j Am Dent Assoc 2000 Padilla 184 95

CLINICAL

PRACTICE

TOPICAL MEDICATIONS FOR OROFACIAL NEUROPATHIC PAIN: A REVIEWMARIELA PADILLA, D.D.S.; GLENN T. CLARK, D.D.S., M.S.; ROBERT L. MERRILL, D.D.S., M.S.

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Background. The authors discuss the local pharmacotherapy for chronic orofacial neuropathic pain disorders such as neuropathies, neuromas and neuralgias. Methods. The authors conducted a systematic literature review on this topic. The focus of the review involved the two most commonly applied medications for neuropathic disorderslocal anesthetics and capsaicin. Other compounds such as nonsteroidal anti-inflammatory drugs, sympathomimetic agents, anticonvulsants and N-methyl-D-aspartate receptor antagonists also were reviewed. The medication delivery and retention methods appropriate for oral and perioral disease and pain control are described in this article. Results. There are an ever-increasing number of agents that can be used to help patients with neuropathic-based oral and perioral pain problems. Moreover, a clear advancement in the delivery of these medications is the development of a vehicle-car-

rier agent (pluronic lecithin organogel) that can penetrate the mucosa and cutaneous tissues and carry the active medication with it to the treatment site. The major caveat underlying these treatment strategies is that except for patient testimony and a few studies, there are limited empirical data on the efficacy of most of these new formulations, and additional research is clearly needed. Conclusions. Because of their rapid onset and low side-effect profile, topical medications offer a distinct advantage over systemic administration for those orofacial disorders that are regional, near the surface and chronic and that demonstrate some response such as pain relief to topical or subcutaneous anesthetics. Clinical Implications. Practicing dentists now have some new tools they can use to help manage patients who have a chronic nerve pain disorder in and around the mouth.

ways to introduce medications locally using injection or topically via lozenges, nebulizers, inhalers, creams and medicated patches.1 In fact, knowing the various delivery options and then selecting the most appropriate medication for the condition being treated is vital to the success of any local therapy.2-4 For patients with conditions in inaccessible regions or with widespread tissue changes, systemic administration of medication via injection or absorption through the gastrointestinal tract is effective. With regional and local disease that is accessible, however, the administration of a medi184

From the earliest times, humans have found

cation to a specific target area (using local injection or topical application over the site) is a safer, more convenient and possibly more effective method of delivery. This article reviews the relevant issues regarding how topically applied (both intraoral and extraoral) pharmacotherapeutic systems can be used in the management of neuropathic orofacial pain conditions.OROFACIAL DRUG DELIVERY

To be delivered locally in the orofacial region by topical application, an agent must penetrate the natural barriers of the facial skin and oral mucosal tissues. In general, the epithelial and

JADA, Vol. 131, February 2000 Copyright 1998-2001 American Dental Association. All rights reserved.

CLINICAL PRACTICEmucosal barriers limit the quantity of a drug that can be delivered by a topical route for either local or systemic treatment. The skin is an efficient barrier to the ingress of materials, allowing only small quantities of a drug to penetrate over a given period. Some factors may alter this barrier, such as skin integrity, local temperature, the patients age and the presence of any dermal diseases. Moreover, the penetration of a drug through this organ varies with the application site, as epithelial tissue varies greatly in thickness and keritinization.5 To overcome the skins resistance to penetration, the pharmaceutical industry has found different ways (such as adhesive patches and sticky bases) to increase the length of contact between the medications and the target tissues.6 The permeability of both skin and mucosa can be increased by use of a medication with chemical moieties that increase lipid solubility. The oral mucosa is a far less efficient barrier than is the skin. As in the skin, the cornified and keratinized tissues in the oral mucosa are morphological barriers to absorption; however, the tissues in many regions of the mouth are extremely thin, allowing water permeability about 10 times greater than that of skin. In addition to the generally higher permeability of the oral mucosa, several other factors enhance mucosal tissue penetration and absorption: age, salivary lubrication, chronic inflammation, infections, physical damage (such as from cheek biting, rough dental fillings and chemical irritants) and dentures. Several topical intraoral medications are used in the treatment of oral ulceration and infections, including antifungal agents; nonsteroidal antiinflammatory drugs, or NSAIDs; and steroidal agents.7-10 In fact, the intraoral use of topical anesthetics before the administration of dental injections is common in dental practice. In contrast, the use of dermal-penetrating medication delivery systems historically is not common in dentistryalthough if it were, dentists might more often treat conditions such as perioral herpetic lesions successfully. Recently, dentists have been using topical agents with increasing frequency as part of the therapeutic protocol for orofacial painful neuropathy.OROFACIAL PAINFUL NEUROPATHIES

