Dose-Response Curves And Treatment Of ADHD, Addictions

A press release that came across my desk last week reminded me of the importance of the concept of “dose-response curves” to the successful medical treatment of a variety of psychiatric illnesses, including ADHD. I thought I’d write a little bit on the subject for those who might benefit.

Dose-response curves are simply graphs of how quickly and intensely different medicines affect people. In these graphs, time is usually graphed on the x-axis (left to right), and the magnitude of the medicine’s effect is graphed on the y-axis (from bottom to top). Medicines that produce a short lived but intense effect are thus represented graphically as a tall and thin “inverted-U” shape (see the yellow line in my crude but good-enough illustration), while drugs that produce a longer lived effect which is smaller in magnitude at any given moment, tend to have a wider, shorter “inverted-U” shape (see the white line). These shapes are the actual “curves” referred to in the phrase “dose-response curve”.

Understanding any given medicine’s dose-response curve helps you to understand what it is likely to be useful for. Some situations, like pain or anxiety management, call for fast acting drugs (with a tall, thin curve) that can quickly head off an acute crisis. More chronic conditions, such as ADHD, call for slower-acting medications (with a wide, flat curve) that deliver their effects evenly over long periods of time.

A drug’s dose-response curve depends on the nature of the drug itself (how the drug molecules are shaped), but also on how efficiently the drug gets into the bloodstream. Certain routes of administration make the drug more available to the body than others. Injecting drugs directly into the bloodstream or inhaling them generally results in a faster, shorter acting and more intense effect, while eating drugs (e.g., taking pills) or injecting them into muscles results in a slower, longer-acting and less intense effect. Modern pharmaceutical companies are also able to create “buffered” versions of drugs in pill form that are “time-released” and thus have a slower onset, and longer but less intense effect than would otherwise be the case.

Over-the-counter pain and allergy drugs provide good examples of this buffering technology. When you have a headache, you want fast pain relief, and are best off with a classic unbuffered pain-killer that will get into the blood fast. When you have a chronic pain situation that you want relief from, however, you’re far better off taking a buffered form of pain-killer that will last longer than unbuffered varieties. The buffering slows down the absorption of the drug into the blood, lessening the immediate impact of the drug, but also insuring that there is a steady supply available to the body for a long duration of time. Even more clever buffering schemes can create a pill with an unbuffered outer layer, and a buffered inner core, providing the best of both worlds for pain relief.

As you might expect, pharmaceutical buffering technology is widely used to alter the dose-response curves of various medications. The medications used to treat ADHD are a good illustration. Originally, it was discovered that ADHD could be effectively treated with regular old amphetamines such as Methylphenidate (Ritalin). Over time, many doctors have switched from unbuffered forms of amphetamine salts (like Ritalin) to buffered forms such as Concerta and Adderall XR, precisely because such buffered forms of the drug make it possible to take fewer pills spaced at longer intervals and still get a good effect, lower the possibility of abuse, and help insure a more even and steady supply of amphetamine to the ADHD-affected brain. When you are treating a chronic attention problem (as opposed to an acute one) you want your drug of choice to have a nice flat and wide dose-response curve so that it is in steady supply all the time (rather than using itself up all at once and then crashing). When you have a short-term attention problem, you’re more likely to want something short acting like an espresso (grin!).

The same does-response curves are at work in addiction medicine as well as in ADHD. Heroin is a short acting drug, particularly given the ways that many heroin addicts tend to use it (e.g., injecting in directly into their veins, snorting it, etc.). The problem with Heroin is that you can’t easily take an addict off of it once they are addicted. The withdrawal pain is too great. The traditional method of handling heroin addiction has thus been to substitute a long-acting (e.g., flat, wide) heroin-like drug known as methadone, for short-acting (tall, thin) heroin itself. Methadone keeps addicts from getting sick, but doesn’t provide the high of heroin. It can be taken once a day, whereas heroin has to be taken multiple times a day. It can be taken in liquid form (like a drink), rather than needing to be injected. Methadone therapy is not perfect, of course, but it is preferable from a health point-of-view to ongoing heroin use.