Opioid

Opioids (from Ancient Greek ὄπιον ópion [ˈɔpiɔn], German 'poppy juice, opium' and Middle Greek εἶδος eidos [ˈiðɔs], German 'shape', together 'resembling opium') is a collective term for a chemically heterogeneous (inconsistent) group of natural and synthetic as well as semisynthetic substances that exhibit morphine-like properties and are active at opioid receptors. The term opiate, on the other hand, stands only for the substances with this effect that occur naturally in opium, which are chemically alkaloids and are obtained from the opium poppy (Papaver somniferum).

A distinction is made between endogenous opioids, which play a role in pain suppression as part of the stress response, and therapeutically or abusively administered (exogenous) opioids.

The spectrum of action of opioids is complex and very diverse. The most important effect is a strong pain relief (analgesia) with low cardiovascular side effects, which makes opioids indispensable and widely used drugs in pain therapy, anesthesia and other areas of application. Among the many other effects, sedation and the euphoric effect should be mentioned; the most important side effects are vigilance reduction and respiratory depression, especially in overdose, as well as constipation and the development of dependence.

Natural opioids and opiates

Endogenous opioids

The endogenous opioids are endogenous peptides that are secreted as part of the stress response and serve to acutely suppress pain and hunger, but also interact with the sex hormones and are involved in the development of euphoria and the regulation of gastrointestinal functions, respiration, thermoregulation and immune responses. They are released during injury, but also by emotional stimuli and UV light. Their secretion is also altered in obesity, mental disorders, and also opioid administration. A precise understanding of these complex functions and regulatory processes is still lacking.

The endogenous opioids can be divided into three groups. The precursor peptide of the endorphins is the pro-opiomelanocortins (POMC), from which the endorphins α, β and γ are derived. Of the group of enkephalins, the variants are met-enkephalin, leu-enkephalin, and met-arg-phe-enkephalin, which differ in their N-terminal amino acids. The dynorphins are divided into dynorphin A and B and α- and β-neoendorphin.

In mammals, the endogenous opioids (neuropeptides) are produced in the hypothalamus and pituitary gland and differ in distribution and receptor affinity.

Opiates/opium alkaloids

Opiates are natural substances found in opium. The opium obtained from opium poppy (Papaver somniferum) consists of about 25 % of these alkaloids. The most important substances are morphine (10 %), codeine (0.5 %) and thebaine (0.2 %) from the phenantrane group, as well as the isoquinoline derivative noscapine (6 %), papaverine (0.8 to 1 %) and narceine (0.3 %), which are benzylisoquinolines.

Kratom alkaloids

The leaves of the kratom tree (Mitragyna speciosa) contain the opioid alkaloids mitragynine and 7-hydroxymitragynine.

In lower concentrations these alkaloids are also found in other members of the genus Mitragyna.

Akuamma

The seeds of the African Akuamma tree (Picralima nitida) contain the opioid Akuammin, which is structurally similar to the kratom alkaloids.

Effects

Analgesia

Pain relief is the desired effect when opioid analgesics are used. It is mediated mainly via the μ-receptors, especially μ1, but also via κ.

The potency of the individual substances is referred to as analgesic potency, which is given relative to morphine, whose value is set as 1. The higher the analgesic potency, the lower the dose of a pharmaceutical required to produce comparable analgesia. Pharmacodynamically, potency can be expressed in terms of the effective dose ED50.
The maximum achievable analgesia states that with low-potency opioids, in contrast to high-potency substances, the analgesic effect only increases up to a certain increase in dose, but a further increase then does not produce greater analgesia, but an increase in adverse effects. Pharmacodynamically, the maximum achievable analgesia is a measure of the intrinsic activity of a drug. These values are also determined to a large extent genetically.

Opioid analgesics are part of the WHO staging system for the treatment of chronic pain. This provides for the administration of a low-potency opioid in addition to a non-opioid analgesic in the second stage (first stage) and the use of a highly potent substance in the third stage. In addition, opioid analgesics are used therapeutically in many other areas of medicine, including induction of anesthesia and many acute pain-associated conditions and injuries in emergency and critical care that cannot be managed with non-opioid analgesics. Opioids are often packaged in safety blisters rather than regular push-through blisters. This is to prevent accidental ingestion or as a child safety device.

For the long-term therapy of chronic, non-tumour-related pain, opioids are only effective to a limited extent and are only indicated if the actual pain relief (ascertainable by means of the visual analogue scale), the possible side effects even of the lower-potency pain medications and the additional use of additional pain-relieving measures are taken into account (see also pain therapy).

Respiratory depression

Respiratory depression is a serious side effect and the major mortality factor of conventional opioids. It is directly proportional to the analgesic potency of the opioid. Respiratory rate and volume decrease.

μ1-Opioid receptors (MOR1) are widely distributed in the network of those brain areas that serve to control respiration and motor control of the upper respiratory tract, including the function of swallowing. These areas are sensitive to opioid-induced respiratory depression (OIAD). The most significant brain structure for OIAD is the pre-Bötzinger complex located in the brainstem, which is an inspiratory rhythm generator that determines the force and timing of inspiration and the expression of active expiration. Approximately 70-140 glutamatergic neurons within this complex are responsible for the most essential features of OIAD. The parabrachial nucleus (Kölliker-Fuse complex) plays an additive role in OIAD. G-protein activation of MOR1 in this complex and in other brain regions leads to hyperpolarization of affected neurons by coupling to the postsynaptic effector GIRK and thus to inhibition of their excitability by transmitters such as glutamate. Experimentally, genetic knockout of MOR1 in the two aforementioned areas drastically reduced the expression of respiratory depression, even to extreme doses of Fentanyl, and in particular maintained a natural respiratory rhythm pattern. Tolerance to respiratory depression develops more slowly and weakly than to analgesic effects. The parabrachial nucleus is not an object of long-term opioidergic tolerance development. Several concepts are being pursued for the development of side-effect-reducing opioids, of which functional selectivity has made it to market. However, the assumption that a preferential G protein biased agonism at MOR1 is mechanistically associated with the reduction of respiratory depression is not proven.

