Annual Pharmaceutical Issue
Pain Management in the Optometric Practice
When patients are in pain, over-the-counter or topical medications usually ease
discomfort. But sometimes, an oral narcotic is necessary to reduce the pain.
Release Date: February 2012
Expiration Date: February 1, 2015
Optometrists occasionally encounter patients who
require pain management. Often, these patients can be treated with
over-the-counter medications or common topical ophthalmic drugs.
To that end, this course reviews both topical and oral medications
that are appropriate for pain relief in the optometric practice. Narcotic
agents, in particular, are also discussed.
Steven Ferrucci, O.D., and Marc
This course is COPE-approved for 2 hour of CE credit. COPE ID is 33851-PH. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
education course is joint-sponsored
by the Pennsylvania College of Optometry.
Dr. Ferrucci is on the advisory board for
Arctic DX, Alcon, Allergan and Reichert. Dr. Bloomenstein is a
consultant and on the speakers’ bureau for Abbott Medical Optics,
Allergan, Alcon Laboratories, Bausch + Lomb, Ista Pharmaceuticals,
RPS and Reichert, and on the speakers’ bureau for Merck and
Odyssey Labs. The authors have no financial interest in any products
aside from their consulting agreements.
As optometrists, we will occasionally come across patients
who require pain management. Although the need for
pain relief is most often acute and
lasts perhaps just 24 to 48 hours or
less, patients certainly appreciate
the cessation of discomfort. Incidences that necessitate pain control
include corneal abrasions, foreign
bodies, trauma, or after refractive
or cataract surgery. Pain may also
be associated with inflammation—
most notably intraocular pain, such
as that associated with episcleritis
or preseptal cellulitis. In certain
circumstances, a bandage contact
lens, ophthalmic ointments or pressure patching may be enough to aid
in patient comfort and augment the
More often, topical agents, such
as non-steroidal agents (NSAIDs),
with or without cycloplegics may
be adequate. Yet in severe cases, an
oral agent in the form of a narcotic
is needed to reduce the pain.
This article reviews the various
agents used for pain relief in the
optometric practice, as well as some
pearls and pitfalls to treating pain.
Know What You Are Treating
Before initiating any treatment
for pain management, you need to
do a thorough medical history that
particularly focuses on allergies and
current medications. Interactions
of drugs and allergic response can aggravate an already unfortunate
problem. Along these same lines,
determine if your patient has any
medical issues that may limit your
ability to prescribe the appropriate
treatment or recommended dose
(e.g., issues with metabolizing or
clearing the meds).
It is imperative to determine the
true cause of the pain, and treat it
accordingly. Otherwise, all we are
doing is masking the pain, without
truly remedying the problem. The
pain may be something that your
patient has experienced before, so
during your history remember the
mnemonic FOLDAR: Frequency,
Onset, Location, Duration, Association and Relief. Asking these
questions can help to localize the discomfort or give you a good indication of the treatment options already
attempted to placate the pain.
The nature of the pain, as well as
its severity, should also be assessed.
Gauging the pain is helpful and can
be accomplished by subjectively asking the patient to assess their pain
on a scale from 0 (“no pain”) to 10
(“the worst pain ever”). While each
person has a different threshold of
pain, it is important to make sure
that as we treat the pain and the
underlying condition, the patient’s
relative discomfort is decreasing, not
increasing. Although the irritation
may sometimes get worse before
it gets better, if the pain is increasing with treatment then we have
to assume we either misdiagnosed
or mistreated the condition. This
indicates that we need to change the
The first line of pain management
often can be initiated with a topical medication. The advantage with
topical formulations—aside from the
medication reaching the superficial
tissue (episclera, cornea, etc.) in higher concentrations—is that there are
fewer side effects and they are more
easily manageable for the patient.
Ideally, we could simply treat
ocular pain with 0.5% proparacaine
to deaden the cornea-rich nerves
and improve the surface pain.
However, the toxicity and potential
abuse of this class of medication
prohibits that practice, and frankly
is not the standard of care.
Yet, there has been a movement
of late, spurred by the discomfort
induced by surface ablation surgeries, to use a diluted proparacaine for
the analgesic effects. Investigators in
Canada conducted a small, randomized, masked study of adults with
corneal injuries.1 Participants were
treated with either 0.05% proparacaine or an artificial tear placebo.
