History and Development
The existence of botulinum toxin has been known for centuries; however, its positive effects have only been appreciated in recent decades. In 1895 Professor Emile Pierre van Ermengem, of Ellezelles, Belgium identified the bacterium Bacillus botulinus. The agent, later renamed Clostridium botulinum, was the precursor to what is now known as botulinum toxin type A (Botox®).
It's believed that botulinum toxin type A was first isolated in purified form as a stable acid precipitate in the 1920s by Dr. Herman Sommer at the University of California, San Francisco. The resulting precipitate provided the basis of raw material for future studies.
In 1946 Edward J. Schantz, Ph.D., and colleagues succeeded in purifying botulinum toxin type A in crystalline form. For the first time, researchers had the raw material they needed to study botulinum toxin type A in greater detail. The first major result of these studies occurred in the 1900s, when Dr. Vernon Brooks discovered that botulinum toxin type A, when injected into a hyperactive muscle, blocked the release of acetylcholine from motor nerve endings, thus inducing a temporary "paralysis" of the targeted muscle. Dr. Brooks' breakthrough sparked new interest in botulinum neurotoxin as a potentially significant therapeutic agent for pain treatment.
In the 1960s and 1970s, Alan B. Scott, M.D., of the Smith-Kettlewell Eye Research Foundation tested botulinum toxin type A in monkeys to determine if the drug might be an effective therapy for strabismus, a type of "ophthalmic dystonia," in humans. Having heard about Dr. Schantz's research with botulinum toxin, Dr. Scott contacted Dr. Schantz at the University of Wisconsin to obtain product samples. Dr. Scott found that by injecting a small amount of botulinum toxin in the hyperactive ocular muscles in monkeys he was able to correct the strabismic condition. For the next 20 years, Dr. Schantz collaborated with Dr. Scott to develop botulinum toxin type A for human treatment.
In the late 1970s, Dr. Scott formed his own company, Oculinum, Inc., where he continued to study botulinum toxin type A. Then, in 1978, Dr. Scott received permission from the Food and Drug Administration (FDA) to test botulinum toxin type A in human volunteers.
In 1988, Allergan acquired the rights to distribute Dr. Scott's botulinum toxin type A product, Oculinum, and the responsibilities to conduct clinical trials of the drug's effectiveness for other indications, including cervical dystonia. In 1989, Oculinum, Inc. received FDA approval to market Oculinum in the United States as an orphan drug to treat strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorder in patients 12 years of age and older.
Shortly after the FDA approved these indications, Allergan Inc., acquired Dr. Scott's company. Based on the success of botulinum toxin type A therapy in the treatment of strabismus and blepharospasm associated with dystonia, Allergan applied for and received FDA approval to change the product's name to Botox® - a modification that aligned the product with Allergan's strategy to develop additional applications.
Mechanism of Action
Botox® has a product license for the following conditions:-
- Cervical Dystonia - severe muscle spasm in the neck and shoulder muscles leading to neck pain and abnormal postures
- Strabismus / Blepharospasm - involuntary muscle spasm around the face and eye
It is also used outside this license in the pain clinic for the following conditions:-
- Myofascial Pain Syndromes - pain arising from skeletal muscles in spasm e.g. neck, shoulder girdle, low back, and hip girdle.
- Spasticity - low back pain and limb pain caused by brain and spinal cord injuries
- Sweating - Botox treatment can help control excessive sweating (hyperhidrosis)
- Migraine - when the source of the migraine is the neck or facial muscles, injecting intramuscular Botox can help to relax the offending muscles for several months, thereby producing pain relief.
Botox® blocks neuromuscular transmission (electrical conduction from nerve to muscle) through a three-step process. This is believed to be followed by the sprouting of new axon (nerve) terminals, which results in the re-establishment of neuromuscular transmission. The following information regarding the mechanism of action of Botox® is based upon animal data, thus the clinical significance is unknown:-
Blockade of neuromuscular transmission
- Binding - Botulinum Toxin Type A binds to the motor nerve terminal (where the nerve attaches to the surface of the muscle). The binding site of the type A molecule appears to be selective for cholinergic nerve terminals, receptors that bind to the impulse transmission chemical, acetyl choline.
- Internalisation - Botulinum toxin type A is taken into the nerve terminal by a process called endocytosis, to form a toxin-receptor vesicle (bubble). The light chain of the molecule is then released into the fluid centre of the cell (cytoplasm). This light chain has been shown to hold the nerve transmission blocking properties.
- Blocking - Botulinum toxin type A blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction. The toxin does not affect the synthesis or storage of acetylcholine or the conduction of electrical signals along the nerve fibre.
Re-establishment of neuromuscular transmission
- Nerve Sprouting - Evidence indicates that chemical denervation of the neuromuscular junction by botulinum toxin type A results in an expansion of the end-plate region and growth stimulation of collateral axonal sprouts.
