What are the effects of opiate and sedation? - Chapter 7

What are opiates used for?

Opium has been used for thousands of years as a medicine and for religious or ritual purposes. Early medical texts already describe opiates as narcotics. The main active substance in opium is morphine. This substance became popular as an anesthetic drug since the 1850s. It has also been used against coughing, as a medicine for fever and diarrhea. Morphine is still widely used today. Since the discovery of morphine, a lot of research has been done to discover an anti-pain medication that is less addictive. This led to, among other things, heroin.

Because opium and heroin were widely available since the nineteenth century, opium addiction became popular. At the beginning of the twentieth century, a legal attempt was made to stop this addiction, unfortunately this had little effect.

Opiates

In opiates, the pharmacologically active substances are morphine, codeine and thebaine alkaloids. Alkaloids are natural constituents that are available in different forms and contain nitrogen. Various attempts have been made to synthesize alkaloids. That is why the book distinguishes between opiates (natural and formed from opium) and opioids (synthetically produced anesthetics).   

Morphine and heroin are injected directly into the blood stream although Codeine and opioids are often taken orally. Once opiates are in the body, they can quickly pass through the blood-brain barrier. For example, only a few seconds after administration, heroin has already reached the brain. This works differently with morphine and codeine. Because of their solubility in water, only twenty to thirty percent reach the brain, while the rest is excreted again. In the liver, morphine and heroin are both converted to morpine-6-glucuronide, which is an active metabolite. Morphine and its metabolite have a half-life of 1-3 hours, so it works relatively long as an anesthetic.       

Opiates have different effects on neural activity including sedation, euphoria and respiratory depression. 

Pain can occur in many different ways. The pain receptors are called nociceptors. The pain signals are transmitted via fast myelinated fiber webs and via slow unmyelinated fiber webs. The myelinated fiber webs cause a sharp, rapid pain, while the unmyelinated fiber webs cause dull and slow pain. This pain often comes after the short, sharp pain in tissue damage. The perception of pain differs per person. Depression makes people more prone to pain.

The excitatory neurotransmitter substance P is released upon activation of the nociceptors. Opiates in the spinal cord can modulate pain. They do this by modulating the activity of serotonin and noradrenergic neurogen in the medulla. The release of substance P is inhibited.

There are different areas of the brain that play a role in the perception of pain. The cingulate cortex plays a role in feeling pain or the sensation of pain. Damage to this area does not stop make you feel pain, but that you do not experience it as your own pain. Other areas are the insular and cingulate cortex and the site in the sensory cortex that receives input from the body are essential for mapping the state of the body and emotions including pain. A study has shown that the regulation of pain by the prefrontal cortex is mediated by endogenous opiates. As a result, opiate drugs are thought to cause analgesia due to neural inhibition in the prefrontal cortex. 

Three different receptors for opiates are known:

μ (mu): is located in the brain and spinal cord. This receptor appears to be most important in anesthesia of pain. Morphine (and similar opiates) often bind to these receptors. These receptors contribute to the regulation of respiration by the ventral medulla and large doses of medication acting on this receptor can thus cause respiratory depression.     

δ (delta): occurs mostly in the striatum and the nucleus accumbens. This receptor appears to be important for anesthesia and euphoria (caused by opiates).

κ (kappa): occurs in the amygdala, the hypothalamus and the pineal gland. This receptor is involved in anesthesia, dysphoria (opposite to euphoria) and thermoregulation.

Shortly after discovery of the above receptors, ligands were detected. Endogenous ligands of the opiate receptors are called endorphins. Endorphins are a type of opiate peptide that develop after degradation of larger peptides in the cell nucleus. 

All receptor subtypes are metabotropic and act on the receiving neuron.

Agents that bind to opiate receptors can cause many effects. Pure agonists are agents that mimic the effects of the ligands (such as morphine, codeine, etc.). Partial agonists are agents that have a selective or lower affinity with the receptor subtypes. Mixed agonist antagonists have agnostic effects on some receptors and antagonistic effects on other receptors. For sedation the best pure antagonists can be used.

A pure antagonist would like to bind to the receptors, but has no physiological effect (they only block). An example of this is naltrexone, this drug is often administered in a heroin overdose. Another pure antagonist, naloxone, is used to treat opiate dependence.

Heroin seems to be one of the most addictive drugs. This is mainly due to the rapid effects on the brain due to the high fat solubility. The rewarding effect of this type of opiates works on structures from the mesolimbic system. This is because the dopamine production is increased. The exact operation is unfortunately not yet known.

Tolerance for opiates arises quickly, but it varies per type of opiate how fast this happens. For example, there is more rapid tolerance for opiates that are anesthetic, than for opiates that lead to respiratory depression. Due to the rapid tolerance there is a risk of overdose.

When opiates are used repeatedly, the opiate is metabolized more quickly because your body has more auxiliary substances ready, this is called metabolic tolerance. However, it is even more important to look at the neurons that have receptors to take up opiates. These neurons adapt to the use of the opiates (cellular tolerance). As a result, the production of other substances can be inhibited. An example is the inhibition of the substance cAMP in chronic use of opiates. This substance is important for the second messenger system at metabotropic receptors. Compensatory mechanisms are needed to restore the amount of cAMP.

Tolerance often depends on previous exposure to drugs. This is called associative tolerance and has to do with the process of classical conditioning of Pavlov. It seems that this process is mediated by the NMDA receptors. By administering an NMDA antagonist the associative tolerance can be disturbed or vice versa. This knowledge contributes to the concept of relapse risk among drug users. For example, drug users often kick off in a controlled, clinical setting. As soon as the user returns to the place he associates with drug use, there are conditioned feelings (such as the craving for drugs). The tolerance and addiction can then immediately be returned after one time usage.

How is an opiate addiction treated?

It is estimated that one million people in the United States depend on heroin or other opiates. In addition to the risk of overdose, these people also have an increased risk of, among other things, HIV, hepatitis and liver diseases. Around ten thousand people die annually because of an overdose. The annual costs of opiate dependency in America are estimated at twenty billion dollars.

The treatment of people with dependency on opiates must focus on the behavioural and pharmacological side. This creates a smaller chance of relapse. Most treatment programs start with methadone maintenance. During this phase, the opiate is replaced by methadone   the   withdrawal symptoms are minimized. Other benefits are that it should be taken less often (half-life from 15-22 hours), taken orally and not "rush" or "high". Often the methadone treatment is started for the clinical treatment, because there are too few places to kick off. Often these patients do not have the strength to stay away from the drugs and they fall back into use. Opponents of methadone use argue that the addiction to one drug is simply replaced by a methadone addiction, since people often have to use methadone for a number of years. In any case, methadone cannot be seen as a medicine for addiction to opiates.