MEPERIDIN

Toxicity Summary:

Meperidin adalah analgesik yang digunakan untuk meredakan nyeri sedang sampai berat. Obat
ini telah digunakan untuk meredakan nyeri pada infark miokard. Meperidin diberikan secara
parenteral untuk sedasi preoperatif.

IDENTIFICATION AND USE: Meperidine is a solid. Meperidine is a strong analgesic used in the
relief of moderate to severe pain. The drug has been used to relieve the pain of myocardial
infarction. Meperidine also is used parenterally for preoperative sedation, as a supplement to
anesthesia, and to provide analgesia during labor.

HUMAN STUDIES: Meperidine is a mu- and kappa-opiate receptor agonist with approximately 20-
25% the potency of morphine. Receptors for opiate analgesics are found in high concentrations
in the limbic system, spinal cord, thalamus, hypothalamus, striatum, and midbrain. They are also
found in tissues such as the gastrointestinal tract, urinary track, and in other smooth muscle.
Meperidine is different from other opioids because its active metabolite, normeperidine, is
neurotoxic. The lethal meperidine blood concentration is 1-3 mg/dL. Common side effects include
nausea, vomiting and hypotension. Meperidine can produce further hypotension in patients who
have blood loss due to trauma. In high doses, it has been associated with seizure. Obstetric
analgesia in the form of meperidine to mothers during delivery has adverse effects on some
aspects of the behavior of their newborn infants. ANIMAL STUDIES: In mice a reversible opacity
of the front of the lens has been observed to develop acutely after systematic administration of
meperidine, because of reduced blinking, exposing the eye to evaporation and causing
dehydration of the lens. Meperidine is reported to inhibit the release of gonadotropins in animals.
Prolonged administration of up to 6 times the recommended therapeutic dose to dogs produces
slight anorexia and loss of weight. Doses of 100 mg or more produce excitement and clonic
convulsions, which can be controlled by barbiturates, in cats. Following an im dose of 10 mg/kg
meperidine, reduction in heart rate and drop in the systemic arterial pressure occur in dogs.
Generally, the fall in blood pressure is moderate, and occurs 10-20 minutes after im injection,
with return to control level in 30 minutes. Subcutaneous doses in excess of 20-30 mg/kg
meperidine can produce excitement and clonic convulsions in cats. The chronic epidural
administration of pethidine in rabbits induces moderate to severe histological changes on the
spinal cord.
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Human Toxicity Excerpts:

/HUMAN EXPOSURE STUDIES/ /The study objective was/ to evaluate the effects of high analgesic
doses of tramadol and meperidine on respiration, plasma catecholamine concentrations, and
hemodynamic parameters. /This was a/ randomized, double-blind, cross-over, controlled
volunteer study /conducted at/ a laboratory at a university hospital /using/ 8 healthy male
volunteers. Tramadol was given as a 150 mg bolus plus a succeeding 3-hour steady infusion of
250 mg (83.3 mg/hr). Meperidine was given in a similar manner as a bolus dose of 112.5 mg
plus 187.5 mg in a 3-hour steady infusion (62.5 mg/hr). Experimental pain was induced using a
tourniquet. Respiration was studied noninvasively with respiratory inductive plethysmography
and pulse oximetry. Arterial line was used for measurement of hemodynamics and blood
sampling. Tramadol did not have any clinically significant effects on respiration, breathing
pattern, or hemodynamics, but an increase in plasma epinephrine levels was noted. Meperidine
bolus decreased tidal volume (p < 0.05, difference from baseline) and pulse oxygen saturation
(from 97% to 94%, p < 0.05), but during the succeeding infusion, the respiratory drive,
measured as mean inspiratory flow, was enhanced (p < 0.05 difference from baseline), and the
respiratory parameters returned to baseline level. No change in hemodynamics was noted, but a
significant increase in plasma norepinephrine and epinephrine levels (from 0.9 to 1.6 nmol/L and
from 0.3 to 0.8 nmol/L, respectively; p < 0.05) was observed after meperidine administration.
Tramadol caused nausea more often than meperidine (p < 0.05, between treatments). Tramadol
exhibited a minimal effect on respiration and breathing pattern in healthy volunteers. The
respiratory effects of meperidine bolus were predictable with decreasing tidal volume and pulse
oxygen saturation. In contrast, during meperidine infusion, adequate respiration was preserved
despite the large amount of meperidine infused.
[Mildh LH et al; J Clin Anesth 11 (4): 310-6 (1999)] **PEER REVIEWED** PubMed Abstract

