The Journal of the American Dental Association
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Am Dent Assoc, Vol 131, No 2, 184-195.
© 2000 American Dental Association
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by PADILLA, M.
Right arrow Articles by MERRILL, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by PADILLA, M.
Right arrow Articles by MERRILL, R. L.
Related Collections
Right arrow Restoratives

CLINICAL PRACTICE

TOPICAL MEDICATIONS FOR OROFACIAL NEUROPATHIC PAIN: A REVIEW



MARIELA PADILLA, D.D.S., GLENN T. CLARK, D.D.S., M.S. and ROBERT L. MERRILL, D.D.S., M.S.


   ABSTRACT
TOP
 ABSTRACT
OROFACIAL DRUG DELIVERY
 OROFACIAL PAINFUL NEUROPATHIES
 TOPICAL MEDICATIONS FOR...
 DELIVERY SYSTEMS FOR THE...
 FUTURE DIRECTIONS
 CONCLUSIONS
 REFERENCES
 
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 disorders—local 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-carrier 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.

From the earliest times, humans have found 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 medication 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
TOP
 ABSTRACT
 OROFACIAL DRUG DELIVERY
OROFACIAL PAINFUL NEUROPATHIES
 TOPICAL MEDICATIONS FOR...
 DELIVERY SYSTEMS FOR THE...
 FUTURE DIRECTIONS
 CONCLUSIONS
 REFERENCES
 
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 mucosal 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 patient’s 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 skin’s 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 anti-inflammatory 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 dentistry—although 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
TOP
 ABSTRACT
 OROFACIAL DRUG DELIVERY
 OROFACIAL PAINFUL NEUROPATHIES
TOPICAL MEDICATIONS FOR...
 DELIVERY SYSTEMS FOR THE...
 FUTURE DIRECTIONS
 CONCLUSIONS
 REFERENCES
 
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 chronic-continuous trigeminal nociceptor neuropathy (with and without sympathetic mediation) (Table 1Go).11–28 The pain mechanisms that generate these problems are different for each neuropathy, and treatment protocols need to be structured and customized accordingly.


View this table:
[in this window]
[in a new window]
  		TABLE 1 NEUROPATHIC PAIN CONDITIONS IN THE OROFACIAL REGION.

 
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 second-order neurons in the trigeminal nucleus, and are mediated by N-methyl-D-aspartate, or NMDA 32,33; {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole-propionic 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 calcium 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. Nevertheless, 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.35–37


   TOPICAL MEDICATIONS FOR OROFACIAL NEUROPATHIC PAIN
TOP
 ABSTRACT
 OROFACIAL DRUG DELIVERY
 OROFACIAL PAINFUL NEUROPATHIES
 TOPICAL MEDICATIONS FOR...
DELIVERY SYSTEMS FOR THE...
 FUTURE DIRECTIONS
 CONCLUSIONS
 REFERENCES
 
Topical medications offer distinct advantages over systemic agents: greater safety, rapid onset of action and low side-effect 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-to-moderate 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 2Go).


View this table:
[in this window]
[in a new window]
  		TABLE 2 TOPICAL MEDICATIONS.

 
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 preparation—a 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 time—several minutes to hours—for 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 skin 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 plastic 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 C-fiber type of primary afferent neurons and on a specific membrane recognition site identified as an ionotropic vanilloid receptor, 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 long-term 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 patient’s 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 capsaicin’s 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 (Orabase-B, 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 analogs—which create less irritation—have 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 benzene-acetic 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 the periphery. It has been shown that injured C fibers express {alpha}1 receptors on their peripheral membranes. Sympathetic activity then would excite the C fibers, signaling pain. Clonidine, an {alpha}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 medication 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. Tetrodotoxin-resistant 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
TOP
 ABSTRACT
 OROFACIAL DRUG DELIVERY
 OROFACIAL PAINFUL NEUROPATHIES
 TOPICAL MEDICATIONS FOR...
 DELIVERY SYSTEMS FOR THE...
FUTURE DIRECTIONS
 CONCLUSIONS
 REFERENCES
 
The purpose of a local delivery system is to apply a medication for a therapeutic action in a site-specific manner. The drug’s 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 properties—in other words, if it is a gel or cream—it 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 3Go).


View this table:
[in this window]
[in a new window]
  		TABLE 3 LOCAL MEDICATION DELIVERY SYSTEMS FOR THE OROFACIAL REGION.

