Opioid analgesics

Opioid analgesics

Opioid analgesics are substances of natural or synthetic origin that are agonists of opioid receptors, that is, stimulants of endogenous opiopeptides in the central nervous system (CNS).

Opioid Membrane Receptors

As mentioned above, opioid analgesics are agonists of opioid receptors. Let us examine opioid receptors in more detail.

Opioid receptors are divided into three main subtypes:

OP1 (δ or delta),
OP2 (k or kappa),
OP3 (μ or mu).

All three of these types of receptors are involved in pain relief. They are located in the central nervous system, but the most important role is played by the OP3 (mu) receptors. Arousal of mu receptors leads to respiratory depression, euphoria and physical drug dependence. Peripheral opioid receptors regulate intestinal motility. With stimulation of the opioid receptors of the intestine, constipation develops.

All types of opioid receptors are associated with a particular G protein. Signal transmission from the membrane receptor is carried out through:

inhibition of adenylate cyclase,
modulation of intracellular calcium,
change in the permeability of potassium channels.

Opioid analgesics disrupt the neural transmission of a pain impulse due to the fact that the release of pain mediators (glutamate, acetylcholine, norepinephrine, serotonin and substance P) into the synaptic cleft decreases and the postsynaptic neuronal membrane is stabilized due to the opening of potassium channels.

In recent years, it has been found that opioid analgesics (endogenous and exogenous) can cause analgesia by also acting on peripheral tissues. At the ends of the peripheral sensory nerves, mu receptors are found. Inflammatory pain is also sensitive to the peripheral effects of opioid analgesics. So, the appointment of opioid analgesics to the knee during arthroscopic surgery on the knee brought a reduction in pain. Therefore, work is now underway to search for opioid analgesics with selective peripheral action for the treatment of inflammatory pain.

Endogenous opioid analgesics differ in affinity for opioid receptors – leu-enkephalin has a high affinity for delta receptors, and dynorphin for kappa. In order to reduce the risk of drug dependence and respiratory depression, a targeted search was made for drugs with a primary effect on kappa receptors. An example of such substances are, for example, opioid analgesics butorphanol and nalbuphine. However, they cause dysphoria and are rather weak.

Opioid analgesics

Classification of Opioid Analgesics

Opioid analgesics and their antagonists can be divided:

by chemical structure and origin,
by its effect on opioid receptors.

For a medical practitioner, it is precisely the second, the so-called clinical classification.
By chemical structure and origin

Natural opioid analgesics (phenanthrene derivatives): morphine, codeine.

Synthetic opioid analgesics:

Derivatives of phenanthrene: heroin, oxymorphone, hydromorphone nalbuphine, buprenorphine;
Derivatives of piperidine: promedol (trimeperidine), meperidine, pyritramide, fentanyl, lofentanil, carfentanil, sufentanil, etc .;
Phenylheptylamines: meptazinol, methadone;
Benzomorphans: pentazocine;
Morphinans: levorphanol, butorphanol, dextromethorphan;
Cyclohexanols: tramadol.

By effect on opioid receptors

Pure agonists

Strong agonists: morphine, trimeperidine (promedol), meperidine, methadone, fentanyl, etc .;
Weak agonists: codeine, propoxyphene, oxycodone, hydrocodone;

Mixed antagonist agonists and partial agonists: buprenorphine, butorphanol, pentazocine, tramadol.

Pure opioid receptor antagonists: naloxone, nalmefen, naltrexone, alvimopan, methylnatrexone.

Pure opioid receptor agonists eliminate the effects of opioid analgesics. Naloxone and nalmefen are indispensable for respiratory depression caused by an overdose of opioid analgesics, naltrexone – in the treatment of opioid addiction, alcoholism. The last two substances do not penetrate the central nervous system and are used to eliminate opioid-induced constipation.

The mechanism of action of opioid analgesics

Opioid analgesics eliminate pain by stimulating specific opioid receptors that regulate the transmission and modulation of pain and are located primarily in the brain and spinal cord. They inhibit the release of exciting mediators from afferent neurons and inhibit the transmission of pain impulses in the dorsal horns of the spinal cord, and at the supraspinal level they disrupt the transmission and modulation of pain.

