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questions about anti-epileptic drugs

Taking medication for epilepsy is much more than just pill-swallowing. Deciding to take anti-epileptic drugs (AEDs) can be a big decision, and you might have lots of questions about how the drugs work before you take that step. Here are some common questions, from how the AED is chosen to what monotherapy and polytherapy are.

Trials and testing

Drugs are produced by drug (or pharmaceutical) companies. Researching and developing drugs is a very long, complicated and expensive process. Each step of the process is designed to make sure that the drug is safe for us to use, that it works (does what it says it will do) and that it can be produced in a way to make sure it is consistent (that each pill is the same as the next one). For every drug that is successfully developed there will be many that fail and never make it to a medicine cabinet.

How are drugs developed?

The first stage of developing drugs is to ‘find’ a possible drug. Researchers look for chemical compounds, which might be similar to a drug that already exists, that they think might work for a particular condition.

Once a compound is found the next stage is to trial it. This involves testing the compound to see if it does the job the researchers expect it to. The first trials might be computer tests (to see whether the compound works in theory). After this, the compound is tested on animals before it is tested on human volunteers. These trials happen in three phases and can take up to six years to complete. Strict guidelines and ethical standards make sure that drug trials are fair, accurate, thorough and give enough information about the drug to know whether it works.

Tests include checking that the drug is safe (and doesn’t cause illness) by testing them on people who do not have the condition (for example testing AEDs on people who do not have epilepsy).

Some drug tests (or trials) are ‘double-blind randomised controlled’ trials. This means that, of a group of volunteers, half are chosen at random to take the drug and the other half take a placebo. Randomly selecting who takes the drugs and who takes the placebo means that the researchers cannot chose who they think will respond best to the drug or treat them different to the volunteers taking the placebo.

Placebo - these are 'dummy' drugs that have no active ingredient in them. They are used controls in drug trials - used to compare the effects of the real drug.

‘Double blind’ means that neither the volunteer nor the researcher knows who has the real drug and who has the placebo. After a certain length of time (which depends on the individual trial) the drugs are ‘crossed over’ – the volunteers are switched from one treatment to the other. So if a volunteer was taking the placebo they will be swapped on to the ‘real’ treatment and if they were taking the ‘real’ treatment they will be swapped to the placebo.

During these trials, the researcher will see how well the drug works and also whether it has any common or predictable side effects. The ideal is to develop a drug that is as effective as possible with the least side effects. The benefits of taking the drugs are compared to the risk of side effects and the risks from not treating the condition. A drug would only be licensed if the benefits out-weigh the risks.

Licensing drugs

Once a drug is discovered, tested, works and is safe, the next stage is to license it. Once a drug is licensed it can be prescribed and used. Drugs are licensed either by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, or the European Medicines Evaluation Agency (EMEA) in the European Union. Licensing can take two to three years.

Once a drug has been licensed it can be manufactured and appear in shops or pharmacies. Getting to this stage can take 12 years!

There are different types of licence:

  1. ‘controlled’ drugs (C) have very strict regulations about how they are used (for example, morphine)
  2. ‘prescription-only’ drugs (POM) are only available on prescription (including AEDs)
  3. ‘over-the-counter’ drugs (OTC) can be bought in a shop without a prescription (like aspirin and paracetamol)

Note: sometimes drugs are prescribed ‘off license’ or for something they do not have a license for. For example, some AEDs are licensed for particular seizure types and not other seizure types. But the AED may be prescribed to someone who has seizures that it is not licensed for, if it is thought to be helpful.  

The young, the old and the pregnant

Drug trails have to be ethical: certain groups of people are not allowed to be have drugs tested on them. This includes children, people aged 60 and over, and pregnant women. There are many reasons for this. Children are not able to understand the possible risks of taking trial drugs and so can’t give their consent (willing agreement) to drug trials. Similarly, unborn babies can be put at risk if the mother takes trial drugs.

The ways that drugs are handled by the body (absorbed and removed) in children, pregnant women and older people can be different to adults in general. Once a drug has been licensed for adults (from 18 – 60 years), further tests are needed for these groups of people: testing first with older people and then with children.

