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How Opioids Trigger Chronic Pain

Could your choice of pain relief be the cause of more pain?

Chronic pain can be caused by opioids. Yes, you read that right. Using opioids to relieve pain can cause and perpetuate chronic pain by activating nervous system cells called glial cells (Echeverria-Villalobos et al. 2023). These activated glial and immune cells can cause paradoxical hyperalgesia; a condition where people taking opioids can actually become more sensitive to pain. Hyperalgesia means amplified pain.

Already have chronic pain? Find out why and ways to combat pain here.

Background on chronic pain

First a little background on chronic pain. Chronic pain is associated with reorganization of pain circuits in the brain and spinal cord. This involves structural and functional changes in nerves, and their managing staff, glial cells (discussion in Tang et al. 2021). Due to this, all your nerves start telling you that they are in pain all the time even when there is no physical cause of the pain. YES, pain can exist for no reason.

Well that stinks...why do your nerves do you dirty like that? Are they just whiny? To answer that question, let's dive into the fascinating world of glial cells or glia, the overlooked cells nobody sings songs about. Glial cells care for neurons in the central nervous system (CNS) and peripheral nervous system (PNS). While your neurons swan around and take all the credit for your brilliant insights and fancy footwork, glia quietly do literally everything else. Glial cells are involved in nursing, housekeeping, obtaining supplies, communication, system regulation and even defense (for more on these vital cells see our pages on Glial Cells Are the Brain's National Guard and Glial Cells Protect the Brain.

Normally your glial cells nurture and care for your neurons. Some even cuddle up around your neurons like soft blankets, swaddling them, protecting them, and healing them. So imagine what happens when some environment factor, such as opioid use, activates glial cells and turns them from loving partners into untrained immune cells.

Glial cells go from loving emotionally supporting cells to overly nervous and trigger happy untrained bodyguards. Suddenly, the neuron goes from being peacefully coddled by supportive friends to being surrounded by a platoon of loud and crazy first-time military recruits eager to fire their chemical weapons at the first thing that moves - including their client! No one is safe from the fallout.

So what does your nerve cell do? Well, what would you do if you were tied down and a crazy person started firing a flamethrower near you? Yes, the stressed out neuron starts calling for help loudly. The way your neurons call for help is loudly tell the brain they are in pain over and over again. After a while these pain messages hot line a direct pathway to the brain. This pain pathway can eventually get hard wired into the nervous system and brain causing chronic pain. At this point, the initial cause of distress or pain can be removed and the dysfunctional neurons will keep firing!

Turkish Opium For Britain- the USE of Opium in British Medicine, UK, 1943. A chemist makes up a doctor's prescription from galenicals. Galenicals are concentrated extracts diluted to make up the medicine.

opoids

Steps to trigger chronic pain

1) Get injured, traumatized, sick or inflamed. Opioids, chemotherapy, inflammation, injury, trauma, pain, viruses, stress, and sensory signals can all activate and/or sensitize glial cells, nociceptors and nerves.

2) The activated glia cells (microglia, astrocytes, oligodendrocytes) in the the peripheral sensory system (PNS) cause chronic neuroinflammation (nervous system and brain inflammation). This happens due to the change in the types of chemicals (neuropeptides, cytokines and chemokines) produced by activated glia compared to nonactivated glia.

3) The influx of inflammatory chemicals increases vascular permeability; in other words your blood vessels get leaky and let all sorts of things crossover. This allows immune cells from the body to infiltrate the central nervous system (CNS) (Echeverria-Villalobos et al. 2023).

4) These new immune cells activate more glia (such as microglia) in the CNS.

5) Activated microglia produce chemicals (neuropeptides, cytokines and chemokines) which increase the sensitivity and firing properties of second order neurons. Second order neurons are the middleman in a sensory pathway. They receive messages about pain, touch, vibration and other stimuli directly from sensory neurons (first order neurons). Second order neurons than pass that message on to third order neurons in the brain where processing occurs.

6) Since the second order neurons are more sensitive, it upregulates pain signaling to the cerebral cortex. This is called central sensitization. It is a vital part of acute pain becoming chronic.

Sensory Pathway

Example of a sensory pathway: You step on a lego. First order neurons deliver a message of pain and pressure to the second order neurons. Second order neurons transmit this message to third order neurons in the brain (thalamus). Third order neurons transmit message to sensory cortex. The sensory cortex processes and interprets messages from your body's senses. It tells you what to do; in this case "swear", "jump around saying ow" and "rub foot".

Note (for all of those who like to know the complete picture): humans also have involuntary reflexes that work faster than nerves can transmit messages. This is why you will instinctively jump off that lego before your brain has a chance to process the information.

Overview:

Sensitive and activated immune and glial cells can alter neuronal function and initiate and maintain pathological/chronic pain. At the same time, activated glia weaken the ability of opioid drugs to reduce pain by contributing to the development of opioid tolerance and dependence. This can cause paradoxical hyperalgesia.

