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Apocodeine — A New Laxative With Exceptional Advantages

Introduction

The more cases of constipation I see the greater is the number in which the cause seems to me to be of a nervous or mental nature. In scores of cases I have seen it come and go according as the patient’s mind was agitated or at rest. This is not so surprising when, as usually happens, the X-ray shows no sign of abnormality in the tract; the remarkable thing is that the same observation can be made in people with definite lesions interfering with colonic action. I know people whose bowels are all matted together after pelvic peritonitis, and yet they have no constipation. Others with similar adhesions, operatively demonstrated, suffer most of the time from an obstinate form of constipation; yet they have had periods of relief lasting weeks together, when the bowel movements were perfectly normal. This occurred generally when they were on a vacation or otherwise mentally at peace. I have seen a man with obstruction so severe that he came near being operated upon, yet his bowels moved perfectly a few days after a tremendous strain let up.

Any thinking physician must wonder also at the ease with which certain cases of constipation can be “cured,” sometimes for months or years. For instance, those of you who have radioscoped many patients can probably call to mind a number of people whose bowels began to move normally the day they were X-rayed. A buzzing sound out of the darkness, a whiff of ozone and a reassuring prognosis must have done it all. Others are cured by a few static sparks, a little high frequency, or some intrarectal electricity. You may not all agree with me that, in this connection, these measures are purely vehicles for psychotherapy; but you will admit that constipation must at times be a psychic disease when one of our osteopathic brethren happens to cure a case by replacing a vertebra that was “two inches out of line.” We know also of Christian Scientists avowedly cured after they have, like the pilgrims of old, hung up their pills and syringes in the temple.

The other day I asked a prominent radiologist if he had ever seen plates indicating an atonic constipation—one in which the colon seemed too weak and flabby to pass on its contents properly. “Not since I have been in business” was his prompt answer. He might have added that the flabby looking colons, full of gas and long sausage shaped masses, are to be found with diarrhoea. After watching the powerful contractions in the small colons of rabbits and cats (the animal is anesthetized and the abdomen opened under salt solution) I am convinced that we greatly underrate the strength of the colonic wall in man. As Keith says, there is enough muscle there to form a mass as large as the biceps of a blacksmith’s arm. It does not seem likely that such a muscle would ever become so weak that it couldn’t pass onward small fecal masses. It might, however, be inhibited, just as the blacksmith’s arm can be paralyzed reflexly by a slight injury to the surfaces in the elbow joint.

Constipation is almost universally associated with the spastic colon which, I believe, works not too little but too much, often pumping the feces backward,, away from the rectum. The trouble might conceivably be due to a spreading to the lower colon of that surcharge of nervous energy which, in such people, often manifests itself in the tenseness of the voluntary muscles. These points have been discussed briefly in a recent paper. It is significant that the best laxative for some of these constipated and overwrought people is a small dose of bromural or adalin (pure hypnotics like veronal) three times a day.

Apocodeine

The Need For Blocking The Nervous Paths To The Digestive Tract

It appears from all this that one of the most needed drugs today is one that will block or lessen the disturbing influences reaching the digestive tract. Before we can block the paths from the nervous system to the bowel we must know where they are. Unfortunately, in spite of much brilliant work by Pavloff, Cannon, Auer, Carlson and others, we still do not know enough of the exact mechanism of these reactions. There are a number of paths by which mental influences can reach the bowel. First may be mentioned the direct connections with the central nervous system. Above, there is the vagus, distributed mainly to the stomach, but reaching in its influence to the lower ileum; below, there are the nerves arising in the sacral plexus and supplying the lower three-fourths of the colon. The latter may have most to do with the production of the spastic colon.

The splanchnics, in connection with the myenteric plexus, carry inhibitory impulses to the tract. Although our experience has emphasized the great importance of this path in animals, it is hard to say how much it has to do with nervous indigestion in man. Our stomachs may seem to be paralyzed after strong emotion but our intestines are not as evidenced by the lively rumbling and sometimes the tendency to diarrhoea. A patient once suggested that he would be alright if life would only furnish him with a certain amount of excitement and worry every day; a little of it constipated him and too much gave him diarrhoea. What he wanted was a happy mean.

Recently Cannon has shown that most of the bodily disturbances seen with fear and anger can be due to an outpouring of epinephrin. As this secretion is oxidized and removed rapidly from the circulation, it does not seem likely that it can play much of a role in the production of such a lasting condition as constipation. I have found in a number of people that intra-muscular injections of adrenalin large enough to produce very annoying circulatory symptoms do not stop the rhythmic sounds of the intestine as heard by a stethoscope. Moreover, even in markedly constipated people, these injections are sometimes followed by one or more large bowel movements.

Circulatory disturbances may also play a large part. Just as we turn pale or blush externally, it is possible that we may do so internally, and such changes in blood supply could markedly influence the activity of the bowel. They may also have much to do with the rapid production of gas, experienced by many people under mental strain. Not only may there be a decreased absorption of the gas normally formed, but it is very probable that there is an excretion of CO2 back into the bowel from the blood.