Opioid analgesics mechanism of action

A particularly important point is the modulation of pain in the descending paths, including the anterior cerebral keel, the gray periaqueductal zone and locus ceruleus. Opioid analgesics suppress all these neurons and contribute to the release of endogenous opiopeptides, which, in turn, act on types of receptors other than opioid analgesics. Therefore, there are no analgesics selective for one type of receptor.

Opioid analgesics

Effects of Opioid Analgesics

The prototype of opioid analgesics is morphine. Other opioid analgesics cause only morphine-like effects. All effects of morphine can be divided into central and peripheral.

Central effects of morphine
CNS depression effects

Analgesia caused by a change in the perception of pain, a change in the reaction to pain (pain is perceived as something extraneous) and euphoria (a strong sense of satisfaction and well-being). Healthy people who do not have pain can sometimes have dysphoria. The most pronounced effect is possessed by strong mu receptor agonists.

Respiratory depression caused by a decrease in the sensitivity of the respiratory center to carbon dioxide. The respiratory rate decreases and in case of an overdose it can be stopped (death). The decrease in respiratory rate caused by morphine is useful for shortness of breath accompanying pulmonary edema (the patient’s fear of shortness of breath is reduced). The accumulation of carbon dioxide while breathing is reduced leads to relaxation of the cerebral vessels and increased intracranial pressure (and this is dangerous for head injuries).

Suppression of the cough center is not proportional to the analgesic effect. So, weak opioid analgesics codeine and dextromethorphan have a strong antitussive effect.

Sleep, which is explained by the consequence of eliminating pain – the patient calms down and falls asleep.

CNS Excitation Effects

Vomiting (due to stimulation of the chemoreceptors of the starting zone of the vomiting center) is more common in patients who are in motion, and is not accompanied by unpleasant sensations. In chronic use, there is no vomiting.

Myosis (narrowing of the pupil), caused by the stimulating effect of parasympathetic innervation on the tone of the core of the oculomotor nerve. This effect persists in chronic use (i.e., no addiction). Myosis, bradyknife (rare breathing) and coma are reliable diagnostic symptoms of an overdose of opioid analgesics.

Cramps. This is an extremely rare effect of meperidine, trimepiridine (promedol) when overdosed against renal failure due to the accumulation of toxic metabolites.

Rigidity of the muscles of the body reduces the volume of respiratory movements and can disrupt the patient’s breathing. It is most pronounced with the rapid intravenous administration of large doses of opioid analgesics with high lipid solubility (fentanyl and related substances). To relieve rigidity (the reason is opioid analgesics act at the supraspinal level), curariform muscle relaxants are prescribed.
Peripheral effects of morphine

Constipation due to the suppression of intestinal motility, while increasing the tone of smooth muscles of the large intestine and spasm of the anal sphincter. All this leads to a slowdown in the progression of the chyme (food lump), the absorption of water and constipation. This effect is widely used for diarrhea of ​​non-infectious origin. With diarrhea, opioid analgesics are considered the most effective group of substances. Loperamide (imodium) and diphenoxylate, which are related in chemical structure with opioid analgesics, are used. They are safe because they do not penetrate the central nervous system and therefore do not cause euphoria, analgesia or drug addiction.

Muscle spasm of the biliary tract (can cause hepatic colic).

Increased tone of the ureter, detrusor and sphincter of the bladder, which can increase the course of renal colic and (with prostate adenoma) cause urinary retention.

The cardiovascular system is changed only by substances with an M-anticholinergic effect. For example, trimeperidine (promedol) and meperidine can cause tachycardia. However, against the background of stress, opioid analgesics can cause slight hypotension due to the release of histamine and a decrease in the tone of the vasomotor center.

The release of histamine from mast cells leads to the expansion of blood vessels of the skin, which is why a slight decrease in blood pressure is possible. There may also be pruritus, urticaria and bronchospasm in asthmatics.

Decreased excretory function of the kidneys: decreased renal blood flow and glomerular filtration.

