Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

with cocaine is not only unnecessary but may be harmful, because cocaine causes sensitization to exogenous epinephrine. Cocaine may loosen the corneal epithelium to a greater extent than other topically applied anesthetics, thus facilitating debridement of the corneal epithelium.

Because cocaine blocks reuptake of norepinephrine and has an adrenergic potentiating effect, its use is contraindicated in patients with systemic hypertension or patients taking adrenergic agonists. The interaction between cocaine and catecholamines contraindicates the use of cocaine in patients taking drugs that modify adrenergic neuronal activity, such as guanethidine, reserpine, tricyclic antidepressants, methyldopa, or monoamine oxidase inhibitors. Additionally, drugs that act directly on adrenergic receptors, such as phenylephrine, are contraindicated with use of cocaine. Because cocaine has a mydriatic effect, it is contraindicated in patients predisposed to angle-closure glaucoma.

The major ocular side effect of cocaine is significant corneal epithelial toxicity. Grossly visible grayish pits and irregularities are readily produced by this drug.These are followed by loosening of the corneal epithelium, which may result in large erosions. Although this characteristic is generally considered to be an adverse effect, it is clinically useful in cases requiring corneal epithelial debridement. However, the corneal epithelial effects of cocaine contraindicate its use in any procedure requiring good visualization through the cornea, such as in retinal detachment surgery or in routine ophthalmoscopy or gonioscopy.

Acute systemic cocaine toxicity may result from as little as 20 mg (10 drops of a 4% solution) of drug. The total dose of cocaine should not exceed 3 mg/kg of

body weight. Typical manifestations of systemic toxicity include excitement, restlessness, headache, rapid and irregular pulse, dilated pupils, nausea, vomiting, abdominal pain, delirium, and convulsions.

Because of the strong abuse potential of cocaine, its distribution and clinical use are subject to federal and state controlled substance regulations under supervision of the Drug Enforcement Administration. Because of its potential ocular and systemic toxicity, cocaine has generally been replaced by the safer synthetic local anesthetics.

Tetracaine

Tetracaine, an ester of para-aminobenzoic acid (PABA), has been widely used for topical anesthesia of the eye. It is currently available in a 0.5% solution. Its onset, intensity, and duration of anesthesia are comparable with those of proparacaine and benoxinate (Figure 6-2). Onset of anesthesia sufficient to permit tonometry or other minor procedures involving the superficial cornea and conjunctiva is 10 to 20 seconds, and duration of anesthesia is 10 to 20 minutes. It has been reported, however, that the 1% solution produces anesthesia lasting nearly an hour. Tetracaine 1% has also been used successfully to provide anesthesia during phacoemulsification cataract surgery and intraocular lens implantation.

Tetracaine causes rapid surface anesthesia, but even repeated applications to the conjunctival surface may fail to achieve effective scleral anesthesia. Preparations of local anesthetics for topical use that include tetracaine should never be injected. Practitioners are cautioned to consider tetracaine a potent and potentially toxic local anesthetic. Dangerous overdoses may occur if it is administered in doses higher than 1.5 mg/kg of body weight.

Figure 6-2 Comparison of onset, intensity, and duration of anesthesia obtained with tetracaine 0.5%, proparacaine 0.5%, and benoxinate 0.4%. (Reprinted with permission from Am J Ophthalmol 1955;40:697–704. Copyright, The Ophthalmic Publishing Company.)

A variety of side effects often accompany the use of topical tetracaine. Tetracaine appears to produce greater corneal compromise than proparacaine, including ultrastructural damage to the cell membrane, loss of microvilli, and desquamation of superficial epithelial cells. Perhaps the greatest objection to the use of tetracaine, however, is the moderate stinging or burning sensation that almost always occurs immediately after its topical instillation. This typically lasts 20 to 30 seconds after drug application. Another problem associated with use of tetracaine is allergic reactions. Local allergy to tetracaine may develop because of repeated use (e.g., in tonometry of glaucoma patients), but this is uncommon. Rarely, tetracaine can exhibit cross-sensitivity with proparacaine.

