Download The antagonism of nondepolarizing neuromuscular

The antagonism of nondepolarizing
neuromuscular blockade
TOM E. JENKINS, CRNA
Winston-Salem, North Carolina
The antagonism of the nondepolarizing
neuromuscular blockade is accomplished many
times in a given day. Fortunately, the
incidents of complications are low. If they do
occur and are not recognized and treated
properly, however, the results can be serious.
In this article, the author reviews the
curariform group of drugs, anticholinesterases,
and anticholinergics, evaluating the
antagonism of the nondepolarizing
neuromuscular blockade.
The return of normal neuromuscular function,
following paralysis with one of the nondepolarizing neuromuscular blockers, is a complex polypharmacological occurrence. The anesthetist must
not only administer the proper mixture of anticholinesterase and anticholinergic drugs; but, he
or she must also be able to assess the effectiveness
of the reversal.
The anesthetist must also be cognizant of the
possible complications that may ensue. The antagonism of a neuromuscular blockade cannot be
accomplished safely and effectively without knowledge of drugs and their sites of action.
The neuromuscular junction
The neuromuscular junction (Figure 1) is
the site of action for nondepolarizing muscle relaxants and their antagonists. At this point, the
452
efferent nerve fiber invaginates the muscle membrane. The electrical impulse from the nerve fiber
is transmitted to the muscle by acetylcholine. The
acetylcholine stimulates the receptor sites of the
muscle membrane, causing the muscle to contract.
Before the acetylcholine can cause a second action
potential, cholinesterase hydrolyses it.1
The curariform drugs
To produce deep muscular relaxation by
means of an inhalational anesthetic, it is usually
necessary to establish a depth of anesthesia in
which the medullary centers of respiration and
circulation are severely depressed. The use of the
neuromuscular blocking drugs makes it possible
to obtain adequate surgical relaxation with a
much lower concentration of inhalational anesthetics. The classification and modes of action of these
drugs are divided into two types: those which
prevent depolarization of the motor end-plate and
those which depolarize it.2
The curariform group of drugs prevents depolarization of the muscle fiber. These include
tubocurarine (dTc), gallamine, and pancuronium.
They bind to the receptor sites, preventing acetylcholine from combining with the receptors and
creating an action potential across the neuromuscular junction.1 Until 75-85% of the receptors
are blocked, there is no interference with neuromuscular transmission.
Clinically, we view the action of the curari-
Journal of the American Association of Nurse Anesthetists
Figure 1.
Neuromuscular Junction
I
Muscle nuclei
form drugs as resembling an iceberg. Most of the
receptors must be blocked before there is any
decrease in twitch response. The anesthetist works
at the top 20-25% of the iceberg; only this small
fraction of receptors must be reblocked as the
curariform agent is eliminated. 3
The onset of neuromuscular blockade is first
seen as motor weakness. Depending upon the
dosage given, this weakness progresses until the
muscle becomes totally flaccid and inexcitable.
Small, rapidly moving muscles (such as those of
the toes, eyes, and ears) are involved before those
of the limbs, neck and trunk. Finally, the intercostals and diaphragm are paralyzed. Facial and
diaphragmatic muscles are the first to recover,
followed in order by muscles of the legs, arms,
shoulder girdle, trunk, larynx, hands, feet and
pharynx.4
The average duration of the curariform drugs
is 20-30 min.5 The curariform blockade may be
enhanced by inhalation anesthetics, acidosis, certain antibiotics and idiosyncratic response of the
patient.
October/1980
Anticholinesterases
Anticholinesterases inhibit the action of
cholinesterase in acetylcholine hydrolysis. The result is the re-establishment of neuromuscular transmission. 5 Randall and Lehmann0 found that the
anticurare action of phenyltrialkalammonium compounds could not be attributed to cholinesterase
inhibition. They suggested that a direct acetylcholine-like stimulant action of anticholinesterases
could account for this activity.
There are two other possible reasons for the
anticurare action of the anticholinesterases. One
may be the direct stimulation of the motor nerve
terminal, which causes an increased release of
acetylcholine. The second may be the displace.
ment of the curariform agent from the receptor
site, permitting the redistribution, elimination
and destruction of the curariform drug. 7
Edrophonium is a rapid-acting phenyltrialkalammonium compound. Its effects are manifested
in 30-60 sec when administered intravenously.
The peak effect is seen in 1-2 min and lasts from
5-10 min. The recommended dose for antagonism
of a competitive blockade is 0.3 mg/kg. 5
453
Katz 7 demonstrated that, in more than half of
curarized patients, edrophonium failed to restore
twitch height to control with usual doses (10-20
mg). Artusio and associates 8 reported that unless
the respiratory minute volume was 20% of control
or greater, edrophonium could not fully reverse
the effects of tubocurarine. Doughty and Wylie 9
found that, in patients who receive 140-160 mg of
gallamine, edrophonium (20-40 mg) could not
adequately restore respiratory function.
Katz 7 attempted to demonstrate recurarization
in ten patients using edrophonium. The twitch
was abolished with tubocurarine, using a 0.1 mg/
kg test dose, followed by 0.5 mg/kg curarization
dose. An abrupt increase in twitch height was
observed in every patient following administration
of 10 mg of edrophonium. This in turn was followed by either a return to a spontaneous rate of
recovery, or by a slightly greater rate of recovery.
In no patient did the twitch height (recorded for
another 45-70 min) decrease following the increase produced by edrophonium. It should be
pointed out, however, that edrophonium, when
used as the sole antagonist, is a poor choice of an
anticholinesterase due to its short duration of
action.
Neostigmine is the most widely used of the
anticholinesterases because of its antagonism of
nondepolarizing muscle blockade. It enhances cholinergic action by facilitating the transmission of
impulses across the neuromuscular junction, and
inhibits the destruction of acetylcholine by cholinesterase. It has been shown that neostigmine may
cause paralysis when given in the absence of a
curariform drug. This depolarizing muscle blockade has been demonstrated with doses of 3.75-5.0
mg of neostigmine. The presence of even the
smallest quantity of a curariform drug will normally prevent such an occurrence. 10
The inhibition of the destruction of acetylcholine not only affects the skeletal muscles, but
it also induces widespread activity throughout the
body. These cholinergic actions are of such a
variety that they are placed into two main groups,
nicotinic and muscarinic. (Table I).
To have an antagonist with as few side effects
as possible, an antimuscarinic is administered
with, just after, or just prior to the injection of
the anticholinesterase. If an overdose of the anticholinesterase is given or the effect of the antimuscarinic drug does not last as long as the anticholinesterase, a cholinergic crisis may occur
(Table II). 4
Foldes 11 published a review of the pharmacology of neuromuscular blocking agents in man.
This study demonstrates that the full effects of
neostigmine are reached within 2-4 min. Others
have found the duration of neostigmine is at least
60 min and, at times, 150 min.12. 13 A significantly
larger amount of neostigmine is needed to antagonize a blockade produced by gallamine than to
antagonize a blockade produced by tubocurarine
or pancuronium. 14
In Katz' 1967 study,7 a dosage of 2.5 mg
neostigmine was adequate for reversal of 85% of
the patients paralyzed with tubocurarine, and all
the patients paralyzed with pancuronium. If an
initial dose of 2.5 mg of neostigmine does not
antagonize the neuromuscular blockade after 5
min., it is recommended that, small doses of neostigmine be given until a total of 5 mg has been
Table II
Cholinergic Crisis
Muscarinic
Salivation
Lacrimation
Diaphoresis
Bradycardia
Hypotension
Bronchoconstriction
Nicotinic
Muscle weakness
Fasiculation
Skeletal muscle paralysis
Respiratory paralysis
(Goodman and Gilman, 1974)
Table I
Cholinergic Receptors
Muscarinic
1. Stimulation or inhibition of smooth
muscles
2. Stimulation of exocrine glands
3. Slows cardiac conduction
4. Decreases myocardial contractility
Nicotinic
1. Stimulates autonomic ganglia (sympathetic and
parasympathetic)
2. Stimulates adrenal medulla to release catecholamines
3. Stimulates skeletal muscles at the motor end plate
(Maree, S. Cardiovascular Pharmacology: A Manual for Nurse Anesthetists)
454
Journal of the American Association of Nurse Anesthetists
administered. More than 5 mg will increase the
likelihood of creating a depolarizing neostigmine
blockade.
Pyridostigmine facilitates the transmission of
impulses across the neuromuscular junction by inhibiting the hydrolysis of acetylcholine by cholinesterase. Katz15 found pyridostigmine to be more
effective than edrophonium and equal to or more
effective than neostigmine because there is a wider
margin of safety and the oropharyngeal secretions
are less.
Pyridostigmine was found to cause less bradycardia, and with it the incidences of arrhythmias
were less as compared to neostigmine. 16 The anticurare dose of pyridostigmine is 0.15-0.25 mg/kg.
An average dose of 0.2 mg/kg is usually sufficient.5
If a repeat dose is needed, it should be one-fifth
of the original dose but not to exceed 2 mg. 1 5 The
duration of action for pyridostigmine is longer
than that of neostigmine; the onset of action for
pyridostigmine is seen in 14-15 min.
Anticholinergics
Reversing neuromuscular blockade by the use
of peripherally-acting anticholinesterases has always entailed the use of an anticholinergic agent.
The anticholinergic protects against the muscarinic
effects of the anticholinesterase. 7
Atropine is a tertiary amide having two actions. The most important therapeutic action is
the inhibition of smooth muscles and glands innervated by the post-ganglionic cholinergic nerves.
