Botulinum Toxin

What is botulinum toxin?

Botulinum toxin is a nerve toxin produced by the bacterium Clostridium botulinum. In medicine and aesthetics, a purified type A form of this toxin is used. It is injected into the target muscle in amounts low enough not to cause poisoning. In everyday language, this treatment is widely known by a brand name. That name came into use from one product; however, there are many commercial products that contain the same active ingredient, each with a different formulation. That is why this page uses the name of the substance rather than a product name.

How the toxin works is understood at the molecular level. The toxin’s heavy chain binds strongly to the nerve ending and allows the toxin to be taken into the cell. Inside the cell, the light chain then cuts the SNARE proteins that the tiny sacs (vesicles) in the nerve ending need in order to fuse with the cell membrane. As a result, acetylcholine, the chemical messenger that carries the nerve’s command to contract to the muscle, cannot be released, and the muscle stays relaxed. This effect is temporary: according to research, the weakness caused by type A toxin usually lasts about three months.

Botulinum toxin is not used only in aesthetics. It is also used for medical conditions such as squint, focal dystonias (involuntary contractions in a particular muscle group), spasm on one side of the face, spasticity (excessive tightness in the muscles), some types of headache, excessive saliva production and excessive sweating. In aesthetics, its most studied use is for facial wrinkles: the comprehensive Cochrane review on this subject brought together 65 randomised controlled trials (comparative trials in which participants are randomly assigned to groups) and 14,919 participants.

The dose, the dilution ratio and the injection points are not the same for everyone. The doctor giving the treatment decides on them individually for each person.

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Forehead lines

Horizontal lines on the forehead become more visible when the forehead muscle (frontalis), which raises the eyebrows, contracts. Botulinum toxin can soften these lines by reducing the movement of this muscle. However, because the forehead muscle is the muscle that lifts the brows, treatment in this area has to consider not only the lines but also the position of the brows.

The forehead has been studied less than the area between the brows: the Cochrane review of facial wrinkles includes only two studies on the forehead. Two more recent, large placebo-controlled trials, with 362 and 368 participants, looked at lines on the forehead, between the brows and at the outer corners of the eyes. In the main results, which also covered forehead lines, the treatment was significantly more effective than placebo (a dummy treatment).

According to an anatomy study of the points where nerves connect to the forehead muscle, these points are concentrated in the middle and upper part of the muscle, along its deep surface. However, these maps should be read as areas of probability, not exact boundaries. The shape and thickness of the forehead muscle also vary from person to person. Research has linked failing to take these anatomical differences into account with unwanted results such as a drooping eyelid and the outer end of the brow lifting upwards (‘Spock brow’, also called ‘samurai brow’; medical name: ‘Mephisto sign’).

For this reason, there is no standard injection pattern for the forehead that suits everyone. If you have drooping brows or excess skin on the upper eyelids as well as forehead lines, this is assessed separately at your consultation. This is because when the forehead muscle relaxes, the force that holds the brows up also decreases.

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Frown lines

The vertical lines between the brows, known as frown lines (glabellar lines), form when the muscles that knit the brows and pull them together contract. This is the area where botulinum toxin has been studied most in aesthetics: 43 of the 65 randomised trials in the Cochrane review of facial wrinkles relate to the area between the brows.

Looking at the results of a single treatment in this review, botulinum toxin type A reduced wrinkles between the brows within four weeks. The strength of the evidence for these results was rated high, moderate or low, depending on which comparison is considered. According to the review, the treatment probably also increases the risk of a drooping eyelid; this is covered in the Known risks section.

An older meta-analysis (an analysis that combines the results of several studies) assessed seven placebo-controlled trials on the area between the brows, with 1,474 participants. The proportion of good results was significantly higher in the treatment groups than with placebo. A subgroup analysis reported that frown lines looked better not only when frowning but also when the face was at rest. In this analysis, there was no significant difference in the frequency of adverse effects between the treatment and placebo groups. However, this finding should be considered together with the result of the more comprehensive Cochrane review on drooping eyelids.

