This material was presented in part at the Annual Meeting of the American Society of Regional Anesthesia, Seattle, WA, May 14-17, 1998.
Opioid receptors are known to be present in the substantia gelatinosa of the dorsal horn of the spinal cord. Beginning in 1979 administration of morphine and other opioids into the epidural and intrathecal (spinal) spaces became popular in many countries to produce intense, and in the case of morphine, long-lasting analgesia for patients having post-surgical pain. In 1988 a sentinel article appeared in Anesthesiology,1 accompanied by an editorial,2 describing one of the first anesthesiology-based acute post-operative pain management services in North America. Such a service had been developed in 1985 at the University of Kiel in Germany, and their experience has been recently reviewed.3 In their article1, Dr. Ready and colleagues described the organization of a university hospital based acute pain service (APS), including: 1) intermittent bolus injection of epidural morphine, 2) implementation of hospital-wide educational programs for measurement of post-operative pain using a visual analog pain scale (VAS) and teaching of ward nurses to inject epidural opioids in response to a VAS pain score > 3/10, 3) pre-printed orders to facilitate patient monitoring and early recognition and treatment of the side-effects and complications of analgesia, and 4) implementation of daily post-operative rounds with a consultant anesthesiologist, anesthesia pain resident or fellow, and the APS nurse (who usually ran the organization), and a pharmacist. The most important new concept proposed by Ready et al was that a well-developed infrastructure that included appropriate patient monitoring and follow-up, along with education of ward nurses, surgeons, and anesthesiologists in the rational and appropriate use of aggressive pain control, can lead to improvement in the quality of post-operative care while minimizing its complications. This model for an acute pain service has since been widely adopted in most North American university hospitals.
In 1988, the practice of post-operative analgesia was influenced by a review article on the subject of peri-spinal opioid analgesia published in Anesthesiology in 1984 by Cousins and Mather.4 While this was the first attempt to comprehensively review this new (at that time) area of anesthesiology, certain "dogma" were perpetuated which lead to persisting clinical practices. One of these dogma held that lipid soluble opioids, such as fentanyl (approximately 800 times more lipid soluble than morphine) and sufentanil (approximately 1600 times more lipid soluble than morphine) would be confined in their spread to areas of the spinal cord close to the site of drug injection, whereas epidural morphine and hydromorphone, which are less lipid-soluble, would have a greater spread in the cerebral spinal fluid (CSF). A corollary of this belief was that the lipid soluble opioids were somehow safer than morphine because the risk of cephalad migration of the opioid within the CSF and thus the risk of delayed respiratory depression, would be less than after epidural morphine. Wide acceptance of the assumption that more lipid-soluble opioids were "safer" than less lipid-soluble opioids (with very little supporting data ) resulted in the preference for epidural fentanyl and fentanyl/bupivacaine infusions, and avoidance of epidural morphine in patients on post-surgical wards in North America.
Another concept widely held in 1988 was that epidural morphine could result in respiratory depression up to 24 hours after injection. This belief originated from a 1982 study by Camporesi et al, 5in which healthy volunteers (Duke University football players), who had no surgical pain to stimulate ventilation, received a large bolus dose (10 mg) of epidural morphine. A depressed ventilatory response to CO2 persisted for a mean of 18 hours after injection. Interestingly, in this cross-over study, ventilatory depression after morphine 10 mg given intramuscularly also persisted for 16 hours. Subsequently, when acute pain services developed standardized orders, post-operative patients who had received any dose of epidural or intrathecal morphine were not allowed to receive additional parenteral or oral opioids for 24 hours.
Because of the belief that lipid soluble opioids were somehow safer than morphine, more highly lipid-soluble opioids such as fentanyl and sufentanil became popular for use in epidural infusions. However, the risk of clinically significant severe respiratory depression during epidural fentanyl infusions has been reported to be as high as 0.6%.6 This compares with reported incidence of 0.07 - 0.5 % in patients receiving epidural morphine.7 Lipid soluble opioids do not appear to carry a lower risk of respiratory depression than more water soluble opioids. In addition, several studies have shown that opioids given by the intramuscular route and by intravenous patient-controlled analgesia (PCA) have an equivalent risk of respiratory depression compared to epidural morphine analgesia.8 Data from clinical studies clearly demonstrate that all opioids, regardless of the route of administration have the potential to cause clinically significant respiratory depression.9 The risk of respiratory depression (and of non-respiratory side-effects) after peri-spinal opioids appears to be dose-dependent, although this has not been well studied.