The proparacaine arm had a significant improvement in pain reduction.
The investigators found no ocular
complications or signs of delayed
healing in either group, and concluded that the use of diluted proparacaine may be an efficacious analgesic
for these acute corneal injuries.
(As described in this study, the
proparacaine was diluted by a factor
of 10, and this can be accomplished
by a pharmacy.1 However, similar
results can be achieved by using
a 3mL sample of artificial tears
diluted with two to three drops of
proparacaine 0.5% solution.)
When this diluted drug is put
into practice, patients who receive
it should be cautioned about the
significant potential for abuse and
potential cornea-related complications. Perhaps even educate the
patient to “not use” these drops—
unless absolutely necessary. Just
knowing that they have it available
to decrease or terminate the acute
pain may provide a psychological benefit for patients to get them
through the worst of the pain, without having to actually use it. Be sure
to ask your patients to bring back
the diluted bottle at a follow-up
appointment (you may be surprised
to see that the bottle is still full), and
discard the remaining drops upon
completion of the treatment.
• Artificial tears. Lubricating
the ocular surface helps reduce
discomfort that may be a concomitant reaction to the inflamed tissue. Moreover, certain treatment
options, such as topical antivirals,
may induce some irritation or dryness that only a lubricating drop
can alleviate. So, the use of artificial tears can provide a minor sense
• NSAIDs. The primary mechanism of action responsible for nonsteroidal anti-inflammatory drugs
(NSAID) and their analgesic effect
is the inhibition of prostaglandin
synthesis by competitive blocking of
cyclooxygenase (COX).2 COX is an
enzyme that is responsible for the
production of inflammatory mediators, such as prostaglandins. The
use of a topical NSAID, frequently
used in surgery patients, can reduce
inflammation, maintain pupil dilation and induce an analgesic effect.
This triad is most useful in the successful management of ocular pain.
Because this class does not work
on the same enzymes as steroids,
there is little concern of any sight
threatening long-term complications. Although some cases of
delayed wound healing and corneal
melts have been reported, the use
of an NSAID for long-term pain management is beneficial; also, the
contributing factors to these corneal
complications may be overuse of the
medication or concomitant systemic
factors, such as diabetes.3 Patients
who report low-grade discomfort,
ocular or periocular allergy or medicamentosa secondary to other medications, as well as acute pain, can
appreciate the analgesic effects.
Unfortunately, the earlier NSAID
formulations sting or burn upon
instillation, so many doctors (and
patients) avoid this line of treatment. However, one strategy to help
patients with the burn upon instillation is to keep the drop in the refrigerator. When the drop is instilled,
it reduces the burning sensation
and provides pain relief like a
For many years, the stalwart
NSAIDs have been Voltaren (diclofenac 0.1%, Novartis) and Acular
LS (ketorolac tromethamine 0.4%,
Allergan). Although both show
a decrease in corneal sensitivity,
these drops require a q.i.d. dosage
and have the added deficiency of
inducing that uncomfortable sting.
Because we want to ameliorate the
pain, not add to it, these side effects
may be a deterrent.
The newer ophthalmic NSAIDs
do not carry the same stinging side
effect and are more readily used for
Acuvail (ketorolac tromethamine
0.45%, Allergan) is the latest
NSAID to be approved by the FDA.
This formulation is preservative
free and is supplied in individual
ampules that are useful for the transient nature of this treatment. This
NSAID is dosed b.i.d. and is indicated for perioperative use one day
prior to cataract surgery. There has
been some concern that this drop
is cost prohibitive. But for patients
who may have recurring pain issues,
such as recurrent corneal erosions,
the availability of a b.i.d.-dosed
analgesic that is preservative free
may justify the price.
Nevanac (nepafenac 0.1%,
Alcon) is a unique NSAID that is a
prodrug. The suspension first touches the cornea as nepafenac, which
delivers the analgesic to the surface
without discomfort associated with
other NSAIDs. As it penetrates
the intraocular tissues, an enzyme
converts nepafenac molecules into
the COX-inhibitor amfenac.4 Alcon
reports that this mechanism of
action gives Nevanac a target-specific activity, maximizing the efficacy
at the intended ocular sites where
pain and inflammation reside.
