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Beyond Botox: other nonsurgical agents in use for correction of facial defects
A plastic surgeon reviews the European experience with injectable agents not yet approved in this country.
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Introduction:
Hyaluronic acid skin fillers are part of the new frontier in facial plastic rejuvenation. Although not all of them have regulatory approval in the United States, these exciting new agents are used for the correction of facial lines such as nasolabial folds. They are also effective for use in lip augmentation.
Advantages of hyaluronic acid over such filler agents as bovine collagen include their present safety record, with few side effects and increased duration of desired effect. Although hyaluronic acid fillers appear safe, further testing is needed as delayed inflammatory skin reactions have been reported at a very low incidence.
Just when your patients thought botulinum toxin was state-of-the-art, something new comes along. The future looks bright for both physicians and patients. Ophthalmologists and oculoplastic surgeons will benefit from the expertise of Dr. Jerome Klein, a specialist in the field of oculoplastic surgery.
Although the European collagens and filler agents I first discussed in Ocular Surgery News (September 1, 2000, p. 70) have yet to reach the U.S. market, a revisit to this subject is both timely and necessary due to the recent increase in publicity and interest in these agents in the lay literature and on television. (See Harper’s Bazaar, April 2002, for a good example.)
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The nonsurgical correction of facial defects plays an increasingly important role in the practice of medicine. During the past year, we have seen a large number of patients for minor corrections that did not require any surgical postoperative recovery period. Also, increasing numbers of new plastic surgery patients are slowly being introduced to the more invasive techniques we have available. Further, many patients are into preventive maintenance, trying to look better in their late 30s and holding off having a facelift until their 40s or later.
Because international companies are reluctant to participate in Food and Drug Administration protocols, the United States is unfortunately currently below the world standard of care in this area, and each year the gap appears to be widening.
Whether you practice in Manhattan or Greenwich, Conn., where you have a large number of international patients as well as patients who spend a significant amount of time both in and out of the United States, or a Beverly Hills practice that caters to patients in the entertainment field who will always seek the most current, cutting-edge treatment whether it is here or in any other country, physicians have to operate literally and figuratively in a global medical and surgical culture.
As evidence of this, see the April issue of Harper’s Bazaar. The author of the Harper’s article read of a new cheek augmentation procedure being done in Europe and immediately flew to London to have it performed.
The hyaluronic acid (HA) fillers discussed here are not yet available in the United States, but physicians need to be informed about these agents so that patients’ questions generated by publicity in the lay literature and by actresses on television can be properly answered.
Hyaluronic acids
Hyaluronic acids, which are essentially complex sugars, are a mainstay of nonsurgical correction of facial defects outside the United States. In the United States most of us know them in other incarnations such as Healon (sodium hyaluronate, Pharmacia) and Synvisc (Biomatrix). They offer the patient an agent free of the risk of animal or human proteins, viral load, prions and/or human serum albumin. Thus they may be even more appealing to both the physician and the patient than Botox and Myobloc, which both contain human serum albumin as a stabilizing agent.
There are essentially no current allergic or rheumatologic concerns with the older-generation filler agents, so no prior testing is necessary with these agents, thereby allowing patients to achieve immediate satisfaction. These agents can thus be tailored to the hopefully reasonable requests of most patients.
Using them is truly an art, much like painting and sculpting. The areas to be treated need to have the agents injected in a fashion that will achieve the desires of a given patient.
The anatomical sites for which patients request these agents largely depends on the age of the patient, but include the nasal labial folds, parallel chin grooves and the volume increase of upper and lower lips and the cheeks. Please see the Harper’s Bazaar article.
Most surgeons need to become familiar with injecting these areas, as there is a great patient demand for improvement of these anatomical sites. And should the fashion change, there is no need to worry because all the corrections with these agents are ultimately reversible, much as is the case of Botox.
Hylaform (Biomatrix, now Genzyme) was the original HA and has been used widely. The Restylane versions from Q Med Esthetics in Sweden (Perlane, Fine Lines and regular Restylane) are now being used extensively.
Q Med continues to progress, and a new drug, Macrolane, not even available to most physicians in its home country, is in the research stage. Its hyaluronic acid appears to be even larger and more complex in molecular size, so it should last much longer. It is theoretically being primed to address the breast implant market but should work well on the facial areas as well.