Some of you will sympathize with a prominent physiologist who said to me, “How I wish sometimes that I could cut my splanchnics and go ahead with my work in peace.” Perhaps some day a drug will be found that will block the nervous impulses, and save us from the after effects of emotion. What a boon it would be if self-conscious girls could perform at recitals, and nervous women could discharge the cook, spank rebellious children, make important decisions or preside at the club without having to pay such a price in indigestion afterwards.

Atropine has been used quite extensively with the view of blocking these nervous influences. Although the experimental evidence is against the probability of medicinal doses having much influence on the bowel, I have seen some obstinate cases of constipation relieved by this drug alone. It can act not only on the vagus endings in the stomach, but on the sacral nerve endings in the colon. Another drug — nicotine — in large doses, paralyzes the ganglia intercalated between the splanchnics and the intestine and stimulates the cells in Auerbachs plexus. The result in animals is increased peristalsis.

Many smokers seem to derive a soothing and laxative effect from their tobacco, but little is known of the actual workings of these smaller doses of nicotinee. To be sure, a cigar often contains enough nicotinee to kill two men, but the smoker absorbs only a part of it. The great toxicity of nicotine, together with its bad effects on heart and arteries, make it too dangerous a drug to prescribe; besides, we can hardly ask the minister’s wife or the president of the women’s foreign missionary society to smoke an extra cigar after meals.

Apocodeine

It is well known that most of the opium derivatives have, besides the sedative effect on the nervous system, a stimulant effect on the bowel. To be sure, some cause constipation, but, as has been shown for morphine, this may be due to too much stimulation, resulting in localized spasms. Codeine acts like a purge on animals. Looking over the literature on this series of drugs, it seemed to me that apocodeine was the most promising one for my purposes. For those who have never heard of it, I will say that it is made from codeine as apomorphine is made from morphine. Just as apomorphine has much less of the sedative action and much more of the emetic action of morphine, apocodeine has lost most of the sedative action and has gained more of the laxative effect of codeine. Besides, it has a pronounced nicotine-like effect, paralyzing the sympathetic nerve cells and blocking inhibitory influences to the bowel. It also improves the tone of the intestinal muscle and by vasodilation, improves its blood supply. This again favors increased peristalsis. Certainly it has the most laxative effect of all the opium derivatives.

Discovered by Matthiesen and Wright in 1870, it was tried out on a few patients in England and in France. Some thought it would be a good expectorant. Others found that it was an excellent hypodermic pugative that could be given, for instance, to the violently insane. Since then, it has remained a laboratory drug, unknown to the profession, but used by physiologists when they wish to paralyze sympathetic ganglia.

Three years ago I obtained some of the drug and soon found that it worked very well with a dosage of from 1/15 to 1/10 of a grain. Ordinarily I have given it with atropine in the following prescription:

Apocod. hydr. gr. 1/15 to 1/10
Atrop. sulf. gr. 1/200 to 1/150
Sacch. lactis gr. ii Ft. caps, tales No. xv
Sig. One b.i.d or t.i.d p.c.

I seldom exceed the smaller dose of atropine as many of the people who need the apocodeine are so sensitive to drugs that even gr. 1/150 makes them uncomfortable.

In suitable cases, such a capsule taken two or three times a day will insure a normal, formed stool without any discomfort. In three years only three people, all of them very sensitive to drugs and to nervous influences, have had to complain of anything more than this mildly laxative effect. They were purged quite actively without griping or other discomfort. When the drug works well there is no need of increasing the dose. A number of people have taken it pretty steadily for three years and still get good results from gr. 1/15 twice a day. Many have remarked upon the ease with which they could taper off and discontinue its use. There is none of that fatigue and emptiness of the bowel which interferes so much with the resumption of normal activity after purgatives.

Although as an opium derivative the drug happens to come under the Harrison act, there is no danger of habit formation as apocodeine gives none of that feeling of well-being and comfort that makes the chance user of morphine wish to repeat his experience. I can state positively that in the three years no patient has shown any tendency to habituation.

Some Suggestions As To The Use Of Apocodeine

It should be emphasized right here that apocodeine is not a sure cure for constipation. We cannot expect it to work well when the trouble is due to binding adhesions, pelvic disease or some form of megacolon. Besides, it has failed in some of the cases that seemed eminently fitted for its use. Possibly larger doses would have worked, but I have never exceeded gr. 1/10 three times a day, for two reasons: one that I often had other cause to suspect that the case was not suitable; the other that, especially since the war began, the drug has been expensive (seventy-five cents a grain, dispensed). A greater experience with the medicine and a better knowledge of the mechanism of constipation may give us an explanation for these failures. In a few cases in which neither liquid petrolatum nor apocodeine worked well enough separately, their combination brought about a most satisfactory action.

The relief of constipation would undoubtedly cure many cases of indigestion, but in order to really help these patients, the emptying of the bowel must be as nearly normal as possible. The thing to be avoided is the production of one big rush which will interfere with absorption and nutrition, and will leave the bowel fatigued, irritable and full of gas. Many of these people will go several days without satisfactory evacuations, and with increasing discomfort and indigestion. They then take a purgative which makes them feel weak and miserable for forty-eight hours or more. During this time they often go to the doctor complaining of “autointoxication^ and flatulence. Then follow two or three days of comfort and the patient wishes he could always feel so well. The bowels fail to move, however, and the same cycle must be gone over again. What seems to be needed is a little extra pressure applied evenly and steadily from above to reinforce the normal gastro-colic reflexes which are most active after meals.