 
Mucoadhesive bases. Several mucoadhesive bases and oral pastes allow medications to be delivered to the intraoral and extraoral tissues with great specificity (Table 3Go). 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 Orabase-B, 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 vehicle’s ability to penetrate the lipophilic epidermal barrier.83 Changing the ratio of lecithin to organogel moderates the cream’s solubility through the lipophilic membrane.

Toothpastes. Standard toothpaste also can be used as a vehicle for local delivery, and compounding pharmacies have medications—such as lidocaine—for neuropathic pain available in a dental paste form. As a delivery vehicle, paste has advantages in that it incorporates a medication protocol in the patient’s 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 a 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 well-tolerated 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 1Go and 2Go) on a stone cast of the patient’s mouth. These tissue stents help maintain the medication in one position, increasing mucosa/medication contact for a longer period and protecting the treatment area from further irritation.



View larger version (97K):
[in this window]
[in a new window]
  		Figure 1. Custom-fabricated plastic stent using a vacuum-formed material on a dental cast.

 


View larger version (103K):
[in this window]
[in a new window]
  		Figure 2. Mixture of capsaicin 0.025 percent and Orabase-B (Bristol-Myers Squibb), covered with a custom-made stent, delivering medication to the maxillary oral mucosa.

 
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
TOP
 ABSTRACT
 OROFACIAL DRUG DELIVERY
 OROFACIAL PAINFUL NEUROPATHIES
 TOPICAL MEDICATIONS FOR...
 DELIVERY SYSTEMS FOR THE...
 FUTURE DIRECTIONS
CONCLUSIONS
 REFERENCES
 
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
TOP
 ABSTRACT
 OROFACIAL DRUG DELIVERY
 OROFACIAL PAINFUL NEUROPATHIES
 TOPICAL MEDICATIONS FOR...
 DELIVERY SYSTEMS FOR THE...
 FUTURE DIRECTIONS
 CONCLUSIONS
REFERENCES
 
This review summarizes the current literature regarding local pharmacotherapy for orofacial neuropathic pain conditions. The main advantage of this 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.


   FOOTNOTES
 

Dr. 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. Address reprint requests to Dr. Clark.


Dr. Merrill is an adjunct associate professor, Section of Orofacial Pain and Oral Medicine, University of California Los Angeles School of Dentistry, Center for the Health Sciences.


The authors offer their sincere appreciation to Dr. John A. Yagiela, professor and chair of diagnostic and surgical sciences, University of California Los Angeles School of Dentistry, for his assistance in editing the manuscript.


   REFERENCES
TOP
 ABSTRACT
 OROFACIAL DRUG DELIVERY
 OROFACIAL PAINFUL NEUROPATHIES
 TOPICAL MEDICATIONS FOR...
 DELIVERY SYSTEMS FOR THE...
 FUTURE DIRECTIONS
 CONCLUSIONS
 REFERENCES
 

  1. Hadgraft J, Pugh WJ. The selection and design of topical and transdermal agents: a review. J Investig Dermatol Symp Proc 1998;3(2):131–5.[Medline]

  2. Manganaro AM, Wertz PW. The effects of permeabilizers on the in vitro penetration of propranolol through porcine buccal epithelium. Mil Med 1996;161(11):669–72.[Medline]

  3. Manganaro AM. Review of the transmucosal drug delivery. Mil Med 1997;162(1):27–30.[Medline]

  4. Needleman IG, Smales FC, Martin GP. An investigation of bioadhesion for periodontal and oral mucosal drug delivery. J Clin Periodontol 1997;24(6):394–400.[Medline]

  5. Ashburn MA, Rice LJ. The management of pain. New York: Churchill Livingstone; 1998:187–95.

  6. Lehr CM. From sticky stuff to sweet receptors: achievements, limits and novel approaches to bioadhesion. Eur J Drug Metab Pharmacokinet 1996;21(2):139–48.[Medline]

  7. Jones DS, Woolfson AD, Djokic J, Coulter WA. Development and mechanical characterization of bioadhesive semi-solid, polymeric systems containing tetracycline for the treatment of periodontal diseases. Pharm Res 1996;13(11):1734–8.[Medline]