Benoxinate

Benoxinate is commercially available only in combination with a vital dye solution. It is most commonly combined with sodium fluorescein 0.25%, but recently it was combined with 0.35% disodium fluorexon (Flurasafe by Accutome). Fluorexon is a high-molecular-weight fluorescein that does not stain hydrogel contact lenses; therefore the use of Flurasafe is intended to allow contact lens patients to resume wear sooner without concern of contact lens staining. Benoxinate 0.4%, an ester of PABA, has an onset, intensity, and duration of anesthesia similar to those of tetracaine 0.5% and proparacaine 0.5% (see Figure 6-2). Because benoxinate is available only in combination with a vital dye, its primary clinical use is for applanation tonometry.Although solutions of fluorescein serve as good culture media for Pseudomonas aeruginosa, the benoxinate–sodium fluorescein combination has been shown to have substantial bactericidal properties. Thus, the benoxinate–sodium fluorescein combination is ideal for use in applanation tonometry, because it does not have the same risk for Pseudomonas contamination characteristic of sodium fluorescein solutions.

Relatively few side effects are associated with the clinical use of benoxinate as an ocular anesthetic. Topical instillation typically produces a sensation of stinging or burning that is greater than that produced by the instillation of proparacaine but less than that produced by tetracaine. In addition, benoxinate appears to cause less corneal epithelial desquamation than proparacaine, but this has not been substantiated by controlled clinical studies. Local allergic reactions to benoxinate are rare. Benoxinate may be safely administered to some patients who are allergic to tetracaine, another ester of PABA, without causing allergic reactions, which suggests that the allergenic potential of benoxinate is extremely low. There is no apparent cross-sensitivity between this agent and proparacaine.

Some individuals demonstrate significant increases or decreases (±10 mcm) in corneal thickness after the instillation of topical benoxinate. This effect must be considered when performing preoperative pachymetry before corneal refractive surgery.

Proparacaine

Proparacaine is commercially available in a 0.5% solution, both with and without sodium fluorescein 0.25% (see Table 6-2).The onset, intensity, and duration of anesthesia from these preparations are similar to those of tetracaine 0.5% and benoxinate 0.4% (see Figure 6-2). Proparacaine, however, does not appear to penetrate into the cornea or conjunctiva as well as tetracaine.

When used without sodium fluorescein, proparacaine is widely used as a general-purpose topical anesthetic. It produces little or no discomfort or irritation on instillation and is therefore readily accepted by most patients. When compared directly with tetracaine, 86% of patients reported that proparacaine caused less pain on administration. Unopened bottles may be stored at room temperature, but once opened the bottles should be tightly capped and, ideally, refrigerated to retard discoloration. Discolored solutions of proparacaine should be discarded.

Proparacaine has few side effects. Although localized allergic hypersensitivity reactions may develop, these are rare and occur less frequently with proparacaine than with tetracaine. Allergic reactions may be characterized by conjunctival hyperemia and edema, edematous eyelids, and lacrimation. After topical ocular instillation in recommended doses, allergic systemic manifestations are extremely rare. Topically instilled proparacaine was reported to have a possible role in the development of a hypersensitivity reaction that resulted in exacerbation of an existing case of Stevens-Johnson syndrome. Proparacaine was also reported to cause allergic contact dermatitis on the fingertips.This rare work-related hazard was confirmed by skin-patch testing. Rarely, proparacaine can exhibit cross-sensitivity with tetracaine.

As with benoxinate, corneal thickness instability can occur for about 5 minutes after proparacaine administration.

90 CHAPTER 6 Local Anesthetics

These changes in corneal thickness should be considered when obtaining measurements for refractive surgery or when performing pachymetry in glaucoma patients.

SIDE EFFECTS

When used in recommended dosages, severe local reactions to topically applied anesthetics are exceedingly rare, and systemic reactions are even more uncommon. Although side effects can occur after use of topical anesthetics, adverse reactions are much more likely to occur with use of local anesthetics injected for infiltration or regional nerve block. Any use of local anesthetics, including topically applied anesthetics, can cause systemic toxicity, but the majority of such systemic reactions occur as a result of overdosage of the drug. Topical ocular use of local anesthetics leading to systemic manifestations of a true allergic hypersensitivity reaction is exceedingly rare.

