Duration of antagonistic effects of nalmefene and naloxone in opiate-induced sedation for emergency department procedures

Duration of Antagonistic Effects of Nalmefene and Naloxone in Opiate-Induced Sedation for Emergency Department Procedures WILLIAM G. BARSAN, MD,* DONNA SEGER, MD,t DANIEL F. DANZL, MD,* LOUIS J. LING, MD,$ ROBERT BARTLETT, MD,” RALPH BUNCHER, ScD,l-l CANDACE BRYAN, PHARMD# Naloxone is an effective opiate antagonist, but its short half-life limits its usefulness. For outpatient procedures, a longer acting opiate antagonist could eliminate two to four hours of nursing obsetvatlon in patients postoperatively. A controlled, Kndomfzed, double-blind trial comparing the effects of nafmefene, nafoxone, and placebo In KveKing opiate-induced sedation was carried out to determine efficacy, dutation of action, and adVeKe effects in patients undergoing outpatient procedures. Each patient received 1.5 to 3.0 mg/kg meperidtne intravenously before the procedure. After the procedun, each patient received either nafmefene, 1.0 mg; naloxone, 1.0 mg; or saline, 1.0 mL intravenously. Vital signs and assessments for alertness were performed for four houK. Nafoxone significantly KVeKed sedation for only 15 minutes, whereas nafmefene was significantly effective (P < .05) for up to 210 minutes. Nalmefene was significantly more effective than nafoxone in reversing sedation at 60,90, and 120 minutes. Nafmefene is an effective agent for the reversal of opiate-induced sedation after outpatient procedures. (Am J Emerg Bled 1989;7:155-161. 0 1989 by W.B. 8aUndeK Company.) Analgesics, including opiate compounds, are frequently administered in the emergency department (ED) before painful procedures such as reduction of From the *Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati; the tSection of Emergency Medicine, University of Arizona College of Medicine, Tucson; the #Department of Emergency Medicine, University of Louisville School of Medicine, Louisville, KY; SHennepin County Medical Center, Minneapolis; “Richland Memorial Hospital, Columbia, SC; the lIBiostatistics/Epidemiology Laboratory, University of Cincinnati, Cincinnati; and #Kendle Research Associates, Cincinnati. Manuscript received April 18, 1988; revision accepted June 1, 1988. Supported by a grant from Key Pharmaceuticals, Inc, Miami, FL. Address reprint requests to Dr Barsan: Department of Emergency Medicine, University of Cincinnati Medical College, 284 Goodman St, Cincinnati, OH 45287-0789. Key Words:

Nalmefene, naloxone, opiates, demerol, emergency

department. 0 1989 by W.B. Saunders Company. 0735-8757/89/0702-000485.00/O

dislocated joints, incision and drainage of abscesses, and dilatation and curettage for incomplete abortions. Despite the availability of potent opiate compounds (morphine, meperidine) for the relief of pain, some studies suggest that patients are undermedicated for the degree of pain experienced.’ Several factors have been identified that may contribute to undermedication with opiate compounds. One important factor identified is the fear of dangerous side effects, mainly hypotension and respiratory depression.’ Because most ED procedures take <30 minutes, a patient receiving an adequate analgesic dose of opiates may need to be observed for two to four hours after a procedure until the respiratory depressant and sedative effects of the opiate have dissipated. Even with shortacting narcotics such as fentanyl, there are reports of delayed respiratory depression occurring hours after the initial dose.2v3 Naloxone is the only commercially available parenteral opiate antagonist that is devoid of agonistic actions. Although naloxone is effective in reversing sedation and respiratory depression from medicinal opiates, its duration of action is usually shorter than the duration of action of the opiate administered.4 Nalmefene is a pure opiate antagonist that is structurally similar to naloxone and naltrexone and may be considered a pure opiate antagonist without agonistic effects.’ Nalmefene is four times as potent acutely as naloxone in antagonizing effects at the ).Lreceptor, and more potent than naloxone in antagonizing effects at the K receptor as well6 The t.~receptor is “morphinelike” and mediates supraspinal analgesia, respiratory depression, miosis, physical dependence, and euphoria, whereas K receptors mediate spinal analgesia, miosis, sedation, and limited respiratory depression. The serum half-life of nalmefene is 10.3 to 12.9 hours, compared with 63 minutes for naloxone.4*7T8 Safety studies have demonstrated that nalmefene is well tolerated in doses up to 24 mg intravenously (IV), without changes in vital signs.’ The only noted side effect was lightheadedness in 2 of 8 placebo patients, 0 of 4 patients receiving 2 mg nalmefene, 1 of 4 patients receiving 6 mg nalmefene, and 3 of 4 patients receiving 12- and 155