Many studies have been undertaken in an attempt to determine the primary location (spinal versus systemic) of analgesic action for epidurally administered fentanyl. These studies have compared dose requirements, analgesia, plasma fentanyl concentrations, and side-effects of intravenous versus epidural fentanyl. Most studies have concluded that there is no difference between epidural and intravenous infusions of fentanyl in these aspects.10- 12 Of all the opioids in common clinical use in North America, only morphine and hydromorphone have been shown to act primarily at a spinal (and not systemic) site. Epidural diamorphine (heroin) is commonly used in the United Kingdom to provide post-operative analgesia, but the site of action (although probably spinal) has not been established.
During recent years, there has been a realization that smaller doses of peri-spinal morphine than were commonly used in the 1980's are effective and have a lower risk of side-effects. Post-operative analgesia using relatively small doses (2-4 mg intermittent boluses or 0.2-0.3 mg/hr infusions) of epidural morphine has shown to be safe on post-surgical wards.11-14 However, the duration of action of peri-spinal morphine appears to be dose-dependent. Duration of analgesia after low-dose epidural morphine (2-3 mg) is less than 12 hours in opioid naive patients who have undergone upper abdominal surgery. The European Society of Regional Anesthesia committee on post-operative analgesia recently concluded that monitoring for respiratory complications at least every two hours for 12 hours (versus 24 hours) after a bolus dose of usual clinical doses of epidural morphine is sufficient.15 Once the analgesia has worn off, the risk of respiratory depression is also low, so that further opioids can be safely given.
Work performed in Denmark by the research group of Prof. Henrik Kehlet and colleagues has been directed at finding the most advantageous combination of local anesthetics and opioids for post-operative epidural infusion. The goal of their research was to be able to facilitate the early return of function (ambulation, coughing, deep breathing, and enteral alimentation) in patients after abdominal surgery, while minimizing the side-effects of the epidural analgesia (motor block, nausea/vomiting, sedation/respiratory depression, and ileus).16 Out of this work has come the realization that a continuous infusion of bupivacaine and morphine (in low doses), and placement of the epidural catheter close to the dermatomes of surgery, will allow the use of the lowest doses of each medication, maximize the concentration of analgesics at the site where the nociceptive fibers enter the spinal cord, and minimize the side-effects and complication of the therapy. An additional contribution of this and other research groups was the realization that systemic non-steroidal anti-inflammatory medications have a role in post-operative pain management by decreasing the need for opioids, and thus probably decreasing the potential for opioid-related complications such as post-operative ileus and respiratory depression.17, 18 Liu et al have since shown that the optimum combination of post-operative analgesia in terms of maximizing recovery of bowel function and analgesia, while minimizing side-effects for patients after partial colectomy is a continuous infusion of low dose bupivacaine/morphine via a thoracic epidural catheter, in combination with a parenteral non-steroidal anti-inflammatory medication.19 In addition, epidural local anesthetics probably have two beneficial effects: they decrease the need for opioids (which reduces the gut-slowing opioid side-effects) and may have direct stimulatory effects on the bowel.
A recent review of the available literature on the effect of epidural analgesia upon gastrointestinal motility has concluded the following:20
The authors of this article agree with these conclusions, although there have been no clinical studies comparing the effects of morphine/bupivacaine to fentanyl/bupivacaine thoracic epidural infusions on post-operative bowel function.
Yeager and Glass reported in 1987 that in high risk patients undergoing thoracic or upper abdominal surgery, hospital costs were decreased in the patients receiving combined "light" general and epidural anesthesia, followed by post-operative epidural analgesia versus those receiving general anesthesia alone, followed by post-operative intravenous opioid analgesia.21 This difference was largely related to earlier tracheal extubation and therefore shorter ICU stays. Total hospital charges were approximately 40% lower in the epidural group than in the group receiving general anesthesia plus parenteral opioids. This study was not well controlled and contained only 53 patients, thus its predictive power was low. This study was criticized at the time of publication for numerous weaknesses. However, similar findings have been published in more recent studies (see below).
