9⃣ OPIOIDES | Anestesia é o Básico #9

A certain day, Hypnos, the God of sleep, and Pasithea, Godess of relaxation and meditation, gave birth to Morpheus, God of dreams. Morpheus has no definite shape. Morpheus can turn into anything that people dream of.

Maybe that's why he's persisted over time in poems, comics and even in one of the most famous movie trilogies. Is that not a trilogy? That character also inspired the name of one of the most famous pain medication, and that's what we're going to see today.

Bring it on! Opioids What's up NAVE crew! In today's Anaesthesia Unravelled video lesson we'll be talking about opioids, one of the main groups in pain management.

This story starts about 4,000 years BC, with the Sumerians. They extracted a kind of milky substance from the poppy that they named opium, which in Greek means 'juice'. They started to notice that this 'juice' made people sleepy, sometimes even relieving pain.

For many years, this was used as pain treatment. In the early 19th century, a scientist called Friedrich Sertürner, I really can't speak German, managed to synthesize the first opium substance, and as this substance caused sleepiness, he honored the God of dreams, Morpheus, and named it morphine. As everyone knows, morphine is still considered one of the best medications to manage moderate to severe pain.

It's considered an opiate because it can also be obtained naturally, by means of the plant. This is also true for codeine. The other substances that are synthetized in the laboratory are considered opioids.

For the sake of our discussion here, we will be considering everyone as opioids, OK? These drugs act on opioid receptors, best known for the Greek letters μ (mu), κ (kappa) and δ (delta). The majority of these receptors are located in the central nervous system, the brain and spinal cord, but we can also find these receptors scattered through different organs of the body.

It's interesting to remember that each type of receptor will trigger a different response. Regarding the μ receptor, it causes analgesia, euphoria, sedation, increased appetite, constipation, respiratory depression, pruritus, decrease in uterine contractions, reduction in inflammation and immunomodulation. κ, on the other hand, acts on analgesia and causes dysphoria, sedation, increased appetite, constipation and diuresis.

Finally, δ causes analgesia, respiratory depression, increased appetite, constipation, thermoregulation and also immunomodulation. The afinity and intrinsic activity of these drugs in opioid receptors will divide them into four categories: in this picture, we can see that opioids are divided in full agonists, which have an affinity for all receptors and relative intrinsic activity, partial agonists, in which opioids have an affinity for some type of receptor, mixed agonist-antagonists, where opioids have affinity for receptors, plus a contrary effect, depending on the drug, and the antagonists, which have an affinity to all receptors but no intrinsic activity. This animation also gives a slightly better idea of what would be a full opioid agonist and an antagonist.

As we can see, the full agonist will activate all opioid receptors, promoting the full effect. In the case of the partial agonist, binding occurs, but it does not activate all receptors, so it promotes a partial effect when compared to the previous example, and finally, there's the antagonist, that binds but does not activate the opioid receptors, promoting no effect. For those who want to check out this entire video, take a look at the link on the description.

This dose-response curve simulates all that, we can see that the morphine and fentanyl, that are full agonists, promote a dose-dependent effect. Buprenorphine, on the other hand, a partial agonist, has a ceiling effect, as we can see here. In the case of naloxone, which is a total antagonist, there's no effect whatsoever.

General effects At first, we’ll be covering the general effects, and afterwards, the particularities of each opioid. Analgesia is, without a doubt, the most desired opioid effect. This effect happens due to the decrease in the release of excitatory neurotransmitters, as serotonin and norepinephrine, and also the hyperpolarization of nociceptors.

The nociceptors are usually found on the C-fibers, the fibers of late pain, which is the reason why opioids are not able to block all the pain of a twinge or a cut, being the A-delta fibers responsible for this. Another desired opioid effect is sedation. This effect is interesting, although not produced by all opioids and also dependent on the species.