  8. Lozada-Nur F, Miranda C, Maliksi R. Double-blind clinical trial of 0.05 percent clobetasol propionate (corrected from proprionate) ointment in Orabase and 0.05 percent fluocinonide ointment in Orabase in the treatment of patients with oral vesiculoerosive diseases. Oral Surg Oral Med Oral Pathol 1994;77(6):598–604.[Medline]

  9. Voute AB, Schulten EA, Langendijk PN, Kostense PJ, van der Waal I. Fluocinonide in an adhesive base for treatment of oral lichen planus: a double-blind, placebo-controlled clinical study. Oral Surg Oral Med Oral Pathol 1993;75(2):181–5.[Medline]

  10. Aleinikov A, Jordan RC, Main JH. Topical steroid therapy in oral lichen planus: review of a novel delivery method in 24 patients. J Can Dent Assoc 1996;62(4):324–7.[Medline]

  11. Merrill RL, Graff-Radford SB. Trigeminal neuralgia: how to rule out the wrong treatment. JADA 1992;123(2):63–8.[Abstract]

  12. Canavan D, Graff-Radford SB, Gratt BM. Traumatic dysesthesia of the trigeminal nerve. J Orofac Pain 1994;8(4):391–6.[Medline]

  13. Jannetta P. Vascular compression is the cause of trigeminal neuralgia. Am Pain Soc Bull 1993;2:217–27.

  14. Burchiel K. Is trigeminal neuralgia a neuropathic pain? Am Pain Soc Bull 1993;2:12–6.

  15. Delcanho RE. Neuropathic implications of prosthodontic treatment. J Prosthet Dent 1995;73(2):146–52.[Medline]

  16. Watson CP. The treatment of postherpetic neuralgia. Neurology 1995;45(12 suppl 8):S58–60.[Abstract/Free Full Text]

  17. Rowbotham MC, Fields HL. The relationship of pain, allodynia and thermal sensation in postherpetic neuralgia. Brain 1996;119(pt 2):347–54.[Abstract/Free Full Text]

  18. Lefkowitz M, Marini RA. Management of postherpetic neuralgia. Ann Acad Med Singapore 1994;23(6 suppl):139–44.[Medline]

  19. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996;67(2–3):241–51.[Medline]

  20. Chasuk R. Treatments for postherpetic neuralgia. J Fam Pract 1997;45(3):203–4.[Medline]

  21. Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 1995;7(4):317–28.[Medline]

  22. Wright JM. Review of the symptomatic treatment of diabetic neuropathy. Pharmacotherapy 1994;14(6):689–97.[Medline]

  23. Ahmedzai S. New approaches to pain control in patients with cancer. Eur J Cancer 1997;33(suppl 6):S8–14.

  24. Shashidhar K. Pain and symptom management in cancer patients. J Fla Med Assoc 1996;83:679–94.[Medline]

  25. Martin LA, Hagen NA. Neuropathic pain in cancer patients: mechanisms, syndromes, and clinical controversies. J Pain Symptom Manage 1997;14(2):99–117.[Medline]

  26. Bruera E, Lawlor P. Cancer pain management. Acta Anaesthesiol Scand 1997;41(1 pt 2):146–53.[Medline]

  27. Twycross R. Cancer pain classification. Acta Anaesthesiol Scand 1997;41(1 pt 2):141–5.[Medline]

  28. Lefkowitz M. Pain management for the AIDS patient. J Fla Med Assoc 1996; 83(10):701–4.[Medline]

  29. Rappaport ZH, Devor M. Trigeminal neuralgia: the role of self-sustaining discharge in the trigeminal ganglion. Pain 1994;56(2):127–38.[Medline]

  30. Wall PD, Devor M. Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve-injured rats. Pain 1983;17(4):321–39.[Medline]

  31. Cline MA, Ochoa J, Torebjork HI. Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 1989;112(pt 3):621–47.[Abstract/Free Full Text]

  32. Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain 1994;56(1):51–7.[Medline]

  33. Yu XM, Sessle BJ, Haas DA, Izzo A, Vernon H, Hu JW. Involvement of NMDA receptor mechanisms in jaw electromyographic activity and plasma extravasation induced by inflammatory irritant application to temporomandibular joint region of rats. Pain 1996;68(1):169–78.[Medline]

