By Wise Young, M.D., Ph.D.
This is the first half of Dr. Wise's frequently asked questions on 4-AP.
4-AP (or 4-aminopyridine) is a drug that improves the function of surviving nerve fibers in your spinal cord. Most people with spinal cord injury still have some connections, but many have lost their myelin (an insulating material) and cannot conduct signals well. 4-AP allows these de-myelinated axons to send signals.
The drug, not approved by the Food and Drug Administration but available in compounding pharmacies with a doctor's prescription. A compounding pharmacy makes drugs from ingredients that doctors prescribe. The FDA allows such drugs to be made even though they have not been formally approved. A list of compounding pharmacies can be obtained from Internet by doing a search for "compounding pharmacies."
4-AP works only while it is taken, and the effect goes away within hours after you stop. It is not an innocuous or miraculous drug. Indeed, it is a powerful substance with beneficial effects on spinal cord injury but with complex effects on the body; it also has interactions with many drugs.
An estimated 10,000 people in the United States with multiple sclerosis or spinal cord injury are taking 4-AP, yet more studies are needed to establish its safety and efficacy.
What Are the Effects of 4-AP?
4-AP's effects can range from reduced spasticity and pain, increases in strength and in some, walking. The worst effect is seizures, but the risk is low when dosage is kept lower than 40 milligrams per day.
Several clinical trials have reported beneficial effects of the drug in multiple sclerosis and spinal cord injury. Over 100 people with spinal cord injury have received various formulations of 4-AP in clinical trials. It appears that about a third of people with spinal cord injury have clinically detectable improvement in spasticity or sensory, bladder, bowel or motor function. Most of these people are more than a year after injury.
Since the mid-1980s, at least five small clinical trials have been carried out reporting that 4-AP can increase sensory and motor function in people with MS.
Many studies have documented the effects of 4-AP on motor function in animals and humans after spinal cord injury. In 1993, Hansebout and colleagues reported that 4-AP significantly improved motor and sensory function in eight patients with chronic spinal cord injury. The drug was given intravenously over two hours. Three patients showed no effect, but the remainder had increased motor control and sensibility below the injury site, with reduction of chronic pain and spasticity. The sensory effects outlasted the motor effects by as long as 48 hours after drug infusion.
When can I Expect to Start Feeling the Effects of 4-AP?
The beneficial effects of 4-AP depend on the symptoms and the injury. Sensory improvement should be fairly rapid (within hours), while motor function may take days or weeks to appear. Spasticity changes should be fast, but bowel and bladder improvements frequently occur within days. For some people, 40 milligrams per day may not be sufficient, but if you are not seeing any beneficial effects within four weeks at 40 milligrams per day, I suggest discontinuing the drug until the sustained-release formulation is available.
Does 4-AP Have Side Effects?
At doses of up to 40 milligrams per day, oral immediate release formulations of 4-AP appear to have few side effects. Sustained-release formulations may allow higher doses with fewer side effects. At high doses, 4-AP may cause hyperexcitability, dystonic movements, seizures, cardiac arrythmias, blood pressure changes and other problems that can be treated with anti-convulsants, adrenergic antagonists and parasympathetic drugs.
Almost all cases of seizures have been reported in people with multiple sclerosis; seizures have not been reported in any spinal-injured patient. People with multiple sclerosis have a higher risk of seizures because the disease also affects the brain. People with a history of seizures, epilepsy and head injury should take 4-AP with caution. Other side effects include restlessness, parasthesias and increased frequency of bowel movements. Most of these side effects can be avoided by ramping up the dose of 4-AP over several weeks.
What are the Long-Term Effects of 4-AP?
The long-term effects of 4-AP have not been systematically studied. Some people, particularly in the multiple sclerosis community, have taken the drug for many years. The drug does not have carcinogenic activity in animal studies, and there has been no report of long-term deleterious consequences of the drug on the heart, liver or kidney.
How Does 4-AP Work?
First, it improves conduction in de-myelinated and dysmyelinated (abnormally myelinated) axons. It does so by blocking the fast voltage-sensitive potassium channels in cells, including neurons, muscle and other excitable tissues. This increases both the speed and reliability of conduction, including the amount of neurotransmitter released per action potential. Neurophysiologists have used the drug for decades.
What are the Dangerous Interactions 4-AP has With Other Drugs?
4-AP is not an innocuous drug. It has powerful effects on the nervous system and interacts with many drugs, including alcohol. I recommend not drinking alcohol while taking 4-AP. Click here for my SpineWire story that summarizes many of the reasons why alcohol (ethanol) and other drugs may interact with 4-AP. Ethanol depresses neuronal excitability. 4-AP may antagonize many of the effects of ethanol and vice versa. Depending on the dose, 4-AP may mask alcohol so that you do not feel the effects of alcohol as much. Likewise, alcohol may oppose the effects of 4-AP and reduce its efficacy. Ethanol withdrawal (the hangover stage), moreover, may be associated with irritability and hyperexcitability of the brain and spinal cord, which may increase the risk of 4-AP-induced seizures. Ethanol may also change the balance of excitability and inhibitory systems that have accommodated to 4-AP.
Many other drugs may interact with 4-AP, as it antagonizes most drugs that depress the neural activity. These include tetrahydrocannabinol, anesthetic agents, neuromuscular blockers, baclofen-induced anti-nociception, and sympathetic and parasympathetic drugs that are used to treat bladder plasticity, intestinal motility, blood pressure and other conditions. Unfortunately, most of these effects of 4-AP and interactions with drugs have not been systematically studied.
