Motil. 2015;27:509–23.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Aryana P, Rajaei S, Bagheri A, Karimi F, Dabbagh A. Acute effect of intravenous Administration of Magnesium Sulfate on serum levels of Interleukin-6 and tumor necrosis factor-alpha in patients undergoing elective coronary bypass graft with cardiopulmonary bypass. Anesth Pain Med. 2014;4:e16316.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Aslan FE, Badir A, Arli SK, Cakmakci H. Patients’ experience of pain after cardiac surgery. Contemp Nurse. 2009;34:48–54.PubMedCrossRefGoogle Scholar
  7. Azzopardi S, Lee G. Health-related quality of life 2 years after coronary artery bypass graft surgery. J Cardiovasc Nurs. 2009;24:232–40.PubMedCrossRefGoogle Scholar
  8. Bainbridge D, Martin JE, Cheng DC. Patient-controlled versus nurse-controlled analgesia after cardiac surgery—a meta-analysis. Can J Anaesth. 2006;53:492–9.PubMedCrossRefGoogle Scholar
  9. Barletta JF. Clinical and economic burden of opioid use for postsurgical pain: focus on ventilatory impairment and ileus. Pharmacotherapy. 2012;32:12S–8S.PubMedCrossRefGoogle Scholar
  10. Barr AM, Tutungi E, Almeida AA. Parasternal intercostal block with ropivacaine for pain management after cardiac surgery: a double-blind, randomized, controlled trial. J Cardiothorac Vasc Anesth. 2007;21:547–53.PubMedCrossRefGoogle Scholar
  11. Bektas SG, Turan S. Does high thoracic epidural analgesia with levobupivacaine preserve myocardium? A prospective randomized study. Biomed Res Int. 2015;2015:658678.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006:CD004603.Google Scholar
  13. Bigeleisen PE, Goehner N. Novel approaches in pain management in cardiac surgery. Curr Opin Anaesthesiol. 2015;28:89–94.PubMedCrossRefGoogle Scholar
  14. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2012;116:1312–22.PubMedCrossRefGoogle Scholar
  15. Bodnar RJ. Endogenous opiates and behavior: 2011. Peptides. 2012;38(2):463–522.PubMedCrossRefGoogle Scholar
  16. Boldt J, Thaler E, Lehmann A, Papsdorf M, Isgro F. Pain management in cardiac surgery patients: comparison between standard therapy and patient-controlled analgesia regimen. J Cardiothorac Vasc Anesth. 1998;12:654–8.PubMedCrossRefGoogle Scholar
  17. Bosilkovska M, Walder B, Besson M, Daali Y, Desmeules J. Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs. 2012;72:1645–69.PubMedCrossRefGoogle Scholar
  18. Boulanger A, Perreault S, Choiniere M, Prieto I, Lavoie C, Laflamme C. Intrathecal morphine after cardiac surgery. Ann Pharmacother. 2002;36:1337–43.PubMedCrossRefGoogle Scholar
  19. Breivik H, Bang U, Jalonen J, Vigfusson G, Alahuhta S, Lagerkranser M. Nordic guidelines for neuraxial blocks in disturbed haemostasis from the Scandinavian Society of Anaesthesiology and Intensive Care Medicine. Acta Anaesthesiol Scand. 2010;54:16–41.PubMedCrossRefGoogle Scholar
  20. Bruce J, Drury N, Poobalan AS, Jeffrey RR, Smith WC, Chambers WA. The prevalence of chronic chest and leg pain following cardiac surgery: a historical cohort study. Pain. 2003;104:265–73.PubMedCrossRefGoogle Scholar
  21. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22:588–93.PubMedCrossRefGoogle Scholar
  22. Camilleri M, Lembo A, Katzka DA. Opioids in gastroenterology: treating adverse effects and creating therapeutic benefits. Clin Gastroenterol Hepatol. 2017;15:1338–49.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Campos JH. Fast track in thoracic anesthesia and surgery. Curr Opin Anaesthesiol. 2009;22:1–3.PubMedCrossRefGoogle Scholar
  24. Caputo M, Alwair H, Rogers CA, Pike K, Cohen A, Monk C, Tomkins S, Ryder I, Moscariello C, Lucchetti V, Angelini GD. Thoracic epidural anesthesia improves early outcomes in patients undergoing off-pump coronary artery bypass surgery: a prospective, randomized, controlled trial. Anesthesiology. 2011;114:380–90.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Carstensen M, Moller AM. Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: a qualitative review of randomized trials. Br J Anaesth. 2010;104:401–6.PubMedCrossRefGoogle Scholar
  26. Chaney MA. How important is postoperative pain after cardiac surgery? J Cardiothorac Vasc Anesth. 2005a;19:705–7.PubMedCrossRefGoogle Scholar
  27. Chaney MA. Cardiac surgery and intrathecal/epidural techniques: at the crossroads? Can J Anaesth. 2005b;52:783–8.PubMedCrossRefGoogle Scholar
  28. Chaney MA. Intrathecal and epidural anesthesia and analgesia for cardiac surgery. Anesth Analg. 2006;102:45–64.PubMedCrossRefGoogle Scholar
  29. Chaney MA. Thoracic epidural anaesthesia in cardiac surgery—the current standing. Ann Card Anaesth. 2009;12:1–3.PubMedCrossRefGoogle Scholar
  30. Chaney MA, Labovsky JK. Thoracic epidural anesthesia and cardiac surgery: balancing postoperative risks associated with hematoma formation and thromboembolic phenomenon. J Cardiothorac Vasc Anesth. 2005;19:768–71.PubMedCrossRefGoogle Scholar
  31. Chaney MA, Furry PA, Fluder EM, Slogoff S. Intrathecal morphine for coronary artery bypass grafting and early extubation. Anesth Analg. 1997;84:241–8.PubMedCrossRefGoogle Scholar
  32. Chaney MA, Nikolov MP, Blakeman BP, Bakhos M. Intrathecal morphine for coronary artery bypass graft procedure and early extubation revisited. J Cardiothorac Vasc Anesth. 1999;13:574–8.PubMedCrossRefGoogle Scholar
  33. Chang CY, Challa CK, Shah J, Eloy JD. Gabapentin in acute postoperative pain management. Biomed Res Int. 2014;2014:631756.PubMedPubMedCentralGoogle Scholar
