Postoperative Epidural Opioid Analgesia

Abstract

Much information is available regarding the use of opioids exclusively and in combination with local anesthetics which has helped to define the clinical applicability and efficacy of these forms of therapy and has contributed to the understanding of the disadvantages of their use. This information can be used to select a treatment based on the patient's particular needs in the perioperative period in order to produce a high quality of pain control and a low incidence of side effects and complications. The role of epidural anesthesia and analgesia in reducing the incidence and severity of perioperative physiologic derangements, in addition to relieving pain has been reported in several studies. This subject has also been the focus of a recent review article [1] which suggests that the use of epidural techniques appears to be justified in the perioperative care of high-risk surgical patients, since these techniques are not only associated with better analgesia [2-4] but, possibly, also with improved postoperative outcome [1]. The United States appears to be moving toward an environment where competition for health care resources will increase [5] as part of health care reform. Consequently, medical practices will undergo cost scrutiny by both internal and external regulators [6]. Thus, it is important that anesthesiologists consider not only cost but also the efficacy of opioids, the incidence of side effects, their associated benefits, and the resources available when making a decision to use postoperative epidural or intravenous analgesia. This review will provide an overview of the current knowledge in the use of opioids for epidural postoperative analgesia. Moreover, protocols for the management of postoperative pain will be recommended. Although we will discuss concentrations and rates of administration which have been effective in our practice, none of these has been clearly shown to be optimal in clinical studies, and thus they do not represent either the ideal or the only combinations. Mechanisms of Opioid Action After Epidural Administration Peripheral nociceptive signals are transmitted to the dorsal horn of the spinal cord via C fiber neurons where neuropeptides, such as tachykinins (substance P and neurokinin A) and glutamate, are released at the presynaptic level. The tachykinins bind to the postsynaptic neurokinin receptors NK1 and NK2 leading, via guanosine triphosphate protein activation, to depolarization and changes in second messengers. Glutamate acts on both the alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid and N-methyl-D-aspartic acid (NMDA) receptors on postsynaptic membranes of the dorsal horn neurons. The ion channels linked to the NMDA receptors are ordinarily blocked by magnesium ions. However, magnesium can be removed by depolarization of the cell, which leads to an influx of calcium and sodium ions causing further depolarization. Spinal opioids exert their analgesic effects by reducing neurotransmitter release at the presynaptic level, and by hyperpolarizing the membrane of dorsal horn neurons at the postsynaptic level [7]Figure 1.Figure 1: A hypothetical simplified arrangement of receptors at the first central synapse in the dorsal horn of the spinal cord. (See text for description.) NK1, NK2 = neurokinin receptors; AMPA = alpha-amino-3-hydroxy-5-methyl-4-isoxazoloproprionic acid; NMDA = N-methyl-D-aspartic acid; cAMP = cyclic adenosine monophosphate; PKC = protein kinase C.Physical and Chemical Properties of Opioids in the Epidural Space Epidural opioids have the advantage of producing analgesia without motor or sympathetic blockade. Studies have determined differences among the frequently used opioids for epidural analgesia. Onset of analgesia is more rapid with the highly lipid soluble opioids. Conversely, lipid insoluble opioids, such as morphine, are retained in the cerebrospinal fluid (CSF), providing a longer supply to the spinal cord and consequently a slower onset, but longer duration of analgesia after the administration of a single dose [8]. The octanol:buffer partition coefficients, the meningeal permeability coefficients and the minimum effective analgesic concentrations (MEAC) in plasma of frequently used opioids are listed in Table 1. Lipophilicity, as assessed by octanol:buffer distribution coefficient, correlates with the meningeal permeability coefficient but in a nonlinear fashion. The optimal octanol:buffer distribution coefficient that results in maximal meningeal permeability is between 129 (alfentanil) and 560 (bupivacaine) [9]. This biphasic relationship between lipophilicity and a drug's meningeal permeability coefficient, may be explained by the dual nature of the arachnoid membrane which is the main barrier. After a drug is deposited in the epidural space, but before it reaches the spinal cord, it must first cross a hydrophilic zone (extracellular and intracellular fluids) and then a hydrophobic zone (cell