Subido por Gianna Gil

Cycloplegics and mydriatics

Tolerance, Habituation, and Addiction
Topical Administration
H. Bruce Ostler, MD
A patient had tolerance, habituation,
and addiction to the topical use of a combination of cyclopentolate hydrochloride
and tropicamide. He also developed a
blotchy, diffuse epithelial keratitis that
disappeared when the drugs were discontinued.
extremely rare phenomenon—
systemic tolerance, habituation,
and addiction to a topically adminis¬
tered drug—has recently been seen in
a patient who responded in this un¬
usual way to the topical adminis¬
tration of a combination of cyclo¬
pentolate hydrochloride (Cyclogyl)
and tropicamide (Mydriacyl) in the
conjunctival sac. A severe, blotchy
epithelial keratitis was also associ¬
ated with the use of these drugs and
disappeared when they were with¬
of a Case
In December 1973, a 25-year-old emo¬
tionally labile white man with a severe bi¬
lateral epithelial keratitis was referred to
I had seen him two years before when
he had a chronic staphylococcal blepharokeratoconjunctivitis with collarettes, re¬
epithelial keratitis, recurrent catarrhal infiltrates, and a nontuberculous
phlyctenular pannus. At that time, he recurrent
Submitted for publication Feb 13, 1974.
From the Francis I. Proctor Foundation for
Research in Ophthalmology and the Department
of Ophthalmology, University of California, San
Reprint requests to Francis I. Proctor Foundation, University of California San Francisco, San
Francisco, CA 94143.
cyclopentolate several times a day. He
instructed to stop all drug therapy,
but when examined every day for the next
four days, the pupils were still dilated and
the epithelial keratitis showed only slight
On the fourth day, the patient was care¬
fully questioned about his use of the cycloplegic-mydriatic type of drop and fi¬
nally admitted that he was using from 100
to 200 drops of tropicamide and cyclo¬
pentolate hydrochloride daily. He was
again admonished to stop all drug therapy,
and over the next four days was able to ta¬
per off so that on the fourth day his pupils
were normal in size (though unresponsive
to light), and the epithelial keratitis had
completely disappeared.
During this tapering off period, the pa¬
tient became very anxious and experienced
Fine diffuse
epithelial keratitis.
sponded very well to lid scrubs, topical ap¬
plications of antibiotics, and the occasional
use of steroids, mydriatics (tropicamide),
and cycloplegics (cyclopentolate 1%).
Then, approximately nine months prior
to his December 1973 visit, the patient de¬
veloped a bilateral diffuse keratitis, more
noticeable below and associated with
photophobia. When treated in the ensuing
months by the referring physician, he
failed to respond to steroids, antibiotics,
lid scrubs, staphylococcus bacteriophage
lysate vaccine, cyclopentolate or tropicamide,
or to a combination of all of these
medications. In fact, both the keratitis and
the photophobia seemed to worsen stead-
When I saw the patient again in Decem¬
ber 1973, there was minimal evidence of
blepharitis. The precorneal tear film was
reduced (Schirmer test: 1 mm of wetting
OD, 5 mm of wetting OS), but the tear
lysozyme level was normal. There was a
blotchy epithelial keratitis, more notice¬
able below but affecting the entire cornea
(Figure). The pupils were widely dilated
and unresponsive to light. The keratitis
suggested the drug-induced toxic type, and
the patient admitted using tropicamide
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excessive salivation, considerable nausea,
vomiting, rigidity, tremors, and a feeling
of urgency. He was given prochlorperazine
(Compazine), 0.005 gm rectally every four
hours for the vomiting. (At this time, the
mother of the patient volunteered that
soon after the onset of his epithelial kera¬
titis, he had begun to sleep most of the
time and had remained largely confined to
his room. Over the nine-month period, he
had lost 14 kg [30 lb].)
For the next three days, he apparently
refrained from using the cycloplegicmydriatic combination, and his eyes were
symptom-free. Although the nausea and
vomiting decreased in amount, the rigidity
and anxiety persisted, and when he was
boarding a commercial plane for his flight
home, seven days after he had stopped all
drug treatment, he became greatly agi¬
tated when his mother would not give him
his eye drops. He assaulted her, verbally
and physically, and had to be physically re¬
strained. He was given chlorpromazine
(Thorazine), hospitalized, and placed on
"crisis observation." The following day,
under medication with chlorpromazine, he
was able to fly home without incident.
