Tramadol is a vasodilator



  Opioid (from Gr. ὄπιον [ˈɔpiɔn] and εἶδος, [ˈidɔs], "similar to opium") is a collective term for a chemically heterogeneous (inconsistent) group of natural and synthetic substances that have morphine-like properties and are effective at opioid receptors. The term opiate, on the other hand, only describes the substances naturally occurring in opium, a drug obtained from the milk of the opium poppy, with this effect, which are chemically alkaloids.

A distinction is made between the body's own (endogenous) opioids, which play a role in suppressing pain in the context of the stress response, from therapeutically or improperly administered (exogenous) opioids.

The spectrum of activity of opioids is complex and very diverse. The most important effect is strong pain relief (analgesia), which makes opioids indispensable and widely used drugs in pain therapy, anesthesia and other areas of application. Among the many other effects, respiratory depression with short-term use as well as with long-term therapy constipation (constipation) and the development of dependence are the most important side effects.

In Germany and Switzerland they are therefore subject to the Narcotics Act and in Austria to the Narcotics Act.

Mode of action

The group of opioids is a chemically heterogeneous subgroup of analgesics:

They develop their properties by interacting with special receptors (molecular binding sites) on the surface of nerve cells and other types of cells throughout the body called opioid receptors.

The body's own ligands of the opioid receptors are endogenous peptides (enkephalins and endorphins) that are important in the stress response. The opioid receptors are most common in the brain at the floor of the 4th ventricle (cerebral ventricle), in other brain regions, and in the spinal cord. They can also be found in the periphery, including in the intestine.

An example of an opioid that acts exclusively outside the central nervous system is loperamide, a remedy for diarrhea. It usually does not cross the blood-brain barrier (Pons passage) and therefore cannot work in the central nervous system, but only peripherally in the body. It causes the intestinal motor skills to slow down.

In contrast to non-opioid analgesics, opioids develop their analgesic effect primarily in the central nervous system (CNS).

Receptors

A distinction is made between several different types and subtypes of opioid receptors

Type localization effect
μ1 and μ2 brain Analgesia, respiratory depression only μ2!, Cardiovascular effects
μ2 spinal Analgesia, gastrointestinal effects, euphoria, addiction
μ peripheral Analgesia, gastrointestinal effects, itching
κ (kappa) Brain, spinal Analgesia, sedation, dysphoria
δ (delta) Brain, spinal, peripheral Gastrointestinal effects, modulating effects
previously unidentified receptor Miosis, nausea, vomiting

Agonists and antagonists

The opioids bind to the various receptors to different degrees depending on the group, whereby they can have an activating (agonist) or inhibitory (antagonist) effect, creating a complex pattern of action (multiple receptor theory). There are four groups:

Pure agonists

Pure agonists have an exclusively activating effect with a high affinity (binding strength) and high intrinsic activity (potency) for μ-receptors and a lower affinity for κ-receptors. It has not yet been possible to produce substances that can be used selectively on the μ1Receptor analgesia without the μ2-mediated respiratory depression. The effect of these substances can be completely neutralized by antagonists. The combination of pure agonists with mixed agonist-antagonists is obsolete, since it weakens the effect. Most of the opioid drugs used in medicine are pure agonists; examples are tramadol, pethidine, codeine, piritramide, morphine, levomethadone and the strong analgesics fentanyl, alfentanil, remifentanil and sufentanil.

Mixed agonist-antagonists

Mixed agonist-antagonists offer a complex pattern of action. At μ-receptors they are ligands with a high affinity, but very weak intrinsic activity, so that an antagonistic effect results. In contrast, affinity and intrinsic activity are high at κ receptors (κ agonists). They also have an agonistic effect on σ-receptors. In contrast to the pure agonists, there is no further increase in the effects with increasing dosage (ceiling effect). Substances in this group are pentazocine, butorphanol and nalbuphine, although the pharmacological importance has declined sharply due to the tendency to dysphoria, hallucinations, disorientation and circulatory stimulation (σ-agonists).

Partial antagonists

The only pharmacologically relevant substance is buprenorphine, which has a very high affinity at μ-receptors with a lower activity than morphine. It is also subject to a ceiling effect, although it cannot be ended by the use of antagonists. Buprenorphine has the longest duration of action of any opioid.

Pure antagonists

Pure antagonists act as competitive antagonists on all receptor types, but with different affinity. They are mostly used to neutralize (antagonize) agonistic opioid effects (termination of anesthesia, antidote in case of intoxication, weaning treatment). The active ingredients used are naloxone and naltrexone.

Effects

analgesia

Pain control is the desired effect when using opioid analgesics. It is mainly via the μ receptors, especially μ1, but also mediated via κ.