In general, patients who are particularly susceptible to the development of adverse reactions include those with known drug allergies, asthma, cardiovascular disease, liver disease, or hyperthyroidism and patients taking acetylcholinesterase inhibitors. Elderly patients, debilitated patients, and infants are also more vulnerable.

Local reactions include relatively minor allergic or toxic involvement of the cornea, conjunctiva, or lids. Although the small amounts of anesthetic normally used in topical ocular applications are usually insufficient to cause toxic systemic effects, systemic toxicity can potentially occur in any patient if the topical anesthetic is applied in dosages exceeding those normally recommended.There was one report of a systemic reaction after topical proparacaine described as a dermatologic allergic reaction in a patient with preexisting Stevens-Johnson syndrome. In general, serious ocular or systemic side effects from local anesthetics have been associated with the use of cocaine or anesthetics for infiltration and regional nerve block or as a result of prolonged use by self-administration.

Toxicity

Ocular

It is not uncommon for topically applied anesthetics, especially benoxinate and tetracaine, to cause mild local stinging or burning after instillation. As discussed previously, however, this lasts only momentarily and requires no specific treatment other than patient reassurance.

In some patients, especially those over age 50 years, a localized or diffuse desquamation of corneal epithelium becomes evident (Figure 6-3). This epithelial reaction usually consists of superficial punctate keratitis and probably results from exposure and tear film instability associated with decreased reflex tearing, infrequent blinking, and increased tear evaporation. The punctate keratopathy is frequently absent immediately after anesthetic instillation but may appear 5 to 30 minutes later (Figure 6-4).

Figure 6-3 Number of epithelial cells (mean ± standard error) irrigated from precorneal tear film at different times. In the 2- to 6-hour period after instillation of 0.5% proparacaine, the number of cells was significantly greater with the anesthetic than with the control (p <.001, paired t-test). (Reprinted with permission from Wilson GS, Fullard RJ. Proparacaine sloughs cells. J Am Optom Assoc 1988;59: 701–702.)

Although it is usually mild and of no clinical significance, occasionally it can be extensive enough to reduce vision to from 20/80 (6/24) to 20/200 (6/60). In its most severe form, it may be characterized by a diffuse, necrotizing, epithelial keratitis with filament formation and corneal edema, but this has been reported to occur in less than 1 of every 1,000 patients receiving a topical ocular anesthetic.The cornea can appear gray because of the epithelial and stromal edema, and folds may develop in Descemet’s membrane. The conjunctiva can be hyperemic, and the patient may complain of blurred vision or photophobia. There may be lacrimation and mild to intense ocular pain, which may occur later because of the initial corneal anesthesia. Because the corneal epithelium begins to regenerate almost immediately, treatment other than reassurance or instillation of ocular lubricating agents is usually not required (see Figure 6-4). In moderate to severe cases the episode should be treated as a superficial corneal abrasion. Toxic reactions should be recorded in the patient’s chart. Particularly severe epitheliopathies may be mediated by an allergic hypersensitivity; therefore a different topical anesthetic should be used on subsequent patient visits.

The repeated administration of topical ocular anesthetics should be avoided because it may significantly retard

A

B

Figure 6-4 (A) Severe toxic corneal epithelial desquamation after instillation of proparacaine 0.5%. (B) Same cornea 24 hours later, demonstrating the rapidity with which healing occurs.

healing of corneal epithelium.Topical anesthetics can be particularly dangerous when given to patients for selfadministration. The diagnosis and treatment of severe corneal toxicity associated with the long-term highfrequency administration of topical anesthetics are discussed later in this chapter.

Systemic

With the exception of one case of grand mal seizure possibly associated with the topical application of benoxinate, no cases of serious systemic reactions caused by topically instilled ocular anesthetics have occurred.

However, because 98% or more of systemic reactions to local injectable anesthetics are due to drug overdose, such systemic toxic reactions can potentially occur with the excessive administration of topical anesthetics to the eye. Topically applied anesthetics are rapidly absorbed into the systemic circulation, and their blood levels rise almost as rapidly as after intravenous injection.

Systemic absorption of topical anesthetics can result in high blood levels by any of the following mechanisms:

(1) too large a dosage of the local anesthetic; (2) unusually rapid absorption of the drug, as in patients with marked conjunctival hyperemia; (3) unusually slow drug detoxification; and (4) slow elimination of the drug.

