Silver diammine fluoride

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Silver diammine fluoride
Before (left) and after (right) use of SDF in people with tooth decay
Names
Trade namesFagamin, Advantage Arrest, others
Other namesDiammine silver fluoride, diamine silver fluoride, silver fluoride, silver ammonium fluoride
  • Diamminesilver(I) fluoride
Clinical data
Main usesTooth decay, sensitive teeth[1]
Side effectsStaining of cavities black, metallic taste[1]
Legal
Legal status
  • US: ℞-only and 510(k) cleared class II medical device
Chemical and physical data
FormulaAgFH6N2
Molar mass160.929 g·mol−1
3D model (JSmol)
  • F[Ag]([NH3])[NH3]
  • InChI=InChI=1S/Ag.FH.2H3N/h;1H;2*1H3/q+1;;;/p-1

Silver diammine fluoride (SDF), also spelled silver diamine fluoride, is a medication used to treat and prevent tooth decay and treat sensitive teeth.[1] It is also useful to identify tooth decay.[1] It is applied to the teeth.[1] It appears more effective than fluoride varnish.[2]

Side effects include permanent staining of cavities black and a metallic taste.[1] While staining of skin may occur, this is temporary.[1] When used twice per year in children the risk of dental fluorosis is low.[1] It contains silver, fluoride, and ammonia ions.[1] It works by blocking dentin tubules, killing bacteria, and improving remineralization of teeth.[1]

Silver diammine fluoride was approved for medical use in Japan in the 1960s and the United States in 2014.[1] It is also available in the United Kingdom and Australia among others.[1] It is on the World Health Organization's List of Essential Medicines.[3] In the United States its use costs about 75 USD as of 2021.[4]

Medical uses

SDF patient information leaflet showing side effect of discolouration of SDF with pictures before and after treatment
An example of a patient information leaflet to allow discussion oftreatment. It shows teeth with tooth decay before, and after, treatment with SDF where the tooth decay has become darkly stained.

SDF is used for:

Cavity progression

  • A review in 2017 analysed the arrest of caries in primary teeth over a 12-month period. SDF was able to arrest caries at a 66% higher (95% CI 41-91%; p < 0.00001) rate than any other active material, and 154% (95% CI 67-85%; p < 0.00001) more than placebos.  Overall, the study concluded that caries arrest was 89% higher (95% CI 49-138%; p < 0.00001) in SDF as compared to using any other active materials or placebos.[10]
  • A further systematic review and meta-analysis by Trieu et al. (2019) concluded that SDF works more effectively for the arrest of dentine caries as compared to high concentration sodium fluoride preparations (e.g. Duraphat varnish). The evidence from this meta-analysis is considered strong.[11]
  • Gao et al. (2016) reviewed 19 studies, 16 of which considered primary (baby) teeth and 3 on permanent (adult) teeth. The associated meta-analysis included 8 studies and revealed that 38% SDF (44,800ppm Fluoride) had achieved caries arrest in 86% of (95% confidence interval [CI], 47% to 98%; P = 0.06) dentinal carious lesions in primary teeth at six months interval, 81% (95% CI, 59% to 93%; P = 0.01) at 12 months and 65% (95% CI, 35% to 86%; P = 0.32) at 24 months. Overall, 81% of active caries lesions had arrested following SDF treatment.[12]
  • Horst (2018) reviewed 10 clinical trials in children and adults and suggested "to skip the rinsing step due to demonstration of safety in young children, start patients with high disease severity on an intensive regimen of multiple applications over the first few weeks, and continue with semiannual maintenance doses as previously suggested."[13]
  • An umbrella review by Seifo et al. (2019) found that SDF was favoured as a treatment option for the arrest and prevention of root caries lesions. As for coronal caries lesions, comparisons were drawn between SDF, fluoride varnish, glass ionomer cement and placebos as treatment modalities.[14] It was found that SDF had the highest caries arrest rate.
  • A systematic review of caries prevention by SDF in children with a low threshold for inclusion - any comparative clinical study with a control or placebo group - found a 61% preventive fraction.[15]
  • One systematic review also presented and concluded that SDF may potentially be a treatment option for the prevention of caries in first permanent molars however the evidence to support this is inconclusive.[16]