AMERICAN JOURNALOF EMERGENCY MEDICINE n Volume 7, Number 2 n March 1989 24-mg doses of nalmefene. Clinical studies have shown that a single 50-mg oral dose of nalmefene will totally prevent effects from IV opiates for 48 hours. lo A single 1-mg IV dose will prevent the respiratory depressant effects of IV fentanyl for up to four hours, and a 2-mg dose will prevent respiratory depression for eight hours.’ In the latter study, the only noted side effect was a gagging sensation in one patient. These data suggest that nalmefene may be useful in reversing opiate-induced sedation after ED procedures. Because of the long half-life of nalmefene, required observation time after procedures could be shortened considerably and patient safety enhanced. In addition, the availability of an effective long-acting drug to reverse opiate effects could make physicians less fearful of administering adequate analgesic doses of opiates for painful procedures. For these reasons, a controlled, double-blind randomized study comparing the antagonistic effects of nalmefene, naloxone, and placebo in opiate-induced sedation was undertaken to determine acute efficacy, duration of action, and adverse effects in patients undergoing ED procedures.

MATERIALS AND METHODS The study was a parallel, double-blind, multicenter evaluation of nalmefene, a positive control (naloxone), and a negative control (placebo) in patients receiving meperidine (1.5 to 3.0 mg/kg) IV in the ED for the performance of a painful procedure. Two hundred nine patients were enrolled in five centers over a 9-month period. All patients were aged between 18 and 65 years and required opiate analgesia for a time-limited painful procedure. Patients who were pregnant or lactating or who had a prior history of drug abuse, recent ingestion of sedating drug(s) including opiates, psychiatric or neurologic impairments which made evaluation difficult, head injury, active liver or cardiorespiratory disease, or medication with clonidine, methyldopa, or guanabenz for hypertension were excluded. Also excluded were patients who were likely to require continued medication with opiates for pain control after the procedure. The investigation was approved by the institutional review boards of each participating center under IND21266. Informed consent was obtained from each patient before entry into the study.

Procedure Before entry, each patient had a brief history and physical examination. Venous blood was obtained for complete blood count, electrolytes, BUN, creatinine, glucose, SGOT, SGPT, lactic hydrogenase, bilirubin, alkaline phosphatase, cholesterol, triglycerides, calcium, total protein, and uric acid. Baseline vital signs 156

and alertness scale scores (see below) were obtained before administration of meperidine. Opiate analgesia was induced with IV meperidine administered over 15 minutes. The patients received 1.5 to 3.0 mg/kg meperidine to assure adequate analgesia up to a maximum total dose of 300 mg. Vital signs (pulse, BP, respiratory rate, oral temperature) and alertness score were again obtained just before the procedure. The procedures were to be ~45 minutes. After the procedure, each patient received 1 mL of either nalmefene (1 mg), naloxone (1 mg), or saline from ampules of identical appearance based on a preassigned random code. Vital signs and alertness scores were then obtained after study drug administration every 15 minutes for one hour, and every 30 minutes thereafter for the remainder of the four-hour period. One to three days later, patients returned for repeat laboratory determinations (same as prestudy).

