Why Do Some People Feel More Pain Than Others? 8 Biological Reasons

TL;DR

A 2017 study published in the journal Pain took more than 300 healthy adults, applied the exact same 118-degree stimulus to each of them, and asked them to rate how much it hurt on a scale of zero to 100. The results ranged from four out of 100 all the way to 100 out of 100. Same stimulus. Same temperature. Wildly different pain experiences. This study is one of the clearest pieces of evidence that pain is not proportionate to tissue damage, and that the mechanisms determining how much pain you feel are biological, not imaginary. This article breaks down eight of those mechanisms, what is actually happening in the body, and why understanding them is the most important step toward changing them.

What Most Patients Are Told

If you have chronic pain, you have almost certainly encountered some version of this experience.

You describe your pain to a provider. The imaging comes back with nothing significant. The physical exam does not explain the severity of what you are feeling. And somewhere in the conversation, either explicitly or in the subtext, the message is delivered that the pain does not match the findings. That what you are experiencing does not align with what can be measured.

This is one of the most damaging and dismissive experiences a chronic pain sufferer can have. Not because the provider is wrong that the imaging looks normal. But because the conclusion drawn from that, that the pain must therefore be exaggerated, psychosomatic, or somehow a personal failing, is based on a fundamental misunderstanding of how pain actually works.

Pain is not a direct readout of tissue damage. It never was. And in 2017, a well-designed study published in one of the most respected pain research journals in the world confirmed in 300+ subjects what many chronic pain patients already knew from lived experience: the same objective physical stimulus can produce wildly different pain sensations from one person to the next.

When poked with an 118-degree probe, study participants were asked to rate their pain on a scale of 0-100. Answers ranged from 4/100 all the way to 100/100. The question is not whether your pain is real. It is. The question is what is determining how much of it you feel, and what can actually be done about it.

Where The Conventional Explanation Breaks Down

The conventional model of pain is built on a relatively simple idea: injury or damage produces a signal, that signal travels to the brain, and the brain produces pain in proportion to the damage. By this model, more damage equals more pain, less damage equals less pain, and no visible damage should equal minimal or no pain.

The 2017 study makes that model untenable. You cannot apply identical stimuli to 300+ people and get a 25-fold range in pain ratings if pain were simply proportionate to the stimulus.

What the study confirms is that there are underlying biological variables that make people more susceptible to pain than others. In people with chronic pain, multiple variables are working simultaneously to amplify the signal, raising the baseline of pain perception far above where it should be.

There are many of them, but eight of them stick out more than the others. Luckily, every single one is something that can be identified, understood, and addressed.

Mechanism One: Your COMT Gene and the Neurotransmitter Problem Nobody Explained

The first mechanism involves genetics, and it centers on a gene called COMT, which stands for catechol-O-methyltransferase.

COMT's job is to clear catecholamines: dopamine, epinephrine, and norepinephrine. These are the neurotransmitters responsible for focus, motivation, stress response, and, critically for chronic pain, the regulation of the spinal cord's pain-filtering system.

A significant subset of the population carries a variant of this gene that clears these neurotransmitters up to 20 percent more slowly than average. At first glance, that might sound beneficial. Dopamine and norepinephrine are associated with wellbeing and are key activators of descending inhibition, the spinal cord's built-in system for filtering out insignificant pain signals. More of them should mean better filtration. Right?

This is where the nuance matters, and where most explanations stop too soon.

Your spinal cord and your peripheral nerves both respond to dopamine, epinephrine, and norepinephrine, but through different types of receptors. In the spinal cord, these neurotransmitters activate the descending inhibition pathway, increasing the pain filter and preventing insignificant signals from reaching the brain. Think about putting on clothes in the morning. You feel them immediately, and then within seconds your brain dismisses the sensation as irrelevant. That is the pain filter working.

In the peripheral nerves throughout your body, however, the same catecholamines bind to a different receptor type. And at that peripheral receptor, they do the opposite: they increase pain sensitivity and actually reduce the amount of descending inhibition the spinal cord can produce.