High blood levels after topical application or injection of anesthetics may potentially cause systemic reactions. Toxic effects may appear in the central nervous system (CNS), cardiovascular system, or respiratory system. CNS toxicity appears initially as stimulation and may manifest itself clinically as nervousness, tremors, or convulsions. CNS depression, observed clinically as loss of consciousness and depression of respiration, usually follows. The earliest signs of cardiovascular involvement are hypertension, tachycardia, and, occasionally, cardiac arrhythmias. Late cardiovascular signs are hypotension, absent pulse, and weak or absent heartbeat. The effects on the cardiovascular system can develop either simultaneously with CNS depression or alone. If allowed to continue, such cardiac depression and resultant peripheral vasodilation are followed by secondary respiratory failure.

The liver, for the amide-type anesthetics, or plasma esterases, for the ester-type, can eliminate large amounts of local anesthetics. Within 30 to 60 minutes sufficient elimination of the overdose usually occurs to make the CNS stimulation or depression short-lived. Management objectives should therefore center on temporary respiratory and cardiovascular support. Administration of supplemental oxygen usually rapidly restores normal CNS function. In patients in whom cardiovascular collapse is evident, vasopressor therapy may take the form of metaraminol bitartrate 1% (Aramine) given intramuscularly or intravenously. The effect of this potent short-acting vasopressor lasts 20 to 60 minutes, depending on route of administration.

Hypersensitivity

Ocular

Although local allergy to topical anesthetics can develop in some patients because of routine diagnostic use over many months or years (e.g., for tonometry), these reactions are extremely uncommon. Allergic episodes occur mainly with use of the ester groups of anesthetics—that is, the commonly used anesthetics for topical ocular use. Although allergic reactions are also possible with the use of the amide group of anesthetics for local injection, such as lidocaine, mepivacaine, and bupivacaine, they occur much less frequently than with the ester group.The usual clinical presentation after topical anesthesia is that of a mild transient blepharoconjunctivitis characterized by conjunctival hyperemia and chemosis, swelling of the eyelids, lacrimation, and itching (Figure 6-5). These signs and symptoms usually appear 5 to 10 minutes after instillation of the anesthetic. Such reactions may be treated with topical decongestants and cold compresses.

92 CHAPTER 6 Local Anesthetics

Figure 6-5 Allergic blepharoconjunctivitis after instillation of proparacaine 0.5%. Conjunctival hyperemia, swelling of the eyelids, lacrimation, and itching occur.

Practitioners should record the event in the patient’s chart and avoid using the same anesthetic on subsequent patient visits. Because there is apparently little crosssensitivity between classes of local anesthetics, practitioners can usually change from proparacaine to an ester of PABA, or vice versa, with little risk of local allergy. Unfortunately, no topical anesthetics approved for ocular use have an amide linkage. Such anesthetics, because of their extremely low allergenic potential, would serve as ideal topical ocular anesthetics.

Systemic

Type I allergic reactions are estimated to account for less than 1% of all adverse reactions to local anesthetics. Moreover, no life-threatening allergic responses to anesthetics applied topically to the eye have been reported. The small amounts of anesthetic absorbed systemically after topical instillation are usually not sufficient to cause systemic reactions. However, topical anesthetics can cause systemic reactions if enough drug is absorbed into the systemic circulation. Most minor drug-induced systemic allergies are characterized by angioneurotic edema, urticaria (hives), bronchospasm, and hypotension. Joint pain and pruritus occur less commonly. Treatment should be directed toward symptomatic relief by the use of systemically administered antihistamines, bronchodilators, or epinephrine.A history of extensive drug allergies should alert practitioners to such a possible consequence of anesthetic administration, but no evidence of immediate hypersensitivity reactions was found when patients with a history of anesthetic allergy were rechallenged, which suggests the relative safety of anesthetic use in such individuals.

Anaphylactoid reactions to local injectable anesthetics are extremely rare. Although these reactions are usually immediate,they may be delayed as long as 15 to 30 minutes. Anaphylactoid reactions are characterized by a sudden circulatory collapse after drug administration. Urticaria, respiratory distress, cyanosis, and hypotension usually occur. Treatment directed at correcting the circulatory collapse and respiratory failure must be initiated promptly, because even a short delay can be fatal.