membrane lipids) of the arachnoid membrane [9]. Thus, before there is diffusion through these two areas, the drug must first dissolve in those environments. Lipophilic drugs (i.e., those with a high octanol:buffer partition coefficients) readily dissolve in the lipophilic component of arachnoid mater and thus cross the region easily. Conversely, they penetrate the hydrophilic zone with difficulty, creating the rate-limiting factor in their diffusion through the arachnoid membrane. Drugs with intermediate lipophilicity move more readily between the lipid and the aqueous zones, and their meningeal permeability coefficients are correspondingly greater (e.g., alfentanil, hydromorphone, meperidine) [9]. These physical and chemical properties of the opioids will also determine vascular permeability. Opioids with high octanol:buffer distribution coefficients, such as fentanyl and sufentanil, move more easily to the intravascular compartment than to the subarachnoid compartment. Thus, spinal cord concentrations of an opioid after epidural administration are the result of the net difference between the rate of uptake and distribution to the vascular and subarachnoid spaces. These differences explain why morphine, despite having a meningeal permeability coefficient similar to fentanyl and sufentanil Table 1, which are well below the optimal range of meningeal penetration, is a useful drug for epidural analgesia.Table 1: Octanol/Buffer Coefficients, Meningeal Permeability Coefficients, and Minimum Effective Analgesic Concentrations (MEAC) for OpioidsBernards and Hill [9] also showed with their in vitro model that the octanol:buffer distribution coefficient for sufentanil was beyond the range of optimal meningeal permeability. Thus, equianalgesic potencies for intravenous administration between fentanyl and sufentanil (10:1) do not apply to epidural administration [16]. Empirically, it has been suggested that sufentanil is about three times more potent than fentanyl after epidural administration [16]. A recent study in human volunteers suggests that this ratio may indeed be correct [17]. This study also suggests that there may be some selective spinal action for the highly lipid-soluble opioids after epidural administration of small doses of these opioids which were administered to relieve pain produced by low-intensity stimuli [17]. However, redistribution of the epidural opioid to the brain (supraspinal effect) via rostral spread in the CSF, absorption into the systemic circulation, or a combination of these two mechanisms did occur when larger doses were given to provide analgesia for pain produced by high-intensity noxious stimuli [17]. Respiratory depression [8,18], somnolence, and pruritus [19] appear to be associated with the degree of rostral migration of the opioid in the CSF. The timing for the appearance of these side effects varies between lipophilic and hydrophilic opioids after epidural administration. Morphine's rostral migration is a phenomenon which is dose-dependent and follows a predictable time course [18]. In contrast, rostral migration as determined by the onset of upper body analgesia [17], and the incidence of respiratory depression after a lumbar epidural bolus of lipid soluble opioids is unpredictable. Gourlay et al. [20] demonstrated that peak cervical CSF concentrations of fentanyl occurred as early as 10 min after lumbar epidural administration and averaged 10% of the peak lumbar CSF concentrations. However, in two of the six patients, peak cervical CSF concentrations were twice the level found in the rest of the patients. In another study [21], sufentanil concentrations were measured after 72 h of a continuous infusion of 14 micro gram/h via a low thoracic epidural catheter. Sufentanil concentrations in plasma and the cisterna magna CSF were 56% and 82%, respectively, the concentrations measured in the lumbar CSF. Thus, lipophilic opioids also exhibit rostral migration, but in a less predictable manner than morphine. This difference suggests that the same level of care used for monitoring respiratory depression after epidural administration of morphine should also be observed when lipophilic opioids are administered for postoperative epidural analgesia. Morphine The first reported opioid used in the epidural space, and perhaps the most widely studied after epidural administration, is morphine. Moreover, morphine was the first opioid approved by the Food and Drug Administration for intraspinal administration. Due to its prolonged analgesic effect, epidural morphine can be administered as an intermittent bolus or as a continuous infusion. It appears that there are some clinical advantages in using continuous epidural morphine infusions over intermittent bolus for epidural analgesia. Studies evaluating morphine's cephalad migration after a lumbar epidural bolus suggest that respiratory depression may occur as a result of a significant amount of the drug reaching the respiratory center in the brainstem