Should Narcotics Be Given to Patients with Abdominal Pain?

Author: Michael C. Bond, MD, Clinical Instructor, University of Maryland School of Medicine, Baltimore

Peer Reviewer: John Santamaria, MD, FAAP, FACEP, Affiliate Professor of Pediatrics, University of South Florida School of Medicine, Tampa, Florida

Introduction

One of the more contested areas between emergency medicine physicians and surgeons is the use of opioids in the treatment of abdominal pain. The belief that narcotics should be withheld was first published widely in 1921 with Sir Zachary Cope's book, Early Diagnosis of Abdominal Pain. Dr. Cope's original recommendation was that all opioid pain medication be withheld until a firm diagnosis of the patient's abdominal pain was made.

In the 1996 edition of Cope's textbook, practitioners began to rethink the approach to narcotic pain medications stating that they could be given but only after being examined by a "responsible surgeon" who had conducted a thorough history and physical. The 20th edition has been changed to read, "The realization, likely erroneous, that narcotics can obscure the clinical picture has given rise to the unfortunate dictum that these drugs should never be given until a diagnosis has been firmly established."

This article will review the latest literature that provides evidence regarding the use of narcotics for patients with abdominal pain.1-4

Current practice: Are narcotics safe?

Source: Wolfe JM et al. Analgesic administration to patients with an acute abdomen: A survey of emergency medicine physicians. Am J Emerg Med 2000 May;18(3):250-3.

This study examined the practice patterns of analgesia administration among emergency physicians (EPs) when caring for a patient with acute abdominal pain. A survey was mailed to 1000 random American College of Emergency Physicians (ACEP) members, and repeated two months later to those members who had not responded to the initial survey. A random subset of persistent nonrespondents was telephoned. Forty-four percent of the surveys were fully completed. Of the respondents, 57% were residency trained in emergency medicine, 77% were men with a mean of 10 years of practice in emergency medicine, 55% worked in teaching hospitals with residents rotating through their department, 41% dealt primary with a resident when consulting surgery, and only 6% had hospital or departmental policies concerning the administration of pain medication to patients with acute abdominal pain. Overall, the survey showed that although 85% of emergency medicine physicians believed that the use of analgesic agents did not change important physical exam findings, 76% choose not to give any analgesic agents until after the patient was evaluated by a surgeon. EPs who dealt primarily with surgical attending physicians rather than surgical residents were more likely to give pain medication before speaking to the surgeon (32% vs 16% [P<0.001]).

When asked what factor most influenced their decision to give analgesic agents, 69% answered that it was the degree of pain the patient was having. Other factors that played a role in their decision were certainty of diagnosis (52%) and length of time to surgical evaluation (58%). Surgical reprimand (9%) did not seem to be a factor for whether to give analgesic agents. Meperidine (67%) was given more often than morphine (57%), and 43% of the respondents stated that they often used a non-steroidal inflammatory drug.

Commentary

This study is interesting because it showed that 85% of EPs who responded to the survey did not believe that administration of analgesic agents altered the physical exam findings, yet 76% waited for surgical evaluation prior to giving any pain medication. Weaknesses of the study include a less than 50% response rate and respondents that were mostly male with a mean of 10 years of practice experience. The authors postulated that the nonrespondents were more likely to be new graduates or younger physicians who had recently moved, thereby causing a sampling bias.

Overall, this study helps provide us with a foundation of what the current practice patterns are concerning the use of analgesic agents in acute abdominal pain.

Current practice: Is the surgeon told?

Source: Nissman, SA et al. Critically reappraising the literature-driven practice of analgesia administration for acute abdominal pain in the emergency room prior to surgical evaluation. Am J Surg 2003 Apr;185(4):291-6.