On the anatomy side, the points where nerves connect to the muscle that knits the brows have been reported to be concentrated mainly in the inner part of the muscle and at a deeper level. However, the location and depth of these points, and how much they overlap, vary from one muscle to another. For this reason, these maps should be read as areas of probability, not exact boundaries, and should be used together with an assessment of the face in motion and the doctor’s clinical judgement.

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Crow's feet

The lines at the outer corners of the eyes (lateral canthal lines, commonly called crow's feet) form when the outer part of the ring-shaped muscle around the eye (orbicularis oculi) contracts, and they become more visible especially when you smile. Botulinum toxin can soften these lines by reducing movement in the outer part of this muscle.

In terms of evidence, this area sits between frown lines and forehead lines: the Cochrane review of facial wrinkles includes seven studies on the outer corners of the eyes. In one of the two large trials that looked at upper-face lines, crow's feet were assessed in a separate group, and in the main results the treatment was significantly more effective than placebo.

In this muscle around the eye, the points where nerves connect to the muscle are spread widely throughout it, unlike the clusters seen in the forehead and between the brows. According to an anatomy review of this area, crow's feet are linked not only to this muscle but also to the surrounding anatomical structures, and injection points can be identified more precisely based on the surface anatomy of the muscle.

Being close to the eye raises a separate question. In a small study that followed 30 patients for three months, treatment of crow's feet was followed by reduced stability of the tear film covering the eye, impaired function of the oil glands in the eyelids, and changes on the surface of the cornea (the clear front layer of the eye). The researchers concluded that the treatment can temporarily disturb the balance of the eye’s surface. Although this was a small study, the finding is a reason to tell your doctor at your consultation if you have dry eye symptoms.

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Other uses described in research

Aesthetic and medical uses of botulinum toxin beyond facial lines have also been studied, and the level of evidence differs from one use to another. These headings are not a list of services offered at the clinic; they summarise what research has shown so far. The doctor decides which of these will be carried out, and this is discussed at your consultation.

Prominent chewing muscle (masseter): For enlargement of the chewing muscle, which can make the lower face look wide, a meta-analysis combining five randomised placebo-controlled trials and 536 participants reported a short-term reduction in muscle thickness and an improvement in appearance. However, there was wide variation between the studies; the evidence is not sufficient to establish the best way to give the treatment, and studies with longer follow-up are needed.

Neck bands (platysma bands): A meta-analysis combining three randomised trials (912 participants) on the vertical bands formed by the thin muscle at the front of the neck (platysma) reported that the treatment significantly increased the proportion of people improving by at least one grade compared with placebo, while the frequency of adverse effects was similar to placebo. This area is also covered separately in the neck rejuvenation article.

Too much gum showing when smiling: A meta-analysis combining 17 studies found that gum visibility was clearly reduced at week two, that the effect then gradually decreased, and that values returned close to baseline at around week 24. According to the researchers, the effect lasts at least 12 weeks; however, variation between the studies was high.

Underarm sweating: In primary excessive underarm sweating, which is not caused by another condition, a meta-analysis combining 12 randomised trials (904 participants) reported that botulinum toxin reduced sweating significantly compared with placebo, and that there was no statistical difference when it was compared with other treatments. Excessive sweating is more of a medical issue than an aesthetic one and is assessed separately.

RELATEDNeck rejuvenation: what changes in the neck?

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Dynamic lines and static lines

Botulinum toxin gives its clearest results on dynamic lines, which appear with muscle movement. Its effect is more limited on static lines, which stay in place even when your face is at rest. This distinction is the first question in working out what you can expect from the treatment. To answer it, your face needs to be assessed both in motion and at rest.

According to a review of cosmetic botulinum toxin treatments, facial wrinkles result from a combination of thinning skin and repeated contraction of the underlying muscle, and the results on dynamic lines are more noticeable than on static lines. In other words, when the muscle relaxes, the line created by contraction does not form; but a mark that has become set in the skin does not disappear on its own just because the muscle has relaxed.