Atropine also has a central nervous system activity."' The timing of atropine administration in
conjunction with an anticholinesterase has been a
long-standing controversial issue.
Most anesthetists are aware of the confusion
and irrational behavior that can result from the
persistence of the effect of the belladonna alkaloids, such as atropine. It is not widely appreciated
that these drugs may, in some cases, be responsible
for the patient failing to awaken after anesthesia
has been discontinued. This syndrome results because the anticholinergic effects of belladonna
drugs within the central nervous system are completely unopposed, giving rise to the signs and
symptoms of a central anticholinergic syndrome
(Table III).'" All of these effects, including prolonged stupor following the use of the belladonna
drugs as part of the reversal, can be quickly terminated by an injection of physostigmine.' 7
Glycopyrrolate, a quaternary ammonium, does
not cross the blood-brain barrier, and therefore,
exerts no influence on the central nervous system
October/ 9S0
Table III
The Central Anticholinergic Syndrome
Agitation
Restlessness
Confusion
Combativeness
Plucking & picking
Uncooperativeness
Hysterical behavior
Memory disturbance
Visual aberration
Visual hallucinations
Auditory hallucinations
Delirium
Dysarthria
Vertigo
Atoxia
Hyperreflexia
Opisthotonos
Convulsions
Stupor
Coma
(Longo, 1966)
(CNS). Glycopyrrolate also diminishes the volume
and free acidity of gastric secretion and controls
excessive pharyngeal, tracheal and bronchial secretion. The onset of action from intravenous injection of glycopyrrolate is seen within one minute.
The recommended dose of glycopyrrolate for its
antimuscarinic effects is 0.2 mg (1.0 ml) for each
1.0 mg of neostigmine or the equivalent dose of
pyridostigmine. 18
A 1977 study of glycopyrrolate revealed that
the drug provides equal short-term and better
long-term protection against cholinergic-induced
bradycardia than that provided by atropine. 7
There is also a considerable reduction in the degree of initial tachycardia produced by atropine
when given in equipotent doses. When 0.2 mg of
glycopyrrolate was given intravenously to healthy,
awake volunteers, it did not cause a significant
tachycardia but did cause a significant reduction in
salivary secretions. 2 0
Antagonist compounds
The ideal antagonist for neuromuscular blockade should be effective against the nondepolarizing
muscle relaxants. Its effects should develop rapidly,
preferably following a single dose. The duration
should be long enough to prevent any "recurarization." This reversing compound should have a
selective action at the pharmacological receptor
site. The side effects of the compound should also
be pharmacologically reversible by appropriate
agents.
The ideal compound, therefore, should consist of one or more reversible anticholinesterases
and one or more plarasympatholytic (atropine-like)
agents. This agent's sole purpose is to antagonize
the undesirable side effects of the anticholinergic
agents. 21
Neostigmine and atropine in combination is
perhaps the most commonly used anticholines-
45 5
terase/anticholinergic pairing. Rosner and associates22 found that both the previous and concomitant administrations of atropine with neostigmine were safe, provided that oxygenation was
maintained. They recommend 20 mcg/kg of neostigmine mixed with atropine 6 mcg/kg, given
slowly over 60 sec. The simultaneous administration is a safe and effective means to terminate a
nondepolarizing neuromuscular blockade 23
It should be pointed out, however, that cardiac arrest and even death have been reported with
the use of atropine/neostigmine mixture. It has
been postulated that the cardiac arrests can be the
result of the cholinergic action of neostigmine and
the initial central vagal stimulation of atropine. A
sudden, parasympathetic dominance may also be
responsible for the arrests. 20
Theoretically, because the doses of belladonna
drugs used for reversal are large and are given at
the end of the surgical procedure, the chance that
the patient will show signs and symptoms of a central anticholinergic syndrome is certainly enhanced. 17
The short duration of action of atropine is
perhaps its biggest disadvantage (Figure 2).10 This
difference in length of action will leave the muscarinic receptors vulnerable to the effects of neostigmine. This parasympathetic dominance could
cause bradycardia, which could lead to hypotension and shock. The increased muscarinic tone has
the possibility of placing certain surgical patients
in undue risk. In 1968, Bell and Lewis reported a
high incidence of surgical bowel anastomosis leaks
(36%) in patients receiving neostigmine. 2 4*
Neostigmine and glycopyrrolate. Klingenmaier
and others found that the combination of glycopyrrolate and neostigmine caused small and slow
changes in heart rate. 25 Furthermore, this compound caused less arrhythmias than did the neostigmine-atropine mixture. The small changes in
heart rate were attributed to the parallel onset of
action of the two components. 20 (See Figure 3.1 6)
Glycopyrrolate offers the same protection against
neostigmine-induced bradycardia as does atropine
with less tachycardia.
The reversing compound should contain 0.2
mg of glycopyrrolate for each 1 mg of neostigmine. 28 The rapid intravenous injection of this
compound has been found to be as effective, and
is safer and smoother than the neostigmine-atropine combination. 25
Pyridostigmine and glycopyrrolate. When pyridostigmine was substituted for neostigmine,
using atropine to combat the muscarinic effects of
pyridostigmine (Figure 418), the resulting mixture
did not work well. It was effective for the antagonism of neuromuscular blockade but had too
many unwanted side effects, primarily due to the
difference in onset and duration of action of the
two agents.
Gyermek 80 found that the combination of pyFigure 3.
Glycopyrrolate and Neostigmine
Schematic pattern (effect vs. time) of changes inheart
rate when glycopyrrolate and neostigmine are combined (Gyermek, 1977).
*Editor's note: More recent findings have refuted this condition.
Figure 2.
Atropine and Neostigmine
Schematic pattern (effect vs. time) of changes in heart
rate when atropine and neostigmine are combined
(Gyermek, 1977).
456
Figure 4.
Atropine and Pyridostigmine
Schematic pattern (effect vs. time) of changes in heart
rate when atropine and pyridostigmine are combined
(Gyermek, 1977).
Journal of the American Association of Nurse Anesthetists
ridostigmine and glycopyrrolate approached the
ideal compound for antagonism of neuromuscular
blockade. Both agents have approximately the same
onset of action. The pyridostigmine bradycardia is
well paralleled with the glycopyrrolate tachycardia
(Figure 51 "). This factor and others including the
decrease in arrhythmias (due to the mild muscarinic action of pyridostigmine),2 8 the lack of central nervous system effects, and greater antisialogogue effects make this compound very desirable
for the antagonism of the nondepolarizing neuromuscular blockade. 2 7 The disadvantage of this
compound lies in its slow (12-15 min.) onset of
action. Compensation for this can be made by
simply initiating the reversal process a little earlier.
Winnie and others1 7 note that with 10 mg of
pyridostigmine, a dose of 0.3 mg glycopyrrolate is
optimal. With each increase of 2.5 mg of pyridostigmine, 0.1 mg of glycopyrrolate should be added
to the mixture.
Gyermek's studies 30 show that the pyridostigmine-glycopyrrolate compound provides a smooth,
safe and effective means of antagonizing a neuromuscular blockade produced by tubocurarine.'
Winnie and others17 have found the same to be
true for the antagonism of blockades produced
with pancuronium.
Pyridostigmine, endrophonium and glycopyrrolate. Gyermek's studies'" also indicate that there
is a need to increase the onset of action of the antagonist mixture. If edrophonium is added to the
mixture, the onset of action will be faster. Of the
pharmacological agents presently available, the
ideal reversal mixture should contain the following agents: edrophonium, pyridostigmine, and
glycopyrrolate.
Suitable amounts of these ingredients can
easily be mixed in one syringe using 1.5-2.0 ml of
edrophonium, pyridostigmine and glycopyrrolate
(edrophonium 0.2-0.4 mg/kg; pyridostigmine 0.10.16 mg/kg; glycopyrrolate 0.004-0.006 mg/kg).
For an average patient weighing 70 kg, usually
4-6 ml of this mixture injected slowly will antagonize the nondepolarizing neuromuscular blockade.
Evaluation of antagonism
Until short-acting nondepolarizing relaxants
are available, the anesthetist must antagonize the
long-acting neuromuscular blockers. Evaluating the
effects of an antagonist regimen can be accom-
Figure 5.
Glycopyrrolate and Pyridostigmine
Schematic pattern (effect vs. time) of changes in heart
rate when glycopyrrolate and pyridostigmine are
combined (Gyermek, 1977).
plished in many ways. Katz1 5 defines the criterion
for adequate reversal of the nondepolarizing muscle relaxants as: the twitch height returning to the
control level and a well-sustained tetanic contraction at 30 Hertz.
Walts, Levin and Dillon8' found that when
there was 90% recovery of twitch force, 16 out of
20 patients had 90% or better recovery of vital
capacity. The other four had 80.5% recovery of
vital capacity. (The vital capacity allows the patient enough lung volume to deep breathe and
cough.) The minute volume may be adequate before vital capacity is restored.8 2
Others recommend the use of the "train-offour"* for evaluating the return of normal function of the neuromuscular junction.8 3 This method
does not require a central response nor does it
cause the degree of discomfort usually associated
with tetanic stimulation. If the fourth response is
60% of the first, the respiratory muscular function
should be more than adequate. However, 70% of
the receptors can be occupied with nondepolarizing muscle relaxants, and a normal "train-of-four"
may still be demonstrated.8 4
Miller3" has compared the reaction of the per.
ipheral nerve stimulator to muscle function and
the number of receptors occupied by nondepolarizing muscle relaxants (Table IV). He showed that
a normal "train-of-four" correlates with 70-75%
of receptor occupancy. This also paralleled a normal expiratory flow rate and vital capacity.