- Nerve Connection Re-established - A nerve sprout eventually establishes a new neuromuscular junction, and muscle activity gradually returns. However, new research suggests that this new nerve sprout retracts and the original junction returns to functionality. In either case, repeat injections of Botox® Purified Neurotoxin Complex may be required to maintain the desired clinical effect.
Botox® (Botulinum Toxin Type A) Purified Neurotoxin Complex is a 900-kilodalton (900-kD) complex containing type A neurotoxin and associated proteins.
There are general structural and functional similarities among all 7 botulinum neurotoxin types (A through G). All are synthesized as single-chain polypeptides with molecular weights of approximately 150 kD.
These single-chain molecules are activated by proteolytic enzymes in a process referred to as Nicking and Cleaving . Activation of botulinum toxin type A is achieved by nicking or cleavage of the neurotoxin protein by endogenous bacterial enzymes.
Once it is nicked or cleaved, the ~150-kD single-chain molecule forms a dichain (double) molecule consisting of an ~100-kD heavy chain linked by disulfide bonding to an ~50-kD light chain. The heavy chain is responsible for high-affinity docking of the neurotoxin to the presynaptic nerve terminal receptor, enabling the internalization of the bound toxin into the cell.
The light chain is a zinc-dependent endopeptidase that cleaves membrane proteins responsible for docking acetylcholine vesicles on the inner side of the nerve terminal membrane. The cleavage of these proteins precludes fusion of the vesicles with the nerve membrane, thereby preventing release of neurotransmitters into the neuromuscular junction.
Botox® belongs to a class of drugs called botulinum toxins. Botox®, a focal muscle-relaxing agent, is the brand of botulinum toxin type A made by Allergan. Botox® is the most studied brand of botulinum toxins and has been used to treat over 1 million patients worldwide for more than 11 years. The following represent frequently asked questions by patients:-
What is Botox ?
- Botox® is a formulation of botulinum toxin type A. It is derived from the bacterium Clostridium botulinum. This bacterium produces a protein that blocks the release of acetylcholine and relaxes muscles. Type A is just one of seven different types of botulinum toxin (A, B, C1, D, E, F, and G), and each has different properties and actions. No two of these botulinum toxins are alike.
- More than 100 years of research have expanded our knowledge of botulinum toxin type A from the identification of the bacterium Clostridium botulinum to the commercialization of botulinum toxin type A as Botox®.
- In the 1960s, the muscle-relaxing properties of botulinum toxin type A were tapped for investigational use in realigning crossed eyes. These early studies paved the way for treating other conditions caused by overactive muscles with botulinum toxin type A.
- Today, Botox® is produced in controlled laboratory conditions and given in extremely small therapeutic doses. It has helped over 1 million patients worldwide with conditions caused by overactive muscles.
- Botox® is indicated for the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and associated neck pain. Botox® is also indicated for the treatment of blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in people 12 years of age and above.
Is Botox a new treatment ?
- No. Botox® has been used for more than 11 years to treat over 1 million patients worldwide, and it is approved by the health ministries of at least 70 countries.
How is Botox different from other botulinum treatments ?
- Botox® is Allergan’s brand of botulinum toxin type A. A brand of botulinum toxin type B is also now available. The two toxins are different in several ways:
- They are different serotypes
- They have different manufacturing processes
- They work differently
- They require different doses
How is Botox different from other oral treatments ?
- Botox® differs from oral therapies in that it is a non-systemic, focal therapy. When drugs are taken orally, they are distributed throughout the body by the blood system. The drugs reach not only their desired site of action but also many additional sites. In contrast, Botox® is administered directly into the desired site of action. Botox® is not expected to be present in the blood stream at measurable levels following injection at the recommended doses.
Why should you have confidence in Botox ?
- Botox® provides targeted relief of symptoms for the treatment of neck pain and abnormal head position in Cervical Dystonia with
- No GI upset
- No fatigue
- No confusion
- No depression
- No liver toxicity
- Botox® has been proven as a safe and effective therapy, and has been widely used for more than 11 years.
- Over the past 20 years, Botox® has been evaluated in more than 200 studies specific to approved indications in the US. Currently, little clinical data are published about botulinum toxin type B.
How does Botox work ?
- Normally, your brain sends electrochemical messages to your muscles to make them contract and move. These messages are transmitted from a nerve to the muscle by a substance called acetylcholine. When too much acetylcholine is released, muscles become overly active and spasm or tense up.
- Botox® blocks the nerve from releasing acetylcholine. As a result, the muscle spasms stop or are greatly reduced, providing relief from symptoms. Your health care provider will know how much Botox® is needed to treat you effectively.
