Personal Reflections on a Sensitive Subject

WHAT’S WRONG WITH SENSITIVE TEETH?

Exposed dentin can be sensitive to several common stimuli, such as cold water, air currents, and tactile stimulation. Dentists in the pre-local-anesthetic days were well-acquainted with the pain their patients experienced when the dentists cut dentin with rotary or hand instruments. Sensitivity was recognized as a feature that distinguishes dentin from insensitive enamel. Researchers in those days attempted to explain why dentin was sensitive and invented topical remedies. Histological observations demonstrated that dentin contained numerous microscopic fluid-filled tubules. It was proposed that pain-evoking stimuli shifted fluid away from the pulp, stimulating the nerves that are intermingled with the odontoblasts (Gysi, 1900). Treatments in the early 20th century consisted of agents such as silver nitrate, intended to coagulate the dentinal fluid, or nerve obtundants, such as cocaine, dissolved in ether. Many of these agents were toxic and stained the teeth. Criteria for an ideal desensitizer—stressing safety, lack of staining, and effectiveness—were set forth by Grossman in 1935. We are still guided by these principles in pursuing new therapies.

The idea espoused by Gysi—that pain-evoking stimuli cause fluid shifts that, in turn, activate pulpal nerve fibers—has accumulated considerable experimental support and is referred to as the ’hydrodynamic hypothesis’. The dentin fluid shifts induced by pain-evoking stimuli, such as air currents, can be measured experimentally. Hydrodynamic forces resulting from certain forms of stimulation can be sufficiently strong to aspirate the odontoblast cell bodies into the tubules (Brännström, 1986). It is possible to demonstrate the relationship between dentinal fluid shifts and intradental nerve activation in animal experiments. The intradental nerves are very sensitive to outward fluid shifts, but relatively insensitive to inward displacements (Matthews and Vongsavan, 1994). Ultrastructural examinations of the dentin surfaces in human teeth demonstrate a relationship between the condition of the dentin surface and degree of sensitivity (Absi et al., 1987). Dentin biopsies and sensitive impression techniques used to create dentin replicas have been methods used to visualize the surface features of living human dentin. Clinically sensitive dentin surfaces have patent tubules. In non-sensitive dentin surfaces, the tubules are solidly filled with mineral.

Pain, especially chronic pain, is a complex clinical phenomenon. Dentin sensitivity, in contrast, is associated with well-defined alterations of the tooth structure, and involves a physiological process linking stimulus and pain via minute dentinal fluid shifts. The hydrodynamic hypothesis has stimulated clinical research by suggesting two methods to desensitize dentin:

Reduce stimuli-evoked fluid shifts in the dentinal tubules by reducing dentin permeability.

As we have seen, dentists in the early 1900s tried to use various drugs and chemicals to act on these therapeutic targets. At that time, investigators lacked laboratory and clinical models with which they could evaluate potentially therapeutic active agents. As late as the 1970s, compounds such as formaldehyde, fluorides, strontium salts, and potassium nitrate were incorporated into desensitizing dentifrices as "actives", without a clear indication of whether these agents affected dentin or the intradental nerves. In addition, few controlled clinical trials of desensitizing agents have been conducted, until recently. The two of us sought to develop experimental models in which the functions of dentin and the intradental nerves can be studied and the effects of potential therapeutic agents assessed.

INACTIVATING THE INTRADENTAL NERVES

As a dental student, I (KM) started working in the laboratory of Dr. Syngcuk Kim at Columbia University. Prior to my arrival, Kim had conducted pioneering studies on physiological factors controlling pulpal blood flow. Our laboratory was also examining the effects of crown preparation and other restorative procedures on circulation in the dental pulp. It was enormously exciting to be involved in work that used state-of-the-art techniques to investigate scientific questions relevant to the everyday practice of dentistry. Kim was also interested in dental pain, and had close contacts with Scandinavian investigators who were recording nerve responses from the teeth of animals and humans. A new project sought to investigate the actions of certain commercially available desensitizing agents, such as KNO₃ and SrCl₂, on intradental nerve activity in animal teeth. These soluble salts were known to have little effect on dentin permeability (Pashley et al., 1984), so testing their actions on nerve excitability appeared to make sense. Having an interest in neuroscience and experience doing nerve recordings, I fit right in with the project.

We needed to find an excitatory stimulus that would allow us to test the actions of potential desensitizers. Our Scandinavian co-workers and others had found that hypertonic NaCl solutions applied to deep dentin cavities were quite excitatory to intradental nerves. In humans, this type of stimulation resulted in pain that correlated with the intensity of the nerve response. So, our in vivo desensitizer test consisted of measuring the nerve responses (in terms of spike frequency) to NaCl before and after the application of experimental desensitizing agents to a deep dentin cavity in animal teeth.