/HUMAN EXPOSURE STUDIES/ The intrathecal injection of 0.7-1 mg/kg meperidine provides
spinal anesthesia of only short duration. In this study, we investigated the effects of three
different doses of meperidine for spinal anesthesia on the duration and level of sensory block and
the incidence of side effects. Forty-five African men were randomly allocated to receive one of
three doses of intrathecal meperidine: Group A = 1.2 mg/kg, Group B = 1.5 mg/kg, and Group C
= 1.8 mg/kg. The duration of sensory block was significantly longer after 1.5 mg/kg compared
with 1.2 mg/kg meperidine (112 +/- 19 vs 79 +/- 27 min; P = 0.001). Increasing the dose to
1.8 mg/kg did not further increase the duration of block. The level and the onset of the block
were not affected by the dose. Common side effects were fatigue (27%), pruritus (20%), and
nausea (7%). Seven patients had respiratory depression and seven had a decrease of systolic
arterial blood pressure (SAP) >30% from baseline. There was no difference in the incidence of
any side effect among groups. Respiratory depression and decreases in SAP were observed 5-50
min after meperidine injection. Twenty-two patients had no pain after the sensory block had
terminated. We conclude that increasing the dose of meperidine from 1.2 to 1.5 mg/kg increased
the duration, but not the level, of sensory block without an increase in side effects. Intrathecal
meperidine 1 mg/kg provides surgical anesthesia for only 40-90 min. We investigated the effects
of three larger doses of meperidine in 45 African men. The 1.5 and 1.8 mg/kg doses provide a
longer duration of anesthesia compared with 1.2 mg/kg. Nausea, pruritus, and respiratory
depression were common in all dose groups. We conclude that increasing the dose of meperidine
from 1.2 to 1.5 mg/kg increased the duration, but not the level, of sensory block without an
increase in side effects.
[Hansen D, Hansen S; Anesth Analg 88 (4): 827-30 (1999)] **PEER REVIEWED** PubMed Abstract

/HUMAN EXPOSURE STUDIES/ The combined spinal-epidural (CSE) technique using bupivicaine-
fentanyl has become an established method of pain control during parturition. One limitation is
the relatively short duration of effective analgesia produced by bupivicaine-fentanyl. In contrast,
subarachnoid meperidine has been shown to provide a long duration of anesthesia in
nonobstetric patients. Therefore, the authors tested the hypothesis that subarachnoid
meperidine produces a significant increase in the duration of analgesia compared with
bupivicaine-fentanyl. Based on a power analysis of preliminary data, the authors intended to
recruit 90 patients for the study, randomized to three groups: 2.5 mg bupivicaine-25 ug
fentanyl, 15 mg meperidine, or 25 mg meperidine. However, after enrolling 34 patients, the
study was discontinued because of a significant increase in nausea or vomiting in the study
patients. Nausea or vomiting was substantially increased in both meperidine groups compared
with the bupivicaine-fentanyl group: 16 with nausea or vomiting in the meperidine groups (n =
21), compared with 1 in the bupivicaine-fentanyl group (n = 11), P = 0.0011. The mean duration
of analgesia provided by 25 mg meperidine was 126 +/- 51 min, compared with 98 +/- 29 min
for bupivicaine-fentanyl and 90 +/- 67 min for 15 mg meperidine. These data were not
significant (P = 0.27). Although intrathecal meperidine could potentially prolong subarachnoid
analgesia during labor, its use was associated with a significant incidence of nausea or vomiting.
These data do not support the use of subarachnoid meperidine in doses of 15 or 25 mg for labor
analgesia.
[Booth JV et al; Anesthesiology 93 (2): 418-21 (2000)] **PEER REVIEWED** PubMed Abstract

/HUMAN EXPOSURE STUDIES/ Intrathecal administration of meperidine, an opioid with local

anesthetic activity, can induce analgesia in patients with intractable cancer pain. However,
continuous intrathecal administration may result in the accumulation of normeperidine,
responsible for central nervous system toxicity. Ten patients with neuropathic cancer pain, not
responding to conventional opioid therapy, were treated with continuous intrathecal
administration of meperidine. In all patients, plasma concentrations of meperidine and
normeperidine were measured the first days after the start of treatment. Visual analog scale
scores were recorded to evaluate pain relief. Quality of life was assessed before and 3 weeks
following the start of intrathecal treatment. In three patients the plasma concentrations of
meperidine and normeperidine increased rapidly. In one patient the plasma normeperidine
concentration was higher than the meperidine concentration. One patient demonstrated transient
symptoms suggestive for central nervous system excitation. Three weeks following the start of
treatment, seven patients were available for evaluation of their quality of life. Pain relief and
overall quality of life improved during the intrathecal treatment. We conclude that continuous
intrathecal administration of meperidine alone, or in combination with clonidine, can provide
significant pain relief in patients with poor pain control despite pharmacological treatment.
However, accumulation of meperidine and normeperidine resulting in central nervous system
toxicity may occur during this treatment.
[Vranken JH et al; Acta Anaesthesiol Scand 49 (5): 665-70 (2005)] **PEER REVIEWED** PubMed Abstract

