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Many off-label treatments fall within optometry’s scope of practice
Medications such as brimonidine, timolol and antihistamines can be useful for nonapproved conditions.
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As knowledge progresses in eye care, we sometimes find that commonly used medications are useful for off-label treatment.
Some fairly common medications are prescribed either by the eye doctor themselves or in consultation with an appropriate specialist off-label to help manage our patients’ conditions more effectively. Although optometrists may not actually prescribe all of the following medications, it is still important for us to know why a comanaged patient is on a certain medication and what ocular findings we need to watch for.
Brimonidine and pupil miosis
Brimonidine is an alpha-2 receptor agonist used for its ability to decrease intraocular pressure in patients with glaucoma or ocular hypertension. It has actions on both the presynaptic terminal and postsynaptic terminal end bulbs of the sympathetic innervation to the eye, specifically the postsynaptic receptors found in the ciliary body and the iris.
However, a relatively unknown side effect of brimonidine is pupillary miosis. Pupillary miosis occurs when norepinephrine (NE) being released in the presynaptic terminal of the sympathetic innervation to the iris is inhibited by brimonidine when the alpha-2 receptors are activated. Because pupillary size is controlled by both parasympathetic innervation for miosis and sympathetic innervation for mydriasis, when NE release is inhibited by brimonidine, its sympathetic response to the iris lessens. This can result in approximately 1 mm to 2 mm of miosis.
The interesting thing about this is that the response is really only present in scotopic conditions. There is negligible to no effect under photopic conditions. This can be extremely beneficial in patients who suffer from glare, halos and other pupil-dependent issues in dark conditions who have had either corneal refractive surgery or orthokeratology. Specifically, this can be helpful in patients who have large pupils whose pupillary diameter is larger than the corneal treatment zone. Brimonidine can be a good option to attempt to reduce pupillary diameter in these patients to ease their symptoms, as one drop in the affected eye(s) will last up to 4 hours, so patients can simply dose themselves with a drop in each eye before going out at night.
This off-label use of brimonidine is definitely within the scope of practice of optometry.
Timolol and superior oblique myokymia
Superior oblique myokymia (SOM) is defined as a monocular quivering of one eye due to sporadic firing of the trochlear nerve, presumably from vascular compression of the dorsal root zone of the trochlear nerve. The sporadic firing can lead to monocular oscillopsia or intermittent diplopia in patients suffering from this. Treatment options in the past have included: observation, medical therapy and surgical interventions. Notably, there have been two case reports in the literature highlighting the use of topical beta-blockers as a possible treatment for this symptomatic neurological problem. Topical betaxolol and timolol have both been anecdotally shown to be a possible treatment option for patients with SOM.
The mechanism of action of these topical medications is only theoretical at this point. Some authors suggest that enough beta-blocker may be absorbed through the conjunctiva to get a systemic effect. Others suggest that the drop works locally on the superior oblique muscle itself or the trochlear nerve endings as they insert into the superior oblique.
As there have been no formal studies on topical beta-blockers for this condition, it is difficult to know for sure how these drugs work. However, in the appropriately screened patients, timolol might be a good starting medication before patients attempt to use other oral medications with more potential serious side effects in the treatment of SOM, such as: carbamazepine, memantine, gabapentin, phenytoin and baclofen.
Of note, it is best left up to the neurologist or neuro-ophthalmologist to prescribe and monitor patients once oral medications are decided on for this condition. But topical beta-blocker use is within the scope of optometry.
Antihistamines and eyelid myokymia
Eyelid myokymia is typically defined as a rhythmic, twitching of the orbicularis oculi muscle and has been associated with elevated stress levels, fatigue, excess caffeine intake, alcohol and tobacco use, and rarely some neurological conditions such as multiple sclerosis. The majority of cases are self-limited and are simply monitored. However, in patients whose symptoms linger or for those who request treatment, one off-label treatment is either topical or oral antihistamine medications such as: ketotifen, epinastine, levocabastine, olopatadine, loratadine and cetirizine. In some rare cases, Botox (onabotulinum toxin-A, Allergan) injections may be necessary to control the patient’s symptoms.
Antihistamines are believed to work on the orbicularis nerve endings to prolong the refractory time of the muscle by relaxing the spasmodic action of the muscle and nerve conduction. However, the topical or oral antihistamine medications may provide a possible treatment option for this condition if needed and certainly would be within the scope of practice of optometrists.
Apraclonidine and Horner syndrome
Horner syndrome (HS) is characterized by ptosis, miosis and anhydrosis of the ipsilateral forehead due to a lesion/disruption of the sympathetic innervation to the ocular tissues. Causes of HS can vary widely, depending on location of lesions, but can include: tumors, strokes, multiple sclerosis, carotid artery dissections, trauma and congenital onset. Typically, with pupil examination the observer will notice anisocoria, which worsens in dim illumination.
Historically, HS has been diagnosed pharmacologically with the use of cocaine solution and hydroxyamphetamine drops. Specifically, absence of dilation with cocaine solution in the affected eye confirms the presence of HS. Once confirmed, hydroxyamphetamine can be instilled 24 to 48 hours later, narrowing down the location of the lesion as either postganglionic vs. central or preganglionic in nature.
Apraclonidine is historically an alpha-agonist glaucoma medication with a stronger affinity for alpha-2 receptors than alpha-1 receptors, but nonetheless it does have a weak alpha-1 effect. With compromised sympathetic innervation to the eye, upregulation of the cell receptors on the iris occurs, making the cells sensitive to sympathetic innervation. The technical term for this is denervation hypersensitivity. When this happens with HS, the involved eye becomes sensitive to apraclonidine’s weak inherent alpha-1 receptor activity and will cause reversal of anisocoria after instillation in both eyes. The noninvolved pupil will remain unaffected by the apraclonidine, and the HS pupil will dilate. In addition, in many cases the ptosis will improve, too, from this weak alpha-1 effect.