after the administration of a bolus dose in the lumbar epidural area [8,18]. In fact, large scale studies suggest that respiratory depression requiring treatment may be higher with intermittent bolus than with continuous infusions. When mean doses between 7 and 13 mg/d were used in the intermittent bolus group and mean doses of 6-14 mg/d were used in the continuous infusion group, the incidence of respiratory depression was different. In the bolus study group, the incidence of respiratory depression was 1:500 [22]. In contrast, in the continuous infusion group, the incidence was 1:1500 [23]. Based on these data, the maximum risks of respiratory depression at the 95% confidence interval are 1:100 vs 1:5000, respectively [22,23]. Moreover, the concurrent use of parenteral opioids for breakthrough pain, a practice which has been discouraged when intermittent dosing of epidural morphine is used [22], may be administered without an increased risk of delayed respiratory depression, even on surgical wards [23]. The quality of analgesia appears to be more complete when using continuous infusions compared with intermittent bolus. A recent study evaluating the quality of analgesia produced by epidural morphine administered, either as bolus doses or via continuous infusion, demonstrated that patients who received continuous infusion of epidural morphine experienced better analgesia than those who received intermittent bolus injections [24]. Thus, based on apparent greater clinical efficacy and a lower incidence of respiratory depression, it would appear that patients would derive a greater benefit from receiving epidural morphine via a continuous infusion. The suggested treatment protocol is presented in Table 2.Table 2: Epidural Opioids Administered by Continuous InfusionaHydromorphone The quality of analgesia experienced after hydromorphone administration appears to be similar to that produced by morphine [25]. Based on unpublished clinical observations, a ratio of 5:1 between morphine and hydromorphone has been used when administering the drug in a bolus form, and a ratio of 3:1 has been recommended for continuous infusions [25]. When 0.005% hydromorphone infusions (0.05 mg/mL) were administered at a rate of 0.15-0.30 mg/h (3-6 mL/h) and compared to 0.015% morphine (0.15 mg/mL) administered at a rate of 0.45-0.90 mg/h (3-6 mL/h), the incidence of pruritus was four times greater in the group of patients who received morphine (44% vs 11%) [25]. However, patients were treated only with lumbar epidural catheters for both abdominal and thoracic procedures. Thus, the majority of the patients received an intraoperative bolus dose of between 5 and 7.5 mg of morphine and 1 and 5 mg of hydromorphone diluted in 10 mL of solution. Since pruritus was significantly higher in the morphine group only during the first 24 h of the study, and the degree of rostral migration of hydromorphone in the CSF is similar to morphine after a bolus dose in the lumbar epidural space [26], the use of hydromorphone may be associated with a lower incidence of pruritus. Moreover, hydromorphone appears to have a faster onset and shorter duration of action than morphine [26]. Hydromorphone's lipid solubility is intermediate between morphine (more lipid-soluble than morphine) and fentanyl (less lipid-soluble than fentanyl) [27]. The degree of spinal analgesia appears to be related in part to lipid solubility [9]. In fact, Liu et al. [28] have demonstrated that patients receiving intravenous (IV) hydromorphone after radical prostatectomies required twice as much opioid as those randomized to the epidural group (3.5-11.5 vs 1.5-5 micro gram centered dot kg-1 centered dot h-1, respectively; P < 0.008) to achieve the same levels of analgesia during the first three postoperative days. Despite this difference, patients in the epidural group had a greater incidence of pruritus. Thus, this study suggests that epidural administration of hydromorphone results in spinally mediated analgesia. However, the epidural administration did not appear to be associated with improved analgesia, patient satisfaction, or enhanced clinical outcome when compared to the IV route [28]. The suggested treatment protocol for continuous infusion epidural hydromorphone is presented in Table 2. Fentanyl As pointed out in the section on physical and chemical properties of opioids, spinal cord concentrations of an opioid after epidural administration are the result of the balance between vascular and meningeal permeability. Fentanyl, which has a high octanol buffer coefficient Table 1, appears to undergo preferential vascular absorption rather than meningeal penetration after epidural administration. In fact, the use of fentanyl for epidural analgesia is controversial. studies have demonstrated that the quality of analgesia, the incidence of side effects, fentanyl and plasma levels after 24 h of infusion are similar between patients receiving either epidural or IV therapy Moreover, after thoracic epidural