Review article

Medication of the dental pulp: a review and proposals

Ciarlone AE, Pashley DH. Medication of the dental pulp: a revitnv and proposals. Endod Dent Traumalol 1992; 8: 1-5. Abstract - For years, dentists have desired to treat the intact dental pulp. Since it is well-known that many substances, including some drugs, arc capable of permeating dentin, we believe it is possible to treat certain types of pulpitis by applying drugs at vhe base of cavity preparations. Useful drugs include local anesthetics to block pain transmission, glucocorticoids or non-steroidal anti-inflammatory agents (NSAIA) to treat inflammation, NSAIA or narcotic analgesics for pain control, and antibiotics to treat infection. The hterature is reviewed and proposals are presented to study medication of the dental pulp. Alfred Edward Ciarlone, David Henry Pashley
Medical College of Georgia, Department of Orai Biology. Augusta, USA

Key words: analgesics; anti-inflammatory agents; dental pulp: dentin; dentin permeability; local anesthesia; glucocorticoids; pulpitis. Alfred E. Ciarlone, Iwledical College of Georgia, School of Dentistry, Department of Oral Biology, Augusta, GA 30912-1128, USA Accepted June 20, 1991

For years dentists have desired to treat the intact dental pulp (i.e. no pulp exposure} with variable degrees of success. One of the earhest attempts to affect such treatment was with the use of sedative, temporary restorations containing zinc oxide and eugenol (ZOE). In those earlier years, the dental profession was not sure of the exact mechanism of action of ZOF- but we did know that it was an effective sedative dressing. Zhic oxide is thought to have slight antiseptic activity, whereas eugenol, while believed to produce some antisepsis, is analgesic (1). Hume (2) attempted to clarify this issue by reporting that eugenol is capable ol being released from ZOE restorations and then permeates dentin to effect pulpal tissues (see Table 1;. Only a few other studies have been published quantitating the permeation of drugs across dentin (Table .1). Pashley et al. (3) and Hastings et al. (4) sludied the permeability of lidocaine across coronal dentin. Abbott et al. (5-8) reported the diffusion of triamcmolone and a tetracycline across both coronal and root dentin, whereas Csukas et al. (9) studied metronidazole diffusion using root dentin. In 1988 and 1989, Ciarlone et al. (10, 11) reported dentin permeabihty to tetracycline and both Grower et al. I 12) and Ciarlone et al. (13) used discs to study the diffusion of indomethacin and epinephrine, respectively, across dentin. Proposal Bacteria and bacterial products that are present in both carious dentin and in dentin due to microleak-

age of restorations, are capable of causing an inflammatory response, i.e. pulpitis (14, 15]. This is presumably due to cytotoxic bacterial products shed into tubules. Conservative treatment would consist of removing the carious dentin and restoring the tooth or replacing the leaking (or defective) restoration with the hope that the reparative and healing ability of the pulp would restore pulpal health. With irreversible pulpitis, endodontic therapy is indicated. However, we believe there is another conservative method of treating reversible pulpitis and perhaps some forms of what is now considered the irreversible type, and that is with the use of drugs. A number of drugs are available to treat pain and inflammation; for example (a) local anesthetics to block pain transmission, (b) glucocorticoids or nonsteroidal anti-inflammatory agents (NSAIA) to treat inflammation, (c) NSAIA or narcotic (opioid) analgesics for pain control, and (d) antibiotics to treat the infection that is associated with pulpitis. Also, the use of antimicrobial drugs to treat certain forms of periodontal disease is growing (16). Of course, drugs will not always be effective; there will be instances of failure. This is because of the difficulties in obtaining accurate puipal diagnoses and because some inflammatory conditions are sterile and some are septic. However, the use of tetracycline to treat a putative pulpal bacterial infection may be helpful even if the pulp is sterile because tetracyclines exhibit the ability to suppress neutrophil functions independent of their antibacterial effects (17). 1