The longer this cycle goes on the more likely it will cause a chronic pain cycle. Learn more about how this happens in What Causes Chronic Pain Loops?

Blue Box of Science: Glia under stress

Astrocytes (a type of glia) that are under stress from extended opioid use lose the ability to remove excess glutamate from neuronal synapses. So what does that mean for you?

Your brain needs glutamine for neurons to communicate; but too much glutamine causes the cells to remain in a state of chronic excitement. Think about it like coffee for the brain. A little glutamine enhances brain productive but excess glutamate causes nerves to remain in prolong states of excitotoxity which can result in damage or death.

To be clear, the glutamine itself does not directly harm cells. However, the activation of neuron's glutamine receptors for too long causes a toxic cascade of reactive oxygen species (ROS), oxidative stress, depolarization of membranes, and mitochondrial dysfunction (see Armada-Moreira et al. 2020 for an excellent summary). This toxic cascade damages neurons, glia and other cells.

Opioids activate glial cells through the classical opioid receptor, MOR, and the innate immune receptor, Toll-like receptor 4 (TLR4) (see Zhang et al. 2020 for a diagram of this mechanism and more on glial activation).

Activated microglial cells induce pro-inflammatory glial activation that leads to MORE chronic pain (Echeverria-Villalobos et al. 2023).

Definitions:

Excitotoxicity: extended overactivation of excitatory neurotransmitters such as glutamate which can lead to neuron damage or death. Basically the neuron is overstimulated.

*Names and some minor identifying details in all stories in this website are changed to protect people's privacy.

This information in this website is for informational purposes only and does not constitute medical advice, diagnosis, or treatment.

So what is the real deal about opioid painkillers?

Right now there is a debate about opioids. For some people they have caused life long pain, for other people they allow them to function. For a while doctors handed out opioids like candy. Now they are overly restrictive which has led some people with chronic pain to take illegal drugs.

Matteo M. (54 year old man): "I am a disabled vet due to driving over a roadside bomb in Iraq. I've had both hips and a knee replaced. Due to the pain I take opioids. I often get treated like I am a drug seeker when I need a medication refill."

I am not going to shame anyone who is in chronic pain and needs opioids to function. If it works for you great. However, I would caution anyone who is not currently taking opioids like oxycodone to avoid them if at all possible. They are extremely addictive and can cause chronic pain instead of preventing it. In particular, you should try to assess if your pain is caused by something other than physical injury. This type of pain is best treated using other methods that deal with the brain dysfunction or the neuron activation that can cause chronic pain.

Some people do have physical or tissue damage and opioids may be the best option. Right now there is a coalition of researchers and doctors working to increase pain management options for people who function best on opioid painkillers. According to their research, the current public health policy that limits the availability of clinically prescribed opioid painkillers has had no affect on the number of opioid treatment admissions or on drug overdose/poisoning mortality (Aubry and Lawhern 2025).

References:

Armada-Moreira A, Gomes JI, Pina CC, Savchak OK, Gonçalves-Ribeiro J, Rei N, Pinto S, Morais TP, Martins RS, Ribeiro FF, Sebastião AM, Crunelli V, Vaz SH. Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases. Front Cell Neurosci. 2020 Apr 24;14:90. doi: 10.3389/fncel.2020.00090. Full article.

Aubry L and Lawhern R. (2025). Relationship Between Patients Dispensed Prescription Opioids, Opioid Treatment Admissions and Overdose Deaths: 2006-2018 and Beyond. Medical Research Archives. 13. 10.18103/mra.v13i3.6440. PDF.

Echeverria-Villalobos M, Tortorici V, Brito BE, Ryskamp D, Uribe A, Weaver T. The role of neuroinflammation in the transition of acute to chronic pain and the opioid-induced hyperalgesia and tolerance. Front Pharmacol. 2023 Dec 15;14:1297931. doi: 10.3389/fphar.2023.1297931. Full article.

Kandy SK, Nimonkar MM, Dash SS, Mehta B, Markandeya YS. Astaxanthin Protection against Neuronal Excitotoxicity via Glutamate Receptor Inhibition and Improvement of Mitochondrial Function. Mar Drugs. 2022 Oct 18;20(10):645. doi: 10.3390/md20100645. Full article.

Tang J, Bair M, Descalzi G. Reactive Astrocytes: Critical Players in the Development of Chronic Pain. Front Psychiatry. 2021 May 28;12:682056. doi: 10.3389/fpsyt.2021.682056. Full article.

Zhang H, Largent-Milnes TM, Vanderah TW. Glial neuroimmune signaling in opioid reward. Brain Res Bull. 2020 Feb;155:102-111. doi: 10.1016/j.brainresbull.2019.11.012. Full article.