Table 6-3

Suggested Maximum Dosages of Topical Anesthetics

Modified from Lyle WM, Page C. Possible adverse effects from local anesthetics and the treatment of these reactions. Am J Optom Physiol Opt 1975;52:736–744.

Psychomotor Reactions

Psychomotor reactions such as vasovagal syncope (fainting) may be readily mistaken for an adverse drug-related systemic reaction. However, such responses are not drug related and usually occur from anxiety related to the office visit.Accordingly, they may occur before, during, or after drug administration. If fainting occurs, patients should be reclined with their head in a low position, tight clothing around the neck loosened, and protected from falling or otherwise injuring themselves. Recovery is usually spontaneous within a few seconds. Respiration and cardiovascular status should be monitored to eliminate drug-induced anaphylaxis as a possible cause of the collapse.

Prevention of Adverse Systemic Reactions

Although it is unlikely that serious systemic reactions will occur from topical ocular application of local anesthetics, practitioners must limit the dosages of the drugs to those compatible with effective anesthesia without substantial risk of systemic toxicity. The determination of exact dosage limits of local anesthetics is impossible, but it has been suggested that the total dose applied topically to mucous membranes such as the conjunctiva should not exceed one-fourth of the maximum allowed for injection. Table 6-3 shows suggested maximum dosages of topical anesthetics based on this formula. It has been reported that the toxicity of local anesthetics increases geometrically rather than arithmetically with increases in concentration.Thus, whereas a given dose of a 1% solution would be four times as toxic as an equal amount of 0.5% solution, a 2% solution would be approximately 16 times as toxic as an equal dose of 0.5% solution.

CONTRAINDICATIONS

Generally, local anesthetics can be used with little risk of significant adverse local or systemic effects.The following specific contraindications should help to ensure the safe and effective ocular use of these anesthetics.

Hypersensitivity

As previously stated, allergic reactions to local anesthetics are rare and are virtually limited to the ester-linked anesthetics (see Box 6-1). Allergy to the amide-linked anesthetics such as lidocaine is extremely rare. Unfortunately, intradermal skin tests and conjunctival and patch tests are not reliable for predicting the possibility of allergic reactions. When administering a topical anesthetic, it is advisable to use a drug from a different chemical family if a patient reports a history of hypersensitivity to a specific anesthetic. For example, an allergic reaction to a paraaminobenzoate derivative, such as procaine, should alert the practitioner to avoid using a similar drug such as tetracaine or benoxinate. In such cases proparacaine can usually be administered safely without causing an allergic reaction. Lidocaine, an amide-linked drug, may be used topically on the eye, but it is not currently approved by the U.S. Food and Drug Administration for such use.

Hypersensitivity to benzalkonium chloride has been reported in association with the use of ophthalmic medications. Because several of the commonly used topical ocular anesthetics contain benzalkonium as a preservative (see Table 6-2), it is reasonable to assume that some of the local allergic reactions to anesthetics may be due to this preservative.

Liver Disease

Local anesthetics containing an amide linkage are metabolized principally by the liver.Thus, patients with hepatic disease may be more likely to exhibit toxic effects from the injectable anesthetics. Local tissue infiltration or nerve blocks should be avoided or performed using minimally effective anesthetic doses in patients with hepatitis, cirrhosis, extrahepatic obstruction (e.g., lithiasis), or other clinically significant hepatic dysfunction.

Concomitant Medications

Local anesthetics containing an ester linkage are metabolized in plasma by pseudocholinesterases. Thus, patients using anticholinesterase medications may be predisposed to exhibit toxic effects from high doses of topical anesthetics. Multiple applications of topical anesthetics are not usually necessary and should be avoided in patients taking systemic anticholinesterase agents such as neostigmine (Prostigmin) and pyridostigmine (Mestinon).

Dry Eye Testing

Topical anesthetics can cause instability of the tear film and diminish reflex aqueous tear production. Because they disrupt the surface microvilli of the corneal epithelium, anesthetics decrease mucous adherence and can contribute to a reduced tear breakup time. Preservatives present in topical anesthetics, such as benzalkonium

chloride, can also shorten the tear breakup time. These anesthetic-induced changes may affect the examination by masking or otherwise confusing the corneal or conjunctival signs of dry eye. Thus, when the use of sodium fluorescein or lissamine green is anticipated for staining of ocular tissues, the practitioner must avoid instilling an anesthetic until after the vital staining and associated evaluation procedures have been performed.

