Silver Diamine Fluoride
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Silver diammine fluoride (SDF), also known as silver diamine fluoride in most of the dental literature, (although this is a chemical misnomer) is a
topical medication A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...
used to treat and prevent
dental caries Tooth decay, also known as cavities or caries, is the breakdown of teeth due to acids produced by bacteria. The cavities may be a number of different colors from yellow to black. Symptoms may include pain and difficulty with eating. Complicatio ...
(tooth decay) and relieve dentinal hypersensitivity. It is a colorless (most products) or blue-tinted (Advantage Arrest), odourless liquid composed of silver, ammonium and fluoride ions at a pH of 10.4 (most products) or 13 (Riva Star).
Ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...
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.
Silver Silver is a chemical element with the Symbol (chemistry), symbol Ag (from the Latin ', derived from the Proto-Indo-European wikt:Reconstruction:Proto-Indo-European/h₂erǵ-, ''h₂erǵ'': "shiny" or "white") and atomic number 47. A soft, whi ...
and
fluoride Fluoride (). According to this source, is a possible pronunciation in British English. is an inorganic, monatomic anion of fluorine, with the chemical formula (also written ), whose salts are typically white or colorless. Fluoride salts typ ...
ions possess antimicrobial properties and are used in the remineralization of enamel and
dentin Dentin () (American English) or dentine ( or ) (British English) ( la, substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by ena ...
on teeth for preventing and arresting dental caries. 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 In coordination chemistry, metal ammine complexes are metal complexes containing at least one ammonia () ligand. "Ammine" is spelled this way due to historical reasons; in contrast, alkyl or aryl bearing ligands are spelt with a single "m". Almost ...
(NH3) groups, not
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
(NH2) groups. Based on the current, best available evidence, SDF can be used by licensed dental professionals. In the UK, this is classified as '
off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...
' use of a topical medicament for arresting caries as it is licensed for treatment of dentine hypersensitivity. It is supported by a robust, extensive evidence base with regard to its efficacy and can be used as long as the following criteria are realised: there is a body of evidence supporting its efficacy; and there is no alternative, licensed medicine. The product was cleared for sale by the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
as a Class II medical device for the treatment of dentinal hypersensitivity, and has been classified as an ‘effective, efficient, equitable and safe caries-preventative agent’ by the Institute of Medicine and the Millennium Goals of the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
in 2009. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
.


Brand names

* 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.)


Indications and Contraindications of SDF


Indications

SDF use is indicated in the clinical scenarios listed below.


Patients

* With severe caries risk due to
xerostomia Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause. This symptom is very common and is often seen as a side ef ...
(dry mouth from reduced salivary flow); * Severe early childhood caries, which does not typically resolve with operative treatment. * Babies and toddlers with
Early Childhood Caries Early childhood caries (ECC), formerly known as nursing bottle caries, baby bottle tooth decay, night bottle mouth and night bottle caries, is a disease that affects teeth in children aged between birth and 71 months.American Academy of Pediatric De ...
; * Pre-cooperative children, to slow down the progress of the
disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
prior to building cooperation for treatment; * Patients with
physical Physical may refer to: *Physical examination In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally co ...
or
cognitive disabilities There are a variety of disabilities affecting cognitive ability. This is a broad concept encompassing various intellectual or cognitive deficits, including intellectual disability (formerly called ''mental retardation''), deficits too mild to pr ...
or
dental phobia Dental fear, or dentophobia, is a normal emotional reaction to one or more specific threatening stimuli in the dental situation. However, dental anxiety is indicative of a state of apprehension that something dreadful is going to happen in relatio ...
for whom more invasive procedures are not appropriate; * Where aerosol generating procedures (AGPs) are unable to be performed or approved; * With no or limited access to dental centres owing to its ease of use and minimal equipment requirement.