The potency of the individual substances is called analgesic potency which is expressed relative to morphine, the value of which is fixed as 1. The higher the analgesic potency, the lower the dose of a drug required to produce comparable analgesia. Pharmacodynamically, the potency can be increased with the effective dose of ED50 can be specified.
The maximum achievable analgesia states that, in contrast to highly potent substances, the analgesic effect of low-potency opioids only increases up to a certain increase in dose, a further increase does not lead to stronger analgesia, but increases the undesirable effects. Pharmacodynamically, the maximum achievable analgesia is a measure of the intrinsic activity of an active ingredient.

Opioid analgesics are part of the WHO graded scheme for the treatment of chronic pain. In the second stage, this provides for the administration of a low-potency opioid in addition to a non-opioid analgesic (first stage), and in the third stage, the use of a highly potent substance. In addition, opioid analgesics are used therapeutically in many other areas of medicine, for example to induce anesthesia in anesthesia and many acute pain-associated diseases and injuries in emergency and intensive medicine that cannot be controlled with non-opioid painkillers.[1], [2]

Respiratory depression

The unwanted respiratory depression (inadequate breathing) is caused by decreased CO2- Sensitivity of the respiratory center (in the reticular formation) over μ2Receptors triggered. It is directly proportional to the analgesic potency of the opioid. Indirectly, it also increases intracranial pressure (intracranial pressure) through vasodilation (widening of the vessels). Hypoventilation (decreased breathing) with only a few breaths per minute occurs as a mild form. It is typical for this that the person concerned complies with a request to actively breathe (so-called Command breathing). At higher doses, breathing stops completely, leading to hypoxia or hypoxemia with an insufficient supply of oxygen to the organs and subsequent death. No clinically relevant respiratory depression occurs with pain-oriented administration of opioids. By using the antagonist naloxone, respiratory depression can be reversed.

Psychotropic Effects

Sedation (calming down) is brought about via κ receptors. It is partly desired (anesthesia, sedation in sedation), partly undesirable (long-term pain therapy). However, even with high doses of opioid analgesics, consciousness is not safely switched off, so that opioids must be combined with inhalative or intravenous hypnotics as part of general anesthesia in order to prevent wakefulness phenomena (Awareness) to avoid.
Opioids also have anti-anxiety and euphoric effects, which are believed to be responsible for the psychological component of opioid addiction. In addition, however, dysphoria and hallucinations can also be caused via σ-receptors, which plays a role in the mixed agonist-antagonists.

Tolerance and dependence

The development of tolerance (habituation) with opioids describes the weakening of the effect and the shortening of the duration of action with repeated administration, which is compensated for by increasing the dose. It is a pharmacodynamic tolerance that is mainly based on an increased enzyme activity of the intracellular adenylate cyclase.[3]

The development of tolerance is characteristically faster for the analgesic, euphoric and respiratory depressive effects than for the spasmogenic peripheral effects and miosis. In the case of endogenous opioids, the development of tolerance is prevented by the uptake and processing of the receptors in the cell.[4] If the opioid intake is interrupted, withdrawal symptoms occur, which are based on an increased release of norepinephrine. This creates a physical dependency.[5]

Nausea and vomiting

By stimulating dopamine-dependent receptors in the trigger zone of the area postrema on the floor of the fourth ventricle, the vomiting center in the formatio reticularis is stimulated, thus triggering nausea and vomiting (emetic effect). This can occur postoperatively during anesthesia (postoperative nausea and vomiting, PONV). This effect can be mitigated by using antiemetics. In higher doses, however, opioids dampen the vomiting center, so that an antiemetic (nausea-reducing) effect then results.
Apomorphine, which is related to morphine, has a pronounced effect on dopamine-2 receptors in the area postrema. For this reason, it can be used to induce vomiting in some cases of poisoning, but is no longer approved in Germany for this indication (in humans).

Other effects

Spastic constipation of the intestine (constipation) is caused by the stimulation of μ-receptors of the myenteric plexus of the intestinal wall with a constriction of the smooth muscles. They are the most relevant side effect in long-term pain treatment and are subject to little tolerance development. Lactulose can be given prophylactically. The constipating effect is desirable when using the morphine derivative loperamide, which is used as an antidiarrheal for the symptomatic therapy of severe diarrhea.
The odd sphincter also constricts, which increases the pressure in the bile duct system, which can lead to colic-like pain.
The same mechanism causes voiding disorders of the urinary bladder with urinary retention.

By dampening the cough center, it has an antitussive (cough-reducing) effect. This has been described selectively for the opiate noscapine. This effect is used in the antitussive codeine and derivatives. With the rapid injection of highly potent synthetic analgesics such as fentanyl during induction of anesthesia, however, a coughing irritation can initially occur, which increases the risk of aspiration.

