What Are Opioid Medications?

We're continuing our in-depth look at the class of drugs known as opioids. How do they work? What's the science behind them?

We all know that analgesia or pain relief is the intended use of opioids like morphine. But before we can talk about how these compounds reduce pain, we need to discuss the physiology of pain perception.

Opioid Science Comes First

Let's start with some biology. The brain and the nervous system are made up of cells called neurons. Each neuron consists of a cell body, which runs the activity of the neurons. The cell body has a number of dendrites, which come of it. These are short fibers that receive signals from other neurons and transmit them to the cell body.

Also attached to the cell body is an axon - a long fiber that takes messages from the cell body and sends them to other dendrites, and from there to other cell bodies. Axons can also end up in other tissues, like muscles, transmitting commands to them when needed. When nerves talk to each other, it is called neurotransmission. They do this by releasing chemical messengers called neurotransmitters across the spaces between cells, which are called synapses.

The chemicals are released from the axons and are picked up by specific molecules called receptors in the dendrites.

There are different receptors all over the body that send messages to your brain when they are exposed to stimuli. There are temperature receptors, that tell you when you are feeling something hot or cold. Mechanical receptors let you know when you are touching something or something is touching you. There are even receptors that detect changes in pH.

When stimuli are interpreters being noxious, meaning that they could cause damage to our tissues, specialized receptors called nociceptors send signals to our brain. Nociceptors are located throughout the body, but we mostly think of them as being in the skin, the walls of organs, and deep within other body tissues like muscles and joints. So, if you've ever smashed your finger with a hammer, splashed hot water on yourself while cooking or rolled your ankle while playing sports, you can thank your nociceptors for sending a message to your brain all about the dumb thing you just did.

We commonly refer to this message as pain, but nociceptors are kind of like the first leg of the journey that a pain signal takes to your brain. When we encounter noxious stimuli, like touching a hot stove, an electrical signal is sent up a primary afferent neuron to a part of the spine cord called the dorsal root ganglia. Their electrical current causes a release of neurotransmitters that pass the pain signal from the primary afferent neuron to a secondary excitatory neuron.

There are several neurotransmitters involved in pain signaling, but the major players are glutamate and substance P. The messages then sent up the spinal cord to different parts of the brain, where its interpreted as pain. One area of the brain that receives the signal is the thalamus, which helps give context to the message. The thalamus relays the message to the hypothalamus and limbic system, which help us learn from our pain and avoid touching hot stoves in the future.

A downside to these parts of the brain receiving pain messages is that they can modify our behaviors and emotions about pain in ways that can be disruptive. Afraid of getting shots because of a traumatic childhood experience at the doctor's office? Yeah, that's probably not the nurse or pediatricians fault. You can thank your limbic system for that one.

So what does all of this have to do with opioids? Well, the cool thing about opioids is that they inhibit the pain signal at multiple steps in the pathway. They work in the brain, the spinal cord and, even in the periphery. In the brain opioids have mood altering effects, cause sedation, and can even decrease the emotional response to pain.

Opioids block the signaling from the primary nociceptors to the secondary neurons. Opioids also work on neurons that descend from the brainstem to the spinal cord that function to modulate pain signals. Those descending pathways have fibers that either amplify or inhibit pain signals being sent to the brain. Opioid compounds suppress the fibers amplifying the signal and enhance the fibers that inhibit the signal.

There is even an evidence that opioids can work peripherally to decrease activation of primary neurons and inhibit immune and inflammatory responses to noxious stimuli.

The fact is, opioid medications are so effective at treating acute pain because they attack it from every neurological angle. Let's get even more science and technical for a second and talk about how opioids work with the neurons in the spinal cord. We will focus on the area where the primary neuron is passing the pain signal to the secondary neuron.

Remember, space where the neurons meet is called the synaptic cleft. The influx of calcium ions causes the release of neurotransmitters into the synapse. Those neurotransmitters will float across the synapse and then bind with receptors on the postsynaptic neuron. This initiates a chain of events within the secondary neuron that further propagates the pain signal to the brain.

There are specific opioid receptors on both the presynaptic and postsynaptic neuron. When an opioid compound attaches to a receptor on the presynaptic neuron, it decreases the number of calcium ions that can enter the cell ultimately decreasing the number of excitatory neurotransmitters that are released into the synapse.

Opioids binding to their receptors on the postsynaptic neuron function to decrease the response to any of the neurotransmitters being released from the presynaptic neuron. The end result is less pain. But wait for a second, why do our nerves have receptors that respond to a compound that miraculously diminishes pain? After all, it doesn't really make sense that mammals would evolve a specific receptor for the sap of the poppy flower.

Humans have known about the analgesic effects of opium for millennia, but we wouldn't really be able to explain exactly why we had opioid receptors until the 1970s. 

It turns out that we have a built-in, or endogenous, analgesic system that modulates pain signals. These endogenous opioids like beta-endorphin and enkephalins and dynorphins are collectively known as endorphins, a name derived from ENDOgenous moRHPHINE.

See what they did there? So things are going to get super-duper sciency here. The beta-endorphins in enkephalins and dynorphins interact with different opioid receptors to varying degrees, but one thing they all have in common is the tetra- peptide sequence Tyrosine, Glycine, Glycine, and Phenylalanine.

This sequence is really important because it's needed for the endogenous opioid to interact chemically with the opioid receptor on a neuron. If this is hard to visualize, think of the opioid receptors is the car's ignition and the tetrapeptide sequence is the key. If the key fits in the ignition just right, then the opioid receptor will be activated and cause a series of changes in the neuron that decreased the pain signal.

Opioid drugs and medications take advantage of this structure-activity relationship. They bind to our opioid receptors in much the same way that endogenous opioids do, but with much more powerful consequences.


Types of Opioid Receptors

opioid receptors

There are three types of opioid receptors: mu receptors, kappa receptors, and delta receptors. When activated with an opioid agonist like morphine, hydrocodone or heroin, they will all produce analgesia. Each one comes with an unpleasant suite of side effects, that we often associate with opioid use.

Kappa receptor stimulation is associated with hallucinations and dysphoria, an overwhelming sense of dissatisfaction, anxiety, and restlessness. Delta and mu receptor agonist can cause respiratory depression because opioid stimulation in the midbrain suppresses the body's ability to appropriately detect carbon dioxide levels in the body. This can cause a person to simply stop breathing for a period of time.

Other unpleasant side effects of opioid drugs are sedation, urinary retention, nausea, vomiting, dizziness and really bad constipation.

One might argue that the most catastrophic side effect of opioids is tolerance, meaning that higher and higher doses are required to get the same level of pain relief. The exact cellular mechanism behind tolerance is unclear. Though, there are many plausible theories in any case opioid tolerance is the harbinger of physical dependence and addiction.