The ability to sustain contraction in response
to a high frequency tetanic stimulation (100 Hertz
or more) is probably the most sensitive index of
antagonism of neuromuscular blockade, but is too
8"
painful for general clinical use.
Factors that influence antagonism
There are many factors which determine the
degree and speed of recovery of a nondepolarized
*Editor's note: In the April 1980 issue of the AANA Journal, Dr. Richard Jones expanded on the advantages of the "train of
four" technique in his article on the Use of the Peripheral Ner'e Stimulator.
October/1980
457
Table IV
Suggested correlations between test of Neuromuscular Transmission
Estimated Receptors
Occupied (%)
Peripheral Nerve Stimulation
Ventilation
Reduced twitch height and sustained
tetanus at 30 Hz for five seconds.
Normal tidal volume
75-80
Normal train-of-four
Normal expiratory flow rate and
vital capacity
70-75
Sustained tetanus at 100 Hz for
five seconds
Normal inspiratory flow rate
50
Sustained tetanus at 200 Hz for
five seconds
Normal head lift and hand grip
test
33
(Miller, 1976)
Table V
Interaction of antibiotics, muscle relaxants, neostigmine & calcium
Neuromuscular block from
antibioticalone, antagonized
by:
Increase in
neuromuscular
block of:
Antibiotics
Neostigmine
Calcium
D TC
V
muscle relaxants, neostigmine & calcium
Table
Interaction
Neomycinof antibiotic=,
Sometimes
Sometimes
Yes
Streptomycin
Sometimes
Sometimes
Yes
Gentamicin
Sometimes
Yes
Yes
Kanamycin
Sometimes
Sometimes
Yes
Paromomycin
Yes
Yes
Yes
Viomycin
Yes
Yes
Yes
Polymyxin A
No
No
Yes
Polymyxin B
No*
No
Yes
Colistin
No
Sometimes
Yes
**
Tetracycline
No
Yes
Lincomycin
Partially
Partially
Yes
Clindamycin
Partially
Partially
Yes
Neuromuscular block from
antibiotic and tubocurarine
antagonized by:
SCH
Neostigmine
Calcium
Yes
Yes
Usually
Yes
Sometimes
Sometimes
Yes
Yes
No
No*
No
Partially
Partially
Partially
Usually
Usually
Yes
Sometimes
Yes
Yes
No
No
Sometimes
Partially
Partially
Partially
**
Yes
**
**
**
Yes
Yes
No
**
**
* Block augmented by neostigmine
** Not studied
(Miller, 1976)
blockade. At the time the reversal is given, the
degree of spontaneous recovery will determine the
speed of complete antagonism. The amount of
spontaneous recovery appears to be a far more important factor in the quantity of antagonist administered than does the total dose of muscle relaxant
given. 40
In studying neostigmine antagonism of tubocurarine-induced neuromuscular blockade, Miller and others" have found that respiratory acidosis and metabolic alkalosis limit and oppose neostigmine's antagonistic effects. This may be seen
when a narcotic is given immediately postoperatively, and the patient hypoventilates. 88
458
Some believe that recurarization may occur in
patients whlo have been hypothermic. McKlveen 3"
was unable to confirm this hypothesis in a study
of dogs. From studies of hypothermia and its effects
on the antagonism of neuromuscular blockade, it
appears that hypothermia, per se, does not affect
the ability or the amount of anticholinesterase
needed.
Still others believe that hypothermia decreases
the ability of the curariform drugs to block the
receptors. If excess amounts of the curariform
drugs are given, it is possible to create a neuromuscular blockade too intense for the average
Journal of the American Association of Nurse Anesthetists
antagonist regimen to reverse.35 This is easily done
in patients who are anephric.
Miller and Cullen 40 feel that the important
measures in preventing "recurarization" are the
following: (1) the use of small doses of nondepolarizing muscle relaxants in combination with
an inhalation agent to potentiate their effects, (2)
more precise monitoring of the neuromuscular
blockade, and (3) the use of pyridostigmine as an
antagonist of the neuromuscular blockade.
Several articles have reviewed the effects of
electrolyte imbalance on the antagonism of a nondepolarizing blockade. These articles report on a
variety of effects, therefore making it difficult to
draw concrete conclusions. Studies of dehydrated
patients who have electrolyte imbalances are
needed to clarify these confusing, and often opposing, opinions.3 5
The relationship of potassium, calcium, and
magnesium to neuromuscular blockade and its
antagonism appears to be of prime interest. Perhaps, the best assumption that can be made now
is that there may be unfamiliar responses to the
curariform drugs and their antagonists in patients
who present with electrolyte imbalances.
It has been well documented that certain antibiotics enhance nondepolarizing muscle blockade
(Table V).35 The particular mechanism of the
antibiotic-induced neuromuscular blockade is not
known,4 1 but is probably different for various antibiotics. Becker and Miller 4 2 suggest the administration of 5 mg/70 kg of neostigmine with 2 mg
of atropine, in divided (oses, to antagonize an
antibiotic-enhanced or induced neuromuscular
blockade.
If this regimen fails, I gm/70 kg calcium
chloride may be given in divided doses, with careful ECG monitoring. If these two efforts still fail
to produce antagonism, ventilatory assistance
should be continued until the neuromuscular
blockade spontaneously terminates.
Conclusions
Until such time as a short-acting, nondepolariz-
ing mscle relaxant is availab~le, the anesthetist
must antagonize thle long-acting, nondepolarizing
drugs. The antagotnit cormpond wrhich is most
effective and h~as t~e least side effects is a mixtre
of edrophon im, pyridostigmine and glycopyrrolate.
The effectiveness of the antagonism is best seen
in the return of adeqate hand grip and the patient's ability to lift hiis or her head. Both of these
measres of nelromuscullar
blockade correspond
withi the adeqacy of respiratory function.
October/1 9804
If a reasonable attempt to restore normal function of the neuromuscular junction fails, ventilatory support should be continued. There is no report of permanent paralysis from the curariform
group of drugs. In the well-oxygenated patient, the
tincture of time will antagonize the most stubborn
of neuromuscular blocks.
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JReiec. October:
16-24.
(1) Phyvsiinrs' D~sk Referenrc. 1977. Medlical Economics Company. Oraell, New j-rsey.
(19)) I.og~o,
V. 1966. Behlavioral
andi Electrocncephalorahic
Effects of Ano~ie andl Related Compounds. Phrnacol Rev.
1: 96T-91.
(20) Mirakhlr, R.. Dundec, J. andi Clark, R. 1977. Glycopyrrolate-Nost Kigine Mixtire for Antagonism of Nourouscular
lockaec:
Comparisln with Atropine-Neostimine
Mlixture. lnrt.
. Atnaesth. 49: 8325.
(21)
crmelk,
I.. 1978il. 'Ihe
Glycopyrrolat-Pyiost igmine
Comnationl. A cstesiology Revie.
March: 19-22.
..
(-Iulbocurarine.
459
Rosner, V., Kepes, E. and Foldes, F. 1971. The Effects of
Neostigmine on Heart Rate and Rhythm. Brit.
(22)
(38)
Hughes, R.
Balance on Neuromuscular
1. Anaesth. 43: 1066.
42: 658-668.
(39) McKlveen,
(23) Ovassapian, A. 1969. Effects of Administration of Atropine
and Neostigmine in Man. Anesth. Analg. 48: 219-223.
(24)
Bell, C.
and
Lewis.
C.
1968.
Effects of Neostigmine
on
Integrity of Ileorectal Anastomosis Brit. Med. J.
(25)
son,
Klingenmaier.
R.
Mixture
1972.
R., Thompson, D. and WatBlockade with a
Neuromuscular
H., Bullard,
Reversal
of Neostigmine
of
and
Glycopyrrolate.
Anesthesia
and
1973.
(26) Ramamurthy, S., Shaker, M. and Winnie, A. 1972. Glycopyrrolate as a Substitute for Atropine in Neostigmine Reversal of Muscle Relaxant Drugs. Canadian Anaesthesiology So-
Jr.,
Blockade
Sokol,
M.,
Absence of Recurarization
in
Gergis,
Upon
Acid-base
Cats. Brit. J.
S.
and
Anaesth.
Dretchen,
Rewarming.
K.
Anesthesi-
ology. 38: 153-156.
(40) Miller, R. and Cullen, D. 1976. Renal Failure and Postoperative Respiratory Failure: Recurarization? Brit. J. Anaesth.
48: 253-256.
(41)
Pittinger, C., Eryasa, Y. and Adamson,
R. 1970. Antibiotic
Paralysis. Anesthesia and Analgesia. 49: 487-501.
Induced
Analgesia. 51(3) : 468.472.
Influence of Changes in
1970. The
Atropine and
(42)
Becker,
L. and Miller, R.
Nondepolarizing
Neuromuscular
1975. Clindamycin
Enhances a
Blockade. Abstract
of Scientific
Papers. 1975. Annual Meeting of the A.S.A. 203-204.
ciety Journal. 19(4): 399-411.
(27) Ostheimer, G. 1977. A Comparison of Glycopyrrolate and
Atropine During Reversal of Nondepolarizing Neuromuscular
Block with Neostigmine. Anesthesia and Analgesia. 56(2): 182-
ACKNOWLEDGMENT
186.
as a
(28) Zsigmond, E. 1972. Pyridostigmine: A Safe and Effective
Anesthetized Man. Clinical
Antagonist to d-Tubocurarine in
Pharmacology and Therapeutics. 13 (1): 155.156.
