Use of Meperidine in Patient-Controlled Analgesia and the
Development of a Normeperidine Toxic Reaction
Thomas T. Simopoulos, MD; Howard S. Smith, MD; Christine
Peeters-Asdourian, MD; Donald S. Stevens, MD
Hypothesis Intravenous patient-controlled analgesia (IV PCA) meperidine
hydrochloride can be used with a reasonable margin of safety.
Design A retrospective review was performed of 355 medical records of
patients receiving IV PCA meperidine treatment. Four groups of patients were
defined, based on daily meperidine dose and the presence or absence of central
nervous system excitation adverse effects. Use of more than 600 mg/d of
meperidine hydrochloride was considered a high dose.
Setting University tertiary care hospital.
Participants Postoperative patients from general, orthopedic, neurosurgical,
gynecological, and urologic procedures receiving IV PCA.
Interventions If patients were judged to have consumed significant amounts of
meperidine, the analgesic regimen was modified to (1) discontinue meperidine
therapy, (2) substitute hydromorphone hydrochloride, or (3) decrease the use of
meperidine by adding oral methadone hydrochloride or transdermal fentanyl
citrate to the regimen.
Main Outcome
Measures Patients who received
less than 10 mg/kg per day of IV PCA meperidine hydrochloride therapy were
unlikely to experience central nervous system excitatory adverse effects and
maintain adequate analgesia.
Results The mean meperidine hydrochloride consumption for those patients
classified as high dose, asymptomatic was 13.3 mg/kg per day (95% confidence
interval, 12.1-14.4 mg/kg per day). This differed statistically significantly (P<.05) from the mean meperidine
hydrochloride dose in patients classified as high dose, symptomatic, which was
16.9 mg/kg per day (95% confidence interval, 14.7-19.2 mg/kg per day). The
duration of meperidine use did not differ among the 4 patient groups. The
incidence of a central nervous system toxic reaction associated with IV PCA
meperidine therapy was 2%.
Conclusions We recommend 10 mg/kg per day as a maximum safe meperidine
hydrochloride dose by an IV PCA device for no longer than 3 days. Daily patient
evaluation is mandatory. Care must also be taken when using this dose to ensure
the absence of renal dysfunction or enhanced hepatic metabolism of meperidine.
Arch Surg. 2002;137:84-88
MEPERIDINE hydrochloride is an opioid frequently
used to treat acute pain. Normeperidine is its only metabolite that has
significant pharmacologic activity.1 Accumulation of
normeperidine can occur and is strongly associated with central nervous system
(CNS) excitation.2-6 Signs and symptoms
of normeperidine-related CNS excitation include delirium, irritability,
tremors, myoclonus, muscle twitches, shaky feelings, and generalized seizures.7
Central nervous system excitation is linked to
plasma normeperidine levels and also to an elevated serum
normeperidine-meperidine ratio.4 Such elevations are
likely to occur with high doses of meperidine, prolonged administration of
meperidine, decreased excretion of normeperidine in patients with impaired
renal function, and increased hepatic metabolism of meperidine in patients
receiving medications that induce hepatic enzyme systems. Central nervous
system toxic reactions related to normeperidine have been reported to occur
with most routes of meperidine administration, including intravenous
patient-controlled analgesia (IV PCA).8-10
The University of Massachusetts Medical Center
has had an aggressive acute pain management service in place for more than 8
years. This study was performed to investigate retrospectively the use of IV
PCA meperidine therapy in a large population of patients receiving IV PCA
opioids. Specifics relating dose and duration of meperidine administered by PCA
devices were determined. As defined earlier the incidence of CNS excitation was
estimated. Recommendations for the safe use of IV PCA meperidine therapy are
proposed.
The files of 5432 patients who received IV PCA
opioids between January 1, 1988, and December 31, 1994, were reviewed. Four
hundred twelve patients were identified as having been given IV PCA meperidine
therapy at any time. Of these patients, the medical records of 355 were
available for review. The discharge summary, physicians' orders, progress
notes, and medication profiles were examined in all patients to determine (1)
the reasons for starting or switching to IV PCA meperidine therapy; (2) the
medical or surgical conditions necessitating analgesic treatment by IV PCA
meperidine therapy; (3) the amount and duration of meperidine use; (4) the
presence of signs and symptoms of CNS excitation; and (5) if high doses of
meperidine therapy were used or CNS excitation was observed, what alternative
methods were then initiated to achieve satisfactory analgesia.
The following 4 groups of patients were defined.