/HUMAN EXPOSURE STUDIES/ Psychomotor skills related to driving and the ability to
discriminate the fusion of flickering light were measured in a double-blind cross-over fashion in
11 healthy volunteers before, and 1, 3, 5, and 7 hours after, intramuscular injection of saline
solution, 10 mg diazepam, or 75 mg meperidine. The late effects of meperidine were tested in
five other subjects 12 and 24 hours after the injection. The effects of diazepam were the most
harmful to coordinative and reactive skills, which were significantly impaired for as long as 5
hours. Meperidine impaired reactive skills for as long as 3 hours and flicker-fusion discrimination
and coordinative skills for as long as 12 hours. It is concluded that patients should not drive or
operate machinery for at least 7 hours after receiving 10 mg diazepam intramuscularly and for
24 hours after receiving 75 mg meperidine intramuscularly.
[Krottila K, Linnoila M; Anesthesiology 42: 685-91 (1975)] **PEER REVIEWED** PubMed Abstract

/HUMAN EXPOSURE STUDIES/ Meperidine has been shown to exhibit a sensory block in
peripheral nerves. However, its motor blockade ability is controversial. The aim of this study was
to investigate, electroneurographically, the ability of meperidine to inhibit conduction in both
sensory and motor fibers in the ulnar nerve. The study was conducted in a double-blind, placebo-
controlled fashion. Eighteen healthy volunteers were randomized into three groups (Saline,
meperidine 1% and meperidine 2%). Three milliliters of the study solution was administered to
the ulnar nerve perineurally at the level of the wrist by the guidance of a nerve stimulator.
Sensory nerve action potential (SNAP) and compound motor action potential (CMAP) amplitudes
were recorded. At least a 20% decrease in the initial response amplitude was accepted as a
block. The number of individuals with sensory and motor block with saline, meperidine 1% and
meperidine 2% were 0/6, 6/6, 6/6 and 0/6, 5/6, 6/6, respectively (P<0.05). The maximum
decrease in the median SNAP and CMAP amplitude values were 4.7% and 8.3% with saline;
38.5% and 46.4% with meperidine 1%; and 100% and 97.8% with meperidine 2%, respectively
(P<0.05). Median values for the duration of sensory and motor block with meperidine 1% and
meperidine 2% were 45, 52.5 and 30, 32.5 min, respectively. Meperidine blocks sensory and
motor nerve conduction in a dose-related manner.
[Ozturk E et al; Acta Anaesthesiol Scand 53 (6): 783-7 (2009)] **PEER REVIEWED** PubMed Abstract

/SIGNS AND SYMPTOMS/ Pethidine ... usually does not affect the pupils or vision in ordinary
dosage. Miosis, if any, is very slight, usually less than 0.5 mm. However, overdosage has been
known to cause miosis in some patients and mydriasis in others. The intraocular pressure in
normal patients is not elevated by 100 mg intramuscularly, but may be reduced about 2 mm Hg.
... In manufacture of pethidine its dust is said to cause blepharitis and conjunctivitis.
[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 713]
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/SIGNS AND SYMPTOMS/ ... Meperidine can produce further hypotension in patients who have
blood loss due to trauma.
[Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver,
WA., Applied Therapeutics, Inc. 1995., p. 7-20] **PEER REVIEWED**

/CASE REPORTS/ Normeperidine, a major metabolite of meperidine, is half as potent as

meperidine as an analgesic but two to three times more potent as a convulsant. Renal failure
significantly increases the plasma half-life of normeperidine. The intensity of the central nervous
system excitation is highly correlated with the plasma concentration of normeperidine. Moreover,
normeperidine toxicity is not reversed by naloxone, which may exacerbate it. We report a patient
with end-stage renal disease undergoing maintenance continuous cycler peritoneal dialysis who
had been receiving meperidine for pain control. The patient subsequently developed myoclonic
contractions and a grand mal seizure. The patient was successfully treated with hemodialysis
(using an F8 dialyzer) for presumed normeperidine-induced seizure. During hemodialysis,
normeperidine average blood clearance was 73 mL/min, average plasma clearance was 50
mL/min, and average percentage of plasma extraction was 24%. There also was a 26%
reduction in plasma concentration of normeperidine over 3 hours of hemodialysis. In conclusion,
our findings suggest that hemodialysis may be used effectively for treating patients with
suspected normeperidine-induced neurotoxicity.
[Hassan H et al; Am J Kidney Dis 35 (1): 146-9 (2000)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ Meperidine is a synthetic opioid analog that is frequently prescribed for acute
pain management. Normeperidine, the only active metabolite of meperidine, is neurotoxic and
can cause significant central nervous system adverse events. A 29-year-old woman (height, 170
cm; weight, 85 kg) presented to Marmara University Hospital Emergency Department, Istanbul,
Turkey, complaining of low back pain she described as "stabbing." Physical examination revealed
impaired lower-extremity mobility and normal vital-sign findings. There was no evidence of foot
drop, head or other trauma, and systemic physical examination was unremarkable. Other
common causes (eg, pyelonephritis, nephrolithiasis, pancreatitis, trauma) of lower back pain
were excluded. To achieve analgesia, meperidine 80 mg was administered intravenously in 100
mL of isotonic saline solution for 20 minutes. Within 20 minutes, analgesia was achieved, but the
patient developed retrograde amnesia, becoming disoriented to time, location, and persons. Her
speech slowed and perceptional changes developed. After the onset of amnesia, a complete
physical examination was conducted. It failed to reveal focal neurologic deficit, and laboratory
(sodium, potassium, magnesium, phosphorus, serum creatinine, blood urea nitrogen, albumin,
bilirubin, hemoglobin, and platelet count) and subsequent vital-sign findings (blood pressure,
150/100 mm Hg; heart rate, 100 beats per minute; respiratory rate, 18 breaths per minute;
body temperature, 37 deg C and pulse oximetry, 99%) were within the normal range.
Noncontrast computed tomography did not reveal any abnormality. Initially, the patient's
condition was attributed to medication error due to incorrect dosage or infusion rate. Despite a
review of medication logs, equipment, and the vital-sign record, the etiology for the phenomenon
could not be identified. Meperidine was discontinued and oxygen and intravenous isotonic saline
solution were initiated as supportive treatment. Three hours after meperidine administration was
discontinued, the amnesia and disorientation spontaneously resolved. Meperidine was probably
associated with reversible amnesia in this healthy patient after a single therapeutic dose.
[Guneysel O et al; Curr Ther Res Clin Exp 69 (2): 159-63 (2008)] **PEER REVIEWED** PubMed
Abstract Full text: PMC3969970

