The cornea is the most densely innervated tissue in the body; thick trunks of nerves enter the stroma and send a large plexus through Bowman’s membrane to just beneath the basal epithelial layer.1 The corneal nerves come from the nasociliary nerve, which originates in the first branch of the trigeminal nerve (V1).2 Because the cornea is so richly innervated, it is incredibly sensitive.

It has been estimated that the density of corneal pain receptors is 300 to 600 times greater than that of the skin, and up to 40 times the density of those found in dental pulp.3 Therefore, any injury to the cornea, such as an abrasion or extensive keratitis, can be an extremely painful experience. Though often short-lived, this pain can be severe enough to include an opioid in the management plan.

The typical method for controlling moderate pain is to prescribe an opioid combination agent containing an opioid (e.g., codeine, hydrocodone or oxycodone) along with a non-opioid analgesic (e.g., acetaminophen, aspirin or ibuprofen). The safety and tolerability of the non-opioid drug—rather than the opioid—is what limits the dosing.

Drugs containing either codeine or hydrocodone that are combined with acetaminophen or an NSAID are all Class III controlled substances. These drugs require a DEA license.

Examples of this type of drug that practitioners are familiar with are Tylenol-Codeine No. 3 (30mg codeine and 300mg APAP) and Lortab (5mg hydrocodone and 500mg acetaminophen), both of which are prescribed up to one to two tablets every four to six hours as needed for pain.

  ABCs of Analgesia

Opioids act centrally, primarily at the mu and kappa receptors, interrupting the pain message and response. This interaction results in an indifference to the pain. This contrasts with non-steroidal anti-inflammatory drugs (NSAIDs), which exhibit their analgesia peripherally by preventing the stimulation and firing of sensory neurons.4

Acetaminophen (Tylenol), which is also known as paracetamol or N-acetyl-p-aminophenol (APAP), is another type of non-opioid analgesic. Its mechanism of action is not fully understood, but it is thought to be multi-mechanistic—working centrally to reduce pain.5

Health Concerns
APAP has been available for many years and is considered safe, but toxicity can occur. This usually is the case when doses are high. Opioid/acetaminophen combination packages now contain a black box warning of the potential for acute liver failure, should the amount exceed 4000mg daily or if more than one product containing APAP is taken at a time.6

In 2006, APAP was implicated in 140,000 poisoning cases, with 100 resultant deaths. APAP toxicity accounts for more emergency room visits than any other drug, and is now the number one cause of acute liver failure.

APAP is found in hundreds of over-the-counter and prescription medications. It is thought to be used by nearly 25% of American adults weekly, while more than one third of the population is totally unaware of the risk.8A study using investigator-conducted interviews found that only 35% knew that APAP overdoses could result in liver damage.9

Perhaps more troubling is that only 17% were aware that overdoses could result in death.9 APAP toxicity may be due to acute overdose, repeated excessive dosing or use of multiple APAP containing medications. The majority of these overdoses are unintentional; 63% are attributed to APAP-hydrocodone combinations.10

It’s possible for APAP liver toxicity to occur even when taken at the recommended doses if the patient has certain risk factors, such as chronic alcohol use (three or more drinks a day), malnutrition or concurrent use of drugs that are metabolized using the cytochrome P450 enzymes (e.g., isoniazid, dapsone and isoflurane).

The Flap Over APAP
Because of these concerns about APAP and the increasing incidence of toxicity, in 2011, the FDA asked manufacturers to limit acetaminophen to a maximum of 325mg per tablet or capsule in all opioid combination drugs by January 14, 2014.11

According to the FDA, no available data demonstrates that more than 325mg of APAP per dosage unit is beneficial enough to outweigh the risk of hepatoxicity.

More than half of the manufacturers of these combination drugs have already voluntarily complied. For example, the Vicodin (Abbott Laboratories) tablet containing 5mg hydrocodone and 500mg of APAP has been discontinued and replaced with a new combination that maintains the 5mg hydrocodone component but reduces APAP to 300mg.