administration of fentanyl only benefit over IV or lumbar epidural administration In a study by et al. patients receiving thoracic epidural fentanyl had better and in 1 and shorter than patients receiving IV However, quality of analgesia, fentanyl and incidence of were similar among the and thoracic epidural Thus, IV fentanyl analgesia to the epidural but with a increased incidence of and Based on these studies, it would appear that there are clinical advantages to administering fentanyl via the epidural route of the of when compared with the IV These suggest that the of postoperative fentanyl analgesia after epidural administration is However, there are also studies which suggest that a spinal may occur after epidural administration of fentanyl et al. demonstrated that thoracic epidural infusions of fentanyl produced analgesia to IV but with both lower doses and plasma levels than in patients who received IV infusions. The suggested treatment protocol for continuous infusion epidural fentanyl is presented in Table 2. Sufentanil sufentanil analgesia via both spinal and effects Studies postoperative analgesia with IV or epidural sufentanil have shown that both the quality of analgesia and plasma levels are similar after either route of administration. However, the incidence of respiratory depression by high levels in of vs 1 of 24 and of vs of appears to be greater in the IV Moreover, as with there is clinical advantage in using thoracic over lumbar epidural administration in patients Epidural sufentanil therapy appears to the results in patients with opioid use greater than of morphine who have opioid suggests that as a result of or of the NK1, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid receptors from the guanosine to prolonged of receptors from the also may result in and action Thus, the to and in the of opioid receptors results in higher dose and and et al. have also the NMDA in the of Moreover, et al. reported that opioid was associated with an increase in the protein kinase C the of the dorsal Since PKC the NMDA results in of a magnesium ion it is also that the of a increase in opioid of the NMDA Administration of opioids and protein kinase A via protein which the of cyclic adenosine The in of intracellular and membrane This is by the administration of opioids. In fact, the level of cyclic adenosine to control or may even increase beyond control levels when opioid These changes have been as a of the opioid from the protein opioid such as morphine, and sufentanil were to have maximum analgesic when doses were used However, it is that maximum drug can be by these opioids they of the available This difference is a of the drugs that low (e.g., are as having high In fact, a study using has demonstrated that sufentanil is more effective than morphine in of efficacy the concentrations of receptors were blocked and morphine was into a Conversely, sufentanil a and retained Moreover, in an model in which were to opioid with opioid a in dose to the same effect) in the for morphine was found than In contrast, the infusion of sufentanil in a significantly (less than This that two drugs that at the same may an group has demonstrated that patients with pain receiving doses of morphine greater than mg/d before to the experienced postoperative pain despite large doses of epidural morphine to administered with they were to sufentanil, pain control was with significantly equianalgesic doses micro Thus, higher efficacy appears to be related to its to exert an analgesic with a lower than morphine, as the of opioid receptors to This not only into better pain but also into significant cost when compared with the large doses of morphine. our the cost of providing a patient with a mg/h infusion of epidural morphine is similar to the cost by administering sufentanil at 14 micro Since patients with opioid did not pain control when receiving epidural morphine at the cost of providing analgesia was less when sufentanil was used The suggested treatment protocol for continuous infusion epidural sufentanil is presented in Table 2. The lipophilicity of is between that of morphine and would appear to be a for postoperative epidural analgesia its coefficient of meningeal permeability is in the optimal range [9]. Thus, the rapid intravascular absorption with lipophilic opioids not occur with Consequently, peak plasma levels after bolus are low However, a bolus dose postoperative analgesia for only about 1 h Thus, a continuous infusion is required for postoperative analgesia. The for this duration of despite ideal is When a bolus was by an gram centered dot kg-1 centered dot via an IV or and epidural patients experienced both a similar quality of analgesia and an incidence of side effects, that there is advantage to the epidural over the IV route However, in this study, the doses were not to a level of pain and the patients received the same amount of by infusion. This in plasma concentrations in the range of of reported in a study of