What is the current clinical practice of EPs as it relates to administering opioid analgesia to patients with acute abdominal pain? Nissman and his colleagues conducted a telephone survey of 60 U.S. emergency medicine attending physicians from 60 different U.S. hospitals (university, university-affiliated, and community hospitals). Fifty-nine of 60 (98.3%) reported that it is their practice to administer analgesia prior to surgical evaluation, and only 9 of 59 (15.3%) reported always informing the surgeon prior to dosing the patient. The researchers used this finding as a starting point to discuss the four studies that have been instrumental in consensus statements by the Canadian Association of Emergency Physicians and the American College of Emergency Physicians. The consensus statements declared that narcotic use is safe, humane, may improve diagnostic accuracy, and has not been shown to increase morbidity and mortality. The authors concluded that the four studies analyzed have design flaws and study limitations that preclude them from declaring that opioid use is safe in the treatment of acute abdominal pain. One major critique is that the patients were examined by the same surgeon before and after the narcotic analgesia or placebo was given. This method prevented true blinding because the surgeon was able to determine which patient had received narcotic pain medication and which ones had not. The fact that the patients were examined prior to the narcotic being given also would factor in the final treatment decisions. The researchers pointed out that none of the referenced studies were equivalence trials, and none looked at patient outcomes as their primary endpoint. Further, they noted that none of the studies looked at a delay in diagnosis when the surgeon is only able to examine the patient after the narcotic analgesia is given. The authors then reinforced their belief that narcotics use results in delays in diagnosis or an incorrect diagnosis by reporting four cases where they believe this happened.

Commentary

This paper illustrates the controversy surrounding the use of narcotics in the treatment of abdominal pain. Four case reports are used to illustrate the authors concerns regarding the use of opioids; although the authors provided critical insight into the weakness of prior studies on the subject, they provided no new statistical evidence to support their beliefs. This study is interesting because it shows that most EPs are comfortable in giving narcotic analgesia to patients with abdominal pain. In their conclusion, the authors also pointed out that only 15.3% always verbally informed the surgeon prior to its use.

The major weaknesses of their survey are the small number of physicians interviewed and the notion that a single physician at a hospital is a judge of how the entire group would practice. The authors made good suggestions for conduct of future studies. An ideal study would look at adverse outcomes and the effects on diagnostic accuracy when the surgeon is not given the opportunity to examine the patient prior to narcotic administration.

Do pediatricians use analgesic agents?

Source: Kim MK et al. Analgesia for children with acute abdominal pain: A survey of pediatric emergency physicians and pediatric surgeons. Pediatrics 2003 Nov;112(5):1122-6.

Kim and colleagues evaluated the current practice of pediatric emergency physicians (PEMs) and pediatric surgeons (PSs) regarding the use of opioid analgesic agents in children with acute abdominal pain. The authors sent a survey to all members of the American Academy of Pediatrics in the Section of Emergency Medicine and to all members of the American Pediatric Surgeons Association. Of the 1387 surveys sent out, 702 were completed (51% response rate) with 574 meeting inclusion criteria; 385 PEMs (67%) and 189 (33%) PSs responded. Physicians (PEMs or PSs) with less than 10 years of experience were both willing to provide analgesic agents (no statistical difference between groups) compared with physicians with more than 10 years of experience (61% of PSs were less likely to provide analgesia compared with 38% of PEMs). Respondents were asked: "What factor(s) influenced your decision to give or withhold analgesia?"

Of note is that 61.7% of PSs vs 41.1% of PEMs stated that opioid analgesia masks the physical examination, and 41.1% of PSs compared with 26.3% of PEMs stated that it delayed the diagnosis. There was also a big disparity between PEMs (22.9%) and PSs (2.8%) regarding whether the literature supports the use of opioid analgesic agents in the treatment of acute abdominal pain.

Commentary

This study helps to establish the current controversy regarding the use of opioid analgesia for children with abdominal pain. Experienced (i.e., older) surgeons are more reluctant to provide pain medication and believe that its use can affect the ability to diagnose the cause of abdominal pain. However, this study does not provide any insight into why there was a difference in practice patterns between the older and younger physicians.

As with any survey study, this study was limited by a less than 51% response rate and a potential sampling bias; those with a more passionate view of analgesic agents use in abdominal pain are more likely to complete the study.

Adverse outcomes with opioid use?

Source: Lee JS et al. Adverse outcomes and opioid analgesic administration in acute abdominal pain. Acad Emerg Med 2000 Sep;7 (9):980-987.

This is one of the only studies that attempts to determine whether there is a link between opioid use and adverse outcomes in the treatment of acute abdominal pain in the ED. Lee and his colleagues performed a prospective observational study in a university teaching hospital to determine the feasibility of conducting a randomized clinical trail of opioid safety in the treatment of acute abdominal pain and to explore the association of opioid administration with adverse outcomes in acute abdominal pain. Patients who were hemodynamically unstable, pregnant, allergic to opioids, or who had traumatic abdominal pain, suspected abdominal aortic aneurysm, recurrent abdominal pain, or those with high clinical suspicion of ureteral colic were excluded from the study.