Bromday (bromfenac 0.09%,
Ista) is a once-a-day selective
NSAID that is indicated for the
treatment of pain and ocular
inflammation following cataract
surgery. Ista reports that this
drop is the most selective and
potent COX-2 inhibitor. The q.d.
dosing may be the perfect solution for the acute pain that your
patients are experiencing and,
from a prophylactic aspect, may
increase patient compliance.
All NSAIDs have the potential
for cross-sensitivity to acetylsalicylic
acid, phenylacetic acid derivatives,
and other nonsteroidal anti-inflammatory agents. So, use caution
when treating individuals who have
previously exhibited sensitivities
to these drugs. Moreover, with the
potential for corneal toxicity and
melting issues, these drops should
be used with precaution when there
is a corneal breach. If there is an
epithelial compromise that lasts longer than a week of treatment, cease
the use of the NSAID.
The NSAIDs are specifically indicated for the treatment of pain and
inflammation in and around cataract surgery; thus, alternative use
would be considered an off-label
treatment. This may become necessary to explain to the pharmacy or
• Cylcoplegics. Often, ocular
pain is related to an intraocular
inflammatory component, or a
superficial corneal problem that
translates internally. An example is
a patient with a foreign body on the
epithelium that also induces an iritis
or internal inflammation. In these
instances, the use of a cycloplegic
agent can help to reduce the excruciating pain your patient is experiencing. Depending on the duration
and extent of cycloplegia and
mydriasis desired (as well as taking
into account that heavily pigmented
irises may require higher strengths),
the exact concentration, dosage and
type of cycloplegic should be determined on a per-case basis.
Cycloplegics block acetylcholine,
a stimulatory neurotransmitter of
the autonomic nervous system.
Because acetylcholine induces
contraction of the iris and ciliary
body, the cycloplegic does the exact
opposite by temporarily inducing
pupil dilation and paralysis of the
ciliary body. The relaxation of the
ciliary spasm induces a reduction
in the pain and stabilizes the bloodaqueous barrier, which reduces the
anterior chamber inflammation.
Atropine, derived from the atropa
belladonna (deadly nightshade)
plant, is the most potent cycloplegic
agent available, with a duration
lasting up to 12 days. Atropine is
available in 0.5%, 1% and 2%
ophthalmic solutions and a 1%
ophthalmic ointment, with a recommended dosage of b.i.d. to t.i.d.
Long-lasting cycloplegia may be
necessary in extreme cases of iritis,
and using such a strong cycloplegic
will also help prevent posterior synechiae formation.
Scopolamine is available in
0.25% ophthalmic solution and
is dosed b.i.d. The choice of scopolamine vs. that of the more
potent atropine should be based
on the severity of the patient’s
Homatropine, another cycloplegic
agent, is available in 2% and 5%
concentrations. With only about
10% the potency of atropine, this is
a very effective drop for those acute
inflammatory pain reactions. It
tends to have a cycloplegic recovery
in one to three days after use.
When a patient presents with a
traumatic corneal injury, such as an
abrasion, consider the use of cyclopentolate instead. Cyclopentolate
is available in 0.5%, 1% or 2%
concentrations. Because this drop is
short-acting, its role is to hold the
potential inflammatory mediators
in the blood vessels and not release
them into the anterior chamber. So,
if you have no other drops at hand,
cyclopentolate is an acceptable
Band-Aid until you can use a stronger cycloplegic.
• Topical steroids. The use of
steroids as adjunctive pain modulators is limited to the cessation of
the inflammation in the eye. As
stated earlier, it is important to find
cause of the discomfort and treat it
accordingly. But, whether that cause
is secondary or idiopathic, steroids
can help treat the underlying inflammation that is producing the pain.
Steroids have a high side-effect
profile and should be limited to
short-term treatment options.
Patients need to be followed more
closely to measure the intraocular pressure (IOP), which may be
raised secondary to the medication. Although some data suggest
that selective steroids, such as
ester-based steroids, have a lower
prevalence of IOP spiking, a good
rule of thumb is to measure the IOP
bi-weekly every time a steroid is
prescribed, regardless of the dosing
and concentration. There are, however, some differences in ophthalmic
steroids, and making a decision of
which would be the most effective
for the patient’s inflammatory pain
should be taken into account.