Ciarlone & Pashloy

Table 1. Drugs whose permeation ot dentin were studied. Drugs epinephrine eugenol . . .. ,indomethadn lidocaine metronidazDie tetracycline+triamcinolone tetracycline Dentin Site coronal coronal coronal coronal radicular coronal & radicular coronal References

13 2 12 3,4 9 5-8
10,11

Wth the possible exception of narcotic analgesics, all the drugs just listed should have a direct therapeutic effect on the pulp. Narcotic analgesics are thought to act within the central nervous system rather than in the periphery. However, two recent reports (18, 19) suggest that dental pulps contain both enkephalin and |3-endorphin. If these opiates are naturally present within pulpal tissues, in all probability pulp soft tissues contain opiate receptors and they are thought to be involved in pain perception and/or conduction (18, 19). Therefore, narcotic analgesics should be considered for study. Problem areas There are a number of problems associated with our proposed conservative treatment of the dental pulp, and we will attempt to address each one of them as part of this review. It is now known trom dentin diffusion experiments, that the concentration of drug reaching the pulp is much lower than the applied concentration due to: (a) the restriction of diffusionai surface area intrinsic in the structure of dentin, (b) the presence of a smear layer which tends to occlude dentinal tubules, and (c) dentin thickness, which tends to dissipate the drug across distance (20, 21). It is wellknown that the density of dentinal tubules increases when approaching the pulp from an occlusal direction (21). As to the smear layer, it can be removed with acids or calcium chelators (22). Also, this topical treatment method should be without drug side effects, since such effects occur from larger systemic dosages. For example, Scott applied a few n:iicroliters of 1.5 mM aspirin directly to a canine incisal cavity of a cat, which completely abolished a heatevoked response from a sensory unit in dentin (23, 24). Other factors that could alter drug permeation are: (a) molecular charge and weight or size of drugs, (b) presence of enamel or cementum which severely restricts diffusion, and (c) the actual site of dentin studied. Pashley et al. (25) have shown that albumin is capable of permeating dentin. Albumin has a molecular weight of about 69,000, whereas

er)'thromycin) one of the largest drugs that one might study, weighs 734 daltons; so restriction because of size of the drug molecule should not be a problem. Removal of enamel or dentin is easily done, and in fact we would propose the medication be placed at the base of a cavity preparation. 7 he dentin site of application of drug is a potential problem, but not a significant one. Although it is known that coronal dentin is more permeable than radicular (26), it may not be significant because we have studied the permeation of epinephrine across radicular dentin (unpublished obser\'ations) and the results suggest that epinephrine is capable of reaching a lower but significant pulpal concentration when compared to coronal dentin (13). Another problem of relying on the delivery of drugs by diffusion is that it requires time (many minutes). If immediate drug action is required, we believe the time for delivery of drug may be significantly reduced by applying filtration principles rather than diffusion. Merchant et al. (27) ha\'e shown this to be true in vitro, and we should be able to apply these principles to the in vivo situation. A cotton pellet can be saturated with drug, placed at the bottom of a cavity preparation, and a soft piece of wax added on top. By having the patient bite down, we can mimic the in vitrofiltrationsituation. This would fill the tubules with a high concentration ol drug that could serve as a slow release depot over time. It also accomplishes drug transport across dentin in seconds rather than tens of minutes (27). In the early part of this century, dentists used to obtain pulpal anesthesia by filhng a cavity with a solution of cocaine and then pushing the fluid across dentin with a rubber plug (pers comm, I. B. Bender). Fluid filtration may cause pain in unanesthetized patients (28). One alternative is to anesthetize them prior to inducing filtration. Alternatively, this method may be employed if one cannot obtain pulpal anesthesia. The area that is anesthetized would be limited to the permeable dentin of the prepared cavity. However, that may be all that is required in some cases. Fluid filtration may also cause pulpal damage. If excessive, it may create a "blister" lesion where the odontoblast layer is displaced away from the predentin. While such lesions should be avoided, only further research will determine the puIpaJ consequences of such a lesion. One could argue that it might not cause significant pulpal irritation and that it could be repaired. It is quite likely that the fluids reaching the pulp would be sterile (29) even if the original solution was not, as dentin behaves as if its "porosity" was 0.10.2 ^m, similar to that of millipore filters used to sterilize solutions. However, the fluid may carry bacterial products into the