KNO₃ reduced the NaCl response, as did other solutions of other potassium salts (Markowitz et al., 1991). The inhibitory effects of potassium compounds on nerve excitability were also demonstrated in studies where these solutions were applied to fine bundles of mammalian non-dental nerves (Peacock and Orchardson, 1995). Although potassium salts inhibited the response to NaCl, its immediate effect on the intradental nerves was extremely excitatory, inducing a burst of nerve activity (Markowitz et al., 1991). The behavior of the intradental nerves in response to K⁺ made sense in view of the important role this ion plays in setting the resting potential and excitability of nerve cells. These changes in resting potential and excitability developed quickly when potassium concentrations were raised and soon returned to normal values when physiologic concentrations were restored. Based on the observation that all tested potassium compounds reduced intradental nerve excitability, potassium chloride was incorporated into desensitizing dentifrices. Potassium salts are still the most commonly used active agent in desensitizing dentifrices.

Although we hoped that this work would establish a mechanism of action for KNO₃, the relevance of our experimental model to the clinical situation in sensitive teeth was open to question. In our experimental model, we placed stimulating and desensitizing solution into deep dentin cavities, removing an important component of tooth sensitivity, the dentin. When people brush with desensitizing toothpastes, the potassium ions must diffuse through a comparatively thick layer of dentin against an ever-present outward flow.

Many aspects of the potassium effects we observed in the laboratory differ from what occurs in clinical use. In the laboratory, nerve inhibition following potassium application was immediate and short-lived, while in clinical trials it typically took at least 2 weeks before significant pain reduction occurred (Tarbet et al., 1982). In our laboratory model, we tested the ability of K⁺ solutions to reduce nerve responses to hypertonic NaCl. People with sensitive teeth experience pain when their teeth are exposed to cold liquids or air-blasts, or are subjected to tactile stimulation from a sharp explorer. Do potassium salts reduce nerve activity evoked by these natural stimuli? When the effects of K⁺ solutions on nerve responses to probing, air-blasting and hypertonic NaCl were compared in the same experiment, it was found that the responses to natural stimuli were not reduced to the same extent as those of hypertonic NaCl (Markowitz et al., 1990). Hydrodynamic stimuli and hypertonic solutions evoke nerve activity by different mechanisms and possibly at different sites along the nerve fiber. Hypertonic solutions and potassium ions reach the intradental nerves by diffusion, exerting their maximum effect at the most peripheral portion of the nerve fiber. Teeth with damage to the superficial pulp tissue can still be sensitive (Lilja et al., 1982), indicating that these natural stimuli induce nerve impulses deep in the pulp tissue. It is interesting to note that, as Gysi observed, local anesthetics applied to the dentin do a very poor job of desensitizing teeth, unless applied in very high concentrations or with inward pressure. Apparently, anesthetizing the peripheral ends of nerve fibers is not sufficient to eliminate their responses to hydrodynamic stimuli.

In view of the problematic nature of potassium diffusion through dentin, and its apparently poor ability to inhibit intradental nerve activity induced by natural (hydrodynamic) stimuli, is the idea that K⁺ ions desensitize the dentin by depolarizing the intradental nerve endings valid? Skepticism has been expressed in the literature concerning the ability of K⁺ ions to depress nerve activity when administered in dental products. Could there be another target for potassium solutions to reduce pain? It has been suggested that potassium acts by stimulating the odontoblasts to synthesize and release nitric oxide (NO), an important physiological mediator, which may act as the nerve-inhibiting agent (McCormack and Davies, 1996). This theory as published awaits experimental support.

PREVENTING DENTIN FLOW FROM ACTIVATING THE NERVE ENDINGS

As we have already seen, the relationship between dentin permeability and tooth sensitivity has been well-documented. If increasing dentin permeability by etching or by fracturing away the protective enamel can make teeth sensitive, then it stands to reason that we can desensitize teeth by reducing dentin permeability. In 1991, I (KM) joined The Block Drug Company, manufacturer of desensitizing toothpastes, to develop improved products that did just that. In the work that my industrial colleagues and I did, examining the ability of agents to alter dentin permeability, we were guided by the methods and publications of David Pashley.