Unfortunately the effects of the drug on pregnant women and their unborn child cannot be seen until it starts to get used, but new drugs will not normally be prescribed to pregnant women until they have been thoroughly tested in other groups. Once a pregnant woman is prescribed a new drug, she will be very closely monitored.  

Types of drugs

There are many different anti-epileptic drugs: some are brand versions some are generic, some are first-line and some are second, some are taken as monotherapy and some as polytherapy. But what do all these terms mean?

Patents

Like many inventions, new drugs are patented. This patent is the legal right the drug company has to be the only company to make that drug for a certain length of time (usually 20 years). During this time no other drug company can make it. Because developing a new drug costs so much, the company has time ‘on patent’ to try and recover some of these costs by selling their drug at a price that reflects the cost of development.

When the drug comes ‘off-patent’ (after the 20 years), other companies can make their own versions of the drug. These versions are called generic (see below). Because other companies have not had the cost of developing the drug from scratch, their versions can be cheaper than the original versions.

What do ‘brand’ and ‘generic’ mean?

AEDs often have two names: a brand (or trade) name and a generic name.

All drugs have an active ingredient. This is the chemical part of a drug that works on the body to control or treat a condition or disease. The generic name of a drug is the name of that active ingredient, and all drugs with the same active ingredient will have the same generic name. Generic names start with a lower case letter such as paracetamol and ibuprofen. Generic AEDs include sodium valproate and carbamazepine.

Some AEDs also have a brand name. The brand name is often the name given by the drug company that developed it, and starts with a capital letter. For example, a brand name for sodium valproate is Epilim, and carbamazepine is Tegretol.

Some drugs have many brand names or are sold by different companies under the generic name. For example, ibuprofen is sold as the brand ‘Neurofen’, and also as ‘ibuprofen’ by Boots, Tesco’s and Sainsbury’s. With AEDs, sodium valproate may be sold as generic ‘sodium valproate’ or branded ‘Epilim’, and carbamazepine as ‘carbamazepine’ or ‘Tegretol’.

Are all forms of a drug exactly the same?

All drugs with the same generic name, or with different trade names but the same generic name, have the same active ingredient. However, the amount of active ingredient may vary a little. And there is more to a drug than just the active ingredient: there are other ingredients such as colourings and binding ingredients. These other ingredients may differ from one form of the drug to another. It’s a bit like soup: all forms of tomato soup contain tomatoes but some contain cream and others contain milk, some have salt and some don’t.

In some cases, the other ingredients can affect how the drug is absorbed into the blood stream and its bioavailability. With AEDs this can be quite important: one particular form of an AED may be effective in stopping seizures for an individual but another form of the same drug might not work as well. This could result in seizures happening. For this reason it is recommended that you take the same form of the same AED (whether branded or generic) all the time.

Bioavailability  – this refers to the presence in your body of the active ingredient of a drug that is 'available to use' where it is needed (with AEDs, for instance, this is in the brain).

My AEDs look different to normal – why is this?

If your drugs look different to normal, there could be several reasons for this.

  • The drug company could have changed how the drug looks.

  • You could have a parallel import of your drug. This is when the drug is made outside the UK and brought back into the country. Some drug companies make their drugs, under strict guidelines, in other countries. Often this is not a problem, but the company may not be able to guarantee how the drug has been stored and this could affect how it works. Some parallel imports have different packaging to UK versions and the patient information leaflets (PIL) may not be in English.

  • You may have been given a different form of the drug - for example, if you usually take a branded form and have been given a generic form, or have been given a different generic form to usual. If your prescription only has the generic name of the drug, a pharmacist can give you any form of the drug with that generic name. However, if your prescription has the brand name of a drug, the pharmacist has to give you that brand.

It is often worth checking that your drugs are the right ones before you leave the pharmacy. If you find out that you don’t have the right drug once you get home, your pharmacist may not be able to change them. They can’t guarantee that you haven’t ‘tampered’ with them, and so they can’t give them to someone else. If you are concerned for any reason, you could talk to your pharmacist and explain the situation.

What does ‘chrono’ mean?

Some drugs are called ‘chrono’ or prolonged release (for example, Epilim chrono and Tegretol prolonged release). Chrono mean ‘slow-release’. If your drug is a slow-release form, the active ingredient is released in your digestive system more slowly, than non-chrono forms of that drug. This prolongs its absorption and means that you don’t have to take it as often as other forms.