Decreased uterine tone, which can cause a slowdown in labor. The mechanism of this effect is unknown.

Pharmacokinetics

The vast majority of opioid analgesics are well absorbed in the digestive tract, then they are metabolized in the liver and excreted in the urine as metabolites (glucuronides, etc.). However, there are differences in the rate and amount of absorption in the gastrointestinal tract (therefore, opioid analgesics are most often administered parenterally, this is a more accurate method) and the characteristics of liver metabolism. For example, the administration of a large dose of morphine against the background of renal damage leads to the accumulation in the body of a neurotoxic metabolite of morphine (morphine-3-glucuronide), which can cause seizures. A similar effect can be with the accumulation of metabolites of meperidine or its analogues. With repeated prescriptions of large doses of opioid analgesics (especially with high lipophilicity, such as fentanyl), their accumulation in adipose tissue is possible, which creates a danger of toxic effects.
Combinations with Opioid Analgesics

The inhibitory effects of opioid analgesics (including analgesia) are enhanced:

antipsychotics (the combination of fentanyl + droperidol is used for antipsychotics),
sedatives and hypnotics, which increases the risk of respiratory depression;
antidepressants – a combination with MAO inhibitors is contraindicated due to the risk of hyperpyrexic coma;
amphetamines paradoxically enhance the analgesia of opioid analgesics.

Opioid analgesics

Comparative Characterization of Opioid Analgesics

Opioid analgesics differ from each other in terms of duration of action, severity (strength) of individual effects, and the risk of drug dependence.

According to the duration of action, opioid analgesics are divided into substances:

short action (about 30 minutes), for example, fentanyl;
medium duration of action (about 6 hours), for example, morphine;
long-acting (about 25 hours), for example, methadone.

By strength:

analgesic effects: for example, morphine is about 70 times weaker than fentanyl;
smooth muscle spasm: least of all is promedol, meperidine, which are similar in structure to atropine;
antitussive action: strong – with codeine, very weak – with promedol (trimeperidine).

According to the risk of drug dependence, opioid analgesics are divided into substances, the purpose of which is associated with:

with a high risk of drug addiction (strong agonists);
with a low risk of drug addiction (mixed antagonist agonists and partial agonists). Although they try to give preference to this group if necessary, long-term treatment, but their effectiveness is not always sufficient to eliminate pain. In addition, they can cause unwanted mental effects: hallucinations, nightmares, anxiety. When taken with potent agonists of opioid receptors, they behave as antagonists – that is, they displace the latter from communication with opioid receptors. In this case, addicts will have withdrawal symptoms, and in patients with pain – a decrease in analgesia.
no risk of addiction: antidiarrheal opioids (loperamide, diphenoxylate) and the antitussive opioid dextromethorphan. Actually, the substances of this group are not true opioid analgesics (since they do not cause analgesia), but they are very close to them in chemical structure.

Comparative Characterization of Opioid Analgesics
Indications for the use of opioid analgesics

Opioid analgesics are used in the following cases:

Severe acute pain (myocardial infarction, injuries, burns, colic) and severe chronic non-inflammatory pain (cancer). Anesthesia should be adequate to the strength of the pain and from time to time be reviewed in the direction of increasing or decreasing dosages. for example, with hepatic or renal colic after the administration of opioids, pain can, on the contrary, increase, not decrease. This is due to an increase in smooth muscle spasm. Therefore, with colic it is important to increase the dose of opioids, which will cause effective analgesia. With inoperable cancer, it is even possible to take the risk of drug dependence in such patients (large doses of substances, continuous administration), but to achieve effective analgesia.

In other cases, preference is given to strong agonists (for acute pain) and partial agonists for chronic pain (due to the low risk of drug addiction). It should be borne in mind that partial agonists are inferior in potency to strong agonists

Anesthesia during surgical operations (premedication and directly during the operation). Especially often used fentanyl and its derivatives.

Pulmonary edema (a decrease in respiratory rate reduces the patient’s fear) and a decrease in preload and afterload on the heart (due to the expansion of venous and arterial vessels). The most commonly used morphine.