Teeth

* Carious
primary teeth Deciduous teeth or primary teeth, also informally known as baby teeth, milk teeth, or temporary teeth,Illustrated Dental Embryology, Histology, and Anatomy, Bath-Balogh and Fehrenbach, Elsevier, 2011, page 255 are the first set of teeth in the ...
showing radiographic evidence of being close to exfoliation; * Non-restorable asymptomatic teeth where extraction is contra-indicated; * With symptomatic Molar-Incisal Hypomineralization (MIH) to ease dentin hypersensitivity and slow down disease progress; * With active root surface carious lesions; * No symptoms of an irreversible inflammation of the
dental pulp The pulp is the connective tissue, nerves, blood vessels, and odontoblasts that comprise the innermost layer of a tooth. The pulp's activity and signalling processes regulate its behaviour. Anatomy The pulp is the neurovascular bundle centr ...
.


Contraindications

The use of SDF is contraindicated in the following scenarios:


Patients

* With an allergy to
Silver Silver is a chemical element with the Symbol (chemistry), symbol Ag (from the Latin ', derived from the Proto-Indo-European wikt:Reconstruction:Proto-Indo-European/h₂erǵ-, ''h₂erǵ'': "shiny" or "white") and atomic number 47. A soft, whi ...
or compounds containing silver; * With ulcerative gingivitis or
stomatitis Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration. In its widest meaning, stomatitis can have a multitude of different cau ...
; due to pain, can be managed with cautious use of a mucosal covering. * Unable to tolerate treatment.


Teeth

* With
irreversible pulpitis Pulpitis is inflammation of dental pulp tissue. The pulp contains the blood vessels, the nerves, and connective tissue inside a tooth and provides the tooth’s blood and nutrients. Pulpitis is mainly caused by bacterial infection which itself is ...
or direct pulp exposure. * Where it is not possible to achieve adequate isolation of tooth and oral tissues.


Mode of action

SDF's mode of action is well documented, but remains contested. Rosenblatt et al. summarized how the constituents in SDF each have a role in the arrest of microbial species that cause
dental caries Tooth decay, also known as cavities or caries, is the breakdown of teeth due to acids produced by bacteria. The cavities may be a number of different colors from yellow to black. Symptoms may include pain and difficulty with eating. Complicatio ...
. The higher the concentration of
fluoride Fluoride (). According to this source, is a possible pronunciation in British English. is an inorganic, monatomic anion of fluorine, with the chemical formula (also written ), whose salts are typically white or colorless. Fluoride salts typ ...
in a compound, the more effective its mechanisms in inhibiting bacterial
biofilm A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular ...
formation. Fluorides can bind to bacterial cell walls, inhibiting enzymatic processes associated with sugar uptake and metabolism of
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...
, therefore producing a surface more resistant to acid dissolution. 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. SDF hardens carious dentin, such that it is twice as hard as healthy dentin


Effect on cariogenic bacteria

Colony Forming Unit In microbiology, colony-forming unit (CFU, cfu or Cfu) is a unit which estimates the number of microbial cells (bacteria, fungi, viruses etc.) in a sample that are viable, able to multiply via binary fission under the controlled conditions. Count ...
counts (CFU) and studies of multispecies carious biofilms were carried aiming to examine the action of SDF on cariogenic bacteria. CFU counts on '' Streptococci mutans'', '' Actinomyces naeslundii'', ''
Lactobacillus acidophilus ''Lactobacillus acidophilus'' (New Latin 'acid-loving milk-bacillus') is a rod-shaped, Gram-positive, homofermentative, anaerobic microbe first isolated from infant feces in the year 1900. The species is most commonly found in humans, specifically ...
,
Streptococcus sobrinus ''Streptococcus sobrinus'' is a Gram-positive, catalase-negative, non-motile, and Anaerobic organism, anaerobic member of the genus ''Streptococcus''. Pathology ''Streptococcus sobrinus'' in conjunction with the closely related species ''Strept ...
,
Lactobacillus rhamnosus ''Lacticaseibacillus rhamnosus'' (previously ''Lactobacillus rhamnosus'') is a bacterium that originally was considered to be a subspecies of '' L. casei'', but genetic research found it to be a separate species in the ''L. casei'' clade, which ...
'' (all of which are bacteria intimately associated with the carious process) were significant lower in both
dentin Dentin () (American English) or dentine ( or ) (British English) ( la, substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by ena ...
surfaces and demineralized dentin treated with SDF when compared to water application. SDF also inhibits the adherence of '' S.mutans'' to tooth surfaces. 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. This shows that SDF as a compound has better bactericidal effects than silver ammonium nitrate and
sodium fluoride Sodium fluoride (NaF) is an inorganic compound with the formula . It is used in trace amounts in the fluoridation of drinking water, in toothpaste, in metallurgy, and as a flux. It is a colorless or white solid that is readily soluble in water. I ...
(commonly found in
toothpaste Toothpaste is a paste or gel dentifrice used with a toothbrush to clean and maintain the aesthetics and health of teeth. Toothpaste is used to promote oral hygiene: it is an abrasive that aids in removing dental plaque and food from the teeth, a ...
s).