Concentration

A review concluded that 30% and 38% concentrations of SDF were most effective for caries arrest.[16] One of the trials in this review found 38% SDF to be more effective for the prevention of caries in primary teeth, with 80% fewer new lesions in primary teeth, and 65% fewer new lesions in first permanent molars.[17] Yee et al. (2009) compared the effectiveness of 38% against 12% SDF, with or without using a reducing agent for the caries arrest. Over a 24-month period, it was concluded that there was a higher rate of lesion arrest in teeth treated with 38% SDF (with and without the reducing agents) as compared to 12% SDF.[18]

Frequency of application

A randomised clinical trial conducted by Zhi et al. (2012) found that increasing the frequency of SDF application from once to twice per year increased the rate of caries arrest.[19] The American Academy of Paediatric Dentistry (AAPD) recommends a 2-4 week follow-up to assess the arrest of carious lesions treated with SDF.[12][20] If the lesions do not appear to have arrested (i.e. dark in colour and tactilely hard), it is suggested by them to reapply. Subsequent restoration of the carious lesion may be indicated following the application of SDF to restore aesthetics. If these lesions are not restored following SDF application, the AAPD recommends application biannually, as this has shown an increased caries lesion arrest rate as compared to annual application.[21]

Maximum dose

Average LD50 in mice and rats 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 (32.5 μL) is ample material to treat 5 teeth, and contains 12.35 mg silver diamine fluoride. Assuming the smallest child with caries would be in the range of 10 kg, the dose would be 1.235 mg / kg child. Based on this, UCSF recommended 1 drop per 10 kg of body weight per visit.[5] The US FDA set a dose limit of 260 µL for any person 12 – 59 months old at the start of the study.

Contraindications

The use of SDF is contraindicated in the following scenarios:

Side effects

The main side effect of SDF is non-medical and is the prominent black staining of carious tooth tissue where the solution is applied.[24]

SDF will stain most things it touches, including skin, mucous membranes, clothing and work surfaces. Chu et al. reported on the first modern clinical trial of SDF that the stain was generally acceptable and "the presence of darkened teeth was mentioned by around 7% of the parents."[25]

Another side effect is an intensely bitter metallic flavor, which subsides in minutes.

No serious adverse reactions (e.g. life-threatening reactions, hospitalization, toxicity or death) have been reported in the scientific literature. Two safety studies have been done in children.[26][27]

Pharmacokinetic studies in adults found no adverse effects and demonstrated a lack of any increase of Fluoride in the blood. Increases in serum Silver were observed.[28]

Systematic reviews[29][5][30][31][32][16][12][9][2] reported adverse reactions following SDF use. These reactions manifested as small, white lesions of the oral mucosa that healed over the course of 48 hours. Furthermore, an umbrella review by Seifo et al. (2020) did not report any serious adverse reactions.[14]

Mechanism of action

SDF's mode of action is well documented, but remains contested. Rosenblatt et al.[2] summarized how the constituents in SDF each have a role in the arrest of microbial species that cause dental caries. The higher the concentration of fluoride in a compound, the more effective its mechanisms in inhibiting bacterial biofilm formation. Fluorides can bind to bacterial cell walls, inhibiting enzymatic processes associated with sugar uptake and metabolism of carbohydrate, therefore producing a surface more resistant to acid dissolution.[33][34]

Similarly, the silver in SDF kills cariogenic bacteria by interacting with DNA and cellular proteins. This leads to cessation of cellular metabolism preventing bacterial cell wall synthesis and DNA synthesis, and ATP production. These actions destroy plaque biofilms, and subsequently arrest dental caries.[34][35]

SDF hardens carious dentin, such that it is twice as hard as healthy dentin[36]