/CASE REPORTS/ We report two cases of postsurgical intramuscular meperidine injection with
injury to the femoral nerve and subsequent vastus lateralis atrophy. The first case is a patient
who had arthroscopic anterior cruciate ligament reconstruction; the second, a patient with a C6-
C7 anterior fusion. Photographs, radiography, and electrodiagnostic studies clearly depict the
nature of the injuries, and their etiology is discussed. ...
[Haber M et al; Arch Phys Med Rehabil 81 (9): 1229-33 (2000)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ We describe the first reported case of generalized tonic-clonic seizures induced
by meperidine premedication for a colonoscopy procedure in a 63-year-old woman with
Alzheimer's disease. The active metabolite of meperidine, normeperidine, is postulated to be the
precipitating cause of the seizures, although a cholinesterase inhibitor and an N-methyl-D-
aspartate receptor antagonist, both routinely used for treatment of Alzheimer's disease, may
have contributed by reducing the seizure threshold. The neuronal changes which occur in
Alzheimer's disease can themselves also predispose to seizures. We recommend avoidance of
meperidine for all flexible endoscopic procedures on patients with Alzheimer's disease and in any
patient with a condition that predisposes to seizures, and suggest the use of alternative opioids.
[Nagler J et al; Dig Dis Sci 53 (1): 62-4 (2008)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ A 35-year-old, 47 kg female presented for elective laparatomy, adhesiolysis

and ileostomy formation. Pre-existing neurological problems precluded placement of an epidural
and IV patient controlled analgesia (PCA) was used for postoperative analgesia. A patient request
for pethidine was allowed. Twenty-three hours postoperatively, a brief generalized seizure
occurred without adverse sequelae. This had been immediately preceded by myoclonic-type
jerking. The cumulative pethidine dose was 3,000 mg and the norpethidine level was 1.8 ug/mL.
Avoidance of pethidine for IV PCA where large cumulative doses are anticipated is advised.
Seizures associated with pethidine/norpethidine toxicity can occur early during pethidine usage,
and there is considerable variation in measured norpethidine levels.
[McHugh GJ; Anaesth Intensive Care 27 (3): 289-91 (1999)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ The syndrome of transient neurological symptoms (TNS) after subarachnoid
use of local anesthetics, particularly lidocaine, has been well described. This syndrome has not
been reported with the subarachnoid use of opioids. This case report describes TNS that occurred
after administration of subarachnoid meperidine, an opioid with local anesthetic properties.
[Lewis WR, Perrino AC Jr; Anesth Analg 94 (1): 213-4, table of contents (2002)] **PEER
REVIEWED** PubMed Abstract