What are ‘first-line’ and ‘second-line’ AEDs?

AEDs are licensed to use for controlling particular types of seizures. ‘First-line’ and ‘second-line’ refers to how AEDs are selected and used for the treatment of epilepsy and particular types of seizures.

First-line AEDs are the AEDs that are usually considered first when starting epilepsy treatment. They tend to be used on their own (monotherapy). They include sodium valproate and carbamazepine. Which one is chosen depends on the type of seizures the person has.

Second-line AEDs are AEDs that are usually taken alongside first-line therapy (also called adjunctive therapy) and therefore they are generally used as polytherapy. They include topiramate and gabapentin. Second-line AEDs also include AEDs that were used as first-line treatments but that are no longer generally considered as a first treatment option when treatment is started.

However, as treatment with AEDs is always individualised, in some cases the neurologist may use his specialist knowledge and decide to put an individual on monotherapy with a second-line rather than first-line drug.

What is monotherapy?

Monotherapy is taking just one drug (mono = one). If you are on monotherapy you usually take a single first-line drug. If you take more than one drug (either more than one first-line drug, or first-line and second-line drugs) this is called polytherapy (poly = many).

Neurologists often use monotherapy at the start of epilepsy treatment. Taking just one AED makes treatment simpler: there are no interactions with other drugs; it reduces the chance of getting side effects; and it is clear to see if the drug works or not. If a single AED does not stop your seizures the options are to try a different first-line drug, or to add-on a second drug.

Taking more than one drug (polytherapy) means that there may be different side effects from each of the different drugs. Your neurologist will have to consider which side effects may be from which drug. He (or she) will also need to be aware of possible interactions between the drugs, and, if your seizures become better controlled, may find it hard to see which drug is working best.

Out with the old and in with the new?

AEDs can be divided into two groups according to when they where developed and how long they have been around for.

Newer drugs (licensed after 1989) include lamotrigine, gabapentin and topiramate. Older drugs (licensed before 1989) include phenytoin, carbamazepine and sodium valproate.

When you compare the older and newer drugs it is not as simple as ‘newer drugs are better because they have been developed more recently’ or that ‘older drugs are better because they have stood the test of time and are still used’. Again, like most things in the treatment of epilepsy, there are positives and negatives to each.

The positives and negatives about older drugs include:

  • Because they have been used over may years the longer-term benefits and side effects are better known
  • We know more about how they work and what seizures they are likely to work for
  • They are known to be very effective for some people (through many years of experience using them)
  • Some have serious side effects or interactions with other drugs.

The positives and negatives about newer drugs include:

  • They often have fewer side effects
  • They are less likely to interact with other drugs
  • They are more expensive (see section on licensing)
  • We don’t have the years of experience to know what types of seizures they work best for.

So the decision about which AEDs to choose is more complicated than their age alone.

Choosing AEDs depends on:

  • The type of seizures you have
  • The AED that is known to work best for that type of seizure
  • Your lifestyle. Some side effects are more important to some people than others: for a student, avoiding an AED that affects their concentration may be important, but for a man, taking an AED that can cause menstrual problems won’t be a problem.

Taking and monitoring AEDs

Some of the most commonly asked questions about taking AEDs, include:

  • To take or not to take?
  • How often should AEDs be taken each day?
  • What is the average dose range of an AED?
  • What is 'blood-level testing'?
  • When you increase a dose, how long does it take to start working?
  • What are side effects?
  • Why do side effects happen?
  • Do side effects always happen?
  • What do terms like 'common' and 'rare' actually mean?
  • Are the side effects the same for all AEDs?
    What should I do if I have side effects not listed in the patient information leaflet? 

To take or not to take?

One of the questions people often ask is: 'Will I have to take this medication for the rest of my life?' Read that sentence again. It’s interesting that they use the term ‘have to’.

The ‘old style’ of patient/doctor interaction was called adherence because patients were expected to stick to the course of treatment their doctor prescribed, without question. In this relationship the doctor ‘knew best’ and the patient ‘did as they were told’. In other words, the patient wasn’t really involved in making decisions about their treatment.

