Article Date: 12/1/2007



Minimize pain by learning about its mechanisms and treatment.

BRUCE E. ONOFREY, O.D., R.PH., F.A.A.O., Albuquerque, New Mexico

Pain is both our friend and enemy. As a friend, it warns us when injury has occurred. As our enemy, it inflicts varying degrees of discomfort.

Here, I discuss the mechanisms of pain and the two principle types of pharmaceuticals to control pain.

Pain mechanisms

The first step to controlling pain is to understand the physiology of its mechanisms and the anatomy of its pathways. Pain receptors are called nociceptors. Chemical, thermal or mechanical stimuli can activate nociceptors. Chemical mediators released following tissue injury can also trigger nociceptors.

During pain, neurons release substance P (preparation) — a neuropeptide that functions as a neurotransmitter and neuromodulator. It's classified as a tachykinin (a member of a group of polypeptides located in the vertebrae) that facilitates transmission of pain signals from the peripheral receptors to the central nervous system (CNS).

Substance P also recruits mast cells that produce prostaglandins and bradykinins (cytokines) that can directly stimulate peripheral pain receptors. Mast cells also release preformed histamine. In addition to substance P's ability to stimulate pain receptors, it also produces local edema and hyperemia in the affected area.

Pain stimuli produce two important responses. The first is a fast reflex response, which doesn't depend on "feeling" the pain. The pain signal reaches the reflex arc, which is located in the spinal cord's dorsal horn. Messages (nerve impulses) out of the dorsal horn then travel via motor nerves that produce the rapid withdrawal response from the pain stimuli. An example: If you perform a contact tonometry without an anesthetic agent, the patient's response is immediate and precedes the brain perceiving the actual pain sensation.

Perception of pain is a cognitive function that occurs when the pain signal transmits from the spinal cord to the thalamus, which is located in the brain stem. This is why the pain pathway is known as the spinal-thalamic tract. The thalamus sends signals to areas of the CNS that control blood pressure, heart rate, breathing and emotions. Therefore, the pain stimulus can produce a rise in heart rate, blood pressure and breathing rate. Once the pain signal reaches and is processed by the primary cortical areas of the brain, the individual perceives the "sensation" of pain. The cortex produces the emotional response to pain. Individuals vary greatly in their relative perception and tolerance of pain.

We (healthcare practitioners) rely on pharmaceutical agents to block or modulate the pain signal or its perception at all levels of the pain pathway. Anesthetics and analgesics work to control pain.


Counsel patients on why a procedure is necessary (the benefit), the expected amount and duration of the discomfort and the way in which you'll reduce the discomfort (anesthetic) before performing any clinical procedure that can induce pain or discomfort. Patients don't like surprises.

Anesthetic agents temporarily block the sensation of pain during diagnostic and therapeutic procedures, making them invaluable to practitioners. They block the action potential in pain fibers by reducing the influx of sodium ions into the nerve cytoplasm. If the sodium ions cannot flow into the neuron, the potassium ions can't flow out, thus inhibiting the depolarization of the nerve. If this process can be inhibited for just a few nodes of Ranvier along the way, then nerve impulses generated downstream from the blocked nodes cannot propagate to the ganglion. To accomplish this feat, the anesthetic molecules must actually enter through the cell membrane of the nerve. Herein lie the differences in the potency, time of onset and duration of the various local anesthetics.

The two major types of local anesthetics are amino-esters and amino-amides. Proparacaine and tetracaine are the most common ester forms of ophthalmic anesthetic agents.1 Ester anesthetics produce an almost instantaneous and significant anesthetic effect when applied to the avascular cornea. This is why they're popular topical agents for corneal foreign-body removal and contact tonometry.

The problem with esther agents: They have a relatively "short-lived" and limited anesthetic effect on vascularized tissues, such as the conjunctiva, limbal corneal area and lachrymal drainage system.1 This is because plasma cholinesterase agents in the blood rapidly metabolize esters. Therefore, to attain adequate anesthesia in vascularized tissues, consider a topical amide anesthetic.

Patient Contraindications for Analgesic Treatment
Drug allergies to analgesic treatment, which can include sulfonamides (NSAIDS)

■ Past drug addiction/abuse
■ Alcoholism
■ Dangerous job (analgesics produce sedation/drowsiness. Therefore there is an increase of on-the-job injuries)

■ Pregnancy
■ Gastric peptic ulcer
■ Renal disease
■ Liver disease
■ Diabetes

■ Current analgesic use
■ Antihistamines
■ Sedatives/sleeping agents

Topical lidocaine 4% is an amide anesthetic. The liver metabolizes amide anesthetics. Consequently, they produce an improved anesthetic effect in the conjunctiva and other vascular tissues of the eye. For this reason, I've found that lidocaine is particularly useful in removing conjunctival cysts, concretions and foreign bodies. I've also noticed that it produces improved comfort when performing lachrymal procedures, such as probing, irrigation and punctual dilation when sizing and inserting punctal plugs.