The author wishes to thank Thomas Irving, M.D., for his
and assistance; Charles Gregg, MI). for his assistance
support
technical proof reader; Toni Brock, CRNA, for her photography; and Gail Jenkins, grammatical proofreader, typist and
wife.
(29) Miller, R., Van Nyhuis, L., Eger, E., Vietz, T. and Way, W.
1974. Comparative Times to Peak Effect and Duration of Action
of Neostigmine and Pyridostigmine. Anesthesiology. 41(1): 27-33.
(30) Gyermek, L. 1975. Clinical Studies in Reversal of the Neuromuscular Blockade Produced by Parcuronium Bromide. I.
The Effects of Glycopyrrolate and Pyridostigmine.
Current
Therapeutic Research. 18 (3): 377-385.
(31) WaIts, L., Levine, N. and Dillon, J.
1970. Assessment of
Recovery from Curare. JAMA 213: 1894-1896.
(32)
Perotti, J.
1977. A Review of d-Tubocurarine
in
Clinical
Usage. AANA Journal 45 (2): 182-185.
(33) Ali, H., Wilson, R., Savarese, J. and Kitz, R. 1975. The
Effects of Tubocurarine on Indirectly Elicited Train-of-Four
Muscle Response and Respiratory Measurements in
Humans.
I)
Brit. J. Anaesth. 47: 570-573.
(34) Wand, B. and Wand, D. 1972. The Relationship Between
the Response to "Train-of-Four" Stimulation and Receptor Occlusion
during Competitive
ology. 37: 413-416.
Neuromuscular
Block.
Anesthesi-
(35) Miller, R. 1976. Antagonism of Neuromuscular Blockade.
Anesthesiology. 44 (4) : 318-328.
(36) Gissen, A. and Katz, R. 1969. Twitch, Tetanus, and Posttetanic Potentiation as Indices of Nerve Muscle Block in Man.
Anesthesiology. 30: 481-487.
(37)
Miller, R., Van Nyhuis, L., Eger, E. and Way, W. 1975.
Effects of Acid-base Balance on Neostigmine Antagonism
d -Tubocurarine-induced Neuromuscular Blockade. Anesthe-
The
of
siology. 42: 377-383.
AUTHOR
Ton Jenkins, CRNA, holds an Associate Degree in Applied
Science (Nursing) from Pitt Technical Institute in Greenville,
North Carolina. He is a recent gradIuate of the Bowman Gray
School of Medicine of Wake Forest University and North Carolina Baptist
Hospital
School
of Nurse Anesthesia,
and
is
cur-
rently practicing in North Carolina.
'Ihis paper was researched when Mr. Jenkins was a senior
student in anesthesia; it was sulbnitted at the recommendation
of Sandra M. Maree, CRNA, BS, assistant director of the North
Carolina
Baptist Hospital
School of Nurse Anesthesia.
Journal of the American Association of Nurse Anesthetists
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I
InnOVar®Injection
1*
FOR INTRAVENOUS OR INTRAMUSCULAR
USE ONLY
The two components of INNOVAR injection, fentanyl and droperidol, have different pharmacologic
actions. Before administering INNOVAR injection, the user should familiarize himself with the
special properties of each drug. particularly the widely differing durations of action.
DESCRIPTION: Each ml. contains (in a 1:50 ratio):
Fentanyl .............
........ ........... ....................
...............
0.05 mg.
as the citrate
Warning: May be habit forming
Droperidol ...
. ................................................................
.............
2.5 mg.
Lactic acid for adjustment of pH to 3.5 ± 0.3
ACTIONS: INNOVAR injection is a combination drug containing a narcotic analgesic, fentanyl, and a
neuroleptic (major tranquilizer), droperidol. The combined effect, sometimes referred to as neuroleptanalgesia, is characterized by general quiescence, reduced motor activity, and profound analgesia;
complete loss of consciousness usually does not occur from use of INNOVAR injection alone. The
incidence of early postoperative pain and emesis may be reduced.
A. Fentanyl is a narcotic analgesic with actions qualitatively similar to those of morphine and meperidine. Fentanyl in a dose ofO. 1 mg. (2.0 ml.) is approximately equivalent in analgesic activity to 10 mg.
of morphine or 75 mg. of meperidine. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation, associated with narcotic analgesics, may last
longer than the analgesic effect. As thedose of narcotic is increased, the decrease in pulmonary exchange
becomes greater. Large doses may produce apnea. Fentanyl appears to have less emetic activity than
other narcotic analgesics.Histamineassays,and skin wheal testing in man, as well as in viv testing in
dogs indicate that histamine release rarely occurs with fentanyl.
Fentanyl may cause muscle rigidity, particularly involving the muscles of respiration.It may also produce
other signsand symptoms characteristic of narcotic analgesicsincluding euphoria, miosis, bradycardia,
and bronchoconstriction.
The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, maximal analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration
of action of the analgesic effect is 30 to 60 minutes fter a single I. V. dose of up to 0.1 mg. Following
intramuscularadministration, the onset of action is from seven to eight minutes, and the duration of
action is from one to two hours.
As with longer-acting narcotic analgesics, the duration of the respiratory depressant effect of
SUBLIMAZE (fentanyl) may be longer than the analgesic effect. The following observations have been
reported concerning altered respiratory response to CO stimulation following administration of fentanyl
to man:
I. DIMINISHED SENSITIVITY TO CO STIMULATION MAY PERSIST LONGER THAN
DEPRESSION OF RESPIRATORY RATE. Fentanyl frequently slows the respiratory rate but this effect
is seldomnoted for over 30 minutes regardlessof the dose administered.
2. Duration and degree of respiratory depression is dose related.
3. The peak respiratory depressant effect of a single intravenous dose of fentanyl is noted 5 to 15 minutes
following injection.
4. Altered sensitivity to CO stimulation has been demonstrated for up to four hours following a single
intravenousdose of 0.6 mg. (12 ml.) fentanylto healthy volunteers.
Seealso WARNINGS and PRECAUTIONS concerning respiratory depression.
B. Droperidol producesmarked tranquilization and sedation. It also produces an antiemetic effect as
evidenced by the antagonismof apomorphine in dogs. It potentiates other CNS depressants. It also
produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor
effect of epinephrine. Droperidol can produce hypotension and decreased peripheral vascular resistance.
It may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the
incidence of epinephrine-induced arrhythmias bu t does not prevent other cardiac arrhythmias. The
onset of action is from three to ten minutes following intravenous or intramuscular administration. The
full effect, however, may not be apparentfor 30 minutes. The duration of the sedative and tranquilizing
effects generally is two to four hours. Alteration of consciousness may persist as long as 12 hours. This is
in contrast to the much shorter duration of fentanyl.
INDICATIONS: INNOVAR injection is indicated to produce tranquilization and analgesia for surgical
and diagnosticprocedures. It may be used as an anestheticpremedication, for the induction of anesthesia.,
and as an adjunct in the maintenanceof general and regional anesthesia. If the supplementation of
analgesia is necessary, SUBLIMAZEa (fentanyl) injection alone rather than the combination drug
INNOVAR injection, shouldusually be used; see Dosage and AdministrationSection.
CONTRAINDICATIONS: INNOVAR injection is contraindicated in patients with known intolerance
to either component.
WARNINGS: AS WITH OTHER CN6 DEPRESSANTS, PATIENTS WHO HAVE RECEIVED
INNOVAR INJECTION SHOULD HAVE APPROPRIATE SURVEILLANCE. RESUSCITATIVE
EQUIPMENT AND A NARCOTIC ANTAGONIST SHOULD BE READILY AVAILABLE TO MANAGE APNEA.
See also discussionof narcoticantagonistsin PRECAUTIONS and OVERDOSAGE.
FLUIDS AND OTHER COUNTERMEASURES TO MANAGE HYPOTENSION SHOULD ALSO BE
AVAILABLE.
The respiratory depressant effect of narcotics persists longer than the measured analgesic effect. When
used with INNOVAR injection, the total dose of all narcotic analgesics administered should be considered by the practitioner before ordering narcotic analgesics during recovery from anesthesia. It is recommended that narcotics, when required, be used in reduced doses initially, as low as (4 to A those
usually recommended.
INNOVAR injection may cause muscle rigidits, particularly involving the muscles of respiration. This
effect is due to the fentanyl component and is related to the speed of injection. Its incidence can be
reduced hy the use of slow intravenous injection. Once the effect occurs, it is managed by the use of
assisted or controlled respiration and, if necessary, by a neuromuscular blocking agent compatible with
the patient's condition.
Drug Dependence: Fentanyl, the narcotic analgesic component, can produce drug dependenceof the
morphine type and therefore has the potentialfor being abused.
Severe and unpredictable potentiation by-MAO inhibitors has been reported with narcotic analgesics.
Since the safety of fentanyl in this regard has not been established, the use of INNOVAR injection or
SUBLIMAZE (fentanyl) in patients who have received MAO inhibitors within 14 days is not recommended.
Head Injurls and Increased Intrracenial Pressure: INNOVAR injection should be used with caution in
patients who may be particularly susceptible to respiratory depression such as comatose patients who
may have a head injury or brain tumor. In addition, INNOVAR injection may obscure the clinical course
of patients with head injury.
Usage in Children: The safety of INNOVAR injection in children younger than two years of age has not
been established.
Usage Ia Prgnancy: The safeuseof INNOVAR injection hasnot beenestablished with respectto possible adverse
effects uponfetal development. Therefore,it should be usedin womenof childbearing potential only when,in the judgment of the physician, the potential benefits outweigh the possible hazards.