The study found that there were 67 (7.8%, 95%, CI =6.1-9.8%) adverse outcomes (e.g., obstruction, perforation, ischemia, hemorrhage, peritonitis, sepsis, or death) occurring within three weeks of enrollment in the 860 abdominal patients enrolled, with 252 patients having received opioids. The adverse outcome rate was 12.7% (95% CI= 9.0% to 17.0%) in those patients who had received opioids. Variables associated with increased risk of adverse outcomes in logistic regression were ED diagnosis of adverse outcome (Odds Ratio [OR] 12.4), age (OR 1.6 per decade), fever (OR 4.6), received opioids (OR 2.1), pain duration (OR 1.5 per day), and leukocytosis (OR 2.0). Because the increased risk of adverse outcome associated with opioids may have been due to a confounding variable, a casual link between opioids and adverse outcome can not be made. The authors proposed that a clinical trial of 1500 patients would be required to establish the equivalent adverse outcome rates of opioids and placebo.

Commentary

The majority of studies on opioid use in patients with acute abdominal pain have looked at whether opioid use changes the physical exam findings, delays diagnosis, or affects diagnostic accuracy. This study specifically looked at the safety of opioid use and its effects on adverse outcomes. Although there may be a link between opioid administration and adverse outcomes, the observational design of this study prevents any statistical conclusions. Because the decision to provide pain medication was not controlled, patients with more severe pain (possibly indicative of a more severe illness) may have been more likely to receive narcotics. This study sets the stage for a much needed prospective, randomized, placebo-controlled trial looking specifically at the safety of opioid use in patients with abdominal pain.

Could morphine also be a diagnostic tool?

Source: Kim MK et al. A randomized clinical trial of analgesia in children with acute abdominal pain. Acad Emerg Med 2002 Apr;9(4):281-7.

This randomized double-blind, placebo-controlled study looked at children 5 to 18 years old with undifferentiated abdominal pain for fewer than 5 days in duration and who had a pain score greater than 5 (visual analog scale 0-10) in a tertiary care children's hospital. Patients were seen in the ED and were examined independently by both the EP (attending physician or fellow) and a surgeon (post-graduate year 1 or 2 resident) before and at 15 and 30 minutes after the study medication was given. Children with systolic blood pressure less than 90 mmHg; who had an allergy to morphine, prior abdominal surgery, sickle cell disease, or history of inflammatory bowel disease; or who refused to take pain medication were excluded from the study. A total of 60 patients were randomized to receive either 0.1mg/kg morphine (29 patients) or an equivalent volume of saline (31 patients). The study's main outcomes were changes in pain score, number of areas of tenderness to palpation and percussion, and the diagnostic accuracy between morphine and saline. Baseline characteristics (e.g., age, sex, ethnicity, pre-study medication pain score, mean area of tenderness) were similar between the study groups. EPs and surgeons completed a standardized form marking the areas of tenderness.

Pain was significantly reduced in the morphine group, and there was no significant change in the mean area of tenderness. All 21 patients in the morphine group who required laparotomy had persistent tenderness. Diagnostic accuracy pre-morphine administration was 21/29 for the EPs, and 23/29 for the surgeons. For post-morphine administration, the diagnostic accuracy was 24/29 for both the EPs and surgeons. Appendicitis was not missed in any patient, and 2 patients initially diagnosed with acute appendicitis had discharge diagnoses of ovarian torsion. Only 2 patients developed side effects related to the morphine (1 pruritus, 1 nausea).

The researchers concluded that morphine significantly reduced pain and did not hinder or delay diagnosis or treatment, but rather increased the diagnostic accuracy of the physicians.

Commentary

Although this study was limited by its small sample size (power 0.18), it is the first study to show that morphine increases diagnostic accuracy in children with abdominal pain. Another weakness of the study is that the surgeon examined the patients before and after the study medication was given, therefore, there is no way to blind the surgeon to his initial exam findings. An ideal study would be to have the patient examined by the surgeon after the study medication is given.