You can enhance the local anesthetic effect of lidocaine by adding a sympathomimetic vasoconstrictor. In injectable forms of lidocaine, the vasoconstrictor epinephrine is included. For topical use, I suggest instilling the vasoconstrictor phenylephrine 2.5%. This slows the absorption and removal of lidocaine from the tissues, prolonging pain relief, and it reduces conjunctival bleeding.

A caveat: Allergic reactions aren't uncommon with anesthetic agents, particularly the esther anesthetics. Allergic reactions can range from local itching, redness and chemosis/edema to a full blown, anaphyalactic reaction. Be certain to question patients about any prior reaction to local anesthetic agents.1 Something else to keep in mind: Occasionally, patients respond to the administration of anesthetics or to a procedure itself with a vasovagal response. To preclude allergic reactions and prevent a patient from falling, obtain a thorough medical history from your patients, which includes questions about these adverse effects.


Analgesic agents help modulate the production and perception of pain for extended periods of time. In other words, they remove pain. An important note: Pain is not a disease. It's a sign of an injury or disorder that you must diagnose in conjunction with managing pain. For instance, although a headache is a common and usually benign condition, it can also signal a serious organic disorder, such as an infectious meningitis. Therefore, practitioners never treat headaches with pain-relieving analgesics until they've identified and managed the cause.

Be very direct when questioning patients about their level of discomfort. Do this by asking about the quality of the pain (is it sharp, aching or burning?). Also, ask how long the patient has experienced the pain (duration) and its level. To grade pain, use a 10-point scale with zero equal to no pain, and 10 being the greatest amount of pain. Some patients are reluctant to request a prescription for a pain-relieving agent, as they fear appearing as a "complainer." Encourage the patient to speak openly and honestly about his level of pain, and educate him on your plan to minimize his discomfort.

Treating Herpes Zoster Patients
Trigeminal neuralgia, a chronic pain condition that affects the trigeminal or fifth cranial nerve (one of the largest nerves in the head), is commonly associated with recurrent Herpes zoster infections ("shingles"). It can be quite severe and resistant to common analgesic drugs. The best way to reduce the incidence of post-herpetic trigeminal neuralgia is the timely use (within 72 hours of initial herpes outbreak) of an oral antiviral agent, such as acyclovir or famciclovir. If trigeminal neuralgia persists past the acute episode of herpes zoster, the use of tricyclic antidepressants, such as amitriptyline, can be very effective as adjunctive therapy in relieving this type of pain. Administration of 25mg of amitriptyline at bedtime not only decreases the pain of trigeminal neuralgia, but also promotes sleep, due to its anticholinergic properties.
Gabapentin (Neurontin, Pfizer) is an FDA-approved oral medication for the management of postherpetic neuralgia (PHN). You must gradually increase and decrease the dosage of this drug to avoid neurological side-effects, such as confusion and dizziness. A common maintenance dose of gabapentin is 1200mg to 1800mg in a divided dose t.i.d. Practitioners have prescribed dosages of more than 300mg, but these result in significant side effects.

Common ocular conditions that require systemic analgesic therapy: corneal abrasion, erosion and micropuncture, Ultraviolet keratitis, thermal/chemical corneal injury, dacryocystitis, scleritis, cellulitis, uveitis and periocular trauma.

Your choice of an analgesic depends on a carefully obtained profile of the patient's medical, social and drug history. (See Patient Contraindications for Analgesic Treatment.") The analgesics from which to choose:

Peripheral agents. These drugs, acetaminophen and Non-steroidal anti-inflammatories (NSAIDs), inhibit the formation of prostaglandins by blocking the enzyme cyclooxygenase (COX). This prevents prostaglandins from stimulating peripheral pain fibers.

Acetaminophen appears to produce analgesia by elevating the pain threshold. The potential mechanism may involve the inhibition of the nitric oxide pathway mediated by a variety of chemical substances that include N-methyl-D-aspartate (NMDA) and substance P. NMDA receptors transmit the pain signal to the brain stem from the spinal tract.

Recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which acetaminophen selectively inhibits and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2.2 Researchers now believe that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the effectiveness of acetaminophen in relieving pain and reducing fever without producing unwanted gastrointestinal (GI) side effects.2

In addition to its direct analgesic effect, acetaminophen enhances the efficacy of opioids and NSAIDs and is commonly found in combination-analgesic compounds.3 Also, acetaminophen produces an antipyretic effect (fever reduction). The mechanism: It appears to inhibit the action of endogenous pyrogens on the heat-regulating centers in the brain by blocking the formation and release of prostaglandins in the CNS. Acetaminophen cannot, however, inhibit the inflammatory response.