/CASE REPORTS/ We report a case of fixed drug eruption (FDE) caused by three unrelated drugs.
A 52-year-old woman presented with a diagnosis of FDE after taking a drug to treat a common
cold. An oral provocation test and a patch test were carried out, and the patient reacted to
promethazine, which is a derivative of phenothiazine. To determine the core structure of the
antigen, we performed patch testing and/or an oral provocation testing with six drugs that are
similar in structure to promethazine. The patient reacted to five of the six drugs, and the
antigenic determinant was identified as a phenothiazine and a tricyclic structure. The patient had
similar eruptions at the same sites 3 years later after taking pethidine. Seven months after that
reaction, a more severe eruption was caused by oral omeprazole. This is an extremely rare case
of FDE caused by three structurally unrelated drugs.
[Kai Y et al; Clin Exp Dermatol 36 (7): 755-8 (2011)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ /The study objective was/ to report a seizure occurring secondary to
meperidine treatment despite normal renal and central nervous system (CNS) function, and to
provide a review of meperidine's role in pain management, including its use in pancreatitis and
sphincter of Oddi dysfunction. A 55-year-old white woman with a history of sphincter of Oddi
dysfunction presented to the emergency department with severe abdominal pain. On admission
to the hospital, the serum creatinine level was 0.6 mg/dL with slightly elevated aspartate
aminotransferase of 56 U/L (normal range 0-31) and alanine aminotransferase of 34 U/L (0-31).
The patient received repeated and escalating doses of intravenous meperidine, resulting in a
generalized seizure on day 4 of hospitalization. The accumulated meperidine dose was 2125 mg.
Buprenorphine was substituted in place of meperidine, and the patient had no further reported
complications. She was then transferred to a tertiary-care facility for sphincter of Oddi
reevaluation. An objective causality assessment revealed the adverse drug event as probable.
Despite alternative opioids, meperidine continues to be used in pain management. Meperidine is
different from other opioids because its active metabolite, normeperidine, is neurotoxic. Patients
with renal insufficiency, liver failure, or CNS dysfunction are at increased risk for adverse drug
reactions related to normeperidine accumulation. Due to normeperidine's extended half-life,
however, accumulation of normeperidine can occur in any patient receiving repeated doses of
meperidine. This case demonstrates the potential hazards that exist when using meperidine in
any patient. Meperidine's inherent risks of both undertreating pain and causing adverse drug
reactions should prompt clinicians and health organizations to restrict its use in pain
management. This restriction should not make exceptions to meperidine's traditional use in
pancreatitis or sphincter of Oddi dysfunction.
[Hubbard GP, Wolfe KR; Ann Pharmacother 37 (4): 534-7 (2003)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ Musculoskeletal injuries secondary to seizures are well documented and have a
variable incidence. Meperidine has been used for many years in the postoperative setting for pain
control; however, in high doses, it has been associated with seizure. We report the case of
patient who experienced a tonic-clonic seizure 5 days after hip revision surgery, resulting in
dissociation of the socket from the acetabulum with an associated acetabular fracture. In this
patient, meperidine administered for patient-controlled analgesia within recommended range
caused the seizure.
[Beaule PE et al; J Arthroplasty 19 (4): 516-9 (2004)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ We present a patient with a history of clomipramine-induced serotonin

syndrome 5 yr prior who developed serotonin syndrome after a single dose of meperidine. This
report heightens appreciation of population at risk and also recognition of potential toxicity in
meperidine.
[Guo SL et al; Br J Anaesth 103 (3): 369-70 (2009)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ Pethidine is an opioid that gains its popularity for the effective pain control
through acting on the opioid-receptors. However, rapid pain relief sometimes brings about
unfavorable side effects that largely limit its clinical utility. Common side effects include nausea,
vomiting and hypotension. In patients with impaired renal and liver function, and those who
need long-term pain control, pethidine may cause excitatory central nervous system (CNS)
effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack.
On the contrary, though not clinically apparent, pethidine potentially causes inhibitory impacts on
the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case
report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes
dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity.
[Dai YH et al; BMJ Case Rep pii: bcr2014203868. doi: 10.1136/bcr-2014-203868 (2014)] **PEER
REVIEWED** PubMed Abstract Full text: PMC3962981

/CASE REPORTS/ Serotonin syndrome has been reported with administration of linezolid and
serotonin reuptake inhibitors. Meperidine blocks the neuronal reuptake of serotonin. Serotonin
syndrome after concomitant linezolid and meperidine therapy has not been described. We
describe serotonin syndrome after concomitant use of linezolid and meperidine in a 27-year-old
man with acute leukemia.
[Das PK et al; Clin Infect Dis 46 (2): 264-5 (2008)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ We present a case of "inverted Tako-Tsubo" syndrome in a woman sedated

with meperidine before undergoing a colonoscopy. We discuss possible etiology of this ventricular
dysfunction.
[Sacco A et al; Med J Malaysia 66 (5): 520-1 (2011)] **PEER REVIEWED** PubMed Abstract

