Opioid agonists, mixed agonist-antagonists and partial agonists

Opioid medications are used mainly to control pain. 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 the shortest duration possible, and slowly increase the 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, named for “endogenous morphine” due to their similar effects in the body. 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 in on a region of the spinal cord that has opioid receptors. Normally, in the absence of endorphins, nociceptive fibers carry pain signals from the body to the dorsal, or posterior, horn of the spinal cord, where they release neurotransmitters like glutamate, substance P and calcitonin gene-related peptide. These neurotransmitters cause pain signals to be transmitted to the brain via ascending pain pathways.

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 neurons called the mu, kappa, and delta receptors.

As endorphins or other opioids bind to these receptors on the presynaptic terminals of nociceptive fibers, they inhibit the opening of calcium channels, preventing calcium influx, and thereby blocking the release of pain-causing neurotransmitters like glutamate, substance P and calcitonin gene-related peptide.

At the same time, endorphins also bind to postsynaptic neurons,

opening potassium channels here, leading to hyperpolarization and decreased excitability of the neuron. These effects together reduce the transmission of pain signals to the brain.

If we move up to the brain’s reward pathway, made up of midbrain regions like the ventral tegmental area, nucleus accumbens, and prefrontal cortex, we find another important effect of opioids.

Here, inhibitory neurons normally release gamma-aminobutyric acid, or GABA, at the presynaptic terminal, which, in turn inhibits postsynaptic dopaminergic neurons, leading to decreased dopamine release.

When endorphins or opioids come in and bind to the opioid receptors on these inhibitory GABAergic neurons, they cause a decrease in GABA release.

With less GABA around, there is less inhibition of dopaminergic neurons, and therefore more dopamine. More dopamine leads to a calming sensation and feelings of pleasure or euphoria.

Now, switching gears from dopamine; some opioids also affect serotonergic pathways. In response to certain opioids, descending tracts from the brain activate neurons that release serotonin in the spinal cord, reducing ascending pain transmission.

An important connection here is that when serotonergic opioids are combined with medications that also increase serotonin levels, it can potentially lead to a life-threatening condition called serotonin syndrome.

Last but not least, let’s take a look at the noradrenergic pathways.

Here, opioids have an inhibitory effect on noradrenergic neurons in the brain, especially in the locus coeruleus, leading to a decrease in norepinephrine release. This contributes to the sedative effects of opioids and is one of the reasons why they may lead to respiratory depression.

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 range of opioid effects like analgesia, euphoria and sedation. These are called full agonists.

Others, like tramadol, activate opioid receptors but have a weaker effect. These opioids are called partial agonists.

There is a “ceiling effect” on the analgesia they can provide, meaning it won’t progress beyond a certain point even with additional dosing. They also cause less respiratory depression and euphoria than full 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. Many routes of medication administration can be used for opioids, but some of the most common are orally, intravenously, or through patches on the skin, as in the case of fentanyl. Fentanyl is a highly potent full agonist and is typically only used to control severe pain that couldn’t be eased with other opioid medications; it’s also used as an anesthetic medication due to its rapid onset and short duration of action. Codeine is a weaker full agonist and is often taken orally with other analgesics like acetaminophen, to treat moderate pain, like after a dental procedure.

Opioids can also act on the brainstem’s cough center to suppress cough, making codeine and hydrocodone useful antitussive options in adults with severe cough that is refractory to other medications.

Historically meperidine was used for labor and other pain management but has fallen out of use due to side effects and the availability of safer alternatives.

Unfortunately, opioids have a high risk of causing dependence, and the euphoric feelings they produce, especially the full agonists, can lead to substance use disorder.

Methadone is full agonist that does not cause the euphoric rush of other opioids, and it has a long half-life, so it’s often given to decrease withdrawal symptoms for people with opioid use disorder. An added benefit is that it also blocks the euphoric feeling that comes from taking other opioids, so it helps to prevent future misuse.

There are also some opioids that don’t have significant analgesic effects. For example, loperamide, a peripherally acting mu-opioid agonist, is used to reduce the motility of the gastrointestinal tract and treat diarrhea. It mostly stays in the gut and is actively transported out of the central nervous system at standard doses, therefore it has less potential for misuse than other opioids.

Now, common partial agonists include buprenorphine, butorphanol, pentazocine, and tramadol. The first three are also classified as mixed agonist-antagonists. Buprenorphine is a partial agonist at the mu receptor, but an antagonist at the kappa receptor, while butorphanol is an agonist at the kappa receptor, but partial agonist or antagonist at the mu receptor. This means that when given alone, it acts as a partial agonist at the mu receptor, but, if a full agonist is present at the same time, butorphanol will block it from binding, acting as an antagonist. Pentazocine is a full agonist at the kappa receptor and a partial agonist and weak antagonist at the mu receptor.

All three can be used to manage moderate pain that is not controlled by other medications; however, butorphanol and pentazocine are rarely used in practice.

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

Now, when these medications compete for the same receptors as full agonists, they lead to a decrease in the overall effect of the full agonist and can even displace them from the receptors.

On one hand, this can be a good thing; as a partial agonist, buprenorphine can stimulate opioid receptors enough to decrease cravings and help with mild withdrawal symptoms in people with opioid use disorder, without triggering euphoric feelings or respiratory depression. However, because they displace full agonists, these medications can cause significant withdrawal symptoms if given to someone with physical dependency on a full agonist.

Okay, let’s move on to side effects. In the central nervous system, stimulation of mu opioid receptors can cause euphoria, but the stimulation of kappa receptors can lead to the opposite, dysphoria, where the person feels unhappy and uneasy. Stimulation of opioid receptors in the GI tract causes a decrease in motility and constipation, but they increase tone in the biliary tract, which can worsen the pain of biliary colic. Other side effects include pinpoint pupils, or pupillary constriction, flushing, and nausea.