Alertness Scale The alertness scale consisted of four categories (Table 1): (1) level of consciousness (0 to 7 points); (2) eye opening (0 to 7 points); (3) speech (0 to 7 points); and (4) commands (0 to 4 points). The eye opening and speech scores were adapted from the Glasgow Coma Scale. ” Level of consciousness was adapted from the Head Injury Watch Sheet,” and the commands section was adapted from the Edinburgh -2 Coma Scale.13 Each of the categories in level of consciousness, eye opening, and speech had two points. The two points allowed for discrimination between patients who responded to gentle stimuli (higher score) and those responding to harsh stimuli (lower score). For TABLE1. Alertness Scale. I. Level of consciousness 8-7, Awake 4-5, Awakens to voice 2-3, Awakens to shaking O-l, Awakens to pain II. Eye opening 8-7, Spontaneous 4-5, To voice 2-3, To pain O-1, None Ill. Speech 8-7, Clear, spontaneous, appropriate 4-5, Clear, appropriate, not spontaneous 2-3, Inappropriate but can say one word O-l, Incomprehensible, garbled, slurred IV. Commands (open/close hands; open/close eyes) 4, Both correct 2, One correct 0, Both incorrect The components of the total alertness scale are listed above with numerical scoring values. The adjusted alertness scale Is identical except that the commands section is deleted.

example, a patient who was fully awake and alert would score a 7 on level of consciousness, a drowsy but nonsleeping patient received a 6, a patient who awakened to conversational tone received a 5, a patient who awakened only to shouting received a 4, etc. Statistical Analysis The results of the alertness scale and vital signs and meperidine dosages were compared among the groups using a one-way analysis of variance (ANOVA). Values of P < .05 were considered statistically significant. RESULTS Subjects Two hundred nine patients were studied at five centers: 117 were male and 92 were female. The mean age was 31.6 (range, 18 to 63) years for men and 30.0 (range, 18 to 56) years for women. All but eight patients completed the study. Seven of the eight who did not stay for the total four hours had received nalmefene and all had alertness scores >22 at the time they left (two at 45 minutes, two at 60 minutes, and four at 120 minutes). The data collected in these patients before dropout from the study were used in the analysis. The majority of patients admitted to the study had a soft tissue abscess (72%). Other diagnoses included dislocated joint, 12%; incomplete abortion, 8%; and other (painful joint injury, burns, laceration, or thrombosed hemorrhoid), 8%. The mean meperidine dose for all patients was 2.48

MEAN

mg/kg, and the mean total dose was 1735 mg (75 to 3 10 mg). The mean meperidine dose among the three groups was not significantly different: placebo, 2.49 mg/kg; nalmefene, 2.51 mg/kg; naloxone, 2.43 mg/kg. The time of analgesia after the meperidine dose was determined for each patient. The mean time from analgesia to study drug administration was 24 minutes. Only seven patients received the study drug after 45 minutes and none received the study drug more than one hour after meperidine administration. Efficacy The alertness scale scores were not significantly different among the three groups at baseline, time of analgesia, or time of study drug administration (time 0), although all three groups showed a decrease in alertness scale scores after meperidine administration (Fig 1). Fifteen minutes after administration of naloxone or nalmefene there was a significant increase in the alertness scale score (nalmefene, P < .002; naloxone, P < .002) compared with placebo. The alertness scores in the nalmefene patients remained significantly higher than placebo until the 210-minute examination (Fig 1). Naloxone was significantly different from placebo for the 15-minute score only. A notable difference was still present at 30 minutes (P < M), but by 45 minutes there was no detectable difference between naloxone and placebo (P = .36). As expected, there was no significant difference between nalmefene and naloxone at the 15- and 3Ominute examination. By 60 minutes, there was a significant difference between nal-

TOTL I 25

24 R

FIGURE I. Meantotal score by drug and time. PRE, alertness scale assessment before administration of any narcotics; MEP, alertness scale score just before the painful procedure; 0, time of the alertness scale score just before administration of the test drug. Placebo (O), n = 71; naloxone (x), n = 68; nalmefene (A), n = 70.

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mefene and naloxone (P < -01) which persisted until the HO-minute examination. All of the variables were tested to see if their distributions could be considered normally distributed for ANOVA calculations. Only the commands section of the alertness scale showed significant nonnormality, serving primarily as a constant in the total alertness score. When the alertness scale is adjusted by deleting the commands sections, the results are almost identical (Table 2). Systolic, diastolic, and mean arterial pressures were not significantly affected by the study drug at any time interval. There was a small but statistically significant rise in respiratory rate at the 15minute examination with both naloxone (P < .Ol) and nalmefene (P < .035) compared with placebo (see Fig 2). By 30 minutes and thereafter, respiratory rates were not different among the groups. Temperatures tended to be slightly higher after study drug administration in the nalmefenetreated patients, but this difference was significantly different from placebo only at the 45 and 60-minute examinations (see Fig 3).

