Opioid analgesics : pharmacodynamics

Analgesic effect of morphine and other opioid analgesics due to their interaction with opiate receptors of different types, but mainly with the m-receptors. Excitation of peripheral opioid receptors and prevents or reduces the activation of nociceptors and primary afferents algogennymi factors. In the CNS activation of opioid receptors causes a suppression of the transmission of pain signals to the segmental (inhibition of afferent input) and suprasegmentarnom level (disturbance of transmission of pain signals in the nuclei of the thalamus) and also stimulates the endogenous antinociceptive system and, consequently, enhances the inhibitory descending control of afferent pain. In addition, at the level of the limbic system opioids cause inhibition of the structures responsible for the formation of negative emotional reactions to pain, and at the same time - excited structures of the "award" that leads to improved mood until the euphoria.

Sedative and hypnotic effects often accompany the action of morphine and are dose-related. Sleep, which can be easily interrupted by any stimulus, is more common in younger than in older people, the ratio of fast and slow phases of sleep while impaired. However, this effect is very useful (and more pronounced), sleep disturbances caused by pain. Sedation, blurred consciousness may be accompanied by a breach of intellectual activity.

Amnesia at the same time, it is insignificant or absent. Morphine potentiates the effects of other substances depressing the central nervous system - general anesthetics, antipsychotics, tranquilizers, sedatives and alcohol.

Respiratory depression. Under the action of morphine is dose-dependent reduction in the frequency and depth of breathing. In cases of acute poisoning seen initially periodic breathing (Cheyne Stokes respiration), and then complete cessation of breathing, which serves as the primary cause of death in acute poisoning. Along with respiratory depression suppresses the cough reflex. Respiratory effect is due to a direct inhibitory action of morphine on neurons of the respiratory center. This reduces the sensitivity of these neurons to the stimulating effect of increased carbon dioxide levels in the blood (RaSO2) and reflex actions. A variety of external stimuli may some time to stimulate the respiratory center in these conditions. When such stimuli are absent, for example, during sleep, respiratory depression effect of morphine is greatly enhanced.

Respiratory depression is more pronounced in children (especially under age 3 years) and elderly persons in connection with the higher permeability of BBB. The drug crosses the placental barrier and can cause asphyxia in the newborn, so it is not used for labor analgesia. Worse than other morphine transfer patients with chronic obstructive pulmonary disease because the drug enhances bronchial tone. Respiratory effects of morphine potentiate neuroleptics, hypnotics and sedatives, and alcohol. To restore the activity of the respiratory center in acute poisoning with morphine as an antagonist naloxone is expedient to apply.

Rigidity of skeletal muscles caused by the action of morphine at the spinal level, leads, including a decrease in the efficiency of respiratory muscles, which further worsens the pulmonary ventilation. The effect is more pronounced during the rapid intravenous injection of large doses of fentanyl and its derivatives (sufentanil, etc.).

Miosis, evolving under the action of morphine is associated with a stimulating effect on the center of the oculomotor nerve. It is implemented with the participation of cholinergic mechanisms, and therefore hindered not only by naloxone but also by atropine. This is a very important diagnostic feature of poisoning by morphine and other opiates (except promedola), because this effect does not develop tolerance or she develops very slowly, and miosis will occur even in drug addicts, tolerant to high doses of drugs.

Nausea and vomiting associated with the activating influence of morphine on the trigger zone hemoretseptornuyu vomiting center. As already mentioned, these effects are usually quickly develops tolerance and they pass with time or, given the right dose. But sometimes required the appointment of antiemetics in the first 1-2 weeks of treatment.

Tolerance, or addiction, manifested by progressive reduction of the pharmacological effects of opioid analgesics like morphine during prolonged use of the drug. Dose-dependent effect. In the appointment of high-dose tolerance can develop very quickly, especially when administered intravenously, as well as in individuals not suffering from pain, and may dictate the need for increased doses of one to two orders of magnitude. But in patients with chronic pain syndrome, it develops slowly. Degree of expression of tolerance for different effects of morphine varies. Expressed tolerance is formed with respect to analgesia, euphoria, sedation, nausea and vomiting, respiratory depression. Minimum tolerance develops with respect to miosis and constipation.

It should be noted that tolerance to eyforiziruyuschemu and respiratory effects of morphine decreases rapidly within a few days after discontinuation of the drug, while resistance to the emetic effect lasts up to several months. Tolerance to morphine is usually accompanied by the development of cross-tolerance to other opiate agonists (but not antagonists).

Euphoria and dependence, usually arising from the application of morphine symptoms, especially when administered intravenously, are interrelated effects.

Euphoria as a pleasant feeling of bliss, indifference to the environment, disappearance of fear and anxiety creates a desire to repeat the drug, ie, generates psychological dependence, which is the first stage of addiction. At this stage, the discontinuation of the drug leads only to the development of negative emotional experiences. With continued use of morphine is formed by a physical dependence or addiction. Addiction - a model of behavior, form a permanent or recurring desire to seek and receive the drug, which differs compulsive (hardly controllable) character. Dependence is much less formed in patients suffering from pain than in healthy persons using morphine with non-medical purposes. Physical dependence develops in parallel with the formation of tolerance to the drug, and if the patient manifested increased tolerance, it is likely that it is formed and dependence.