Perforating Ocular Injury

Topically applied anesthetics may cause corneal endothelial toxicity when used after perforating ocular trauma or when used topically for cataract extraction. When injected intracamerally, benzalkonium chloride, the primary preservative used in topical ocular anesthetics, can cause irreversible corneal edema in rabbits.

Cultures

Whenever possible, culture specimens from the lid margins or conjunctiva should be obtained without the prior instillation of an anesthetic. Preservatives in topical anesthetics exhibit varying degrees of antibacterial and antifungal activity. Moreover, the anesthetic agent itself is often toxic to microorganisms. Proparacaine, when used without preservative, fails to inhibit the growth of

Staphylococcus areus, Pseudomonas aeruginosa, and

Candida albicans. Accordingly, it has been suggested that proparacaine, in single-dose containers without preservative, should be used when topical anesthesia is desired before obtaining material for culture.

Self-Administration of Topical Anesthetics

When evaluating an acute injury of the cornea, the practitioner is sometimes tempted to prescribe a topical anesthetic for administration at home by the patient for relief of ocular pain. This practice is extremely dangerous, however, and in numerous instances has led to severe infiltrative keratitis and even loss of the eye from anesthetic misuse or abuse by the patient.Topical anesthetics must be used only for the purpose of obtaining initial relief of ocular pain and never as part of a prolonged therapeutic regimen.The potential corneal toxicity of topical anesthetics precludes their use as self-administered drugs.

A syndrome has been described resulting from the frequent use of topical anesthetics over prolonged periods ranging from 6 days to 6 weeks. Severe corneal lesions and permanent reduction of visual acuity can occur in any eye that has been subjected to prolonged application of topical anesthetics as a means of relieving the pain of minor injuries. Patients using topical anesthetics on their own and those who have received prescriptions for anesthetics as part of their initial treatment may continue to instill the drugs despite warnings from

94 CHAPTER 6 Local Anesthetics

practitioners to discontinue their use. Furthermore, many of the patients in whom the syndrome has occurred have a medical or paramedical background and thus have easy access to the offending anesthetic.

The numerous signs and symptoms characterizing the syndrome develop over days or weeks. The continuous use of anesthetics, even for only a few days, may cause loss of the corneal epithelium and inhibit the healing of existing epithelial defects. Loss of the epithelial microvilli results in instability and rapid breakup of the tear film, which compounds the drying effect from the decreased blinking secondary to the anesthetic-induced corneal hypoesthesia. Clinically, these changes result in a chronic nonhealing epithelial defect.As the condition progresses, deeper manifestations can include stromal edema with folds in Descemet’s membrane, disciform cellular infiltrations into the corneal stroma, keratic precipitates, anterior uveitis, hypopyon, and hyphema. Additional findings may include eyelid edema, conjunctival hyperemia and papillary hypertrophy, mucopurulent discharge, and corneal vascularization. The primary sign allowing objective diagnosis of this disease appears to be a yellowish white, dense, stromal ring surrounding the primary disease process (Figure 6-6).A history of topical anesthetic abuse, if obtainable, also serves to confirm the diagnosis.

Although the syndrome is easily treated once the cause is known, its recognition may be delayed by deceit on the part of patients.The most important requirement in the management of these patients is discontinuation of the topical anesthetic. Treatment consists of cycloplegic agents, broad-spectrum antibiotics, and possibly a bandage contact lens. Pain must be controlled with systemic analgesics (see Chapter 7). Once the topical anesthetic has been discontinued, remarkable corneal clearing can occur for as long as 6 months.

Figure 6-6 Dense corneal stromal ring associated with abuse of topical anesthetics. (Reprinted with permission from Burns RP, Forster RK, Laibson P, Gipson IK. Chronic toxicity of local anesthetics on the cornea. In: Leopold IH, Burns RP, eds. Symposium on ocular therapy. New York: John Wiley & Sons, 1977;10:31–44.)