How do I Get 4-AP?
The drug has not yet been approved by the FDA but nonetheless can be prescribed by doctors. It is dispensed by compounding pharmacies. Note that the FDA is attempting to regulate the compounding pharmacies, and 4-AP may be one of the first drugs that the FDA may withdraw from the compounding formulary because of concerns of variable formulation.
Because many doctors have not heard of 4-aminopyridine or do not know the drug well, they are often reluctant to prescribe it. It is important that you find a doctor who is willing to read some of the literature on the drug, learn about its use and limitations, and prescribe it for you. 4-AP must be taken under a doctor's supervision.
I do not personally know doctors who are prescribing the drug in each region of the country. I am sure, however, that there are people on the interactive SpineWire forum who know doctors in each region who are experienced with 4-AP treatment.
I have written several articles on the subject for SpineWire, and there are many postings on the subject. Click here for the most recent article and do a search for "4-AP" to find the rest. They should provide all the information that you are asking for.
How Much does 4-AP Cost?
The cost of 4-AP will depend on the amount of the drug that is taken. The prices range from $50 to $150 per month for the immediate-release formulation.
Do I Need to Take 4-AP Under a Doctor's Supervision?
Many people are now experimenting with 4-AP without adequate medical supervision. More important, the information is not sufficient for many doctors to supervise the use of 4-AP. The main reason why doctors should and must be involved is that they can take care of complications if they should arise.
Is 4-AP For Me?
The drug does not work for everybody. In clinical trials to date, the drug appears to improve the function of 30 to 40 percent of people with spinal cord injury. People with some preserved function below the injury tend to benefit more.
How Much Should I Take?
The effective dose of 4-AP varies substantially from person to person, with the recommended dose at 40 milligrams per day in divided doses for safety reasons. Many factors influence drug effect. The compounded drug is variable in potency and because it has a short half-life, it tends to have lower potency, especially when it is kept on the shelves for a long time. In addition, different people absorb different amounts of the drug when it is ingested, and its penetration into the nervous system is probably quite variable. The drugs that people are taking for spasticity and pain also affect 4-AP. Hence, the dose of the drug therefore must be carefully and individually titrated.
Some people have gone up to 60 milligrams per day, but this should be done under medical supervision. Some may require higher doses but please don't keep pushing the dose higher if you get any significant side effect of the drug. Others may show beneficial effects at 20 milligrams per day.
Much needs to be done to define the optimal 4-AP dosing approach in humans. One of the reasons 4-AP is still going through clinical trials is to find out more about the optimal dose, including whether the dose should be related to body weight and if it needs to be different for men and women.
With the immediate release formulation, 10 milligrams taken three to four times a day is the currently recommended approach. Some people are taking more, such as 15 milligrams four times per day. I would not recommend higher doses until more is known. Finally, don't expect miracles from this drug.
What are the Chances that 4-AP Will Have any Effect on Me?
About a third of people with spinal cord injury show neurologically measurable beneficial effects from 4-AP. Although 4-AP is believed to have more effects on people with "incomplete" spinal cord injury, I think that it may have some effects on people with so-called "complete" spinal cord injury for the following reasons.
First, most people have some preserved motor and sensory function below the injury site even though they have complete spinal cord injury. 4-AP should improve such function.
Second, de-myelination may be the major reason why some people with spinal cord injury have functional loss. Many people with multiple sclerosis are paralyzed and have sensory loss from de-myelination.
Third, 4-AP does more than improve the function of de-myelinated axons. It increases the amount of neurotransmitters released by axonal activity.
Fourth, it should increase reflexes in the spinal cord. Despite this,
4-AP has beneficial effects on spasticity.
What Different Formulations of 4-AP are Available, and What Effects Does Each Have?
4-AP is available in two kinds of formulations: immediate release and timed release.
Most compounding pharmacies provide the immediate-release version, which is just the chemical 4-aminopyridine mixed with some filler material in gel caps. 4-AP reacts with many different kinds of fillers, leading to a shortened shelf life and lower potency.
For example, some formulations of 4-AP may lose as much as 10 to 20 percent of its potency per week. It is likely that many of the 4-AP pills out there do not have the potency that they are said to have.
In addition, the immediate-release formulation results in a peak plasma dose within 30 minutes. Plasma levels fall by about a half within three to four hours. Immediate-release formulations therefore tend to produce higher peak levels and greater variations in plasma levels. Peak levels determine side effects, one of the reasons why a sustained or timed-release formulation of the drug is desirable. In fact, with sustained-release formulations where the drug is released slowly over time, it may be possible to give two times higher doses of 4-AP with fewer side effects.
A company called Acorda Therapeutics (Note: I am a founder and a member of the scientific advisory board and board of directors of Acorda Therapeutics. Please take this into consideration when you read what I say about Acorda Therapeutics and its drugs.) is developing a time-release, or sustained-release, version of the drug.
This formulation has not yet been approved by the FDA and therefore is not available. That version of the drug is currently undergoing phase 2 clinical trials. Click here for more information.
It may take two years, depending on the current trial, for the FDA to approve Acorda's drug. And once these trials are completed, there will be a lot of data associated with the drug to enable researchers to determine how to reduce side effects while improving efficacy.
In the meantime, the FDA may ask Acorda Therapeutics to do a limited, open-label clinical trial, in which Acorda would provide the drug at cost to people now getting compounded 4-AP.
The FDA has not, to my knowledge, decided whether it will withdraw the compounded version and replace it with the time-release version. It is difficult to predict because there is no precedent for this situation.
(This story was posted on 16 May 2000)