Characteristic manifestation of physical dependence is the opiate withdrawal syndrome (withdrawal). It appears that if you can not get another dose of morphine or other narcotic drug in humans develop agitation, restlessness, anxiety, hostility, insomnia, yawning, chills, watery eyes and runny nose, piloeorektsiya ("goose bumps"), muscle pain, mydriasis, vomiting and diarrhea, tachycardia and other symptoms. If necessary, discontinuation of the drug gradually decrease the dose of morphine (eg, at 20% per day) significantly reduces the risk of withdrawal symptoms in a patient [2].

It should be noted that in case of pain caused by inoperable cancer and other terminal conditions, all the fears of dependence must be put aside and provide quality patient analgesia. To avoid problems associated with the development of tolerance in these patients, using WHO-recommended scheme of gradual strengthening of drug analgesia.

To the peripheral effects of morphine is spasmogenic effect. Morphine increases the tone of the smooth muscle of many organs, mainly due to the interaction with peripheral m-opioid receptors. The development effect plays a role and gain (disinhibition) of parasympathetic influences. As a result, increases the tone of the intestines and bowel sphincter, it slows down peristalsis, slows the transit of food and chyme, therefore, increases the absorption of water from it. Often end up developing constipation (constipation). Contributes to the development of constipation and general weakness, low physical activity the patient. If necessary, such patients are prescribed laxatives. Morphine increases the tone of the bile duct and sphincter of Oddi, disrupting flow of bile and pancreatic juice into the intestine. The drug also increases the tone of the ureters and the urinary sphincter, thereby making it difficult urination. Given the spasmogenic action of morphine, the drug is not indicated for the relief of spasmodic pain ("colic"), or used in conjunction with mandatory antispasmodics (papaverine, drotaverine, atropine). An alternative to morphine in spastic pain may serve omnopon containing papaverine in its composition, or promedol with independence myotropic antispasmodic effect.

Opioid analgesics: ways to improve the treatment of pain syndromes

The most effective pain relievers are opiates (opium alkaloids) and their synthetic analogs - opioid analgesics. The most severe and acute pain, causing the shock reaction, or moderate, but persistent, exhausting the patient's pain can be stopped in the first place with opioid analgesics. Alternative to them in severe cases can only serve as general anesthetics (nitrous oxide, ketamine), and in some situations - for clonidine and local anesthetics. In outpatient practice, the principal cause of the suffering of patients is a chronic pain syndrome in incurable cancer in the terminal stage. In this situation, opioid analgesics are absolutely non-alternative means of therapy. To take full anesthesia and the increase of comfort being in the last weeks or months of life of these patients a physician must navigate the modern medical forms and be able to competently apply them.

Major achievement for pharmacology of analgesics in the 70's and 80's. XX century was the discovery of opiate receptors, a demonstration of their heterogeneity, deciphering the molecular structure and effector mechanisms, the discovery of endogenous ligands - opioid peptides, of which the best known enkephalins, endorphins and dynorphin. Formulated the concept antinociceptive system. It implies that pain impulses causes simultaneous excitation of several brain structures that inhibit further transmission of pain impulses. The main structures of antinociceptive systems are okolovodoprovodnoe gray matter of the midbrain, a large core of the joint, and the giant paragigantokletochnoe nucleus of the reticular formation of medulla oblongata. Axons of neurons in these nuclei are sent down the dorsolateral cord spinal cord, resulting in superficial layers of dorsal horn neurons. These descending fibers in contact with the neurons of posterior horns of the spinal cord, release of serotonin, norepinephrine and GABA.

Many of them modulate nociceptive impulses, highlighting the enkephalins or other opioid peptides, which stimulate opioid receptors [1-3].

Opiate receptors are found in the peripheral areas of painful afferent C-fibers, they are available on the terminals of C fibers in the posterior horns of the spinal cord, located in the same neurons are gelatinous substance, and besides - in the brain structures involved in the transmission and perception of pain signals . There are three major types of opioid receptors - m (mu), k (kappa) and d (delta), relating to the family of serpentine receptors related to G-protein. These major types of opioid receptors are also divided into subtypes (m1, m2, k1, k2, k3), which can differ not only in structure, but also mediated their reactions. Creation of highly selective drugs may be useful, for example, a selective agonist of m1-receptor may cause analgesia without respiratory depression (realized by m2-receptors). Most opioid analgesics have a marked analgesic effect due to affinity and agonism (mimetic action) in relation to m-receptors. Commonly used synthetic opioids has analgesic effects due to preferential excitation of k-opioid receptors [1,4,5].

