Probability that PHT Is Effective: Page 2

Evidence

Over the years frustration has caused me to write a few stories about evidence. Put together they are pertinent.

The Placebo

When one is trying to determine if a medicine is effective, the use of a placebo is sensible. If a doctor gives a patient a medication with the expectation of helping a patient, the patient may pick up on that expectation and rationalize that it’s going to help him. Psychologically this might actually help for a while. If a medication is useful, comparing it to a placebo will demonstrate that it was not expectation that made the patient feel better, but the medication itself. A placebo is not needed with a drug that is effective in a clearcut fashion. But initially that might not be known, so starting with a placebo makes sense.

The Negative Placebo

Suppose a patient has a disorder and the doctor gives him a drug with the hope it will help him. Suppose the patient rationalizes that it’s going to help and gets a psychological lift, which wears off after a while. Then the doctor prescribes a second drug to the patient. This time the patient is less optimistic, but a little bit of wishful thinking may be left. This drug doesn’t work and the doctor gives a third one. This time the patient’s wish-thinking device is depleted and he’s not expecting any results. You could say he’s placebo-proof. Let’s say that drug doesn’t work either, and a fourth drug is given. By now, there’s a negative expectation by the patient. He expects the drug not to work because, if the first three didn’t, why should the fourth? There are thousands of studies on PHT in which a variety of drugs had been tried. These are well-controlled studies—the drugs that had been used had the effect of a placebo/ In many, they might have been better than placebo studies—there might have been a negative placebo effect.

Substantial Evidence

In the Federal Food, Drug and Cosmetic Act the FDA is required to have “substantial evidence of effectiveness.” The word substantial, in this context, cannot mean quantity. A study of 10,000 cases could be inconclusive. The evidence from a few cases can be “substantial.” Let’s take one example of how the evidence from just eight cases could be substantial.

For the purpose of this example, we eliminate the possibility of collusion or hoax. Suppose there is a government station in North Carolina that is set up to receive reports of UFOs. On average they receive one call a day. Suppose that one night, between 3:00 and 3:10, eight calls come into this station all reporting similar observations, to wit, that a huge ball of fire was seen slowly floating a few hundred yards overhead, and that suddenly at tremendous speed it went upward, and disappeared from sight. Remembering our premise that collusion is eliminated, what are the probabilities that this really happened?

Since one call a day, at random times, is the average, the first call at 3:00 AM means no more than any other call received by the station. The second call could have been a coincidence. However, because it was within a ten-minute span of the first, this coincidence would occur, on average, once in 144 days (there are 144 ten-minute spans in twenty-four hours). The third call would be one heck of a coincidence, one hundred forty-four times one hundred forty-fourths of a chance. By the eighth call, the odds that there had been an unusual occurrence around 3 AM would be:

1/144 x 1/144 x 1/144 x 1/144 x 1/144 x 1/144 x 1/144, or 1,283,918,464,548,864–to–1.

This is “substantial evidence.”

Now, in the UFO example, we took a premise that we couldn’t take in real life, that collusion or hoax were impossible. The fact is that collusion would seem far more likely than anything else, and the investigators of this matter would spend a lot of time proving or disproving this.

We now come to the real life proposition, the evidence that PHT is a widely versatile medicine. Here the probability of collusion is ruled out by applying common sense to the facts.

Let’s look at the facts before we apply the common sense. Physicians in at least thirty-eight countries have reported PHT to be useful for more than seventy symptoms and disorders, in over 400 medical journals, written in seventeen different languages. This information started appearing in the literature in 1938 and has increased steadily to this date. It’s obvious that the reporting physicians did not know of the work of more than a few of their colleagues. Common sense rules out collusion. Thus, the probability that PHT is a widely versatile drug is of the same order of magnitude as in the UFO example.

The Rules of Evidence

The Rules of Evidence have something in common with the Law of Gravity. Neither can be amended by Congress nor by any branch of Government. The Rules of Evidence are simple. They are the application of common sense to probability.

Let us apply the Rules to the question of whether or not phenytoin is useful for thought, mood and behavior disorders. The material on which this exercise is based is found in the Thought, Mood and Behavior section of The Broad Range of Clinical Use of Phenytoin.

There are many kinds of evidence: Studies with placebo. Studies in which a drug is effective after other drugs have failed. Trials in which a drug is found effective—is withdrawn and symptoms return, reinstituted and symptoms disappear. Clinical studies in which improvements are confirmed by laboratory means. All of these methods have been used in establishing PHT’s effectiveness.

Before arriving at a probability figure for thought, mood and behavior disorders, we will define them, for these purposes, to be problems of excessive anger and related symptoms such as impatience, irritability, impulsivity, hostility and violence; excessive fear and related symptoms such as worry, anxiety, apprehension, depression; also uncontrolled thinking, occupied by negative thoughts and interfering with concentration.