  34. Ochoa JL. Pain mechanisms in neuropathy. Curr Opin Neurol 1994;7(5):407–14.[Medline]

  35. Devor M. Neuropathic pain and injured nerve: peripheral mechanisms. Br Med Bull 1991;47(3):619–30.[Abstract/Free Full Text]

  36. Galer BS. Neuropathic pain of peripheral origin: advances in pharmacologic treatment. Neurology 1995;45(12 suppl 9):S17–25.[Abstract/Free Full Text]

  37. Fromm G. Physiological rationale for the treatment of neuropathic pain. Am Pain Soc Bull 1993;2:1–7.

  38. Claoue C. Delivery of topical anesthesia. J Cataract Refract Surg 1996;22(2):155–6.[Medline]

  39. Backonja MM. Local anesthetics as adjuvant analgesics. J Pain Symptom Manage 1994;9(8):491–9.[Medline]

  40. Neidle E, Yagiela J. Pharmacology and therapeutics for dentistry. 3rd ed. St. Louis: Mosby; 1989:236–46.

  41. Bangha E, Maibach HI, Elsner P. Toxicology of topical local anesthetics. Skin Pharmacol 1996;9(6):376–80.[Medline]

  42. Cooper HA. Methemoglobinemia caused by benzocaine topical spray. South Med J 1997;90(9):946–8.[Medline]

  43. Lee E, Boorse R, Marcinczyk M. Methemoglobinemia secondary to benzocaine topical anesthetic. Surg Laparosc Endosc 1996;6(6):492–3.[Medline]

  44. Jong R. Local anesthetics. St. Louis: Mosby; 1994:357–67.

  45. Chiang YY, Tseng KF, Lih YW, Tsai TC, Liu CT, Leung HK. Lidocaine-induced CNS toxicity: a case report. Acta Anaesthesiol Sin 1996;34(4):243–6.[Medline]

  46. Svensson P, Petersen JK, Svensson H. Efficacy of a topical anesthetic on pain and unpleasantness during scaling of gingival pockets. Anesth Prog 1994;41(2):35–9.[Medline]

  47. Gupta AK, Sibbald RG. Eutectic lidocaine/prilocaine 5 percent cream and patch may provide satisfactory analgesia for excisional biopsy or curettage with electrosurgery of cutaneous lesions: a randomized, controlled, parallel group study. J Am Acad Dermatol 1996;35(3 pt 1):419–23.[Medline]

  48. Donaldson D, Meechan JG. A comparison of the effects of EMLA cream and topical 5 percent lidocaine on discomfort during gingival probing. Anesth Prog 1995;42(1):7–10.[Medline]

  49. Litman SJ, Vitkun SA, Poppers PJ. Use of EMLA cream in the treatment of post-herpetic neuralgia. J Clin Anesth 1996;8(1):54–7.[Medline]

  50. Meechan JG, Donaldson D. The intraoral use of EMLA cream in children: a clinical investigation. ASDC J Dent Child 1994;61(4):260–2.[Medline]

  51. Vickers ER, Marzbani N, Gerzina TM, McLean C, Punnia-Moorthy A, Mather L. Pharmacokinetics of EMLA cream 5 percent application to oral mucosa. Anesth Prog 1997;44(1):32–7.[Medline]

  52. Svensson P, Petersen JK. Anesthetic effect of EMLA occluded with Orahesive oral bandages on oral mucosa: a placebo-controlled study. Anesth Prog 1992;39(3):79–82.[Medline]

  53. Cordell GA, Araujo OE. Capsaicin: identification, nomenclature, and pharmacotherapy. Ann Pharmacother 1993;27(3):330–6.[Abstract]

  54. Biro T, Acs G, Acs P, Modarres S, Blumberg PM. Recent advances in understanding of vanilloid receptors: a therapeutic target for treatment of pain and inflammation in skin. J Investig Dermatol Symp Proc 1997;2(11):56–60.[Medline]

  55. Szallasi A, Blumberg PM. Vanilloid receptors: new insights enhance potential as a therapeutic target. Pain. 1996;68(2–3):195–208.[Medline]

  56. Fusco BM, Giacovazzo M. Peppers and pain: the promise of capsaicin. Drugs 1997;53(6):909–14.[Medline]

  57. Markovits E, Gilhar A. Capsaicin: an effective topical treatment in pain. Int J Dermatol 1997;36(6):401–4.[Medline]

  58. Lincoff NS, Rath PP, Hirano M. The treatment of periocular and facial pain with topical capsaicin. J Neuroophthalmol 1998;18(1):17–20.[Medline]