Here is the critical detail. The peripheral receptor is stronger than the spinal cord receptor. It wins the competition between the two. So when the sluggish COMT gene keeps more dopamine and norepinephrine circulating for longer, the net effect is that the peripheral amplifying receptor gets more activation, not the spinal cord's protective one. The result is a biological predisposition toward higher pain sensitivity that is baked into your DNA.

This same genetic variant has a second consequence that is directly relevant to anyone on opioid medication. People with the sluggish COMT gene express more opioid receptors than those without it. That sounds like it would mean opioids work better for them. In practice, it means the opposite. With more receptors present, the same dose of medication leaves a larger number of receptors unsatisfied, producing less complete pain relief. A person with a normal functioning COMT gene may achieve adequate relief at a standard dose. A person with the sluggish variant may need a significantly higher dose to reach the same level of relief, which has nothing to do with drug-seeking behavior and everything to do with receptor expression.

The important clarification here is that while you cannot change your genetics, you can change your epigenetics: the nutritional and lifestyle inputs that determine which genes are expressed and how strongly. The interventions covered throughout this content library, addressing inflammation, gut health, neurotransmitter production, and mitochondrial function, all influence the epigenetic environment that determines how significantly this genetic variant impacts your pain.

Mechanism Two: Sex Hormones and Why Women's Pain Is Not Fixed

The second mechanism explains something that frustrates a significant proportion of chronic pain sufferers, particularly women: why pain is not consistent from day to day, week to week, or across different phases of life.

The sex hormones estrogen and progesterone are not stable background hormones. They fluctuate continuously across the menstrual cycle, shift dramatically during pregnancy, and undergo major transitions around perimenopause and menopause. And both of them have direct effects on the spinal cord's pain-filtering system.

Estrogen increases the synthesis of serotonin, helps keep it active in the synapse for longer, and improves the sensitivity of serotonin receptors. Serotonin is one of the two primary neurotransmitters that power the descending inhibition pathway in the spinal cord. More estrogen means more serotonin activity means a stronger pain filter.

Progesterone drives the production of GABA, the nervous system's primary inhibitory neurotransmitter. GABA also works directly on the descending pain pathways in the spinal cord, contributing to the same filtering mechanism that prevents insignificant stimuli from being processed as pain.

When estrogen and progesterone are high, the filter is stronger. When they drop, as they do during the luteal phase (second half) of the menstrual cycle, during postpartum periods, or during and after menopause, the filter weakens. The same physical stimulus that produced minimal pain when hormones were adequate may produce significant pain when they are not.

This is not a psychological response to hormonal fluctuation. It is a direct neurochemical consequence of losing the raw materials that power the spinal cord's pain-regulation system. For any chronic pain sufferer whose pain varies with hormonal cycles, or whose pain significantly worsened around pregnancy or menopause, this is not a coincidence.

Mechanism Three: Chronic Inflammation Has Raised Your Pain Baseline

The third mechanism is one that most chronic pain patients have heard about in general terms, but almost never had explained precisely enough to understand what it means for their experience.

Chronic inflammation is not the same as the inflammation you can see and feel after an injury. It is low-grade, systemic, and invisible. It produces no swelling you can observe, no heat you can feel, no redness that signals a problem. It builds silently in the background, driven by the four inflammatory pathways covered in the previous article in this series, and it does something very specific to your pain experience.

It raises your baseline.

In a person without chronic inflammation, a painful stimulus might register as a three out of ten. Their pain filter is working, their nervous system is calm, and the signal is processed proportionately.

In a person with chronic systemic inflammation, that same stimulus may register as an eight. Not because the stimulus was stronger. Because the chronic inflammation has primed the nervous system, sensitized the pain receptors, and shifted the entire system toward a higher state of reactivity before the stimulus even arrived.

This is one of the most important explanations for why people with chronic pain describe pain to things that should not cause pain, or describe ordinary sensations as significantly more intense than they should be. The stimulus has not changed. The baseline has shifted.

