Download The Use of Nalmefene for Intrathecal Opioid

LCDR Robyn C. Ward, CRNA, MSN,
NC, USN
Camp Pendleton, California
LT Robert L. Lawrence, CRNA, MSN,
NC, USN
Bethesda, Maryland
LT Robert J. Hawkins, CRNA, MSN,
NC, USN
CDR Steven E. DiChiara, CRNA,
MSNA, NC, USN
Portsmouth, Virginia
CDR Andrew R. Biegner, CRNA,
MSNA, NC, USN
Jacksonville, Florida
CAPT Charles A. Vacchiano, CRNA,
PhD, NC, USN
Pensacola, Florida
The aim of this study was to compare the severity of nausea and
incidence of emesis in laboring
parturients who received intravenous nalmefene or placebo following an intrathecal opioid
(ITO).
We randomly assigned 60
ASA class I or II multiparous
women to receive nalmefene or
placebo. Subjects received fentanyl, 25 µg, and morphine, 250
µg, intrathecally on request for
analgesia. Thirty minutes after
vaginal delivery, the experimental group received nalmefene,
20 µg, and the placebo group
received an equivalent volume
of normal saline intravenously.
Visual analog scale nausea
scores and data about episodes
of emesis were obtained during
labor and during the first 24
hours postpartum.
There were no significant differences in age, weight, duration of labor, volume of intravenous fluids infused, time from
last meal to delivery, or time
from administration of the ITO to
injection of the study drug.
There were no significant differences in mean visual analog
scale nausea scores or frequency of emesis for any time
interval.
Nalmefene, 20 µ g, given
intravenously within 30 minutes
of vaginal delivery does not significantly reduce the nausea and
vomiting associated with the
use of ITOs for labor analgesia.
Key words: Intrathecal opioid,
nalmefene, nausea, pregnancy,
vomiting.
The use of nalmefene for intrathecal
opioid–associated nausea in
postpartum patients
I
ntrathecal opioids (ITOs) are a
safe and effective method of providing pain control to laboring
parturients. The benefits of ITO
include a rapid onset with a long
duration of action during the first stage
of labor, minimal effect on the progress
of labor, and absence of motor blockade,
permitting earlier ambulation and discharge from the hospital.1 The management of ITOs is less labor intensive than
for epidural analgesia. Administration
of ITOs is often the preferred technique
at small to midsize community hospitals
where anesthesia resources are limited.2
Potential side effects of ITOs include
pruritus, nausea, vomiting, urinary
retention, and respiratory depression.3
Pruritus, nausea, and vomiting are dose
dependent and are the result of the presence of opioids in the cerebrospinal
fluid or the vascular system. The presence of an opioid in the cerebrospinal
fluid results in cephalad migration of
the drug and subsequent interaction
with the trigeminal nucleus in the
medulla and opiate receptors in the area
postrema, also known as the chemoreceptor trigger zone.3 Activation of the
chemoreceptor trigger zone triggers the
vomiting reflex by mechanisms that are
not completely understood.4
Chaney,3 in a 1995 review of the literature, reported a 30% incidence of nausea within 4 hours of injection of an
ITO. This study suggested the incidence
of nausea may be related to the dose of
ITO used and may be higher when
intrathecal morphine is administered,
due to its hydrophilic properties and
prolonged presence in the cerebrospinal
fluid.3 In a similar study, Herpolsheimer
and Schretenthaler2 examined the use of
intrathecal fentanyl (25 µg) and morphine (250 µg) analgesia in laboring par-
turients. They concluded that ITOs provided satisfactory pain relief without disrupting the normal course of labor; however, the incidence of nausea was 44%.
A review of 99 parturients with spontaneous vaginal delivery who received
intrathecal fentanyl (25 µg) and morphine (250 µg) for labor analgesia at our
institution showed a 41% incidence of
nausea and a 21% incidence of vomiting. The benefits of ITOs generally outweigh the side effects; however, finding
viable treatments to reduce nausea and
vomiting is of obvious importance.
A potential treatment for ITO-related
side effects is the administration of an
opioid receptor antagonist. Wittels et al5
compared the effects of opioid agonistantagonists and pure antagonist administered immediately after umbilical cord
clamping on maternal analgesia, overall
satisfaction, and side effects after
cesarean section with epidural morphine.