New to the market is Juvéderm (Cornéal), which offers different rheologic attributes and is packaged as two vials, which may be more economical for the patient. It comes in densities of 12, 24 and 30. Clinically Juvéderm appears to leave a much smoother, softer-volume augmentative effect using the threading technique than is the case with the other preparations. Rheologically it appears more cohesive, viscous and thicker than the Restylanes.
However, there is a difference between needle size and apparent needle appearance under loupe magnification among these products that may lead the practitioner to use his or her own 27-gauge needles. Also, because the surgeon sometimes uses excessive hydraulic pressure to inject, the Luer lock may not hold. If the needle is not stabilized it can dislodge and possibly become a projectile, putting at risk any anatomical structures in the surrounding area.
Which density should the practitioner use? It is recommended that the physician start with the mid-level density (ie, Restylane or Juvéderm 24) into the mid-dermis to develop a comfort level with these agents. The heavier densities need to be injected into the deeper dermis, and thin overlying tissues like the eyelid and nasal dorsum should be avoided with the higher densities. Should the patient then desire a more aggressive filling of the cheeks or nasal labial folds, one can advance to Perlane or Juvéderm 30.
Adequate patient preparation and education is paramount, as these products do not create a “night-and-day” correction. Repeat sequential closely timed injections are often necessary. Also, more is not always better. The use of these materials is more art and technique than quantitative science.
All the companies recommend that different formulations not be mixed or placed in the same areas of a given patient to avoid incompatibilities of the diverse materials. Further, the HAs with higher concentrations should not be injected around the eyes or nasal dorsum to avoid irregular deposition and overlying tissue necrosis respectively.
Regarding complications with the use of these agents, Otávio Roberti Macedo, MD, of Sao Paulo, Brazil, reported on four patients who experienced bruising and erythema followed by papulocystic nodules that became exudative and scarred if not imminently treated with steroids. And Maria Elisa R. Lenzi, MD, of Brazil, reported on similar experiences with lip augmentation, also with good response to steroids.
In general, HA’s (as with other filler agents) should not be injected into blood vessels because of embolic risk (beware of the nasal jugal area where the angular vein is) or into areas of inflammation, infection or acute acne. Physicians should not inject patients with a history of hypertrophic or keloidal scarring; autoimmune abnormalities, frank disease or immune modulation; hypersensitivity to these materials; pregnant or breast-feeding patients; or children. Also, injection into the upper or lower eyelids can cause a worm or pellet appearance if done with the usual threading or serial technique.
Patients should avoid concomitant or imminent peels, laser therapy, suntanning and/or any variation of dermabrasion or power peels. Physicians should avoid using quaternary ammonium salts like Zephiran to sterilize or cleanse the overlying skin pre-injection to avoid precipitation of the HA’s.
Silicone still controversial
Long-time (ie, older-generation) plastic surgery patients have experienced what they consider the wonders of silicone. Without a doubt, in the right hands and in the right clinical setting, silicone is an excellent drug with long-lasting results. However, should you have an untoward result, it is equally daunting for both the patient physician, especially if the patient reacts to the silicone preparation.
AdatoSil (Bausch & Lomb), a viscous silicone approved for ophthalmic use by the FDA in 1994, is one such product, but has very different rheologic attributes than the thinner silicone used historically for this purpose. Most older-generation physicians often mixed it with another agent to avoid the potential for migration. Our dermatologic colleagues will use silicone, and having one version of silicone FDA-approved makes it easier to use.
AdatoSil used by plastic surgeons for cosmetic use is becoming even more controversial. Although under law the FDA cannot interfere with a physician prescribing a legally marketed device, it appears the agency is not happy with this off-label use and the advertising of it by some plastic surgeons for filler use.
Silskin (RJ Development Corp.), a silicone derivative, is beginning trials for cosmetic use. Bioplastique (Uroplasty BV) is a biphasic material. According to the company, it consists of solid silicone particles (ranging in size from 100 mm to 400 mm) suspended in a poly-vinylpyrrolidone carrier. There is a question (as with all silicones) with respect to migration, but because of the size of the molecules and its carrier molecule allowing low-grade inflammation to occur, resulting in encapsulation, this risk may be diminished. A number of urologic agents for urinary incontinence may eventually make the transition to the soft tissue filler market. So expect to hear of many new variations of these European materials in the coming months. But the silicone/silica market remains very fluid, controversial and risky.