Even so, this distinction is not clear-cut. In the meta-analysis combining seven randomised trials on the area between the brows, a subgroup analysis also reported improvement in how the frown lines looked with the face at rest. This shows that the appearance at rest can also be partly affected; but it does not mean that a deep, set-in line will disappear completely.

A movement problem and a volume problem are different things and call for different treatments. The article Botulinum Toxin or Fillers? explains in detail how to tell these two problems apart, how they can occur together in the same face and why the order of treatment matters.

RELATEDBotulinum Toxin or Fillers?

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When does it start to work, and how long does it last?

The effect is not visible straight after the injection. According to a review of cosmetic treatments, the effect usually takes two weeks to develop fully and lasts about three to four months. The Cochrane review of facial wrinkles also found that the treatment reduced wrinkles within four weeks.

According to another review that focused on how long the effect lasts, this ranges from two to six months: in most people, the strongest contraction is reduced for three to four months, and the effect can sometimes last up to six months. However, the studies did not measure the effect using a shared definition; so the answer to ‘how long does it last?’ depends on what is counted as an effect.

A meta-analysis combining randomised trials in which the forehead, the area between the brows and the outer corners of the eyes were treated together calculated that the time until participants lost their response to treatment was 182 days. This figure comes from studies using a specific product and dosing regimen; it cannot be used as a guide to what you personally can expect.

The evidence also has a limit: the Cochrane review states that there is a lack of evidence on how long the effect lasts and on the results of repeated treatments. For this reason, a timeframe specific to you can only be discussed at a consultation; the duration that may apply to you depends on the product used, the area treated and your individual characteristics.

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Repeated treatments and antibody formation

When the effect wears off, the treatment can be repeated. With repeated treatments, another issue has also been studied: the body developing antibodies that make the toxin inactive (neutralising antibodies), so that a treatment that used to work loses its effect. This is called secondary non-response.

A large review that brought together five systematic reviews (203 studies, 17,815 patients) found that the frequency of neutralising antibodies was clearly higher in therapeutic uses in dystonia, spasticity and urology, and so low as to be almost negligible in excessive sweating and aesthetic uses. For three widely used products (formulations), the overall rate is between 1% and 2.1%. A meta-analysis of 43 studies covering therapeutic uses found an overall frequency of 1.8%, and a longer duration of treatment was associated with a higher frequency.

In aesthetics, the picture is not yet clear. According to the consensus view of an international expert panel, the true frequency of antibodies in aesthetics is probably underestimated because of limitations in the published data; as the doses used in aesthetics get closer to therapeutic doses, this frequency may increase. The panel recommends that patients are informed about this risk.

A review of non-response in aesthetic treatments lists the following among the factors that may trigger it: treatments given less than three months apart, high total doses, and additional injections given within three weeks of the first treatment. Data on how often non-response occurs in aesthetic treatments are more limited than for therapeutic uses. For this reason, at your consultation you will be asked when and how often you have had previous treatments.

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Limits of this treatment

Botulinum toxin is a treatment that targets muscle movement: it does not add volume, does not tighten sagging skin and is not permanent. If a facial line has a cause other than movement, botulinum toxin does not remove that cause and will not meet your expectations.

In concrete terms, this limit means the following:

• Volume that decreases with age (in the temples, cheeks and under the eyes) is not replaced by botulinum toxin; this is a volume problem.

• Skin laxity and sagging are not corrected by relaxing the muscles.

• In deep, static lines that are visible even when your face is at rest, results are more limited than in dynamic lines that appear with movement.

• The effect wears off on its own; the treatment has to be repeated for the effect to continue.

A meta-analysis combining upper-face treatments found a clear reduction in wrinkle severity, but there was a high level of variation between studies; in other words, there is no single result that applies to everyone.