There are opioids that will promote euphoria instead of sedation, and this is one of the issues we'll face with the use of opioids in some species. If we look up older literature, excitation in cats and horses is frequently mentioned. That obviously happens, but there are two details that are relevant on this front: one is if the animal is in pain or not, and also the dose.

In some opioids, the higher the dose, the greater the chance of it promoting euphoria and not sedation. In general, cardiovascular impacts are very slight, especially in small animals. Something we may see, depending on the opioid, is some bradycardia, but nothing that'll alter the patient's cardiac output.

An interesting effect that we should remember is that morphine and meperidine promote the release of histamine, especially when administered intravenously. In this case, we may have hypotension. So, it is recommended avoiding these drugs as intravenous premedication in small animals.

This effect is not seen with other opioids. Adequate doses of opioids generally do not promote much impact in the pulmonary system. What we need to be careful about is newborns, which are more sensitive to respiratory depression.

A rare effect that we may see, especially with fentanyl, is chest wall rigidity, also known as wooden chest syndrome. There can be thoracic rigidity mainly in the expiratory phase, resulting in the animal being unable to breathe. In this case, the best course of action is to reverse the effects of the opioid using an antagonist.

The effects over the digestive system are, undoubtedly, one of the main barriers for the use of opioids, mainly in large animals. The first effect is emesis, mostly with morphine and meperidine, as they cause emesis in dogs and cats. If we do it intravenously, then, it's almost certain to happen.

My apologies, Father, I used morphine. The neuroleptic association of morphine and acepromazine, for example, decreases the occurence of emesis. Regarding motility, what actually happens is not a full stop of the gut movements, but a decrease in the propulsion of the intestine.

The concentric movements continue, they even get more intense, but what happens clinically is a decrease in gut movements. If we consider large animals, this has to be taken into account. Then we will start that argument between the surgeon and the anesthetist, one does not want to use opioids, as they decrease motility, and the other wants to use opioids to decrease pain.

that, historically, people had the habit of using extremely high doses, resulting in colic due to stopped bowel movements. Currently, there is a myriad of scientific works that standardize doses that are safe for intestinal motility, but that also produce analgesia. I, particularly, use opioids in all horse surgeries, including colic, and I never had a problem.

In ruminants, we need to be be careful, because stopping rumen movements can harm the animal more quickly, but given that we use an opioid that is adequate for the species and the situation, there will be no problem. An undesirable effect that has been widely discussed is immunosuppression, generally related to morphine. Some studies have found that the use of opioids causes a decreased in lymphocyte activity and interferon, and this will lead to immunosuppression.

Several of these studies are important, from well-respected journals, but we need to understand the context. Most studies have been conducted with patients in the ICU, patients who are addicted or who have been taking opioids for an extended period of time. However, there are some studies that suggest that this can happen after a single dose.

Which leads to that discussion about anesthesia with or without opioids. We cannot forget that opioids make up one of the most effective groups for pain management, mostly acute pain. This immunossupression effect needs to be better investigated, for us to understand if a therapy of 3 to 4 days on the postoperative period will harm the patient.

On the other hand, we also need to deal with the patient's pain, because the painful process also results in immunossupression. Following this general approach, we will briefly go through the main opioids used in veterinary medicine, highlighting the particularities of these drugs, mainly in relation to the species and the usual doses. Morphine Morphine is the "golden opioid", it is the basis for all comparisons with others opioids.

It is extensively used in small animals, in large animals, exotic animals and laboratory animals. It's also administered by several routes and in the most diverse ways. The only that is not advisable is the oral route, as it is inactivated by enterohepatic circulation and in the rumen, for ruminants, and the subcutaneous route, which I particularly think isn't very efficient, especially in the postoperative period.

On the one hand it causes analgesia and sedation in some species and, on the other hand, it causes nausea, constipation, histamine release and possible immunomodulation. Remember that these effects are related to the dose. Here we can see the route, doses and frequency of administration of morphine in small animals, highlighting the intramuscular route for premedication, the intravenous route for continuous infusion and the epidural route for trans and postoperative analgesia.