Group 1 (low dose) consisted of 291 patients who used less than 600 mg/d of
meperidine hydrochloride and had no CNS excitatory signs or symptoms. Patients
in this group, therefore, received a clinically acceptable dose of meperidine
without adverse effects. The total daily amount of 600 mg of meperidine
hydrochloride therapy used to separate groups of patients was based on the
long-standing practice of intramuscular administration meperidine (100 mg every
4 hours as needed). Group 2 (high dose, asymptomatic) consisted of 51 patients
who used more than 600 mg/d of meperidine hydrochloride and had no CNS
excitatory signs or symptoms. Group 3 (high dose, symptomatic) consisted of 7
patients who used more than 600 mg/d of meperidine hydrochloride and had CNS
excitatory signs or symptoms. Group 4 (other) consisted of 6 patients who
experienced symptoms of CNS excitation that either were idiosyncratic or were
confounded by the patient's medical history or the presence of other
medications. One patient had a history of seizures and had a subtherapeutic
phenytoin level. Another patient had a transdermal fentanyl citrate patch added
to the regimen prior to developing confusion and irritability. The remaining 4
patients had a low meperidine dose administered only for a few hours. Central
nervous system toxic reaction due to accumulated normeperidine was very
unlikely in patients in this group.
Each patient in this study was visited daily by
members of the acute pain management service. The total daily meperidine dose
was calculated for the previous 24 hours. If the patient was judged to have
used a high dose of meperidine or if signs or symptoms of CNS excitation were
present, the analgesic regimen was modified. Such modifications included the
following: (1) substitution of IV PCA hydromorphone hydrochloride therapy for
IV PCA meperidine therapy; (2) discontinuation of use of a continuous
meperidine infusion (if such administration was used); (3) reduction in the
amount of meperidine required by the use of supplemental analgesics (eg, oral
methadone or transdermal fentanyl); or (4) discontinuation of usage of the PCA
device followed by the administration of oral morphine sulfate (immediate or
sustained release) or a combination of acetaminophen and oxycodone or codeine.
Records of patients in groups 2 and 3 (high
dose, asymptomatic and high dose, symptomatic, respectively) were examined in
detail. For each of these patients, their age, sex, weight, medical history,
concurrent use of other medications (eg, phenothiazines, barbiturates,
benzodiazepines, or phenytoin sodium), and serum creatinine level were noted.
Additionally for patients in group 3, electrolyte, glucose, serum urea
nitrogen, creatinine, calcium, and magnesium levels also were noted to be
within normal limits. Serum meperidine and normeperidine levels were also
available for 2 patients in group 3.
For groups 2 and 3, the arithmetic mean and 95%
confidence interval (CI) for patient meperidine dose per day normalized to body
weight was calculated in milligrams per kilograms per day. The mean and 95% CI
for the duration of meperidine administration was also determined. After
determination of the F ratio, the t
test was used to determine the statistical significance. The frequency of the
CNS toxic reactions in patients receiving IV PCA meperidine therapy was
determined.
REASONS FOR USE OF IV PCA
MEPERIDINE THERAPY
Of the 5432 patients who received IV PCA opioids 89% were initially
administered morphine and continued to receive this opioid. When a history of
allergy or adverse effect to morphine was present, either meperidine or
hydromorphone was prescribed instead. These other opioids were also used if
adverse effects developed once treatment with morphine by IV PCA was started.
Four hundred twelve patients (7.6%) were administered IV PCA meperidine; 185
patients (3.4%) were administered IV PCA hydromorphone. Of the 23% who either
had a history of allergy or had an adverse reaction to morphine therapy, 43%
experienced nausea or vomiting, 20% had pruritus, and 14% had dysphoria,
constipation, hallucinations, or urticaria.
DEMOGRAPHICS OF GROUPS 1
THROUGH 3 FOR MEDICAL OR SURGICAL CONDITION
Table 1
gives the breakdown of groups 1 through 3 as differentiated by broad medical or
surgical condition. Patients with gastrointestinal disease or who underwent
abdominal surgery demonstrated a tendency to use high doses of IV PCA
meperidine therapy more often than patients with other painful processes.
AMOUNT AND DURATION OF IV PCA
MEPERIDINE USE
Group 2 (high-dose, asymptomatic) patients (n = 51) received meperidine
hydrochloride therapy at a mean dose of 13.3 mg/kg per day (95% CI, 12.1-14.4
mg/kg per day) for a mean of 1.7 days (95% CI, 1.4-2.0 days). Group 3
(high-dose, symptomatic) patients (n = 7) received meperidine hydrochloride
therapy at a mean dose of 16.9 mg/kg per day (95% CI, 14.7-19.2 mg/kg per day)
for a mean of 2.2 days (95% CI, 1.5-3.0 days). There were no statistically
significant differences for age, sex, and renal function (Table 2).