Thereareinsufficient dataregarding placentaltransferandfetaleffects; therefore,safety for the infant in
obstetrics hasnot been established.
PRECAUTIONS: Theinitial doseof INNOVAR injection should be appropriately reducedIn elderly,
debilitated and other poor-risk patients. Theeffectof theinitial doseshould be considered in determining
incremental doses.
Certainforms of conduction anesthesia,
such asspinal anesthesia
andsomeperidural anesthetics,
can
alter respiration by blocking intercostalnerves,andcancauseperipheral vasodilation andhypotension
because of sympathetic
blockade. Through othermechanisms
(seeActions), fentanyl anddroperidol also
depress
respiration andblood pressure.
Therefore,whenINNOVAR injection is usedto supplement
these
forms of anesthesia,
the anesthetist
mustbe familiar with the physiological alterations involved, and be
prepared
to managethemin thepatientsselectedfor this form of anesthesia.
If hypotension occurs, the possibility of hypovolemia should be considered andmanagedwith appropriate parenteral
fluid therapy.Repositioning the patientto improve venousreturn to the heartshould be
considered whenoperative conditions permit. It should be notedthatin spinal and peridural anesthesia,
tilting the patientinto a headdown position etun
mayresult
a higher
level iofthemovng
anesthesia
than
as
nd isndesirable.
psitonigso
execisd
houdin h
ipai vesasCre
wedstosheheat.
well as impair venous return to the heart. Care should be exercised in the moving and positioning of
patients because of a possibility of orthostatic hypotension. If volume expansion with fluids plus these
other countermeasuresdo not correctthe hypotension, then the administration of pressor agents other
than epinephrine should be considered. Epinephrine may paradoxically decrease the blood pressurein
patientstreated with INNOVAR injection due to the alpha-adrenergic blocking action of droperidol.
The droperidol component of INNOVAR injection may decrease pulmonary arterial pressure. This fact
should be consideredby those who conduct diagnosticor surgicalprocedureswhere interpretationof pulmonary arterial pressure measurementsmight determinefinal managementof the patient.
Vital signsshouldbe monitored routinely.
INNOVAR injection, and SUBLIMAZE (fentanyl), should be used with caution in patientswith chronic
obstructive pulmonary disease, patients with decreased respiratory reserve, and others with potentially
compromised ventilation. In such patients narcotics may additionally decrease respiratory drive and
increaseairway resistance.During anesthesiathis can be managedby assistedor controlled respiration.
Postoperativerespiratory depression causedby narcotic analgesics can be reversed by narcotic antagonists. Appropriate surveillance should be maintained because the duration of respiratory depression of
doses of fentanyl (asSUBLIMA ZE (fentanyl) or INNOVAR) employed during anesthesia may be longer
than the duration of the narcotic antagonist action. Consult individual prescribing information (levallorphan. nalorphine and naloxone) before employing narcotic antagonists.
Should respiration be compromised by muscle rigidity, assistedor controlled respiration and possibly a
neuromuscular blocking agent will be required. The occurrenceof muscle rigidity is related to the speed
of intravenousinjection and the incidence can be reducedby slow intravenousinjection,
Other CNS depressantdrugs (e.g. barbiturates, tranquilizers, narcotics, and general anesthetics)have
additive or potentiating effects with INNOVAR injection. When patients have received such drugs, the
dose of INNOVAR injection required will be less than usual. Likewise, following the administration of
INNOVAR injection, the dose of other CNS depressantdrugsshould be reduced.
INNOVAR injection should be administeredwith caution to patients with liver and kidney dysfunction
because of the importance of these organs in the metabolism and excretion of drugs.
The fentanyl component may produce bradycardia, which may be treated with atropine; however,
INNOVAR injection should be used with caution in patients with cardiac bradyarrhythmias.
When the EEG is used for postoperative monitoring, it may be found that the EEG patternreturnsto normal slowly.
ADVERSE REACTIONS: The most common serious adverse reactions reported to occur with
INNOVAR injection are respiratory depression, apnes, muscular rigidity, and hypotension; if these
remain untreated, respiratoryarrest, circulatory depression orcardiac arrestcould occur.
Extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed following
administration of INNOVAR injection. Restlessness, hyperactivity and anxiety which can be either the
result of inadequate tranquilization or part of the symptom complex of akathisia may occur. When
extrapyramidal symptomsoccur, they can usuallybe controlled with anti-Parkinson agents.
Elevated blood pressure, with and without preexisting hypertension, has been reported following administration of INNOVAR injection. This might be due to unexplained alterationsof sympathetic activity following large doses; however, it is also frequently attributed to anesthetic or surgical stimulation during
light anesthesia.
Other adversereactionsthat have been reported are dizziness, chills and/or shivering, twitching, blurred
vision, laryngospasm, bronchospasm, bradycardia, tachycardia, nausea and emesis. diaphoresis.
emergence delirium, and postoperative hallucinatory episodes (sometimes associated with transient
periodsof mentaldepression).
Postoperativedrowsiness is alsofrequently reported.
DOSAGE AND ADMINISTRATION: Dosage should be individuali:ed. Some of the factors to be considered in determining dose are age, body weight, physicalstatus, underlying pathological condition, use
of other drugs, the type of anesthesia to be used. and the surgical procedureinvolved.
Vital signs shouldbe monitored routinely.
Most patients who have received INNOVAR injection do not require narcotic analgesics during the
immediate postoperativeperiod. It is recommendedthat narcotic analgesics, when required, be used initially in reduced doses, as low as '4 to ' those usuallyrecommended.
Usual Adult Dosage:
I. Premedication--(o be appropriately modified in the elderly, dbilitated, and those who have received
other depressantdrugs)-0. 5 to 2.0 ml. may be administeredintramuscularly 45 to 60 minutes prior to
surgerywith or without atropine.
II. Adjunct to General Anesthesia-Induction-I ml. per 20 to 25 pounds of btody weightmay be
administered slowly intravenously.Smaller doses may be adequate.
The total amount of INNOVAR injection administeredshould be carefully titrated to obtain the desired
effect basedon the individual patient's response.
There are severalmethods of administration of INNOVAR injection for induction of anesthesia.
A. Intravenous injection-To allow for the variable needs of patients INNOVAR injection may he
administered intravenously in fractional pu.ts of the calculated dose. With the onset of somnolence, the
general anesthetic may be administered.
B. Intravenousdrip-10 ml. of INNOVAR injection are added to 250 ml, of 5% dextrose in water and
the drip given rapidly until the onset of somnolence At that time, the drip may be either slowed or
stopped and the general anesthetic administered.
Maintenance-INNOVAR injection is not indicated as the sole agent for the maintenance of surgical
anesthesia It is customarily used in combination with other measuressuch as nitrous oxide-oxygen.
other inhalation anesthetics,and/or topicalor regionalanesthesia.
To prevent the possibility of excessive accumulationof the relatively long-actingdroperidol component,
SUBLIMAZE (fentanyl) aloneshould be used in increments of 0.025 to 0.05 mg. (0.5 to I.0 ml.) for the
maintenanceof analgesia in patients initially given INNOVAR injection as an adjunct to general anesthesia. (See SUBLIMAZE (fentanyl) package insert for additional prescribing information.) However, in
prolonged operations, additional 0,5 to 1.0 ml amounts of INNOVAR injection may be administered
with caution intravenously if changesin the patient'scondition indicate lightening of tranquilization and
analgesia.
III. Use Without a General Anesthetic in Diagnostic Procedures-Administer the usual I.M. premedication (0.5 to 2.0 ml.) 45 to 60 minutes before the procedure. Tb prevent the possibility of excessive
accumulation of the relatively long-acting droperidol component, SUBLIMAZE (fentanyl) aloneshould
be used in increments of 0.025 to 0.05 mg. (0.5 to 1.0 mi.) for the maintenance of analgesia in patients
initially given INNOVAR injection. (See SUBLIMAZE (fentanyl) packageinsert for additional information). However, in prolonged operations, additional 0.5 to 1.0 ml. amounts of INNOVAR injection may
be administeredwith caution intravenously if changes in the patient's condition indicate lightening of
tranquilization and analgesia.
Note: When INNOVAR injection is used in certain proceduressuch as bronchoscopy,appropriate topical
anesthesiais still necessary.
IV. Adjunct to Regional Anesthesia-I to 2 ml. may be administered intramuscularly or slowly
intravenouslywhen additional sedationand analgesia are required.
Usual Children's Desage:
I. Premedication---O25 ml. per 20 Ibs. body weight administeredintrunuscularli 45 to 60 minutes prior
to surgery with or without atropine.
II. Adjunct to General Anesthesia-The total combined dosefor induction andmaintenance averages0 5
ml. per 20 Ibs. bodyweight. Following induction with INNOVAR injection, SUBLIMAZE (fentanyl)
alonein a doseof (, to A that recommended
in the adult dosagesectionshould usually be usedwhen
indicated to avoid thepossibility of excessiveaccumulation of droperidol. However, in prolonged operations, additional increments of INNOVAR injection may be administered with caution when changesin
the patient's condition indicate lightening of tranquilization andanalgesia.
See Warnings and Precautionsfor use of INNOVAR injection with other CNS depressants,and in
patientswith alteredresponse.
OVERDOSAGE: Manlfestations: Themanifestations of INNOVAR injection overdosagearean extension of its pharmacologic actions.