/EPIDEMIOLOGY STUDIES/ Little is known about risk factors that increase the risk of
development of opioid side effects. Our objective was to evaluate the effect of the type of opioid,
age, gender, and race on the incidence of side effects from short-term opioid use. A secondary
analysis of a retrospective cohort study in 35 community-based and tertiary hospitals was done.
There were 8855 black or white subjects aged 16 years and older. Patients received meperidine
(INN, pethidine), morphine, or fentanyl as part of their treatment. Measurements were made to
assess the presence of nausea and vomiting and respiratory depression. Of the patients, 26%
had nausea and vomiting and 1.5% had respiratory depression after opioid administration. After
adjustment for opioid dose, route of administration, age, gender, and race, meperidine produced
less nausea and vomiting (odds ratio [OR] = 0.7; 95% confidence interval [CI], 0.5-0.8) and less
respiratory depression (OR = 0.6; 95% CI, 0.2-0.9) than morphine. The risk of respiratory
depression increased with age. Compared with patients aged between 16 and 45 years, those
aged between 61 and 70 years had 2.8 times the risk of development of respiratory depression
(95% CI, 1.2-6.6); those aged between 71 and 80 years had 5.4 times the risk (95% CI, 2.4-
11.8); and those aged older than 80 years had 8.7 times the risk (95% CI, 3.8-20.0). Men had
less nausea and vomiting than women (OR = 0.5; 95% CI, 0.4-0.6). White subjects had more
nausea and vomiting than black subjects (OR = 1.4; 95% CI, 1.1-1.7). Meperidine produced
fewer side effects than morphine during short-term use. The risk of respiratory depression
increases substantially after 60 years of age. Women have nausea and vomiting more often than
men. The effect of race deserves further investigation.
[Cepeda MS et al; Clin Pharmacol Ther 74 (2): 102-12 (2003)] **PEER REVIEWED** PubMed Abstract

/EPIDEMIOLOGY STUDIES/ With increasing use of opioids for chronic noncancer pain comes
concern about safety of this class of drugs. Opioid-induced hypogonadism, which could increase
the risk for myocardial infarction (MI), has recently come to the attention of clinicians. To
evaluate this concern we examined the association between opioid use for noncancer pain and
risk of MI amongst adults. We conducted a nested case-control study using the UK General
Practice Research Database. Amongst 1.7 million opioid users during 1990-2008, we identified
11,693 incident MI cases aged 18-80 years, and randomly selected up to four controls matched
by age, gender, index date (date of onset symptoms or diagnosis of first-ever MI) and general
practice via risk-set sampling. Cases and controls were required to have no cancer and no major
risk factors for MI before the index date. Adjusted odds ratios (ORs) and 95% confidence
intervals (CIs) were estimated from conditional logistic regression. Compared with nonuse,
current use of opioids was associated with a 1.28-fold (95% CI 1.19-1.37) risk of MI. Cumulative
use of opioids with 11-50 (OR = 1.38, 95% CI: 1.28-1.49) or > 50 (OR = 1.25, 95% CI: 1.11-
1.40) prescriptions, was also marginally associated with increased risk of MI. The risk was
particularly increased in users of morphine (OR = 1.71, 95% CI: 1.09-2.68), meperidine (OR =
2.15, 95% CI: 1.24-3.74) and polytherapy (OR = 1.46, 95% CI: 1.22-1.76). Current use of any
opioids and cumulative use of 11 or more prescriptions are associated with a small increased risk
for MI compared to nonuse and the risk was greater in morphine, meperidine and polytherapy
users. Residual confounding, particularly confounding by indication, should be considered in
interpreting our results.
[Li L et al; J Intern Med 273 (5): 511-26 (2013)] **PEER REVIEWED** PubMed Abstract

/EPIDEMIOLOGY STUDIES/ This study was undertaken to evaluate whether the administration of
meperidine decreases the length of labor in patients with a diagnosis of dystocia during the first
stage of labor. Women with term singleton pregnancies who received a diagnosis of dystocia and
required an active management of labor were randomly assigned to receive either 100 mg of
meperidine or placebo. The primary outcome measure was length of labor. Four hundred seven
pregnant women were included. There were no significant statistical differences between
meperidine and placebo groups in length of labor and operative delivery rates such as forceps
and cesarean section by intention-to-treat analysis. Low Apgar scores, umbilical artery acidosis,
and admission to neonatal care units were increased in the meperidine group. Because of the
absence of any benefits in patients with dystocia in labor and the presence of harmful effects on
neonatal outcomes, meperidine should not be used during labor for this specific indication.
[Sosa CG et al; Am J Obstet Gynecol 191 (4): 1212-8 (2004)] **PEER REVIEWED** PubMed Abstract

/EPIDEMIOLOGY STUDIES/ The objective of our study is to identify and compare the prevalence
of nausea after parenteral administration of opioids in the Emergency Department (ED). This
prospective study utilized a convenience sample at a community-based ED with a volume of
60,000 annual visits. Patients who were in acute pain or had an exacerbation of chronic pain
requiring treatment with an opioid analgesic agent were eligible. Demographic and historical
features were recorded on a standardized closed data collection form. The main study endpoint
was the occurrence of nausea. The prevalence of nausea and vomiting was compared between
morphine and meperidine. There were 37 patients in the morphine group and 156 in the
meperidine group. The two groups were similar with respect to mean age, gender, and weight.
The reported nausea was 0 of 37 in the morphine group and 20 of 156 (12.8%) in the
meperidine group. This difference between morphine and meperidine groups of 12.8% (95%
confidence intervals 2-24%) was statistically significant. In our patient population, morphine
caused significantly less nausea then meperidine when it was used as an analgesic in the ED.
[Silverman ME et al; J Emerg Med 27 (3): 241-3 (2004)] **PEER REVIEWED** PubMed Abstract