Pulp medicatioi pulp and create more pulpal irritation. Only further research will clarify these speculations. Another problem associated with treatment of pulp with drugs by diffusion is pulpal blood flow. Kim (30) reported that pulpal blood flow is relatively high (0.4 ml/min/gm of tissue) whereas diffusion across dentin is rather low. Therefore, some drugs may not ever reach therapeutic concentrations in the pulp. Two solutions to this problem are possible: (a) use of very potent drug, or (b) add a vasoconstrictor to the study drug's solution to prevent the pulpal clearance of the therapeutic agent by pulpal microcirculation. Consider the situation of the topical use of local anesthetics to relieve pain. Since most local anesthetics are vasodilators (one exception is cocaine), these drugs can actually increase pulpal clearance and a vasoconstrictor is probably an absolute requirement for use. Moreover, once enamel or cementum is removed from a tooth in silu, there is a nattiral movement of dentinal fluid from the pulpal side of dentin to the external surface which tends to oppose diffusion (pers comm, B. Matthews) and is driven by pulpal pressure. This further inereases the need for a vasoconstrictor which lowers pulpal pressure to near zero thereby abolishing the normal movement of dentinal fluid and facilitating inward diffusion of drug. Of course the correct dose (or range of doses) of vasoeonstrictor would have to be established because at higher doses the vasoconstrictor may cause a pulpal ischemic response that lnay result in pulpal tissue damage. The plasma therapeutic concentrations of most drugs are known (31) and therefore various applied concentrations can be studied to produce a pulpal coticentration that falls within the range of the desired response. For example, the plasma anti-inflammatory concentration of aspirin is reported to be 150-300 Hg/ml (31). The application of a single drop of a saturated solution of aspirin in water may achieve these pulpal concentrations without the necessity of systemic absorption of the drug, gastric irritation, etc. Research proposals I he use of topical application of local anesthetics to dentin can be evaluated using simple elinical experiments. For instance, in patients who require bilateral extraction of premolars for orthodontic purposes, shallow Class V cavities could be prepared into their buccal surfaces after using PDLadministered loeal anesthetic. This minimizes the volume of local anesthetic and provides sufficient time for eavity preparation but only about 20 min of local anesthesia (32). Approximately 1 hr after preparing the cavities, an electric pulp tester placed on the pulpal floor of the dentin could be used to test for the restoration of neural responses. Ideally, the pulp tester should be a constant current deviee. Test solutions of local anesthetics could be applied to the dentin and the vitality of the pulpal nerves re-evaluated every 5 min for the next 20-30 minutes or until local anesthesia was obtained via difliusion across dentin. After obtaining local anesthesia in the buccal cavity, test eavities could be prepared on the lingual side of the same teeth to determine if the loeal anesthesia was general or was eonfined to the buecal dentin. The experimental variables that could be evaluated inelude: type of loeal anesthetie, concentration, pH, removal of smear layer, remaining dentin thickness, iontophoresis, fluid filtration, ete. As those teeth are scheduled for extraction, they are also available for histologic study. Determination of the efficacy of anti-inflammatory agents on the elinical course of pulpal inflammation is more difTieult. Ideally, animal models should be developed that can reproducibly develop pulpal inflammation. The topical use of sonicates of baeterial plaque by Bergenholtz (14, 15) to cavity dentin is a good example of such a model. Putative anti-inflammatory drugs could be mixed with the cell-free bacterial sonicate to determine how well they were able to express their anti-inflammatory potential. The extent of the histopathologic pulpa! reaction to control plaque sonicates versus anti-inflammatory agent plus plaque sonicates could be quantilated over time using morphometric teehniques (33). That is, lyophilized plaque made up in a known molarity of a NSAIA should produce less pulpal inflammation than the same lyophilized plaque made up with isotonic saline at any obser\ ation time. Similar studies could actually be done on patients seheduled for extraetion of premolars for orthodontic purposes. The important experimental variables would include type of anti-inflammatory drug, concentration, remaining dentin thiekness, presence or absence of smear layers, time, etc. In many inflammatory conditions, local blood flow is reduced by elevations in loeal tissue pressure. This may occur because of a low compliance environment (i.e. pulp, bone or nail bed) or due to abseess formation. Traditional treatment has often included ineising and drainage of the area to relieve tissue pressure and remove toxic products. In endodontics, periapical exudates are drained through an opened root eanal. One wonders if pulpal abseesses could be drained through intact dentin. That is, the dentin could be excavated or thinned until the remaining dentin thiekness was small (i.e. 0.5 mm)\ The smear layer eould be removed by acid-etching, the dentin rinsed and dried and then observed for 3-5 min. Permeable dentin permits fluid to aceumulate slowlv on its surface. Under reflected light, the

