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GENERAL ARTICLES

The Role of Postoperative Analgesia in Delirium and Cognitive Decline in Elderly Patients: A Systematic Review

School of Medicine, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; Purdue University, West Lafayette, Indiana

Address correspondence and reprint requests to Jacqueline M. Leung, MD, MPH, University of California, San Francisco, Department of Anesthesia and Perioperative Care, 521 Parnassus, San Francisco, CA 94143-0648. Address e-mail to leungj{at}anesthesia.ucsf.edu.

	Abstract

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Postoperative delirium and cognitive decline are adverse events that occur frequently in elderly patients. Preexisting patient factors, medications, and various intraoperative and postoperative causes have been implicated in the development of postoperative delirium and cognitive decline. Despite previous studies identifying postoperative pain as a risk factor, relatively few clinical studies have compared the effect of common postoperative pain management techniques (IV and epidural) or opioid analgesics on postoperative cognitive status. A systematic search of the PubMed and CINAHL databases identified six studies comparing different opioid analgesics on postoperative delirium and cognitive decline and five studies comparing IV and epidural routes of administering analgesia. Meperidine was consistently associated with an increased risk of delirium in elderly surgical patients, but the current evidence has not shown a significant difference in postoperative delirium or cognitive decline among other more frequently used postoperative opioids such as morphine, fentanyl, or hydromorphone. The available studies also suggest that IV or epidural techniques do not influence cognitive function differently. However, future investigations of sufficient study size and more standardized methods of defining outcomes are necessary to confirm the current findings.

	Introduction

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Delirium is an acute confusional state with alterations in attention and consciousness (1). In contrast, cognitive decline is defined as changes in one or more neuropsychological domains and is often more subtle than delirium (2,3). Health care professionals frequently under-estimate cognitive decline because its determination requires administration of neuropsychological tests. Consequences of cognitive status changes include poor functional recovery and increased morbidity (4–6). Elderly patients in particular are more susceptible to developing postoperative cognitive decline (POCD) (7,8) and delirium (9–12). After noncardiac surgery, the incidence of POCD ranges from 7%–26% (8,13,14) and the incidence of delirium ranges from 10%–60% (11). After cardiac surgery, POCD and delirium occur in 24%–80% (2,15,16) and 3%–47% (2) of patients, respectively. The varied incidence rates are likely a result of differences in study methodology and patient population characteristics such as age. These statistics will likely increase because of an aging population and more elderly patients presenting for major surgery. Given their common occurrence and evidence for their long-term effects on functioning (8,17–19), POCD and delirium are thus clinically important issues in the perioperative management of the elderly patient.

The etiology of POCD and delirium is still not well understood. Conclusions from previous studies have not always been in complete agreement, and the distinction between delirium and POCD has often been blurred. However, studies do agree that a variety of medications can precipitate delirium and acute cognitive decline in both medical and surgical patients (Table 1). Among elderly surgical patients in particular, preexisting patient factors as well as intraoperative and postoperative causes are also involved (Table 2). Some studies have also highlighted important intraoperative factors that have not been shown to increase POCD or delirium. For example, comparisons between general and regional anesthesia as potential risk factors for POCD (14,20,21) and delirium (22–24) have not revealed a significant difference between the two techniques. A systematic review of intraoperative anesthesia techniques on POCD has also not shown a difference (3).

Among the multitude of factors associated with POCD and delirium, are there management options that can reduce the incidence of these events? Because preoperative patient-related factors are not modifiable, intraoperative anesthetic types and management have not been shown to influence outcomes, and the postoperative period has received little attention in previous studies, we chose to investigate management strategies pertaining to the postoperative setting. This review will focus on the use of opioids and postoperative analgesic modalities. The rationale for choosing these two areas is several-fold. First, opioids are the drugs most commonly given to patients after major surgery. Second, few reports have investigated the role of postoperative analgesia in cognitive decline and delirium. Furthermore, because postoperative pain has been shown to be associated with delirium (25,26) and cognitive decline (27), and opioids routinely used to treat postoperative pain can have central effects, it is of particular interest to ascertain if there are any analgesic drugs or methods that reduce patients’ risk for these events. Accordingly, we conducted a literature search to identify studies that compared: 1) the effects of different opioid analgesics and 2) IV versus epidural modes of analgesia on POCD or delirium.

