Opioids;receptors, side effects and main drugs

Opium is a substance extracted from a plant that belongs to the family of Poppies, popularly called Poppy. Only the species Papaver somniferum and Papaver bracteatum produce opium in relevant quantities, but the latter does not participate significantly in trade.

It is believed that the Papaver somniferum has evolved from a species from Asia Minor or a named species Papaver setegirum that grew around the Mediterranean.

Poppies were described by the Sumerians as the ” plant of joy ”, and therefore, the knowledge of opium is very old. In addition, Poppy seeds and capsules were found in the Neolithic era in Switzerland, reinforcing the idea that opium has been known since prehistoric or remote times.

In the 15th century BC, remnants of opium were found in an Egyptian tomb, and at the same time, there were plantations of this substance around Thebes, becoming known then as ” Thebaic opium ”. Centuries later, an alkaloid from this ” Thebic opium ” was given the name Tebaína.

However, it was from the Romans, that the analgesic property of opium came to be recognized, assuming the symbolism of sleep and death for this civilization.

With the Arabs, opium was used with Cicuta, Mandrake and Hyoscin, as an inhalation anesthetic for surgical procedures. Subsequently, they introduced opium into India and China, through commercial dominance in the Indian Ocean.

The name opium is of Greek origin and, as scientific research has progressed, its derivatives have undergone changes in nomenclature over the years. They have been called narcotics, hypnoanalgesics and narcoanalgesics, and included other drugs that also caused sleep.

The 19th century was already full of events with regard to opioids, since Friedrich Serturner, in 1803, isolated the Opium alkaloid which he called Morphine, in honor of Morpheus, the Greek god of sleep.

However, it is now known that a quarter of the opium powder consists of at least twenty-five alkaloids and, since then, new opioids have been discovered and started to be used.

Substances originating from opium, but extracted directly from the poppy stem, such as Morphine, Codeine and Tebaine, are considered natural. The semi-synthetic ones, on the other hand, are obtained through a partial modification of the original substance and, as an example, we have Heroin – the first to be described, Oxycodone, Hydroxycodone, Oxymorphone and Hydroxymorphone.

On the other hand, synthetic calls, such as, mainly, Methadone, Meperidine, Pethidine, Fentanyl and Levo-a-acetylmetadol (LAAM), are obtained in the laboratory through the replication of the chemical structure of opiates.

In general, opium substances act as agonists for specific pre- or post-synaptic opioid receptors, located in different locations, but mainly in the Central Nervous System and the Peripheral Nervous System.

Therefore, opioids are indicated as analgesics for acute pain that is difficult to control and for chronic pain, used by millions of users worldwide.

Types of opioid receptors

Opioid receptors are part of the endogenous opioid system, which includes a large number of opioid-binding peptides (enkephalins, endorphins and dynorphins) that appear to have the physiological role of neurotransmitters, neuromodulators and neurones.

The concept of receptors had been discussed by several researchers for a long time, based on the stereospecificity common to drugs and the possibility of finding a specific antagonist through changes in the structure of agonists.

Only in 1973, two researchers in the United States and one in Sweden, in independent studies, confirmed the existence of opioid receptors.

Through research with ileum of rodents it was possible to identify three receptors of the opioid classes and they were then named with Greek letters according to each substance used to stimulate it.

It was called mu (µ) to that activated by Morphine, Kappa (k) to that stimulated by Ketocyclazocine and Sigma (σ) to that activated by the substance SKF 10047, and later the Sigma receptor was not considered as an opioid receptor.

Kappa (k) receptors have Norbinaltorfimin as an antagonist, with a potent action. On the other hand, mu (µ) receptors have Naloxone as an antagonist.

Subsequently, a new receptor was identified and was called Delta (δ), whose main agonists are Deltorfin (an Endorphin), which has low selectivity, but high specificity, and SIOM, derived from Naltrexone – more selective and potent.

As an antagonist of the latter substance, Naltridiol is found, also coming from Naltrexone and synthesized in the laboratory.

Characteristics of opioid receptors

Some actions are well defined depending on the subtype and the location of the receptors in the Nervous System.

Delta (δ) receptors are responsible for analgesia and for modulating cognitive and physical dependency functions. They are located in the pointed nuclei, tonsils, olfactory bulb, deep cerebral cortex and in the peripheral sensory neurons.

The Kapa (k) receptors have the function of nociception, thermoregulation, control of diuresis and neuroendocrine secretion. They are present in the Hypothalamus, periaqueductal gray substance, gelatinous substance and in the gastrointestinal tract.

