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Analgesic activity of tricyclic antidepressants.

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with intravenous phenytoin and diazepam in the emergency
room. The patient recovered consciousness quickly. Examination demonstrated a severe impairment of memory consistent with Korsakoff s psychosis as well as lateral and upgaze
nystagmus, but was otherwise unremarkable. CT scan was
normal, and the EEG showed minimal bilateral frontal slowing. The CSF findings are given in Table 3. The patient was
thought to have a posttraumatic seizure disorder.
Discussion
CSF pleocytosis directly related to seizures is an uncommon phenomenon; it occurred in only 2% of patients in the present study. The results of this study are
subject to certain limitations. First, an unrepresentative
proportion of the patients we studied had seizures due
to alcohol withdrawal or posttraumatic epilepsy. The
incidence of postictal pleocytosis could vary with seizure type.
Second, not every patient with seizures has a CSF
examination. It is possible that our series of 98 episodes is weighted toward the more serious seizure disorders and that the true incidence of postictal pleocytosis is therefore less than 2%. Patients with less severe
problems (for example, single uncomplicated seizures
in known epileptics) either are not admitted, or, if admitted, do not have a CSF examination.
Review of the patients previously reported by
Schmidley and Simon {GI, as well as those described
here, suggests that pleocytosis tends to follow repeated
or prolonged seizures. One of Schmidley and Simon’s
patients had three generalized tonic-clonic seizures, another had four, 3 had “repeated” convulsions, and 1
was admitted in status epilepticus. Of the 2 patients
reported here, 1 had six tonic-clonic seizures within a
few hours, the other a continuous seizure for 30
minutes.
Roger P. Simon, MD, is a recipient of Teacher Investigator Award
1K07NS00437-0 1.
We wish to thank the members of the neurology house staff of the
University of California at San Francisco, especially Dr W. J.
Schwartz, for their help in finding patients for this study.
References
1. Fishman RA: Cerebrospinal Fluid in Disease of the Nervous System. Philadelphia, Saunders, 1980
2. Glaser GH: Convulsive disorders. In Merritt HH (ed): Textbook
of Neurology. Sixth edition. Philadelphia, Lea & Febiger, 1979
3. Glaser GH: The epilepsies. In Beeson PB, McDermott W, Wyngaarden JB (eds):Textbook of Medicine. Fifteenth edition. Philadelphia, Saunders, 1979, p 857
4. Matthews WB: Practical Neurology. London, Blackwell, 1975, p
Analgesic Activity
of TGcyclic Antidepressants
Katharyn Spiegel, BS,*$ Robert Kalb, MD,”
and Gavril W. Pasternak, MD, PhD’tS
~
~~
Amitriptyline (median effective dose [EDS0}1.2 mg per
kilogram of body weight), imipramine (ED502.3 mg/kg),
and their demethylated derivatives nortriptyline (ED5”
1.9 mg/kg) and desimipramine (EDS03.2 mg/kg) are
active analgesics as indicated by the mouse writhing
assay. Although not as potent as morphine (EDSo0.2
mg/kg), the antidepressants were up to 70 times more
potent than aspirin (EDs0 91 mg/kg). The actions of
amitriptyline were not affected by the specific opiate
antagonist naloxone but were markedly attenuated in
animals whose monoamine levels had been depleted
with reserpine. Central mechanisms appear important
since amitriptyline (ED504.6 pg) was potent when
administered intracerebroventricularly.
Spiegel K, Kalb R, Pasternak GW: Analgesic
activity of tricyclic antidepressants.
Ann Neurol 13:462-465, 1983
The tricyclic antidepressants are now used widely in
the clinical management of pain. Although these drugs
are reportedly effective in the treatment of migraine
and neuropathic pain associated with a variety of conditions [ 2 , 4 , 9 , lo}, the mechanisms through which they
help control pain remain unknown. Since depression is
commonly associated with pain, their relief of pain may
result from their actions on depression. Alternatively,
the drugs may themselves possess direct analgesic actions. One study has suggested that the ability of amitriptyline to relieve migraine was independent of its
antidepressant actions {2]. To help resolve this question, we investigated the actions of a series of tricyclic
antidepressants in an animal nociception model.