None of the patients in either group were prescribed phenothiazines (including
antiemetics), barbiturates, phenytoin, or benzodiazepines. Renal function was
intact in both groups.
Specific signs and symptoms of CNS toxic
reactions for each patient in group 3 are listed in Table 3.
At the time of the CNS toxic reaction, all patients had serum electrolyte,
glucose, calcium, and magnesium levels within normal limits, and renal function
was within normal limits. There was no history of seizures or neurologic
disease. Computed tomographic scan of the head in 2 of the 7 patients did not
demonstrate any focal abnormalities to explain the observed neuroexcitatory
symptoms. Serum meperidine and normeperidine levels were obtained in 2
patients, as listed in Table 3.
The mean dose rate of group 3 (high-dose,
symptomatic) patients differed significantly (P<.05)
from the mean dose rate of group 2 (high-dose, asymptomatic) patients. The
duration of IV PCA meperidine use did not differ between the 2 groups. In our
study, the overall incidence of CNS toxic reactions resulting from IV PCA
meperidine use was 7 (2%) of 355 patients. The apparent incidence rises sharply
and significantly to 7 (12%) of 58 patients as more than 600 mg/d of meperidine
hydrochloride is used.
ALTERNATIVE METHODS OF
ANALGESIA CHOSEN
Using the alternative analgesic regimen described earlier, no patient in group
2 had any CNS adverse effects. Group 3 patients had these modifications made
after the CNS excitatory signs or symptoms had begun. The 1 patient who
experienced a seizure sustained a right temporal lobe contusion when the
patient fell during the seizure. The patient also experienced hallucinations
for 5 days after the right temporal lobe injury. All other patients had
resolution of the CNS excitatory signs or symptoms within 3 days after
discontinuing meperidine therapy.
The management of acute pain has been
substantially improved by the use of IV PCA when compared with conventional
intramuscular therapy.11 Morphine is the
opioid most commonly used when IV PCA is administered. This study indicates
that IV PCA morphine provides satisfactory analgesia without intolerable
adverse effects in 89% of patients treated. However, 11% of our patients
required an alternative opioid.
Hydromorphone is an alternative to morphine,
which is most often used for IV PCA in patients with adverse effects and/or
problems (but not true allergic reactions) from morphine therapy.12 In general the use of
IV PCA meperidine therapy is considered by some to be ill advised; however,
there may be occasions when IV PCA meperidine therapy remains a reasonable
option. Additionally, dosing principles of meperidine most probably apply to
intramuscular bolus administration, which remains a popular and effective
perioperative analgesic regimen with some surgical teams.
There are special potential problems associated
with meperidine administration. The biotransformation of meperidine involves
either hydrolysis to meperidinic acid, or N-demethylation
to normeperidine.13 Normeperidine in turn
undergoes hydrolysis to normeperidinic acid.14 The metabolites of
meperidine are primarily eliminated in urine. If the rate of hepatic formation
of normeperidine exceeds its renal elimination, CNS excitation may result from
the accumulation of normeperidine in plasma.4 Enhanced metabolism of
meperidine resulting from induction of microsomal enzymes by chlorpromazine,
phenobarbital, and phenytoin may predispose the patient to a CNS toxic
reaction.15-17 Renal
clearance of normeperidine has been correlated with creatinine clearance,18 which accounts for
the susceptibility of patients in renal failure to CNS excitation due to
normeperidine accumulation. Increasing the dosage and duration of meperidine
administration has also been linked to a CNS toxic reaction.4
In this study, group 2 (high-dose, asymptomatic)
patients used a statistically significantly lower (P<.05) mean dose of 13.3 mg/kg per day (95% CI, 12.1-14.4
mg/kg per day) than did group 3 (high-dose, symptomatic) patients. The mean
meperidine hydrochloride dose rate leading to CNS excitation was 16.9 mg/kg per
day (95% CI, 14.7-19.2 mg/kg per day), which was in the absence of renal
impairment and of medications promoting normeperidine formation. The duration
of IV PCA meperidine use was 2.2 days (95% CI, 1.5-3.0 days). From these data,
it becomes apparent why previously reported cases of a CNS toxic reaction
associated with IV PCA meperidine therapy occurred.9 The 3 patients
described in that report used IV PCA meperidine hydrochloride at a dose of 24
to 25 mg/kg per day for approximately 2 days. In our study, if a CNS toxic
reaction was noted, it was manifest after approximately 2 days in all cases.