Adverse Reactions Fifty-eight adverse reactions occurred in 35 patients (placebo, 13; naloxone, 23; nalmefene, 22; see Table 3). Only two patients receiving nalmefene experienced severe reactions. One patient had vertigo with nausea and vomiting which was not thought to be related to study drug administration. One patient had significant irritability and paranoia after study drug administration which resolved within 20 minutes with reassurance alone. This was felt to be probably related to drug administration. Only two patients received naloxone in an unblinded fashion for what was considered to be a dangerous degree of respiratory depression. One of these patients had received an inadvertent overdose of meperidine. Neither of these patients was included in the data analysis.

TABLE2. Adjusted Alertness Scale (P Values)

Baseline Postanalgesia 15 min 30 min 45 min 60 min 90 min 120 min 150 min 180 min 210 min 240 min

Nalmefene

Naloxone

PlacYebo

PfacYeb0

Nalmefene ” Naloxone

,307 ,720 ,003’ ,069 ,396 ,677 ,793 ,426 .I93 ,722 ,912 .074

,795 ,760 946 ,717 ,107 ,026 ,010 .039’ .320 ,102 ,147 ,672

,256 503 ,002’ .030’ ,013’ ,006 ,019’ 9045’ .024’ .047’ ,117 ,030

Differences in adjusted alertness scale between the different treatment groups over time are presented. *Statistically significant difference.

DISCUSSION Naloxone is an effective opiate antagonist that has been used successfully for years to reverse the effects of opiate compounds. Although the serum half-life of naloxone is approximately one hour, its duration of effectiveness in reducing respiratory depression and sedation from opiates is probably less than one hour.4 Evans et al found that the effect of naloxone in reversing respiratory depression from morphine started to dissipate within 15 minutes and was completely gone by 45 minutes after naloxone administration. I4 They also noted that “the return of ventilatory depression was always associated with the return of the subjective effects of morphine.“‘4 Others have also demonstrated the short-lived effects of naloxone.‘5916 This short half-life rather limits the therapeutic usefulness of naloxone in reversing the effects of opiates administered for painful procedures. The half-lives of most commonly used opiate analgesics (morphine, meperidine) are much longer than the half-life of naloxone, and there is a real danger of renarcotization.” Even fentanyl may produce respiratory depression as long as four hours after administration.2*3 For this reason, a patient who received high-dose narcotics in the ED probably would have to be observed for two to four hours even if naloxone was administered. This prolonged observation time could make physicians less likely to administer effective, potentially sedating doses of medication to perform painful procedures. More likely, patients are given light doses of opiate and expected to endure a certain degree of pain and discomfort. This underdosage of opiate analgesics has been noted to occur.’ Our observations of the duration of action of naloxone on alertness are similar to the findings in other studies. Because respiratory depression occurs with sedation, the duration of action of naloxone on this important function is probably very much the same. Naloxone was shown to be effective for 15 to 30 minutes in this study. By 45 minutes, it was not significantly different from placebo. Because of this short duration of action, patients receiving doses of meperidine similar to those used in this study would probably need to be observed for several hours before being safely discharged home. Nalmefene has been shown in previous studies to have a long duration of action depending on the dose used. A 2.0-mg dose of nalmefene will prevent any sedative or respiratory depressant effects from fentanyl (2 pg/kg) administered up to eight hours later.* Nalmefene was shown in the present study to have a similar duration of action. Nalmefene was significantly more effective than placebo in reversing sedation from IV meperidine at each observation time up to 240 minutes after administration of nalmefene, with one ex-

BARSAN ET AL R NALMEFENE IN OPIATE SEDATION

MEAN RESP 20

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+ p
Naloxcme

t

Nalmefene

p
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FIGURE 2. Changes in respiratory rate over time among the three groups. Placebo (O), n = 71; naloxone (x), n = 68; nalmefene (A), n = 70.