Pain during childbirth. In the CIS, an analog of foreign meperidine is used – trimeperidine (promedol). It weakly, in comparison with morphine, depresses the breath of the fetus. In addition, its metabolism (rapid demethylation) is safe for the fetus, compared with the metabolism of morphine (slow conjugation in the liver). Unlike other opioid analgesics, trimeperidine and meperidine do not weaken, but enhance labor.

Cough: codeine, dextromethorphan;

Diarrhea (not infectious): diphenoxylate (reasek), loperamide (imodium).
Opioid analgesics differ from each other in terms of duration of action, severity (strength) of individual effects, and the risk of drug dependence.

According to the duration of action, opioid analgesics are divided into substances:

short action (about 30 minutes), for example, fentanyl;
medium duration of action (about 6 hours), for example, morphine;
long-acting (about 25 hours), for example, methadone.

By strength:

analgesic effects: for example, morphine is about 70 times weaker than fentanyl;
smooth muscle spasm: least of all is promedol, meperidine, which are similar in structure to atropine;
antitussive action: strong – with codeine, very weak – with promedol (trimeperidine).

According to the risk of drug dependence, opioid analgesics are divided into substances, the purpose of which is associated with:

with a high risk of drug addiction (strong agonists);
with a low risk of drug addiction (mixed antagonist agonists and partial agonists). Although they try to give preference to this group if necessary, long-term treatment, but their effectiveness is not always sufficient to eliminate pain. In addition, they can cause unwanted mental effects: hallucinations, nightmares, anxiety. When taken with potent agonists of opioid receptors, they behave as antagonists – that is, they displace the latter from communication with opioid receptors. In this case, addicts will have withdrawal symptoms, and in patients with pain – a decrease in analgesia.
no risk of addiction: antidiarrheal opioids (loperamide, diphenoxylate) and the antitussive opioid dextromethorphan. Actually, the substances of this group are not true opioid analgesics (since they do not cause analgesia), but they are very close to them in chemical structure.

Side effects of opioid analgesics

Opioid analgesics have side effects that are a continuation of their pharmacological action: respiratory depression, constipation, drug dependence, nausea, vomiting and (toxic doses of trimeperidine, meperidine, tramadol, less commonly morphine) seizures. Agonists may have psychotomimetic reactions (hallucinations, nightmares and anxiety).
Contraindications

Accordingly to side effects, opioid analgesics are contraindicated in:

respiratory depression (except for patients on mechanical ventilation);
with an attack of bronchial asthma or with its severe form even outside the attack;
with paralytic ileus.

Opioid analgesics

Drug Dependence and Opioid Analgesics

Opioid Analgesics

The cause of drug dependence is not fully understood. Among the possible causes are a change in the functioning of opioid receptors with the constant administration of opioid analgesics (a decrease in the number of receptors and their affinity for agonists), dysfunction of the structural interaction of the chain: receptor – G-protein – secondary cell mediators – ion channels. In particular, great importance is attached to a specific complex with ion channels – the NMDA receptor (it was found that ketamine, an NMDA receptor antagonist, blocks the development of addiction and physical dependence).

Characterization of drug dependence of opioid addiction. It is very severe (mental and physical) and is accompanied by a pronounced addiction (tolerance) to all the effects of opioid analgesics, with the exception of myosis and constipation. A person dependent on them (an addict) needs a larger and larger dose of opioid analgesics, and stopping their administration causes an extremely serious (but usually not fatal withdrawal syndrome).

Withdrawal syndrome is a sign of physical drug dependence. Initially (the first 12 hours after taking the last dose of morphine), there are signs of mental dependence, nervousness, sweating, and a thirst for the drug. They are moderated by the appointment of a placebo. Then there are signs of severe physical dependence, most of which are associated with a dysfunction of the autonomic nervous system: mydriasis, tachycardia, goose bumps, intestinal colic, muscle pain, vomiting, diarrhea, shortness of breath, fever, yawning, tremors, sneezing, lacrimation, and anorexia and depression. In morphine, the maximum withdrawal symptoms fall by 1-2 days, and its duration is about 5 days. In most cases, the addict does not withstand it and returns to drugs.