Addressing the inflammation is not an add-on to chronic pain treatment. It is one of the most direct and impactful interventions available, and the four pathways through which chronic inflammation must be addressed, NF-κB, the arachidonic acid pathway, inflammatory cytokines, and the NLRP3 inflammasome, each require specific and targeted approaches that anti-inflammatory medications alone do not provide.

Mechanism Four: Your Gut Microbiome Is Regulating Your Pain Filter

The fourth mechanism is the one that surprises most chronic pain patients because the connection is so counterintuitive: the bacteria in your gut are directly influencing how much pain you feel.

When the balance between beneficial and harmful bacteria in the gut is healthy, those bacteria produce three things that matter enormously for pain: serotonin, GABA, and short-chain fatty acids. All three of these signal to the vagus nerve, the primary communication pathway between the gut and the brain, that the internal environment is stable and safe. That calm signal travels up the vagus nerve to the brainstem, where it strengthens the descending inhibitory pathways in the spinal cord. The pain filter goes up. Less gets through.

When gut dysbiosis is present, when harmful bacteria are dominating and the beneficial ones are depleted, the opposite happens. Serotonin and GABA production fall. Short-chain fatty acids decrease. LPS (toxins) from harmful bacteria enters circulation. And danger signals travel up the vagus nerve instead of calming ones. The brainstem interprets a threat environment and weakens the descending inhibition system in response.

The particularly important detail here is the speed of this connection. A nervous impulse is nearly instantaneous. This means that even small, day-to-day changes in gut microbiome composition can produce relatively rapid shifts in pain levels. It is one of the most plausible explanations for the day-to-day variability in pain intensity that so many chronic pain sufferers experience and so rarely get a satisfying explanation for.

Mechanism Five: The NMDA Receptor Has Learned to Keep You in Pain

The fifth mechanism is the one with perhaps the most direct research support, and the one most consistently absent from conventional chronic pain management.

Every second of every day, your body is receiving thousands of sensory inputs. The sensation of clothing on skin. The pressure of a chair. The mild tension of normal joint movement. Your brain cannot process all of it consciously, and it should not need to. The vast majority of it is insignificant and should never reach conscious awareness.

Your spinal cord manages this through the descending inhibition pathway. It acts as a wall, a filter, preventing the insignificant signals from passing through to the brain. The NMDA receptor plays a central role in regulating whether that wall stands.

Under healthy conditions, the NMDA receptor activates when something genuinely significant arrives. The wall drops, the signal gets through, the brain processes it as pain. The stimulus resolves, the wall comes back up, and the filter is restored.

The NMDA receptor has a memory, though. If it is stimulated repeatedly, through ongoing injury, persistent inflammation, chronic stress, or any combination of the contributors to chronic pain, the wall drops with each activation. But after repeated stimulation, when the stimulus finally resolves, the wall does not come back up. The receptor has learned, from history, to keep the gate open.

Now every signal gets through. Pain to things that should not cause pain. Pain disproportionate to stimuli that would register as trivial in a healthy nervous system. Central sensitization, the defining feature of virtually all chronic pain conditions, is the result.

The important reassurance here is that a sensitized NMDA receptor is not permanent damage. It is a learned state. And learned states can be unlearned through the same categories of intervention that contributed to the sensitization in the first place: resolving chronic inflammation, restoring gut health, supporting neurotransmitter production, improving sleep quality, and removing the environmental and metabolic inputs that are keeping the receptor primed.

Mechanism Six: Vagal Tone Determines How Much Threat Your Brain Perceives

The sixth mechanism involves a concept called vagal tone, which refers to the functional capacity of the vagus nerve to deliver calming information from the body to the brain.

The vagus nerve is the primary parasympathetic nerve in the body. It connects the brainstem to the heart, the lungs, and the gut, and its primary function is not sending signals down to those organs. Eighty percent of its activity runs in the other direction, collecting information from the body and delivering it to the brain.