Treatment: In the presenceof hypoventilation or apnea,oxygen shouldbe administered
and respiraion
should be assistedor controlled as indicated. A patentairway mustbe maintained; an oropharyngeal
airway or endotrachealtube might be indicated. If depressedrespiration is associatedwith muscular
rigidity, an intravenous neuromuscular blocking agentmight be required to facilitate assistedor controlled respiration. The patient should be carefully observedfor 24 hours; bodywarmth and adequate
fluid intake should be maintained. If hypotension occurs and is severe or persists,the possibility of
hypovolemia should be considered andmanaged
with appropriate parenteral
fluid therapy. A specific narcotic antagonistsuchas nalorphine. levallorphan or naloxone should he available for useas indicated to
manage
respiratory depression
causedby the narcotic component fentanyl. This doesnot preclude the use
of more immediate counter-measures.
The duration of respiratory depression
following overdose of tentanyl may he longer than the duration of narcotic antagonist
action. Consult the packageinsertsof the
individual narcotic antagonists
for
details aboutuse.
®
HOW SUPPLIED: INNOVAR injection is supplied in 2 ml. and5 ml.ampuls, in packages
of 10.
U.S. PatentNo. 3,141,823
Rev. 1/80
Sublimznaz
(fentanyl) injection
~R
DESCRIPTION: Each mi. contains:
Fentanyl ............................................................
0.05 mg
as the citrate
Warning: May be habit forming.
Sodium hydroxide for adjustment of pH to 4.0-7.5.
FOR INTRAVENOUS OR INTRAMUSCULAR USE ONLY
ACTIONS: SUBLIMAZE (fentanyl) is a narcotic analgesic with actionsqualitatively similar to those of
morphine and meperidine. SUBLIMAZE (fentanyl) in a dose of 0.1 mg. (2.0 ml.) is approximately
equivalent in analgesic activity to 10 mg. of morphine or 75 mg. of meperidine. The principal actionsof
therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation,
associatedwith narcotic analgesics, may last longer than the analgesiceffect. As the dose of narcotic is
increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnea.
SUBLIMAZE (fentanyl) appears to have less emetic activity than other narcotic analgesics. Histamine
assays and skinwheal testing in man, as well as in in vivo testing in dogs, indicatethat histaminerelease
rarely occurs with SUBLIMAZE (fentanyl).
SUBLIMAZE (fentanyl) may cause muscle rigidity, particularly involving the musclesof respiration. It
may also produce other signs and symptomscharacteristic of narcotic analgesics including euphoria.,
miosis, bradycardia, and bronchoconstriction.
The onset of action of SUBLIMAZE (fentanyl) is almost immediate when the drug is given intravenously; however, the maximal analgesicand respiratory depressant effect may not be noted for several
minutes. The usual durationof action of the analgesic effect is 30 to 60 minutes after a single I.V. dose of
up to 0. I mg. Following intramuscularadministration, the onset of action is from seve to eight minutes,
and the durationof action is oneto two hours. As with longer acting narcotic analgesics,the durationof
the respiratory depressanteffect of SUBLIMAZE (fentanyl) may be longer than the analgesic effect. The
following observationshave been reported concerningaltered respiratory response to COs stimulation
following administrationof fentanyl to man:
I. DIMINISHED SENSITIVITY TO COs STIMULATION MAY PERSIST LONGER THAN
DEPRESSION OF RESPIRATORY RATE. Fentanyl frequently slows the respiratory rate, but this
effect is seldom noted for over 30 minutesregardlessof the dose administered.
2. Duration anddegree of respiratory depressionis dose related.
3 The peak respiratory depressanteffect of a single intravenousdose of fentanyl is noted 5 to 15 minutes
following injection.
4. Altered sensitivity to COs stimulation has been demonstratedfor up to four hoursfollowing a single
intravenousdose of 0.6 mg. (12 ml.) fentanylto healthy volunteers.
See also WARNINGS and PRECAUTIONS concerningrespiratory depression.
INDICATIONS: SUBLIMAZE (fentanyl) is indicated:
-for analgesic action of short duration during the anesthetic periods, premedication, induction, and
maintenance,and in the immediate post-operativeperiod (recovery room) as the need arises.
- for use as a narcoticanalgesicsupplementin general or regional anesthesia.
-for administration with a neuroleptic such as INAPSINE (droperidol) injection as an anesthetic
premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and
regional anesthesia.
CONTRAINDICATIONS: SUBLIMAZE (fentanyl) is contraindicatedin patientswith known intoleranceto the drug.
WARNINGS: AS WITH OTHER CNS DEPRESSANTS, PATIENTS WHO HAVE RECEIVED
SUBLIMAZE (FENTANYL) SHOULD HAVE APPROPRIATE SURVEILLANCE. RESUSCITATIVE EQUIPMENT AND A NARCOTIC ANTAGONIST SHOULD BE READILY AVAILABLE TO
MANAGE APNEA.
See also discussionof narcotic antagonistsin Precautionsand Overdosage.
If SUBLIMAZE (fentanyl) is administeredwith a tranquilizer such as INAPSINE (droperidol), the user
should familiarize himself with the specialproperties of each drug, particularly the widely differing durations of action. In addition, when such a combination is used fluids and other countermeasures to
manage hypotension should be available.
As with other potent narrotics. the respiratory depressant effect of SUBLIMA ZE (fentanyl) persists
longer than the measured analgesic effect. The total dose of all narcotic analgesics administered should
he considered hv the practitioner before onlering narcotic analgesics during recover /fromn anesthesia.
It is recommended that narcotics, when required, should he used in reduced doses initially,as low as 'i
to 'A those usually recommended. SUBLIMAZE (fentanyl) may cause muscle rigidity, particularly
involving the muscles of respiration. The effect is related to the speed of injection and its incidencecan
be reduced by the use of slow intravenousinjection. Once the effect occurs, it is managed by the use of
assisted or controlled respiration and, if necessary,by a neuromuscularblocking agent compatible with
the patient'scondition.
Dru Depeadence: SUBLIMAZE (fentanyl) can produce drug dependenceof the morphine type and
therefore has the potential for being abused.
Severe and unpredictable potentiation by MAO inhibitors has been reported with narcotic analgesics.
Since the safetyof fentanyl in thisregard has not been established, the use of SUBLIMAZE (fentanyl) in
patientswho have received MAO inhibitors within 14days is not recommended.
Head Ijuaries and lacreased InlacranialPressure: SUBLIMAZE (fentanyl) should be used with caution in patientswho may be particularly susceptibleto respiratorydepression,such as comatose patients
who may have a head injury or brain tumor. In addition. SUBLIMAZE (fentanyl) may obscure the
clinical courseof patientswith head injury.
Usage
in Chldren: The safety of SUBLIMAZE (fentanyl) in children younger than two years of age has
not been established.
Usage n Pregnancy: The safe use of SUBLIMAZE (fentanyl) has not been established with respect to
possibleadverseeffects upon fetal development. Therefore, it should be used in women of childbearing
potential only when, in the judgment of the physician, the potential benefits outweigh the possible hazards. There are insufficient data regarding placental transfer and fetal effects; therefore, safety for the
infant in obstetricshas not been established.
PRECAUTIONS: The initial dose of SUBLIMAZE (fentanyl) should be appropriately reduced in
elderly, debilitated and other poor-risk patients. The effect of the initial dose should be considered in
determining incremental doses.
Certain forms of conductionanesthesia,such as spinal anesthesiaand some peridural anesthetics, can
alter respiration by blocking intercostalnerves. Through other mechanisms(seeActions) SUBLIMAZE
(fentanyl) can also alter respiration. Therefore, when SUBLIMAZE (fentanyl) is used to supplement
these forms of anesthesia,the anesthetistshouldbe familiar with the physiological alterations involved,
and be prepared to manage them in the patientsselectedfor theseforms of anesthesia. When used with a
tranquilizer such as INAPSINE (dropendol), blood pressure maybe altered andhypotension can occur.
Vital signsshould be monitored routinely.
SUBLIMAZE (fentanyl) should be used with caution in patients with chronic obstructive pulmonary
disease, patients with decreased respiratory reserve, and others with potentially compromised respiration. In such patients, narcotics may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration. Respiratory
depressioncausedby narcotic analgesicscan be reversedby narcotic antagonsts. Appropriate surveillance should be maintained becausethe duration of respiratory depressionof dosesof fentanyl
employed during anesthesia
may be longer than theduration of the narcotic antagonist action. Consult
individual prescribing information (levallorphan, nalorphine and naloxone)before employing narcotic
antagonists
Whena tranquilizer suchas INAPSINE (droperidol) is usedwith SUBLIMAZE (fentanyl), pulmonary
arterial pressure
maybe decreased.
This fact shouldbe considered by thosewho conduct diagnostic and
surgical procedures
whereinterpretation of pulmonary arterial pressuremeasurements
might determine
final management
of thepatient.
Other CNS depressant
drugs (e.g. barbiturates,tranquilizers, narcotics, andgeneral anesthetics)will
haveadditive or potentiating effects with SUBLIMAZE (fentanyl). When pataents
havereceived such
drugs, the doseof SUBLIMAZE (fentanyl) required will be less than usual.Likewise, following the
administration of SUBLIMAZE (fentanyl), thedoseof other CNSdepressant
drugs should be reduced.
SUBLIMAZE (fentanyl) should be administered
with caution to patientswith liver andkidney dysfunction because
of the importance
of theseorgansin themetabolism andexcretion of drugs.