Effect on organic content on dentin

The affected layer of carious
dentin Dentin () (American English) or dentine ( or ) (British English) ( la, substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by ena ...
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. SDF inhibits proteolytic activities such as enzymatic degradation of collagen fibres by
matrix metalloproteinases Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs ...
MMP-2, 8 and 9. Furthermore, SDF stops the degradation of
cysteine cathepsin Papain-like proteases (or papain-like (cysteine) peptidases; abbreviated PLP or PLCP) are a large protein family of cysteine protease enzymes that share protein structure, structural and catalytic mechanism, enzymatic properties with the group's n ...
s, which are also responsible for dentine collagen degradation.


Recommended concentration

A systematic review conducted by Contreras et al. in 2017 concluded that 30% and 38% concentrations of SDF were most effective for caries arrest. One of the clinical trials in this systematic review found 38% SDF to be significantly 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. 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.


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. The American Academy of Paediatric Dentistry (AAPD) recommends a 2-4 week follow-up to assess the arrest of carious lesions treated with SDF. 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.


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 ''μ''L) 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. The US FDA reviewed the dose limit based on all evidence for the US multi-centered clinical trial sponsored by the NIH and FDA run by UM, NYU, and UIowa, and set a dose limit of 260 µL for any patient 12 – 59 months old at the start of the study. ClinicalTrials.gov Identifier: NCT03649659.


Precautions and adverse 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. 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." 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. 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. Systematic reviews 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.


Arresting caries progression

* A systematic review and meta-analysis from 2017 by Chibinski et al. 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
placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
s.  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. * 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 Sodium fluoride (NaF) is an inorganic compound with the formula . It is used in trace amounts in the fluoridation of drinking water, in toothpaste, in metallurgy, and as a flux. It is a colorless or white solid that is readily soluble in water. I ...
preparations (e.g. Duraphat varnish). The evidence from this meta-analysis is considered strong. * 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 I 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. * 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." * 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 Fluoride varnish is a highly concentrated form of fluoride which is applied to the tooth's surface, by a dentist, dental hygienist or other health care professional, as a type of topical fluoride therapy. It is not a permanent varnish but due to ...
,
glass ionomer cement A glass ionomer cement (GIC) is a dental restorative material used in dentistry as a filling material and luting cement, including for orthodontic bracket attachment. Glass-ionomer cements are based on the reaction of silicate glass-powder (calc ...
and placebos as treatment modalities. 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. * 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.


History

* Dental use of
silver nitrate Silver nitrate is an inorganic compound with chemical formula . It is a versatile precursor to many other silver compounds, such as those used in photography. It is far less sensitive to light than the halides. It was once called ''lunar caustic' ...
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 Fluoride varnish is a highly concentrated form of fluoride which is applied to the tooth's surface, by a dentist, dental hygienist or other health care professional, as a type of topical fluoride therapy. It is not a permanent varnish but due to ...
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. * 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 canal A root canal is the naturally occurring anatomic space within the root of a tooth. It consists of the pulp chamber (within the coronal part of the tooth), the main canal(s), and more intricate anatomical branches that may connect the root c ...
s. * SDF was developed by Reichi Yamaga, Misuho Nishino, and colleagues to prevent and treat dental caries. * 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. * 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.


References

{{reflist Dentistry Silver compounds Fluorides Ammine complexes World Health Organization essential medicines