The sticking point with this is that it may take up to 5 to 7 days to actually develop denervation hypersensitivity, and usually longer. So if apraclonidine is used too early, a false negative result is also possible. Effectively, apraclonidine replaces cocaine solution in determining the presence or absence of a HS, as cocaine is a controlled substance and difficult to obtain for the vast majority of practitioners. Of note, hydroxyamphetamine or neuroimaging will still be required to localize the lesion after apraclonidine testing. Nonetheless, apraclonidine is a good tool to have in our optometric toolkit.
Topiramate and pseudotumor cerebri/idiopathic intracranial hypertension
Pseudotumor cerebri (PTC) is defined as an increase in intracranial pressure (ICP) in the absence of brain tumors or other causes of increased ICP. In about 95% of cases, PTC will show papilledema upon ocular examination, and approximately 90% of patients will complain of a headache as well. The usual patient with this condition is a young, overweight female.
Historically, PTC has been managed with weight loss and oral acetazolamide. The choroid plexus on the floors of the third and fourth ventricles is responsible for the production of cerebrospinal fluid (CSF) in the brain. As the choroid plexus and ciliary body processes responsible for aqueous formation are extremely similar tissues histologically, acetazolamide can reduce both aqueous production as well as CSF production, leading to decreased ICP via its carbonic anhydrase inhibiting (CAI) actions.
Topiramate is as an oral anticonvulsant medication used in many different neurological conditions and has multiple mechanisms of action. It is still considered a secondary medication behind acetazolamide for PTC, however it is gaining popularity in patients with PTC because topiramate is a partial CAI-inhibitor and it has a propensity to cause anorexia and subsequently help with weight loss. In one study, after 1 year of treatment with topiramate, the mean weight loss was 7.3% of body weight. Because we know a mild amount of weight loss (5% to 10% of body weight) can be curative in some patients with PTC, this two-for-one effect of topiramate helps reduce CSF production as well as encourage weight loss.
It is important to note that topiramate does have the potential for unwanted ocular side effects. Specifically, the two most common side effects are acute angle closure glaucoma and an induced myopic shift, which, if they are to occur, usually do so within the first 2 weeks of starting the medication in 85% of the cases. Treatment of these two possible ocular complications is simply discontinuing the medication, although this should be done under the supervision of the prescribing doctor, usually a neurologist or neuro-ophthalmologist, as to not induce seizures or migraines.
Azithromycin and MGD
Topical azithromycin (AzaSite, Akorn) has been a topic of discussion for off-label use in meibomian gland dysfunction (MGD) for several years now. For MGD, azithromycin is typically prescribed as one drop every day in both eyes for 30 days while rubbing the excess into the eyelashes and along the lid margin due to the increased viscosity of the medication’s vehicle delivery component. Treatment can be discontinued or continued pending the patient’s individual response at his or her 1-month follow up appointment.
To date, some studies have shown that the primary way azithromycin helps MGD is by reorganizing/reordering the abnormal lipids of the meibomian glands into more normal configurations that are more conducive to transportation out of the glands into the tear film. In addition, because azithromycin is an antibiotic in the macrolide family, its ability to reduce the bacterial load on the eyelids and meibomian gland orifices via topical administration can help reduce bacterial lipases that degenerate the normal physiologic lipids found in the meibomian glands and tear film. It is also commonly held that azithromycin contains some anti-inflammatory properties, again, because it is a macrolide antibiotic that is believed to help with the underlying inflammation associated with MGD via inhibition of pro-inflammatory cytokines and matrix metalloproteinases.
It is clear that topical azithromycin is a viable and reasonable option for patients suffering from MGD and, subsequently, it is commonly prescribed by practitioners for this condition despite being FDA-approved for a different clinical use, bacterial conjunctivitis.
Stay abreast of new indications
Although medications must get FDA approval before coming to market, practitioners must be aware that off-label indications do exist for some that we may use in the eye care practice. It is important for us to stay abreast of new ideas and new ways to potentially use medications that have been around a while. Some physicians may be leery of using medications off-label, but in some cases it may be one of the best options for patients.
For example, the topical steroid, difluprednate (Durezol, Alcon), was first approved for inflammation associated with cataract surgery. But after clinical use confirmed its potency, it quickly became one of the “go-to” medications for patients with stubborn or severe iritis despite not being FDA-approved to do so. Naturally, however, this FDA-approved indication for iritis treatment came later. Nonetheless, it is important for practitioners to be comfortable using medications off-label and to stay up-to-date on those that may be helpful in our clinical practices.
- References:
- Ben-Manachem E, et al. Obes Res. 2003;11(4):556-562.
- Bibby K, et al. Br J Ophthalmol. 1994;78(11):882.
- Borgman CJ. J Optom. 2012;doi:10.1016/j.optom.2012.05.001.
- Borgman CJ. J Optom. 2014;doi:10.1016/j.optom.2013.06.004.
- Davagnanam I, et al. Eye (Lond). 2013;doi:10.1038/eye.2012.281.
- Faulkner W. J Cataract Refract Surg. 2003;29(3):423.
- Foulks GN, et al. Cornea. 2010;29(7):781-788.
- McDonald JE, et al. J Cataract Refract Surg. 2001;27(4):560-564.
- Miller NR. Surv Ophthalmol. 2011;doi:10.1016/j.survophthal.2011.02.005.
- For more information:
- Christopher J. Borgman, OD, FAAO, is a clinical instructor at the Southern College of Optometry in Memphis, Tenn., where he can be reached at: cborgman@sco.edu.
Disclosure: Borgman reports no relevant disclosures.