Finally, the mu (µ) receptors, which regulate functions such as nociception, the respiratory cycle and gastrointestinal transit, being located in blades III and V of the cerebral cortex, in the thalamus, periaqueductal gray substance, gelatinous substance and gastrointestinal tract.

These receptors are coupled to protein G in the cell membrane and, when stimulated by an opioid, there is inhibition of the enzyme Adenylate Cyclase, resulting in reduced levels of cyclic Adenosyl monophosphate.

Therefore, voltage-dependent calcium channels close at the presynaptic endings, reducing both the release of neurotransmitters and the activation of receptors, without closing the potassium channels in the postsynaptic membrane.

This leads to a hyperpolarization of the neuron, partially blocking the transmission of the painful stimulus.

There is also another mechanism described at the cellular level, in which opioids promote the inhibition of GABAergic transmission in a local circuit, such as the brainstem, where GABA acts by inhibiting the pain inhibitory neuron. This opioid inhibitory action has the effect of exciting the descending inhibitory circuit.

Some molecular biology scholars have proposed changing the nomenclature of the mu (µ), Kappa (k) and Delta (δ) receptors to, respectively, MOR, KOR and DOR, but there are controversies. Since then, the International Union of Pharmachologists  (IUPHAR) has defined a nomenclature based on the historical cloning sequence of the recipients.

They would then be appointed by OP followed by a subscribed number indicating the cloning order, example: DOR was called OP 1, OP 2 KOR , etc. In addition, subtypes of the receptors (µ) and (k) were also observed.

In addition, new receptor subtypes are being studied, such as ε (epsilon) receptors, which are located in lymphocytes and have a high affinity for beta-endorphin, ζ (zeta) receptor, which is present in skin, cornea and brain cells and activated by methekephalin, both of which are involved in tumor cell growth.

Receptors I (iota) whose enkephalin has high affinity, present in the ileum of rabbits and λ (lambda) with affinity for epoxymorphine, being found in cell membranes of rats.

 General effects of opioids

Analgesia: opioid receptors are linked to inhibitory G proteins. When stimulated, there is activation of these proteins that trigger a cascade of events: closure of voltage-dependent calcium channels, reduction in the production of cyclic adenosine monophosphate (AMPs) and stimulation of potassium efflux resulting in cellular hyperpolarization.

Thus, there is the final effect, which is the reduction of neuronal excitability, resulting in a reduction in the neurotransmission of nociceptive impulses and generating analgesia.

Sedation: by acting on kappa receptors – mainly – located in the Central Nervous System, they cause drowsiness and altered consciousness.

Respiratory depression: opioid receptors are abundantly present in the respiratory center of the cerebral cortex, thalamus, carotids and lungs. Their stimulation leads to irregular and slow breathing, generating hypercapnia and hypoxia.

Constipation: receptors are widely distributed throughout the autonomic nervous system (ANS), including the gastrointestinal autonomic nervous system.

When the agonist activates the opioid receptor, bowel motility slows down, mediated by the inhibition of acetylcholine by myenteric neurons and also partially inhibiting the release of purine and nitric oxide from inhibitory motor neurons.

Orthostatic hypotension and syncope: as opioid receptors are also present in cardiac tissue, when activated, they lead to hyperpolarization of membranes and activation of the vagus nerve.

Therefore, peripheral vasodilation and bradycardia occur, which end up causing hypotension. In addition, there is the release of histamine that contributes to the peripheral vasodilation being further exacerbated.

Endocrine abnormalities: there are opioid receptors located in the Hypothalamus, which, when activated, inhibit the release of GnRH, resulting in a reduction in the secretion of estrogen and testosterone. This chronic activation leads to osteoporosis and sexual dysfunction, with decreased libido.

In addition, the activation of these receptors results in a reduction in the activity of the hypothalamic-pituitary-adrenal axis, generating low levels of ACTH and cortisol. The low level of cortisol causes clinically nonspecific symptoms such as: nausea, vomiting, abdominal pain, weakness and anorexia.

Inadequate ADH secretion syndrome (SIADH): Some studies have shown that activation of receptors in the hypothalamus led to higher levels of ADH by stimulating the posterior pituitary.

The stimulated receptors cause inhibition of GABA, which then loses its inhibitory effect on the stimulation of ADH secretion. Hypersecretion of ADH can even lead to hyponatremia in more severe cases.

