Opioids

Textbooks refer to agents like codeine and hydrocordone as mu-receptor agonists. When the opiate binds to the mu receptor, a variety of things happen; Ca++ entry is blocked, potassium channels are opened up. Its mediated through a cyclic AMP coupled to an adenylate cyclase. But the main thing that occurs is that there appears to be a decreased release of neurotransmitters; these ionic intracellular events alter that neuron so that the release of neurotransmitters is blunted or blocked. The net effect is that the neuron loses its excitability. So here we have an agonist, the drug that is producing blockade of pain is acting as an agonist on its receptor. The net effect of the agonist is to decrease the firing of that neuron in the pain pathway, which is essential.



The so-called penta-peptides such as the endorphins and enkephalins also bind to the mu receptor, they are the ligands. The kappa receptor and delta receptor are not really understood as far as the patho-physiology of pain, although some drugs do bind more selectively to the kappa receptor. But the medicinal agents used to manage moderate to severe pain are mu-receptor agonists. Clearly at that same receptor, if we wanted to block it we could give a drug like naloxone, which is a mu-antagonist and would block it without producing any analgesic effect; this is a pure competitive receptor antagonist.



Morpine is a natural opium derivative and is used as a prototype of the entire class. The important part is that it has an inhibitory effect on pain. It causes drowsiness, decreased mental alertness and sedation. So it’s not an ideal agent. This also applies to the codeine and hydrocodone; we cannot separate the analgesia properties from the drowsiness and decreased mental alertness. What is the risk of repressing respiratory centers? This probably does not occur anywhere near therapeutic dosages. In the acute setting in oral surgery, if you’re injecting I.V. Demerol and the dose is not correct you’ll get respiratory arrest. The effect on the heart is minimal. The other effects you see listed here can be translated into therapeutic effects for other things like diarrhea.


The stimulatory effects are paradoxical. Most importantly, if a pt is abusing an opiate drug, he/she will have pinpoint pupils (miosis). Paradoxically, some pts will show euphoria. This is especially true for the parenteral opiates, it may be a desirable effect; if you get euphoria coupled with analgesia the pt feels a lot better. This leads to the issue if you have drug seeking behavior. Sometimes the pt will seek the use of a narcotic for its euphoric effects. Other effects on the bladder, for example, are important because the pt may have difficulty urinating.



Codeine is one of the mainstays in dentistry, although not alone… you’ll always write a prescription in combination with acetominophen or other compounds. Codeine is really a weak analgesic, it produces constipation, has a weak effect at producing respiratory depression, and has a variable effect at producing addiction liability. When you’re using codeine, even for a fairly long regimen, you’re not likely to get dependence, but you’re also not getting a profound analgesic effect like you would with Demerol or a different drug. So some of these drugs have an advantage over codeine, but there is a linkage between usage and side effects such as constipation. By the way, if a pt says they’re “allergic to codeine” it usually means that they don’t like the side effects, such as constipation. Allergies to the opiates are very rare as compared to the NSAIDs.


Oxycodone is presently undergoing scrutiny by the DEA because there is a popular sustained release oxycodone product called oxycontin, and is widely prescribed in medicine. Oxycontin is now a very popular street drug, so is under scrutiny by the Feds. Street value may be above that of heroin.


Propoxyphene has variable effect on constipation, doesn’t repress respiration, and has little abuse liability. It was widely promoted to dentists, and is called Darvon. Propoxyphene is closely related to methadone. So chemists were looking for the narcotic benefits of methadone without the side effects. What they ended up with was a weak analgesic. Propxyphene alone will not manage pain any better than a placebo. However, if you prescribe Darvocet (Darvon plus Acetominophen… whenever you see –cet at the end of a drug it means that it includes acetominophen) it is effective.



Half-life is an important determinant of duration of action. Generally there is a good linkage between the biologic half-life and its pharmacologic therapeutic duration of action. Codeine can be given orally, its therapeutic duration of action is only 4-6 hours. Its got a half-life of three hours. So if you prescribe it, its usually a t.i.d. or q.i.d. drug (taken 3-4 times a day). Methadone, which is always used as maintenance therapy in a former heroin addict, where they don’t want the pt injecting I.V. heroin but the habit is maintained by taking oral methadone. The half-life is 23 hours, so its usually taken once a day. Naloxone and Naltrexone are both opiate receptor antagonists, competitive receptor antagonists. Naloxone must be given by injection- in your emergency kit in your dental office you will have a carp of this. It has a very short half-life so you must use more than one dose. Naltroxone however is orally effective and has a half-life of 24 hours.

Category: Pharmacology Notes