Was recently discovered so-called orphan receptors (opiate receptors - ODA). These receptors have a lower affinity for morphine than other types of opiate receptors, they have not yet found an endogenous ligand is unknown, and prospects of application of agonists or antagonists. Table 1 summarizes the effects that are mediated by the main types of opioid receptors.

Opioid Analgesics : Physical addiction

For reduction of risk of development of mental dependence at application opioid analgesics it is recommended:

• to hold preliminary testing of patients before an initiation of treatment;
• to include narcotic analgetics in complex therapy of a painful syndrome, applying them simultaneously
• regularly to supervise efficiency of treatment.

On narcogene potential, i.e. ability to cause a drug dependence opioid analgesics divide on not narcotic and narcotic. To not narcotic опиоидам are carried tramadol a hydrochloride, butorphenol. The listed preparations aren't included in lists of narcotics, and ranked as strong preparations.

Use of all narcotic analgetics is under the strict state control assuming legal responsibility of doctors and pharmacologists.

Opioid Analgesics : naloxon

Opioid analgesics — the analgesics,

which action it is caused by interaction with opoiod receptors. Typical effects opioid analgesics: analgesia, calm, drowsiness, breath oppression, euphoria or disphoria, a bradycardia, a nausea and vomiting, reduction diurez, cough suppression, mioz, the lock and bilious ways, etc. Depending on character of interaction with opioid receptors are allocated agonists, partial agonists, with agonisty-antagonists; agonist opioid receptors tramadol has additional monoaminegic a component in the mechanism of soothing action. Opioids — one of the basic means of the general anesthesia and postoperative anesthesia. Almost all effects opioid are eliminated by the competitive antagonist opioid receptors naloxon. The metabolism of all opioid analgesics is carried out mainly in a liver.

Opioid Analgesics : Principles of anesthesia in the postoperative period

The fight against pain is one of the most important problems in the postoperative period. Effective opioid analgesics promotes early rehabilitation of patients reduced the incidence of postoperative complications and chronic pain syndromes.

Currently, there are a wide range of drugs and drug-free pain relief, but many studies in different countries have shown a lack analgesia early postoperative period, almost 50% of patients. Therefore, the knowledge of modern principles of anesthesia after surgery is of great practical importance.

Stages of adequate pain relief are:

1. Preoperative assessment of the intensity and duration of pain

2. Construction plan of treatment of pain (analgesic (s), route of administration, frequency, etc.)

3. Treatment of pain.

4. Postoperative evaluation of the effectiveness of pain relief (to adjust the plan for treatment of pain in low analgesia).

To determine the quality of analgesia after surgery most widespread visual analogue scale (Fig. 1). The patient puts on the vertical lines mark the appropriate level of pain. Analgesia found to be adequate if the patient does not note pain at rest and during movement, coughing occurs moderate pain, not restrict them.

Opioid analgesics implement its action through opioid receptors located at the spinal and supraspinal levels, and are a major group of drugs for the treatment of pain in the postoperative period.

At the same time after major intracavitary surgery to achieve adequate analgesia in each third patient required the introduction of opioids in doses exceeding the recommended standard. Increasing the dose of opioids is accompanied by severe side effects (drowsiness, respiratory depression, nausea, vomiting, paresis of the gastrointestinal tract, urinary disorders), so it is now recognized that monotherapy with opioids are not always effective enough, and sometimes even dangerous.

In addition, the traditional subcutaneous and intramuscular injection is difficult to maintain an optimal concentration of opioids in the plasma, which may be accompanied by a respiratory depression, or inadequate anesthesia.

Bolus intrathecal opioids or epidural analgesia provides good up to 24 hours, but even small doses of drugs administered (ten times less than with intramuscular) may be accompanied by adverse and toxic effects.

Tramadol (Tramal)

- this is an opioid agonist, standing alone among all members of this class of opioids, primarily because unlike them he does not belong to a drug. This is confirmed by extensive clinical experience of its use worldwide, and special research potential of its drugs.

In contrast to other opioid agonists Tramadol has a dual mechanism of action. Established that the analgesia induced by tramadol is not completely eliminated by opioid antagonist naloxone, and along with the opioid mechanism is implemented by additional inhibition of pain impulses, with the participation of serotonin-and adrenergic systems. Ie on the mechanism of analgesic action of tramadol are not completely identical to other opioid agonists.

The analgesic potential of tramadol according to different authors, ranging from 0.1 to 0.2 on the capacity of morphine, it is equal to or slightly exceeds the capacity of codeine, on the effectiveness of 50 mg of tramadol equivalent of 1000 mg metamizol, ie Tramadol belongs to analgesics intended for the treatment of pain of a strong and moderate intensity.

In numerous studies have not found significant respiratory depression in postoperative patients under the influence of Trueman in the range of therapeutic doses of 0.5 to 2 mg per 1 kg of body weight, even after intravenous bolus administration, whereas morphine at a therapeutic dose of 0.14 mg / kg significantly and significantly reduces respiratory rate and increase the voltage of CO2 in exhaled air.