Opioids cause central sympathicolysis (reduced activity of the sympathetic nervous system). This and an increase in the activity of the vagus nerve and direct vasodilation lead to a drop in heart rate (bradycardia), blood pressure (hypotension) and cardiac output. In the usual therapeutic dosage, the impairment of the cardiovascular function is only minor. With restricted circulatory regulation such as volume deficiency (shock), anesthesia, as well as with antihypertensive drugs (blood pressure lowering drugs) a critical drop in blood pressure is possible. In the therapy of acute myocardial infarction (heart attack) and acute left heart failure (cardiac insufficiency), the circulatory depressant effect is used to relieve the cardiac function and to reduce myocardial oxygen consumption.

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

Bolus injections of highly potent opioids during anesthesia can trigger muscle rigidity, which primarily affects the thorax (chest) and abdomen (abdomen) (wooden chest), which makes mask ventilation more difficult when anesthesia is induced. The mechanism is unclear. This undesirable effect is particularly pronounced with alfentanil and remifantanil. In the context of modern combination anesthesia, this phenomenon only plays a subordinate role due to the muscle relaxants used.

Opioids can still cause itching (pruritus). This comes about through an overlap of pain- and itch-associated peripheral mediators and receptors.[6]

Opioids are not triggers for malignant hyperthermia and have no toxic (poisonous) effects on the liver or kidneys. They don't release histamine.

Natural opioids

Endogenous opioids

The endogenous opioids are endogenous peptides that are released as part of the stress response and serve to suppress acute pain and hunger, but also interact with the sex hormones and are involved in the development of euphoria and the regulation of gastrointestinal functions, breathing, thermoregulation and immune reactions. They are released in the event of injuries, but also in response to emotional stimuli and UV light. Their secretion is also changed in the case of obesity, mental disorders, but also opioid administration. A precise understanding of these complex functions and regulatory processes has so far been lacking.

The endogenous opioids can be divided into three groups. The precursor peptide of the endorphins is the pro-opiomelanocortine (POMC), from which the endorphins α, β and γ arise. From the group of enkephalins are the variants Met-Enkephalin, Leu-Enkephalin and Met-Arg-Phe-Enkephalin, which differ in the N-terminal amino acids. The dynorphins are divided into dynorphins A and B as well as α- and β-neoendorphin.

The endogenous opioids (neuropeptides) are produced in mammals in the hypothalamus and pituitary gland and differ in distribution and receptor affinity.[7]  

Opiates / opium alkaloids

Natural substances found in opium are called opiates. The opium that comes from opium poppies (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 group of Phenantrans as well as noscapine (6%), papaverine (0.8-1%) and narceine (0.3%), the Benzylisoquinolones are.[8]

Overview of key pharmacological data for common opioids

Surname relative potency minimal duration of action classification Remarks
Sufentanil1000~1000 3030 min Agonist BTM. Most powerful human analgesic
Remifentanil200~100-200 8-108-10 min Agonist BTM. Very short half-life, therefore very easy to control. Mainly used in the context of TIVA.
Fentanyl 120 3030 min Agonist BTM. Suitable for neuroleptanalgesia
Alfentanil 30-40 1010 min Agonist BTM
Buprenorphine30~30 360-6206-8 h partial agonist BTM. Has an analgesic effect when administered alone, and antagonistic in combination with agonists
Hydromorphone 7,5 180-6003-5 h (without delay) Agonist BTM
Oxycodone 3 210-4203.5 - 7 h (without delay) Agonist BTM
Diacetylmorphine (heroin) 2,5 180-2403-4 h (metabolites) Agonist not marketable
Levomethadone 2 300-4205-7 h Agonist BTM
Hydrocodone 1,5 240-4804-8 h Agonist BTM
Morphine 1 120-2402-4 h Agonist BTM. Reference substance for opioids
Piritramide 0,7 240-3604-6 h Agonist BTM
Nalbuphine 0,5-0,7 180-3603-6 h mixed agonist-antagonist
Pentazocine 0,3 120-2402-4 h mixed agonist-antagonist BTM
Codeine 0,2 2404 h Agonist (BTM, concentration-dependent)
Dihydrocodeine 0,2 180-2403-4 h Agonist (BTM, concentration-dependent)
Pethidine 0,1 120-2402-4 h Agonist BTM
Tramadol 0,1-0,2 2404 h Agonist
Tilidine 0,1-0,2 180-2403-4 h Agonist
Naloxone0.01 versus 0 60-2401-4 h pure antagonist intravenous administration only
Naltrexone0.01 versus 0 1800 to 24 h pure antagonist oral administration
Loperamide0.01 versus 0 Antidiarrheal, only on peripheral opioid receptors
Apomorphine0.01 versus 0 Emetic, on dopamine receptors in the area postrema

Legal Aspects

The national laws are the basis of the standard convention on narcotics, formerly the international opium convention.