An incidental finding of this study suggested that parturients who received naltrexone, a long acting form of naloxone,
had significantly less pruritus, nausea,
and vomiting.5 Methylnaltrexone, a longacting intravenous opioid antagonist that
is structurally similar to naloxone, has
been shown to significantly reduce the
incidence of pruritus, nausea, and vomiting in postcesarean and postsurgical
patients after administration of epidural
or intravenous morphine, respectively.6
Nalmefene, a methlyated form of naltrexone, is an intravenous preparation with a
terminal elimination half-life of approximately 10.8 hours.7 Frye et al7 examined
the pharmacokinetics of nalmefene and
found that it effectively reversed postoperative opioid respiratory depression
without diminishing the analgesic
response to subsequently administered
opioids.
AANA Journal/February 2002/Vol. 70, No. 1
57
We therefore hypothesized that the administration
of a long-acting opioid antagonist following labor analgesia with intrathecal opioids would reduce postdelivery nausea and vomiting. The specific aim of this study
was to measure the severity of nausea using visual analog scale (VAS) scores and the incidence of emesis in
subjects receiving intravenous nalmefene following
labor analgesia with intrathecal fentanyl and morphine.
Methods
Following institutional review board approval, 60 ASA
class I or II multiparous women older than 18 years of
age were enrolled in this randomized, prospective,
double-blind, placebo controlled study. Subjects were
in active labor with cervical dilatation of 3 to 7 cm and
uterine contractions increasing in duration and frequency, and they were requesting intrathecal labor
analgesia. Parturients with a history of complicated
pregnancy or chronic nausea or vomiting or who
received opioid agonist or agonist-antagonist medication before administration of an ITO were excluded
from the study. Data for subjects who requested or
required additional analgesia after an ITO or required
cesarean section were removed from the data pool.
Written informed consent was obtained from each
subject. Consecutively numbered syringes that randomly contained either 20 mg of nalmefene
hydrochloride (Revex, Ohmeda, Decatur, Ill) or an
equivalent volume of normal saline were prepared by
the pharmacy department. All subjects received 25 µg
of fentanyl and 250 mg of preservative-free morphine
intrathecally on request for labor analgesia. Data collection included age, weight, time of last meal, duration of labor (defined as time of admission to delivery), time of ITO administration, and total volume of
intravenous fluids infused. A baseline VAS nausea
score was obtained after subjects were enrolled.
Within 30 minutes after vaginal delivery, a VAS
score was obtained and subjects received either 20 mg
of intravenous nalmefene (experimental group) or an
equivalent volume of intravenous normal saline
(placebo group). Subjects were instructed in the use
of the VAS tool, and a VAS score was obtained for the
most severe episode of nausea that occurred before
transfer to the postpartum ward, immediately before
each meal, and at bedtime. Data were collected for the
first 24 hours after delivery. Selection of the specific
time intervals for VAS assessments provided similar
postdelivery time periods for data analysis between
groups. In the event of emesis, the time and whether
treatment was requested were documented. Investigators observed each subject throughout the study to
confirm adherence to the protocol.
The VAS tool for nausea consists of a 100-mm horizontal line anchored at one end with “no nausea” and
with “worst nausea ever experienced” at the other
end. Subjects were instructed to place a single vertical
mark on the line indicating the severity of nausea
experienced at the various time intervals.
Data were analyzed using descriptive and inferential statistics. Demographics and labor experiences
were compared between groups using unpaired t tests.
The VAS nausea scores were compared using an analysis of variance with the Bonferroni multiple comparison post hoc test. The incidences of emesis and treatTable 1. Demographics*
Placebo (n = 23) Nalmefene (n = 25)
Mean ± SD Range Mean ± SD Range
Age (y)
27 ± 5
20-39
29 ± 4
21-36
Weight (kg)
81 ± 14
58-109
81 ± 12
65-113
* No significant differences between groups (P > .05).