Similarly, Vicodin ES (7.5mg hydrocodone) now contains 300mg APAP instead of the previous 750mg, and Vicodin HP (10mg hydrocodone) has a reduced dosage per tablet of APAP from 660mg to 300mg. Prescribing two tablets at once (600mg APAP per dose) is still thought to be acceptable if it is necessary to manage a patient’s pain.

Because limiting the amount of APAP is currently voluntary, some products still contain more than the recommended upper limit of 325mg. The FDA is recommending that pharmacists who receive prescriptions for a product containing more than 325mg APAP should contact the prescriber to discuss the possibility of an alternative with a lesser amount of APAP.

Additionally, the FDA plans to begin proceedings in the near future to withdraw approval of combination products containing more than 325mg APAP. If there are questions about this change, contact the Division of Drug Information at (888) 463-6332 or [email protected].12

So, now when prescribing an opioid combination for a corneal abrasion or other source of ocular pain, one must not only select the appropriate opioid but should also carefully consider any non-opioid medication contained in the product.

A review by the Cochrane Oral Health Group comparing the effectiveness of APAP to ibuprofen to relieve pain following dental surgery concluded that ibuprofen was superior to APAP for analgesia.13 If this carries over for ocular pain, a combination to consider would be Vicoprofen (AbbVie, Inc.), which contains 7.5mg hydrocodone and 200mg ibuprofen.

To avoid APAP altogether, the FDA approved Zohydro ER (Zogenix) on October 25, 2013—the first single-entity product containing only hydrocodone. It is indicated for management of severe pain requiring long-term, daily, around-the-clock opioid treatment. Unlike hydrocodone combination products (e.g., Vicodin, Vicoprofen), it is classified as a Schedule II drug.

Zohydro ER is available in six strengths: 10mg, 15mg, 20mg, 30mg, 40mg and 50mg extended-release capsules. Dosing is every 12 hours. Because Zohydro ER is not recommended when dosing for as-needed pain management, this product will have limited use in managing ocular conditions. While the liver toxicity concern is removed, the potential for abuse certainly exists; therefore, judicious prescribing will be essential.

Another impending regulation change is the likely reclassification of hydrocodone combination products to Schedule II. The FDA was expected to submit a formal recommendation to the Department of Health and Human Services urging this reclassification. If the National Institute on Drug Abuse concurs, the review process will continue and lead to a final decision by the DEA. Should hydrocodone products be reclassified to Schedule II, Tylenol-Codeine No. 3 will still remain in Schedule III.

This expected change will have a significant impact on practitioners, as many states have therapeutic privileges allowing Schedule III medications, but only a handful allow prescribing Schedule II drugs.

Acute ocular pain can be severe; therefore, appropriate management is essential. Opioids are effective analgesics, so they should be used (as your licensing permits) when choosing a treatment regimen. But, it is important to keep in mind the potential risks and recent changes that may impact our ability to prescribe these drugs.

1.Woreta FA, et al. Management of post-photorefractive keratectomy pain. Surv Ophthalmol. 2013;58(6):529-35.
2. Yanoff M, Duker JS. Ophthalmology, 4th edition. Elsevier Saunders, 2014.
3.Belmonte, C, Gallar J. Corneal Nocicepter. Neurobiology of Nociceptors. Oxford University Press p. 146.
4.Bartlett JD, Siret DJ. Clinical ocular pharmacology, 5th edition Butterworth Heinemann Elsevier, 2008.
5.Hyup LJ, Lee CS, Ultracet ER Study Group. A study to evaluate the efficacy and safety of the extended-release tramadol hydrocholoride/acetaminophen. Clin Ther. 2013;35(11):1830-40. December 2013.
7.Schilling A,et al. Acetaminophen: old drug, new warnings. Cleve Clin J Med. 2010;77(1):19-27.
9.Charpiat B, et al. Overdosed parecetamol (acetaminophen) prescriptions. Ann Pharm Fr. 2013;71(6):410-7.
10.Michna E, et al. Removal of opioid/acetaminophen combination prescription pain medications. Pain Med. 2010;11(3):369-378.
11.Updating changes to acetaminophen-containing opioid products.
13.Bailey E, et al. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth. Cochrane Database Syst Rev. 2013;12:CD004624.