Immune dysfunction: there are receptors in the cells of the immune system, such as natural killer cells (NK) and phagocytes, which, when activated, lead to suppression of cellular activity, causing healing to be delayed.

Sleep disorders: when opioid agonists stimulate the receptors present in the region of the middle pontine reticular formation, there is an increase in the duration of light sleep, decreasing the duration of deep sleep.

Mood swings: chronic stimulation of mu (µ) receptors mainly reduces neuronal flexibility and neuron production in the hippocampus region, leading to mood dysregulation and, eventually, social withdrawal.

Itching: some opioids trigger the release of histamine by mast cells, causing itching, bronchospasm and hives.

Miosis: stimulation of the oculomotor nerve nuclei mediated by mu (µ) and kappa (k) receptors leads to miosis.

Muscle stiffness: high doses of opioids can cause generalized muscle stiffness, especially in the chest wall musculature, which can interfere with ventilation.

Effects on pregnancy and neonates: all opioids cross the placental barrier and, if used during delivery, can cause respiratory depression in the newborn. In addition, chronic use by pregnant women can result in fetal physical dependence, with severe withdrawal syndrome in the immediate postpartum period.

Nausea and vomiting: the activation of opioid receptors located in the chemoreceptor zone of the vomiting trigger (posterior area of ​​the bulb) can trigger nausea and vomiting.

Urinary retention: its occurrence is not dose-dependent or related to systemic absorption. The mechanism involves opioid receptors in the sacral spinal cord, with inhibition of the parasympathetic nervous system and relaxation of the detrusor muscle, resulting in increased bladder capacity.

Hallucinations: mainly after the use of kappa (k) agonist opioids. However, mu (µ) agonists can also trigger hallucinations.

Tolerance and dependence: tolerance is believed to be related to the down-regulation of opioid receptors. Addiction, on the other hand, when the use of the drug is prolonged and it is abruptly withdrawn, can trigger irritability, excessive salivation, sweating, vomiting and diarrhea.

Depression of the cough reflex: it is not well understood yet, but it is known that it is not closely related to the analgesic and sedative effects of the drug. The receptors involved are believed to be mu and kappa.

Euphoria and dysphoria: results from the release of dopamine in the dopaminergic mesolimbic pathway, the so-called Reward Zone. Euphoria is more related to the activation of mu receptors, while dysphoria is more related to activation of kappa receptors.

Opioids most used in practice

Morphine: it is a potent analgesic with good sedative and anxiolytic effects, effects mediated by MOP receptors, being an agonist of opioid receptors. Morphine has presentations for several routes. The main three are: oral, venous and subcutaneous.

By oral route or its prolonged release presentation, it is usually used for chronic pain or ambulatory use, while the intravenous form is more used for acute pain, sedated or unconscious patients. It is important to remember that due to absorption, the oral dose must be three times greater than the intravenous dose.

It can generate euphoria, dysphoria and hallucinations, in addition to respiratory depression and suppression of the cough reflex. Although it has few cardiovascular effects, it can lead to bradycardia and hypotension.

Nausea, vomiting and miosis are common side effects, and can still lead to the appearance of rash, itching and bronchospasm due to the release of histamine it causes. It is worth remembering that it is a substance capable of causing tolerance and dependence.

Codeine: it is a natural opioid, one of the main alkaloids derived from opium and has low affinity for opioid receptors – greater predilection for μ receptors and lower for δ and k receptors.

Its presentation is injectable and tablet forms, and can be used by the oral, intramuscular and subcutaneous routes. In addition, it can also be used as antitussive and antidiarrheal medication.

Its use can cause mild euphoria, disorientation and anxiety. However, it causes less sedation and respiratory depression than Morphine, and constipation is a common side effect of this drug.

Meperidine: Meperidine is a synthetic opioid agonist, which has 10% of the potency of Morphine. It binds to μ eke receptors, in addition to analgesia, it causes sedation, drowsiness and decreased cerebral blood flow. It can lead to myocardial depression and hypotension.

It exists only in an injectable form and can be used by intravenous, intramuscular or subcutaneous routes.

Nalbuphine: syntactic opioid, agonist of type k opioid receptors and antagonist of type μ receptors, presenting the same analgesic potency as Morphine. It has a single form of presentation that is injectable and can be used by intravenous, intramuscular and subcutaneous routes.

In addition to generating analgesia, it leads to good cardiovascular stability and reduced adrenocortical response to stress. It is important to note that it can precipitate withdrawal syndrome in patients who are tolerant and dependent on opioid agonists.