Indirectly, respiratory depression also results in an increase in intracranial pressure due to vasodilation. A mild form of the disease is hypoventilation (reduced breathing) with only a few breaths per minute. Typical of this is that the affected person complies with a request to breathe actively (so-called command breathing). At higher doses, breathing comes to a halt. Respiratory depression can be reversed by using the antagonist naloxone. With pain-oriented administration of opioids, no clinically relevant respiratory depression usually occurs, as long as the opioid administration is oriented to the extent of pain reduction and an overdose is avoided. Pain is an opioid antagonist with regard to respiratory depression.

Respiratory distress therapy in palliative care

Opioids can be administered in the treatment of dyspnoea resulting from advanced diseases such as COPD, at least in the terminal stage of the disease, provided that the aim is to relieve symptoms and not to accelerate the dying process. In addition, opioids are also useful in relieving respiratory distress in COPD patients outside of a terminal stage that cannot be treated in any other way. For example, morphine can be used by intravenous or subcutaneous injection; another option is the administration of nasally administered fentanyl.

Psychotropic effects

Sedation is caused by κ-receptors. It is partly desirable (anaesthesia, analgesia), partly undesirable (long-term pain therapy). Even at high doses of opioid analgesics, however, there is no certain elimination of consciousness, so that opioids are generally combined with inhaled or intravenous hypnotics in the context of general anaesthesia (narcosis) in order to avoid wakefulness phenomena (awareness).

Opioids continue to have anxiety-relieving and euphoric effects, which are considered responsible for the psychological component of opioid dependence. In addition, however, dysphoria and hallucinations can also be caused via σ-receptors, which plays a role in the mixed agonist-antagonists.

Nausea and vomiting

Stimulation of dopamine-dependent receptors in the trigger zone of the area postrema at the base of the IV ventricle stimulates the vomiting centre in the formatio reticularis, thus inducing nausea and vomiting (emetic effect). In the context of anaesthesia, this can occur postoperatively (postoperative nausea and vomiting, PONV). This effect can be alleviated by antiemetics. In higher doses, however, opioids dampen the vomiting centre, so that an antiemetic (nausea-reducing) effect then results.

Apomorphine, which is related to morphine, has a pronounced effect on the dopamine-2 receptors of the area postrema. For this reason, it can be used to induce vomiting in some poisonings, but is no longer licensed for this indication (in humans) in Germany.

Constipation

Spastic constipations of the intestine (constipation) are caused by stimulation of μ-receptors of the myenteric plexus of the intestinal wall with smooth muscle constriction. They are the most relevant side effect in long-term pain treatment and are subject to little tolerance development. Prophylactically, lactulose can be administered.

The obstipating effect is desired in the use of the morphine derivative loperamide, which is used as an antidiarrheal for the symptomatic treatment of severe diarrhea.

Other effects

Furthermore, there is a constriction of the sphincter oddi, which increases the pressure in the bile duct system, which can lead to colicky pain. In addition, a secretion stasis of the pancreas and subsequently a pancreatitis is possible.

By the same mechanism occur voiding disorders of the urinary bladder with urinary retention.

The attenuation of the cough centre results in an antitussive (cough-relieving) effect. (Selectively, this is also described for the non-morphine-like opium alkaloid and isoquinoline derivative noscapine). This effect is used with the antitussive codeine and derivatives. However, rapid injection of highly potent synthetic opioids such as fentanyl during induction of anaesthesia may initially produce a coughing stimulus.

Opioids cause central sympathicolysis (reduction in the activity of the sympathetic nervous system). This, together with an increase in the activity of the vagus nerve and direct vasodilation, leads to a decrease in heart rate (bradycardia), blood pressure (hypotension) and cardiac output. In usual therapeutic dosage, the impairment of cardiovascular function is only slight. However, in cases of impaired circulatory regulation such as volume deficiency (shock), anaesthesia as well as under antihypertensives (blood pressure lowering drugs), a crisis-like drop in blood pressure is possible. In the treatment of acute myocardial infarction (heart attack) and acute left heart failure (cardiac insufficiency), the circulatory depressant effect is used to relieve cardiac function and reduce myocardial oxygen consumption.

Miosis (constriction of the pupil) is caused by stimulation of the parasympathetic Edinger-Westphal nucleus in the midbrain and the resulting contraction of the sphincter pupillae muscle. In the presence of opioid intoxication with oxygen deficiency (see below), mydriasis (dilation of the pupil) may also occur.

Bolus injections of highly potent opioids during anaesthesia can induce muscle rigidity, mainly affecting the thorax and abdomen (wooden chest), making mask ventilation difficult during induction of anaesthesia. The mechanism is unclear. This adverse effect is particularly pronounced with alfentanil and remifentanil. In the context of modern combination anaesthesia, this phenomenon plays only a minor role due to the muscle relaxants used.

Opioids can also induce pruritus. This occurs due to an overlap of pain- and itch-associated peripheral mediators and receptors.

Opioids are not triggers for malignant hyperthermia and have no toxic (poisonous) effect on the liver and kidney. They release histamine.