Loteprednol etabonate is an
ester-based steroid marketed by
Bausch + Lomb
in two concentrations of topical
etabonate 0.2%) and Lotemax
(loteprednol etabonate 0.5%), as
well as an ointment (loteprednol
proven effective in
the reduction of
ocular inflammation. Subsequently,
in a post hoc
analysis of data
provided statistically significant
relief of postoperative pain following
cataract surgery.5 This translates into
superior use for
in your patients
with mild inflammatory conditions.
Durezol (difluprednate 0.05%
emulsion, Alcon) is the first and
only FDA-approved steroid indicated for the treatment of pain
following cataract surgery. The
recommended dosage is one drop,
b.i.d to q.i.d., postoperatively.
Durezol has been shown to be
as effective q.i.d. as prednisolone
acetate administered eight times a
day in resolving inflammation and
pain associated with endogenous
anterior uveitis.6 This suggests that
Durezol can be effectively used at a
lower dosage than other steroids.
Before initiating any oral pain
management, a more thorough medical history of the patient is warranted. Be sure to ask about alcohol use,
antidepressant use, smoking, history
of stomach ulcers and pregnancy
in appropriate patients, because
these may be contraindications for
certain treatments. Also, be sure to
ask about any current medications
as well as over-the-counter (OTC)
preparations that the patient may be
taking—especially warfarin, digoxin
and antidepressants, because these
have interactions with many other
medications. Additionally, check the
patient’s medical history for kidney
or liver disease, as medications may
be metabolized and cleared less
quickly with liver or renal status.
Lastly, make sure to inquire about
a history of previous allergy to any
medications, especially aspirin, and
In general, start with the simplest,
most cost-effective treatment and
work up, depending on the patient’s
level of pain, symptoms, etc. So,
OTC agents are often the first line
treatment for mild to moderate
pain. Yet, caution your patients
about the notion of “more is better,” because the side effects of
these medications, although OTC,
may be significant.
• Over-the-counter options. There are several OTC preparations that can be recommended for
Aspirin (acetylsalicylic acid) is
available in a variety of forms and
is very inexpensive. However, it is
not great for pain relief, and a low
dose (81mg/day) is generally used
more for stroke, myocardial infarction and blood clot prevention than
for true pain relief. Dosage for analgesia is typically 650mg to 975mg
every four hours. It is contraindicated in patients with a history of
aspirin allergy, bleeding ulcers or
other bleeding disorders as well as
in patients who consume more than
three alcoholic beverages a day,
or are pregnant as it is category D
medication (positive evidence of
risk). Another consideration: Avoid
aspirin in patients less than 18 years
of age or with viral illnesses, such as
the flu or chicken pox, due to concerns of Reye’s syndrome.
Acetaminophen is also available in many preparations, such
as brand-name Tylenol (McNeil) or as a generic. It is much better
at relieving pain than aspirin, but
does not have any platelet or antiinflammatory properties like aspirin
or NSAIDs. The new recommended
dosage is 650mg to 975mg every
four hours for pain relief, with a
maximum daily dose of 3,000mg
to prevent liver toxicity. It is safe to
use during pregnancy, with bleeding
disorders, and in children with viral
infections because there is no danger
of Reye’s syndrome, as with aspirin.
It is contraindicated in patients with
liver disease, alcoholism or a history
of acetaminophen hypersensitivity.
Over-the-counter NSAIDs are
readily available as well, and are
effective for mild to moderate pain
relief. They have the added benefit
of anti-inflammatory control; due
to this dual effect, they are often a
good choice for a patient with ocular pain from iritis, for example.
Ibuprofen is available OTC as
brand-name Motrin (McNeil) or
as ageneric. It can be dosed from
200mg to 800mg every four hours,
with a maximum daily dose of
2,400 mg. The side effects of ibuprofen—stomach upset and GI
toxicity—can be lessened if the daily
dose is kept under 1,600mg per day.
Naproxen sodium is another OTC
NSAID option, available as Aleve
(Bayer Healthcare) and as a generic.
Dosage is 220mg every eight to 12
hours, with a maximum dose of
1,500mg per day. Many doctors recommend two pills as a loading dose
and then one pill every eight to 12
hours thereafter, with no more than
three pills in a 24-hour period.