The most common neuropathic pain syndromes in the orofacial region include trigeminal neuralgia; traumatic neuropathy; trigeminal neuroma; postherpetic neuralgia; diabetic neuropathy; cancer-related neuropathy; neuropathy induced by acquired immunodeficiency syndrome, or AIDS; and chroniccontinuous trigeminal nociceptor neuropathy (with and without sympathetic mediation) (Table 1).11-28 The pain mechanisms that generate these problems are different for each neuropathy, and treatment protocols need to be structured and customized accordingly. Specific mechanisms of action result in neuropathic pain. After a crushing or cutting nerve injury to nociceptive neurons, for example, the nerve will attempt to restore its continuity through axonal sprouting. If the nerve sheath is substantially damaged, a persistent neuroma

can form. These new nerve sprouts and neuromas are sensitive to mechanical, thermal and chemical stimulation, which causes them to emit spontaneous painful discharges. Peripheral sensitization of nociceptors also can induce sustained pain sensation. This may occur in response to prolonged excitation of subcutaneous peripheral sensory nerves.29 Additionally, painful ectopic neuronal discharges occur secondary to demyelination disorders (such as multiple sclerosis) and vascular compression of nerves, as in trigeminal neuralgia. Also, after peripheral injury, a small percentage of dorsal root ganglion neurons begin to fire spontaneously, sending low-level A- and C-fiber activity orthodromically into the central nervous system, or CNS, and antidromically into the periphery.30 Regardless of the mechanism, peripheral nerve damage can and does lead to chronic peripheral nociceptor irritability. This occurs through release of inflammatory and excitatory mediators (such as substance P, calcitonin gene-related peptide and other pain-producing agents at the site of injury) and atypical sodium channel expression.31 In addition to changes in the peripheral nerve, central neural changes can develop. These changes occur as a direct result of neuronal injury and prolonged or excessive stimulation of nociceptors. In the orofacial region specifically, central changes involve the secondorder neurons in the trigeminal nucleus, and are mediated by Nmethyl-D-aspartate, or NMDA 32,33; -amino-3-hydroxy5-methyl-4-isoxazole-propionic185


CLINICAL PRACTICETABLE 1

NEUROPATHIC PAIN CONDITIONS IN THE OROFACIAL REGION.CONDITION Trigeminal Neuralgia QUALITY OF PAIN Electriclike, sharp, shooting, lancinating Regional aching sensation with local dysesthesia Electriclike and sharp Burning Loss of sensation, burning, tingling Variable TEMPORAL PATTERN Episodic with periods of remission POSSIBLE ETIOLOGY Vascular compression in the trigeminal nerve root area

Traumatic Neuropathy

Continuous, but may have sharp pain episodes

Neuronal trauma or intense and prolonged inflammation of peripheral nerve

Trigeminal Neuroma Postherpetic Neuralgia Diabetic Neuropathy

Triggered by physical contact or movement Recurrent, persisting pain Continuous pain

Neuroma that develops after transection of the nerve branch Herpes zosterinduced nerve damage Metabolic and vascular abnormalities producing neural damage

CancerRelated Neuropathy

Variable to continuous

Tumor compression of nerves Tumor infiltration of neural structures Metabolic nerve damage due to chemotherapy or radiation therapy

AIDS*-Induced Neuropathy

Variable

Variable

Human immunodeficiency virus induced nerve and central nervous system damage Metabolic nerve damage due to chemotherapy

Trigeminal Nociceptor Neuropathy

Aching, burning or both

Continuous

Mechanism unknown, but most likely caused by peripheral and/or central nociceptor sensitization (central demylination or neoplastic disorders must be ruled out with the use of magnetic resonance imaging) Peripheral and/or central nociceptor sensitization with sympathetically maintained nociceptor activity as determined by lack of response to somatic blocking and positive response to sympathetic ganglion block

