Periodontal disease is the most widespread chronic disorder in the world today not to mention its effect on other systemic diseases such as heart disease and diabetes. An estimated $6.5 billion is spent annually to treat the condition in the United States alone. Moreover, according to the ADA, only 7.5 million of the approximately 50 million Americans with periodontal disease are currently receiving treatment. Therefore, innovations for the treatment of periodontal disease that are less invasive, less painful, less costly and faster are the objectives of several pharmaceutical companies.

v PerioChip ®

The first of these is PerioChip (chorhexidine gluconate, 2.5mg). PerioChip does have FDA final approval and is manufactured and sold by Astra Pharmaceuticals. It is a small "chip" that measures 4 mm x 5 mm x 350 µm in a biodegradable matrix of hydrolyzed gelatin that contains 2.5 mg of the broad-spectrum antimicrobial agent, chlorhexidine gluconate. Its purpose is to deliver subgingival sustained-release chlorhexidine for the adjunctive treatment of periodontal pockets > 5 mm.

PerioChip, about the size of a baby’s fingernail, is inserted directly into infected periodontal pockets following scaling and root planing to remove plaque and calculus deposits. It takes less than one minute to insert PerioChip in to the periodontal pocket. PerioChip stays in place, releasing chlorhexidine (an antimicrobial) and is fully bioabsorbable in seven to 10 days, so there is no need for patients to come back for its removal. It does not visibly stain teeth or alter taste perception. Insertion in clinical studies required no anesthesia. For the ease of insertion the "chip" should be stored under refrigerated conditions at 2 to 8 degrees Centigrade and only be removed at the time of usage. The shelf life is two years. PerioChip may be inserted every three months if pockets remain 5mm or greater and may be used as part of a periodontal maintenance program that includes good oral hygiene and scaling and root planing.

Results of two large multicentre clinical studies in the U.S. indicated that the adjunctive use of PerioChip with scaling and root planing resulted in significantly greater reduction of periodontal pockets compared with scaling and root planing alone. At the end of the nine-month study period, patients who received PerioChip in addition to scaling and root planing showed a .95mm reduction in pocket depth compared to only a .65mm improvement with scaling and root planing alone.

In the scaling and root planing group the main reduction in pocket depth occurred between baseline and three months, after which point it stabilised. However, after three months in the PerioChip group, the reduction was statistically the same as the scaling and root planing alone group, but then continued to improve.

Because a decrease of 2 mm or more in pocket depth may have a significant impact on a patient’s treatment plan, including the possibility of treating a patient non-surgically rather than surgically, researchers also looked at the proportion of patients who experienced a 2 mm or more reduction in pocket depth.

In the scaling and root planing alone group, about 13.5 percent of patients had more than a 2 mm reduction at the end of the nine-month study period. When PerioChip was added to the regimen, that number more than doubled to 30.3 percent, a significant difference, statistically and clinically.

One PerioChip is inserted into a periodontal pocket with probing pocket depth (PD) > 5 mm. Up to 8 PerioChips may be inserted in a single visit. Treatment is recommended to be administered once every 3 months in pockets with PD remaining > 5 mm.

The periodontal pocket should be isolated and the surrounding area dried prior to chip insertion. The PerioChip should be grasped using forceps (such that the rounded end points away from the forceps) and inserted into the periodontal pocket to its maximum depth. If necessary, the chlorhexidine gluconate dental chip can be further maneuvered into position using the tips of the forceps or a flat instrument. The PerioChip does not need to be removed since it biodegrades completely.

In the unlikely event of chlorhexidine gluconate dental chip dislodgement (in the two pivotal clinical trials, only 8 chips were reported lost), several actions are recommended, depending on the day of chlorhexidine gluconate dental chip loss. If dislodgement occurs 7 days or more after placement, the dentist should consider the subject to have received a full course of treatment. If dislodgement occurs within 48 hours after placement, a new chlorhexidine gluconate dental chip should be inserted. If dislodgement occurs more than 48 hours after placement, the dentist should not replace the chlorhexidine gluconate dental chip, but reevaluate the patient at 3 months and insert a new chlorhexidine gluconate dental chip if the pocket depth has not been reduced to less than 5 mm.

Adverse Reactions

In these studies and one additional study involving a total of 619 patients, there was no reporting of visible staining or altered taste perception after the use of PerioChip.