Contraindications to all the
NSAIDs include GI bleeding, avid
alcohol use and pregnancy (because
it is category C, an unknown risk).
Also, they should be avoided in
patients with a known hypersensitivity to NSAIDs and used in caution
with patients with an aspirin allergy,
as there may be a crossover effect.
There are also many NSAIDs
available by prescription only, such
as naproxen. Its recommended dose
is 500mg initially, then 250mg every
six to eight hours thereafter for
reduction of pain and inflammation.
Indomethacin is also a commonly
used NSAID for the pain, tenderness, swelling and stiffness caused
by arthritis, but it has no indication
for general pain. However, it is used
frequently in eye care for the treatment of scleritis, typically 25mg to
50mg three times a day.
• Narcotics. When greater pain
relief is needed, the next step is a
narcotic. Narcotics should be used
judiciously; but when used appropriately, they are great options for
patients in moderate to severe pain.
Rules governing prescribing of narcotics by optometrists vary state by
state, so be familiar with your particular state’s rules. As an example,
an optometrist in California can prescribe Schedule III narcotics if there is a direct indication for ocular pain.
(See “States That Permit Optometrists to Prescribe Controlled [Narcotic] Legend Drugs, below”)
|Source: AOA State Government Relations Center
Last Revised April 28, 2011
2. Treatment for ocular pain and inflammation.
3. Treatment with only those oral analgesic drugs included in
4. Therapeutically-certified ODs may utilize any pharmaceutical
agent rational to the treatment of eye disease.
5. Treatment with controlled analgesic drugs over 72 hours may
not be done without consultation with the patient’s physician.
6. Within the Schedule II category - topical only is permitted
(this would be the one controlled drug available for diagnostic
7. Within the Schedule III category - no agents containing dihydrocodeinone
| other Schedule III drugs limited
to Rx not to exceed 96 hours.
8. Prescriptions limited to dosages for no more than 72 hours.
9. Treatment with acetaminophen plus 30mg of codeine only.
10. Prescription of analgesics for a duration of no more than
11. Compounds containing codeine or hydrocodone only.
12. Treatment with Schedule III analgesics longer than 7 days
requires consultation with an MD.
13. Plus may prescribe dihydrocodeinone combination drugs, no
matter what class they are scheduled in.
14. Prescription for controlled narcotic substance may not be for
more than 7 days for a single condition, trauma, episode.
15. Rx of narcotic for 48 hours only. May be followed with one
|additional 48 hour Rx if warranted by follow-up exam.
16. Prescriptions limited to analgesics in dosages for no more than 72 hours.
17. Prescriptions limited to 4 days quantity.
18. Prescriptions limited to one 5 day supply of analgesics in
Schedules III, IV, and V.
State optometry acts specifically prohibiting optometrists from
prescribing controlled (narcotic) legend drugs: Delaware, Hawaii,
Indiana, and Massachusetts (when referring to this list of states
which specifically prohibit the prescription of controlled drugs,
remember that other states not listed here authorizing “topical
agents only” or “specific categories only” could essentially prohibit
the use of controlled narcotic drugs as well.)
Codeine is a very useful narcotic
for mild to moderate pain relief. It is
not typically prescribed by itself, but
rather in conjunction with either
aspirin or Tylenol. When combined
with aspirin, it has the added benefit
of inflammatory control. However,
when combined with Tylenol, the
codeine and the Tylenol work on
separate areas of the central nervous
system to produce a synergistic
effect and very good pain relief.
The most common form of
codeine is Tylenol #3, which has
30mg of codeine and 300mg of acetaminophen. (Tylenol #1 has 15mg
codeine and Tylenol #4 has 60mg
of codeine—each with the same
amount of acetaminophen, 300mg).
Its recommended dose is one to two
tablets every four to six hours, with
a maximum daily dose of 360mg
codeine and 4,000mg Tylenol.
Empirin (Glaxo Wellcome) with
codeine #3 is 30mg of codeine combined with 325mg of aspirin. Empirin with codeine #4 is 60mg codeine
with 325mg aspirin. Recommended
dose of either is one tablet every
four to six hours, with a maximum
daily dose of 360mg of codeine.
