Recognizing causes, manifestations of chronic ocular pain

San Francisco-Chronic pain can occur after refractive surgery, but it also can occur in patients with non-surgical ocular disease. It is important to distinguish both the causes and the manifestations of pain before one can successfully treat it, according to Todd P. Margolis, MD, PhD.

“I’m interested in pain largely from a different perspective,” said Dr. Margolis, professor of ophthalmology, director of the Francis I. Proctor Foundation, and director of the Ralph and Sophie Heintz Research Laboratory, University of California, San Francisco. “I don’t do refractive surgery, but I see a lot of patients with herpetic eye disease, particularly herpes zoster, where we have postherpetic neuralgia.”

For example, many patients with herpetic eye disease present to Dr. Margolis with post-herpetic neuralgia, he noted.

In post-herpetic neuralgia, the trigeminal ganglion undergoes damage. This nerve damage causes post-herpetic neuralgia about 1 month or so after the initial disease presents.

Such pain is known as neuropathic pain, which is characterized by burning pain, hyperalgesia, and allodynia. Hyperalgesia describes conditions in which less intense stimuli are perceived as painful; and allodynia, when innocuous stimuli are perceived as painful.

“If you’re going to take care of these patients, it’s really important to differentiate chronic pain and understand these things,” he said.

Dr. Margolis explained that many patients present reporting chronic pain after refractive surgery, yet with perfectly normal appearing eyes. These patients complain of the same symptoms: allodynia, hyperalgesia, burning pain, and spontaneous pain.

“After the first month, most of the abnormal sensations are not due to dryness,” he said. “If you look at the literature, most of the studies suggest that tear metrics are normal. To call it dry eye after that is doing a disservice. These changes follow neural injury. Not surprisingly, there’s nerve damage, just like in zoster.”

Molecular breakdown

Dr. Margolis touched on the molecular basis of nociception, specifically on the different channels that mediate nociceptive input, as well as different types of receptors that mediate different kinds of pain. These include:

• TRPV1 channel: Heat responsive TRPV1 receptors will respond to sustained stimuli, heat, and inflammatory mediators with poorly localized pain and burning.

• TRPM8 channel: Here, cold responsive receptors will respond to tear evaporation and regulate tear secretion.

• MrgprDr channel: These mechanically responsive receptors, will signal a turned-in eyelash with very acute and sharp well-localized pain.

• TLR7 channel: These receptors are itch responsive.

“Mechanoreceptors will give you sharp, acute, well localized pain,” Dr. Margolis said. “Cold receptors give you feeling of dryness in response to cold and evaporation. Polymodal receptors give you burning pain in response to chronic stimuli.”

Surgery and/or trauma increase the sensitivity of cold receptors, thus increasing the sensation of dryness. Allergies increase the sensitivity of polymodal receptors, but decrease the sensitivity of cold receptors. Finally, inflammation increases the sensitivity of the polymodal receptors.

Acute versus chronic

The ability to distinguish between acute pain and chronic pain is very important in this assessment, Dr. Margolis continued.

“They are not the same thing,” he stressed.

Acute pain is proportional to stimulus, fairly well localized, and rapidly dissipating.

Chronic pain is characterized by hyperalgesia, allodynia, and a burning sensation.

Dr. Margolis related that chronic pain is not just prolonged acute pain, but a maladaptation of the nervous system, and it is characterized by a dramatic anatomical and biochemical re-organization of the nervous system.

Dr. Margolis detailed the proper steps to take in assessing ocular pain:

• Take a careful history. Find out if the pain is localized or not.

• Assess adnexal structures, he said, “because the whole eye and everything around it is complicated. Sinuses can give you pain, things in the orbit can give you pain, things from the teeth can give you pain, so you have to sort this out.”

• Test corneal sensation to find out whether it is intact.

• Evaluate the patient’s tears and ocular surface.

• Stain the ocular surface, not just with fluorescein but with lissamine green or rose Bengal.

• Palpate the globe, lids, and sinuses.

In his patient assessments, Dr. Margolis also considers the effects of topical anesthesia, cycloplegia, corticosteroids and other agents, confocal of the corneal nerves, and MRIs of the orbits and sinuses to rule out other problems.

“If I put topical anesthesia in and the pain doesn’t go away, we’re not talking about ocular surface disease; we’re talking about something else, and immediately, you can divvy it up into different categories,” he said.

“If the cycloplegia makes it go away, then you’re dealing with inflammation that affects the anterior chamber,” Dr. Margolis said. “I also look at the effects of steroids, and not just topical steroids but also systemic steroids. I will give up to 80 mg of prednisone for a couple of days to see if decreasing inflammation anywhere in the body will decrease the pain. If it doesn’t, you know it’s probably not inflammatory and once again, know we’re talking more about neuropathic pain.”

Managing pain

Managing chronic ocular pain includes talking to the patient, treating underlying conditions, reducing exposure and evaporative tear loss, and reducing ocular manipulation, Dr. Margolis added.

“It’s really important to talk to these patients,” he said. “No one is listening to them. All the other doctors have told them they have dry eye; they’ve put plugs in them; they’ve done various other things. That’s usually not what is going on.”

To treat chronic pain, ophthalmologists must also familiarize themselves with all of the systemic medications used to treat chronic pain, Dr. Margolis stressed.

“We’re all trained as general physicians,” he said. “There is no reason why you should not be able to do this.”

These agents include not just pregabalin (75 to 150 mg BID) and gabapentin (330 to 1,200 mg TID), but the following agents as well, all of which are approved for not just chronic pain but neuropathic pain as well:

• Duloxetine (30 to 60 mg QD)(Cymbalta, Eli Lilly and Co.);

• Amitriptyline (25 to 150 mg/d);

• Baclofen (10 to 20 mg TID) (Baclosan, Beklo, Gablofen, Kemstro, Liofen, Lioresal); and

• Carbamazepine (100 to 400 mg BID) (Carbatrol, Equetro, Tegretol, Tegretol XR).

In addition, Dr. Margolis related that for acute pain, he will use opiates, such as tramadol (50 to 100 mg q4 to 6 hours)(Conzip, Ryzolt, Ultram, Ultram ER) for short periods. Tramadol is an opiate that has less abuse potential and is better tolerated than other opioids. It has a dual mechanism of action and affects the mu (μ) opiate receptor and inhibits serotonin/norepinephrine uptake. Therefore, this agent is good for both neuropathic pain and mood.

Finally, he advised, physicians can engage in some ophthalmic psychiatry:

• Show interest;

• Validate that the pain is real;

• Reduce ocular manipulation;

• Provide positive reinforcement; and

• Help patients manage their anxiety.

“We must remember that chronic pain is a disease in and of itself and not necessarily just an ocular surface problem,” he concluded.

Todd P. Margolis, MD, PhD

P: 415/502-0298

E: Todd.Margolis@ucsf.edu

Dr. Margolis has no financial disclosures.

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