Materials and Methods
All assays were performed using 25-gm to 30-gm male mice
(Crl:CD-l[ICRIBR) purchased from Charles River Breeding
Laboratories, Inc (Wilmington, MA). Analgesia was assessed
in the writhing and tailflick assays [3, 61. In the writhing
assay, groups of mice (n = 8) received either vehicle or a
From the Totzias Laboratory of Neuro-Oncology, Memorial SloanKettering Cancer Center, and Departments of ?Neurology and
$Pharmacology, Cornell University Medical College, New York,
N Y 10021.
14
5. Merritt HH, Fremont-Smith F: The Cerebrospinal Fluid. Phila-
Received for publication June 10, 1982, and in revised form Aug 10,
1982. Accepted for publication Aug 15, 1982.
delphia, Saunders, 1937, pp 176-179
6. Schmidley JW, Simon RP: Postictal pleocytosis. Ann Neurol
953-84. 1981
Address reprint requests to: Dr Pasternak, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave,
New York. N Y 10021.
462
I
x
r
L
g
T
1
I
60
-- 50%
50-
3
0
c
'
I
9
c
c
01
1
I0
100
Dose (mglkg)
single dose of drug 25 minutes prior to the intraperitoneal
injection of 0.03% phenylquinone (0.01 mug,). Animals
were then observed for 1-minuteintervals 5 and 10 minutes
later.
The response was calculated using the following formula:
Percentresponse =
1;i
0
Fig 1 . Dose response of aspirin, amitriptyline, and morphine
analgesia. Groups of mice were assayed in the writhing tat with
various intraperitonealdoses of the three drugs. Curves were fitted
by linear regression of a log-probit analysis. Slopes of the three
lines do not differ significantly but their respective EDjo values
do (p < 0.03). Note: intraperitoneal administration lowers the
potency of morphine and amitriptyline slightly but greathi enhances the potency of aspirin.
j
No. writhes, test drug
x 100.
No. writhes, control drug
Values for median effective dose (ED,,) were determined by
linear regression analysis of a log-probit plot using at least
three different drug dosages. Intraventricular injections were
performed under Ethrane/Oz anesthesia which permitted all
animals to recover from anesthesia prior to nociception testing. The tailflick assay measures the latency, or time of exposure, of a rat's tail to radiant heat. In this test, analgesic action
is defined as a doubling of the baseline latency of an individual animal, with an arbitrary cutoff of 10 seconds to minimize
tissue damage to the tail.
Results
Initially we tested amitriptyline in the writhing assay, a
sensitive screening procedure for analgesics [b].Amitriptyline at doses under 5 mg per kilogram of body
weight potently inhibited the writhing response. However, amitriptyline at doses up to 20 mg/kg was inactive
in the tailflick assay, a test which detects only the most
potent analgesics [31. We therefore routinely used
writhing assays for the remainder of our studies. Amitriptyline was then compared directly to both aspirin
and morphine to determine the relative potencies of
each drug after intraperitoneal injection (see Fig 1). All
three drugs inhibited the writhing response in a dosedependent manner with slopes that did not differ
significantly from each other. Although less active than
morphine, amitriptyline in these assays was approximately ten times more potent than aspirin.
F ig 2. Analgesicpotency of amitriptyline, nortriptyline, imipramine, desipramine, and aspirin afer subcutaneous and intraperitoneal administration. Groups of mice were treated with a
minimum of four doses of each drug administered both subcutaneously and intraperitoneally. Median effectic'e dose (EDSO)values
were calculated in the writhing assay using least square linear
regression fit of log-probit analysis. Each value presented is the
mean +SEM of three separate EDjodetermtnations with the exception of intraperitoneal imipramine where n = 5 and aspirin
wheren = 2.
We next studied a series of four antidepressants
(amitriptyline, nortriptyline, imipramine, and desipramine) using two routes of administration (see Fig 2).