  34. Chaudhary V, Chauhan S, Choudhury M, Kiran U, Vasdev S, Talwar S. Parasternal intercostal block with ropivacaine for postoperative analgesia in pediatric patients undergoing cardiac surgery: a double-blind, randomized, controlled study. J Cardiothorac Vasc Anesth. 2012;26:439–42.PubMedCrossRefGoogle Scholar
  35. Chen LK, Wang MH, Yang HJ, Fan SZ, Chen SS. Prospective observational pharmacogenetic study of side effects induced by intravenous morphine for postoperative analgesia. Medicine. 2017a;96:e7009.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Chen Y, Qin Y, Li L, Chen J, Zhang X, Xie Y. Morphine can inhibit the growth of breast cancer MCF-7 cells by arresting the cell cycle and inducing apoptosis. Biol Pharm Bull. 2017b;40:1686–92.PubMedCrossRefGoogle Scholar
  37. Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, Carter T, Cassidy CL, Chittenden EH, Degenhardt E, Griffith S, Manworren R, McCarberg B, Montgomery R, Murphy J, Perkal MF, Suresh S, Sluka K, Strassels S, Thirlby R, Viscusi E, Walco GA, Warner L, Weisman SJ, Wu CL. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17:131–57.PubMedCrossRefGoogle Scholar
  38. Correll D. Chronic postoperative pain: recent findings in understanding and management. F1000Res. 2017;6:1054.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Cruickshank M, Henderson L, MacLennan G, Fraser C, Campbell M, Blackwood B, Gordon A, Brazzelli M. Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review. Health Technol Assess. 2016;20:v–xx, 1–117.PubMedCrossRefGoogle Scholar
  40. Cuthbert AW. Lubiprostone targets prostanoid EP(4) receptors in ovine airways. Br J Pharmacol. 2011;162:508–20.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Dabbagh A. Clonidine: an old friend newly rediscovered. Anesth Pain. 2011;1:8–9.CrossRefGoogle Scholar
  42. Dabbagh A. Postoperative pain management in cardiac surgery. In: Dabbagh A, Esmailian F, Aranki S, editors. Postoperative critical care for cardiac surgical patients. 1st ed. New York: Springer; 2014. p. 257–94.CrossRefGoogle Scholar
  43. Dabbagh A, Rajaei S. The role of anesthetic drugs in liver apoptosis. Hepat Mon. 2013;13:e13162.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Dabbagh A, Elyasi H, Razavi SS, Fathi M, Rajaei S. Intravenous magnesium sulfate for post-operative pain in patients undergoing lower limb orthopedic surgery. Acta Anaesthesiol Scand. 2009;53:1088–91.PubMedCrossRefGoogle Scholar
  45. Dabbagh A, Rajaei S, Shamsolahrar MH. The effect of intravenous magnesium sulfate on acute postoperative bleeding in elective coronary artery bypass surgery. J Perianesth Nurs. 2010;25:290–5.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Dabbagh A, Moghadam SF, Rajaei S, Mansouri Z, Manaheji HS. Can repeated exposure to morphine change the spinal analgesic effects of lidocaine in rats? J Res Med Sci. 2011;16:1361–5.PubMedPubMedCentralGoogle Scholar
  47. Dabbagh A, Bastanifar E, Foroughi M, Rajaei S, Keramatinia AA. The effect of intravenous magnesium sulfate on serum levels of N-terminal pro-brain natriuretic peptide (NT pro-BNP) in elective CABG with cardiopulmonary bypass. J Anesth. 2013;27:693–8.PubMedCrossRefGoogle Scholar
  48. Daly DJ, Myles PS. Update on the role of paravertebral blocks for thoracic surgery: are they worth it? Curr Opin Anaesthesiol. 2009;22:38–43.PubMedCrossRefGoogle Scholar
  49. Dauri M, Faria S, Gatti A, Celidonio L, Carpenedo R, Sabato AF. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009;10:716–33.PubMedCrossRefGoogle Scholar
  50. Davies RG, Myles PS, Graham JM. A comparison of the analgesic efficacy and side-effects of paravertebral vs epidural blockade for thoracotomy—a systematic review and meta-analysis of randomized trials. Br J Anaesth. 2006;96:418–26.PubMedCrossRefGoogle Scholar
  51. Derry S, Moore RA. Single dose oral celecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2012;3:CD004233.PubMedCentralPubMedGoogle Scholar
  52. Dick F, Hristic A, Roost-Krahenbuhl E, Aymard T, Weber A, Tevaearai HT, Carrel TP. Persistent sensitivity disorders at the radial artery and saphenous vein graft harvest sites: a neglected side effect of coronary artery bypass grafting procedures. Eur J Cardiothorac Surg. 2011;40:221–6.PubMedCrossRefGoogle Scholar
  53. Ding X, Jin S, Niu X, Ren H, Fu S, Li Q. A comparison of the analgesia efficacy and side effects of paravertebral compared with epidural blockade for thoracotomy: an updated meta-analysis. PLoS One. 2014;9:e96233.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Djafarzadeh S, Vuda M, Takala J, Jakob SM. Effect of remifentanil on mitochondrial oxygen consumption of cultured human hepatocytes. PLoS One. 2012;7:e45195.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute postoperative pain management: I. Evidence from published data. Br J Anaesth. 2002;89:409–23.PubMedCrossRefGoogle Scholar
  56. Dowling R, Thielmeier K, Ghaly A, Barber D, Boice T, Dine A. Improved pain control after cardiac surgery: results of a randomized, double-blind, clinical trial. J Thorac Cardiovasc Surg. 2003;126:1271–8.PubMedCrossRefGoogle Scholar
  57. Duan L, Zhang CF, Luo WJ, Gao Y, Chen R, Hu GH. Does magnesium-supplemented cardioplegia reduce cardiac injury? A meta-analysis of randomized controlled trials. J Card Surg. 2015;30:338–45.PubMedCrossRefGoogle Scholar
  58. Eason MJ, Wyatt R. Paravertebral thoracic block-a reappraisal. Anaesthesia. 1979;34:638–42.PubMedCrossRefGoogle Scholar
  59. Eftekhar-Vaghefi S, Esmaeili-Mahani S, Elyasi L, Abbasnejad M. Involvement of mu opioid receptor signaling in the protective effect of opioid against 6-hydroxydopamine-induced SH-SY5Y human neuroblastoma cells apoptosis. Basic Clin Neurosci. 2015;6:171–8.PubMedPubMedCentralGoogle Scholar