	Methods

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A broad search of the PubMed database of the National Library of Medicine and CINAHL database from 1966 to 2005 was conducted using the following MESH terms: "Pain, postoperative OR analgesia, epidural OR analgesia, patient-controlled OR analgesics, non-narcotic OR analgesics, opioid OR anesthesia, epidural OR anesthesia, spinal" AND "cognition OR cognition disorders OR confusion OR delirium OR memory/drug effects OR mental processes/drug effects OR psychological tests." Although our focus was on opioids, non-opioid analgesics were included in the search so that we could assess the overall available evidence for postoperative analgesia. We also looked for studies primarily comparing the effect of type of anesthesia (general, epidural, or spinal) on cognitive decline or delirium, as the intraoperative techniques may continue into the postoperative period for analgesia, thus allowing a secondary comparison of epidural or spinal and IV methods. We also searched for articles not indexed for Medline, using the "pubmednotmedline" qualifier in the search command. All references within relevant papers were further investigated for additional studies.

For this systematic review, clinical trials and observational (cohort and case-control) studies were included. Studies must have compared different modes of analgesia delivery (IV versus epidural or spinal) or types of opioid analgesics in the postoperative period for an association with cognitive decline or delirium and defined methods to assess cognitive function or delirium. Studies were included even if POCD or delirium was not the primary outcome of interest.

Eight-hundred-twenty-one articles were retrieved. Studies that did not assess delirium or cognitive decline during the postoperative period were excluded (724 articles). Studies that investigated postoperative delirium or cognitive decline but did not compare different opioid analgesic drugs or modalities were also excluded (85 articles). Because this review focuses on evaluating potential differences in contemporary postoperative analgesia techniques, older studies that compared IV versus IM or subcutaneous analgesia techniques were not included (2 articles).

The first reviewer (HKF) screened all abstracts per inclusion and exclusion criteria. A second reviewer (JML) validated all the entry criteria for the remaining 10 studies before the data extraction process and also validated any articles to be excluded when uncertainty arose. Per established guidelines on study design, these studies were stratified into levels of evidence that ranged from I to IV where level I: systematic review of randomized controlled trials, level II: randomized controlled trials, level III: non-randomized controlled trials or from cohort or case-control analytical studies, and level IV: expert opinion. Furthermore, randomized controlled trials were assigned a quality score on a 1–5 scale (Table 3) (28). For each study included in this report, the following information was recorded: study sample characteristics (number of subjects, type of surgery, age range of subjects), interventions being compared, criteria for defining POCD or delirium, methods of neuropsychological assessment, methods of measuring pain relief between groups, outcomes or findings related to the primary research question, and any statistical information given in the studies. Where possible, study power was calculated by comparing the proportion of the group of patients with the higher rate of delirium against a hypothesized decrease of 10% given the sample sizes presented in the study.

	Results

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Studies Comparing Different Opioid Analgesics in the Postoperative Period
Our search of the literature demonstrates that there has not been a systematic review of randomized controlled trials (level I evidence) comparing different analgesic drugs and methods for an association with postoperative delirium and POCD. From existing studies, the best evidence is provided by randomized controlled trials (level II evidence).

From the literature search, 3 randomized trials (29–31) and 3 observational studies (32–34) (level III evidence) compared different opioid analgesics (Table 4). With 2 exceptions, studies enrolled mainly elderly patients. Three of these studies investigated postoperative delirium, 2 assessed POCD, and 1 examined both. For all studies, assessments of cognitive status were conducted for at least 2 days into the postoperative period or until patient discharge. Comparisons of analgesic drugs used as well as the methods of defining POCD or delirium were quite heterogeneous across the 5 studies. Given these limitations, particularly the nonstandardized method of defining outcomes, a meta-analysis of available data could not be conducted.

The other three studies with level III evidence compared meperidine to one or more other opioid drugs, and all showed that meperidine was associated with a significantly more frequent incidence of postoperative delirium. However, whether there is a difference in the efficacy of pain relief between groups cannot be ascertained from the presented data. The first study by Adunsky et al. (34) compared morphine and meperidine in a group of 92 patients undergoing hip surgery. A similar comparison of morphine and meperidine was made in the second study by Morrison et al. (32), who studied 541 elderly patients with hip fracture. The third investigation is a case-control study by Marcantonio et al. (33) that compared meperidine, morphine, fentanyl, oxycodone, and codeine, although cases and controls mainly received morphine and meperidine. Of the five medications, meperidine was the only one associated with a significantly more frequent incidence of postoperative delirium. In all three studies, delirium was identified by the Confusion Assessment Method (CAM) (39), a commonly used screening tool for acute confusional states adapted from the Diagnostic and Statistical Manual of Mental Disorders (40). One study (34) also used the MMSE in addition to using CAM, but MMSE scores were not significantly different between the two groups.