This extra stimulus may be either chemical or mechanical. In turning away from the drastic purgatives of our fathers, it seems to me that we have gone to the opposite extreme, and have developed an unreasoning dread of chemical laxatives. Instead, it has become the fashion to fill up the bowel with indigestible substances such as fresh fruits, salads, green vegetables and bran. Although much good may come out of this in deterring people from taking strong purgatives, and in popularizing the use of paraffin oil and agar, a great deal of harm is also being done by the routine prescription of these rough diets. This indigestible material often does not relieve the constipation, and the patient only suffers the more from flatulence, distress and under-nutrition. This is particularly true of the enteroptotics and asthenics — people who seldom can stand much cellulose in their diet, and who must always be making an effort to keep up their nutrition.

I cannot see why we should not use chemical laxatives in many of these cases, but I think we must follow the practice of some of the older clinicians and give them, not in one large dose, as we so often do, but in small divided doses after meals. The good results obtained with apocodeine may be due partly to its use in this way. There is none of that depression and flatulence experienced after ordinary purgation. In fact, apocodeine has often proven useful in relieving flatulence, dependent as it probably often is upon disturbances in motility. If the current would always set evenly down the tract, there would be ho gas.

There are yet other reasons why a rough diet should not be prescribed for many of the cases in which apocodeine is indicated. I have shown in a recent paper that food goes down the bowel because the duodenum and jejunum pump faster, harder and more continuously than does the ileum. The force with which the bowel propels its contents appears to be graded downwards from the pylorus to the ileocecal valve. In health the tract may be likened to a sewer which has a good “drop” so that anything will go through it on time. (It must be emphasized here that I am comparing the force of gravity acting on the contents of the sewer with the muscular forces of the intestinal wall. Gravity has very little to do with the progress of material through the digestive tract, and I hope that no one will misunderstand me at this point. There are enough surgeons already who tinker at the bowel as if it were a coil of rigid tubing always held in one position.) If the upper end of the sewer be lowered or the lower end be raised, the “drop” will be lessened and there may even be some stretches in which the pipe runs uphill. Such a sewer will pass liquids without much trouble, but it will soon clog if paper, rags or other refuse be thrown in. In a similar way the gradient of forces in the digestive tract may be lessened either by a loss of tone in the stomach and duodenum (as in asthenics and enteroptotics) ; or by increased tone in the lower parts of the tube (as in chronic appendicitis, colitis, etc.). Our experience with the X-ray shows that under these circumstances, the current through the tract is slowed.

A similar slowing can be obtained in dogs by reversing short stretches of small intestine. At autopsy, there is always found a ballooning of the bowel at the upper suture where the normal downward current and the reversed current in the loop conflict. The dogs can be kept in good health if great care be taken that they do not get hold of straw, bone knuckles and other indigestible materials. Apparently, liquids and mushy material can be forced against the current through the reversed loop, but all rough substances are held back so firmly at the upper suture that the animal dies of intestinal obstruction when enough rubbish has accumulated to block the passage.

I believe there are many people who have a similar tendency to reverse peristalsis in some parts of their intestine. I have in mind particularly those cases, all too frequent, in which the appendix has been removed, and yet there are symptoms of chronic appendicitis and the X-ray shows marked stasis in the lower ileum. Perhaps much as the dogs are kept alive, these people can also often be kept comfortable and in health on a smooth, cellulose-poor diet. Besides guarding against the introduction of food that will not go well against the current, we may, as has already been suggested, try to increase the downward pressure by giving divided doses of a mild laxative. Such treatment has often given me excellent results. I have already remarked elsewhere that the relief that the so-called “bilious” get from a dose of calomel may be due to the driving of a normal current down the bowel again, overcoming those reverse waves that have been carrying more than the usual amount of bile back into the stomach, and which have been causing the acid regurgitation, the belching, the “dark-brown” taste and the coated tongue.

The hypodermic use of apocodeine to relieve severe post-operative vomiting deserves further trial. If such vomiting should be, as I believe it often is, a manifestation of reverse peristalsis throughout the tract, it might be stopped by restoring the normal downward waves. In the few cases in which the drug has been tried, the results have been very encouraging; in some so striking that it seemed as if we could say definitely that they were propter hoc and not only post hoc. Shortly after the injection, normal bowel movements took place, and the nausea and vomiting ceased.

Although the theories which have led me to use this drug may prove to be erroneous, and later pfrarmacologic studies may show that in medicinal doses its direct stimulant action on the bowel overshadows its effect on the splanchnics, nevertheless the properties of apocodeine should always commend it to the profession. If others should find it as useful as I have done, it can then be manufactured in larger amounts at a much reduced price.

Walter C. Alvarez, M. D., San Francisco (Sept., 1916, California State Journal Of Medicine)

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