  60. Eljezi V, Duale C, Azarnoush K, Skrzypczak Y, Sautou V, Pereira B, Tsokanis I, Schoeffler P. The analgesic effects of a bilateral sternal infusion of ropivacaine after cardiac surgery. Reg Anesth Pain Med. 2012;37:166–74.PubMedCrossRefGoogle Scholar
  61. Ellenberger C, Sologashvili T, Bhaskaran K, Licker M. Impact of intrathecal morphine analgesia on the incidence of pulmonary complications after cardiac surgery: a single center propensity-matched cohort study. BMC Anesthesiol. 2017;17:109.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Esme H, Apiliogullari B, Duran FM, Yoldas B, Bekci TT. Comparison between intermittent intravenous analgesia and intermittent paravertebral subpleural analgesia for pain relief after thoracotomy. Eur J Cardiothorac Surg. 2012;41:10–3.PubMedGoogle Scholar
  63. Fabritius ML, Geisler A, Petersen PL, Nikolajsen L, Hansen MS, Kontinen V, Hamunen K, Dahl JB, Wetterslev J, Mathiesen O. Gabapentin for post-operative pain management—a systematic review with meta-analyses and trial sequential analyses. Acta Anaesthesiol Scand. 2016;60:1188–208.PubMedCrossRefGoogle Scholar
  64. Fairley JL, Zhang L, Glassford NJ, Bellomo R. Magnesium status and magnesium therapy in cardiac surgery: a systematic review and meta-analysis focusing on arrhythmia prevention. J Crit Care. 2017;42:69–77.PubMedCrossRefGoogle Scholar
  65. Ferasatkish R, Dabbagh A, Alavi M, Mollasadeghi G, Hydarpur E, Moghadam AA, Faritus ZS, Totonchi MZ. Effect of magnesium sulfate on extubation time and acute pain in coronary artery bypass surgery. Acta Anaesthesiol Scand. 2008;52:1348–52.PubMedCrossRefGoogle Scholar
  66. Floettmann E, Bui K, Sostek M, Payza K, Eldon M. Pharmacologic profile of Naloxegol, a peripherally acting micro-opioid receptor antagonist, for the treatment of opioid-induced constipation. J Pharmacol Exp Ther. 2017;361:280–91.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Frampton C, Quinlan J. Evidence for the use of non-steroidal anti-inflammatory drugs for acute pain in the post anaesthesia care unit. J Perioper Pract. 2009;19:418–23.PubMedCrossRefGoogle Scholar
  68. Fujita T, Kumamoto E. Inhibition by endomorphin-1 and endomorphin-2 of excitatory transmission in adult rat substantia gelatinosa neurons. Neuroscience. 2006;139:1095–105.PubMedCrossRefGoogle Scholar
  69. Furue H, Katafuchi T, Yoshimura M. Sensory processing and functional reorganization of sensory transmission under pathological conditions in the spinal dorsal horn. Neurosci Res. 2004;48:361–8.PubMedCrossRefGoogle Scholar
  70. Gallagher R, McKinley S, Dracup K. Post discharge problems in women recovering from coronary artery bypass graft surgery. Aust Crit Care. 2004;17:160–5.PubMedCrossRefGoogle Scholar
  71. Gandhi K, Heitz JW, Viscusi ER. Challenges in acute pain management. Anesthesiol Clin. 2011;29:291–309.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Geng X, Zhao H, Zhang S, Li J, Tian F, Feng N, Fan R, Jia M, Guo H, Cheng L, Liu J, Chen W, Pei J. Kappa-opioid receptor is involved in the cardioprotection induced by exercise training. PLoS One. 2017;12:e0170463.PubMedPubMedCentralCrossRefGoogle Scholar
  73. George JA, Lin EE, Hanna MN, Murphy JD, Kumar K, Ko PS, Wu CL. The effect of intravenous opioid patient-controlled analgesia with and without background infusion on respiratory depression: a meta-analysis. J Opioid Manag. 2010;6:47–54.PubMedCrossRefGoogle Scholar
  74. Graterol J, Linter SP. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2012;26:e26; author reply e26.PubMedCrossRefGoogle Scholar
  75. Griesdale DE, Neufeld J, Dhillon D, Joo J, Sandhu S, Swinton F, Choi PT. Risk factors for urinary retention after hip or knee replacement: a cohort study. Can J Anaesth. 2011;58:1097–104.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Guimaraes-Pereira L. Persistent postoperative pain and the problem of strictly observational research. Pain. 2016;157:1173–4.PubMedCrossRefGoogle Scholar
  77. Guimaraes-Pereira L, Farinha F, Azevedo L, Abelha F, Castro-Lopes J. Persistent postoperative pain after cardiac surgery: incidence, characterization, associated factors and its impact in quality of life. Eur J Pain. 2016a;20:1433–42.PubMedCrossRefGoogle Scholar
  78. Guimaraes-Pereira L, Valdoleiros I, Reis P, Abelha F. Evaluating persistent postoperative pain in one tertiary hospital: incidence, quality of life, associated factors, and treatment. Anesth Pain Med. 2016b;6:e36461.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Guimaraes-Pereira L, Reis P, Abelha F, Azevedo LF, Castro-Lopes JM. Persistent postoperative pain after cardiac surgery: a systematic review with meta-analysis regarding incidence and pain intensity. Pain. 2017;158:1869–85.PubMedCrossRefGoogle Scholar
  80. van Gulik L, Janssen LI, Ahlers SJ, Bruins P, Driessen AH, van Boven WJ, van Dongen EP, Knibbe CA. Risk factors for chronic thoracic pain after cardiac surgery via sternotomy. Eur J Cardiothorac Surg. 2011;40:1309–13.PubMedGoogle Scholar
  81. Gunther T, Dasgupta P, Mann A, Miess E, Kliewer A, Fritzwanker S, Steinborn R, Schulz S. Targeting multiple opioid receptors—improved analgesics with reduced side effects? Br J Pharmacol. 2017.Google Scholar
  82. Guo P, East L, Arthur A. A preoperative education intervention to reduce anxiety and improve recovery among Chinese cardiac patients: a randomized controlled trial. Int J Nurs Stud. 2012;49:129–37.PubMedCrossRefGoogle Scholar