Trigeminal Nociceptor Neuropathy With Sympathetic Mediation

Aching, burning or both

Continuous

* AIDS: Acquired immunodeficiency syndrome.

acid; and the kainate and other receptors. In addition, there is a family of glutamate metabotropic receptors that function through guanine nucleotide regulatory G proteins (secondary messengers). Activation of the NMDA receptor causes a cascade of events, including an influx of calcium186

ions and production of the gaseous neurotransmitter nitric oxide. Nitric oxide is able to diffuse out of the second-order neurons to affect presynaptic neurons and manifest a neurotoxic influence on the postsynaptic inhibitory system. It is through this process that central sensitization, secondary

allodynia (pain in response to nonpainful stimuli) and secondary hyperalgesia (exaggerated pain in response to painful stimuli) develop.34 Of course, the exact relationship between the various neurotransmitters and receptors is complex and, as yet, incompletely understood. Neverthe-


CLINICAL PRACTICEless, an understanding of peripheral and central changes that occur in neuropathic pain is critical to the establishment of an adequate treatment protocol. For example, sometimes the applications of topical anesthetics or diagnostic blocks with local anesthetics help differentiate between peripheral and central mechanisms of pain. If the anesthetic blocks the pain effectively, the neuropathy may be peripherally driven, and local medications would be useful.35-37TOPICAL MEDICATIONS FOR OROFACIAL NEUROPATHIC PAIN

Topical medications offer distinct advantages over systemic agents: greater safety, rapid onset of action and low sideeffect profile. However, if local pharmacotherapeutics are to work, the targeted disorders should be regional and chronic and should demonstrate a pain relief response to topical anesthetics. Complete cessation of pain on application of topical anesthetic may not be possible, as some of the neuronal changes may be central or due to neuropathic changes not easily reached by most topical anesthetics. Nevertheless, topical medications are useful for neuropathic pain due to peripheral nerve sensitization, as well as for centralized neuropathy that is accompanied by local allodynia. In the latter situation, the topical medication is used over the trigger site to reduce the ongoing neural stimulation that maintains the central sensitization. In cases of mild-tomoderate pain, the local therapy might be the sole intervention. For moderate-to-severe pain, the use of systemic medications as well as local topical

medications is more appropriate. In addition, a locally applied medication can offer faster relief while a centrally acting medication is being titrated up to effective levels. The medications often used for oral and perioral neuropathies are the topical anesthetics benzocaine or lidocane and the neuropeptide capsaicin; however, use of other compounds such as NSAIDs (diclofenac, ibuprofen or ketoprofen), the sympathetic agent clonidine, the NMDA-blocking agent ketamine hydrochloride, the anticonvulsant carbamazepine, the tricyclic medication amitriptyline, and the antispasmodic baclofen have been reported to be beneficial (Table 2). Topical anesthetics. As neuropathic pain frequently is associated with a peripheral ectopic generator (for instance, a triggering zone near the tissue surface in trigeminal neuralgia), it is logical to use a topical anesthetic to desensitize the painful site. This approach may decrease the neuronal firing and relieve the pain.38,39 Local anesthetics are prepared for topical use in several different forms, such as aqueous or viscous gels, sprays and ointments. With neuropathic conditions, the application of the anesthetic usually is limited to a small area, and in those cases, a sticky ointment or viscous gel often is preferred. Topical lidocaine and benzocaine are used frequently on the oral mucosa. Benzocaine is available in different concentrations and presentations, the most common being paste and gel of 20 percent strength. It is important to prescribe the paste, rather than the benzocaine gel, because as the gel