Addiction is treated with methadone. It is a long-acting strong opioid receptor agonist similar to morphine. The peak of withdrawal symptoms (much milder than morphine) is the first week, the duration is three weeks. Instead of methadone, a partial opioid agonist buprenorphine is increasingly being used. Both substances are prescribed in tablets with a gradual decrease in the daily dose until they are completely canceled. A long-acting (48 hours) opioid receptor antagonist naltrexone is prescribed internally in the treatment of drug addicts. It eliminates the point of taking opioid drugs by drug addicts who are being treated, as it blocks the opioid receptors and prevents all the effects that opioid analgesics carry out. For the treatment of drug addicts, clonidine (clonidine) has recently been used, which eliminates the symptoms of hyperactivity of the sympathetic nervous system observed with opioid withdrawal.

Opioid Analgesic Poisoning

Intravenous administration of an antagonist of opioid analgesics naloxone. Within 30 seconds, it removes opioid analgesics from the cells of the respiratory center and restores normal breathing of the poisoned person. Its effect is short (1-2 hours), which requires repeated administration of naloxone with prolonged exposure to active opioid analgesics. In the latter case, preference is given to nalmefene (duration of action is about 8-10 hours), which is a derivative of naltrexone, but is prescribed only intravenously.

Opioid analgesics

List: opioid analgesics and their features
Morphine

morphine

Morphine belongs to the group of opioid analgesics – their prototype. It is slowly and in individually varying amounts absorbed internally, undergoing a strong first-pass effect. Therefore, its parenteral administration gives a more predictable effect. Effective for a long time (about 4-6 hours). The liver of newborns weakly metabolizes metformin (conjugation with glucuronic acid) compared with adults. Because of this, morphine can not be prescribed for pain relief in childbirth and newborns.

Almost identical to morphine in properties, although pyritramide is not similar in structure to it. The only difference from morphine hydromorphone and oxymorphone is a longer duration of action. Omnopon is a newgalenic opium preparation containing morphine and other opium alkaloids, including papaverine. It acts similarly, but is weaker than morphine. However, spasm of smooth muscles in urine and biliary tract is less, since it contains an antispasmodic – papaverine.

Promedol

Trimeperidine (promedol) belongs to the group of opioid analgesics, it is weaker than morphine and less depresses the respiratory center. Therefore, this substance is considered the drug of choice in obstetrics and pediatrics. It has weak M-anticholinergic properties, therefore it does not cause such a strong spasm of smooth muscles as morphine, which can cause tachycardia, dry mouth and dilated pupils. It does not have a noticeable antitussive effect, which may be useful in patients with lung diseases when it is necessary to maintain a cough reflex. also does not have a clinically significant staple effect. It is better than morphine absorbed in the digestive tract, but inferior to it in strength and duration of action (2-4 hours). Trimeperidine is close in structure and properties to the foreign analog of meperidine. A characteristic effect of an overdose of these substances is neurotoxicity (tremors and convulsions).

Metadon

Metadon otnositsya k gruppe opioidnyye anal’getiki, polnost’yu vsasyvayetsya v ZHKT, obladayet boleye dlitel’nym deystviyem (period poluvyvedeniya okolo 24 chasov), chem morfin i ne ustupayet yemu po sile, no iz-za medlennogo nastupleniya effekta vyzyvayet men’shuyu eyforiyu. Dlitel’noye deystviye i khoroshaya vsasyvayemost’ pri priyeme vnutr’ delayut yego osnovnym preparatov dlya osvobozhleniya narkomanov ot stradaniy, vyzvannykh abstinentnym sindromom (tak kak iz-za dlitel’nogo deystviya metadon vyzyvayet znachitel’no boleye myagkiy abstinentnyy sindrom, chem morfin i drugiye sil’nyye agonisty opioidnykh retseptorov). Pri etom metadon dayut v postepenno ubyvayushchey sutochnoy doze. Levorfanol ochen’ pokhozh po svoystvam na metadon, no boleye sil’nyy.

