Modern understanding of drug dependence and possible preventative treatment

[rhudson]

Recently much research has been conducted into the physiological mechanisms of opioid addiction and dependence. As of yet, these are still phenomena have not been satisfactorily explained, though there are some simplistic processes (upregulation of the mu-opiate receptors, desensitization of the dopamine pathways, changes is the metabolism of endoenous opiods, etc.) which are known to be involved. What science can say with certainty is that, as already alluded to, the process of becoming habituated to the use of opioids consists of two separate but related processes:

The first is the phenomenon of drug addiction itself. This is a distinct phenomenon from the development of physical opioid dependence. That is to say, one can be addicted without being dependent or vice versa, the latter often being the case for patients who use opaites for legitimate medical purposes. While this may seem paradoxical (most users mistakenly believe that physical dependence and addiction are the same or at least always coexist) drug addiction is nevertheless a physiological condition which results in physical changes in the brain which are completely distinct from those caused by opiate dependence and actually occur in more or less the same manner regardless of what drug the user is addicted to (cocaine, amphetamine, heroin, nicotine, alcohol, etc). As alluded to earlier, probably the most significant of these changes is the desensitization of the dopamine pathways in the brain (dopamine being the most significant "reward" chemical in the brain). This makes it difficult for drug addicts (even those who use drugs that don't cause significant dependence) to experience pleasure and hence encourages habitual drug use. Drug addiction also attenuates neurogenesis (the development of new neurons) in a certain region of one's brain though it is not clear if this is actually linked to the addiction process or merely an undesirable byproduct.

The most significant factor in the development of this kind of physiological addiction is the speed with which the drug takes effect. This observation has been corroborated in scientific research many times and can be explained by noting that in order to become truly addicted the brain needs to form a strong unconscious (reflexive) association of the positive effects of the drug with the act of taking it, similar to the manner in which Pavlov's dogs associated a bell with food. This process is not as facile for drugs which take a long time to "hit," which explains why people who use drugs orally have a much lower incidence of addiction as compared with other users, even when their drug of choice has a very high oral bioavilability (e.g. amphetamine, benzodaizpines, etc.). It also explains why users come to associate the positive effects of the drug with its use reflexively, but the same can rarely be said of the negative effects of taking the drug. Again this is because the first comes immediately after use, whereas the latter is significantly delayed, sometimes by days. These observations result in some simple ramifications for drug users: Smoking or injecting your drugs is the most additive route. Insufflation is modestly less addictive and oral use is by far the least addictive. Again it is worth stressing that this refers to drug addiction itself and not the development of tolerance and dependence, which will not depend on the route of administration provided the bioavailabilities are roughly equal across all ROA's.

The second facet of opioids addiction is unfortunately the development of physical tolerance and dependence to opioids. This process is, despite common belief, caused by several different effects and not yet well understood by science. Undoubtedly one of the most relevant of these is the upregulation of the mu-opiate receptors and most people know this. However it is also known that when one becomes physically dependent, the brain reinforces certain anti-opioid systems (think of them as opioid antibodies) in an attempt to maintain homeostatis. These systems break down opioid drugs when they are administered and hence contribute to tolerance, and also affect endogenous (naturally produced) opiates, contributing to withdrawal symptoms upon the cessation of use.

There are modern drugs which interfere with these anti-opioid systems and their use does indeed dramatically reduce opioid tolerance for the duration of their effect. Sadly these cheap drugs are not readily available to the common addict or the quality of his or her life might be significantly improved by reducing the economical burden of his or her habit. Still, there is another class of medications which does show some promise in the prophylaxis (prevention) of both drug addiction and physical dependence as well as their retroactive treatment. This is the NMDA anatagonist class of medications, e.g. dextrometphoran, ketamine, etc., the former being available to the general population over the counter in the form of cough suppressants. The exact processes by which these attenuate or slow the formation of addiction and dependence are again not completely understood but it is not altogether surprising that they do so as it is well known that NMDA antagonists interfere with the formation of certain kinds of conscious and unconscious brain memory. This also perhaps helps explain why methadone appears to be considerably more addictive than similar orally administered opiates, as methadone is actually an NMDA agonist (the opposite of dextromethorphan) and this probably helps to accelerate the development of dependence and addiction.

At this time there have been many studies (google it) which do indeed demonstrate that doses of NMDA antagonists, specifically dextromethorphan or DXM, help to prevent or slow the development of physical addiction and dependence when administered at the same time or slightly before an addictive drug. Preparations of morphine in conjunction with dextromethorphan have been used clinically for this purpose (Deximorph) and it was found that patients who received the combination used significantly less analgesic than patients who received pure morphine. Remarkably, in addition to helping prevent tolerance and dependence, dextromethorphan also showed some efficacy at actually reversing opiate tolerance and interrupting compulsive addictive behavior, though it is by far more efficient at preventing these than treating them after the fact. Even more amazing is that NMDA antagonists are also able to help prevent or slow the development of dependence on or addiction to other classes of drugs (alcohol, benzodiazipines, etc.) showing that they somehow treat the generalized process of addiction and dependence rather than something specific to opioids.

Still, I strongly advise users not to assume that dextromethorphan or anything else can allow them to use opiates without developing significant physical addiction and dependence. The only true prevention for these things is abstinence and, failing this, infrequent use ideally via the oral route of administration. I've written this short review mostly in the spirit of harm reduction, i.e. those of you who are going to be foolish and tempt fate anyways by using some of the most insidious addictive substances on the planet would do well to at least look into this because SWIM knows from personal experience that NMDA antagonists do help significantly. It is unfortunate that virtually no needle exchanges dispense advise regarding the pharmacological prevention of dependence, because in my humble opinion it is at least as relevant as fresh needles. Again, however, it should be stressed that this is not a "cure" or a get out of addiction free card.

How many times has opium supposedly been denatured of its addictive properties? First morphine was supposedly less addictive. Then heroin. And finally methadone, and we now realize that each substance was progressively more addictive than the last. So be skeptical and be careful.

Yours in science and empathy,
-rhudson

Reputation Comments on this post:

Interesting read, thanks