hardens it leaves a residue on the teeth and can irritate the mucosa. Although systemic toxic reactions are almost nonexistent with prolonged or repeated use of this agent, allergic sensitization may occur. Methemoglobinemia, an emergency medical condition characterized by cyanosis and dyspnea, has been reported in association with the use of benzocaine but is rare.40-43 Topical lidocaine is available in different concentrations as a viscous solution, a liquid and an aerosol spray. The 5 percent viscous gel is most commonly used for oral topical anesthesia, and it is at least as effective as 20 percent benzocaine paste. Maximum recommended doses are 4.5 milligrams per kilogram, up to a total dose of 300 mg, to avoid lidocaine toxicity, which is characterized by CNS changes.44,45 Another topical anesthetic is a eutectic mixture of lidocaine and prilocaine (lidocaine 25 mg and prilocaine 25 mg per cubic centimeter) for mucosal and skin anesthesia. The preparationa eutectic mixture of local anesthetic, or EMLA (AstraZeneca)consists of 2.5 percent lidocaine and 2.5 percent prilocaine. Although it is effective, it has the inconvenience of a low melting point, being liquid at room temperature. Nevertheless, in the oral mucosa, this mixture is a superior topical anesthetic agent for pain reduction, although it requires an extended contact timeseveral minutes to hoursfor the area to be anesthetized.46-50 The plasma concentrations of lidocaine and prilocaine showed peak concentrations well below known toxic levels 45 minutes after skin187



TOPICAL MEDICATIONS.MEDICATIONS EXAMPLES OF TOPICAL PREPARATIONS FOR ORAL AND PERIORAL USE Benzocaine in Orabase (BristolMeyers Squibb) cream (20%)* (for intraoral use only) Lidocaine gel, viscous solution, ointment, spray and adhesive patch (for intraoral use only) Eutectic mixture of local anesthetic (EMLA cream, AstraZeneca) (lidocaine and prilocaine) (for intraoral and extraoral use) Neuropeptides: Capsaicin Nonsteroidal Anti-inflammatory Drugs Cream in 0.025%* and 0.075%* strengths (for intraoral and extraoral use) Ketoprofen (10-20%) in a pluronic lecithin organogel, or PLO, base (for extraoral use only) Diclofenac (10-20%) in PLO base (for extraoral use only) Sympathomimetic Agents: Clonidine NMDABlocking Agents: Ketamine Anticonvulsants Tricyclic Medications: Amitriptyline Antispasmodics: Baclofen * Patch (for extraoral use only) 0.01% in PLO base (for intraoral use only) 0.5% in PLO base or in Orabase (for intraoral use only) Antagonist to NMDA receptor Influences peripheral alpha adrenergic activity Inhibition of peripheral nociceptor terminal function Blocks prostaglandin production through cyclooxygenase inhibition MECHANISM OF ACTION

Topical Anesthetics

Sodium channel blockade

Carbamazepine (2%) in a PLO base (for extraoral use only) 2% in PLO base (for extraoral use only) 2% in PLO base (for extraoral use only)

Blocks use-dependent sodium channel activity Blocks sodium channels

Gamma-aminobutyric acid

Available over the counter. Must be prescribed but can be filled at any pharmacy. Must be prescribed and can be filled only at a compounding pharmacy. N-methyl-D-aspartate.

application of 8 grams of 5 percent occluded EMLA.51 The general principle of treatment for topically responsive neuropathic pain is to apply the anesthetic agent several times each day. The goal is to maintain local numbness, reduce ectopic neuronal firing and thereby reduce the peripheral neural sensitization. For extraoral application, covering a treatment site with a plastic188

adhesive sheet keeps the anesthetic in the desired area. Custom-fabricated tissue stents can be used intraorally to hold the anesthetic paste (or other topical medications) in place and protect the paste from salivary contamination and dissolution.46,47,52 Delivery vehicles and topical application methods are discussed in more detail below. Vanilloid compounds (capsaicin). Capsaicin, the

active pungent ingredient in hot peppers, is used commonly as a topical medication for neuropathic pain conditions of the skin or oral mucosa.53 Capsaicin exerts strong pharmacological effects on the peripheral system and the CNS. Of particular interest is its effect on the Cfiber type of primary afferent neurons and on a specific membrane recognition site identified as an ionotropic vanilloid