postoperative analgesia with IV infusion of Thus, regarding spinal effects of can be from the results in this et al. compared epidural analgesia with IV for postoperative analgesia. did not a continuous infusion in either group, thus patients received bolus of micro gram of with a interval of 10 min in the epidural group and 5 min in the IV This difference in the interval was based on their results in a study which showed that of via the epidural route was longer than via the IV route that there were clinical advantages to the epidural administration of when compared with the IV Despite a lower mean and a significantly mean dose of for of the study by patients in the epidural group, the incidence of was similar between the two the of this difference in opioid is a cost of micro gram of alfentanil, then the mean cost of treatment would have been for the epidural group for the IV patients received 5 of the would amount to Since there is for the of the epidural as it is part of the this difference in cost may be The suggested treatment protocol for continuous infusion epidural is presented in Table 2. and human studies evaluating pain and postoperative pain have demonstrated the effects between local anesthetics and and opioids and Conversely, et al. showed in patients either or abdominal and thoracic the addition of did not the quality of analgesia produced by fentanyl However, of their study may for these randomized to the and received the same amount of fentanyl during the course of the Since patients in the fentanyl treatment group experienced analgesia, of a larger of patients would have been to determine the effects of A more study would have been to determine the quality of analgesia at rest and during after a of the epidural doses of fentanyl when with the may have shown differences between the two the of epidural opioids with concentrations of local anesthetics are important for three in the dose of both drugs is or of the degree of pain is and in the incidence of effects produced by both opioids local anesthetics is et al. have demonstrated that these three be when fentanyl micro was to reported that the quality of analgesia was the degree of motor was less with than when was administered Since the concentrations of fentanyl and used in this study are than the doses to achieve analgesia when either of these two drugs are used their results suggest between the two recent study demonstrated that patients experienced analgesia and a low incidence of side effects when mg/mL) was with morphine mg/mL) at rates between and monitoring was used and most patients were treated on the surgical wards with for levels of analgesia and or of side of and fentanyl or sufentanil may define the of using highly lipophilic opioids for postoperative epidural analgesia. administering doses of epidural opioids, the incidence of side effects may be less than that experienced with the IV However, studies have not been in to determine the ideal between opioids and local It is important to that the ratio at which the opioid and the local are administered is et al. found that the of spinal morphine produced by is Although the of morphine to opioid receptors is its most effect, the of opioid to spinal receptors is at large doses of Thus, it is important to consider this when epidural local anesthetics and opioids. The for drugs the has not been used in human studies evaluating of local anesthetics and opioids for epidural analgesia. This is has been and has the advantage of making about the mechanisms of action or the of the The is the of only three is required for the of the between two drugs at a When using this dose are determined for Drugs A and as well as for a combination of Drugs A and these the is determined dose to produce of the maximal The for Drug A is then on the and the of Drug is on the of an A the two the for The of that effects should the confidence of this Conversely, it significantly to the of the of is demonstrated this the between and morphine was demonstrated after spinal administration The suggested protocols based on clinical for epidural and local are presented in Table Epidural Administered by Continuous The administration of hydrophilic opioids via a continuous infusion results in selective spinal analgesia with a low incidence of side Lipophilic opioids may also be associated with spinal However, the doses required to produce postoperative analgesia also produce plasma concentrations the Thus, in clinical practice it may not be to epidural doses of lipophilic opioids to those associated with spinal analgesia. of the of epidural administration of lipophilic opioids may clinical advantages over the IV epidural administration of small doses of lipophilic opioids in combination with local anesthetics may significant clinical advantages over systemic administration of opioids studies will be to determine the ideal concentrations of opioids and local as well as the of the two drugs to optimal analgesia with incidence of side