- It’s important to remember that botulinum toxin treatment is not a cure. For many people, however, its effects have been dramatic. With Botox®, the nerve will take about 3 months to recover and begin to release acetylcholine, and the muscles may become overactive again. At that point, another injection will be needed to provide relief, as long as no allergic reactions or other significant side effects occurred and clinical response was obtained.
How long can I be treated with Botox ?
- Each treatment typically lasts 3 months and can be repeated as long as your condition responds to Botox® and you do not have any serious allergic reactions or other significant side effects. Botox® has been used for more than 11 years to treat more than 1 million patients worldwide, and although formal, long-term clinical evaluations have not been conducted, its safety in long-term use has been well established.
- Although most people continue to respond to Botox® injections, some people have experienced a diminished response over time. There may be several explanations for this:
- Changes in your condition - If the pattern of your muscle activity changes, your health care provider may need to inject new muscles and/or change your dose. Identifying and injecting the affected muscle can be difficult, complicated by the changing pattern of muscle involvement and progression of the disorder.
- Setting appropriate expectations - You may believe your first Botox® injection was more helpful than subsequent injections. That’s because your condition was perhaps quite severe when you had your first injection. Subsequent injections are usually given before your condition becomes that severe again. Therefore, the relief you experienced with subsequent injections may not have been as dramatic as the first time.
- Antibody formation - When foreign proteins, like botulinum toxins, enter your body, antibodies may form. If antibodies to botulinum toxin develop, you may no longer respond to treatment.
- Because botulinum toxins are usually used to treat chronic conditions, it’s important to preserve responsiveness to therapy.
How can I help maintain my response to Botox ?
- While the critical factors for neutralizing antibody formation have not been well characterized, you may be able to help maintain your response to Botox® by minimizing your total exposure. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.
How is Botox given ?
- Botox® is injected into the affected muscle(s). Your doctor will determine which muscles need to be treated.
Does the injection hurt ?
- Some people report minor, temporary discomfort from the injection. Botox® is reconstituted with sterile, preservative-free, normal saline for injection. The neutral pH of the injected solution, in combination with the fine-gauge needle your doctor will use, can help to minimize any injection-related pain.
When will Botox start to work ?
- If you’re receiving Botox® for cervical dystonia, you’ll usually see the effects within 2 weeks of the injection. If you’re receiving Botox® for blepharospasm, you’ll usually see effects within 3 days.
How long will the effect last ?
- Botox® offers sustained relief, dose after dose. The relief you’ll feel from one treatment of Botox® will normally last for about 3 months. Treatments can be continued as long as your condition responds to Botox®, and you do not have any serious allergic reactions or other significant side effects. When the relief begins to fade, you’ll return to your doctor for your next treatment.
- Usually, Botox® treatment is required approximately four times per year. Because symptoms can change over time, the amount and duration of relief you’ll experience can vary. Consult your doctor, who can determine how to achieve the best possible results with Botox®.
What side effects have been seen with Botox ?
- The most frequently reported adverse reactions in patients receiving Botox® for the treatment of cervical dystonia are dysphagia (difficulty swallowing, 19%), upper respiratory infection (such as a cold or flu,12%), neck pain (11%), and headache (11%). Dysphagia is a commonly reported adverse event following treatment of cervical dystonia patients. In these patients, there are reports of rare cases of dysphagia serious enough to require the insertion of a gastric feeding tube (a tube for introducing nutritious, high-calorie fluids into the stomach.)
- The most frequently reported treatment-related adverse reactions in patients receiving Botox® for the treatment of blepharospasm are ptosis (droopy eyelids, 20.8%), superficial punctuate keratitis (inflammation of the cornea characterized by small erosions of the tissue covering the cornea, 6.3%), and eye dryness (6.3%). Reduced blinking from Botox® injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect (a defect in the corneal covering) and corneal ulceration (a hollowed-out cavity in the cornea), especially in patients with VII nerve disorders.
- In general, adverse reactions occur within the first week following injection of Botox® and, while generally transient, may last several months. Localized pain, tenderness and/or bruising may be associated with the injection. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of adjacent muscles may also occur due to spread of toxin.
- Please seek immediate medical attention if swallowing, speech, or respiratory (breathing) disorders arise.
Is Botox right for me ?
- Your doctor can help you decide if Botox® is right for you. In order to make the right treatment decision, you should discuss the following:-
- Clinical experience with the drug
- Effectiveness and side effects
- Make sure your doctor knows if you are pregnant, nursing, or taking any medications before receiving Botox® injections. Additionally, you should not receive Botox® if you have an infection at the injection site.
- Botox® should be used with caution if you have other neurological diseases or disorders, or if you are taking aminoglycoside antibiotics or other drugs that interfere with neuromuscular transmission. Be sure to tell your health care provider about any prescription or over-the-counter medications you are taking before receiving Botox®.
Adapted from information held at www.botox.com