SUBLIMAZE (fentanyl) may producebradycardia,which may be treatedwith atropine; however,
SUBLIMAZE (fentanyl) should be usedwith caution in patientswith cardiac bradyarrhythmias.
WhenSUBLIMAZE (fentanyl) is usedwith a tranquilizer such as INAPSINE (droperidol), hypotension
can occur. If this occurs, the possibility of hypovolemia should be considered
andmanaged
with appropriateparenteralfluid therapy. Repositioning thepatientto improve venousreturnto the heartshould be
considered when operative conditions permit. Care should he exercised in moving and positioning of
patients becauseof the possibility of orthostatic hypotension. If volume expansion with fluids plus other
countermeasures do not correct hypotension, the administration of pressor agents other than epinephrine
should be considered. Because of the alpha-adrenergic blocking action of INAPSINE (droperidol),
epinephrine may paradoxically decrease the blood pressurein patients treated with INAPSINE (droperidoll When INAPSINE (droperidol) is used with SUBLIMAZE (fentanyl) andthe EEG is used for postoperative monitoring, it may be foundthat the EEG patternreturns to normal slowly.
ADVERSE REACTIONS: As with other narcotic analgesics,the most common serious adverse reactions reported to occur with SUBLIMAZE (fentanyl) are respiratory depression,apnea, muscular rigidity, and bradycardia;if these remain untreated, respiratory arrest,circulatory depressionor cardiac arrest
could occur. Other adversereactions that have been reported are hypotension, dizziness, blurred vision,
nausea, emesis, laryngospasm, anddiaphoresis.
When a tranquilizer such as INAPSINE (droperidol) is used with SUBLIMAZE (fentanyl), the following
adverse reactions can occur: chills and/or shivering, restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms
(dystonia, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. When
they occur, extrapyramidal symptomscan usually be controlled.with anti-parkinson agents. Postoperative drowsinessis also frequently reported following the use of INAPSINE (droperidol).
Elevated blood pressure, with and without preexisting hypertension, has been reported following
administration of SUBLIMAZE (fentanyl) combined with INAPSINE (droperidol). This might be due to
unexplained alterations in sympathetic activity following large doses; however, it is aho frequently
attributedto anesthetic andsurgical stimulation during light anesthesia.
DOSAGE AND ADMINISTRATION: Dosage should be individualized. Some of the factors to be considered in determining the dose are age, body weight, physicalstatus, underlying pathological condition,
use of other drugs, type of anesthesia to be used, andthe surgical procedure involved.
Vital signsshouldbe monitored routinely.
UssulAdulDosaye:
I. Premedication (to be appropriately modified in the elderly, debilitated, and those who have received
other depressant drugs)-0.05 to 0.1 mg. (I to 2 ml.) may be administeredintramuscularly 30 to 60
minutes prior to surgery.
II. Adjunct to General Anesthesia Induction-0.05 to 0.1I mg. (I to 2 ml.) may be administered initially
intravenously and may be repeated at 2 to 3 minute intervals until desired effect is achieved. A reduced
dose as low as 0.025 to 0.05 mg. (0.5 to I ml.) is recommendedin elderly and poor-risk patients.
Maintenance-0.025 to 0.05 mg. (0.5 to I ml.) may be administered intravenously or intramuscularly
when movement and/or changesin vital signsindicate surgical stressor lighteningof analgesia.
If INNO VAR injection is administered in addition to SUBLIMAZE (fentanyl). the calculation of the
recommendeddose of SUBLIMAZE (fentanyl) should include the fentanyl contained in the INNO VAR
injection. SeeINNO VAR injection Package Insert for full prescribinginformation.
III. Adjunct to Regional Anesthesia-O.05 to 0.1 mg. (I to 2 ml.) may be administered intramuscularly
or slowly intravenouslywhen additional analgesia is required.
IV. Postoperaively (recovery room)-0.0S to 0. mg. (I to 2 ml.) may be administered intramuscularly
for the control of pain, tachypnea andemergence delirium. The dose may be repeated in one to two hours
as needed.
Usual Children's Do
: For induction andmaintenance in children two to 12 years of age, a reduced
dose as low as 0.02 to 0.03 mg. (0.4to 0.6 ml.) per 20 to 25 pounds isrecommended. See W rnings and
Precautions for use of SUBLIMAZE (fentanyl) with other CNS depressants, and In patients with altered
response.
OVERDOSAGE: Mas tatdions: The manifestationsof SUBLIMAZE (fentanyl) overdosage are an
extension of its pharmacologic actions.
Treatumes: In the presence of hypoventilation or apnea, oxygen should be administeredand respiration
should be assistedor controlled as indicated. A patent airway must be maintained; an oropharyngeal
airway or endotracheal tube might be indicated. If depressedrespiration is associated with muscular
rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assistedor controlled respiration. The patient should be carefully observed for 24 hours; body warmth and adequate
fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of
hypovolemia shouldbe considered and managed with appropriate paenteral fluid therapy. A specific narcotic antagonistsuch as nalorphine, levallorphan, or naloxone should be available for use as indicated to
managerespiratory depression.This does not preclude the use of more immediate countermeasures.The
duration of respiratorydepression following overdosageof fentanyl may be longer than the duration of
narcotic antagonistaction. Consult the packageinsert of the individual narcotic antagonists for details
about use.
SHOW SUPPLIED: 2 ml. and 5 ml. ampuls-packages of 10.
U.S. Patent No. 3,164,600
Rev. 1/80
Committed to research...
because so much remains to be done.
H
JANSSEN PHARMACEUTICA INC., NewBrunswick.
NewJersey
08903
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Remove the Block Yourself
Reverse with
REGONOL
pyridostigmine bromide
Regonol rapidly restores full neuromuscular transmission.
It produces fewer oropharyngeal secretions and less
bradycardia than neostigmine.
Brief Summary (Please consult full package insert, enclosed in every
package, before using Regonol).
INDICATIONS-Regonol (pyridostigmine bromide) is useful as a reversal
agent or antagonist to nondepolarizing muscle relaxants.
CONTRAINDICATIONS-Known hypersensitivity to anticholinesterase
agents; intestinal and urinary obstructions of mechanical type.
WARNINGS-Use with particular caution in patients with bronchial asthma or
cardiac dysrhythmias. Transient bradycardia may occur and be relieved by
atropine sulfate. Atropine should also be used with caution in patients with
cardiac dysrhythmias. Because of the possibility of hypersensitivity in an
occasional patient, atropine and antishock medication should always be
readily available.
Usage in Pregnancy-The safety of pyridostigmine bromide during pregnancy or lactation in humans has not been established. Therefore its use in
women who are pregnant requires weighing the drug's potential benefits
against its possible hazards to mother and child.
ADVERSE REACTIONS-Side effects are most commonly related to overdosage and generally are of two varieties, muscarinic and nicotinic. Among
the former group are nausea, vomiting, diarrhea, abdominal cramps,
increased peristalsis, increased salivation, increased bronchial secretions,
miosis and diaphoresis. Nicotinic side effects are comprised chiefly of muscle
cramps, fasciculation and weakness. Muscarinic side effects can usually be
counteracted by atropine. As with any compound containing the bromide
radical, a skin rash may be seen in an occasional patient. Such reactions
usually subside promptly upon discontinuance of the medication. Thrombophlebitis has been reported subsequent to intravenous administration.
DOSAGE AND ADMINISTRATION-Prior or simultaneous administration of
atropine sulfate (0.6 to 1.2 mg; IV) is recommended to minimize the side
effects (excessive secretions, bradycardia). Usually 10 or 20 mg of pyridostigmine bromide will be sufficient for antagonism of the effects of the
nondepolarizing muscle relaxants. Although full recovery may occur within
15 minutes in most patients, others may require a half hour or more.
Satisfactory reversal can be evident by adequate voluntary respiration,
respiratory measurements and use of a peripheral nerve stimulator device. It
is recommended that the patient be well ventilated and a patent airway
maintained until complete recovery of normal respiration is assured. Once
satisfactory reversal has been attained, recurarization has not been reported.
Failure of pyridostigmine bromide to provide prompt (within 30 minutes)
reversal may occur, e.g. in the presence of extreme debilitation, carcinomatosis, or with concomitant use of certain broad spectrum antibiotics or
anesthetic agents, notably ether.
CAUTION-Federal law prohibits dispensing without a prescription.
HOW SUPPLIED-Regonol is available in: 2 ml ampuls-5 mg/ml boxes of 10.
NDC 0052-0460-10
organon
A PART OFAzOna INC
Organon Pharmaceuticals
. A Division of Organon Inc.
West Orange, N.J. 07052
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NURSE
ANESTHETISTS
Openings for nurse anesthetists ina
521-bed university affiliated
teaching hospital. Candidates must
We can offer you the opportunity for
personal and professional growth in the
largest privately funded non-profit
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be qualified graduate nurse
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For more information, write or call
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Betsy Jessup, RN
Nurse Recruiter
Personnel Office
GEORGETOWN UNIVERSITY
Washington, D.C. 20057
i
Paulette M. Mason
Norfolk General Hospital
600 Gresham Drive
Norfolk, Virginia 23507
Call Collect:
800-446-8158
202/625-3270
An Equal Opportunity/Affirmative
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00
anestesia
afety
Last~at th AecaSoitofnshioissCneto.Oi
yea
JUNE 1979
NUBAJN® WAS INTRODUCED
nalbuphine HCI
TODAY
PYICLANS ARE
USING NUBAJN
AS A SAFE AND EFFECTIVE ALTERNATIVE
TO MEPERIDINE HCI (DEMEROL")
The analgesic potency of NUBAJN Iscompar t
that of meperidine HCI. It may be administerd In
indivdual doses of 10 mg/70 kg up to 20* v h
maximum daily dose of 160 mg. Onset
effect are comparable to that of meperdfr
:
r
(50-150 mg).
anpa
FOR LESS RESPIRATORY DEPRESSION
POTENTIAL
At dosages of 10 mg/70 kgS NUBAIN 'i
to morphine inrespiratory dpeso.At
increase respiratory depression, as does
(see
Precautions).
x
FOR A LOW LEVEL OF SIDE EFFECT
Inclinical trials, NUBAIN caused
voiin h
meperidine HCI or morphine.
less
This. is arn iR tflOe
consideration for the general surge :or
anesthesiologist.