The Cochrane review states that there is a lack of evidence on the effects of repeated treatments and on long-term results.

Other methods for volume loss and sagging have also been studied; treatments using substances that stimulate collagen production are described on the Liquid Facelift with Collagen Stimulators page. Which route makes sense for you (botulinum toxin, another method or none) is decided by the assessment at your consultation and by your own decision.

RELATEDLiquid Facelift with Collagen Stimulators

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Known risks

A botulinum toxin injection is a medical procedure using a prescription-only medicine, and it has side effects. Most reported effects are mild and temporary; however, you also need to know about side effects that can be serious. The rates given here come from other studies and cannot be used to calculate your personal risk.

Common effects: Mild bruising and swelling can occur at the injection site. A meta-analysis combining non-surgical facial treatments calculated a treatment-related adverse effect rate of 18% for botulinum toxin treatments in the upper face; the most frequently reported effect was headache. In a study that followed 102 patients, headache occurred after treatment in 12.7% of them; it was usually described as mild or moderate, short-lived and resolving on its own.

Drooping eyelid or brow, asymmetry: According to the Cochrane review, the treatment probably increases the risk of a drooping eyelid (ptosis); squint and altered sensation in the eyelid are also among the known risks. A systematic review covering 8,787 people reported the following rates. In the upper face: drooping eyelid in 2.5%, drooping brow in 3.1% and eye-related sensory disturbances in 3%. In the lower face: lip asymmetry and imbalance in 6.9%. All of these were reported to have resolved on their own. One review described temporary drooping of the eyelid and brow as complications related to injection technique.

Spread of the toxin’s effect: Most complications caused by botulinum toxin, at the injection site and in distant areas, are thought to result from its biological effect spreading unintentionally to nearby or distant muscles; the injected volume and the dilution ratio can affect this spread. A review that looked for serious and long-term side effects reported problems such as difficulty swallowing (dysphagia), breathing difficulties and generalised muscle weakness. These are more common with therapeutic use, but they can also occur after cosmetic use.

At your consultation, your doctor will tell you which symptoms after the treatment mean you should contact the clinic, based on her own treatment protocol.

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Situations that need extra caution

Research shows that in some situations botulinum toxin treatment needs extra caution. These are the topics that stand out in the scientific literature; they are not a list of situations in which the clinic does not give the treatment. That assessment is made by the doctor and discussed at your consultation.

Neuromuscular disorders: A review of cosmetic botulinum toxin treatments lists the following among the situations in which the treatment should not be given (contraindications): neuromuscular disorders such as myasthenia gravis (a condition that causes muscle weakness and muscles that tire quickly), a tendency to form keloids (raised, excessive scars) and allergy to any of the product’s ingredients. A systematic review of the link between myasthenia gravis and botulinum toxin reported that marked muscle weakness developed in all eight people who had undiagnosed myasthenia and received cosmetic or therapeutic treatment. In eight of ten people with known myasthenia who received therapeutic treatment, symptoms were reported to improve with dose adjustment and appropriate treatment of the myasthenia. So the picture is not one-sided; even so, if you have a known neuromuscular disorder or unexplained muscle weakness, it is important to mention this at your consultation.

Pregnancy and breastfeeding: According to a review of the safety of cosmetic treatments during these periods, the safety data on botulinum toxin are insufficient. Although the amount of toxin that passes into the blood and crosses the placenta to the baby is thought to be negligible, stronger evidence is needed before a firm recommendation can be made. According to a more recent review, elective (optional) cosmetic procedures are postponed during pregnancy, whereas during breastfeeding an individual risk assessment is made; these two periods should not be handled in the same way.

A review of use during pregnancy and breastfeeding in neurological conditions also reports that the available evidence is limited and largely observational, and that data on breastfeeding are even more limited. In short, safety during these periods is not a proven fact; it is a clear gap in the data. You need to tell your doctor at your consultation if you could be pregnant and whether you are breastfeeding.

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