/EPIDEMIOLOGY STUDIES/ /A hypothesis was proposed that/ intravenous patient-controlled

analgesia (IV PCA) meperidine hydrochloride can be used with a reasonable margin of safety. 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. /The study was performed at
a/ university tertiary care hospital /using/ postoperative patients from general, orthopedic,
neurosurgical, gynecological, and urologic procedures receiving IV PCA. 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. 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. 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<0.05) 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%. 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.
[Simopoulos TT et al; Arch Surg 137 (1): 84-8 (2002)] **PEER REVIEWED** PubMed Abstract

/EPIDEMIOLOGY STUDIES/ Shivering causes various adverse disturbances and interferes with
monitoring. The optimal dose of intrathecal meperidine to prevent shivering without producing
other side-effects remains unknown. This prospective randomized double-blinded study was
conducted to compare the antishivering effects of two different doses of intrathecal meperidine.
Seventy two parturients, scheduled for elective cesarean section under spinal anesthesia, were
enrolled in three different groups. Spinal anesthesia consisted of bupivacaine 0.5% (10 mg) for
the control group (M0), and the same dose of bupivacaine with meperidine 12.5 or 25 mg for the
experimental groups (M1, M2). Blood pressure, heart rate, skin and core temperatures, sensory
level, capnometry, pulse oximetry, Apgar scores, shivering intensity and intrathecal opioid-
related side-effects were evaluated and recorded by a blinded observer. Data were analyzed
using analysis of variance, chi-squared test, Kruskal-Wallis H-test and Mann-Whitney U-test. A P
value less than 0.05 was considered to be significant. Shivering was more intense in group M0
than in groups M1 and M2 with P values of 0.003 and less than 0.001, respectively. The intensity
of shivering was comparable in groups M1 and M2. As regards the incidence of significant
shivering, it was found to be highest in M0 (4/24 approximately = 16.7%) in comparison with M1
(0/24) and M2 (0/24) (P = 0.03). Nausea and vomiting occurred more frequently with higher
doses of meperidine (P < 0.001 and P = 0.003, respectively). Other complications were
comparable. The use of intrathecal meperidine for cesarean section during spinal anesthesia for
the prevention of shivering cannot be recommended as its use is associated with increased
incidence of nausea and vomiting.
[Khan ZH et al; Eur J Anaesthesiol 28 (3): 202-6 (2011)] **PEER REVIEWED** PubMed Abstract

/EPIDEMIOLOGY STUDIES/ The aim of this study was to evaluate the effectiveness of
meperidine, administered during the first stage of labor in patients with uterine dystocia, on the
duration of labor and neonatal acid-base status at birth. We randomly assigned 240 nulliparous
women with a singleton pregnancy at term who were diagnosed with uterine dystocia in labor at
4-6-cm cervical dilatation to receive either a single dose of 50 mg meperidine in 10 mL of saline
(slow intravenous injection over 2 min) or 10 mL of isotonic saline (control group). The primary
outcome measures were duration of labor (from the time of beginning of the intervention to the
time of the expulsion of the fetal head) and umbilical cord arterial acid-base status. The evidence
revealed no statistically significant difference between the two groups in length of labor (188.2
+/- 92.3 min in the meperidine group compared to 205.4 +/- 96.1 min in the placebo group, P =
0.159). The pH of the umbilical cord arterial samples was lower in the meperidine group than in
the control group, although the difference was not statistically significant (P = 0.089). Because
of the absence of any beneficial effect of meperidine on uterine dystocia, its use in labor should
be limited to pain relief in the absence of epidural analgesia.
[El-Refaie TA et al; J Obstet Gynaecol Res 38 (2): 383-9 (2012)] **PEER REVIEWED** PubMed Abstract

/PREGNANCY AND HUMAN REPRODUCTION/ Obstetric analgesia in the form of pethidine

(meperidine) to mothers during delivery has adverse effects on some aspects of the behavior of
their newborn infants. The non-nutritive sucking (NNS) pattern of nine healthy full-term infants
exposed to pethidine in utero was compared to that of a control group of infants. The pattern
was analyzed and quantified using an automatic computer-based method. The results are
discussed in the context of endogenous and exogenous opiates and their effect on brain-stem
rhythm generators. The typical NNS pattern with alternating sucking activity (bursts) and pauses
is preserved in the exposed infants. There is a significantly lower sucking frequency (md 1.74 vs
1.90 Hz, p = 0.030) and a tendency to a less stable rhythm in pethidine-exposed infants.
[Hafstrom M, Kjellmer I; Acta Paediatr 89 (10): 1196-200 (2000)] **PEER REVIEWED** PubMed Abstract