Ciarlone & Pashlev surface changes from matte to shiny. This indicates that fluid is able to move across the dentin, that it is thin enough, that the smear layer has been removed and that there is an elevated tissue pressure below that dentin (34). A piece of dry absorbant material could then be placed over the dentin followed by a thin film o^ Teflon to protect the abf sorbant material from the temporary restorative material used to seal the cavity until the next appointment. After outward fluid movement recedes, one can then recover the saturated absorbant material for analysis and replace the dry absorbant material with a cotton ball saturated with an appropriate medicament. This could be sealed in to permit time for the drug effect and for pulpal healing. If the cavity can not be sealed between visits, then the medicaments will be washed away and bacteria will colonize the dentin surfaces further irritating the pulp. If one wished to accelerate the process, one could apply a negative pressure to the cavity (34) to relieve the tissue pressure more rapidly. However, if too much negative pressure is applied, it may not only disrupt odontoblasts but injure the subodontoblastic capillary bed as well. All of these comments presume that one can accurately diagnose the presence and location of a pulpal abscess. Accurate pulpal diagnostic techniques such as laser Doppler flowometry (35-38) to determine if the pulp is being perfused by blood is a useful new research tool that may have diagnostic utility. Collection and analysis of dentinal fluid for the presence of biologic markers of inflammation is another recent proposal thai has merit (34). Such approaches may have to wait for further advances in endodontic diagnostic procedures. However, the research that would be required to apply such knowledge to the conservative treatment of putpal inflammation should proceed. References
1. ACCEPTED DENTAL THERAPEUTICS. 40th ed. Chicago: The

American Dental Association, 1984; 328-330. 2. HUME \V"R. An analysis of the release and the diffusion through dentin of eugenol from zinc oxide-eugeno! mixtures. J Dent Re.^ 1984; 63: 881-4.
3. PASHLEY DH, LIVINGSTON MJ, OUTHWAITE WC. Dentin per-

meability: changes produced by iontophoresis. J Dent Res 1978; 57.- 77-82.

4. HASTINGS CE, HOLLINGER JO, VINCENT JW, SWAVZE DR.

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diffusion through human coronal dentine in vitro of triamcinolone and demeclocyline from Ledermix paste. Endod Dent Traumatot 1989; 5; 92-7.
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Conclusions Advances in our knowledge of dentin dynamics, the role of smear layers, pulp blood flow, etc, suggest therapeutic approaches to the treatment of selected pulp diseases are now possible. Although there are many difficulties with this approach, some of the recommendations in this article conceivably should be scientifically evaluated. This will permit the area of endotontics to expand to one in which the preservation of the pulp will be emphasized instead of its removal by endodontic therapy. Acknowledgements ~ This work was supported, in part, by Grant' DE 06427 from the NIDR and by the Medical College of Georgia Research Center.

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KiLLMAR J, DESIDERIO DM. Effects of orthodontic forces on methioninc enkephaiin and substance P concentrations in human pulpal tissue. Am J Orthod Dentofac Orthop 1989; 95: 479-89.
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21. OUTHWAITE WC, LIVINGSTONE MJ, PASHLEY DH. Effects of

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