FOR FAVORABLE HEMODYNAMKCPC L
NUBAIN has the effect of slightly I
cardiac work load and can be used
Ml (use cautiously where emesis isIrYOl'a)
t
FOR LONGER DURATiON OF ACT O9N *ICW
MAY PROVIDE GREATER PATIENT CQ #P
UNINTERRUPTED SLEEP
LONGER DAYflME RELIEF
The analgesic effect of NUBAJN lasts
hours, so the patient has fewv~ i
activties and may sleep better.
NUBAIN isan Endio registered U.S. trademwk'
$
k }r4
V
Jp &
bfI
I
NUBAIN"
nalbuphine HCI
information
Briefsummary
of fullprescribing
canalsobe
toseverepain.NUBAIN
Forthereliefofmoderate
INDICATIONS
to surgicalanesthesia,
usedforpreoperative
analgesia,as a supplement
andforobstetricalanalgesiaduringlabor.
topatientswho
shouldnotbeadministered
NUBAIN
CONTRAINDICATIONS
toit
arehypersensitive
NUBAIN
hasbeenshowntohavealowabuse
WARNINGS
DrugDependence
with
When
compared
tothat ofpentazocine
whichis approximate
potential
that
it has beenreported
drugswhicharenotmixedagonist-antagonists,
potentialforabusewouldbe lessthan thatof codeineand
nalbuphine's
andphysical
dependence
andtolerancemay
propoxyphene.
Psychological
cautionshouldbe
followtheabuse or misuseofnalbuphineTherefore,
it for emotionallyunstablepatients,or for
observedin prescribing
of narcoticabuse Such patientsshouldbe
individuals
with a history
whenlong-term
therapyis contemplatedCareshould
closelysupervised
which
of administration
betakentoavoidincreasesin dosageorfrequency
Abrupt
in susceptibleindividuals mightresultin physicaldependence.
use has beenfollowedby
following
prolonged
of NUBAIN
discontinuation
i.e.,abdominalcramps.nauseaand
symptomsof narcoticwithdrawal,
rhinorrhea,
lacrimation.
restlessness,anxietyelevatedtemperavomiting,
mayimpairthe
Patients NUBAIN
UseinAmbulatory
tureandpiloerection
for the performance
of potentially
mentalorphysicalabilitiesrequired
Therefore,
tasks suchas drivinga caroroperatingmachinery.
dangerous
patientswho
withcautiontoambulatory
NUBAIN
shouldbeadministered
shouldbewarnedtoavoidsuchhazards Usein EmergencyProcedures
untilrecovered
fromNUBAIN
effects
Maintain
patientunderobservation
dangeroustasks Use in
that wouldaffect drivingor otherpotentially
administration
topatientsunder18
Clinicalexperience
tosupport
Children
(other than labor)Safe
yearsisnotavailableatpresentUseinPregnancy
animal
has notbeenestablishedAlthough
use of NUBAIN
in pregnancy
reproductive
studieshavenotrevealed
teratogenic
orembryotoxic
effects,
to pregnant
womenwhen.in the
nalbuphine
shouldonlybeadministered
thepossible
the potentialbenefitsoutweigh
of thephysician,
ludgement
and Delivery
NUBAIN
can producerespiratory
hazards UseDuringLabor
depressionin the neonate It shouldbe used withcautionin women
delveringpremature
infants HeadInjuryand Increased Intracranial
Pressure Thepossiblerespiratory
depressant
effectsandthe potentialof
fluidpressure(resultingfrom
potentanalgesicstoelevatecerebrospinal
vasodilation
following
CO,retention)
maybemarkedly
exaggerated
inthe
presenceofheadinluryintracranial
lesionsor a pre-existing
increasein
intracranal pressureFurthermore,
potentanalgesicscanproduce
effects
whichmayobscurethe clinicalcourseof patients withhead injuries
Therefore.
NUBAIN
shouldbe used in these circumstances
onlywhen
essential,and then shouldbe administeredwith extremecaution
InteractionWithOtherCentralNervousSystemDepressants Although
NUBAIN
possesses narcoticantagonistactivitythereis evidencethat in
nondependent
patientsit will not antagonizea narcoticanalgesic
administered
lust before,concurrently
orlustafteraninlectionofNUBAIN
Therefore,
patients receiving
a narcoticanalgesic,generalanesthetics.
phenothiazines.
or othertranquilizers,
sedatives,hypnotics,
orotherCNS
depressants
(includingalcohol)
concomitantly
withNUBAIN
mayexhibit
an
additiveeffect.Whensuchcombined
therapyis contemplated,
thedoseof
oneorbothagents shouldbereduced
PRECAUTIONS
Impaired
Respiration
Attheusualadultdoseof 10mg/70
kg,NUBAIN
causes somerespiratory
depression
approximately
equalto
that producedby equaldoses of morphineHowever,
in contrastto
morphine,
respiratorydepression
is notappreciably
increased
withhigher
doses of NUBAIN
Respiratory
depressioninducedby NUBAIN
can be
reversedby NARCAN
(naloxone
hydrochlonde)
whenindicatedNUBAIN
shouldbeadministered
withcaution
atlowdosestopatientswithimpaired
respiration
(e.g. fromothermedication,
uremia,bronchial
asthma,severe
infection,
cyanosisorrespiratory
obstructions)
Impaired
RenalorHepatic
Function
BecauseNUBAIN
is metabolized
in theliverandexcretedbythe
kidneys,
patientswithrenalorliverdysfunction
mayoverreact
tocustomary
doses.Therefore,
intheseindividuals,
NUBAIN
shouldbeusedwithcaution
andadministered
inreducedamountsMyocardial
InfarctionAswithall
potentanalgesics, NUBAIN
shouldbe used withcautionin patientswith
myocardial
infarction
whohavenauseaorvomitingBiliaryTractSurgery
As withall narcoticanalgesics,NUBAIN
shouldbe usedwithcautionin
patientsaboutto undergo
surgery
of thebiliary
tractsince it maycause
spasmofthesphincter
of Odds
ADVERSE
REACTIONS
Themostfrequentadversereactionin 1066patients
treatedwithNUBAIN
is sedation(381)36% Lessfrequentreactionsare:
sweaty/clammy
(99) 9%. nausea/vomiting (68) 6% dizziness/vertigo
(58) 5%,drymouth(44) 4%,and headache(27) 3% Otheradverse
reactionswhichmayoccur(reported
incidenceof 1%or less) are:CNS
Effectsnervousness,
depression,
restlessness,crying,euphoria,
floating,
hostilityunusualdreams,confusion,
faintness,hallucinations,
dysphorna,
feelingof heaviness,numbness,tingling, unrealityTheincidenceof
psychotomimetic
effects,suchas unrealitydepersonalization,
delusions,
dysphoria
andhallucinations
has beenshownto be lessthan thatwhich
occurs with pentazocne Cardiovascular
Hypertension,
hypotension,
bradycardia.tachycardia. gastrolntestinal Cramps, dyspepsia, bitter
taste.Respiration
Depression,
dyspnea,asthma Dermatological
Itching,
burning,urticaria Miscellaneous
Speech difficulty urinary urgency.
blurredvision,flushing and warmth Patients Dependent on Narcotics
Patients whohave been takingnarcotics chronicallymay experience
withdrawalsymptoms uponthe administration of NUBAIN
If unduly
troublesome,
narcotic withdrawalsymptomscan becontrolled bythe slow
intravenousadministration ofsmall increments of morphine,untilrelief
occurs.If the previousanalgesic was morphine,meperidine, codeine,or
other narcotic with similar duration of activity one-fourth of the
anticipated dose ofNUBAIN
can be administered initiallyand thepatient
observedfor signs of withdrawal.ie. abdominal cramps, nausea and
vomiting,lacrimation. rhrnorrhea.anxiety restlessness, elevationof
temperature or piloerection If untoward symptoms do not occur,
progressively
larger doses maybe triedat appropriate intervals untilthe
desiredlevel of analgesia is obtained with NUBAIN
Management
of
OverdosegeThe immediateintravenous administration of NARCAN'
(naloxonehydrochlonde)
is a specificantidote Oxygen,intravenous fluids,
vasopressors and othersupportivemeasures shouldbe used as indicated.
Theadministration ofsingle doses of 72mg ofNUBAIN
intramuscularly to
eightnormalsubjects has been reportedto have resulted primarilyin
symptomsofsleepiness and milddysphoria
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EDO-835B680
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for
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If
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GARY W SMITH. President
Natlional Medical Registry
776
StateStreet
Suite 101
Ukiah. California 95482
OR
CALL TOLL FREE
(800) 358-9132
In California, call collect
(707) 468-9187
ARNOLD SLADEN, M.D.
Professor of Clinical Anesthesiology
& Director, Surgical Intensive Care
University of Pittsburgh
Honorary Consultant