Fig. 11.1
A schematic representation of thoracic paravertebral block, demonstrating the spine body and other parts of the spine, spinal cord, and its nerve roots and the location where paravertebral needle is introduced (on right)
Besides, it should be kept in mind that among a number of factors which could affect the patient outcome, the quality of “acute postoperative pain management” is an important and considerable one; since if we manage acute postoperative pain in a qualitative manner, we could help 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).
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).
In this chapter a brief explanation of the pathophysiologic mechanisms in patients is explained first. Then, different pharmacologic and non-pharmacologic approaches of acute pain management are discussed with a brief explanation of their usage methods, risks, and benefits.
11.2 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 causes 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”; this response 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 some studies have neglected the exact relationship between postoperative pain and sympathetic tone to consider other factors such as the severity of surgical lesion and “surgical trauma” much more important than the amount of sympathetic tone severity (Liu and Wu 2007; Ledowski et al. 2011; Wolf 2012a, b).
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” (Jayr 1998; Popping et al. 2008a).
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 limitations due to the coagulation disturbances after administration of anticoagulation and antiplatelet agents to be discussed later in this chapter (Schwann and Chaney 2003; Milgrom et al. 2004; Stritesky et al. 2004; Lena et al. 2008; Popping et al. 2008a, b; Campos 2009; Katz and Seltzer 2009; Cogan 2010; Muehling et al. 2011; Huffmyer et al. 2012; Mugabure Bujedo 2012; Nishimori et al. 2012; Romeyke and Stummer 2012; Usichenko et al. 2013).
11.3 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 (Simpson et al. 1996; Aida et al. 2002; Milgrom et al. 2004; Leal et al. 2005; Anderson and Cutshall 2007; Ballan and Lee 2007; Lee 2008; Aslan et al. 2009; Azzopardi and Lee 2009; Parry et al. 2010).
11.4 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 originating from the chest wall (including the muscles, bony structures, tendons, and ligaments) (Jayr 1998; Acharya and Dunning 2010; Borgermann et al. 2010).
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 considerable 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, 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 (Jayr 1998; Ledowski et al. 2011, 2012; Bodnar 2011; Brock et al. 2012; Nishimori et al. 2012; Oderda 2012; Torigoe et al. 2012; Urell et al. 2012; van Ojik et al. 2012).
11.5 The Etiologic Factors Aggravating Pain After Cardiac Surgery
There are a number of different potential etiologic risk factors for acute pain in these patients which are presented in Table 11.1.
Table 11.1
A summary of etiologic risk factors for acute pain in cardiac surgery patients and their pain sources
Etiologic factor | |
|---|---|
1 | Incision site pain after sternotomy or thoracotomy |
2 | Intraoperative tissue retraction and surgical dissection |
3 | The arterial and venous vascular cannulation sites |
4 | The site of vein harvesting |
5 | The chest and abdominal sites for chest tubes |
Usually the pain location varies being a function of time; in other words, during the early postoperative days (usually the three postoperative days), the pain is mainly in the thoracic area, while, afterwards, 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 first 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 are current evidence that demonstrate the minimally invasive vein-graft harvesting method (endoscopic harvesting) which claim this harvesting method “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 (Meehan et al. 1995; Moore 1995; Wipke-Tevis and Stotts 1998; Mueller et al. 2000a; Greenfield et al. 2001; Kalso et al. 2001; Bruce et al. 2003; Gallagher et al. 2004; Hudcova et al. 2006; Lahtinen et al. 2006; Koukis et al. 2008; Rubens and Boodhwani 2009; Garvin et al. 2010; Parry et al. 2010; Tennyson et al. 2010; Kiani and Poston 2011; Mazzeffi and Khelemsky 2011; Ucak et al. 2011; van Gulik et al. 2011; Papadopoulos et al. 2013).
11.6 Chronic Pain in Cardiac Surgery Patients
Chronic pain is not infrequent after cardiac surgery; its incidence has been reported to be about 20–55 %, though recent studies have demonstrated high 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 chronic postoperative pain states are all interrelated in these patients. There are some patients being affected by chronic pain after cardiac surgery 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 (Jonjev et al. 2000; Mueller et al. 2000a, b; Kalso et al. 2001; Bruce et al. 2003; Hirose et al. 2003; Bar-El et al. 2005; Lima Canadas et al. 2005; Hassan et al. 2006; Lahtinen et al. 2006; De Cosmo et al. 2009; Peivandi et al. 2009; Cogan 2010; Gjeilo et al. 2010; Lee et al. 2010; Dick et al. 2011; Farrell and McConaghy 2012).
There are a number of potential risk factors for occurrence of postoperative chronic pain in cardiac surgery patients during the postoperative period. Table 11.2 is a summary of the main factors among these possible etiologies; these should be differentiated from etiologic factors mentioned later in Table 11.3.