There were no serious adverse events reported. The most frequently observed adverse events in the two pivotal trials (PerioChip versus placebo group) were toothache (51 percent versus 41 percent), upper respiratory tract infection (28 percent versus 26 percent), headache (27 percent versus 28 percent) and sinusitis (14 percent versus 13 percent) respectively.

Most oral pain or sensitivity occurred within the first week of the initial chip placement, was mild to moderate in nature and resolved within days. These reactions were observed less frequently with subsequent chip placement at three and six months.

PerioChip should not be used in any patient who is hypersensitive to chlorhexidine. The use of PerioChip in an acutely abscessed periodontal pocket has not been studied and therefore is not recommended. Management of patients with periodontal disease should include consideration of potentially contributing medical disorders, such as cancer, diabetes, and immunocompromised status.

The effectiveness of the "chip" has not been studied in sites with recurrent periodontal disease, acute periodontal abscesses, furcations or other intrabony lesions.

Patients should avoid dental floss at the site of PerioChip insertion for 10 days after placement, because flossing might dislodge the chip. All other oral hygiene may be continued as usual. No restrictions regarding dietary habits are needed. Dislodging of the chlorhexidine gluconate dental chip is uncommon; however, patients should be instructed to notify the dentist promptly if the chlorhexidine gluconate dental chip dislodges. Patients should also be advised that, although some mild to moderate sensitivity is normal during the first week after placement of chlorhexidine gluconate dental chip, they should notify the dentist promptly if pain, swelling, or other problems occur.

Source: Astra USA, Inc. Westborough, MA 01581

v Atridox ®

The second anti-microbial innovation is Atridox (8.5% doxycycline in the Atrigel ® Delivery System). The Atrix Laboratories, Inc. develops, manufactures and markets dental and medical products based on its proprietary Atrigel biodegradable polymeric technology, which can be used for a broad range of drug delivery. Atridox presently does have final approval by the FDA. Atridox combines the biodegradable polymer with doxycycline which is a site-specific anti-microbial delivery system intended for use in the nonsurgical treatment of chronic adult periodontitis. It is applied as a liquid to the affected area, where it conforms to the shape of the periodontal pocket and solidifies, releasing doxycycline over a period of seven days as it is bioabsorbed. Anesthesia is not required.

Supposedly Atridox does not require an initial treatment of root planing and periodontal scaling as with the "chip." This would be a major advantage as when done thoroughly, scaling and root planing is very time-consuming and usually requires the use of a local anesthetic.

The Phase III clinical studies that led to this product’s approval were the largest trials ever conducted for the treatment of periodontal disease. They included data from 822 patients at 20 study centers across the United States. The studies showed that Atridox use resulted in a 1.2 millimeter (mm) reduction in pocket depth and a 0.8 mm gain in attachment, the two most commonly used criteria to assess clinical effectiveness. Scaling and root planing–the traditional mechanical removal of bacterial buildup– resulted in a 1.1 mm pocket depth reduction and 0.7 mm attachment gain. Analysis of data from these pivotal studies was published in the May 2000 issue of the Journal of Periodontology. Data from another clinical trial also confirmed a significant decrease in disease-causing bacteria at sites treated with Atridox without an increase in resistance to doxycycline.

Post-marketing study results, which will be published in an upcoming major dental journal, demonstrated added benefits for Atridox as an "everyday use" product. In the United States, where the adult periodontitis population is more clearly defined, approximately 11 million people, or about 75 percent of all patients, have moderate periodontal disease (pockets 5 to 6 mm). In sites such as these, Atridox was applied following the routine dental procedures of measuring pockets and thorough teeth cleaning without local anesthesia. Pocket depths of 5 and 6 mm were reduced to 4 mm or less approximately 70 percent of the time (3 mm or less in normal, healthy gums). This is a level where the patient may not need any additional surgical periodontal treatment.

Presently there are no clinical studies that address the use of Atridox in other periodontal diseases such as LJP and RPP or to address specific sites such as furcation and intrabony lesions.

In clinical trials, the most common side effects associated with the Atridox product included tooth sensitivity, gum soreness and infections of the respiratory system. Atridox should not be used by patients who are hypersensitive to doxycycline or any other drug in the tetracycline class.