The data showing a clear improvement in clinical outcome and/or decreased cost with using of post-operative epidural analgesia are limited to a few categories of patients and surgical procedures.22 However, the studies where a definite advantage has been shown are quite helpful to the clinician because they suggest areas where post-operative epidural analgesia is clearly indicated when the risk and benefits of this technique are considered. Several studies of patients randomized to receive either general anesthesia plus intravenous opioids versus epidural anesthesia plus post-operative epidural analgesia have shown better outcomes when epidural anesthesia/analgesia is used. Examples are:
Outcome data demonstrating a clear advantage of post-operative peri-spinal analgesia in other patient groups and for other surgical procedures is difficult to come by.
One issue not addressed by any of the published studies is the issue of how the anesthetic is managed in the operating room can effect post-operative recovery of function. The intra-operative conduct of the anesthetic may have a greater influence on duration of post-operative tracheal extubation and ventilation and Intensive Care Unit (ICU) costs than the use of post-operative epidural analgesia per se. For example, a major advantage of placing a pre-operative thoracic epidural catheter is to allow the use of minimal doses of general anesthetic agents so that the patient can rapidly emerge from general anesthesia and have early tracheal extubation at the end of surgery. Despite major abdominal surgery lasting several hours, the patient can be rapidly awakened and can cough, deep breath, take oral fluids, ambulate, and be able to participate in his early post-operative care, if a continuous epidural anesthetic is maintained during surgery and the general anesthetic agents appropriately reduced. If the intra-operative anesthetic is not conducted in a fashion to take advantage of this possibility, the patient will be too sleepy in the early post-operative period, and this potential advantage in terms of having an alert patient, who is able to cough, deep breathe, and take oral fluids will be lost. The issue of how the combination of "light" general anesthesia plus thoracic epidural anesthesia should be conducted for various clinical situations has not been studied. Therefore, at present, we do not know what is the optimum method to manage this combination of anesthetic techniques.
There are several important questions concerning post-operative epidural analgesia, which have yet to be answered. For example, which patients undergoing which surgical procedures are most likely to benefit from post-operative epidural analgesia? In other words, in which patient groups is the risk/benefit ratio < 1.0, where:
Risks/Benefits = (added costs of epidural anesthesia/analgesia + cost of complications) /(savings due to earlier return of function and earlier ICU and/or hospital discharge + benefit to patient of having optimal analgesia).
What are the optimum doses of opioids/local anesthetics/non-steroidal anti-inflammatory medications for various surgical indications in patients of various ages, physical status, and opioid tolerance? How can we minimize the doses of opioids used to avoid their potential gastroenterological and respiratory complications? A question recently posed by Prof. Henrik Kehlet, a noted Danish general surgeon, is: "Can we avoid opioids altogether for some patients?"28 What is the optimum combination of peripheral nerve blocks and oral analgesics needed to provide analgesia for outpatients undergoing painful procedures such as anterior cruciate ligament (of the knee) reconstruction and shoulder reconstructive surgery? The answer to these questions will require well-designed clinical studies.
Over the last ten years, the implementation of anesthesiology-based acute pain services has allowed patients undergoing potentially painful surgical procedures to have a more comfortable post-operative recovery than was previously possible using parenteral opioid analgesic techniques. In addition, clinical studies have shown improved outcomes for patients undergoing peripheral vascular surgery, abdominal surgery such as hysterectomy and bowel resection, and radical retropubic prostatectomy under epidural anesthesia with post-operative epidural analgesia. The combination of low doses of morphine and bupivacaine appear to provide better outcomes with a lower incidence of side-effects than opioids alone when given via an epidural infusion, particularly when the epidural catheter is placed close to the surgical dermatomes. Administration of opioids (morphine or fentanyl) alone without a local anesthetic via a lumbar epidural catheter is probably no more efficacious than using intravenous morphine PCA in terms of post-operative recovery of function. As the shift of potentially painful procedures from the inpatient to the outpatient setting progresses, further clinical studies are necessary to find optimal techniques of post-operative analgesia in outpatients.
References
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