A nonsilicone agent, Profil, is a polyethylene bead suspension with a “carrier molecule” similar to two-phase materials to be described later.
Fat injections
Fat injections, popularized in their current incarnation by Dr. William Coleman III as permanent filler agents, remains a very interesting field. However, several negative attributes makes fat an unappealing filler for me. You must harvest and inject often under deep sedation. The patient can appear quite swollen and bruised for weeks. The learning curve is difficult. What you see at the time of surgery is often not what you get as a permanent result. One cannot easily do touchups, and the stored material is problematic for obvious reasons.
There can be prolonged ecchymosis, hypesthesia and contour irregularities. Even in the best of hands the results can be unpredictable and the complications severe. But when it works, the results are permanent and the patient is very pleased.
Two-phase materials
A number of new agents such as Artecoll (Canderm Pharma Inc.) and Dermalive (Derma Tech) are again endeavoring to compete in this area outside the United States. These agents are based on PMMA and/or acrylic hydrogels that are combined (as in the case of Artecoll) with a fast-acting collagen, or (as in the case of Dermalive) with hyaluronic acid.
Statistics show that approximately one in 10,000 patients or less may have a significant untoward effect that may even require surgical excision of these agents. From Russia/Ukraine we have Formacryl (Bioform), comprising 95% apyrogenous water and 5% on a polyacrylamide basis, a synthetic polymer “used in cosmetics,” and there is Metacrill from Brazil.
How do the newer neuroparalytic agents — Botox-C for cosmetic use, Myobloc and the European Dysport clinically fit into one’s practice?
The new Botox-C (Botox Cosmetic), according to the company, is pharmacologically exactly the same as the medical Botox and has the same unit packaging and dosing size. In other words, Botox-C is the same as Botox with just a different label.
Unfortunately, although many of us have asked for smaller vials with smaller unit dosing so we do not have to either waste the unused Botox or risk injecting nonpotent stored Botox that had been refrigerated or frozen, it appears that our requests again will not be answered with this new version.
Originally the company said they would not make Botox in smaller packages because it would require re-application to the FDA, which would be time-consuming and, more important, too costly for them to accomplish.
With this new cosmetic preparation, (just recently FDA-approved but only for glabellar lines in adults under 65 years of age; crows feet and neck injections may still not be FDA-approved indications), the company now appears to state that despite previous FDA and monetary concerns, it is now a manufacturing difficulty of putting fewer units of the powder in the vial and assuring adequate and consistent bioavailability. Thus the company will not make it easier at this time either for physicians to treat one patient by reducing the number of units in a vial.
Physicians should be aware of some of the newer clinical settings that may pose possible difficulties for the injection of these agents: patients with a history of Lyme disease, and patients who are avid sushi and deep-sea fish eaters (who have a chance of higher mercury blood and tissue levels than patients in the average population. These subgroups have occasionally experienced untoward results with the clostridium botulinum toxins.
In addition, an article published in the Journal of the American Academy of Dermatology reported on a group at patients who reported headaches within a couple days of Botox injections. Headaches lasted 2 to 4 weeks and were often constant, despite treatment with pain medicines. One woman described the pain as the “worst headache [she] ever had.”
The problem appears to be quite rare. Four of 320 people whom the researchers followed developed a severe headache. In my practice Botox will occasionally cause a mild headache for one-half to 1 day that is readily responsive to Tylenol, aspirin, etc. However, it now appears that some patients may now suffer from severe, long-lasting, debilitating headaches after Botox injections.
Also of note, it has been reported by Alam et al that Botox can possibly be diluted with saline containing benzyl alcohol as a preservative, and once reconstituted in this manner it can remain potent, if refrigerated, for up to 5 weeks. There is also less discomfort with this diluent than with nonpreserved saline.
In my experience, stored Botox’s bioavailability can at times be perfect and other times nonexistent. In my hands this is always unpredictable. But what is consistent is that patients do not like to be reinjected both from a time issue and from an injection pain concern.
Myobloc (clostridium botulinum type B, Elan Corp.) is an excellent drug and plays an important role in my practice. It usually has a rapid and forceful clinical manifestation in half the time of Botox.
However, this is truly a double-edged sword, because it also kicks out sooner and has a more rapid and complete withdrawal of effect compared to Botox, which slowly loses it paralyzing effect.