  83. Hakim SM, Narouze SN. Risk factors for chronic saphenous neuralgia following coronary artery bypass graft surgery utilizing saphenous vein grafts. Pain Pract. 2015;15:720–9.PubMedCrossRefGoogle Scholar
  84. Hansdottir V, Philip J, Olsen MF, Eduard C, Houltz E, Ricksten SE. Thoracic epidural versus intravenous patient-controlled analgesia after cardiac surgery: a randomized controlled trial on length of hospital stay and patient-perceived quality of recovery. Anesthesiology. 2006;104:142–51.PubMedCrossRefGoogle Scholar
  85. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain—a systematic review of randomized controlled trials. Pain. 2006;126:91–101.PubMedCrossRefGoogle Scholar
  86. Holzer P. Non-analgesic effects of opioids: management of opioid-induced constipation by peripheral opioid receptor antagonists: prevention or withdrawal? Curr Pharm Des. 2012;18(37):6010–20.PubMedCrossRefGoogle Scholar
  87. Hong RA, Gibbons KM, Li GY, Holman A, Voepel-Lewis T. A retrospective comparison of intrathecal morphine and epidural hydromorphone for analgesia following posterior spinal fusion in adolescents with idiopathic scoliosis. Paediatr Anaesth. 2017;27:91–7.PubMedCrossRefGoogle Scholar
  88. Horlocker TT. Complications of regional anesthesia and acute pain management. Anesthesiol Clin. 2011a;29:257–78.PubMedCrossRefGoogle Scholar
  89. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011b;107(Suppl 1):i96–106.PubMedCrossRefGoogle Scholar
  90. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, Brown DL, Heit JA, Mulroy MF, Rosenquist RW, Tryba M, Yuan CS. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35:64–101.PubMedCrossRefGoogle Scholar
  91. Hoshijima H, Takeuchi R, Kuratani N, Nishizawa S, Denawa Y, Shiga T, Nagasaka H. Incidence of postoperative shivering comparing remifentanil with other opioids: a meta-analysis. J Clin Anesth. 2016;32:300–12.PubMedCrossRefGoogle Scholar
  92. Huang AP, Sakata RK. Pain after sternotomy—review. Brazilian J Anesthesiol. 2016;66:395–401.CrossRefGoogle Scholar
  93. Hudcova J, McNicol E, Quah C, Lau J, Carr DB. Patient controlled opioid analgesia versus conventional opioid analgesia for postoperative pain. Cochrane Database Syst Rev. 2006:CD003348.Google Scholar
  94. Hughes MM, Atayee RS, Best BM, Pesce AJ. Observations on the metabolism of morphine to hydromorphone in pain patients. J Anal Toxicol. 2012;36:250–6.PubMedCrossRefGoogle Scholar
  95. Ing Lorenzini K, Daali Y, Dayer P, Desmeules J. Pharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. A minireview. Basic Clin Pharmacol Toxicol. 2012;110:219–26.PubMedCrossRefGoogle Scholar
  96. International Pain Summit of the International Association for the Study of Pain. Declaration of Montreal: declaration that access to pain management is a fundamental human right. J Pain Palliat Care Pharmacother. 2011;25:29–31.PubMedCrossRefGoogle Scholar
  97. Ishii Y, Iida N, Miyauchi Y, Mackenzie PI, Yamada H. Inhibition of morphine glucuronidation in the liver microsomes of rats and humans by monoterpenoid alcohols. Biol Pharm Bull. 2012;35:1811–7.PubMedCrossRefGoogle Scholar
  98. Jabbary Moghaddam M, Ommi D, Mirkheshti A, Dabbagh A, Memary E, Sadeghi A, Yaseri M. Effects of clonidine premedication upon postoperative shivering and recovery time in patients with and without opium addiction after elective leg fracture surgeries. Anesth Pain Med. 2013;2:107–10.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Jalkut MK. Ketorolac as an analgesic agent for infants and children after cardiac surgery: safety profile and appropriate patient selection. AACN Adv Crit Care. 2014;25:23–30; quiz 31–22.PubMedCrossRefGoogle Scholar
  100. Jeleazcov C, Saari TI, Ihmsen H, Schuttler J, Fechner J. Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass. Br J Anaesth. 2012;109:698–706.PubMedCrossRefGoogle Scholar
  101. Karadeniz U, Ozturk B, Yavas S, Biricik D, Saydam GS, Erdemli O, Onan B, Onan IS, Kilickan L, Sanisoglu I. Effects of epidural anesthesia on acute and chronic pain after coronary artery bypass grafting. Biomed Res Int. 2013;28:248–53.Google Scholar
  102. Karagoz HY, Sonmez B, Bakkaloglu B, Kurtoglu M, Erdinc M, Turkeli A, Bayazit K. Coronary artery bypass grafting in the conscious patient without endotracheal general anesthesia. Ann Thorac Surg. 2000;70:91–6.PubMedCrossRefGoogle Scholar
  103. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77:1048–56.PubMedCrossRefGoogle Scholar
  104. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367:1618–25.PubMedCrossRefGoogle Scholar
  105. Khan M, Fraser A. Cox-2 inhibitors and the risk of cardiovascular thrombotic events. Ir Med J. 2012;105:119–21.PubMedGoogle Scholar
  106. Klockgether-Radke AP. F. W. Serturner and the discovery of morphine. 200 years of pain therapy with opioids. Anasthesiol Intensivmed Notfallmed Schmerzther. 2002;37:244–9.PubMedCrossRefGoogle Scholar
  107. Kocabas S, Yedicocuklu D, Yuksel E, Uysallar E, Askar F. Infiltration of the sternotomy wound and the mediastinal tube sites with 0.25% levobupivacaine as adjunctive treatment for postoperative pain after cardiac surgery. Eur J Anaesthesiol. 2008;25:842–9.PubMedCrossRefGoogle Scholar
  108. Komatsu R, Turan AM, Orhan-Sungur M, McGuire J, Radke OC, Apfel CC. Remifentanil for general anaesthesia: a systematic review. Anaesthesia. 2007;62:1266–80.PubMedCrossRefGoogle Scholar
  109. Kossowsky J, Donado C, Berde CB. Immediate rescue designs in pediatric analgesic trials: a systematic review and meta-analysis. Anesthesiology. 2015;122:150–71.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Kuip EJ, Zandvliet ML, Koolen SL, Mathijssen RH, van der Rijt CC. A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients. Br J Clin Pharmacol. 2017;83:294–313.PubMedCrossRefGoogle Scholar