  59. Robbins WR, Staats PS, Levine J, et al. Treatment of intractable pain with topical large-dose capsaicin: preliminary report. Anesth Analg 1998;86(3):579–83.[Abstract]

  60. Biesbroeck R, Bril V, Hollander P, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther 1995;12(2):111–20.[Medline]

  61. Epstein JB, Marcoe JH. Topical application of capsaicin for treatment of oral neuropathic pain and trigeminal neuralgia. Oral Surg Oral Med Oral Pathol 1994;77(2):135–40.[Medline]

  62. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 1997;15(8):2974–80.[Abstract]

  63. Liu L, Lo Y, Chen I, Simon SA. The responses of rat trigeminal ganglion neurons to capsaicin and two nonpungent vanilloid receptor agonists, olvanil and glyceryl non-amide. J Neurosci 1997;17(11):4101–11.[Abstract/Free Full Text]

  64. Butron F, Galicia A, Zamora G, Martinez-Zurita F. Single blind study to evaluate the efficacy and safety of naproxen gel compared with diclophenac emulgel in the treatment of soft tissue injuries. Proc West Pharmacol Soc 1994;37:153–6.[Medline]

  65. Dominkus M, Nicolakis M, Kotz R, Wilkinson FE, Kaiser RR, Chlud K. Comparison of tissue and plasma levels of ibuprofen after oral and topical administration. Arzneimittelforschung 1996;46(12):1138–43.[Medline]

  66. Heyneman CA. Topical nonsteroidal antiinflammatory drugs for acute soft tissue injuries. Ann Pharmacother 1995;29:780–2.[Abstract]

  67. Grahame R. Transdermal non-steroidal anti-inflammatory agents. Br J Clin Pract 1995;49(1):33–5.[Medline]

  68. Gurol Z, Hekimoglu S, Demirdamar R, Sumnu M. Percutaneous absorption of ketoprofen. I. In vitro release and percutaneous absorption of ketoprofen from different ointment bases. Pharm Acta Helv 1996;71:205–12.[Medline]

  69. Patel RK, Leswell PF. Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice: general practice study group. Clin Ther 1996;18:497–507.[Medline]

  70. Tharion G, Bhattacharji S. Aspirin in chloroform as an effective adjuvant in the management of chronic neurogenic pain. Arch Phys Med Rehabil 1997;78:437–9.[Medline]

  71. Olson EE, Hogan QH, Abram SE. Comments on topical clonidine for relief from allodynia. Pain 1993;54:361.[Medline]

  72. Kinnman E, Levine JD. Sensory and sympathetic contributions to nerve injury-induced sensory abnormalities in the rat. Neuroscience 1995;64:751–67.[Medline]

  73. Epstein JB, Grushka M, Le N. Topical clonidine for orofacial pain: a pilot study. J Orofac Pain 1997;11(4):346–52.[Medline]

  74. Byas-Smith MG, Max MB, Muir J, Kingman A. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage ‘enriched enrollment’ design. Pain 1995;60(3):267–74.[Medline]

  75. Karlsten R, Gordh T. How do drugs relieve neurogenic pain? Drugs Aging 1997;11:398–412.[Medline]

  76. Broadley KE, Kurowska A, Tookman A. Ketamine injection used orally. Palliat Med 1996;10:247–50.[Medline]

  77. Lipman AG. Analgesic drugs for neuropathic and sympathetically maintained pain. Clin Geriatr Med 1996;12:501–15.[Medline]

  78. Mathisen LC, Skjelbred P, Skoglund LA, Oye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain 1995;61:215–20.[Medline]

  79. Warncke T, Stubhaug A, Jorum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. Pain 1997;72(1–2):99–106.[Medline]

  80. Felsby S, Nielsen J, Arendt-Nielsen L, Jensen TS. NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. Pain 1996;64:283–91.[Medline]

  81. Rabert DK, Koch BD, Ilnicka M, et al. A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A. Pain 1998;78(2):107–14.[Medline]

  82. Tanelian DL, Brose WG. Neuropathic pain can be relived by drugs that are use-dependent sodium channel blockers: lidocaine, carbamazepine, and mexiletine. Anesthesiology 1991;74:949–51.[Medline]