Today, many doctors recognise that people know a lot about their medical condition and want to play a part in any decisions about treating it. For some of us this approach can feel strange; obviously, a doctor has trained for years in medical school to learn about conditions and treatments whereas we, as patients, don’t have that training — so how can we know which treatment is right?

The basis of this new approach is called concordance, or informed decision-making, in which the doctor gives enough information about the options for treatment so that we can decide, in partnership with the doctor, what we want to do.

The keys to concordance are information and choice: knowing the risks and benefits of taking — or not taking — treatments so that together we can discuss the options and together decide what we want to do.

With regard to epilepsy and AEDs, weighing up the risks and benefits of taking or not taking treatments can include the following issues:

  • the possible risks of taking AEDs, including side effects
  • the possible benefits of taking AEDs, including stopping seizures
  • the possible risks of not taking AEDs, including continuing to have seizures (and accidents and injuries because of them)
  • the possible benefits of not taking AEDs, including not having side effects.

How important these risks and benefits are will vary from one person to another and will depend on individual circumstances: the risk of accidents or injuries due to seizures will depend on the type of seizures you have, how often they happen, and how they affect you; the effects of taking AEDs will vary depending on the AED and how your body responds to it. Ultimately the decision is yours, but having the input and support from your doctors can help you to weigh up these points and come to a decision that you are happy with. Taking part in making this choice may also help you to feel more in control, which might be important if your epilepsy makes you feel you have lost some control over your life.

How often should AEDs be taken each day?

How often you take an AED (once, twice or possibly three times each day) depends on its half-life. The half-life of a drug is the length of time it takes for the original amount of the drug to reduce by half. The half-life is used to measure the concentration of the drug in the blood, which is not exactly the same as the dose of drug you take.

When you take a drug it takes time to be absorbed into your blood. When it is in your blood the amount can be measured; this is expressed as the drug’s ‘concentration’ or ‘level’, which relates to how much of the active ingredient of the drug is available to work. Once the drug has done its work it becomes metabolised (broken down) and eliminated (removed) from the body. In simple terms, when the drug reaches its half-life half of it is still in the blood and half of it has been metabolised and eliminated.

Active ingredient - the chemical part of a drug that works on the body to control or treat a condition or disease.

The aim of taking AEDs regularly is to keep the level in the blood as stable as possible. Some AEDs have a half-life of 24 hours so they are taken once a day. Those that have a half-life of 12 hours are taken twice a day, and those with a half-life of eight hours are taken three times a day. The shorter the half-life of the AED the more often it is taken.

What is the average dose range of an AED?

When considering how much medication someone takes we look at two different things. Firstly, we look at their ‘average’ dose — this is a measure of the number of tablets they take and how much active ingredient each tablet contains. For example, for an adult an average dose range for carbamazepine is 600–2000mg per day and for sodium valproate it is 400–2000mg per day. But how helpful is this? These figures are a very general guide but they are not individualised to each person: some people may have their seizures controlled on a dose lower than the bottom dose or higher than the top dose.

The second way of monitoring medication is to look at the amount of an AED in the blood and compare this to a reference range. The reference range is a range of concentrations of an AED within which most people will get a benefit from the drug (that is, it will stop the seizures). Below the reference range the drug is unlikely to work (that is, it will not stop the seizures) whereas above it, toxic effects (that is, reactions because the dose is too high) are likely to happen. Again, this is a general guide and not specific to an individual.

By monitoring drug levels in an individual and seeing what amount of an AED gives them the best seizure control, it is possible to work out an individualised therapeutic range for them. This range will vary from one person to another but will often fall within the general reference range for that AED. 

What is ‘blood-level testing’?

Blood-level testing, or therapeutic drug monitoring (TDM), is a system of monitoring the AED levels in an individual to help manage their epilepsy treatment.

TDM involves taking blood samples to measure the amount of the drug in the blood that is ‘available’ to work (its bioavailability). So this is a good way of measuring how much of the drug your body is getting. This is not the same as looking at how much of the drug you take (that is, your daily dose), although they are connected: the higher the dose you take the more you would expect to be in your blood.

Although we call it ‘blood-level’ testing it is sometimes also referred to as ‘plasma-level’ or ‘serum-level’ testing because the drug is measured in the liquid part of the blood (the plasma or serum) and not the blood cells.

