Opioid agonists, mixed agonist-antagonists and partial agonists

Opioid agonists are medications used mainly to control acute or chronic pain in particular situations.

Some of them are also used to treat diarrhea and cough. When treating pain, the goal should be to use short-acting opioids at the lowest effective dose for just a few days, and slowly increase their dose only as needed.

As a class, opioids share one thing in common, they bind to opioid receptors in the brain, spinal cord, and gastrointestinal tract.

Some are endogenous, meaning they are produced naturally by the body, like endorphins, short for endogenous morphine.

But others are exogenous, meaning they come from outside the body, like heroin and morphine, which come from the opium poppy; a flowering plant that oozes a milky white liquid.

To understand how opioids work, let’s zoom into a region of the brain tissue that has opioid receptors.

Normally, in the absence of endorphins, inhibitory neurons secrete a neurotransmitter called gamma-aminobutyric acid, or GABA, that prevents nearby neurons from releasing neurotransmitters like dopamine, serotonin, and norepinephrine.

Now, let’s say someone goes to play a rigorous game of badminton. Exercise releases endorphins which activate the three major opioid receptors located on the inhibitory neurons, called the mu, kappa, and delta receptors.

As endorphins bind to these receptors, they block the inhibitory neuron from releasing GABA, allowing the dopamine, serotonin, and norepinephrine secreting neurons to freely unload their neurotransmitters, which then get picked up by another neuron in the same area.

Norepinephrine and serotonin release takes place in pain processing regions of the brain like the thalamus, brainstem, and spinal cord, resulting in a decreased sensitivity to pain.

When dopamine release takes place in reward pathway regions like the ventral tegmental area, nucleus accumbens, and prefrontal cortex, the result is a calming sensation that feels really good.

Okay, so even though all opioids bind to opioid receptors, not all of them have the same effect.

Some opioids, like morphine, act just like endorphins, and when they bind to the opioid receptors, they trigger a full response that results in the complete inhibition of GABA release.

These are called full agonists. Others, like tramadol, have a weaker effect since they only partially inhibit GABA release.

These opioids are called partial agonists.

Now, some opioids act preferably on mu receptors, others on kappa or delta receptors.

In fact, they can have an agonist effect on one receptor, and an antagonist effect on others.

These are called mixed agonist-antagonists.

First, let’s look at some full agonists.

Commonly used medications in this class include morphine, methadone, fentanyl, meperidine, codeine, hydrocodone, and oxycodone.

Although not a medication, heroin is also a full agonist.

Since opioids are the strongest analgesics available, they can typically be given perorally, intravenously, or through patches in the case of fentanyl, to control severe pain that couldn’t be eased with non-opioid medications.

Fentanyl is the most potent full agonist and it’s also used as an anesthetic medication due to its rapid onset and short duration of action.

Meperidine can be used to relax uterine muscles and inhibit contractions during labor. However, it can produce respiratory depression in the baby.

Codeine is a weaker full agonist and is often taken perorally with other analgesics like acetaminophen, to treat moderate pain like headaches.

Due to an unknown mechanism, codeine and hydrocodone are also useful as an antitussive, to relieve cough in adults.

Unfortunately opioids have a high risk of causing opioid dependence.

Since they cause a wonderful euphoric feeling, there’s an increased risk of abuse and addiction.

Methadone is an opioid that does not cause euphoria and it has a long half-life, so it’s often given to decrease withdrawal symptoms for people with opioid use disorder or heroin addiction.

An added benefit is that it also blocks the euphoric feeling that comes from taking other opioids, so it helps to prevent future abuse.

There are also some opioids that don’t have any analgesic effects. For example, dextromethorphan is only used for its antitussive properties.

Loperamide can’t cross the blood brain barrier so it’s used to reduce the motility of the gastrointestinal tract and treat diarrhea.

Now, common partial agonists include buprenorphine, butorphanol, pentazocine, and tramadol.

The first three are mixed agonist-antagonists. Buprenorphine is a partial agonist at the mu receptor, but an antagonist at the kappa receptor, while butorphanol is a partial agonist at the kappa receptor, but an antagonist at the mu receptor.

Pentazocine is a partial agonist at the mu receptor and kappa receptor. All three can be used to manage moderate pain.

Tramadol is a partial agonist at the mu receptor and is used for moderate to severe pain, often after surgery.

Now if these medications are given with a full agonist, they’ll compete for the same receptors and decrease the overall effect.

Now, this can also be a good thing; as a partial agonist, buprenorphine can stimulate opioid receptors enough to decrease cravings and withdrawal symptoms in people with opioid use disorder.

However, it’s not potent enough to cause an overdose or trigger the euphoric feeling, which makes it a safer alternative to methadone.

Okay, let’s move on to side effects. In the central nervous system, excessive stimulation of opioid receptors can cause euphoria, but sometimes also dysphoria where the person feels unhappy and dissatisfied.