CLINICAL PRACTICEreceptor, or VR1.54,55 The action of capsaicin on this receptor opens an ion channel that is permeable to both monovalent and divalent cations in a ratio of 1:10, with Ca++ being most preferred. The inward ion flow causes neuronal depolarization. The normal physiological purpose of these receptors remains undetermined, as an endogenous correlate of capsaicin has not been identified; however, it has been noted that the channel is opened by heat. The VR1 receptor is found primarily on C-nociceptors. Capsaicin stimulates the nociceptors to release substance P and other peptide neurotransmitters, not only at the peripheral site of application, but also centrally. The peripheral release causes local excitation and sensitization, manifested as prolonged cutaneous pain, histamine release, erythema and thereby primary hyperalgesia and allodynia. The central release of excitatory aminoacids and neuropeptides resulting from the peripheral stimulation of the C-fiber nociceptors by capsaicin causes central sensitization that results in the phenomena of secondary hyperalgesia and an expanded skin response area for the sensitized neurons. It was initially postulated that chronic application of capsaicin depleted the peripheral sensory fibers of substance P, but now it is suggested that repeated capsaicin application actually only inhibits the peripheral terminal function.56 It should be noted that when the capsaicin application has been discontinued, the pain typically returns. Unfortunately, no controlled quantitative longterm studies of the effect of capsaicin on oral neuropathic sensations have been performed. Because of the limited penetration of this medication, capsaicin would be most useful when the patients complaint is one of superficial peripheral pain, usually characterized by burning, tingling and allodynia that responds to topical or local anesthetics.57 It also can be used in patients who exhibit a superficial trigger area for a deeper pain. In general, the application of capsaicin cream to a large area of the face is not recommended.58 While the onset of action of this therapy is immediate, it may take up to four weeks before long-term neuropathic pain desensitization (for example, a lessening of the burning feeling) occurs. In cases in which capsaicins side effects are objectionable, or in which a small amount has not proven helpful, it is recommended that the clinician use local anesthetic before the application to minimize pain perception.59 Capsaicin has been used successfully to control pain in dental traumatic neuropathy, trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy, postsurgical sensory disturbance involving the trigeminal nerve and other conditions of neuropathic pain, such as pain from oral mucositis after chemotherapy or radiation.60-62 Capsaicin (0.025 percent and 0.075 percent) is available in an over-the-counter form and can be mixed with a gelatin, pectin, methylcellulose and benzocaine cream (OrabaseB, Bristol-Myers Squibb) for intraoral use to improve its consistency and to incorporate the local anesthetic effect of benzocaine. Finally, as capsaicin has some clinical problems related to the initial pain and burning sensation at application, synthetic analogswhich create less irritationhave been studied. Some examples of these analogs are olvanil, glyceryl nonivamide and sodium nonivamide acetate. These analogs are less irritating than capsaicin because they activate different subtypes of receptors and have a slower action; however, their effect on pain is yet to be determined.63 Topical NSAIDs. Topical NSAIDs have shown effectiveness in relieving pain in acute and chronic conditions, with lower incidence of adverse gastrointestinal effects than they have when taken orally. 64-66 Some of the medications used topically for pain include ketoprofen (a propionic acid derivative), diclofenac (a benzeneacetic acid derivative), aspirin and ibuprofen.67-69 Although many other NSAIDs are available, there are few data comparing efficacy of one NSAID with that of another applied in a transdermal preparation. In general, more studies of ketoprofen have been published than of the other NSAIDs. Topical aspirin also has been specifically studied for dermal neuropathic pain, providing analgesia within 20 to 30 minutes.70 Details on the nature and appropriate use of transdermal penetrating carriers with which NSAIDs and other medications are compounded are described below, in the section on delivery systems. Sympathomimetic agents. Sympathomimetic agents may be useful in some forms of chronic neuropathic pain where nociceptor activity is being stimulated by sympathetic fiber release of norepinephrine in the189


CLINICAL PRACTICEperiphery. It has been shown that injured C fibers express 1 receptors on their peripheral membranes. Sympathetic activity then would excite the C fibers, signaling pain. Clonidine, an 2-adrenergic agonist, has been used as a topical agent for neuropathic pain because it is able to interrupt the peripheral release of norepinephrine, thereby decreasing the C-fiber stimulation.71,72 The use of transdermal clonidine was evaluated in 41 patients with painful diabetic neuropathy, and approximately one-quarter of them appeared responsive to the medication. Patients who described their pain as sharp and shooting had a greater likelihood of responding to clonidine.73,74 Clonidine for local extraoral therapy is available as a transdermal patch. For intraoral use, it is better to have clonidine compounded into a transdermal penetrating cream and dispensed in a calibrated syringe so that the dose can be better controlled. NMDA-blocking agents. Recent studies have shown that NMDA-receptor antagonists may be useful in the treatment of neurogenic pain.75-78 Several studies have been conducted in which orally administered ketamine, a NMDA antagonist, has shown effectiveness in alleviating refractory neuropathic pain. Although this medication has promise for the treatment of neuropathies, it can cause adverse effects such as hallucinations and dysphoria, which necessitate a low dose.79,80 Since there are NMDA receptors in the periphery, topical ketamine may be useful, but specific studies are needed to evaluate this therapeutic alternative. As with clonidine, this medication190