Table 11.2
A summary of the main potential risk factors for chronic pain after cardiac surgery
Possible etiologic chronic pain factor | |
|---|---|
1 | Patients undergoing extensive surgical procedures (e.g., CABG plus valve surgery is associated with increased incidence of postoperative chronic pain than CABG alone) |
2 | Prolonged time of the procedure (especially surgeries more than 3 h) |
3 | Severe acute postoperative pain (with numeric rating scale ≥4) |
4 | Patients with ASA classifications >III |
5 | Any underlying history of preoperative or postoperative depression |
6 | Any underlying history for psychological vulnerability; preoperative or postoperative |
7 | Nonelective operations |
8 | Redo operations needing sternotomy |
9 | Increased needs for analgesic use during the first few postoperative days |
10 | Female patients |
Table 11.3
A summary of the main etiologic mechanisms involved in chronic pain after cardiac surgery
Possible etiologic chronic pain factor | |
|---|---|
1 | Physical effects of sternotomy |
2 | Surgical dissection and harvesting of the IMA, either skeletonized or pedicled |
3 | Direct damage to the trauma to the thoracic nerve branches including the anterior rami of intercostals nerve branches nerves |
4 | Pressure of the retractor |
5 | Surgical tissue destruction, fractures of the ribs |
6 | Separation of the costochondral junction |
7 | Surgical scar formation |
8 | Postoperative infection of the sternum |
9 | Sternal stainless-steel wire sutures |
10 | Inappropriate positioning of the body organs or suboptimal positioning of the arms before commencement of the surgical procedure |
11 | Intraoperative or postoperative injury to the brachial plexus |
12 | Pressure effects of rib fracture fragments |
13 | Placement of central venous catheter |
11.6.1 Chronic Chest Pain
Although maybe 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 etiologic factors mentioned as potential mechanisms for chronic pain in cardiac surgery patients, which might contribute to the appearance of chronic postoperative pain and postoperative neuropathies including a summary of etiologic mechanisms which is presented in Table 11.3; however, these should be discriminated from the risk factors presented in Table 11.2.
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
11.6.2 Chronic Leg Pain
Chronic pain may also occur in the leg, primarily due to postoperative neuralgia of the saphenous nerve which happens after saphenous veins 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.
11.7 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):
Reducing underlying pain and anxiety by effective treatments
Restoration 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 blocks, 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 opioids 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.
11.8 Pharmacologic Alternatives Used for Treatment of Acute Cardiac Surgery Patients
The pharmacologic methods used for alleviation of acute pain are very vast and include a large list, from opioids to nonopioids. In Table 11.4, a summary is presented and more discussions could be found in the text.
Table 11.4
A brief summary of pharmacologic methods for treatment of acute pain in cardiac surgery
1 | Opioids |
2 | Alpha 2 agonists |
3 | Nonsteroidal anti-inflammatory drugs (NSAIDs) |
4 | Paracetamol |
5 | Other pharmaceutical agents (ketamine, MgSO4, gabapentin, pregabalin) |
6 | Multimodal analgesia |
7 | Patient-controlled analgesia |
11.8.1 Opioids
Morphine was detected by Friedrich Sertürner in 1803–1806, and its analgesic activity was used afterwards (Klockgether-Radke 2002; Jurna 2003; Rachinger-Adam et al. 2011). However, the routine clinical administration of opioids for acute pain suppression began in 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.
11.8.1.1 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 present modulatory role than analgesic role, at both 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; this 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 (Leung 2004a, b; Waldhoer et al. 2004; Rachinger-Adam et al. 2011; Vadivelu et al. 2011; Awad et al. 2012; Bortsov et al. 2012; Granier et al. 2012; Sacerdote et al. 2012).
11.8.1.2 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 (Barletta 2012; Glaser et al. 2012; Hertle et al. 2012; Laorden et al. 2012).
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 (Nikoda et al. 1994; Bell et al. 2004; Gehling and Tryba 2009; Meylan et al. 2009; Mota et al. 2010; Mugabure Bujedo 2012; Nishimori et al. 2012; Walker and Yaksh 2012).
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 are as follows which are the steps of the effect of opioids on respirations:
1.
Decreased respiratory rate.
2.
Decreased tidal volume would happen after respiratory rate decrease.
3.
Disturbed rhythmic function and generation of the respiration.
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.
Decreased sensitivity to hypoxia leading to decreased ventilator drive to hypoxia.
6.
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 (White and Irvine 1999; George et al. 2010; Olofsen et al. 2010a; Geller 2011; Jungquist et al. 2011; Macintyre et al. 2011; Angst et al. 2012; Hicks et al. 2012; Phillips et al. 2012; Yamanaka and Sadikot 2013).
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 (Everts et al. 1998; Hanna et al. 2005; Bodnar 2011; Due et al. 2012; Shekar et al. 2012).