All the drugs were stronger analgesics than aspirin. In
fact, amitriptyline administered subcutaneously was
over 70 times more potent than aspirin. The dibenzocycloheptadione derivatives (amitriptyline and nortriptyline) were more potent than the dibenzazepines
(imipramine and desipramine) and the tertiary amine
compounds (amitriptyline and imipramine) were
slightly more active than their corresponding secondary amine derivatives (nortriptyline and desipramine).
More important, all the antidepressants were more effective subcutaneously than intraperitoneally, in contrast to aspirin, which was four times less potent subcutaneously. These results raised the possibility of a
central mechanism for the antinociceptive actions of
the antidepressants. To examine this possibility more
directly, the actions of amitriptyline were assayed after
intracerebroventricular injection (see Fig 3). Amitriptyline effectively inhibited writhing with an EDsoof 4.6
pg per mouse, far less than an equally potent systemic
dose (about 30 pg per mouse) administered subcutaneously.
One major central pain modulating system involves
the endogenous opioid peptides [ 1, 7). To determine
whether the actions of the antidepressants might work
through the andogenous opioid system we tested the
ability of the specific opiate antagonist naloxone to
block their antinociceptive actions. Control groups of
mice (n = 8) received a dose of either amitriptyline
Brief Communication: Spiegel et al: Antidepressant Analgesia
463
O
80%
1
50%
20 %
2
5
Arnitriptyline dose (pg. I C V )
10
Fig 3. Analgesic actions of intracerebroventricularamitriptyline.
GroupJ of mice received the stated doses of amitriptyline dissolved
in 5 kl administered intracerebroventricularly(icv) under
Ethane102 anesthesia. The animals were then tested in the
writhing assay. All animals recovered from the anesthesia fully
before analgesia testing.
(2 mg/kg intraperitoneally) or morphine (0.5 mg/kg intraperitoneally), both of which inhibited writhing 50%.
In additional groups of mice (n = 8) naloxone (1 mg/kg
intraperitoneally) totally prevented the analgesic actions of morphine but had no effect on the antinociceptive actions of amitriptyline. Thus, the opioid peptides
do not appear to be directly involved in the analgesic
actions of the antidepressants.
The extensive interactions between the tricyclic antidepressants and the monoamines have been known for
many years [ S ] . Monoamines appear important in the
analgesic actions of the antidepressants. Groups of animals (n = 8) received either saline or reserpine (0.4
mg/kg) 24 hours before amitriptyline (4 mg/kg intraperitoneally) was tested in the writhing assay.
Whereas writhing was inhibited 66% in the control
groups, writhing was blocked only 30% in the group
pretreated with reserpine.
Discussion
Our results suggest that the tricyclic antidepressants
were potent centrally active analgesics in an animal
antinociception assay. Although not as potent as morphine, they were up to 70 times more effective than
aspirin. The writhing assay {G} is a very sensitive antinociceptive assay in which virtually all analgesics, mild
or strong, are active. In contrast, only very potent
drugs are effective in the tailflick assay [3]. A drug
active in the writhing but not in the tailflick assay might
be considered to demonstrate a “ceiling effect.” Although the drug might relieve mild to moderate pain, it
may be ineffective for severe pain regardless of its
dose. Amitriptyline has been tested in the tailflick assay
extensively by others without demonstrating analgesia.
464 Annals of Neurology Vol 1 3 No 4 April 1983
Our inability to elicit an analgesic response with amitriptyline at doses up to 20 mg/kg is consistent with a
ceiling effect.