would be best compounded into a transdermal penetrating cream and dispensed in a calibrated syringe. Anticonvulsants. Recent studies have focused on sodium channel activity in the periphery. Studies have suggested that an accumulation of voltage-gated sodium channels at the site of peripheral nerve injury is a primary precursory event for subsequent afferent hyperexcitability. Tetrodotoxinresistant PN3-type sodium channels have been identified with C fibers. These channels may provide a novel and valuable target for specific drug therapy in the future.81,82 Sodium channel accumulation in and of itself is expected to cause hyperalgesia and abnormal spontaneous firing of the neuron. This would be augmented by concurrent accumulation of stimulus-specific receptors. It is now felt that although each peripheral pathophysiological pain condition may have its own molecular or membrane protein signature, all such conditions share the common denominator of ectopic hyperexcitability. Antispasmodic agents and tricyclic antidepressants. Gamma-aminobutyric acid, or GABA, is a central inhibitory neurotransmitter that also has been demonstrated to exist in the peripheral tissues. Baclofen is a GABA-B agonist and exhibits an analgesic effect via central modulation of the GABA system. There is little support for topical application of baclofen as an antispasmodic in cases of striated muscle spasm. Likewise, tricyclic antidepressants have been used for their central analgesic effect, which occurs through modulation of

the serotonin system. While it is known that there are serotonin receptors in peripheral nerves residing outside the CNS, it is unclear if this fact is important to the topical effect of tricyclic antidepressants, which are known to block the reuptake of serotonin. Additionally, cyclobenzaprine, a tricyclic antidepressant analog, is used as a muscle relaxant. It has been used for peripheral application for muscle trismus and spasm, but adequate studies supporting this use are lacking.DELIVERY SYSTEMS FOR THE OROFACIAL REGION

The purpose of a local delivery system is to apply a medication for a therapeutic action in a sitespecific manner. The drugs molecular structure and its pharmacological behavior dictate the delivery site and system. Use of topical medications in the orofacial region is accompanied by some inconveniences. For example, when applied intraorally (such as in a dissolving lozenge), these agents will dissolve in saliva and consequently spread throughout the mouth and down the throat. If the topical agent does have some mucoadhesive propertiesin other words, if it is a gel or creamit can be painted on the appropriate site, but, again, it will wash away from the area quickly. Several forms have been developed to counter this problem: toothpaste; chewing gum; candy; adhesive patches and powders; dissolving tablets, lozenges and lollipops; tissue-covering stents; dissolving polymeric devices; mouthwashes; and medicated lipsticks (Table 3). Mucoadhesive bases. Several mucoadhesive bases and oral pastes allow medications to



LOCAL MEDICATION DELIVERY SYSTEMS FOR THE OROFACIAL REGION.SYSTEM Mucoadhesive Creams Transdermal Creams: Pluronic Lecithin Organogel Toothpaste ADVANTAGES Best for intraoral use on specific tissue sites with stent covering site Best for extraoral use DISADVANTAGES Can irritate the oral tissues

Does not penetrate to deeper tissues and can cause skin rash or allergic reaction

Incorporation of the therapeutic agent into the patients regular daily routine Patients keep the gum or candy in the mouth for long periods, which provides increased drug/target area contact Best when problem is located on tongue (either dorsal or ventral surface), palate or cheek Best for intraoral use on specific tissue sites

Not good for regional oral tissue site delivery May aggravate temporomandibular joint problem Does not deliver agent to regional oral tissue sites Medication is swallowed and moves down throat Patches must be replaced frequently Less durable than tissue-covering stents when needed for long-term use

Medicated Chewing Gum and Candy Such as Lollipops Dissolving Tablets or Lozenges Adhesive Patches and Powders