In 1973, I (DP) had recently earned a PhD in physiology and was looking for a challenging research area. It occurred to me that no one had applied membrane physiology principles to study the permeability properties of dentin. Our work began by developing various types of split-chamber devices that could be used to control dentin thickness and surface area. Using radioisotopes, we began to study the permeability properties of normal dentin. It quickly became apparent that various anatomic features of dentin, such as tubule density and radius, were the principal factors determining flow. Flow was found to be proportional to the size of the radius raised to the 4th power, making this determinant particularly critical. Since the movement of dentinal fluid is the direct nerve stimulus in the hydrodynamic theory of dentin sensitivity, we devoted considerable effort to developing methods for measuring fluid flow in vitro (see (Pashley, 1990), for review) and in vivo (Ciucchi et al., 1995).

Using these techniques, we examined the effects of many chemicals and physical manipulations on dentin permeability as a means to decrease sensitivity. When dentin is cut, its surface is covered with a smear layer composed of tiny bits of mineral and denatured collagen. The presence of the smear layer severely restricts dentin fluid movements. The responses of intradental nerves to hydrodynamic stimuli could be elicited only after smear layer removal (Hirvonen et al., 1984), indicating that the smear layer reduces sensitivity. These observations explain why dentists used to burnish sensitive roots with a wooden stick. Smear layers are labile, however, being lost when exposed to acidic foods or drinks. The simple laboratory equipment that we developed to permit measurements of fluid flow across dentin also allowed us to discover how acidic solutions of oxalate can be used to reduce fluid movement in vitro and reduce dentin sensitivity in vivo (Camps and Pashley, 2003). Today, several oxalate-containing desensitizing solutions are on the market. Our studies revealed that vital dentin is a moist permeable environment, rich in organic material and quite different from enamel. Dentin-bonding agents used in restorative dentistry have to be able to interact with and adhere to this wet substrate. Others have used our chambers to determine how well adhesive resins seal dentin, preventing leakage and sensitivity following restorative procedures.

Effective desensitizing agents have to be able to reduce the dentin fluid movements that are triggered by pain-evoking stimuli. In most dentin permeability studies, flow driven by hydrostatic pressure is the only parameter measured. When both pressure- and air-blast-evoked flows were measured in the same dentin specimens, it was observed that treatments which markedly reduced pressure-driven flow had a more modest effect on air-blast-induced flow (Pashley et al., 1996). Creation of a smear layer on the dentin surface reduced the pressure-driven flow by approximately 90%, but reduced the air-blast-induced flow by only 50%. The smear layer is composed of fine particles surrounded by fluid-filled spaces. It allows dentinal fluid to pass through it when air-blasts cause evaporation, so the flow reduction to this type of stimulation is only partial.

The frustrating fact is this: We know that by increasing dentin permeability (for instance, by fracturing off the enamel), we can make teeth more sensitive. We do not yet know how much dentin permeability needs to be reduced to reduce sensitivity effectively.

LOOKING TOWARD THE FUTURE

Both of our experiences highlight the need for laboratory models to evolve as new information is acquired. Recent insights from neurobiology and mineralized tissue research should have important implications for tooth sensitivity and provide new targets for therapeutic intervention.

The intradental nerves that respond to dentin stimulation are mechanoreceptors preferentially activated by outward fluid flow. Certain fluorescent dyes can be taken up by these nerve endings when they are placed into deep dentin cavities. Once taken up by the intradental nerves, the dyes are transported to the cell bodies in the trigeminal ganglion, allowing for the identification and isolation of these cells (Cook and McCleskey, 2002). Researchers can then examine the physiological and pharmacological properties of these mechanoreceptors and test the effects of new drugs that would inhibit the initial responses of the nerve fibers to mechanical stimulation. This type of approach is being used to find analgesics that act by blocking the capsaicin receptor, an important mediator of inflammatory pain.

Most orally exposed dentin is not sensitive, because the tubules are non-patent, being occluded by mineral. Many animal species have continuously erupting teeth, where dentin permeability drops rapidly following oral exposure by wear. Nature has apparently evolved methods of plugging tubules by mineral formation. The intrinsic biological processes that reduce dentin permeability should serve as inspiration for biomimetic treatments for tooth sensitivity. When dentin forms, the odontoblasts secrete highly phosphorylated proteins in the area of the mineralization front, that attach to collagen and bind calcium (Veis, 2004). Materials that simulate the function of these proteins can be used to induce mineralization of the dentin surface. Dentin treated by mineralizing agents should, in addition to being less sensitive, have reduced susceptibility to damage from acid or mechanical actions.

In the future, increasing numbers of people are likely to be affected with this condition and the predisposing dental lesions. Also, new etiological factors of dentin sensitivity, such as the use of tooth-whitening systems, are becoming popular. Rather than being complacent with existing treatments, the academic and industrial branches of the dental research community must work together to bring new discoveries into clinical practice. The phenomenon of tooth sensitivity has engaged many scientific minds for many decades. Much has been learned, but there is still more to learn.