Codeine can be fairly sedating, so
advise caution, especially if a patient
has not used it previously. Also, GI
disturbances are common, with constipation being the most reported
Hydrocodone is about six times
as potent as codeine, and may cause
less constipation and sedation than
codeine. Like codeine, hydrocodone
is a Schedule III drug and is commonly co-formulated with either
Tylenol or ibuprofen. The most
commonly prescribed form is Vicodin (Abbott Laboratories), which
is 5mg hydrocodone with 500mg
acetaminophen. Recommended dose
is one to two tabs every four to six
hours, with a maximum dose of
eight tablets per day, or 4,000 mg
It is also available as Vicodin ES
(extra strength), which is 7.5mg
hydrocodone and 750mg acetaminophen, with a maximum dose of five
tablets per day. Vicodin HP (high
potency) is 10mg hydrocodone with
660mg acetaminophen, with a maximum of six tablets per day.
Hydrocodone also can be combined with ibuprofen for added
inflammatory control in the form
of Vicoprofen (Abbott Laboratories), which is 7.5mg hydrocodone
and 200mg ibuprofen, given one
to two tabs every four to six hours,
with a maximum dose of five tablets per day.
Tramadol is a synthetic analogue
of codeine; but it is non-narcotic,
so it is not DEA classified. Tramadol has similar potency as Tylenol
#3, but its abuse and addiction
potential is very low. It has minimal side effects, including dizziness, headaches, nausea, vomiting
and drowsiness. However, it has
many interactions with other drugs,
including tegretol, digoxin, warfarin
and others. Also, it should be avoided in patients with a history of seizures. Recommended dose is 50mg
to 100mg every four to six hours
with a maximum dose of 400mg
a day. (Individuals 75 years and
older should be limited to 300mg
a day.) When combined with acetaminophen, it is called Ultacet (37.5
Ortho-McNeil-Janssen) with a recommended dose of one to two tablets every four to five hours.
Side effects of these narcotics
include drowsiness, respiratory
depression, liver toxicity, renal failure and urinary retention, nausea
and vomiting, and abuse or addiction potential. However, when used
appropriately for the short term,
many of these side effects are never
realized. Further, addiction and
abuse potential is very low when
used for such a short period of time.
The treatment of pain is not
limited to on-label indications, and
finding the right dosing should be individualized. A realistic goal is to
provide relief of the discomfort the
fastest way possible with the least
amount of side effects. Bear in mind
that there is sometimes a disconnect between the severity of the
pain and the physical signs. Yet, we
as clinicians need to balance both
when helping patients get back to
Looking for a topical solution is
optimal and yet is not always possible. Combining treatments may be
the best solution; so don’t be afraid
to write multiple prescriptions to
alleviate your patient’s discomfort.
At the end of the day, your
patient just wants to feel better.
Dr. Ferrucci is chief of optometry
and residency director at the Sepulveda VA Ambulatory Care Center
and Nursing Home in North Hills,
Calif. He is also an associate professor at Southern California College
of Optometry. Dr. Bloomenstein is
the director of optometric services at
Schwartz Laser Eye Center in Scottsdale, Ariz. He is the immediate past
president of the Optometric Council
on Refractive Technology.
- Ball IM, Seabrook J, Desai N, et al. Dilute proparacaine for the management of acute corneal injuries in the emergency department. CJEM.
- Vane JR. Inhibition of prostaglandin synthesis as a mechanism of
action for aspirin-like drugs. Nat New Biol. 1971 Jun 23;231(25):2325.
- Congdon NG, Schein OD, von Kulajta P, et al. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. 2001 Apr;27(4):622-31.
- Gamache DA, Graff G, Brady MT, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced
ocular inflammation: I. Assessment of anti-inflammatory efficacy.
Inflammation. 2000 Aug;24(4):357-70.
- Comstock TL, Paterno MR, Singh A, et al. Safety and efficacy of
loteprednol etabonate ophthalmic ointment 0.5% for the treatment of
inflammation and pain following cataract surgery. Clin Ophthalmol.
- Foster CS, Davanzo R, Flynn TE, et al. Durezol (Difluprednate Ophthalmic Emulsion 0.05%) compared with Pred Forte 1% ophthalmic
suspension in the treatment of endogenous anterior uveitis. J Ocul
Pharmacol Ther. 2010 Oct;26(5):475-83.