Botulinum toxin (Botox®)

Botox is a treatment option for adults with chronic migraine

Introduction

Botox® (onabotulinum toxin A) was licensed specifically for the treatment of chronic migraine in July 2010 by the Medicines and Healthcare products Regulatory Agency (MHRA). Botox® has not been shown to be effective for any other headache type (e.g. episodic migraine, tension-type headache, cluster headache) as yet. The information below outlines the evidence for the use of botulinum toxin in headache.

What is botulinum toxin?

Botulism – paralysis of muscles caused by high doses of botulinum toxin – was first described in 1817. The responsible bacterium, Clostridium botulinum, was not isolated until 1895. Seven different subtypes of botulinum toxin (A-G) are known. A highly dilute preparation of botulinum toxin type A (Botox®) was introduced in clinical practice in the 1970s and 1980s to treat squint and blepharospasm. Since then it has found uses in other areas of medicine including dystonia (including writer’s cramp), post-stroke spasticity, and hyperhidrosis. Other botulinum toxin preparations are available, both of type A (Dysport and Xeomin) and type B (Neurobloc or Myobloc), but these have never been tested in headache disorders.

Botulinum toxin and headache

In the mid-1990s a number of people reported improvement in headaches in patients receiving botulinum toxin for other reasons. Well-conducted clinical trials of botulinum toxin in various types of headache followed, but the results were disappointing, with no difference over placebo being found in tension-type headache, episodic migraine, and undifferentiated chronic headache. Detailed analysis of the results suggested, however, that there might be a subgroup of patients with chronic migraine who could benefit, and further trials were undertaken.

Botox® in chronic migraine: the PREEMPT trials

Two Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials recruited 1384 patients with chronic migraine, and randomised them to treatment with Botox® or placebo. These patients were suffering on average 20 days of headache each month, of which 18 were moderate or severe. Those randomised to Botox® received fixed-site, fixed dose injections every 12 weeks over 56 weeks. These injections covered seven specific areas of the head and neck, with a total dose of between 155-195 units. At six months, after two cycles of treatment, those treated with Botox® had on average eight less days of headache each month. After 12 months, 70% of those treated had ≤50% the number of headaches that they had done originally. Botox® was well-tolerated, the commonest side effects being neck pain (6.7%), muscular weakness (5.5%), and drooping of the eyelid (3.3%). No serious irreversible side effects have ever been reported in trials of Botox® in headache.

How does botulinum toxin work in chronic migraine?

The simple answer is that we don’t know fully. A recent US study by Rami Burstein et al using animal models suggested that botulinum toxin inhibits pain in chronic migraine by reducing the expression of certain pain pathways involving nerve cells in the trigeminovascular system. The trigeminovascular system is a sensory pathway thought to play a key role in the headache phase of a migraine attack.

Unlike many of the other conditions in which it is used, it is not thought to work by relaxing overactive muscles. Botulinum toxin has been shown to reduce pain in a number of disease states, including cervical dystonia, neuropathic pain, lower back pain, spasticity, myofascial pain, and bladder pain.

More research into the mechanism of action of botulinum toxin will hopefully shed light into all the pathways that it acts upon.

Is Botox® right for me?

Only patients with chronic migraine are eligible for treatment with Botox®. Chronic migraine is defined as headaches occurring on 15 or more days each month, at least half of which have migrainous features. There are, however, other treatments available to patients with chronic migraine, and it is important that patients have an informed discussion of their headaches and the options for treatment with a practitioner experienced in the diagnosis and management of headaches before a decision to use Botox® is taken.

Who can inject Botox® for chronic migraine?

At present the use of Botox® is restricted to a few specialist headache centres, but as time goes on there should be increasing numbers of trained injectors available. In all cases, however, you should ensure that the person injecting has received appropriate training, both in the diagnosis and management of chronic migraine, and in the delivery of Botox® according to the proven PREEMPT schedule.

Please note that the referral process differs for each location.  In the first instance, patients who are struggling to manage their symptoms should discuss this with their general practitioner (GP) and if appropriate, seek referral to a specialist with an interest in headache disorders.  Read more about seeking medical advice.

On visiting a migraine clinic a detailed history of the patient’s condition will be taken, including symptoms, frequency of attacks and any medication tried in the past or currently taking.  Keeping a diary can help with this.

Availability of Botox® for treating chronic migraine on the NHS

The National Institute for Health and Clinical Excellence (NICE) issued guidance in June 2012 recommending Botox® is made available on the NHS as a preventive treatment option for adult patients with chronic migraine – this applies to NHS settings in England and Wales.

The Scottish Medicines Consortium (SMC) has advised NHS Scotland not to offer Botox® for the prophylaxis of headaches in adults with chronic migraine (2011 and reviewed in 2013 following resubmission).  This guidance may be reviewed in future.

Following the NICE guidance, local NHS healthcare providers in England and Wales had three months to ensure the funding and resources were in place for suitable patients to access the treatment following recommendation by a suitably qualified health professional.  This time frame has now elapsed and the treatment should be available locally on the NHS for those meeting the criteria.  Access to treatments that have been recommended by NICE for use in the NHS, if your doctor says they are clinically appropriate for you, is a patient right enshrined in the NHS Constitution.

If your health professional has recommended that you are suitable for this treatment, but you or your health professional are having difficulty accessing the funding or resources for you to receive Botox® from your local NHS healthcare provider, then The Migraine Trust’s Advocacy Service may be able to provide further support.

For further information please read:

Q&A

I have read that Botox® injections for chronic migraine should be given every 12 weeks, but my doctor can’t see me for my next Botox® appointment until two weeks after the 12 week interval. Will the treatment still work, and if so, how much variation to the 12 week intervals can there be in practice?

Answer kindly provided by Dr Brendan Davies in Migraine News journal, Issue 112, March 2016.

In general, the current standard of care for the treatment of chronic migraine with Onabotulinum toxin type A (Botox®) is injections every 12 weeks. It is generally worthwhile having at least two treatment sessions to assess treatment response. If individuals have not responded by two to three treatment sessions it is generally considered that the individual is a non-responder. As experience increases with the use of Botox® as a preventative treatment for chronic migraine some clinicians are identifying that longer periods between injections may sometimes be acceptable.

The choice of 12 weeks between treatments with Botox® for chronic migraine is largely based on the pivotal research studies that were used to gain its treatment approval. In day-to-day clinical headache practice it is not unusual to vary the duration between Botox® treatments in some patients. Experience has shown that some individuals not only gain benefit over the 12 weeks following their last Botox® injection, but also sometimes for further weeks afterwards. In such scenarios doctors who administer Botox® may suggest increasing the time intervals between injections. However, it is difficult to generalise about such decisions as they are often made on an individualised basis.

In general terms cranial Botox®, or Botox® for other conditions, is usually administered approximately every 12 weeks due to the treatment response being considered more reliable over this time period. It is unfortunate when patients experience a wearing off effect of any preventative treatment effect 10 to 12 weeks after the last injection, but the logistics of care delivery i.e. clinic capacity, staff availability or other factors are sometimes responsible for extending the time between injections.

There is no good evidence to suggest that cranial Botox® is less likely to work if delayed more than 12 weeks. In fact, in patients who may be considered equivocal or borderline Botox® treatment responders, some headache clinics choose to wait a further month or two beyond 12 weeks to assess whether any relapse to more frequent migraine occurs compared to the immediate few months post treatment. This sometimes allows an assessment about whether further Botox® is actually needed.