General effects of standard opioids

Central effects:

 

  • reduce the sensation of pain by stimulating opioid receptors (analgesic effect): the descending, pain-relieving system is activated, nociceptive impulses are suppressed at the spinal level, the experience of pain is changed in the limbic system (the pain is no longer perceived as unpleasant and threatening ; Shortness of breath is processed like pain). This also explains why the patient can localize the pain point despite being completely free of pain when given normal doses of opioids (the pain afference is still available (except possibly with high doses of potent opioids that already enter the hypnotic area), you can feel it Pain in many cases too,
  • In therapeutic doses do not normally affect other sensory qualities (see, feel, …) negatively – but the ability to react may be limited!
  • reduce mental activity (sedative effect), but can also increase creativity through the euphoric effect.
  • cause almost no amnesia.
  • eliminate feelings of conflict and fear (tranquilizing effect)
  • often increase the mood (euphoric effect), can have a dysphoric effect in some patients, but this is quite rare.
  • inhibit the respiratory and cough centers (respiratory depressive and antitussive effect)
  • Initially, by stimulating the vomiting center, they often trigger nausea (nausea) and vomiting (vomiting) – but later, by inhibiting the vomiting center, they trigger an antiemetic effect.
  • cause miosis (miotic effect)
  • increase the release of the antidiuretic hormone (antidiuretic effect)
  • can lead to the development of tolerance with repeated use, but usually do not lead to psychological dependency if used correctly and as directed (in pain therapy under medical supervision or according to a strict intake schedule ).

 


peripheral effects:

 

  • are also analgesic via peripheral opioid receptors
  • delay gastric emptying by pyloric contraction
  • reduce motility and increase the tone of the smooth muscles of the gastrointestinal tract (spastic constipation)
  • the sphincters contract in the area of ​​the biliary tract
  • increase the tone of the urinary bladder muscles and the bladder sphincter
  • decrease the tone of blood vessels with the risk of orthostatic reactions
  • The release of histamine can cause reddening of the skin, urticaria and itching, as well as bronchospasm in asthmatics


How the opioids work:

 

Opioids mediate their effect by attaching to receptors (special proteins (protein molecules)) and interacting with them. various effects are triggered by this interaction. Which effects are triggered depends on the binding to the respective receptor types:

 

    • µ-Receptors: The µ-Receptors are most important for the effect of opioids. There are 2 subtypes: µ1 and µ2.

With agonization (connect & interact) the following processes are triggered:

    • µ1: supraspinal / spinal analgesia, euphoria, low dependency potential, miosis, bradycardia (decreased pulse rate), hypothermia, urinary retention.
    • µ2: spinal analgesia, respiratory depression, high potential for dependence, severe constipation.
  • [Delta] receptors: supraspinal / spinal analgesia, respiratory depression, high potential for dependence, low-grade constipation, urinary retention.
  • [kappa] receptors: supraspinal / spinal analgesia, dysphoria, low potential for dependence, miosis, hyperthermia, diuresis.
  • [sigma] receptors: psychomimetic effects. This type of receptor is not a specific opioid receptor, since other substances such as phencyclidine (“PCP”) also bind to it.

So opioids bind to receptors. How strongly they bind depends on the affinity (= attraction). An agonist is a substance that binds to a certain type of receptor.

 

Thus, µ-agonists bind to the µ-receptors. Another decisive factor is intrinsic potency: it indicates how strongly an agonist interacts with the receptor after agonization. An antagonist is a substance that binds to a certain type of receptor, but whose intrinsic potency is so low that it does not interact with the receptor (although experts sometimes disagree as to whether “interaction” is defined by binding to the receptor In this case one would have to speak of “connecting, but without conveying an effect”.

 

Another factor that determines the effectiveness of opioids is the lipophilicity (fat solubility) of an opioid. Opioids with high lipophilicity cross the BBB (Blood-Brain-Barrier) very well (only highly lipophilic substances can cross the BBB and bind well to receptors). Opioids with high lipophilicity usually flood very quickly (lipophilicity, for example, is a factor that is responsible for the fact that diacetylmorphine floods so quickly). The therapeutic potency is thus made up of intrinsic potency, affinity and, in some cases, lipophilicity. For example, fentanyl has only a slightly higher intrinsic potency than morphine. For the fact that this opioid is about 100 times stronger

 

Mixed acting agonists / antagonists are substances that have an agonistic effect on certain receptors, but an antagonistic effect on others, or none at all. Most are highly affine and can therefore competitively displace many agonists. In return, other types of receptors are agonized in order to maintain an – often analgesic – effect, albeit in a weakened form. Typical representatives are nalbuphine, pentazocine and butorphanol. These opioids have an antagonistic effect on µ-receptors and therefore agonistic on [kappa] or [delta] receptors.

 

Furthermore, there are partial agonists that act like antagonists, with the exception that after displacing the competitor with a lower intrinsic potency they interact with the receptor, thus maintaining part of the effect.

 

Antagonists are substances that bind to certain receptors (depending on the antagonist) and thereby displace many other substances from them, but do not mediate their own effect via the receptor.

 


Down-regulation:
If opioids are taken continuously over a longer period of time, a so-called “down-regulation” of the opioid receptors takes place: The opioid receptors change their state so that the effects they mediate are weakened and a higher amount of the opioid has to be taken accordingly in order to achieve roughly the same effects – although a long-lasting opioid turn no longer produces what is possible from a psychological point of view, which is possible with a consumption pattern with sufficient breaks!
However, this down-regulation also plays a major role for pain patients, because they are urgently dependent on your medication and cannot even take a break. Pain patients are disadvantaged in a special way.

 

In addition, the body shuts down the production of endogenous (= endogenous) opioids such as ß-endorphin [µ], dynorphin [delta], and leu-enkephalin [kappa] if the patient is continually supplied with opioids, which increases the withdrawal symptoms even more if the patient is suddenly stopped .

 

Elimination half-life (HWZ):
The half-life indicates how long it takes on average for a substance in the blood or plasma to drop to half of its original value through elimination.

 

Affinity:
Affinity is a unit of measurement used to describe the attraction of a substance to the respective receptor. A higher affinity substance can displace a lower affinity substance of the same type from the receptor.

 

Potency and effectiveness
The therapeutic potency indicates how strongly the respective substance works in contrast to another, that is to say: from a substance with a potency 10 times as high you only need a tenth of the amount for the same effect that you would have needed from the less potent . The reference substance is morphine. The information regarding the potency can, however, vary depending on the source, since the potency cannot be determined 100% exactly). The potency should not be confused with the effectiveness of an opioid, because the effectiveness indicates how strong the opioid is overall: you need less of a higher-potency substance for the same effect, but it may well be
Even if parallels to potency can often be drawn (see morphine <=> fentanyl), there are exceptions and it is not the case with every opioid with a higher potency that a stronger maximum effect can be achieved than with a less potent one can – however, it is sometimes even more difficult to determine the exact effectiveness than the potency, because substances have a different effect on each person (due to metabolism, constitution, number of opioid receptors, receptor population, …), especially when partial agonists come into play!

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