The signs and symptoms of CNS excitation from a
normeperidine toxic reaction are nonspecific, making the chances of detection
somewhat difficult (especially retrospectively). Although grand mal seizures
can occur without apparent mild to moderate symptoms of CNS excitement; in
general, shaky feelings, tremors and/or twitches, and multifocal myoclonus
precede seizure activity.
The symptoms of CNS excitement due to a
normeperidine toxic reaction are irreversible and may even be exacerbated by
opioid antagonists (eg, naloxone). Naloxone will reverse the respiratory
depression of a meperidine overdose but may potentially precipitate seizures.
The approach to a meperidine overdose or a toxic reaction is generally to
support respiratory function (while protecting the airway by intubation with a
cuffed endotrachial tube and/or mechanical ventilatory assistance), to treat
any seizure activity with benzodiazepines or other anticonvulsants, to
immediately discontinue meperidine therapy, and lastly, to substitute another
opioid for pain (eg, morphine).4
Based on the dose ranges for symptomatic and
asymptomatic patients, 10 mg/kg per day is proposed as a maximum dose. This
value probably offers a reasonable safety margin in most patients and is simple
to recall. With the institution of 10 mg/kg per day as a cutoff limit for 5
years, there were no instances of CNS excitation except in 2 cases (included in
group 3) where the limit was ignored and meperidine therapy was continued.
Also, before using maximum doses, one should carefully ensure that renal
disease is absent as well as any other factors that might predispose to a CNS
toxic reaction (ie, seizure disorder or concurrent administration of
medications that increase meperidine metabolism by hepatic enzyme induction).
The plasma half-life of meperidine in normal
subjects is roughly 3½ hours.3 The half-life of
normeperidine may vary considerably (eg, approximately 14-21 hours in patients
with cancer vs 34 hours or longer in patients with renal failure), and does not
approach steady state until 3 to 6 days after the start of meperidine
administration.3 Normeperidine is
believed to exert an excitatory effect on the CNS, while meperidine itself is a
depressant. When normeperidine levels rise, and concomitantly meperidine levels
decline, CNS excitement can occur. In general, a normeperidine-meperidine ratio
of greater than 1 represents a potential for CNS excitation.4 However, there is no
direct predictive correlation in that seizures can occur at low
normeperidine-meperidine ratios (ie, <1).3, 4
A maximum dose of 10 mg/kg per day for a 3-day
period will obviate normeperidine-induced CNS excitation. Our data limit us
from commenting on additional duration of IV PCA meperidine use, since most
devices are discontinued between days 2 and 3. The length of time a patient
receives meperidine therapy is an important factor leading to the development
of a CNS toxic reaction.4, 7 This point is
supported by 4 asymptomatic patients in the present study (in group 2) who received
doses of IV PCA meperidine hydrochloride of more than 20 mg/kg per day, but for
only 1 day or less (specific data not shown). These patients did not develop
CNS excitation, presumably because they did not accumulate enough normeperidine
in their short duration of exposure to meperidine to have a toxic reaction.
However, smaller doses of meperidine given over a longer period can lead to
normeperidine accumulation and a potential toxic reaction.
The frequency of adverse effects in hospitalized
medical patients receiving parenteral meperidine therapy has been estimated in
the Boston Collaborative Surveillance Program Study.5 Adverse effects were
preponderantly neuropsychiatric and occurred in 3.1% of patients.5 This is similar to the
2% incidence of a CNS toxic reaction observed in our study patients receiving
IV PCA meperidine therapy. This incidence may change significantly when doses
exceed 14 mg/kg per day for longer than 2 days.
Daily evaluation of each patient using IV PCA
meperidine therapy should include determination of a 24-hour dose, as well as
the presence or absence of signs and symptoms of CNS excitation. It is
recommended that the dose of meperidine hydrochloride should be limited to 10
mg/kg per day in patients with normal renal function who are not also taking
medications that induce hepatic metabolism of meperidine. If the daily dose of
meperidine exceeds this level, alternative methods of analgesia should be used.
Author/Article Information
From the Department of Anesthesiology and Critical Care, Postoperative Pain
Services (Dr Simpoulos), Cancer Pain and Palliative Care (Dr Smith), and the
Arnold Pain Management Center (Dr Peeters-Asdourian), Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, Mass; and the Department of Anesthesiology,
University of Massachusetts Medical Center, Worcester (Dr Stevens).
Corresponding author: Thomas T. Simopoulos, MD, Department of Anesthesiology
and Critical Care, Postoperative Pain Services, Beth Israel Deaconess Medical
Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 (e-mail: [log in to unmask]).
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Edward E.
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Diplomat American
Board of Family Practice.
Diplomat American
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