  111. Lahtinen P, Kokki H, Hendolin H, Hakala T, Hynynen M. Propacetamol as adjunctive treatment for postoperative pain after cardiac surgery. Anesth Analg. 2002;95:813–9, table of contents.PubMedGoogle Scholar
  112. Lahtinen P, Kokki H, Hakala T, Hynynen M. S(+)-ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery. Anesth Analg. 2004;99:1295–301; table of contents.PubMedCrossRefGoogle Scholar
  113. Langford RM, Mehta V. Selective cyclooxygenase inhibition: its role in pain and anaesthesia. Biomed Pharmacother. 2006;60:323–8.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Ledowski T, Stein J, Albus S, MacDonald B. The influence of age and sex on the relationship between heart rate variability, haemodynamic variables and subjective measures of acute post-operative pain. Eur J Anaesthesiol. 2011;28:433–7.PubMedCrossRefPubMedCentralGoogle Scholar
  115. Ledowski T, Reimer M, Chavez V, Kapoor V, Wenk M. Effects of acute postoperative pain on catecholamine plasma levels, hemodynamic parameters, and cardiac autonomic control. Pain. 2012;153:759–64.PubMedCrossRefPubMedCentralGoogle Scholar
  116. Leffert LR, Dubois HM, Butwick AJ, Carvalho B, Houle TT, Landau R. Neuraxial anesthesia in obstetric patients receiving thromboprophylaxis with unfractionated or low-molecular-weight heparin: a systematic review of spinal epidural hematoma. Anesth Analg. 2017;125:223–31.PubMedCrossRefPubMedCentralGoogle Scholar
  117. Leung K. [6-O-methyl-11C]Diprenorphine. 2004a.Google Scholar
  118. Leung K. (20R)-4,5-alpha-Epoxy-17-methyl-3-hydroxy-6-[11C]methoxy-alpha,17-dimethyl-alpha- (2-phenylethyl)-6,14-ethenomorphinan-7-methanol. 2004b.Google Scholar
  119. Li J, Halaszynski T. Neuraxial and peripheral nerve blocks in patients taking anticoagulant or thromboprophylactic drugs: challenges and solutions. Local Reg Anesth. 2015;8:21–32.PubMedPubMedCentralGoogle Scholar
  120. Liu SS, Wu CL. Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg. 2007;104:689–702.PubMedCrossRefPubMedCentralGoogle Scholar
  121. Liu H, Ji F, Peng K, Applegate RL 2nd, Fleming N. Sedation after cardiac surgery: is one drug better than another? Anesth Analg. 2017a;124:1061–70.PubMedCrossRefPubMedCentralGoogle Scholar
  122. Liu X, Xie G, Zhang K, Song S, Song F, Jin Y, Fang X. Dexmedetomidine vs propofol sedation reduces delirium in patients after cardiac surgery: a meta-analysis with trial sequential analysis of randomized controlled trials. J Crit Care. 2017b;38:190–6.PubMedCrossRefPubMedCentralGoogle Scholar
  123. Loboz KK, Shenfield GM. Drug combinations and impaired renal function—the ‘triple whammy’. Br J Clin Pharmacol. 2005;59:239–43.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Mahler DA. Opioids for refractory dyspnea. Expert Rev Respir Med. 2013;7:123–34; quiz 135.PubMedCrossRefGoogle Scholar
  125. Mansouri M, Bageri K, Noormohammadi E, Mirmohammadsadegi M, Mirdehgan A, Ahangaran AG. Randomized controlled trial of bilateral intrapleural block in cardiac surgery. Asian Cardiovasc Thorac Ann. 2011;19:133–8.PubMedCrossRefGoogle Scholar
  126. Mathews ET, Abrams LD. Intrathecal morphine in open heart surgery. Lancet. 1980;2:543.PubMedCrossRefGoogle Scholar
  127. Mugabure Bujedo B. A clinical approach to neuraxial morphine for the treatment of postoperative pain. Pain Res Treat. 2012;2012:612145.PubMedPubMedCentralGoogle Scholar
  128. Mathews TJ, Churchhouse AM, Housden T, Dunning J. Does adding ketamine to morphine patient-controlled analgesia safely improve post-thoracotomy pain? Interact Cardiovasc Thorac Surg. 2012;14:194–9.PubMedCrossRefGoogle Scholar
  129. Mota FA, Marcolan JF, Pereira MH, Milanez AM, Dallan LA, Diccini S. Comparison study of two different patient-controlled anesthesia regiments after cardiac surgery. Rev Bras Cir Cardiovasc. 2010;25:38–44.PubMedCrossRefPubMedCentralGoogle Scholar
  130. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Br J Anaesth. 2011;106:292–7.PubMedCrossRefGoogle Scholar
  131. May G, Bartram T. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. The use of intrapleural anaesthetic to reduce the pain of chest drain insertion. Emerg Med J. 2007;24:300–1.PubMedCrossRefGoogle Scholar
  132. McDaid C, Maund E, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess. 2010;14:1–153, iii–iv.PubMedCrossRefGoogle Scholar
  133. McDonald SB, Jacobsohn E, Kopacz DJ, Desphande S, Helman JD, Salinas F, Hall RA. Parasternal block and local anesthetic infiltration with levobupivacaine after cardiac surgery with desflurane: the effect on postoperative pain, pulmonary function, and tracheal extubation times. Anesth Analg. 2005;100:25–32.PubMedCrossRefGoogle Scholar
  134. McNicol ED, Ferguson MC, Hudcova J. Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain. Cochrane Database Syst Rev. 2015:CD003348.Google Scholar
  135. McNicol ED, Ferguson MC, Haroutounian S, Carr DB, Schumann R. Single dose intravenous paracetamol or intravenous propacetamol for postoperative pain. Cochrane Database Syst Rev. 2016:CD007126.Google Scholar
  136. Michelet P, Guervilly C, Helaine A, Avaro JP, Blayac D, Gaillat F, Dantin T, Thomas P, Kerbaul F. Adding ketamine to morphine for patient-controlled analgesia after thoracic surgery: influence on morphine consumption, respiratory function, and nocturnal desaturation. Br J Anaesth. 2007;99:396–403.PubMedCrossRefPubMedCentralGoogle Scholar