Source: Atrix Laboratories, Inc.

v Periostat ®

The third pharmaceutical drug is Periostat. It is manufactured by CollaGenex Pharmaceuticals and received final approval from the FDA in Sept. 1998. Periostat is a systemically delivered collagenase inhibitor available as a 20 mg capsule of doxycycline hyclate for oral administration. It is usually administered BID with the intended result of reducing the elevated collagenase activity in the gingival crevicular fluid of patients with adult periodontitis. Periostat is to be used following scaling and root planing (SRP) to improve the effectiveness of this standard periodontal procedure.

This is the first FDA approved systemic drug for host modulation as an adjunct to scaling and root planing in the treatment of periodontitis. Periostat reduced the elevated collagenase activity in the gingival fluid of patients with adult periodontitis.

Clinical studies have shown that Periostat administered after SRP improved clinical attachment level by up to 52 percent and reduced pocket depth by as much as 67 percent compared to SRP plus placebo. These benefits were observed as early as three months into the study and were maintained over the nine-month period of the trial.

CollaGenex Pharmaceuticals, Inc. recently announced the results of a new clinical trial designed to evaluate the efficacy of Periostat, as an adjunct to scaling and root planing (SRP), the most prevalent therapy for moderate to severe periodontal disease and the "gold standard" in currently available treatments for this disease.

Previous pivotal clinical studies carried out by the company evaluated the efficacy of Periostat in conjunction with a typical dental scaling and prophylaxis. The latest study is the first to establish that Periostat can significantly enhance the efficacy of SRP. In this study, 190 adult patients with periodontal disease were administered SRP at the outset of a nine-month, double-blind placebo-controlled clinical trial at five university dental centers in the United States. Patients were then randomly assigned to take either Periostat or a placebo. Measurements of probing pocket depth (PPD) and clinical attachment level (cALv) were made every three months using a periodontal probe.

Results were compared with measurements taken immediately prior to the course of SRP. In the group receiving Periostat, statistically significant improvements in PPD and cALv (compared with placebo) were seen in all diseased sites as early as three months following SRP and at all time points thereafter. As in previous clinical studies conducted by the company, the more severely diseased sites improved the most, with PPD and cALv improvements of approximately 1.7 millimeters and 1.6 millimeters, respectively, at nine months following SRP in sites with an initial PPD of seven millimeters or greater.

Periostat is the only treatment for adult periodontitis that has been shown to suppress the tissue-destroying activity of collagenase, an enzyme overproduced by the body in response to bacterial infection in the periodontal pocket.

Collagenase breaks down the supporting structures (gums, ligaments, bone) that hold the teeth in place. Recent research has demonstrated that periodontitis, the leading cause of adult tooth loss, is most effectively combated with a treatment approach that addresses the two key components of the disease–bacterial infection and the enzymes that destroy connective tissues.

In particular, CollaGenex has developed inhibitors of certain chronic degenerative processes that lead to the destruction of connective tissue during inflammation. These inhibitors have shown the potential to treat a variety of diseases including periodontal disease and inflammatory diseases of the musculoskeletal, respiratory and gastrointestinal systems.

Source: CollaGenex Pharmaceuticals, Inc.

On the basis of the present medications and there clinical findings it is obvious that further long-term studies should be conducted to determine whether these innovations will be beneficial to actual tooth survival and which patients are most likely to benefit from their treatment modalities. The lack of any significant results makes one question the usefulness of these innovations in the long-term treatment of periodontal diseases.

When considering using Periostat or other adjuncts to SRP, clinicians must consider the expected results in view of the severity of the defects being treated. Furthermore, it should be noted that adjunctive procedures to enhance conventional therapies are not a substitute for meticulous home care, professional root planing and appropriate treatment designed to minimize bacterial load and facilitate proper home care. In this regard, each practitioner must determine the usefulness of various pharmaceuticals options in light of the available data and needs of the individual patient.

1. Caton J,.Submicrobial doxycycline therapy for periodontitis (Abstract) J Dent Res 1997;76:1307.
2. Caton J, Ciancio S, Crout R, Hefti A, Polson A. Adjunctive use of subantimicrobial doxycycline therapy for periodontitis. J Dent Res 1998;77:1001 (Abstract # 2957).
3. Polson AM. Multi-center comparative evaluation of subgingivally delivered sangunarine and doxycyline in the treatment of periodontitis. II Clinical results. J Perio 1997;68:119-126.
4. Soskoine WA. Clinical and microbiological effects of sustained release chlorhexidine in the treatment of periodontitis: a multi-centered study. J Perio 1997;68:32-38.

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