The same goes for large animals. Fentanyl Fentanyl is another full agonist, widely used in medicine and also in veterinary medicine, mainly in small animals. Fentanyl is 100 to 200x more potent than morphine.

This does not mean that fentanyl is a better analgesic than morphine, but that the dose of fentanyl needs to be 100 to 200x lower than morphine to promote the same effect. Fentanyl has an interesting feature, its period of action is very short, about 20 to 25 minutes, so one interesting use of fentanyl is as premedication or during anesthesia in successive boli, something that I don’t really like, or intravenous infusion. In this picture we can see the routes, doses and frequency of administration of fentanyl in domestic animals.

In dogs and cats, it's common to use it intravenously or intramuscularly. In large animals, fentanyl is usually used only as a transdermal patch, once it promotes excitation and sudden stop of gut movements. Remifentanil Remifentanil is from the group of fentanilas, where there's still sufentanil and alfentanil.

Remifentanil is considered one of the best opioids for intravenous infusion, because it is biotransformed by plasma esterases, so that its period of action is approximately four to five minutes. This can be good and bad. It's great because we can do intravenous infusion in patients with liver disease without a problem, on the other hand, is also not very interesting because it does not promote residual analgesia.

In the board we can see the recommended doses of remifentanil for continuous infusion in dogs, cats and horses. In horses, it should be done only under general anesthesia, as it can promote excitation during recovery. Methadone Methadone a very popular opioid, mainly in Europe and Brazil.

Besides acting on opioid receptors, methadone also acts on the NMDA receptor, promoting antagonism. This is an effect of interest, especially regarding chronic pain. In theory, using equipotent doses, methadone causes more sedation than morphine in dogs and it also increases blood pressure because of vasopressin release.

Here we can see the routes, doses and frequency of administration of methadone in small animals. It is also used as intravenous infusion for transoperative analgesia and also via epidural route for trans and postoperative analgesia. Methadone is also widely used in horses as premedication and post-operative analgesia, but in ruminants, it has been established only the epidural route so far.

Meperidine (pethidine) Meperidine, also known as pethidine, is an opioid that used to be very popular, although its use has been decreasing. It is ten times less potent that morphine, meaning that the dose of meperidine needs to be ten times higher than that of morphine to promote the same effect. Today, there is a heated debate to discuss if meperidine even promotes analgesia.

Besides, we shouldn't forget that meperidine causes the release of histamine. Other effects that weigh against meperidine is the 1 to 2 hours action period. In cats, it has no analgesic effect whatsoever, and in horses, there have been reports of excitation, convulsion and anaphylactic shock.

The only thing that’s, perhaps, interesting about meperidine compared to other opioids, in dogs, is that it produces good sedation. The use of meperidine is advised exclusively in small animals and intramuscularly. Buprenorphine Buprenorphine is a partial agonist, that is, it has a ceiling effect.

This can be a disadvantage, if we consider animals that are under intense pain, but it can also be interesting, because it brings a certain safety associated to the use of this medication. Buprenorphine has a very cool characteristic, its period of action is very long. In some situations, its analgesia reaches 12 hours.

In adequate doses, it has no physiological impact considering small animals. In horses, causes analgesia and some excitation. One interesting fact is that buprenorphine is considered one of the best opioids for pain management in cats.

The board highlights the doses, routes and frequency of administration of buprenorphine in dogs, cats and horses. Tramadol Tramadol is usually considered a partial agonist. It's not considered an opioid because it acts in other ways as well, but in practice, we consider tramadol as an opioid.

Tramadol is a strange molecule and it has an affinity 6,000 times lower than morphine for μ receptors. In reality, what triggers the analgesic effects are the metabolites of tramadol, especially O-Desmethyltramadol. Besides the effects on opioid receptors, the metabolites of tramadol also act to inhibit the reuptake of serotonin and noradrenaline.