ANESTHESIA OF THE SKIN

Patients with a reported history of allergic responses to ester and amide anesthetics pose a challenge, especially when regional anesthesia is necessary. Two alternatives may be considered when minor ophthalmic surgical procedures are performed. A 1% solution of diphenhydramine may be prepared by diluting the 5% solution (Benadryl Steri-Vials) with sterile saline. Additionally, injecting preserved sterile saline alone has been shown to be effective for superficial surgical procedures such as papilloma removal and shave biopsies.

If injectable anesthesia is not possible, several different delivery routes are available that provide sufficient local anesthesia for most minor ophthalmic procedures. Keratinized skin usually provides a barrier preventing diffusion of topical pharmaceutical agents, which makes achieving anesthesia of the skin difficult by topical application. However, a combination of 2.5% lidocaine and 2.5% prilocaine allows high concentrations of the anesthetic bases to be applied to the skin without local irritation. This combination is classified as a eutectic mixture of local anesthetics (EMLA), meaning the melting point of the combination is lower than that of either lidocaine or prilocaine alone. EMLA should be applied in a thick layer (1 to 2 g/10 cm2) to intact skin and covered with a patch of Tegaderm or clear plastic wrap to aid penetration through the epidermis. Anesthesia is achieved by blocking transmission of the dermal neuronal receptors. The preparation should be left on for 1 to 2 hours before the minor surgical procedure. It has been shown to be 87% effective in patients undergoing excisional surgery. EMLA should not be used on mucous membranes because of its increased rate of absorption and risk of greater side effects.

Iontophoresis is a means of penetrating the skin with a topical anesthetic using mild electric current. Lidocainesoaked sponges are applied to the skin, and electrodes are placed on top of the anesthetic pads. Anesthesia can be obtained within 15 to 30 minutes, achieving an anesthetic depth of 1 to 2 cm.This route is infrequently used due to the expense and inconvenience of the apparatus.

Finally, various anesthetic patches are available, such as Lidoderm, although their efficacy in achieving anesthesia before procedures has not been studied. Lidoderm patches contain 5% lidocaine and are approved for treatment of postherpetic neuralgia. Up to three patches can be used at one time for a maximum of 12 hours per day.

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Primary eye care practitioners often encounter patients who are experiencing substantial pain from an underlying ocular disease. For example, patients with corneal or conjunctival foreign bodies, abrasions, or traumatic hyphema usually complain of pain as their primary symptom. This chapter considers the basic mechanisms of pain and its pharmacologic relief. In addition, it offers guidelines for the selection and use of oral analgesics in various situations as well as the management of side effects associated with nonnarcotic and narcotic agents.

MECHANISMS OF PAIN

AND ANALGESIA

Pain is an unpleasant sensory and emotional experience associated with actual or potential damage to tissues. Although pain is a subjective phenomenon, it has both biologic and psychological components that must be addressed if a satisfactory response to pain is to be achieved. Pain can be acute or chronic, and each is a very different clinical entity that requires different approaches to therapy.This chapter discusses only acute ocular pain, which generally has a specific and obvious cause, such as recent trauma or surgery. Such pain is predictable, of limited duration, and resolves when the source of the pain is detected and treated. Fortunately, many ophthalmic patients can be effectively managed with topical agents and local measures (see Chapter 26), which generally have fewer side effects and complications than systemic medications. However, some patients may require additional analgesics, in which case oral agents can be very useful.

The pain signal is initiated at specialized pain endings in peripheral tissues known as nociceptors. These nerve endings are found in the viscera, musculoskeletal system, skin, blood vessels, fascia, subcutaneous tissue, and periosteum, including those structures constituting the eye and orbit. Nociceptors can be activated not only by strong mechanical stimulation, such as trauma, but also by chemical compounds released in response to injury. These chemical mediators involve substances such as serotonin,

bradykinin, and histamine. Arachidonic acid metabolites, including prostaglandins and leukotrienes, do not directly stimulate these nerve endings but rather sensitize the nociceptors to mediators such as bradykinin or histamine, which then interact with substance P to stimulate the nerve endings. Figure 7-1 illustrates the sensitization of nociceptors by prostaglandins and other chemical mediators to produce pain and inflammation in ocular tissues.