A limited degree of tolerance to the
belladonna alkaloids has been ob¬
served in man,1 but since they can be
absorbed directly from the conjuncti¬
val sac to only a limited extent, and
since it is impossible to calculate the
amount that can reach the nasal mu¬
cosa and gastrointestinal tract for
absorption, an estimate of the total
amount that can be absorbed is a
matter of guesswork. We do know,
however, that delirium and psychosis
have occurred in children receiving
only two drops of cyclopentolate hy¬
drochloride 2%2; and several adult
patients of mine have complained of
dryness of the mouth and a "strange,
unreal feeling" after the instillation
of cyclopentolate 2% for refractive
purposes. However, the patient de¬
scribed in this report used more than
25 drops at a time of either tropic¬
amide 1%, cyclopentolate hydrochlo¬
ride 1%, or both, without side effects,
suggesting that he had developed a
considerable degree of tolerance.
Although vomiting, malaise, sweat¬
ing, and excessive salivation have
been noted in patients with Parkin¬
son disease when belladonna drugs
have been suddenly withdrawn, habit¬
uation and addiction have not been
thought to occur.1 Nevertheless, in our
patient's case, withdrawal was ac¬
companied by increased anxiety, ex¬
cessive salivation, rigidity, tremors,
and severe nausea and vomiting, all
of which persisted for more than a
week after the drugs had been with¬
drawn. This certainly suggested
physical habituation. In addition, his
compulsive use of the medications,
with overdosing, profound psycholog-
ical involvement, and the aggression
shown by the attack on his mother in
his effort to obtain the drops, all sug¬
gested true addiction.
The patient had to be frequently
reassured that he was responding to
treatment as he should. His mother
stated that at the onset of his eye
problem, he began taking four drops
every two hours instead of two drops
every four hours as instructed. Then,
when not relieved of the photophobia
for which the medication had been
prescribed, he gradually increased the
The patient is
an only child living
dominant mother and
an alcoholic father. His means of han¬
dling his anxiety and conflicts by pas¬
sive avoidance (as suggested by his
withdrawal from society while on the
medication), and his physical abuse
of his mother only when his anxiety
reached a high peak, suggest the be¬
havior of a narcotic addict3 rather
than an alcoholic.4 The prognosis for
cure of his addiction, and the pre¬
vention of other types of addiction,
depend on whether both the patient
and his parents take the psychia¬
trist's advice that each of them begin
intensive individual psychotherapy
and pharmacotherapy.
One can only speculate on the cause
of the epithelial keratitis. Was it in¬
duced by the preservative (benzalkonium [Zephiran] chloride 1:10,000 in
cyclopentolate or phenylmercuric ni¬
trate 0.002% in tropicamide), or by the
drugs themselves—one or the other or
in combination? The diminished tear¬
ing, as manifested by the drop in the
Schirmer reading, interfered with
normal dilution of the drugs when
they were instilled into the eye, and
this of course provided a higher than
normal concentration of both the
drug and the preservative to act on
the epithelial surface. To this extent,
at home with
mydriatic played at least a sec¬
ondary role in the production of the
keratitis. It was interesting, however,
that the tears that were produced
contained the normal amount of lythe
sozyme so that the modification was
in quantity only and not in quality.
Benzalkonium has been known to
induce epithelial keratitis in dilutions
of 1:3,500 and 1:1,000,5 but not in a di¬
lution of 1:10,000. Phenylmercuric ni¬
trate has apparently never been
known to cause epithelial keratitis,
but it must be borne in mind that in
the case reported here, the amount of
medication that reached the corneal
epithelium daily
What effect such
amount of either
nitrate or ben¬
zalkonium could have on the epithe¬
lium can of course only be conjec¬
Key Words.—Tolerance; habituation; ad¬
diction; cycloplegics; mydriaties; epithelial
keratitis; preservatives.
Names and
Trademarks of Drugs
Chlorpromazine-CAfor-Pz, Cromedazine,
1. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan
Co, 1965, p 530.
2. Binkhorst RD, et al: Psychotic reaction induced by cyclopentolate (Cyclogyl): Results of pilot study and a double-blind study. Am J Ophthalmol 55:1243-1245, 1963.
3. Zimmering P, et al: Drug addiction in relation to problem of adolescence. Am J Psychiatry
109:272-278, 1952.
4. Zwerling I, Rosenbaum M: Alcoholic addiction and personality (nonpsychotic condition), in
Arieti S (ed): American Handbook of Psychiatry.
New York, Basic Books Inc, Vol 1, 1951, pp 623\x=req-\
5. Swan KC: Reactivity of the ocular tissues to
wetting agents. Am J Ophthalmol 27:1118-1122,
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