Tissue-Covering Stents

Best for labial and palatal mucosal sites Durability and ease of fabrication

Cannot be used for movable mucosal sites such as cheek, tongue or soft palate

Dissolving Polymeric Devices Mouthwashes Medicated Lipstick

Typically fabricated as a retainer; medication is swallowed as the device dissolves Possibility of delivery to the oropharyngeal area Specific therapy for the lips Convenient application technique

As these are experimental devices, they are not available at this time Duration of application is usually less than 60 seconds None if used for lip therapy only

be delivered to the intraoral and extraoral tissues with great specificity (Table 3). One common mucoadhesive base that is very useful for oral neuropathic pain is available over the counter already compounded with a local anesthetic agent (for example, in OrabaseB, which contains 20 percent benzocaine). This mucoadhesive base remains in place for several hours after application. It also is used frequently as a carrier vehicle for applying other

medications (such as capsaicin) to the oral mucosa. Transdermal creams. Recently, a new medication vehicle preparation has been developed that provides rapid dermal and mucosal penetration and lends itself to being compounded with other medications. The transdermal cream is a pluronic mixture of lecithin and organogel. The organogel provides a hydrophilic vehicle for binding and carrying the admixed medication, while the

lecithin increases the vehicles ability to penetrate the lipophilic epidermal barrier.83 Changing the ratio of lecithin to organogel moderates the creams solubility through the lipophilic membrane. Toothpastes. Standard toothpaste also can be used as a vehicle for local delivery, and compounding pharmacies have medicationssuch as lidocainefor neuropathic pain available in a dental paste form. As a delivery vehicle, paste has191


CLINICAL PRACTICEadvantages in that it incorporates a medication protocol in the patients daily routine, which may increase his or her compliance with therapy. However, no studies have shown the efficacy of this vehicle. Medicated chewing gum and candy. The use of other systems such as medicated candies and chewing gum can provide the possibility of implementing a slow-release therapy or a gradient in the concentration of different medications.84,85 Oral capsaicin has been used in a hard-candy vehicle, producing significant but temporary pain reduction in patients with oral mucositis resulting from cancer therapy.86 Local anesthetics also have been compounded as a lollipop candy, for a continuous delivery in the oral mucosa. The technique is not well-developed yet and needs to be studied. It is still unclear if the response to these delivery systems may be achieved through systemic delivery, rather than a local effect or combination, and additional research is needed in this arena. Dissolvable tablets and lozenges. The use of dissolvable tablets or lozenges is another way to achieve a slow delivery of medications to the oral mucosa. In a study with dissolvable tablets, it was shown that a drug released in the upper buccal sulcus would migrate in an anterior direction. A tablet placed in the lower buccal sulcus showed a larger local concentration of the drug around the delivery system, and the widest distribution of medication was achieved with the tablet placed under the tongue.87 Adhesive patches and powders. In most cases, the mucosal retentive ability of a192

cream or gel is not adequate for clinical application without a protective covering device. For example, most intraoral topical anesthetics come in a gel form, which can be difficult to confine and easily becomes diluted in the mouth, reducing its efficacy. Occlusion with an oral bandage may be a simple solution to this problem. Several types of adhesive patches can be used, such as lidocaine patches for the oral mucosa and for cutaneous application.88 The lidocaine transoral delivery system, or intraoral patch, is a small adhesive strip that contains approximately 46 mg (in the 20 percent patch) or 23 mg (in the 10 percent patch) of lidocaine. This system delivers 5 mg in a 15-minute period, yielding a mean systemic lidocaine concentration of 16 to 22 mg per milliliter. Clinical trials have demonstrated that the transmucosal patch effectively numbs the area covered in about two minutes and remains effective for up to 45 minutes.89,90 Extraoral topical lidocaine also comes in a cutaneous patch, which has been successfully used to treat a painful cutaneous post-herpetic neuropathic condition.91 The study used 5 percent lidocaine patches over a painful area on the upper back. All subjects had allodynia and reported that patches containing lidocaine significantly reduced the intensity of their pain. The highest blood lidocaine level measured was 0.1 micrograms per milliliter, indicating minimal systemic absorption of lidocaine. Application of the patch had no systemic side effects, and the patch was welltolerated when applied on allodynic skin for 12 hours. EMLA also is available as a