That means the patient has to be able to metabolize tramadol to have the analgesic effect, and that's where the problem lies. Cats can biotransform tramadol without a problem, so tramadol tends to be a good choice for them. Dogs, on the other hand, have a little difficulty in biotransforming tramadol, so its analgesic therapy in this species is slightly questionable.

Let's not even begin to talk about horses. There're several works in literature from different study groups, and all agree unanimously that tramadol has no analgesic effect in the acute pain of horses. That happens because the O-Desmethyltramadol is practically not formed in the horse, the horse transforms tramadol in N-Desmethyltramadol, which has no analgesic effects.

Some studies in literature suggest a possible analgesia in chronic pain, but it has to be better understood. The thing is, everybody uses tramadol today. People use it for earache, castration, arthritis, thoracotomy, brain transplant, the whole problem is that, in fact, the person may not be prioritizing the actual treatment, but prescribing some analgesic therapy, and tramadol is the only opioid a person can buy without a prescription.

But we need to remember that it's not because tramadol is easy to acquire that we should be prescribing it for anything. It does NOT work for severe pain. As we already stressed, tramadol is efficient only in small animals and in the board we can see the doses, routes and frequency of administration.

Butorphanol Butorphanol is an agonist-antagonist opioid, it acts as agonist at the κ receptors and antagonist at the μ receptors. During a long time butorphanol was extensively used in horses as the best opioid or maybe even the only choice, because of this effect, so, in theory, it did not cause a decrease in gut motility, but we see that it actually does. There's a theory that the κ receptors are more frequently associated with visceral pain, while μ receptors with somatic pain.

I don't particularly agree with that. But, anyway. .

. Another important thing about butorphanol is that it was considered the best choice of opioid for birds and reptiles. Particularly, I think this is nonsense, because this originated from the article onscreen, that showed that pigeons have more κ than μ receptors.

If we analyze this data, we can notice that there are also mammals with different types of opioid receptors, showing that we can't just place all birds and all reptiles in one basket. Besides, there are several studies with birds, snakes and lizards which prove that morphine can be a much better opioid for them. Anyway, let's focus here on butorphanol.

The gut motility decrease after butorphanol is, indeed, less intense than that of full agonists, but it also causes hypomotility. Butorphanol results in good sedation. Analgesia, on the other hand, it's not that intense, especially because it comes solely from the activation of the κ receptors.

In addition, it has a short duration, approximately two to three hours. The board shows the doses, routes and frequency of butorphanol administration in both small and large animals. Opioid antagonists Finally, there are opioid antagonists, which have a high affinity for μ, κ and δ receptors, but has no intrinsic activity.

The most popular is naloxone, but yet another antagonist is naltrexone, which differs from naloxone in its period of action, that is longer. In general, naltrexone is used in zoo or wild animals. After we administer the opioid antagonist, what'll happen is a displacement of the opioid agonist administered previously, causing the effect to be interrupted.

The dose of naloxone is 10 to 40 µg/kg, and that of naltrexone is 0. 5 to 1. 5 mg/kg.

Keep in mind that these reversers must the titrated according to the response, that is, we start with very small doses and, if it doesn't achieve the necessary response, we gradually increase it. Why is that? If we end up administering a very high dose of these reversers, we may promote excitation and hyperalgesia.

As a conclusion to this video lesson we have that opioids comprise one of the main groups in analgesic therapy, especially post-operative. Their effects are dependent on their interaction with each type of opioid receptor, and we can also observe a difference in effects according to the species, breed and even the patient's genotype. Therefore, we need to choose the opioid and the dose according to the patient and each situation.

It is worth remembering that this group has reversers and they should be considered in case of adverse effects. Well, guys, I hope you have enjoyed this video lesson about opioids. We’ll also be talking about AINEs and analgesic adjuvants, but let's save them for a next time, all right?

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