In Germany, the legality of narcotics is regulated by the Narcotics Act.[11] Opioids are largely subject to this in all concentrations (see also overview table), sometimes only to a certain concentration (codeine, tilidine with naloxone, dextropropoxyphene) and sometimes not at all (tramadol, metamizole, nalbuphine).

Similar laws apply in Switzerland and Austria (Narcotics Act (Switzerland) [12], Addictive Substances Act (Austria)).

withdrawal

Withdrawal symptoms immediately after stopping all opiates and other medications can include restlessness, an unfounded sensation of pain, depression, vomiting and stomach cramps, diarrhea, exhaustion or flu-like symptoms. Seizures do not occur with opioid withdrawal.

Withdrawal from opioids is extremely tedious. For example, if it has been used regularly, after-effects such as sleep disorders or nightmares can still occur a year later, but these decrease in frequency and severity over time.

See also: withdrawal syndrome

Intoxication

Acute poisoning with opioids can occur in the context of an overdose in the case of addiction, mostly with ignorance of the opioid concentration and with suicidal intent, accidentally (unintentionally), iatrogenically (as a result of medical treatment) or in the case of a body-packer syndrome in drug couriers .

The typical symptom triad of opioid intoxication consists of respiratory depression, coma that cannot be awakened, and miosis with pupils the size of a pinhead. Mydriasis can also occur if the patient is deeply unconscious. The inadequate breathing results in hypoxia (lack of oxygen) with cyanosis, possibly leading to pulmonary edema. Cheyne-Stokes breathing may be observed. In addition, there is poor circulation with bradycardia (slow pulse) and hypotension (drop in blood pressure). The muscle tone is reduced, the reflexes are weakened or lost. A possible differential diagnosis is clonidine poisoning, the appearance of which can be very similar.

Treatment of opioid poisoning is primarily symptomatic and consists in safeguarding vital functions. The most important measure is to keep the airways free in the case of respiratory insufficiency, if necessary through endotracheal intubation and controlled ventilation with oxygen. Circulatory insufficiency requires shock treatment with volume administration via large-lumen intravenous cannulas. If cramps occur, they are treated with benzodiazepines.

As a specific antidote, naloxone is used, which acts as an antagonist on all opioid receptors. This is used in repetitive doses until the clinical symptoms have improved significantly (titration antagonization). Caution is advised with addicts, in whom this can trigger an acute withdrawal syndrome. When antagonizing longer-acting opioids, a rebound phenomenon, remorphinization, can occur due to the very short half-life of naloxone.[9]

swell

  • Pichlmayr I.: Intravenous narcotics and anesthetic adjuvants. In: Pichlmayr, Jaeger: Kompendium Anästhesiologie; ecomed, 2004 ISBN 3-609-71360-7.
  • Karow, Lang-Roth: general and special pharmacology and toxicology. 14th edition 2005. Self-published.

Individual evidence

  1. McQuay H: Opioids in pain management. Review. Lancet. 1999 Jun 26; 353 (9171): 2229-32 PMID 10393001
  2. ab Jochen Schulte am Esch, Hanswerner Bause, Eberhard Kochs: Anesthesia, intensive care medicine, emergency medicine, pain therapy. Thieme, Stuttgart; 3rd edition 2006. ISBN 3-13-119083-3
  3. Freye E, Latasch L: Development of tolerance under opioid administration - Molecular mechanisms and clinical significance. Anesthesiol Intensivmed Emergency Med Schmerzther. 2003 Jan; 38 (1): 14-26. PMID 12522725
  4. Koch T et al .: Receptor endocytosis counteracts the development of opioid tolerance. Mole pharmacol. 2005 Jan; 67 (1): 280-7 PMID 15475572
  5. Cami J, Farre M: Drug addiction. N Engl J Med. 2003 Sep 4; 349 (10): 975-86. Review. PMID 12954747
  6. Ikoma A et al:The neurobiology of itch. Nat Rev Neurosci. 2006 Jul; 7 (7): 535-47. Review. PMID 16791143
  7. Rowbotham DJ:Endogenous opioids, placebo response, and pain. Lancet. 2001 Jun 16; 357 (9272): 1901-2. PMID 11425407
  8. Lüllmann, Mohr: Pharmacology and toxicology, 15th edition 2003. ISBN 3133685155
  9. ab Karow, Lang-Roth: general and special pharmacology and toxicology. 14th edition 2005. Self-published.
  10. Frank Detlev, Richling Schneider: Facts. Medicines 2007. Thieme, Stuttgart 2006, ISBN 3-13-140543-0
  11. Law on Narcotics Traffic (online)
  12. Federal Act on Narcotics and Psychotropic Substances (Narcotics Act, BetmG) (online)

See also

Categories: Opioid | Substance group