Morphine's effects on diagnostic accuracy

Source: Thomas SH, et al. Effects of morphine analgesia on diagnostic accuracy in emergency department patients with abdominal pain: A prospective, randomized trial. J Am Coll Surg 2003 Jan;196(1):18-31.

This study by Thomas and Silen (editor of the latest edition of Cope's Early Diagnosis of the Acute Abdomen) was a prospective, randomized, double-blind trial looking at the effects of morphine on the diagnostic accuracy of patients with abdominal pain. Inclusion criteria included age greater than 18 years, non-pregnant status, abdominal pain less than 72 hours in duration, and severe pain that the patient thought would require more than acetaminophen or ibuprofen for relief. Patients were excluded if they were hypotensive (SBP < 90 mmHg), allergic to morphine, if emergency interventions or treatment precluded study enrollment, or if early opioid analgesia was clearly indicated (e.g., high suspicion for biliary or renal colic, or pancreatitis.) Of the 899 patients approached, 74 patients were randomized (36 in the control group, 38 in the morphine group). Most patients were excluded because pain was not severe enough (245), duration of pain was too long (222), or the treating physician believed the patient was ineligible due to an abdominal process that would require early analgesic use (204).

Once the baseline physical exam and demographics were obtained, the patient received study medication that was titrated over an hour to a maximum dose of 15 mg morphine or an equivalent volume of saline. Patients were allowed to receive any other type of medication during the one-hour study period except for other analgesic agents. The standardized form was completed at the end of the study hour, and the physician was again asked to commit to a diagnosis. Final diagnosis was obtained by reviewing hospital records (admitted patients) or the ED chart (discharged patients). Discharged patients were followed for a minimum of 7 days.

Baseline characteristics and ultimate diagnoses were similar between groups. Patients in the morphine group had significant reductions in their pain scores (>12mm drop in the visual analog score) (morphine 73.7% vs control 41.7%). There was no statistically significant difference in severity of tenderness (37% vs 35.3%) (RR 1.07, 95% CI 0.64-1.78), change in location of pain (34% vs 41.2%) (RR 0.82, 95% CI 0.50-1.36), and diagnostic accuracy (64.2% vs 66.7%) (RR 0.96, 95% CI 0.73-1.27).

The researchers concluded that their study supports the use of early morphine analgesia in patients with undifferentiated abdominal pain.

Commentary

This study is strong because it did not require the patients to be evaluated by a surgeon before and after the study medication was given, but it is not ideal because the same physician performed both examinations. As discussed earlier, the prior examination will influence the physician's opinion on the second exam. The inclusion criteria allowed any patient with abdominal pain to be considered for the study, but the large number of patients who were excluded for pain not being severe enough, and those excluded due to the physician's determination that they would require early analgesic agent use, increases the risk for selection bias. The final number of patients enrolled was too small to achieve enough power to prove statistical significance. The study also did not address the accuracy of the surgery consultant's diagnosis that was done after the study medication was given.

Despite limitations, this study helps to provide evidence that opioid analgesic agents do not alter peritoneal signs or affect diagnostic accuracy in patients with undifferentiated abdominal pain.

Opioid use in appendicitis patients

Source: Wolfe JM et al. Does morphine change the physical examination in patients with acute appendicitis? Am J Emerg Med 2004 Jul;22(4):280-5.

This prospective, randomized, double-blind crossover design study conducted at a tertiary care community teaching hospital evaluated opioid use in patients who presented to the ED with clinical signs of acute appendicitis who were scheduled for emergent appendectomy. Exclusion criteria included pregnancy, age less than 16 years, allergy to morphine, or ED analgesic agent administration before enrollment. After the patients were randomized to group A or B, each patient received either morphine (0.075 mg/kg) followed 30 minutes later by an equivalent volume of saline (Group A), or saline then morphine (Group B). Then, the patient was examined by a surgical house officer (postgraduate year 2 through 4) before and at 30 minutes after the first medication, and the patient was examined by the EP before and at 30 minutes after the second medication.

The study was stopped after 34 subjects were enrolled due to difficulty in coordinating the examinations and having enough time to complete the protocol prior to the patient being taken to the operating room. Of the 34 patients enrolled, only 22 completed the entire protocol (11 in each group). There was no significant difference in baseline characteristics, final visual analog pain score, or presence of appendicitis by pathology report. There was good agreement between surgeon and EP exam findings. The authors also noted no significant change in rebound tenderness, right lower quadrant tenderness, guarding, referred pain, cough pain, or position pain. They noted a change in disposition from "needing immediate surgery" to "observe" in two subjects receiving morphine and in one receiving placebo. Of interest: the EPs were only able to correctly identify patients who had received morphine 58% of the time, and the surgeons were correct 63% of the time.