Studies Comparing Mode of Postoperative Analgesia Delivery
The literature search retrieved 4 randomized trials (level II evidence) and 1 case-control study (level III) that compared IV and epidural analgesia in the postoperative period (Table 5) (10,20,33,41,42). Study patients were mainly older subjects. Three studies identified delirium as the outcome, and 2 studies investigated cognitive impairment. Similar to the studies comparing analgesic drugs, some of these investigations were limited by small sample sizes and heterogeneous criteria to define POCD or delirium.

Marcantonio et al.’s case-control study (33) was the only observational study that compared epidural and IV methods. In this investigation, the epidural route was associated with a significant increase in delirium. However, the researchers explain that meperidine was the medication used in 85% of the epidurals, while the remaining 15% consisted of fentanyl. In this study, meperidine was associated with a more frequent incidence of postoperative delirium when compared with either morphine or fentanyl. The authors did not perform multivariate analysis to determine the relative importance of medication type versus route of drug delivery on the occurrence of postoperative delirium. A comparison of pain relief between groups was also not conducted.

	Discussion

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Studies Comparing Different Opioid Analgesics in the Postoperative Period
Our review focuses on opioid analgesics administered to patients postoperatively because these are the drugs most commonly given to patients after major surgery. Furthermore, elderly patients are especially susceptible to adverse drug effects resulting from the use of multiple drugs, drug-drug interactions, reduced renal clearance, and possible impaired hepatic function.

Opioid analgesics commonly used in the postoperative period include morphine, fentanyl, and hydromorphone. The 3-glucuronide metabolites of both morphine and hydromorphone can lead to neuroexcitation, whereas fentanyl undergoes hepatic biotransformation to inactive metabolites. Patients with renal insufficiency may have impaired elimination of active metabolites, resulting in undesirable side effects such as delirium (44–46). Morphine also undergoes hepatic conjugation to form morphine-6-glucuronide, an opioid agonist. Although some studies have examined the relative analgesic efficacy and adverse effects profile of morphine compared to morphine-6-glucuronide, none has evaluated their impact on postoperative delirium (47). Meperidine, a now infrequently used opioid analgesic, has a relatively long half-life and its metabolite, normeperidine, is a central nervous system stimulant with anticholinergic properties that may induce seizures and delirium (48,49). Accumulation of normeperidine will occur in patients with renal dysfunction. Meperidine is sometimes used in a smaller dosage to treat postoperative shivering. The effect of this smaller dose of meperidine on delirium and cognition has not been investigated.

Of the six studies that compared specific opioid analgesics, all three studies that compared meperidine with another opioid confirmed that meperidine is associated with a significantly increased risk of delirium in elderly surgical patients. However, there is a significant limitation in these three studies because they did not discuss whether analgesia was similar between the groups of patients. Of the remaining studies that investigated other opioids, one did not show a significant difference between fentanyl and morphine on the occurrence of postoperative confusion, while the other showed that patients receiving hydromorphone performed more poorly on tests of cognitive function compared with those who received morphine, but only one of the two tests used showed a significant difference. In both of these studies, pain relief between the two patient groups was not significantly different.

Despite the differences in pharmacokinetics among the different opioid analgesics, there are no convincing data to indicate which opioids, excluding meperidine, increase the risk of POCD or delirium.

The lack of a standardized approach to measuring delirium and cognitive decline presents an additional difficulty in comparing results across studies. Cognitive decline involves changes in several neuropsychological domains, including memory, executive function, perceptual organization, language, psychomotor function, attention, and concentration (3,50). Among the three randomized controlled trials reviewed (Table 4), the cognitive tests included the MMSE, the SPMSQ, the Digit Symbol Substitution Test, and the Trail Making B Test. However, these tests do not all assess the same cognitive domains (3) and they may not be equally sensitive in detecting changes in cognition or differences between study groups. For example, the MMSE and SPMSQ are considered screens for the presence of dementia, as used in Herrick et al.’s study (29), but they are not as sensitive as other cognitive tests for detecting the cognitive effects of drugs. This difference in test sensitivity could explain why test results were discordant when more than one neuropsychological assessment was used in the same study.