Fentanyl

Fentanyl belongs to the group of opioid analgesics, acts much stronger than morphine, but for a short time (up to 30 minutes). Often used with antipsychotics droperidol, which enhances its effect. This combination is used to anesthetize surgical operations (neuroleptanalgesia). Fenthanyl, sufentanil, remifentanil are close in properties to fentanyl.

Codeine

Codeine belongs to the group of opioid analgesics – a weak analogue of opioid receptors, therefore, rarely and only with prolonged use in large doses creates a risk of drug addiction. like other weak agonists (hydrocodone, oxycodone, propoxyphene) it is used in combination with paracetamol or aspirin to eliminate mild pain. It is perfectly absorbed in the digestive tract. It is highly effective for coughing at doses that do not cause analgesia, but at present it is supplanted by dextomethorphan, since the latter does not cause drug addiction at all.

Pentazocine

Pentazocine belongs to the group of opioid analgesics – it acts briefly, absorption from the gastrointestinal tract is incomplete. It belongs to the opioid receptor antagonist agonists, that is, it excites some receptors (kappa), and blocks others (mu). In contrast to morphine, pentazocine causes tachycardia and increased blood pressure (contraindicated in coronary heart disease). In addicts, it causes withdrawal symptoms, that is, it acts as an antagonist of opioid receptors. Often causes dysphoria (due to the excitement of sigma receptors), so addiction rarely develops. Desocin is chemically close to pentazocine (however, it is primarily a mu agonist and then a kappa receptor).

Buprenorphine

Buprenorphine belongs to the group of opioid analgesics, has a great affinity for mu receptors, but it excites them weakly. It acts as an antagonist on delta and kappa receptors. That is, it belongs to agonists-antagonists of opioid receptors, so the risk of drug addiction is small. Buprenorphine has a long-lasting effect and is also used to treat opioid addiction. Valid for a long time, about 9 hours. Can be given under the tongue. The risk of drug addiction from buprenorphine itself is low. It does not cause constipation, does not affect CCC, but often when using pentazocine. It is used for postoperative pain, severe pain in the abdominal organs.

Tramadol

Tramadol (tramal) belongs to the group of opioid analgesics, in chemical structure resembles codeine. Compared to morphine, it is a relatively selective but weak agonist (= partial agonist) of mu receptors. In addition, the effects of tramadol are also associated with increased serotonergic processes (blockade of neuronal reuptake of serotonin) in the central nervous system. Tramadol does not affect the respiratory center and CCC. It has a significant sedative effect (can not be assigned to drivers, etc.). When using high doses (400 mg), drug dependence may occur. A specific side effect of tramadol is an increased risk of seizures due to a decrease in the seizure threshold. Withdrawal syndrome is also accompanied by convulsions. The use is similar to other partial agonists, and is also prescribed for atypical pains (chronic neuropathic pain) caused by the destruction of nerve fibers (herpetic, diabetic neuropathy and so on).
Heroin

heroin

Heroin (diacetylmorphinon) belongs to the group of opioid analgesics – due to its high lipophilicity it penetrates the central nervous system very quickly and causes severe euphoria. Therefore, addiction develops to it very quickly, which is why it is not used in medicine.
Propoxyphene

Propoxyphene belongs to the group of opioid analgesics – a derivative of methadone. Weak analgesic (even weaker than codeine). It is used orally, most often in combination with paracetamol or acetylsalicylic acid (aspirin). In case of an overdose, respiratory depression and cardiotoxic effects occur.

Butorphanol

Butorphanol belongs to the group of opioid analgesics – a stronger analgesic than petnazocine. Butorphanol and nalbuphine primarily stimulate kappa receptors. These two substances have a small risk of drug dependence and respiratory depression, however, they cause dysphoria and are rather weak. Butorphanol is used, most often with postoperative pain. For an unknown reason, it is significantly more effective in women than in men.
Nalbufin

Nalbuphine belongs to the group of opioid analgesics – a strong Kappa receptor agonist and mu receptor antagonist, less respiratory depression than morphine. Does not affect CCC (safe for coronary heart disease).

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