  137. Moghadam MJ, Ommi D, Mirkheshti A, Shadnoush M, Dabbagh A. The effect of pretreatment with clonidine on propofol consumption in opium abuser and non-abuser patients undergoing elective leg surgery. J Res Med Sci. 2012;17:728–31.PubMedPubMedCentralGoogle Scholar
  138. Monico E, Quiñónez Z. Postoperative pain management in patients with congenital heart disease. In: Dabbagh A, Conte AH, Lubin L, editors. Congenital heart disease in pediatric and adult patients: anesthetic and perioperative management. 1st ed. New York: Springer; 2017. p. 871–87.CrossRefGoogle Scholar
  139. Neal JM, Bernards CM, Hadzic A, Hebl JR, Hogan QH, Horlocker TT, Lee LA, Rathmell JP, Sorenson EJ, Suresh S, Wedel DJ. ASRA practice advisory on neurologic complications in regional anesthesia and pain medicine. Reg Anesth Pain Med. 2008;33:404–15.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Nigro Neto C, do Amaral JL, Arnoni R, Tardelli MA, Landoni G. Intrathecal sufentanil for coronary artery bypass grafting. Braz J Anesthesiol. 2014;64:73–8.PubMedCrossRefPubMedCentralGoogle Scholar
  141. Oehler B, Mohammadi M, Perpina Viciano C, Hackel D, Hoffmann C, Brack A, Rittner HL. Peripheral interaction of Resolvin D1 and E1 with opioid receptor antagonists for antinociception in inflammatory pain in rats. Front Mol Neurosci. 2017;10:242.PubMedPubMedCentralCrossRefGoogle Scholar
  142. Ogus H, Selimoglu O, Basaran M, Ozcelebi C, Ugurlucan M, Sayin OA, Kafali E, Ogus TN. Effects of intrapleural analgesia on pulmonary function and postoperative pain in patients with chronic obstructive pulmonary disease undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2007;21:816–9.PubMedCrossRefPubMedCentralGoogle Scholar
  143. van Ojik AL, Jansen PA, Brouwers JR, van Roon EN. Treatment of chronic pain in older people: evidence based choice of strong-acting opioids. Drugs Aging. 2012;29:615–25.PubMedCrossRefGoogle Scholar
  144. Okitsu K, Iritakenishi T, Iwasaki M, Imada T, Kamibayashi T, Fujino Y. Paravertebral block decreases opioid administration without causing hypotension during transapical transcatheter aortic valve implantation. Heart Vessel. 2016;31:1484–90.CrossRefGoogle Scholar
  145. Olofsen E, Boom M, Nieuwenhuijs D, Sarton E, Teppema L, Aarts L, Dahan A. Modeling the non-steady state respiratory effects of remifentanil in awake and propofol-sedated healthy volunteers. Anesthesiology. 2010;112:1382–95.PubMedCrossRefPubMedCentralGoogle Scholar
  146. Owusu Obeng A, Hamadeh I, Smith M. Review of opioid pharmacogenetics and considerations for pain management. Pharmacotherapy. 2017;37:1105–21.PubMedCrossRefPubMedCentralGoogle Scholar
  147. Ozaki N, Ishizaki M, Ghazizadeh M, Yamanaka N. Apoptosis mediates decrease in cellularity during the regression of Arthus reaction in cornea. Br J Ophthalmol. 2001;85:613–8.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Ozturk NK, Baki ED, Kavakli AS, Sahin AS, Ayoglu RU, Karaveli A, Emmiler M, Inanoglu K, Karsli B. Comparison of transcutaneous electrical nerve stimulation and parasternal block for postoperative pain management after cardiac surgery. Pain Res Manag. 2016;2016:4261949.PubMedPubMedCentralCrossRefGoogle Scholar
  149. Paliwal B, Kamal M, Chauhan DS, Purohit A. Off-pump awake coronary artery bypass grafting under high thoracic epidural anesthesia. J Anaesthesiol Clin Pharmacol. 2016;32:261–2.PubMedPubMedCentralCrossRefGoogle Scholar
  150. Papadopoulos N, Hacibaramoglu M, Kati C, Muller D, Floter J, Moritz A. Chronic poststernotomy pain after cardiac surgery: correlation of computed tomography findings on sternal healing with postoperative chest pain. Thorac Cardiovasc Surg. 2013;61(3):202–8.PubMedPubMedCentralGoogle Scholar
  151. Pearce A, Lockwood C, Van Den Heuvel C. The use of therapeutic magnesium for neuroprotection during global cerebral ischemia associated with cardiac arrest and cardiac bypass surgery in adults: a systematic review protocol. JBI Database System Rev Implement Rep. 2015;13:3–13.PubMedPubMedCentralGoogle Scholar
  152. Pergolizzi JV Jr, LeQuang JA, Berger GK, Raffa RB. The basic pharmacology of opioids informs the opioid discourse about misuse and abuse: a review. Pain Ther. 2017;6:1–16.PubMedPubMedCentralCrossRefGoogle Scholar
  153. Peters ML, Sommer M, de Rijke JM, Kessels F, Heineman E, Patijn J, Marcus MA, Vlaeyen JW, van Kleef M. Somatic and psychologic predictors of long-term unfavorable outcome after surgical intervention. Ann Surg. 2007;245:487–94.PubMedPubMedCentralCrossRefGoogle Scholar
  154. Pettersson PH, Jakobsson J, Owall A. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2005;19:306–9.PubMedCrossRefPubMedCentralGoogle Scholar
  155. Phillips SN, Fernando R, Girard T. Parenteral opioid analgesia: does it still have a role? Best Pract Res Clin Anaesthesiol. 2017;31:3–14.PubMedCrossRefPubMedCentralGoogle Scholar
  156. Plein LM, Rittner HL. Opioids and the immune system—friend or foe. Br J Pharmacol. 2017.Google Scholar
  157. Popping DM, Elia N, Marret E, Remy C, Tramer MR. Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic surgery: a meta-analysis. Arch Surg. 2008a;143:990–9; discussion 1000.PubMedCrossRefPubMedCentralGoogle Scholar
  158. Popping DM, Zahn PK, Van Aken HK, Dasch B, Boche R, Pogatzki-Zahn EM. Effectiveness and safety of postoperative pain management: a survey of 18 925 consecutive patients between 1998 and 2006 (2nd revision): a database analysis of prospectively raised data. Br J Anaesth. 2008b;101:832–40.PubMedCrossRefPubMedCentralGoogle Scholar
  159. Rachinger-Adam B, Conzen P, Azad SC. Pharmacology of peripheral opioid receptors. Curr Opin Anaesthesiol. 2011;24:408–13.PubMedCrossRefPubMedCentralGoogle Scholar