Risk factors for acetaminophen hepatoxicity include dehydration or fasting, alcohol abuse, concurrent use of isoniazid (tuberculosis treatment), zidovudine (Acquired Immune Deficiency Syndrome and Human Immuno-deficiency Virus treatment) or a barbiturate, and overdosage. (See "Acetaminophen Dosages," right.)

All existing NSAIDs, except celecoxib (Celebrex, Pfizer, Inc.), non-selectively inhibit COX 1 and COX 2 — the two principle COX compounds, Celecoxib selectively inhibits COX 2.4 This selectivity for COX 2 somewhat lessens GI side effects.

NSAIDs are associated with a number of side effects. The frequency of side effects varies among the drugs. The most common side effects: nausea, vomiting, diarrhea, constipation, decreased appetite, rash, dizziness, headache and drowsiness.3 NSAIDs may also cause fluid retention, leading to edema. The most serious side effects: kidney failure, liver failure, ulcers and prolonged bleeding after an injury or surgery.3

Some individuals are allergic to NSAIDs and may develop shortness of breath after use. Asthmatics are at a higher risk than non-asthmatics for experiencing serious allergic reactions to NSAIDs. Further, individuals with a serious allergy to one NSAID are likely to be allergic to a different NSAID.4

Do not prescribe aspirin and non-aspirin salicylates to children and teenagers who have suspected or confirmed chicken pox or influenza. The use of these agents in conjunction with these conditions has been associated with the development of Reye's syndrome.

All NSAIDs have the potential to increase the risk of bleeding, however acetylsalicylic acid (aspirin) irreversibly inhibits blood platelets and therefore is a potent anti-clotting agent. It's particularly important to avoid their use in patients who are or may be pregnant, as they have the potential to produce fetal abnormalities, such as renal toxicity.5

Acetaminophen Dosages4
WELL-HYDRATED CHILD: 15 mg/kg every four to six hours
DEHYDRATION RISK: 10 mg/kg every four to six hours
a. Age >2 months (5 kg): 80mg per dose
b. Age >4 months (6.5 kg): 100mg per dose
c. Age >6 months (8 kg): 120mg per dose
d. Age >12 months (10 kg): 160mg per dose
e. Age >2 years (13 kg): 200mg per dose
f. Age >3 years (15 kg): 240mg per dose
g. Age >5 years (19 kg): 280mg per dose
MAXIMUM: 90 mg/kg/day (to four grams per day)

Currently, 21 NSAIDs are approved in the United States. Among them: aspirin, ibuprofen, indomethacin, ketoprofen and naproxen.

All NSAIDs exhibit analgesic, anti-inflammatory and anti-pyretic effects. The major differences among NSAIDs is their potency and duration of effect. There is very little difference in efficacy when you administer the drugs in equivalent dosages. For example, a dose of 600mg to 800mg of ibuprofen q.i.d. is roughly equivalent to 250mg to 500mg of naproxen.

Central analgesics. The classic, central-acting analgesic compounds are all opiate derivatives. An opioid is a chemical family that has a morphine-like action in the body. The drugs in this class are either natural or semi-synthetic derivatives of the opium alkaloids or, as in propoxyphene, a fully synthetic compound. Opiates modify the perception of pain by binding to opioid receptors in the CNS and GI tract. The receptors in these two organ systems mediate both the beneficial and the undesirable effects of these agents. The three principle opioid receptors are mu, kappa and delta, all located throughout the CNS.6 In addition to their sensitivity to opiates, they also bind endogenous endorphins.

The mu receptor is the classic opioid receptor. The physiologic effect of mu receptors include analgesia, sedation, decreased blood pressure, itching, nausea, euphoria and respiratory depression.6 These receptors exhibit a tolerance effect, with declining efficacy, resulting from continued use of these agents. Patients exposed to opiate agents for the first time are particularly prone to respiratory depression and nausea.6 These adverse effects decline, however, with continued use.

Kappa receptors also induce an analgesic effect. Unfortunately, they produce significant nausea and diaphoresis (sweating).6 The endogenous (natural) neurotransmitters that bind to the kappa receptors are called dynorphins. These receptors are located near peripheral pain neurons.

The delta receptors can produce "ischemic preconditioning." This is a protective physiologic response that induces an increase in blood flow to tissues surrounding an ischemic area. Researchers have postulated a cardioprotective effect.6 The endogenous neurotransmitter for delta receptors are known as enkephalins.