  83. Marek CL. Issues and opportunities: compounding for dentistry. Int J Pharm Compounding 1999;3:4–7

  84. Simons D, Kidd EA, Beighton D, Jones B. The effect of chlorhexidine/xylitol chewing-gum on cariogenic salivary microflora: a clinical trial in elderly patients. Caries Res 1997;31(2):91–6.[Medline]

  85. Alsagoff F, Lee HP. Nicotine-replacement products in smoking cessation: a review. Singapore Med J 1993;34:505–10.[Medline]

  86. Berger A, Henderson M, Nadoolman W, et al. Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J Pain Symptom Manage 1995;10(3):243–8. (Published erratum appears in J Pain Symptom Manage 1996;11:331.)[Medline]

  87. Peppas NA, Sahlin JJ. Hydrogels as mucoadhesive and bioadhesive materials: a review. Biomaterials 1996;17:1553–61.[Medline]

  88. Inada T, Uesugi F, Kawachi S, Inada K. Lidocaine tape relieves pain due to needle insertion during stellate ganglion block. Can J Anaesth 1997;44:259–62.[Medline]

  89. Hersh EV, Houpt MI, Cooper SA, Feldman RS, Wolff MS, Levin LM. Analgesic efficacy and safety of an intraoral lidocaine patch. JADA 1996;127(11):1626–34.[Abstract/Free Full Text]

  90. Houpt MI, Heins P, Lamster I, Stone C, Wolff MS. An evaluation of intraoral lidocaine patches in reducing needle-insertion pain. Compend Contin Educ Dent 1997;18(4):309–16.[Medline]

  91. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 1996;65(1):39–44.[Medline]

  92. Oguchi M, Shikama N, Sasaki S, et al. Mucosa-adhesive water-soluble polymer film for treatment of acute radiation-induced oral mucositis. Int J Radiat Oncol Biol Phys 1998;40:1033–7.[Medline]

  93. Union Carbide Corporation Web site. Union Carbide NET: Product guide—Polyox. Available at: "http://www.unioncarbide.com/business/busprgde.html". Accessed Aug. 13, 1999.

  94. Vlachou M, Choulis NH, Efentakis M, Andreopoulos AG. The effect of modification of acrylic resins on controlled release and bioadhesion. J Biomater Appl 1996;10:217–29.[Abstract/Free Full Text]

  95. Kuntz RM, Saltzman WM. Polymeric controlled delivery for immunization. Trends Biotechnol 1997;15:364–9.[Medline]

  96. Truhlar MR, Shay K, Sohnle P. Use of a new assay technique for quantification of antifungal activity of nystatin incorporated in denture liners. J Prosthet Dent 1994;71:517–24.[Medline]

  97. Anlar S, Capan Y, Hincal AA. Physicochemical and bioadhesive properties of polyacrylic acid polymers. Pharmazie 1993;48:285–7.[Medline]

  98. Waaler SM, Rolla G, Skjorland KK, Ogaard B. Effects of oral rinsing with tri-closan and sodium lauryl sulfate on dental plaque formation: a pilot study. Scand J Dent Res 1993;101(4):192–5.[Medline]

  99. Yates R, Moran J, Addy M, Mullan PJ, Wade WG, Newcombe R. The comparative effect of acidified sodium chlorite and chlorhexidine mouthrinses on plaque regrowth and salivary bacterial counts. J Clin Periodontol 1997;24:603–9.[Medline]

  100. Yel L, Tezcan I, Hasturk H, Ersoy F, Sanal O, Yavuzyilmaz E. Oral findings, treatment and follow-up of a case with major aphthous stomatitis (Sutton’s disease). J Clin Pediatr Dent 1994;19(1):49–53.[Medline]




This article has been cited by other articles:


Home page
 JAOA: Journal of the American Osteopathic AssociationHome page
G. H. Pharo and L. Zhou
Controlling Cancer Pain With Pharmacotherapy
J Am Osteopath Assoc, December 1, 2007; 107(suppl_7): ES22 - ES32.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
J. Sawynok
Topical and Peripherally Acting Analgesics
Pharmacol. Rev., March 1, 2003; 55(1): 1 - 20.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by PADILLA, M.
Right arrow Articles by MERRILL, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by PADILLA, M.
Right arrow Articles by MERRILL, R. L.
Related Collections
Right arrow Restoratives

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS