J.W. Martin Kim, D.M.D.
University of Minnesota
Department of Periodontology
Since there is clear evidence of a microbial etiology in periodontal disease, the use of systemic antibiotics has been proposed in the treatment of this disease. The use of antibiotics can further be attractive as periodontal pathogens can be found broadly in extra-sulcular oral tissues such as the tonsils and tongue.1 Logically this would imply that there is limited effectiveness to conventional scaling and root planing since there is a constant risk of re-colonization and re-infection of the periodontal tissue from other oral niches. However, haphazard use of systemic antibiotics has been discouraged by numerous experts as antibiotics have limitations in function and as they can potentially cause adverse effects in certain individuals. Most importantly, a majority of periodontal diseases can be managed with mechanical therapy alone. This does not imply, however, that antibiotics should completely be ruled out for every case of periodontal therapy.
Some of the obvious benefits to antibiotics include their simplicity of use (generally no special skills needed); they are readily available and relatively inexpensive; and it may be possible to target multiple sites and delay the re-colonization from exogenous oral tissues.2,3 Despite these potential benefits, the advantages and efficacy must be analyzed against the limitations and risks of antibiotics.
Haphazard prescription of systemic antibiotics for periodontal patients is further discouraged because antibiotics have failed to show consistent benefits to everyone.4 The various reasons pertaining to the failure of systemic antibiotics in becoming the panacea of periodontal treatment are well reviewed by Walker et al (2004). For instance, periodontitis is a complex disease that requires not only the pathogen but also a susceptible host at risk of this disease due to factors such as genetic, environmental, and complex psychosocial components. To complicate matters further, the subgingival flora is inhabited by approximately 500 bacterial species that have various susceptibilities to different antibiotics. This community also forms a complex glycocalyx biofilm which provides resident bacteria several-fold increase in resistance. Walker et al attribute this protective mechanism to (1) the inability of the antibiotics to penetrate the biofilm, (2) communal protection by sharing genetic information and secretion of antibiotic resistance products to their surroundings, and (3) the promotion of gene expressions which strengthen cells to survive the harsh biofilm environment and thus antibiotic attacks as well. Finally, in order for antibiotics to be effective, the active molecule must be present in sufficient concentrations at the site of infection. In the case of periodontal disease, the gingival crevicular fluid must attain adequate quantities of the antibiotic to reach the minimal inhibitory concentration (MIC) of periodontal pathogens. Nevertheless, higher concentrations than the MIC are often required in most cases due to the protective biofilm coating the pathogens.5
In addition to the limitations encountered with antibiotics, the therapist should also be concerned with the adverse effects. Commonly, these include hypersensitivity, especially with penicillins; diarrhea, particularly with clindamycin, penicillins, and macrolides; nausea/vomiting, with the use of metronidazole or fluoroquinolones; photosensitivity, in the case of tetracyclines, fluoroquinolones, or clarithromycin; and as with any medication, there are potentials for harmful drug interactions.6
Finally, the most alarming consequence of negligent use of systemic antibiotics stems from the development of resistant pathogens, as this has implications not only to a single individual but for others who become exposed to these pathogens.7 It is well documented that periodontal pathogens can gain accelerated resistance to antibiotics from overuse and poor compliance.8 Epidemiological evidence of this alarming trend is expressed by Walker (1996), who stated that 15-30% of bacterial isolates from patients with adult periodontitis exhibited resistance to penicillin, while 20-30% were unresponsive to tetracycline.9
In order to reduce the emergence of bacterial resistance, susceptibility testing has been recommended to test for putative pathogens which may linger following mechanical therapy and to determine the antibiotic most likely to eliminate the pathogen.2 However, there have been queries regarding the accuracy of susceptibility test results, as bacteria grown in laboratories are generally weaker than biofilm bacteria actually present in the patient. In fact, Kleinfelder et al (2000) found that F. nucleatum and P. micros were not susceptible to systemically administered amoxicillin/clavulanate even though post-treatment Epsilometer (E-test) techniques revealed susceptibility.10 Although susceptibility testing has not been completely discouraged, the result of this study warrants that in some cases the therapist must be wary when interpreting laboratory susceptibility test results, as in vitro tests do not always reflect in vivo conditions.
Again, when clinicians decide to prescribe antibiotics, careful analysis must be done to determine if the benefits of antibiotics outweigh the risks. According to the Research, Science and Therapy Committee of the American Academy of Periodontology,2 candidates who will benefit most from systemic antibiotics are those who fail to show an arrest in disease progression despite conventional mechanical therapy (possibly due to persistent pathogens or impaired host response); those who suffer from aggressive periodontitis; those who have medical conditions predisposing them to periodontal disease; and finally those who suffer from acute or severe periodontal infections (such as abscesses or acute necrotizing gingivitis/periodontitis) with systemic manifestations of fever, malaise, or lymphadenopathy. However, clinical evidence seems to discourage the use of antibiotics for chronic (adult) periodontitis. Although non-surgical periodontal treatment does not completely eliminate all subgingival bacteria, mechanical treatment with regular cleaning can successfully control most periodontal diseases without the use of antibiotics.11 In addition, there are limited benefits for the treatment of recurrent periodontitis, as long-term observations (>_3 years) fail to show clinically significant benefits to mechanical therapy alone.12
Finally, antibiotics should not be the sole treatment for any form of periodontal disease, but instead should be supplemented with mechanical disinfection to reduce the bulk of the bacterial load and to disrupt the bacterial aggregate/biofilm that can serve as a protective barrier against antibiotics.13 It is important to remember that the above indications and contraindications are only recommendations and not the absolute rule. Clinical judgment is left to the clinician, who can cater to each patient on a case-per-case basis.
In the cases where antibiotics are indicated for periodontal therapy, there are several suggested regimens. At the University of Minnesota, Graduate Periodontics, the antibiotic that is commonly prescribed includes a combination of Amoxicillin 500 mg (2 caps immediately, then 1 cap every 8 hours for 7 days), with Metronidazole 250 mg (1 tab every 8 hours for 7 days). In patients with penicillin allergy, Azithromycin 250 mg is prescribed (2 tabs immediately, followed by 1 tab once a day for 7 days), or in many cases a standardized Zithromax Z-Pak kit is prescribed. It must be noted that these prescriptions should not be considered the sole option. But when antibiotics are indicated, a clinical decision must be made in order to form a prescription regimen that will best benefit the patient in question.
In conclusion, it can be stated that currently no indications exist for the use of systemic antibiotics, either in the case of most chronic adult periodontitis patients or as a sole periodontal treatment without mechanical debridement. Additional studies are necessary to overcome the shortcomings of antimicrobial therapy before antibiotics are more routinely and safely used in periodontal treatment.
1. Addy M, Martin MV. Systemic antimicrobials
in the treatment of chronic periodontal diseases:
a dilemma. Oral Dis 2003;9 Suppl 1:38-44.
2. American Academy of Periodontology Position Paper (Primary author Slots J); Research, Science and Therapy Committee. Systemic antibiotics in periodontics. J Periodontol 2004 Nov;75(11):1,553-65.
3. López NJ, Socransky SS, Da Silva I, Japlit MR, Haffajee AD. Effects of metronidazole plus amoxicillin as the only therapy on the microbiological and clinical parameters of untreated chronic periodontitis. J Clin Periodontol 2006 Sep;33(9):648-60.
4. Walker CB, Karpinia K, Baehni P. Chemotherapeutics: antibiotics and other antimicrobials. Periodontol 2000 2004;36:146-65.
5. Kleinfelder JW, Muller RF, Lange DE. Antibiotic susceptibility of putative periodontal pathogens in advanced periodontitis patients.
J Clin Periodontol Jun;26(6):347-51, 1999.
6.Slots J, Ting M. Systemic antibiotics in the treatment of periodontal disease. Periodontol 2000 2002; 28:106-76.
7. Rams TE, Babalola OO, Slots J. Subgingival occurrence of enteric rods, yeasts and staphylococci after systemic doxycycline therapy. Oral Microbiol Immunol 1990 Jun;5(3):166-8.
8. van Winkelhoff AJ, Herrera D, Oteo A, Sanz M. Antimicrobial profiles of periodontal pathogens isolated from periodontitis patients in The Netherlands and Spain. J Clin Periodontol 2005 Aug;32(8):893-8.
9. Walker CB. Selected antimicrobial agents: mechanisms of action, side effects and drug interactions. Periodontol 2000 1996 Feb;10:12-28.
10. Kleinfelder JW, Müller RF, Lange DE. Bacterial susceptibility to amoxicillin and potassium clavulanate in advanced periodontitis patients not responding to mechanical therapy. J Clin Periodontol 27 (11) 846-53, 2000.
11. Mombelli A. Heresy? Treatment of chronic periodontitis with systemic antibiotics only.
J Clin Periodontol 2006 Sep;33(9):661-2.
12. Serino G, Rosling, B, Ramberg P, Hellström MK, Socransky SS, Lindhe J. The effect of systemic antibiotics in the treatment of patients with recurrent periodontitis. J Clin Periodontol May; 28 (5) 411-418, 2001.
13. Berglundh T, Krok L, Liljenberg B, Westfelt E, Serino G, Lindhe J. The use of metronidazole and amoxicillin in the treatment of advanced periodontal disease. A prospective, controlled clinical trial. J Clin Periodontol May;25(5):354-62, 1998.
Jody Schilling, D.D.S.
University of Minnesota School of Dentistry
Department of Periodontology
Five years after the documentation of jaw necrosis in bisphosphonate patients,1 we are beginning to understand the etiology, incidence, prevention, and treatment of the condition that is correctly referred to as bisphosphonate-induced osteonecrosis of the jaws (BIONJ).2 The following three characteristics must be met for a diagnosis of BIONJ:3 (1) presence of exposed, necrotic bone in the maxillofacial region that does not heal within eight weeks, (2) current or previous exposure to bisphosphonates, and (3) a negative history for radiation to the craniofacial region.
The leading theory of BIONJ development proposes reduced bone remodeling due to death of osteoclasts. Nitrogen-containing bisphosphonates have a strong affinity for bone, especially sites of high bone turnover such as the jaws. Bisphosphonates are not metabolized, and instead remain sequestered in the osseous structure until the bone is resorbed by osteoclasts. Due to their long half-life (>10 years in slow bone turnover areas), bisphosphonates become concentrated in the bone for a prolonged period.4 Once ingested by osteoclasts, bisphosphonates inhibit the essential mevalonate pathway, leading to loss of function and apoptosis of mature osteoclasts as well as a toxic effect on early osteoclast precursors.5 Without osteoclasts, bone remodeling is impaired after trauma or dentoalveolar surgery.
Physicians and dentists should inform patients of the benefits and risks of bisphosphonate therapy. Due to the novelty of the condition and the lack of a central reporting mechanism, the true incidence of BIONJ is unknown, and likely underreported. The mean time to onset of BIONJ is related to cumulative dose of bisphosphonates. The intravenous (IV) forms of bisphosphonates are more potent and carry a greater risk of BIONJ to the patients. Zoledronic acid (Zometa) and pamidronate (Aredia) are used for the treatment and prevention of bone lesions in multiple myeloma and metastatic carcinomas of the breast, prostate, kidney, and lung. Estimated risk of BIONJ from IV bisphosphonates is 1-10%, depending upon the duration of treatment.6 Since IV bisphosphonates increase the quality and quantity of life in patients with malignancies, the obvious benefit is worth the higher BIONJ risk.
Ideally, patients should seek dental consultation and have all invasive dental procedures completed and healed before beginning IV bisphosphonate therapy. Non-restorable, abscessed, periodontally-hopeless, and failing endodontically-treated teeth should be extracted. Periodontal treatment should be augmented with oral hygiene instruction. The dentition should be stabilized so that invasive procedures are not necessary after the first four to six months of IV bisphosphonate therapy.2 Restorative and prosthodontic procedures can continue during intravenous therapy. New dental implants and orthodontics are contraindicated in these patients.2
As of August 2007, an annual 5 mg intravenous infusion of zoledronic acid (Reclast) is available for the prevention of osteoporosis. Although zoledronic acid is the most potent bisphosphonate, this dose is considerably smaller than the 4 mg administered every three to four weeks to cancer patients.4 Studies thus far have shown IV bisphosphonate doses for osteoporosis prevention are similar in BIONJ risk to oral bisphosphonates.7 However, more studies will have to be completed as patients are treated by this therapy for a longer duration. Dentists should ask all post-menopausal women if they receive Reclast infusions, as patients may forget to include this annual intravenous treatment in their medication list.
Popular oral bisphosphonate medications for the treatment of osteoporosis/osteopenia include alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva). These oral bisphosphonates have a decreased potency and dosage. Therefore, the oral BIONJ risk, estimated to be between 1 in 10,000 and 1 in 100,000 patient treatment years, is lower than that of IV bisphosphonates.6 Since the absorption of oral bisphosphonates is also reduced, the BIONJ risk is negligible with exposure of less than three years. However, the risk increases proportionately with each year of oral bisphosphonate exposure beyond three years.8 Systemic prednisone, methotrexate, or ranitidine in conjunction with oral bisphosphonates may result in BIONJ lesions that are more severe and seen earlier than three years.2 A dental examination is not required before commencement of oral bisphosphonates.6 However, patients should be encouraged to achieve a stable dentition prior to three years of bisphosphonate therapy. Since oral bisphosphonates significantly reduce the morbidity and mortality associated with osteoporotic fractures, the benefits of bisphosphonate therapy outweigh the low risk of BIONJ. When discussing oral BIONJ risks with patients, dentists should stress the importance
of regular dental visits and oral hygiene rather than discourage bisphosphonate use.
The millions of women on bisphosphonate therapy for osteoporosis offset the low incidence of oral BIONJ. In 2007, Marx documented 30 cases of oral BIONJ. Of these cases, 95% occurred in the posterior mandible, 50% occurred after an oral surgery procedure, and the remaining 50% of the cases occurred spontaneously.9 BIONJ lesions from oral bisphosphonates tend to occur less frequently, be less severe, and resolve more easily than lesions from their IV counterparts.10 The size of the exposed bony lesion correlates with the duration of oral bisphosphonate use.9
Prevention of BIONJ
Medical history forms should include questions about bisphosphonate therapy, specifically requesting the drug name, administration method, dosage, frequency, and duration.11 All bisphosphonate patients should be informed of the signs/symptoms of BIONJ and the importance of oral hygiene and regular dental visits to prevent the need for dentoalveolar surgery. Removable oral appliances should be adjusted to prevent soft tissue trauma. ONJ lesions are apparent in panoramic radiographs and CT imaging. However, these imaging techniques are not helpful in determining pre-procedural risk of ONJ development. A signed informed consent form should accompany all extraction and surgical procedures performed on oral bisphosphonate patients. A sample form is available from the ADA website.
For cancer patients with past or present IV bisphosphonate therapy, orthodontics and all surgical procedures, including extractions and implants, are contraindicated.2 Symptomatic teeth should be treated with appropriate non-surgical endodontic and periodontal therapy. Non-restorable teeth should be treated with a root canal and crown amputation rather than extraction.2 If possible, mobile teeth should be splinted together. Failing endodontically-treated teeth should be retreated rather than pursuing of extraction or periapical surgery.2
For patients with at least a three-year history of oral bisphosphonate therapy, the following recommendations apply.6 If appropriate, non-surgical periodontal therapy is recommended. Surgical periodontal therapy with modest bone recontouring may be considered to reduce active sites of periodontal disease. However, ideally this surgical treatment would be performed earlier in the bisphosphonate therapy. Endodontic therapy is preferred to extraction or periapical surgery. The benefit in function and esthetics gained from implant placement must be weighed against patient risk of BIONJ, based on duration of treatment. Oral bisphosphonates are not currently considered a contraindication for dental implant placement.6, 12
Marx has proposed morning fasting serum C-terminal telopeptide of type I collagen (CTX) testing to reflect the effect of the oral bisphosphonate on the mature osteoclast activity. He predicts the BIONJ risk in osteoporosis patients based on the CTX values as follows: <100pg/mL high risk, 100-150pg/mL moderate risk, >150pg/mL low risk.9 When patients took a six-month drug holiday from oral bisphosphonates, Marx saw an increase in CTX values of approximately 26pg/mL per month. This change from the high to low risk CTX values was accompanied by a clinical healing of established oral BIONJ lesions. Due to greater accumulation of bisphosphonates in the bone and exhaustion of the osteoclast precursor supply in IV bisphosphonate-treated cancer patients, a drug holiday did not result in resolution of lesions.10 Further studies are required to establish the validity of CTX serum markers and oral bisphosphonate drug holidays in the prevention and treatment of BIONJ.