So this material is ideal for those patients who need a quick augmentation and for whom you are worried about developing Botox tolerance or using a reconstituted Botox that may have lost it potency during storage, especially because it is normally kept refrigerated and is thus easily stored for repeated use at any time. The company recommends immediate and complete use once reconstituted, but I have found refrigerated and repetitive storage of the residual Myobloc is clinically viable for up to 1 month.
In some patients, because of its somewhat acid pH level, Myobloc will leave anywhere from a warm feeling at the injection sites (which patients like because they feel it has immediately treated the wrinkles) to infrequent severe burning at the injection site, which can be worrisome to the practitioner who has minimal experience with this product.
However, this effect can be thwarted in advance by mixing it with lidocaine to normalize the pH. My dosing for the infrequent Botox augmentation patient is usually 1 cc of 2,500 Myobloc units/0.5-cc bottle, along with 2 cc of 0.9% sodium chloride nonpreserved, resulting in a total of 2.5 cc of injectable material at a concentration of 1,000 Myobloc units/cc, which is roughly equivalent to 20 Botox units at a 50 Myobloc unit-to-one Botox unit ratio. It is possible that higher doses may cause longer paralysis but the cost becomes a major factor.
Neuromuscular paralysis may be potentiated by co-administration or overlapping of different botulinum serotypes. Side effects with cervical dystonia injections with 10,000 units dosing are dry mouth (34%), dysphagia (25%), injection site pain (15%) and dyspepsia (10%). It is formulated at pH 5.6 with 0.05% human serum albumin, 0.1 M sodium chloride.
Dysport (Ipsen Ltd.) comes as a 500-unit vial. Is available only outside the United States, and comes as a powder like Botox and unlike Myobloc. It must be refrigerated like Myobloc but not frozen. It has an nonreconstituted shelf life of 1 year and a reconstituted shelf life of 8 hours.
Dysport is a preparation of clostridium botulinum type A toxin and contains 125 mcg of human albumin and 2.5 mg of lactose. (Botox has 500 mcg human albumin and no lactose.) Dysport’s recommended dilution is 2.5 mL of sodium chloride at 9%. This dilution gives 100 units of Dysport for each 0.5 mL, 20 units for each 0.1 mL and 10 units for each 0.05 mL.
It will be interesting to see if patients who have become resistant to Botox respond to the preparation in Dysport.
The recommended doses are:
- For the glabellar region: 20 to 30 Dysport units in three to five injections.
- For the crows feet area: 20 to 30 Dysport units in three to five injections.
- For the forehead: 20 to 40 Dysport units in five to seven injections.
The maximum dose of Dysport for men is 77 to 150 units and the maximum dose for women is 50 to 125 units, approximately a 3:1 ratio Dysport to Botox. According to these doses, we can use one vial of Dysport for treating four or five patients if we are treating the glabellar region, the crows feet area and the forehead. The unopened Dysport vial must be maintained at temperatures between 2º C and 8º C due to the lower concentration of human albumin and the addition of lactose.
The future looks exciting. I only wish that it was here now.
A note from the editors :
Except for Botox, Myobloc and AdatoSil, the agents mentioned in this article are not FDA-approved in the United States at this time, but some are in pre-FDA approval stages. Healon and Synvisc are not approved for this procedure.
For Your Information:
References:
- Jerome R. Klein, MD, FACS, is an assistant professor of ophthalmic surgery at the University of California Los Angeles Medical Center, Jules Stein Institute, Division of Aesthetic Surgery, 9454 Wilshire Blvd., Beverly Hills, CA 90212; (310) 550-7006; 465 Park Ave., New York, NY 10022; (212) 371-7373; e-mail: plastic-surgeon@prodigy.net. Dr. Klein has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Macedo OR. Complications after Hyaluronic acid gel injections. Presented at the International Academy of Cosmetic Dermatology 2nd World Congress, November 9-11, 2000, Rio de Janeiro.
- Lenzi MER. Granulomatous reaction to hyaluronic acid gel. Presented at the International Academy of Cosmetic Dermatology 2nd World Congress, November 9-11, 2000, Rio de Janeiro.
- Alam M, Arndt KA, Dover JS. Severe, intractable headache after injection with botulinum A exotoxin: report of 5 cases. J Am Acad Dermatol. 2002;46:62-65.
- U.S. Food and Drug Administration Product Approval Information and Licensing Action, Myobloc. 12/08/2000.