Other systems are also affected by the effects of opioids:
Immune System
Demonstrated as opioid-induced 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 could be 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 (Bodnar 2011; Bortsov et al. 2012; Hutchinson et al. 2012; Kwok et al. 2012; Lewis et al. 2012; Saadat et al. 2012)
Gastrointestinal Tract
Opioids, especially morphine, not only decrease the mobility of the GI tract ending in constipation but also at times aggravate the centrally mediated nausea and vomiting, which are well-recognized unwanted side effects of opioids 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 to soften the stool and increase motility and defecation (Cuthbert 2011; Bodnar 2011; Bove et al. 2012; Brock et al. 2012; Ishihara et al. 2012; Kapoor 2012; Smith et al. 2012; Tack and Corsetti 2012; Valdez-Morales et al. 2013).
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 is 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; Brock et al. 2012; Holzer 2012; Oderda 2012; Shi et al. 2012).
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 (Bortsov et al. 2012; Djafarzadeh et al. 2012; Eschenroeder et al. 2012; Polanco et al. 2012; Tsai et al. 2012; Allegaert et al. 2013).
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 (Andrieu et al. 2009; Blaudszun et al. 2012; Bodnar 2011; Engelman and Marsala 2013; Ishihara et al. 2012; Na et al. 2012; Oderda 2012; Torigoe et al. 2012).
11.8.1.3 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 (Chap. 2).
Morphine
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 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; van Ojik 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 half-life being 8 min; however, the equilibration half-life of morphine is very much longer, 2–3 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 (Lotsch 2005; Ing Lorenzini et al. 2012).
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 pharmacokinetic and pharmacodynamic indicators, time to equilibrate after start of infusion and “CSHL” are two very important factors that could help us chose 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” (Bennett and Stanley 1979; Hachenberg 2000; Servin 2003, 2008; Murphy 2005; Guggenberger et al. 2006; Servin and Billard 2008; Futier et al. 2012).
Fentanyl
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 lungs; so nearly two thirds of fentanyl is inactivated in the first pass of the lung.
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 longtime infusion. Pharmacologically speaking, context-sensitive halftime 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 (Hachenberg 2000; Hudson et al. 2002; George et al. 2010):
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, and end tidal CO2.
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
Sufentanil is another opioid synthetic compound which is about 5–10 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 (Kapila et al. 1995; Bosilkovska et al. 2012; Jeleazcov et al. 2012).
Alfentanil
Alfentanil is another opioid compound similar to fentanyl but 5–10 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 (Kapila et al. 1995; Bosilkovska et al. 2012; Jeleazcov et al. 2012).
Remifentanil
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 pharmacologic and clinical features of remifentanil (Kapila et al. 1995; Hachenberg 2000; Servin 2003; Lotsch 2005; Murphy 2005; Scott and Perry 2005; Lahtinen et al. 2008; Servin and Billard 2008; Staahl et al. 2009; Olofsen et al. 2010a, b; Ing Lorenzini et al. 2012):
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 in both 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 regarding its metabolism.
11.8.2 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 through intravenous administration. The mechanism of action in these agents is creation of sedation through stimulation of α2-receptors in the locus ceruleus and creation of analgesia through stimulation of α2-receptors within the locus ceruleus 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. Their perioperative effects include increased stability of the hemodynamic parameters accompanied with decreased perioperative myocardial ischemia; also, decreased need for analgesic agents is another potential benefit of these agents while these agents could decrease postoperative opioid consumption, pain intensity, and nausea, accompanied with decreased use of analgesics, beta-blockers, antiemetics, epinephrine, and diuretics when used as sedative for post-CABG patients. Also, they might have 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 (Hogue et al. 2002; Herr et al. 2003; Buvanendran and Kroin 2009; Blaudszun et al. 2012; Lin et al. 2012).
11.8.3 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 suppression of 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 (Griffin 1998; Tenenbaum 1999; Visser et al. 2002; Aldington et al. 2005; Brown et al. 2006; Langford and Mehta 2006; Munir et al. 2007; Rainsford 2007; Dajani and Islam 2008; McCormack 2011; Moore et al. 2011; Barletta 2012; Derry and Moore 2012; Khan and Fraser 2012).
The most important adverse effects of NSAIDs are as follows:
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.
Increased risk of bleeding which could be a potential complication in patients receiving neuraxial block for postoperative pain suppression.
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 (Bainbridge et al. 2006a; Ong et al. 2007; Buvanendran and Kroin 2009; Frampton and Quinlan 2009; Acharya and Dunning 2010; Barletta 2012).
11.8.3.1 Paracetamol
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. Its analgesic properties are not so much considerable, especially in cardiac surgery patients and the drug is recommended just as part of a multimodal analgesic regimen (Lahtinen et al. 2002; Fayaz et al. 2004; Pettersson et al. 2005; McDaid et al. 2010; Maund et al. 2011; Tzortzopoulou et al. 2011).
11.8.4 Other Pharmaceutical Agents
Among the other pharmaceuticals used for acute pain suppression in cardiac surgery patients, a number of other agents could be mentioned, including the following:
11.8.4.1 Ketamine
This 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, is 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; Bell et al. 2006; Michelet et al. 2007; Buvanendran and Kroin 2009; Suzuki 2009; Carstensen and Moller 2010; Mathews et al. 2012).
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