BIONJ Stages and Treatment
A qualified dental specialist should manage established BIONJ lesions. In fact, the American Association of Oral and Maxillofacial Surgeons (AAOMS) has developed staging and treatment guidelines for BIONJ. Supplementary guidelines were developed by Wade and Suzuki to incorporate Marx’s CTX testing measurements in oral bisphosphonate patients. These guidelines recommend serum CTX testing and a medical consult with the physician regarding a drug holiday until CTX values >150pg/ML.13 There is minimal clinical evidence to support serum markers, and thus no standard of care for drug holidays and CTX testing in oral bisphosphonate patients. Practitioners should use clinical judgment in regard to these strategies until larger-scale, controlled studies are available.14
Stage 1: Patient presents with asymptomatic, exposed bone. Providers should prescribe chlorhexidine rinses (0.12%, 30mL tid)2 and encourage patients to maintain excellent oral hygiene to prevent painful secondary infections. Follow-up visits at four-month recalls are recommended.
Stage 2: Patient presents with exposed bone and pain, soft tissue/bone inflammation, or infection. Patients should be treated with chlorhexidine rinses, pain medication, and an antibiotic regimen. Penicillin V potassium (500mg qid) is recommended due to its ability for long-term usage without the development of candidiasis or “super infections”. Prescribe Levofloxacin (500 mg qd for <21 days) to patients with penicillin allergies. Metronidazole (500 mg tid for 10 days) can be added to refractory cases. Clindamycin is not recommended because of low activity against the common BIONJ-associated organisms.2 Microbial cultures can aid in the choice of antibiotic.
Stage 3: Patient presents with exposed bone lesion and inflammation, pain, or infection that is unresponsive to antibiotics. The lesion may include an extraoral fistula, pathologic fracture, and osteolysis extending to the inferior border. Employ conservative surgical management to debride the lesion. Gently remove sharp bone edges and loose bony sequestrum to prevent future soft tissue trauma. Segmental jaw resection and reconstruction may be required in rare instances.
In conclusion, careful treatment planning minimizes BIONJ risk in patients with bisphosphonate exposure. The drug type, dose, potency, and duration are important factors in determining the cumulative effect on bone remodeling and resultant risk of BIONJ. Dentists and physicians should work closely to balance the risks of the oral and systemic conditions surrounding bisphosphonate use. A critical assessment of current literature is necessary to best serve our patients. n
1. Marx RE. Pamidronate (aredia) and zoledronate (zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003 Sep;61(9):1,115-7.
2. Sawatari Y, Marx RE. Bisphosphonates and bisphosphonate induced osteonecrosis. Oral Maxillofac Surg Clin North Am 2007 Nov;19(4):487,98, v-vi.
3. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007 Mar;65(3):369-76.
4. Zahrowski JJ. Comment on the American Association of Oral and Maxillofacial Surgeons statement on bisphosphonates. J Oral Maxillofac Surg 2007 Jul;65(7):1,440-1.
5. Van Beek ER, Lowik CW, Papapoulos SE. Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: The role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors. Bone 2002 Jan;30(1):64-70.
6. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E. American Society for Bone and Mineral Research: Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007 Oct;22(10):1,479-91.