Studies Comparing Mode of Analgesia Delivery
The mode of analgesia delivery is also an important consideration in managing postoperative pain. For acute postoperative pain control, current widely used methods involve IV or epidural modalities, with or without a patient-controlled device. IV and epidural methods differ in their efficacy in relieving pain and profile of drug-related effects (51).

Mechanistically, epidural analgesia allows opioids to be delivered in close proximity to opioid receptors on the spinal cord, resulting in a smaller dosage of opioid used than IV administration to reach a similar level of pain relief. Theoretically, by having less of a systemic effect than parenteral analgesia, epidurals should be associated with a decreased incidence of postoperative delirium or POCD. The site-specific nature of epidural drug delivery also enables local anesthetics to be given epidurally and therefore allows an opioid-sparing effect.

Despite the beneficial effects of epidural analgesia, the four randomized trials in this review did not find a significant difference between epidural and parenteral analgesia with respect to postoperative delirium or cognitive decline. However, the small number of available studies and study power (3%–4%) significantly limits the validity of this conclusion. In addition, there are variations in the spinal level at which an epidural catheter may be inserted (thoracic or lumbar) as well as the medication used (local anesthetic only, opioid only, or both). These options further reinforce the necessity for more comprehensive clinical trials comparing epidural and IV analgesia.

Only 3 of the 5 studies compared pain relief between groups. The studies by Mann et al. (41) and Eriksson-Mjoberg et al. (42) that found significantly less pain in patients receiving an epidural did not find a concurrent improvement in rates of delirium. A low study power in the Mann et al. study may have prohibited such a finding, whereas study power could not be ascertained from the investigation by Eriksson-Mjoberg et al.

The few available studies also differ methodologically in the assessment of delirium. The different tests used included DSM-III criteria plus Abbreviated Mental Test (41), the CAM (33), and DSM III criteria only (10).

There are further limitations in the comparisons of analgesia techniques. One study (41) used morphine for the IV group but used bupivacaine with sufentanil for the epidural patients. The authors noted that because sufentanil is a highly lipid soluble opioid, a potential reduction in systemic effect via the epidural route may not have been observed. The Riis et al. (20) study did not provide the specific analgesics used, and in the Marcantonio et al. (24) study, meperidine, an analgesic with a high deliriogenic potential, was used in patients who received epidural analgesia.

Implications for Clinical Practice and Future Directions for Research
In addition to the nonpharmacological risk factors that have been shown to influence POCD or delirium (Table 2), our review is the first to systematically evaluate the literature on whether management of postoperative pain is important to reducing the risk of developing POCD and delirium. Our review demonstrates that this important postoperative period has been largely ignored in previous research on postoperative cognitive assessment, as there are only a few clinical trials that compare opioid analgesics or analgesic modalities. Thus far, meperidine appears to be the only drug that should clearly be avoided based on results from existing studies. There is insufficient evidence to discern significant differences among morphine, fentanyl, hydromorphone or other drugs. Similarly, the data did not demonstrate any difference on postoperative cognitive outcomes between IV versus epidural methods of postoperative analgesia.

It must be reiterated that prior studies have not always made a clear distinction between delirium and cognitive decline and have often erroneously used these terms interchangeably. Diagnostic criteria differ for these two entities, as do predictive factors and potential prognostic significance. Only by using appropriate and uniform outcome measures will results be collectively useful. This review highlights the importance that future investigations should use more standardized measures of cognitive decline and delirium to allow proper comparison between studies, use neuropsychological tests to target domains sensitive to drug effects, and, most importantly, enroll a sufficient sample size to adequately discern a difference in effect size. Finally, because both pain relief and neuroexcitation may be induced by opioids, which may influence delirium in opposite directions, future studies on postoperative delirium and POCD must include the assessment of postoperative pain.

	Footnotes

 
Supported, in part, by institutional funds and the National Institute of Aging, National Institutes of Health, Grant #1K24 AG00948-05 awarded to Dr. Leung.

Accepted for publication October 28, 2005.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999