Cariogenic bacteria

Colony Forming Unit counts (CFU) and studies of multispecies carious biofilms were carried aiming to examine the action of SDF on cariogenic bacteria.[33] CFU counts on Streptococci mutans, Actinomyces naeslundii, Lactobacillus acidophilus, Streptococcus sobrinus, Lactobacillus rhamnosus (all of which are bacteria intimately associated with the carious process) were significant lower in both dentin surfaces and demineralized dentin treated with SDF when compared to water application. SDF also inhibits the adherence of S.mutans to tooth surfaces.[33]

Targino et al. (2014) reported that minimum bacterial concentration and minimum inhibitory concentration of SDF for S.mutans were 50.0 ug/ml and 33.3 ug/ml respectively.[37] This shows that SDF as a compound has better bactericidal effects than silver ammonium nitrate and sodium fluoride (commonly found in toothpastes).[38][39]

Organic content on dentin

The affected layer of carious dentin in teeth can be identified by the presence of intact collagen fibres. Studies have revealed that a larger amount of intact collagen fibres remain on dentine surfaces (perpendicular to the enamel dentine junction) when treated with SDF as compared to water.[33]

SDF inhibits proteolytic activities such as enzymatic degradation of collagen fibres by matrix metalloproteinases MMP-2, 8 and 9.[33] Furthermore, SDF stops the degradation of cysteine cathepsins, which are also responsible for dentine collagen degradation.[35]

Chemistry

It is a colorless or blue-tinted, odourless liquid composed of silver, ammonium and fluoride ions at a pH of 10.4 or 13.[33] Ammonia compounds reduce the oxidative potential of SDF, increase its stability and helps to maintain a constant concentration over a period of time, rendering it safe for use in the mouth.[40]

History

  • Dental use of silver nitrate can be traced back to Japan around 1000 AD, where it was used for cosmetic purposes of blackening of teeth. Silver nitrate followed by application of fluoride varnish was the only non-invasive option available for caries treatment before the advent for silver diamine fluoride (SDF). Cases of carious lesions treated and arrested by the application of silver nitrate date to 19th century. Medical research study that dates back to 19th century showed 87 of 142 treated carious lesions were arrested.[40]
  • Silver diamine was formed when ammonia was added to silver nitrate to make it stable and effective as an antibacterial for application to caries lesions and infected root canals.[41]
  • SDF was developed by Reichi Yamaga, Misuho Nishino, and colleagues to prevent and treat dental caries.[42]
  • SDF was approved by PMDA (equivalent of FDA) in 1970 in Japan and has been used there since.
  • SDF has been widely used in Australia and Brazil since 1980 with in vivo studies done in the respective countries.[40]
  • In 2014 the FDA cleared SDF as a medical device for treating dental hypersensitivity.
  • In January 2016 in the US, a new Code on Dental Procedures and Nomenclature (CDT), D1354, allowed billing claims for off-label use of SDF as an interim caries-arresting medicine.
  • In 2017, Canada approved use to treat dental caries.

Names

SDF is also known as diammine silver fluoride, silver fluoride, and silver ammonium fluoride. It is frequently spelled "silver diamine fluoride" (with one m); however, this is a misnomer, as SDF contains two ammine (NH3) groups, not amine (NH2) groups.[43]

  • Argentina: 38% SDF solution, Fluoroplat, NAF Laboratories, Buenos Aires, Argentina. 38% SDF Solution, FAgamin, Bv. of the Poles 6136, Córdoba, Argentina.
  • Japan: 38% SDF solution, Saforide, Toyo Seiyaku Kasei Co. Ltd., Osaka, Japan.
  • USA: 38% SDF solution, Advantage Arrest, Elevate Oral Care LLC, West Palm Beach, Florida, USA.
  • India: 38% SDF solution, e-SDF (Kids-e-dental LLP, India)
  • Australia: 38% SDF solution, Riva Star, unit doses, SDI, TOPAMINE
  • (there are 30%, 12%, and 10% SDF's available from Argentina and Brazil. CarieStop and others.)

References

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