Commentary

This study is unique in that it looked specifically at patients already scheduled to go to the operating room for appendicitis to see if narcotic analgesic agents altered their physical exam findings. A prior retrospective study by Aydelotte and colleagues suggested that narcotic use did affect peritoneal findings on physical examination.5 This study, though limited by its small sample size and possible selection bias, showed that the physical examination was not changed by narcotic analgesic agent use. The selection bias is that patients with more severe pain or physical exam findings are more likely to have received analgesia prior to study enrollment, resulting in being excluded from the study. This study showed that narcotic analgesic agents can significantly reduce pain without changing physical exam findings.

Undifferentiated abdominal pain

Source: Kokki H et al. Oxycodone vs placebo in children with undifferentiated abdominal pain: A randomized, double-blind clinical trial of the effect of analgesia on diagnostic accuracy. Arch Pediatr Adolesc Med 2005 Apr;159 (4):320-5.

This randomized double-blind placebo-controlled trial conducted at a University Hospital in Finland during a two-year period from 2001 to 2003 looked at the use of buccal oxycodone in children with undifferentiated abdominal pain. Oxycodone was chosen because it is noninjectable and does not cause the histamine release believed to cause the nausea and vomiting, sedation, and neurological adverse effects that are associated with morphine use. Children between the ages of 4 and 15 years were eligible for enrollment if they presented to the ED with undifferentiated abdominal pain of less that 7 days duration, and had a pain score greater than 5 cm on a 10-cm visual analog scale. Exclusion criteria included abdominal trauma, history of asthma, hypotension (SBP < 90 mm Hg), known contraindication to oxycodone, and analgesic agent use prior to ED arrival. After randomization, the children either received oxycodone (0.1 mg/kg) or an equivalent amount of normal saline (both substances were made to look and taste alike). Sixty-three children met the inclusion criteria; 32 were randomized to the treatment arm. The patients were examined by a surgeon prior to the study medication being given, and again one hour after administration. If a final disposition and diagnosis were not established at the one-hour exam, the patient was reexamined at 3.5 hours, 6 hours, and 9 hours as needed. Patients discharged with a diagnosis of nonspecific abdominal pain were followed for 4 weeks.

The study found a significant summed pain intensity difference (i.e., the sum of the patient's pain scores taken every half hour for 3.5 hours after the study medication was given) of 22±18 in the oxycodone group compared with 9±12cm in the placebo group. It also found that the initial diagnostic accuracy in the oxycodone group was lower than 72% when compared with the placebo group's rate of 84%, though this was not statistically significant. The accuracy of the oxycodone group improved to 88% post administration of the study medication, where the placebo accuracy rate was unchanged at 84%. Researchers noted that 7 children altered the guarding seen on their physical exam. All children who demonstrated guarding after the study medication was administered were taken for surgery. Seventeen children in the oxycodone group and 14 in the placebo group underwent exploratory laparotomy, with 12 children in the oxycodone and 9 children in the placebo group having histologically confirmed appendicitis.

Commentary

This study showed that a noninjectable form of pain medication can significantly reduce the pain in children with abdominal pain without having an adverse affect on diagnostic accuracy. Like prior studies on this subject, this study is limited by its small sample size that leaves it underpowered to statistically prove that diagnostic accuracy and safety are not affected by the use of buccal oxycodone. The study also is limited by the fact that the same surgeon examined the patient before and after the study medication was given.

Analgesia prior to surgical evaluation

Source: Green R et al. Early analgesia for children with acute abdominal pain. Pediatrics 2005 Oct;116(4):978-83.

This study is the first prospective randomized double-blind placebo-controlled trial that looked at early use of analgesia in acute abdominal pain prior to a surgical evaluation. This trial looked at 108 5- to 16-year-old children presenting to the ED of a tertiary care, academic children's hospital with a chief complaint of acute abdominal pain believed by the attending physician to require a surgical consultation. The primary outcome was missed appendicitis among children who received intravenous morphine. Exclusion criteria included allergy to opiates, previous opiate use in the prior four hours, hypotension, or the absence of a parent.