The beneficial effects of opioids through extended periods diminish unless one raises the dose. This effect is known as drug tolerance and is a result of several factors. First, the number of receptors becomes reduced. This physiologic response is called receptor down-regulation. Second, stimulation of the NMDA receptors results in increased dorsal horn sensitivity in the spinal-thalamic tract. This enhances the transmission of the pain signal to the brain, resulting in an increase in pain perception.

Because opiate analgesic agents are deemed controlled substances (their addictive nature), the DEA monitors their distribution.

The opiate analgesic agents are deemed controlled substances, due to their addictive nature. In fact, the Federal Drug Enforcement Agency (DEA) monitors their distribution.

If you wish to prescribe these drugs, your state must allow you to do so. You must then obtain a state-controlled substance license and a DEA license. Further, you must supply the DEA registration number to a pharmacy to fill a narcotic prescription.

The DEA has classified narcotic agents individually by their potential for abuse. It has classified commercially available drugs with the greatest abuse potential as schedule II drugs. The least abuse potential fall into category V. The prescription of Schedule I agents, such as heroin and marijuana, is against Federal law.

I've found that Acetaminophen and aspirin are two of the most common adjuvants to opiates, due to their synergistic painrelieving benefits. The most popular of the analgesic combination drugs are acetaminophen with codeine #'s 2,3 and 4.4 This consists of a fixed dose of acetaminophen (325mg) with variable amounts of codeine 15mg (#2), 30mg (#3) and 60mg (#4). The most popular of this group is acetaminophen #3. Its ratio of acetaminophen to codeine maximizes the dosage of both ingredients and allows for very flexible dosing.

Minimizing abuse and side effects

Patient counseling is critical when prescribing narcotics. Document that the patient isn't allergic to these agents. Opiate allergy is one of the most commonly reported drug allergies after penicillins and sulfonamides.3 Also document that you advised the patient of the most common opiate side effects: sedation, GI upset and the potential for interactions with other agents, particularly antihistamines, sedatives and alcohol.

Proper documentation is important to avoid legal complications that may arise from narcotic-induced accidents or injury.

Write out the number of tablets on the prescription and the number of refills in both numerals and in the script to prevent prescription alteration.

Signs of potential drug abuse:

► symptoms exceed expected amount of pain;

► patient exhibits a suspicious knowledge of narcotics;

► patient exhausts supply of medication faster than expected and requests repeated refills;

► patient "loses" his medication or prescription and requests a "replacement;"

► slurred speech or diminished cognition during office visits;

► patient is a known drug abuser.

When you don't want to prescribe a narcotic agent, the patient doesn't want a narcotic or is allergic to opiates, or you're not licensed to prescribe narcotics, an excellent alternative treatment is an NSAID combined with acetaminophen. An example of this therapy: 400mg to 600mg of ibuprofen combined with 1000mg of acetaminophen used up to q.i.d. prn pain. This combination is only indicated for adults who have no contraindications to either NSAIDs or acetaminophen.

By being aware of the physiology of pain mechanisms, the anatomy of pain pathways, how anesthetics and analgesics work, the patient's medical history and disease pathophysiology, you'll be able to prescribe the appropriate pain medications. Proper medication can greatly improve the patient's clinical experience and his quality of life. OM


1. Biscoping J, Bachmann-Mennenga MB. Local anesthetics from ester to isomer. Anasthesiol Intensivmed Notfallmed Schmerzther. 2000 May;35(5):285-292 [German].

2. Scwab JM, Beiter T, Linder JU, et al. COX-3--a virtual pain target in humans? FASEB 2003 Dec;17(15):2174-5.

3. Onofrey BE. "Clinical Optometric Pharmacology and Therapeutics" Lslf edition. Lippincott Williams & Wilkins; 1998

4. "Drug Facts and Comparisons 2007: Published by Facts & Comparisons" 61 Har/Cdr edition, Indianapolis, Ind. Lippincott Williams & Wilkins; 2006

5. Fardet L, Nizard J, Genereau T. Non-selective and selective non-steroidal anti-inflammatory drugs, administration in pregnancy and breast feeding. Presse Med 2002 Sep 28;31(31):1462-8.

6. Zimmerman TJ, Kooner KS, Sharir M, Fechtner RD. "Textbook of Ocular Pharmacology" Philadelphia, Pa. 3Rev edition Lippincott Williams & Wilkins, 1997.

Dr. Onofrey is chief of optometry services and vice-chair of eye services at Lovelace Medical Center in Albuquerque, N.M. He is an adjunct professor at several colleges of optometry. E-mail him at

Optometric Management, Issue: December 2007