Fentanyl: synthetic derivative of phenylpiperidine that is 100 times more potent than Morphine and acts mainly on μ receptors. Its main form of presentation is the injectable form and more recently it appeared as a transdermal patch. It can be used by intravenous and intramuscular routes.

Many properties of Fentanyl are similar to those of Morphine. It produces dose-dependent respiratory depression and is used in cardiac surgery in order to inhibit the metabolic response to stress. When used in very high doses, it can cause profound sedation, unconsciousness and muscle stiffness, which can affect ventilation.

Alfentanil: it is a synthetic derivative of phenylpiperidine that has a structure similar to that of Fentanyl, but with 10 to 20% of its potency. It has the injectable form as a presentation and uses intravenous or intramuscular routes. It acts on μ receptors and its effects are the same as Fentanyl, but with a faster onset and shorter duration.

Sufentanil: acts on μ receptors and, to a lesser extent, on k receptors. It has the injectable form of presentation and can be used intravenously or intramuscularly. It is an analgesic 5 to 10 times more potent than Fentanyl and has similar effects to it.

It generates analgesia, sedation, reduces the cerebral metabolic need for oxygen, without altering cerebral blood flow and cranial pressure. In addition, it can lead to dose-dependent bradycardia with reduced cardiac output.

Remifentanil: Used for analgesia and anesthesia, Remifentanil is a synthetic phenylpiperidine derived from Fentanyl, with similar potency, but with an ultra-short duration. It is a selective agonist of μ receptors and is rapidly degraded by plasma and tissue esterases, which determines a short elimination half-life.

In addition, the only form of presentation is injectable and uses only the intravenous route, the maximum effect of the drug being 1 to 3 minutes and its duration from 3 to 10 hours. However, it is noteworthy that high doses require great caution due to the possibility of side effects, such as: bradycardia, hypotension, apnea and muscle stiffness.

Tramadol: Tramadol is a phenylpiperidine analog of codeine classified as a weak opioid receptor agonist, with greater affinity for MOP receptors. It inhibits neuronal reception of norepinephrine, inhibits nociceptive descending pathways and enhances the release of serotonin.

It has as forms of presentation: capsules, tablets, drops, ampoules and suppositories. The administration routes include intravenous, intramuscular, oral and rectal.

The severity of respiratory and cardiovascular depression after using Tramadol is very low when compared to equipotent doses of morphine, with constipation being less frequent.

It shares the same side effects as other opioids (dizziness, nausea and vomiting) and should be contraindicated in patients using monoamine oxidase inhibitors (MAOIs) or a history of epilepsy.

Methadone: opioid with high analgesic potential, good absorption and oral bioavailability (75%). Mainly used as a substitute for opioids, such as diamorphine (heroin), in cases of abuse, as its high latency and prolonged duration reduce the incidence of withdrawal symptoms.

However, it can cause addiction. It has an ampoule and tablets as a form of presentation and as oral, subcutaneous, intramuscular and intravenous administration routes. Its analgesic potency is 3 times greater than Morphine and acts on μ opioid receptors.

Oxycodone: indicated for analgesia and is found only as slow-release pills. Therefore, there is only the oral route. It is an agonist of μ opioid receptors, acting mainly on the Central Nervous System and on organs that have smooth muscles.

Its use leads to analgesia, sedation, hypotension and reduced adrenocortical response to stress.

Opioid antagonists

We talked a little about the main opioids that we have in our midst. However, they are widely used drugs and on a large scale and can cause poisoning. Faced with opioid intoxication, it is necessary to use opioid antagonists, they are:

Naloxone: pure opioid antagonist that reverses the effects on MOP, KOP, DOP receptors, although it has a greater affinity with MOP receptors. It is the drug of choice in the treatment of opioid-induced respiratory depression.

The duration of the antagonism is 30 minutes, so when used to reverse the effects of long-acting agonists, new boluses or continuous infusion should be administered to maintain the plasma level of the antagonist.

In addition, in opioid-dependent patients, caution is required when administering Naloxone because of the possibility of triggering acute withdrawal with hypertension, pulmonary edema and cardiac arrhythmias.

Naltrexone: has a mechanism of action similar to Naloxone, but with some pharmacokinetic advantages. Naltrexone has a prolonged half-life, close to 24 hours if administered orally. Used to treat opioid dependence and binge eating in patients with morbid obesity.


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