Using a standardized form, the following data were recorded before and 15 minutes after the administration of the study medication (morphine 0.05 mg/kg [max 10 mg]) or an equivalent volume of saline: the attending physician's clinical data, his/her confidence in his/her clinical diagnosis, and the pain of the patient (assessed using a color analog scale). Patients could receive a second dose of medication under the discretion of the attending physician if still having pain. No child was permitted more than two doses of pain medication prior to surgical evaluation. The surgeon (attending physician or postgraduate year 4 or higher resident) assessed the child within 1 hour and completed a similar data collection form. Each subject was monitored for two weeks.

Of the 108 enrolled children, 52 received morphine, and 56 received a placebo saline solution. There was no statistical difference between the groups (morphine vs placebo) for baseline demographics, rate of diagnosis of appendicitis (31 vs 26 patients), perforated appendicitis (15 vs 12), or the number of children who were observed and then underwent laparotomy (7 vs 6). Appendicitis was missed in only one child who had been randomized to the placebo arm and returned 5 days later with acute appendicitis. There was a significant difference in pain relief (2.2 cm vs 1.2 cm), and no effect on the physician's confidence in their diagnosis. EP confidence in diagnosis increased from 68.9% to 69.5% in the morphine group, and 65.5% to 70.9% in the placebo group. Surgeon confidence (only examined post narcotic administration) was 73.8% in the morphine group and 73.6% in the placebo group.

Commentary

This is a landmark study because it is the first one to look at analgesia use for abdominal pain prior to a surgeon's evaluation. This study's greatest strength is that the surgeon was blinded to the use of narcotic analgesic agent and did not have the opportunity for a pre-analgesia examination that could potentially affect his/her diagnostic accuracy and treatment plan.

As in all the studies that have been done to date, this one is limited by its sample size, which does not have enough power (0.16) to detect a difference in missing the diagnosis of appendicitis. Care also must be taken when extrapolating this study to adults who are more likely to have diagnoses other than acute appendicitis as the cause of their acute surgical abdomen. A multicenter trial using this study design in children and adults is needed to definitively answer the question: Can narcotic analgesic agents be given safely prior to surgical evaluation?

Conclusion

From the articles presented, EPs as a group are more likely than surgeons to provide narcotic analgesic agents to patients with acute abdominal pain. Although no single study has enrolled enough patients to achieve sufficient power, the current clinical trials have shown that narcotic analgesic agents alleviate pain and do not decrease diagnostic accuracy. Several studies have shown that diagnostic accuracy improves after narcotic administration. Overall, the studies cited here have not shown any statistically significant change in physical exam findings when narcotics were administered.

Only one article (Nissan et al) attempted to refute the use of analgesic agents, and does so by citing several cases where narcotics may have played a role in a delay in diagnosis. The authors did provide a critical appraisal of the current literature, but did not provide any statistical evidence to support their case.

The final study discussed by Green and colleagues showed that even when surgeons are blinded to whether a child has received narcotic analgesic agents, there is no statistical difference in the rate of diagnosis of appendicitis, perforated appendix, or the number of children who were observed and then underwent laparotomy. Only a single case of appendicitis was missed in this study, and the child had been randomized to the placebo arm. This study is the strongest evidence to date that supports the use of narcotics in patients with abdominal pain.

This review of the current literature does not support the original recommendations of Sir Zachary Cope. Narcotics may be used in patients with abdominal pain prior to a surgeon's examination, and its use has not been associated with a deleterious effect on diagnostic accuracy or outcomes.

References

1. Zoltie N, et al. Analgesia in the acute abdomen. Ann R Coll Surg Engl 1986;68:209-10.

2. Attard AR, et al. Safety of early pain relief for acute abdominal pain. BMJ 1992;305:554-6.

3. Pace S, et al. Intravenous morphine for early pain relief in patients with acute abdominal pain. Acad Emerg Med 1996; 3:1086-92.

4. LoVecchio F, et al. The use of analgesics in patients with acute abdominal pain. J Emerg Med 1997;15:775-9.

5. Aydelotte JD et al. Analgesic administration prior to surgical evaluation for acute appendicitis. Curr Surg 2004 Jul-Aug;61(4): 373-5.