Once the pain signals are initiated at the nociceptive nerve endings in ocular tissue, they are conveyed through the trigeminal nerve to the brainstem.There they impinge on cells of the sensory and spinal nuclei of the trigeminal nerve. The trigeminal nucleus in turn sends the pain message ultimately to the somatosensory cortical areas of the brain, where the degree and location of the pain are perceived.

Although much attention is given to the emotional effects of the pain process, the physiologic effects of pain can be quite significant and can lead to harmful cardiorespiratory responses, including tachycardia, systemic hypertension, and tachypnea. Increases in peripheral vasoconstriction, blood pressure, and workload of the heart can create a dangerous situation for patients with preexisting cardiovascular disease. These physiologic changes mandate that in certain patients the pain be rapidly terminated, not only to make the patient more comfortable, but also to moderate the increased cardiovascular risks. If not appropriately relieved, pain can also lead to emotional distress manifested by poor sleep patterns, anxiety, and even uncooperativeness, all of which may result in slow and unsatisfactory resolution of the ocular condition that is initiating the pain.

Acute ocular pain almost always responds to pharmacologic intervention. Analgesic drugs act in three principal ways:

1.Peripherally acting agents. These drugs act on the peripheral pain receptors and prevent sensitization and discharge of the nociceptors. Nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, block the formation of inflammatory and pain mediators, such as prostaglandins, at the cyclooxygenase pathway.

PAIN

Opioids block perception of and emotional response to pain

CNS

NOCICEPTOR

Damaged Cell Membrane

Arachidonic Acid

NSAIDs block

generation of Cyclooxygenase pain signal by

inhibiting synthesis of PGE2

PGE2

Histamine

2.Anesthetic agents.The nociceptive signal can be interrupted between its peripheral source and its central target in the brain or spinal cord. However, the longterm use of topical anesthetics for treatment of acute ocular pain can lead to serious complications and is thus discouraged.

3.Centrally acting agents. These drugs interact with specific receptors in the central nervous system (CNS), interrupting both the pain message and its emotional responses. Patients who take centrally acting analgesics are usually indifferent to perceived pain. The opioid (narcotic) analgesics act in this manner.

The peripherally acting and centrally acting analgesics

are the mainstay of pain management in outpatient practice.

The most useful agents in each class are discussed in the following sections.

NONOPIOID (NONNARCOTIC)

ANALGESICS

The nonopioid analgesics are the drugs of choice for treating mild to moderate pain. Among these, the NSAIDs are typically the most effective and are usually safe for short-term use. Although some clinicians regard the NSAIDs as generally less effective but safer than narcotic analgesics, this presumption is misleading, because both types of analgesics have a significant sideeffect potential.The NSAIDs are effective for many types of acute ocular pain, especially when the pain is associated with inflammation. Acetaminophen is also useful as an analgesic for mild to moderate pain but has no effect on inflammation.

Salicylates

Pharmacology

The salicylate aspirin (acetylsalicylic acid) is the oldest nonopioid analgesic. In addition to analgesic effects, the salicylates have important anti-inflammatory and antipyretic properties.Acting primarily in peripheral tissues, aspirin reduces pain by inhibiting synthesis of the prostaglandin E2 by irreversible acetylation and inactivation of cyclooxygenase (see Figure 7-1). The pharmacologic properties of aspirin are predominantly analgesic at lower doses but assume anti-inflammatory effects at higher doses. Full anti-inflammatory effects, however, generally require doses of at least 3 to 4 g daily.

Although aspirin relieves pain primarily through its activity in peripheral tissues (e.g., cornea or conjunctiva), it is also believed to have some central activity by influencing the perception of pain in the hypothalamus. The central mechanisms of action have not been elucidated, but it is clear that when used in therapeutic doses, the salicylates generally produce no clinically significant changes in sensorium or mood. This central activity probably accounts for the analgesic efficacy of aspirin in pain states not associated with inflammation.

All nonnarcotic analgesics, including the salicylates, have a “ceiling effect,” that is, a dosage beyond which no further analgesia occurs. Because the salicylates and other nonnarcotic analgesics do not produce tolerance or physical or psychological dependence, they are relatively safe and nonaddicting.