cream that is placed on the skin and covered with a dermal adhesive patch. Another type of patch for intraoral use is a mucoadhesive water-soluble polymer film containing anesthetics and antibiotics for the treatment of oral mucositis after radiation therapy. This system alleviates oral pain and prevents secondary oral infections, without inducing adverse reactions such as fungal superinfections.92 Ethylene oxide polymer is water-dispersible and is used to enhance the viscosity of aqueous products.93 As it has a high capacity for binding with water, it binds well to mucous membranes. Polymer powder is used alone as a protective agent (oral bandage) or mixed with a medication to maintain long-term contact with the affected oral mucosa being treated. When the powder is puffed onto the tissue, it slowly hydrates as it binds moisture in the oral cavity and forms a thick patch of adhesive gel on the mucosa. As the incorporated drug dissolves, it slowly migrates through the thick polymer matrix to the mucous surface, where it then produces its specific effect. Tissue-covering stents. Custom-made intraoral tissue stents appear to be the best method for holding a medication in place inside the mouth. These devices can be fabricated using either acrylic materials or vacuum-formed polyvinyl materials in a dental laboratory (Figures 1 and 2) on a stone cast of the patients mouth. These tissue stents help maintain the medication in one position, increasing mucosa/medication contact for a longer period and protecting the treatment area


CLINICAL PRACTICEfrom further irritation. Dissolving polymeric devices. Because of recent advances in biomaterial science, it is now possible to modify acrylic resins to incorporate medications directly into a resin that will dissolve in the mouth. These resins can be molded into oral stents that provide direct mucosal bioadhesion and controlled release of medications as the acrylic resin dissolves, providing a predictable therapeutic delivery system.94-97 Unfortunately, these experimental systems are not yet commercially available. Mouthwashes. A mouthwash can be held in the oral cavity for up to several minutes without significant discomfort. It then may be swallowed or ejected (the latter if one wishes to reduce the potential of systemic drug delivery). The main use for mouthwashes is oral hygiene, reduction of plaque formation and control of stomatitis.98-100 The potential use of this system for neuropathic intraoral conditions is linked with its ability to reach a wide area of tissue with each application. Medicated lipstick. When local delivery to the lips is indicated, a lipstick vehicle can be a suitable alternative. This system will allow easy application of the medication, and patients accept it readily. If an ectopic generator or trigger zone of a neuropathy is located in the lips, this might be an adequate therapeutic option.FUTURE DIRECTIONS

Figure 1. Custom-fabricated plastic stent using a vacuum-formed material on a dental cast.

Figure 2. Mixture of capsaicin 0.025 percent and Orabase-B (BristolMyers Squibb), covered with a custom-made stent, delivering medication to the maxillary oral mucosa.

Treatment options for peripheral orofacial neuropathic pain have improved over the past few years. This is partly the result of a better understanding

of the pathophysiology and pharmacology of pain, as well as development of delivery systems that improve contact between the affected area and the applied medication. As research is expanding in this area, some of the methods reviewed here are not available to dental practitioners in the United States. Furthermore,

many of the delivery systems and formulations being used need to be tested further for safety and efficacy.CONCLUSIONS

This review summarizes the current literature regarding local pharmacotherapy for orofacial neuropathic pain conditions. The main advantage of193


CLINICAL PRACTICEthis therapeutic modality is the potential ability to provide pain relief without the side effects of a systemic approach. The new bioadhesive medication delivery systems eventually will eliminate most of the problems with intraoral therapy by improving and increasing the agents contact with the treatment area. The pharmaceutical industry is producing these promising systems, and it is its responsibility to promote and conduct adequate research to assess the safety, efficacy and utility of these agents and delivery systems in treating peripheral painful trigger areas. sDr. Padilla is a research associate, Section of Orofacial Pain and Oral Medicine, University of California Los Angeles School of Dentistry, Center for the Health Sciences. Dr. Clark is professor and chair, Section of Orofacial Pain and Oral Medicine, University of California Los Angeles School of Dentistry, Center for the Health Sciences, Room 43-009, 10833 Le Conte Ave., Los Angeles, Calif. 90095-1668. 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