(ĐTĐ) - An opioid is a chemical that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.

 

The analgesic (painkiller) effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance. The side effects of opioids include sedation, respiratory depression, and constipation. Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect. Physical dependence can develop with ongoing administration of opioids, leading to a withdrawal syndrome with abrupt discontinuation. Opioids can produce a feeling of euphoria, motivating some to recreationally use opioids.

Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to only the natural alkaloids found in the resin of the opium poppy (Papaver somniferum).

Classification

There are a number of broad classes of opioids:

  • Natural opiates: alkaloids contained in the resin of the opium poppy, primarily morphine, codeine, and thebaine, but not papaverine and noscapine which have a different mechanism of action; The following could be considered natural opiates: The leaves from Mitragyna speciosa (also known as Kratom) contain a few naturally-occurring opioids, active via Mu- and Delta receptors. Salvinorin A, found naturally in the Salvia divinorum plant, is a kappa-opioid receptor agonist.
  • Semi-synthetic opioids: created from the natural opiates, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, diacetylmorphine (heroin), nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine and buprenorphine;
  • Fully synthetic opioids: such as fentanyl, pethidine, methadone, tramadol and dextropropoxyphene;
  • Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.
  • There are also drugs such as tramadol and tapentadol that are chemically not of the opioid class, but do have agonist actions at the µ-opioid receptor. Although their exact mechanism of action is not fully understood, they both have a dual mode of action, the second mode of action appearing to be on the noradrenergic and serotonergic systems. This second mechanism of action was discovered during testing in where the drugs showed signs of analgesia even when naloxone, an opioid antagonist, was administered.

Some minor opium alkaloids and various substances with opioid action are also found elsewhere , including molecules present in Kratom, Corydalis, and Salvia divinorum plants and some species of poppy aside from Papaver somniferum and there are strains which produce copious amounts of thebaine, an important raw material for making many semi-synthetic and synthetic opioids. Of all of the more than 120 poppy species, only two produce morphine.

Amongst analgesics are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain—a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine and/or some other antihistamines. Tricyclic antidepressants have painkilling effect as well, but they're thought to do so by indirectly activating the endogenous opioid system. The remainder of analgesics work peripherally (i.e., not on the brain or spinal cord). Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns. Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotoninergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity. It has recently been discovered that most or all of the therapeutic efficacy of paracetamol is due to a metabolite ( AM404, making paracetamol a prodrug) which enhances the release of serotonin and also interacts as with the cannabinoid receptors by inhibiting the uptake of anandamide.

It has been discovered in 1953, that the human body, as well as those of some other animals, naturally produce minute amounts of morphine and codeine and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to the well known endogenous opioid peptides. Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively.

Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own.

Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid analgesic effect at all despite their structural similarity to other opioids; instead they are potent NMDA antagonists and sigma 1 and 2-receptor agonists and are used in many over-the-counter cough suppressants.

Salvinorin A is a unique selective, powerful ?-opioid receptor agonist. It is not properly considered an opioid nevertheless, because 1) chemically, it is not an alkaloid; and 2) it has no typical opioid properties: absolutely no anxiolytic or cough-suppressant effects. It is instead a powerful hallucinogen.

Pharmacology

Opioids bind to specific opioid receptors in the central nervous system and other tissues. There are three principal classes of opioid receptors, µ, ?, d (mu, kappa, and delta), although up to seventeen have been reported, and include the e, ?, ?, and ? (Epsilon, Iota, Lambda and Zeta) receptors. Conversely, s (Sigma) receptors are no longer considered to be opioid receptors because: their activation is not reversed by the opioid inverse-agonist naloxone, they do not exhibit high-affinity binding for classical opioids, and they are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for laevo-rotatory isomers. In addition, there are three subtypes of µ-receptor: µ1 and µ2, and the newly discovered µ3. Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to µ-opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAergic neurotransmission.The pharmacodynamic response to an opioid depends upon the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the µ1 receptor; respiratory depression and physical dependence by the µ2 receptor; and sedation and spinal analgesia by the ? receptor. Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as µ1 and µ2 for example) providing even more measurably specific responses. Unique to each opioid is its distinct binding affinity to the various classes of opioid receptors (e.g. the µ, ?, and d opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits high-affinity binding to the µ-opioid receptor, while ketazocine exhibits high affinity to ? receptors. It is this combinatorial mechanism that allows for such a wide class of opioids and molecular designs to exist, each with its own unique effect profile. Their individual molecular structure is also responsible for their different duration of action, whereby metabolic breakdown (such as N-dealkylation) is responsible for opioid metabolism.

Drug Relative Potency Nonionized Fraction Protein Binding Lipid Solubility
Morphine 1 ++ ++ +
Meperidine 0.1 + +++ ++
Hydromorphone 10
Alfentanil 10-25 ++++ ++++ +++
Fentanyl 75-125 + +++ ++++
Remifentanil 250 +++ +++ ++
Sufentanil 500-1000 ++ ++++ ++++
Etorphine 1000-3000
+ very low, ++ low, +++ high, ++++ very high

See also

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