The pharmacological mechanism of action of the
tricyclic antidepressants remains unknown. The inability of naloxone to influence their analgesic actions,
coupled with their very low affinity for opiate receptors
(Spiegel and Pasternak, unpublished observations,
April 1982) appears to rule out a direct role for the endogenous opioid system. The tricyclics interact extensively with a number of putative neurotransmitter
systems, many of which have been implicated in the
modulation of pain. The drugs not only bind with high
affinity to a number of neurotransmitter receptors, but
also influence the uptake mechanisms for the monom i n e s IS]. Thus it is difficult to determine which interactions might be responsible for the analgesic actions reported here. Although more extensive testing
is needed to make definitive conclusions, the decrease
in the potency of amitriptyline following pretreatment
with reserpine strongly points to the monoamines as
having a role in analgesic action. Of the monoamines,
serotonin has been implicated most strongly in pain
modulation. The trend toward greater potency for the
tertiary consequences would be consistent with a
serotonergic mechanism of action. However, the other
monoamines cannot be ruled out. This is particularly
true since norepinephrine, dopamine, and serotonin all
have dramatic effects on opiate analgesia [8].
It is tempting to extend these findings to explain the
actions of antidepressants in pain relief in humans. For
a great number of analgesics, animal nociceptive assays
have been correlated with analgesic potency in humans.
Actual drug dosages in animals rarely correspond to
those active in humans, but relative potencies between
drugs usually are consistent. For example, the EDso
value for morphine sulfate in mice is about 0.5 mgikg,
a dose almost four times greater than that needed in
humans. Thus, the doses of tricyclics active in these
animal studies might be expected to correspond to dosages used clinically. The demonstration of central antinociceptive actions of amitriptyline supports the possibility of a direct analgesic action for these drugs.
However, significant differences exist between the discomfort induced by these animal nociception models
and clinical pain. Clinical pain remains a complex subjective sensation subject to a great variety of physical
and emotional factors. The antidepressant actions of
tricyclics also may prove important in the clinical relief
of pain. Many of the neurotransmitter mechanisms important in depression [ 5 ] also appear to be important in
pain modulation [8]. Distinguishing between two separate physiological systems composed of similar neurotransmitters and a single system modulating both pain
and depression may prove very difficult.
~
~
~~~~~
Supported in part by grants from the American Cancer Society (PDT
169) and The David B Kriser Oro-Facial Pam Center Dr Pasternak
is supported by a Teacher Investigator Award from NINCDS (NS
004 15)
We thank Drs Wald, Posner, Curro, and Greenfield for rheir
assistance
References
Basbaum AI, Fields H L Endogenous pain control mechanisms:
review and hypothesis. Ann Neurol 4:457-462, 1978
Couch JR, Ziegler DK, Hassanein R: Amitriptyline in the prophylaxis of migraine. Neurology 26:121-127, 1976
DAmour FE, Smith DL: A method for determining loss of pain
sensation. J Pharmacol Exp Ther 72:74-79, 1941
Diamond S, Baltes BJ: Chronic tension headache treated with
amitriptyline: a double blind study. Headache 11:lIO-116,
197 1
5. Fuller RWG: Enhancement of monoaminegic neurotransmission by antidepressant drugs. In Enna SJ, Malick JB, Richelson E
(eds): Antidepressants: Neurochemical, Behavioral and Clinical
Perspectives. New York, Raven, 1981, pp 1-12
6. Hendershot LC, Forsaith J: Antagonism of the frequency of
phenylquinone writhing in the mouse by weak analgesics and
nonanalgesics.J Pharmacol Exp Ther 125:237-240, 1959
7. Snyder SH: Opiate receptors in the brain. N Engl J Med
296:266-271, 1977
8. Sparkes CG, Spencer PSJ: Antinociceptive activity of morphine
after injection of biogenic mines in the cerebral ventricles of
the conscious rat. Br J Pharmacol 42:230-241, 1971
9. Taulb A, Collins WF: Observations on the treatment of denervation dysesthesia with psychotropic drugs: postherpetic neuralgia,
anesthesia dolorosa, peripheral neuropathy. In Bonica JJ (ed):
Advances in Neurology, Vol. 4.New York, Raven, 1974, pp
309-3 15
10. Woodeforde JM, D y e r B, McEwen BW, et al: Treatment of
postherperic neuralgia. Med J Aust 2:869-872, 1965
Brief Communication: Spiegel et al: Antidepressant Analgesia
465
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