7. Grbic JT, Landesberg R, Lin SQ, Mesenbrink P, Reid IR, Leung PC, Casas N, Recknor CP, Hua Y, Delmas PD, Eriksen EF. Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial Research Group. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial. JADA 2008 Jan;139(1):32-40.
8. Russo N, Jeffcoat M, Marx R, Fugazzotto P. Current issues forum: ONJ. JOMI 2007;22(1):146-153.
9. Marx RE, Cillo JE,Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007 Dec;65(12):2,397-410.
10. Marx RE, Cillo JE,Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007 Dec;65(12):2,397-410.
11. Marx RE. Bisphosphonate-induced osteonecrosis of the jaws: A challenge, a responsibility, and an opportunity. Int J Periodontics Restorative Dent 2008 Feb;28(1):5-6.
12. Grant BT, Amenedo C, Freeman K, Kraut RA. Outcomes of placing dental implants in patients taking oral bisphosphonates: A review of 115 cases. J Oral Maxillofac Surg 2008 Feb;66(2):223-30.
13. Wade M.L., Suzuki J.B. Issues related to diagnosis and treatment of bisphosphonate-induced osteonecrosis of the jaws. Grand Rounds in Oral-Systemic Medicine 2007;2(2):46-7.
14. Koka S. Osteonecrosis of the jaw and biomarkers: What do we tell our patients? The International Journal of Oral & Maxillofacial Implants 2008;23(2).
BIONJ in 67-year-old female patient with history of metastatic breast carcinoma treated with 48 Zometa and 12 Aredia infusions. Patient presented with spontaneous exposed necrotic bone in the mandibular lingual posterior and paresthesia in the mental nerve distribution of V3. Photos and radiographs demonstrate impaired healing of this established BIONJ lesion after biopsy.
Photos and radiographs courtesy of Dr. David Basi, University of Minnesota Division of Oral and Maxillofacial Surgery.
Joseph R. Wilson, D.D.S., Lois J. Kehl, D.D.S., and Soraya Beiraghi, D.D.S.
Division of Pediatric Dentistry
University of Minnesota
In 1974, Louis Gangarosa extracted 13 deciduous incisors using iontophoresis of 2% lidocaine for 10 minutes. In 12 out of 13 trials, the patients reported no discomfort. No needles were needed for these 12 painless extractions. The profoundness of the anesthesia obviated the need for needle injections. This is hugely significant considering that fear of needles is the number one reason for fear and anxiety relating to dental treatment of children. Iontophoresis, despite other similar studies, never “caught on” to mainstream dentistry for the purpose of enhancing topical anesthesia, possibly because of the requisite time needed to produce a significant effect (i.e., 8-10 minutes).
In the 1990s, researchers at Georgia Tech invented microneedles made of silicon. They made them in both solid and hollow forms. Since then, numerous applications for microneedles have been developed. Applications now include hormone therapy and recombinant gene therapy. Several independent researchers have demonstrated microneedles to be completely painless and safe. Although microneedles unimpregnated with drugs are currently unavailable to independent researchers, modified acupuncture needles have been used to simulate their effects on transdermal drug delivery.
It has long been known that the stratum corneum layer of the skin is the only significant barrier to the diffusion of molecules transdermally or transmucosally. The stratum corneum consists of 5-20 layers of dead skin cells that provide a formidable barrier to the diffusion of any substance across the skin. Many different chemicals (e.g., alcohols, unsaturated fatty acids) and physical means (e.g., microdermabrasion, tape stripping) have been suggested and tested as a means to facilitate the introduction of medicines into the body in a relatively non-invasive manner. Microneedle treatment has been found to be the most desirable and expedient method of physically overcoming the barrier of the stratum corneum. Microneedles are 1-3 micrometers in diameter and long enough to penetrate the stratum corneum layer (i.e., 150 -250 micrometers) but short enough to avoid nociceptor stimulation. They don’t induce bleeding because they do not extend beyond the epidermis.