Table 2. Study independent variables*
Placebo (n = 23)
Mean ± SD
Range
Nalmefene (n = 25)
Mean ± SD
Range
Time intervals (min)
Last meal to vaginal delivery
648 ± 326
164-1,203
778 ± 256
206-1,266
Intrathecal opioid to study drug injection
225 ± 146
65-555
189 ± 85
49-406
Duration of labor
342 ± 199
102-888
407 ± 245
54-899
19 ± 8
3-33
17 ± 7
3-30
2,184 ± 563
800-3,029
2,172 ± 633
800-3,800
Vaginal delivery to study drug injection
Total intravenous fluids (mL)
* No significant differences between groups (P > .05).
58
AANA Journal/February 2002/Vol. 70, No. 1
Figure 1. Comparison of mean visual analog scale
(VAS) nausea scores between the nalmefene and the
placebo groups*
Figure 2. Comparison of the percentage of subjects in
the nalmefene (n = 25) and placebo (n = 23) groups
with at least 1 episode of emesis during the first 24
hours after delivery (nalmefene group, 14 [61%];
placebo group, 12 [48%]*
50
Placebo
100
40
30
Subjects with emesis (%)
Mean VAS score
Nalmefene
20
10
0
li
se
Ba
ne
r
y
fe
er
ns
liv
a
e
r
D
T
d1
ar
W
d2
ar
W
d3
ar
W
d4
ar
W
75
50
25
0
Placebo
Nalmefene
Time interval
* There was no significant difference in reported nausea severity between
groups at any time interval examined (n = 48; P > .05). Data shown are the
means; error bars indicate SEM. Ward 1, 2, 3, and 4 indicate before breakfast,
lunch, dinner, and bedtime, respectively.
ment were compared using the Fisher exact test. Data
are given as mean ± SEM and percentages. A P value
of less than .05 was considered significant.
Results
A total of 60 subjects were enrolled. Twelve subjects
did not complete the study due to protocol violations.
The majority of protocol violations resulted from subjects requiring additional analgesia after ITO administration or subsequent cesarean section.
Table 1 illustrates the demographic characteristics
of the experimental and placebo groups. There were
no statistically significant differences in demographic
variables between groups (P> .05). Table 2 provides a
comparison of independent variables between the 2
groups. The time from last meal to delivery, time from
ITO administration to study drug injection, duration
of labor, time from delivery to study drug administration, and total volume of intravenous fluids administered were compared. There were no statistically significant differences between the 2 groups (P> .05).
Figure 1 compares the mean VAS nausea scores
between the experimental and placebo groups at various
time intervals. These intervals included baseline
obtained at enrollment, within 30 minutes after delivery,
before transfer to the postpartum unit, before each meal,
and at bedtime for the first 24 hours after delivery. There
* There was no significant difference between groups in incidence of emesis
(n = 48; P > .05).
was no statistically significant difference in reported
nausea severity between the groups at any time interval
examined (P>.05). Figure 2 compares the percentage of
subjects in the experimental and placebo groups with at
least 1 episode of emesis during the first 24 hours after
delivery. There was no statistically significant difference
between the 2 groups (P>.05). Figure 3 compares the
percentage of subjects requesting and receiving treatment for nausea or emesis in the experimental and
placebo groups. There was no statistically significant
difference between the groups (P>.05).
Discussion
This study measured the severity of nausea and the
incidence of emesis in subjects receiving intravenous
nalmefene following labor analgesia with an ITO. The
administration of nalmefene immediately after delivery did not reduce the severity of nausea or the incidence of emesis associated with ITO administration.
This finding is in agreement with a study by Pellegrini
et al,8 who concluded that 0.25 µg/kg of nalmefene
did not reduce the incidence of ITO-related side
effects following cesarean section and had a detrimental effect on postoperative analgesia.
There was a rising trend in mean VAS scores for the
experimental and the placebo groups before transfer
from the labor and delivery unit to the postpartum
unit, which remained elevated at the time of the first
postpartum reporting period. This may be attributed
to the peak onset of intrathecal morphine. The rostral
AANA Journal/February 2002/Vol. 70, No. 1
59
Figure 3. Comparison of the percentage of subjects
requesting and receiving treatment for nausea and/or
emesis in the nalmefene (n = 25; treated, n = 11 [44%])
and the placebo (n = 23; treated, 6 [23%]) groups*
Subjects treated for
nausea or emesis (%)
100
REFERENCES
75
50
25
0
Placebo
Nalmefene
* There was no significant difference between groups in the incidence of
treatment (n = 48; P > .05).
spread of morphine by passive flow with its subsequent effects on the chemoreceptor trigger zone often
is cited as a cause of nausea after ITO administration.