(In four papers PHT was not found “significantly” effective (not necessarily ineffective). For these purposes we allowed the four papers to eliminate ten positive papers that we have assessed the chance of being correct of one in two.) To arrive at an overall probability figure of PHT’s usefulness for thought, mood and behavior, we assess individual probability figures to each of the studies. This is done by estimate, but since most of the authors assess the chance of their own work being correct in excess of 19-to-1 or 99-to-1, the following estimates are conservative:

Probability that PHT is effective

  1 in 2
For each of the first seven reports, 1 in 2
controlled by phenobarbital 1 in 2
and/or bromides, we assess 1 in 2
the probability of being correct of 1 in 2
1 chance in 2. 1 in 2
 

1 in 2

Lindsley and Henry, the first paper in

non-epileptics, in problem children

1 in 2
Brown and Solomon, in delinquent boys 1 in 2

Silverman, in a jail study, 64 prisoners, double-blind crossover, placebo—also other drugs

5 in 6
Bodkin, observations of 102 nervous patients 3 in 4
Goodwin, 20 patients out of 20 nervous patients 2 in 3

Walker and Kirkpatrick, 10 behavioral problem children out of 10, all improved

2 in 3

Zimmerman, 200 children with severe behavior disorders, 70 percent of cases improved

3 in 4

Chao, Sexton and Davis, 296 children, response rapid, often striking

4 in 5
Jonas, in his book, Ictal and Subictal Neurosis 162 patients—over 12 years 3 in 4
Lynk and Amidon, 125 delinquents 3 in 4
Dreyfus, 80 patients 1 in 2
Rossi, behavioral problem children 1 in 2
Turner, 46 of 56 adult neurotic patients 2 in 3
Tec, 15 years’ experience 2 in 3

Boelhouwer, et al., 78 patients, double-blind crossover and placebo

4 in 5
Baldwin, 109 children with behavior problems 3 in 4

Stephens and Shaffer, double-blind, 30 adult outpatients

4 in 5

Goldberg and Kurland, double-blind, 47 retardates, ages 9 to 14

3 in 4
Daniel, aged patients 1 in 2
Bozza, 21 slightly brain damaged retarded children 1 in 2
Alvarez, in a book covering 25 years’ experience 5 in 6

Stephens and Shaffer, second double-blind with 10 patients

3 in 4

Maletsky, episodic dyscontrol, 22 adults—other drugs had failed.

3 in 4

Maletsky and Klotter, episodic dyscontrol, 24 adults, double-blind with placebo

4 in 5
Solomon and Kleeman, 2 cases episodic dyscontrol 1 in 2

Bach-Y-Rita, et al., 130 adults with assaultive and destructive behavior

3 in 4

Kalinowsky and Putnam, 60 psychotic patients, improvement in over half

1 in 2

Freyhan, 40 psychiatric patients, behaviorial problems

2 in 3

Kubanek and Rowell, double-blind, 73 psychotic patients unresponsive to other drugs.

4 in 5
Haward, double-blind, 20 psychotic patients 3 in 4
Haward, three double-blind studies: 3 in 4
concentration—last study, 59 pilots
3 in 4

Smith and Lowrey, 20 adult volunteers, double-blind—cognitive function

3 in 4

Smith and Lowrey, 10 aged adults, double-blind crossover—cognitive function

2 in 3

Stambaugh, hypoglycemia, unresponsive to dietary management—including 6 hour glucose test

3 in 4

Wermuth, et al., double-blind crossover, 19 “binge eaters”

2 in 3
   

Based on the foregoing, the chance that PHT is useful for Thought, Mood and Behavior disorders is:

8,453,784,125,030,400,000-to-1.

PHT’s parameters of safety have been established over a fifty-six–year period, by millions of people taking it daily, for long periods of time. It has properties, which, viewed together, set it apart from other drugs. It acts promptly, calms without sedation, energizes without artificial stimulation, and has beneficial side effects. PHT is not habit-forming.

Conclusion—Having PHT listed in the Physicians’ Desk Reference (PDR) only as an anticonvulsant is a grave injustice to the American public.

The Tuna Fish Story

Once upon a time some people were shipwrecked on a desert island. Their only food was tiny fish they caught daily. To get the most from the fish they constructed a machine that ground them up, including the heads and tails. A year went by and all the food the people ate went through the machine. Five years went by, ten years, and still their food went through the machine.

One day a man caught a tuna. “Now we will all have plenty to eat,” he said.  “Put it through the machine,” the people told him. “It’s too big,” he said, “it won’t fit.” “Then we can’t eat it,” they said. The phenytoin story is too big. It won’t fit in the FDA machine.

Next Section: Observations on PHT

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