In 2007, X.M. Wu reported transdermal transport of high molecular weight drugs by combination of iontophoresis and microneedle pretreatment to be much more efficient than either treatment used alone. More significantly, Jia-You Fang et al used a similar method to enhance transport of a molecule very similar in size, weight, and charge to lidocaine (i.e., buprenorphine). Electroporation, instead of microneedles, was used to induce the formation of aqueous channels through stratum corneum. This was followed by iontophoresis of buprenorphine through mouse skin ex-vivo. This combination method resulted in a significantly reduced lag time compared to individual methods of topical delivery.
Imagine how well this combination method of topical delivery could work for a smaller molecular weight molecule such as lidocaine! Instead of 8-10 minutes, perhaps it may now be possible to iontophoretically achieve profound anesthesia in two to four minutes. The possibility of literally pain-free dental procedures without a major investment of time is an exciting prospect that could markedly enhance the dentist-patient relationship by allaying the seemingly ubiquitous fear associated with needle injections.
My research project utilized acupuncture needles modified to be less than 500 micrometers. The treatment site is the hard palate. Acupuncture pretreatment is followed by three-minute iontophoresis of 4% lidocaine. Subsequently, subjective pain perception is tested by a “pin prick test”. This test involves advancement of a 27 gauge needle 3 millimeters into the hard palate one minute and three minutes after the iontophoresor is turned off. The subject reports pain perception on a VAS scale. Passive diffusion of 20% benzocaine gel and 4% lidocaine liquid will be used as controls. Also, 4% lidocaine iontophoresis without acupuncture pretreatment will serve as a control to demonstrate the enhancement effect of stratum corneum perforation.
I concede that the acupuncture needles used in this study may cause some mild discomfort (e.g., 2 on a 10 scale VAS). However, smaller diameter acupuncture needles exist that are 1/3 the diameter of a 30 gauge needle. And hopefully, actual microneedles, unimpregnated with drugs, will be available within the next two years so that they may be used in combination with iontophoresis for any drug that has a net charge.
The aforementioned research project has just begun, with results supporting the hypothesis that this combination treatment produces anesthesia to a depth of three millimeters in three minutes or less. My hope is that this study will encourage more research directed toward pain abatement in pediatric dentistry. n
1. Fang J-Y, Sung KC, Wang J-J, Chu C-C, and aChen KT. The effects of iontophoresis and electroporation on transdermal delivery of buprenorphine from solutions and hydrogels. J Pharm and Pharmacol 2002 October;54(10):1,329-37.
2. Wu XM, Todo H, Sugibayashi. Effects of pretreatment of needle puncture and sandpaper abrasion on the in vitro skin permeation of fluorescein isothiocyanate (FITC)-dextran. Int J Pharm 2006 June 19;316(1-2):102-8. Epub 2006 April 4.
3. Verbaan FJ, Bal SM, Van Den Berg DJ, Groenink WH, Verpoorten, Luttege R, Bouwstra JA. Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin. J Controlled Release. 2007 Feb 12;117(2):238-45. Epub 2006 Nov. 17.
4. Kaushik S, Hord AH, Denson DD, McAllister DV, Smitra S, Allen MG, Prausnitz MR. Lack of pain associated with microfabricated microneedles. Anesth Analg. 2001 Feb;92(2):502-4.
5. Zempsky WT, Anand KJS, Sullivan KM, Fraser D, Cucina K. Lidocaine iontophoresis for topical anesthesia before intravenous line placement in children. J Pediatr 1998 June;132(6):1,061-1,063.
6. Tharian EB. Iontophoresis: A novel drug administration for extraction of deciduous teeth. A clinical evaluation. Indian J Dent Res 1994 July-Sept;5:97-100.
7. Davis WT. Use of iontophoresis for oral mucosal anesthesia. South Carolina Dental Journal. 1981 Spring;53-57.
8. Gangarosa LP. Iontophoresis for surface local anesthesia. JADA 1974 January;88:125-8.
9. Singh P, Roberts MS. Iontophoretic transdermal delivery of salicylic acid and lidociane to local subcutaneous structures. J Pharm Sci 1993 February;82(2):127-31.