The time to reach peak brain concentration of morphine after ITO administration is approximately 3
hours.9 The mean time from administration of an ITO
to transfer to the postpartum unit for all subjects was
258 ± 123 minutes. This places the transfer time and
the postintrathecal morphine peak brain concentration within reasonable proximity and may account for
the notable increase in both groups in VAS nausea
scores at this time. The maximum plasma concentration of intravenous nalmefene is achieved approximately 5 to 15 minutes after administration with an
elimination half-life of 10.8 hours.10 Although the
peak plasma level of nalmefene would not have coincided with the peak concentration of morphine, there
should have been a therapeutic level of nalmefene
available at the time the VAS score was measured.
Although not statistically significant, subjects who
received nalmefene generally had higher postpartum
VAS nausea scores and were treated more frequently
for nausea or emesis. One possible explanation is that
nausea and emesis are potential side effects associated
with nalmefene administration. The incidence of nausea in clinical trials was 18%10
The intravenous administration of 20 µg of nalmefene immediately after vaginal delivery did not significantly alter the severity of nausea or the incidence of
emesis following labor analgesia with intrathecal morphine and fentanyl. Based on theses findings, we do
60
not recommend the use of nalmefene in this manner.
Areas for further research should include the delineation of a nalmefene dose-response curve, prophylactic administration before ITO administration,
administration of a second rescue dose upon subject
request, and nalmefene administration at a time that
coincides with peak morphine levels in the brain.
AANA Journal/February 2002/Vol. 70, No. 1
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epidural morphine for postcesarean analgesia: maternal outcomes.
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of age on the pharmacokinetics of the opioid antagonist nalmefene. Br J Clin Pharmacol. 1996;42:301-306.
8. Pellegrini JE, Bailey SC, Faut-Callahan M, Graves L, Shott S. The
impact of nalmefene on side effects from intrathecal morphine at
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9. Cousins MJ, Bridenbaugh PO, eds. Neural blockage. In: Carr DB,
Cousins, MJ. Clinical Anesthesia and Management of Pain. 3rd ed.
Philadelphia, Pa: Lippincott; 1998:915-983.
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Ohmeda Pharmaceutical Products Division; 2000.
AUTHORS
LCDR Robyn C. Ward, CRNA, MSN, NC, USN, is a staff nurse anesthetist at Naval Hospital, Camp Pendleton, Calif.
LT Robert L. Lawrence, CRNA, MSN, NC, USN, is a staff nurse
anesthetist at National Naval Medical Center, Bethesda, Md.
LT Robert J. Hawkins, CRNA, MSN, NC, USN, is a staff nurse anesthetist at Naval Hospital, Portsmouth, Va.
CDR Steven E. DiChiara, CRNA, MSNA, NC, USN, is a clinical
instructor, Navy Nurse Corps Anesthesia Program, Naval School of
Health Sciences, Naval Hospital, Portsmouth, Va.
CDR Andrew R. Biegner, CRNA, MSNA, NC, USN, is clinical
instructor and clinical research coordinator, Navy Nurse Corps Anesthesia Program, Naval School of Health Sciences, Naval Hospital, Jacksonville, Fla.
CAPT Charles A. Vacchiano, CRNA, PhD, NC, USN, is research
physiologist, Clinical Research Division, Naval Aerospace Medical
Research Laboratory, Pensacola, Fla.
ACKNOWLEDGMENTS
We thank LCDR Nicholas Kalynych, CRNA, MSHS, NC, USN; LT Kimberly Haas, RN, BSN, NC, USN; LTJG Anne Rogers, RN, BSN, NC,
USN; and Joseph Kapcinskas for their assistance with this study.
DISCLAIMER
The views expressed in this article are those of the authors and do not
reflect the official policy or position of the Department of the Navy, the
Department of Defense, or the US Government.