/PREGNANCY AND HUMAN REPRODUCTION/ /The study objective was/ to investigate the effects
of maternal pethidine administration on pulmonary function tests in newborn infants. The study
was carried out in the Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj
Hospital. The study group consisted of 20 infants exposed to pethidine within 4 hours prior to
delivery. Twenty infants whose mothers received no analgesic drug or regional anesthesia were
randomly selected as the controls. /CNS depressant/ related respiratory depression was
determined by Apgar scores, the need for ventilatory support in the delivery room and abnormal
pulmonary function measurements. There was no difference in birth weight and gestational age
between the two groups of infants. Pethidine was given to mothers at a dose of 72.5 +/- 7.6
mg/kg with a mean drug-delivery interval of 152 +/- 61 minutes. One infant in each group had a
1-minute Apgar score less than 7, but there was no statistical difference in the mean Apgar score
between the two groups. None of the infants whose mothers received pethidine required
ventilatory support, but oxygen was provided to eight infants who were apparently cyanosed at
birth. Pulmonary function measurements were performed at the age of 7.4 +/- 2.3 hours in the
controls and 6.0 +/- 2.5 hours in the study group. There was no significant difference in
respiratory rate, tidal volume, inspiratory time, functional residual capacity, compliance and
resistance between the two groups of infants. Severe /CNS depressant/ related respiratory
depression was uncommon in this study. In the first 12 hours of life, there was no significant
difference in pulmonary function of the infants exposed to pethidine. It is quite safe to allow the
baby to room-in with the mother if respiratory depression is not presented at birth.
[Kolatat T et al; J Med Assoc Thai 85 Suppl 2: S463-8 (2002)] **PEER REVIEWED** PubMed Abstract

/PREGNANCY AND HUMAN REPRODUCTION/ There is no information about an effect of pethidine

labor analgesia on newborn vital signs in the first hours after the delivery. The aim of the study
was to assess changes in heart rate, blood pressure and oxygen saturation during the first 24
hours of life in neonates born after using pethidine for labor analgesia. 55 full-term neonates, 34
from intramuscular pethidine labor anesthesia in doses 50-100 mg and 21 born to mothers
without any pharmacological form of anesthesia, were studied. Heart rate, oxygen saturation and
blood pressure (SBP and DPB) were monitored using a Nellcor Oxi Max monitor N5500 (Tyco
Healthcare), and recorded at 1, 6, 12 and 24 hours. No significant differences in the heart rate
(144; 139; 141; 142,5 versus 142; 140,5; 138; 141 beats/minute), oxygen saturation (97%;
98%; 98%; 98,5%; versus 98%, 98%, 98%, 98%), SBP (66,5; 67; 66; 66,5 versus 68,5; 65;
64; 64,5 mm Hg) and DBP (33,5; 35; 37; 40 versus 34; 32; 32; 38 mm Hg) at 1, 6, 12 and 24
hours between pethidine and controls groups were found. Intramuscular pethidine analgesia
during the first stage of labor in doses 50-100 mg does not significantly modify the oxygen
saturation, heart rate and blood pressure in infants during the first 24 hours of their life.
[Konefal H et al; Ginekol Pol 83 (5): 357-62 (2012)] **PEER REVIEWED** PubMed Abstract

/ALTERNATIVE and IN VITRO TESTS/ Arterial grafts are prone to vasospasm. Opioid analgesics
are commonly used in the perioperative course of cardiac surgical procedures. Therefore, we
investigated the direct effects of morphine, meperidine, fentanyl and remifentanil on the human
radial artery. Radial artery segments, obtained from 20 patients, were precontracted with
phenylephrine. Using the organ bath technique, the endothelium-independent vasodilatation was
tested in vitro by addition of cumulative concentrations of morphine, meperidine, fentanyl and
remifentanil in separate organ baths, in the presence or absence of naloxone. Indomethacin and
NG-nitro-L-arginine methyl ester was added to all organ bath in order to determine the effects of
prostaglandins and nitric oxide, respectively. Morphine (10(-8) - 10(-4) mol/L), meperidine (10(-
10) - 10(-6) mol/L), fentanyl (10(-10) - 10(-6) mol/L) and remifentanil (10(-8) - 10(-4) mol/L)
caused a concentration-dependent vasorelaxation in the human being artery rings. The
relaxations in the presence of naloxane did not change. The maximal relaxant effects of
meperidine and fentanyl were significantly greater than those of morphine and remifentanil (P <
0.05). These findings indicate that morphine, meperidine, fentanyl and remifentanil produce
concentration-dependent and endothelium-independent relaxations in human being radial artery
rings. Meperidine and fentanyl are more potent relaxant agents than morphine and remifentanil
in the human being radial artery in vitro.
[Gursoy S et al; Eur J Anaesthesiol 23 (6): 496-500 (2006)] **PEER REVIEWED** PubMed Abstract