  160. Rafiq S, Steinbruchel DA, Wanscher MJ, Andersen LW, Navne A, Lilleoer NB, Olsen PS. Multimodal analgesia versus traditional opiate based analgesia after cardiac surgery, a randomized controlled trial. J Cardiothorac Surg. 2014;9:52.PubMedPubMedCentralCrossRefGoogle Scholar
  161. Ravven S, Bader C, Azar A, Rudolph JL. Depressive symptoms after CABG surgery: a meta-analysis. Harv Rev Psychiatry. 2013;21:59–69.PubMedPubMedCentralCrossRefGoogle Scholar
  162. Rawal N. Epidural technique for postoperative pain: gold standard no more? Reg Anesth Pain Med. 2012;37:310–7.PubMedCrossRefPubMedCentralGoogle Scholar
  163. Richardson J, Sabanathan S. Thoracic paravertebral analgesia. Acta Anaesthesiol Scand. 1995;39:1005–15.PubMedCrossRefPubMedCentralGoogle Scholar
  164. Richardson J, Lonnqvist PA, Naja Z. Bilateral thoracic paravertebral block: potential and practice. Br J Anaesth. 2011;106:164–71.PubMedCrossRefPubMedCentralGoogle Scholar
  165. Royse CF. High thoracic epidural anaesthesia for cardiac surgery. Curr Opin Anaesthesiol. 2009;22:84–7.PubMedCrossRefPubMedCentralGoogle Scholar
  166. Saadat H, Ziai SA, Ghanemnia M, Namazi MH, Safi M, Vakili H, Dabbagh A, Gholami O. Opium addiction increases interleukin 1 receptor antagonist (IL-1Ra) in the coronary artery disease patients. PLoS One. 2012;7:e44939.PubMedPubMedCentralCrossRefGoogle Scholar
  167. Sangesland A, Storen C, Vaegter HB. Are preoperative experimental pain assessments correlated with clinical pain outcomes after surgery? A systematic review. Scand J Pain. 2017;15:44–52.PubMedCrossRefPubMedCentralGoogle Scholar
  168. Scarci M, Joshi A, Attia R. In patients undergoing thoracic surgery is paravertebral block as effective as epidural analgesia for pain management? Interact Cardiovasc Thorac Surg. 2010;10:92–6.PubMedCrossRefPubMedCentralGoogle Scholar
  169. Schachner T, Bonatti J, Balogh D, Margreiter J, Mair P, Laufer G, Putz G. Aortic valve replacement in the conscious patient under regional anesthesia without endotracheal intubation. J Thorac Cardiovasc Surg. 2003;125:1526–7.PubMedCrossRefPubMedCentralGoogle Scholar
  170. Schwann NM, Chaney MA. No pain, much gain? J Thorac Cardiovasc Surg. 2003;126:1261–4.PubMedCrossRefPubMedCentralGoogle Scholar
  171. Scott LJ. Fentanyl iontophoretic transdermal system: a review in acute postoperative pain. Clin Drug Investig. 2016;36:321–30.PubMedCrossRefPubMedCentralGoogle Scholar
  172. Servin F. Remifentanil; from pharmacological properties to clinical practice. Adv Exp Med Biol. 2003;523:245–60.PubMedCrossRefPubMedCentralGoogle Scholar
  173. Servin FS. Update on pharmacology of hypnotic drugs. Curr Opin Anaesthesiol. 2008;21:473–7.PubMedCrossRefPubMedCentralGoogle Scholar
  174. Servin FS, Billard V. Remifentanil and other opioids. Handb Exp Pharmacol. 2008:283–311.Google Scholar
  175. Smith TH, Grider JR, Dewey WL, Akbarali HI. Morphine decreases enteric neuron excitability via inhibition of sodium channels. PLoS One. 2012;7:e45251.PubMedPubMedCentralCrossRefGoogle Scholar
  176. Stenman M, Holzmann MJ, Sartipy U. Association between preoperative depression and long-term survival following coronary artery bypass surgery—a systematic review and meta-analysis. Int J Cardiol. 2016;222:462–6.PubMedCrossRefPubMedCentralGoogle Scholar
  177. Stephens RS, Whitman GJ. Postoperative critical care of the adult cardiac surgical patient. Part I: routine postoperative care. Crit Care Med. 2015a;43:1477–97.PubMedCrossRefPubMedCentralGoogle Scholar
  178. Stephens RS, Whitman GJ. Postoperative critical care of the adult cardiac surgical patient. Part II: procedure-specific considerations, management of complications, and quality improvement. Crit Care Med. 2015b;43:1995–2014.PubMedCrossRefPubMedCentralGoogle Scholar
  179. Suzuki M. Role of N-methyl-D-aspartate receptor antagonists in postoperative pain management. Curr Opin Anaesthesiol. 2009;22:618–22.PubMedCrossRefPubMedCentralGoogle Scholar
  180. Svircevic V, Nierich AP, Moons KG, Diephuis JC, Ennema JJ, Brandon Bravo Bruinsma GJ, Kalkman CJ, van Dijk D. Thoracic epidural anesthesia for cardiac surgery: a randomized trial. Anesthesiology. 2011a;114:262–70.PubMedCrossRefPubMedCentralGoogle Scholar
  181. Svircevic V, van Dijk D, Nierich AP, Passier MP, Kalkman CJ, van der Heijden GJ, Bax L. Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery. Anesthesiology. 2011b;114:271–82.PubMedCrossRefGoogle Scholar
  182. Swartjes M, Mooren RA, Waxman AR, Arout C, Van De Wetering K, Den Hartigh J, Beijnen JH, Kest B, Dahan A. Morphine induces hyperalgesia without involvement of mu-opioid receptor or morphine-3-glucuronide. Mol Med. 2012;18(1):1320–6.PubMedPubMedCentralGoogle Scholar
  183. Tabatabaie O, Matin N, Heidari A, Tabatabaie A, Hadaegh A, Yazdanynejad S, Tabatabaie K. Spinal anesthesia reduces postoperative delirium in opium dependent patients undergoing coronary artery bypass grafting. Acta Anaesthesiol Belg. 2015;66:49–54.PubMedGoogle Scholar
  184. Talebi ZPH, Dabbagh A. Cellular and molecular mechanisms in perioperative hepatic protection: a review of current interventions. J Cell Mol Anesth. 2017;2:82–93.Google Scholar
  185. Tanaka K, Kersten JR, Riess ML. Opioid-induced cardioprotection. Curr Pharm Des. 2014;20:5696–705.PubMedPubMedCentralCrossRefGoogle Scholar
  186. Tejada MA, Montilla-Garcia A, Cronin SJ, Cikes D, Sanchez-Fernandez C, Gonzalez-Cano R, Ruiz-Cantero MC, Penninger JM, Vela JM, Baeyens JM, Cobos EJ. Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice. Proc Natl Acad Sci U S A. 2017;114:8396–401.PubMedPubMedCentralCrossRefGoogle Scholar
