UCSF Protocol for Caries Arrest Using Silver Diamine Fluoride: Rationale, Indications and Consent
Longer studies are needed to determine whether caries arrest and prevention can be maintained with decreased application after two to three years, and whether more frequent use would enhance efficacy. Traditional or nontraditional restorative approaches such as the atraumatic restorative technique( ART) 44 and Hall crowns 45 should be performed as dictated by the response of the patient, disease progression and the nature of individual lesions.
SAFETY
Maximum Dose and Safety Margin The margin of safety for dosing is of paramount concern. In gaining clearance from the FDA, female and male rat and mouse studies were conducted to determine the lethal dose( LD50) of silver diamine fluoride by oral and subcutaneous administration. Average LD50 by oral administration was 520 mg / kg and by subcutaneous administration was 380 mg / kg. The subcutaneous route is taken here as a worst-case scenario. One drop( 25 μL) is ample material to treat five teeth and contains 9.5 mg silver diamine fluoride. Assuming the smallest child with caries would be in the range of 10 kg, the dose would be 0.95 mg / kg child. Thus, the relative safety margin of using an entire drop on a 10 kg child is 380 mg / kg LD50 / 0.95 mg / kg dose = four-hundredfold safety margin. The actual dose is likely to be much smaller, for example 2.37 mg total for three teeth was the largest dose measured in six patients. 46 The most frequent application monitored in a clinical trial was weekly for three weeks, annually. 43 Thus we set our recommended limit as one drop( 25 μL) per 10 kg per treatment visit, with weekly intervals at most. This dose is commensurate with the Environmental Protection Agency’ s( EPA) allowable short-term exposure of 1.142 mg silver per liter of drinking water for one to 10 days( Agency for Toxic Substances and Disease Registry, ATSDR, 1990).
Cumulative exposure from lower-level acute or chronic silver intake has no real physiologic disease importance, but the bluing of skin in argyria should obviously be avoided. The EPA set the lifetime exposure conservatively at 1 gm to safely avoid argyria. The highest applied dose for three teeth measured in the pharmacokinetic study, 2.37 mg, would enable > 400 applications. 46 Silver nitrate( typically a 25 % solution) has been used for more than 100 years in the U. S. without incident, including acceptance by the ADA, and in other countries for arresting dental caries. 3
ADVERSE EFFECTS Not a single adverse event has been reported to the Japanese authorities since they approved silver diamine fluoride( Saforide, Toyo Seiyaku Kasei Co. Ltd., Osaka, Japan) more than 80 years ago. 47 The manufacturer estimates that more than 2 million multi-use containers have been sold, including > 41,000 units in each of the last three reporting years.
In the nine randomized clinical trials in which silver diamine fluoride was applied to multiple teeth to arrest or prevent dental caries, the only side effect noted was for three of 1,493 children or elderly patients monitored for one to three years who experienced“ a small, mildly painful white lesion in the mucosa, which disappeared at 48 [ hours ] without treatment.” 29, 31-33, 35, 38, 40, 41, 48 The occurrence of reversible localized changes to the oral mucosa was predicted in the first reports of longitudinal studies. 49 No adverse pulpal response was observed.
Gingival responses have been minimal. In a pharmacokinetic study of silver diamine fluoride application to three teeth in each of six 48 to 82 year olds, no erythema, bleeding, white changes, ulceration or pigmentation was found after 24 hours. Serum fluoride hardly went up from baseline, while serum silver increased about tenfold and stayed high past the four hours of measurement. 46 In a two-site hypersensitivity trial of 126 patients in Peru, at baseline 9 percent of patients presented redness scores of 2( 1 being normal, 2 being mild to moderate redness and 3 being severe); and after one day 13 percent in silver diamine fluoride treated patients versus 4 percent in controls. All redness was gone at seven days. Meanwhile, gingival index improved slightly in silver diamine fluoride treated patients. 7 Nonetheless, gingival contact should be minimized. In our experience, it has been adequate to coat the nearby gingiva with petroleum jelly, use the smallest available microsponge and dab the side of the dappen dish to remove excess liquid before application.
Concerns for fluoride safety are most relevant to chronic exposure, 50 whereas this is an acute exposure. Chronically high systemic fluoride results in dental fluorosis. The ubiquitous use of fluoride-based gas in general anesthetics has shown that the first acute response is transient renal holding, and is rare. 51 Concerns have been raised about poorly controlled silver diamine fluoride concentrations 52 and fluorosis appearing in treated rats. 53 However, silver and fluoride levels are closely monitored for the U. S. product, and the Health Department of Western Australia conducted a study that found no evidence of fluorosis resulting from long-term proper use of silver diamine fluoride. 54 Therefore, we have concluded that the development of fluorosis after application of the U. S.-approved product is not a clinically significant risk.
Silver allergy is a contraindication. Relative contraindications include any significant desquamative gingivitis or mucositis that disrupts the protective barrier formed by stratified squamous epithelium. Increased absorption and pain would be expected with contact. Heightened caution and use of a protective gingival coating may suffice.
JANUARY / FEBRUARY 2017 | PENNSYLVANIA DENTAL JOURNAL 21