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ception. The difference between nalmefene and placebo was significant at the 210-minute interval (P = .12), although by this time the sedative effects of meperidine were almost gone. The duration of sedation seen in the placebo group was expected given the halflife (3.2 hours) and suggested dosing intervals for meperidine . ” The finding of interest in this study is the significant difference between nalmefene and naloxone in reversing sedation induced by meperidine. By 60 minutes, there was significantly less sedation in the nalmefene group than in the naloxone group; this difference persisted until the 150-minute observation time. Although MEAN

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the difference between naloxone and nalmefene was not significant after this point, there was little sedative effect remaining in the placebo or naloxone groups by this time. The placebo group and naloxone group each had alertness scores close to normal by these times and were not significantly different from each other. Because the effect of nalmefene outlasted the duration of action of meperidine, it would be possible to discharge a patient from the ED after a single dose of nalmefene without a prolonged observation time. Another finding of interest is the relative lack of effect of nalmefene and naloxone on vital signs. Systolic BP, diastolic BP, and pulse all increased with

TEMP

FIGURE 3. Changes in oral temperature among the three groups over time. Placebo (O), n = 71; naloxone (x), n = 68; nalmefene (A), n = 70.

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TABLE3. Adverse Reactions

Dizziness Hypotension Nausea Vomiting Chest pain Paranoia Arrhythmia Chills Dyspepsia Nervousness Other’ Total

Placebo

Naloxone

Nalmefene

1 1 3 6 0 0 1 0 0 0 1 13

4 3 3 2 1 0 0 2 1 0 6 23

1 1 5 4 2 2 0 1 0 1 3 22

Palpitations, paresthesias, tremor, vasodilation, vertigo. l

sweating,

tachycardia,

tinnitus,

meperidine administration but decreased after the procedures were performed. Although patients were more alert after treatment with naloxone and nalmefene, their BPS and pulse rates were not significantly affected. Body temperatures were higher at all times in the nalmefene-treated patients, and this was signiticantly different from placebo at two time intervals. This would suggest that nalmefene may reverse the hypothermic effects of opiates similarly to naloxone, although the difference in body temperature was not large.‘8*19 Respiratory rate was not dramatically affected by administration of meperidine, except in a few patients, nor was it affected much by administration of an opiate antagonist. The difference in respiratory rate between patients receiving an opiate antagonist and those receiving placebo was significant only at the H-minute time interval. This difference, although statistically significant, was small. Because nalmefene is a long-acting opiate antagonist, we excluded any patients from the study in whom postprocedural pain requiring narcotics was deemed likely. Patients experiencing pain after the procedure were given oral ibuprofen, 400 mg, which was effective in controlling pain. Follow-up visits with patients at 24 to 72 hours did not reveal that patients had experienced pain not controlled with oral analgesics. Although the serum half-life of nalmefene is >lO hours, a 1.O-mg dose will prevent respiratory depression from fentanyl challenge from only four hours, and a 2.0-mg dose will prevent respiratory depression for up to eight hours. A 1-mg dose of nalmefene might also be expected to block the analgesic effects of opiates for four hours. It would seem prudent to titrate the dose of nalmefene based on the duration of action of the narcotic used for analgesia. If a narcotic with a duration of action of four hours is used, a l.O-mg dose of nalmefene should provide reversal of sedative and respiratory depressant effects for this period. A narcotic

antagonist would not be indicated after a procedure in which moderate to severe postoperative pain is anticipated. CONCLUSIONS Nalmefene was shown to effectively reverse the sedative effects of meperidine administered for painful procedures in the ED for up to four hours. Nalmefene was significantly more effective than placebo in reversing the effects of meperidine at all time intervals except one for up to four hours. Although naloxone significantly reversed the sedative effects of meperidine, the effect was significant for only 15 to 30 minutes. Nalmefene was significantly superior to naloxone in reversing sedation from 60 to 150 minutes after administration. The side effects observed with nalmefene were similar in type and number to those seen with naloxone, and none was life-threatening. Nalmefene could be useful in eliminating prolonged observation of patients who have received high doses of narcotics for outpatient procedures.

The authors thank James Amsterdam, DMD, MD, Scott Syverud, MD, and Jerris Hedges, MD, MS, for their help in the conduct of this study. We also thank John Howes, PhD, and James Gourzis, MD, PhD, for their contributions in planning and final analysis of the data.

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