  187. Thavaneswaran P, Rudkin GE, Cooter RD, Moyes DG, Perera CL, Maddern GJ. Brief reports: paravertebral block for anesthesia: a systematic review. Anesth Analg. 2010;110:1740–4.PubMedCrossRefGoogle Scholar
  188. Toda A, Watanabe G, Matsumoto I, Tomita S, Yamaguchi S, Ohtake H. Monitoring brain oxygen saturation during awake off-pump coronary artery bypass. Asian Cardiovasc Thorac Ann. 2013;21:14–21.PubMedCrossRefGoogle Scholar
  189. Tzortzopoulou A, McNicol ED, Cepeda MS, Francia MB, Farhat T, Schumann R. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain. Cochrane Database Syst Rev. 2011:CD007126.Google Scholar
  190. Ucak A, Onan B, Sen H, Selcuk I, Turan A, Yilmaz AT. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824–9.PubMedPubMedCentralCrossRefGoogle Scholar
  191. Valdez-Morales E, Guerrero-Alba R, Ochoa-Cortes F, Benson J, Spreadbury I, Hurlbut D, Miranda-Morales M, Lomax AE, Vanner S. Release of endogenous opioids during a chronic IBD model suppresses the excitability of colonic DRG neurons. Neurogastroenterol Motil. 2013;25:39–46.e34.PubMedCrossRefGoogle Scholar
  192. Vosoughian M, Dabbagh A, Rajaei S, Maftuh H. The duration of spinal anesthesia with 5% lidocaine in chronic opium abusers compared with nonabusers. Anesth Analg. 2007;105:531–3.PubMedCrossRefGoogle Scholar
  193. Walker SM, Yaksh TL. Review article: neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data. Anesth Analg. 2012;115:638–62.PubMedPubMedCentralCrossRefGoogle Scholar
  194. Watanabe G, Tomita S, Yamaguchi S, Yashiki N. Awake coronary artery bypass grafting under thoracic epidural anesthesia: great impact on off-pump coronary revascularization and fast-track recovery. Eur J Cardiothorac Surg. 2011;40:788–93.PubMedGoogle Scholar
  195. White PF, Rawal S, Latham P, Markowitz S, Issioui T, Chi L, Dellaria S, Shi C, Morse L, Ing C. Use of a continuous local anesthetic infusion for pain management after median sternotomy. Anesthesiology. 2003;99:918–23.PubMedCrossRefGoogle Scholar
  196. Whiteside GT, Boulet JM, Walker K. The role of central and peripheral mu opioid receptors in inflammatory pain and edema: a study using morphine and DiPOA ([8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid). J Pharmacol Exp Ther. 2005;314:1234–40.PubMedCrossRefGoogle Scholar
  197. Wolf AR. Effects of regional analgesia on stress responses to pediatric surgery. Paediatr Anaesth. 2012;22:19–24.PubMedCrossRefGoogle Scholar
  198. Wu SY, Dun SL, Wright MT, Chang JK, Dun NJ. Endomorphin-like immunoreactivity in the rat dorsal horn and inhibition of substantia gelatinosa neurons in vitro. Neuroscience. 1999;89:317–21.PubMedCrossRefGoogle Scholar
  199. Xie N, Khabbazi S, Nassar ZD, Gregory K, Vithanage T, Anand-Apte B, Cabot PJ, Sturgess D, Shaw PN, Parat MO. Morphine alters the circulating proteolytic profile in mice: functional consequences on cellular migration and invasion. FASEB J. 2017;31(12):5208–16.PubMedCrossRefGoogle Scholar
  200. Xu JT, Sun L, Lutz BM, Bekker A, Tao YX. Intrathecal rapamycin attenuates morphine-induced analgesic tolerance and hyperalgesia in rats with neuropathic pain. Transl Perioper Pain Med. 2015a;2:27–34.PubMedPubMedCentralGoogle Scholar
  201. Xu ZZ, Kim YH, Bang S, Zhang Y, Berta T, Wang F, Oh SB, Ji RR. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med. 2015b;21:1326–31.PubMedPubMedCentralCrossRefGoogle Scholar
  202. Yamanaka T, Sadikot RT. Opioid effect on lungs. Respirology. 2013;18:255–62.PubMedCrossRefGoogle Scholar
  203. Yeung JH, Gates S, Naidu BV, Wilson MJ, Gao SF. Paravertebral block versus thoracic epidural for patients undergoing thoracotomy. Cochrane Database Syst Rev. 2016;2:CD009121.PubMedGoogle Scholar
  204. Yousefshahi F, Predescu O, Colizza M, Asenjo JF. Postthoracotomy Ipsilateral shoulder pain: a literature review on characteristics and treatment. Pain Res Manag. 2016;2016:3652726.PubMedPubMedCentralCrossRefGoogle Scholar
  205. Zhang K, Li M, Peng XC, Wang LS, Dong AP, Shen SW, Wang R. The protective effects of Sufentanil pretreatment on rat brains under the state of cardiopulmonary bypass. Iran J Pharm Res. 2015a;14:559–66.PubMedPubMedCentralGoogle Scholar
  206. Zhang X, Zhao X, Wang Y. Dexmedetomidine: a review of applications for cardiac surgery during perioperative period. J Anesth. 2015b;29:102–11.PubMedCrossRefGoogle Scholar
  207. Zhang R, Xu B, Zhang MN, Zhang T, Wang ZL, Zhao G, Zhao GH, Li N, Fang Q, Wang R. Peripheral and central sites of action for anti-allodynic activity induced by the bifunctional opioid/NPFF receptors agonist BN-9 in inflammatory pain model. Eur J Pharmacol. 2017;813:122–9.PubMedCrossRefGoogle Scholar
  208. Zheng H, Schnabel A, Yahiaoui-Doktor M, Meissner W, Van Aken H, Zahn P, Pogatzki-Zahn E. Age and preoperative pain are major confounders for sex differences in postoperative pain outcome: a prospective database analysis. PLoS One. 2017;12:e0178659.PubMedPubMedCentralCrossRefGoogle Scholar
  209. Ziesenitz VC, Vaughns JD, Koch G, Mikus G, van den Anker J. Pharmacokinetics of fentanyl and its derivatives in children: a comprehensive review. Clin Pharmacokinet. 2018;57(2):125–49.PubMedCrossRefGoogle Scholar
  210. Ziyaeifard M, Azarfarin R, Golzari SE. A review of current analgesic techniques in cardiac surgery. Is epidural worth it? J Cardiovasc Thorac Res. 2014;6:133–40.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cardiac Anesthesiology Department, Anesthesiology Research Center, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran

Personalised recommendations