At the moment blood-level testing is not done very often, but there are many situations in which it can help to manage epilepsy treatment. For example, it can be used to see if you are getting the right amount of a drug for you, or if you are taking toxic amounts of drugs, or to monitor how different situations affect your medication (for example, if you are a woman and you become pregnant, or you start taking medication for another condition which might affect your AEDs). 

When you increase a dose, how long does it take to start working?

This varies from one AED to another and depends on the half-life of the drug. Generally, you can see the effect of an increase in five half-lives’ time, so if the half-life of the AED is 24 hours you will see the effect five days (that is, 5 x 24 hours) later. If the half-life is 12 hours you will see the effect two-and-a-half days (that is, 5 x 12 hours) later.    

Side effects

One of the biggest concerns people have when taking medication is the risk of side effects. But what, exactly, are side effects, why do they happen, and will you get them?

What are side effects?

Side effects (also called adverse drug reactions) are the unexpected or unintended effects of a drug. Generally, these are not the effects you want to happen. However, while some side effects (for example, feeling tired or drowsy) may be unwelcome, some can have a beneficial effect (for example, by reducing your appetite if you are overweight, or by lowering your cholesterol).

Why do side effects happen?

When you take a prescribed drug you are obviously taking it for a reason, which is to make something happen such as preventing a condition or treating a symptom. The aim of AEDs is to stop seizures happening. But when you take a drug — any drug — there is also a possibility of side effects.

Medication usually needs to get into your body, and around it, in your bloodstream to reach the area it needs to work on (called the site of action) before it is removed from the body. As the medication makes this journey it can have other, sometimes unwelcome, effects.

Do side effects always happen?

The list of side effects for any drug, including AEDs, can be very long and quite off-putting. But side effects are only possible effects: they do not always happen. Generally, most people take drugs without having serious side effects (that is, side effects that mean they want, or need, to stop taking the drug). Whether these side effects happen or not depends on the individual because different people can respond differently to the same drug.

Patient information leaflets use terms like ‘common' and ‘rare’. But what do these terms actually mean?

These terms are the same for all drugs and refer to the likelihood that a side effect will happen. This likelihood is shown by how many people will get it:

  • Very common means that more than one-in-10 people will get it
  • Common means that one-in-100 to one-in-10 people will get it
  • Occasional means that one-in-1,000 to one-in-100 people will get it
  • Rare means that less than one-in-1,000 people will get it
  • Very rare means that less than one-in-10,000 people will get it
  • Extremely rare means that less than one-in-100,000 people will get it

These terms tell you how many people are likely to get the side effect, but they cannot tell you how likely you are to get it.

Knowing what these terms actually mean may help you to put side effects into perspective. This can be helpful when you are making decisions about taking - or not taking - medication.

Are side effects the same for all AEDs?

No, they vary from one drug to another. When drugs are developed they are tested on many people and the common side effects are listed on the patient information leaflet (PIL) that comes with each drug. If the side effects are very serious the drug may not continue to be developed.

Although the tests are done on many people, once a drug is licensed and prescribed it may be used by thousands of people over long periods of time. Some side effects, particularly those that are extremely rare or ‘idiosyncratic’ (that is, unique to you) may not have come to light during the trials and may not be seen until the drug is being widely used. Also, some side effects only happen if the drug is taken over a very long period of time, possibly over many years or decades, and so will not be seen during the trials.

What should I do if I have a side effect that is not listed in the PIL?

If you have a side effect that is not listed in the drug’s PIL you can report it to the Medicines and Healthcare products Regulatory Agency (MHRA), the government agency which makes sure that drugs work and are safe to use. The MHRA runs the Yellow Card Scheme for reporting side effects from drugs, including prescription drugs, over-the-counter medicines and herbal remedies. If you think you have a side effect from a drug you can complete a Yellow Card by:

  • asking your pharmacist or GP for one
  • calling the Yellow Card hotline on 0203 080 6701 or
  • completing a form online at yellowcard.mhra.gov.uk 

The MHRA looks at all the side effects reported through this scheme and, if necessary, can take action - for example, by making sure that a new side effect is listed in the PIL, or by issuing a warning to particular people who may experience the side effect.