When the heart is healthy and its rhythm is regular, when the lungs are functioning well and breathing is full, when the gut microbiome is balanced and the intestinal environment is calm, the vagus nerve delivers consistent, reassuring signals to the brain. The brain interprets a stable internal environment, maintains its pain filter at a higher threshold, and allows the descending inhibition system to work effectively.

When any of those systems are struggling, when cardiovascular fitness is poor, when breathing is shallow and limited, when the gut is inflamed and dysbiotic, the signals traveling up the vagus nerve tell a different story. They deliver a picture of internal instability and potential threat. The brain responds as it is designed to respond to threat: by heightening sensitivity, lowering the pain threshold, and allowing more sensory information through to conscious awareness because in a threat environment, you cannot afford to miss anything.

Improving vagal tone does not require running a marathon. It requires finding any daily activity that elevates heart rate, even briefly. Infrared sauna has demonstrated cardiovascular benefits comparable to moderate physical exercise in research settings and represents one of the most accessible options for people whose chronic pain limits conventional exercise. Breathwork specifically expands lung capacity and directly influences vagal nerve activation. And gut health interventions are among the most direct available means of improving the quality of the signals the vagus nerve delivers.

Mechanism Seven: Mitochondrial Dysfunction Is Depriving Your Pain System of Energy

The seventh mechanism is one of the most consistently overlooked in chronic pain management: the mitochondria are not working well, and your pain system is paying the price for it.

Mitochondria are present in virtually every cell in the body. Their primary function is producing ATP, the energy molecule of the body. Tissue repair requires energy. Clearing inflammatory waste requires energy. Maintaining the structural and functional integrity of pain receptors and the neurons that regulate them requires energy. All of it depends on adequate mitochondrial output.

When mitochondria are functioning optimally, that energy is available and the system runs as designed. When mitochondrial function is impaired, and in chronic pain conditions it consistently is, two things happen simultaneously. ATP production falls, depriving every energy-dependent process in the body of the fuel it needs. And mitochondria that are not functioning properly begin generating free radicals as a byproduct of their impaired energy production.

Those free radicals drive oxidative stress, which drives inflammation. Which drives central sensitization, degrades the NMDA receptor, impairs the gut lining, and raises the pain baseline.

Mitochondrial dysfunction is not just one factor among many in chronic pain. It is a foundational contributor that compounds and worsens nearly every other mechanism on this list. And improving it is achievable through targeted nutritional and lifestyle interventions that are accessible without a prescription.

Mechanism Eight: Your Emotions Are Physically Changing Your Pain Filter

The eighth mechanism is the one that requires the most careful framing, because it is the one most likely to be misunderstood, and the one that has caused the most harm when it has been communicated carelessly.

Your emotions are influencing your pain. Not because the pain is imaginary. Not because the pain is in your head. But because fear, anxiety, and catastrophizing thoughts around pain activate a brain structure called the periaqueductal gray, which sits at the intersection of the brainstem and the brain and plays a central role in pain modulation and defensive behavior.

Under normal conditions, the periaqueductal gray helps regulate the descending inhibition system, contributing to the filter that prevents insignificant signals from reaching conscious pain awareness. When it is activated by threat, whether that threat is physical or emotional, the filter weakens. The brain's logic is straightforward and appropriate in genuine danger: when your life might be at risk, you cannot afford to miss any sensory information. Every sensation becomes potentially important. Everything gets through.

The problem in chronic pain is that the periaqueductal gray has the same kind of memory as the NMDA receptor. Repeated activation, through repeated episodes of fear around pain, repeated anxiety about what the day will bring, repeated catastrophizing about whether the pain will ever end, trains it to maintain a lower threshold. Over time, it defaults to a threat state.

It is worth saying clearly what this means for the chronic pain sufferer: it is not a weakness. It is not an attitude problem. It is completely understandable to be afraid of pain when every movement seems to provoke it. It is completely understandable to wake up anxious when you do not know what your pain level will be that day or what it will prevent you from doing. Anyone experiencing that would feel what you feel. The fear and anxiety are a natural response to a genuinely difficult situation.

But understanding the physiology means understanding that those emotional states are feeding back into the pain through a documented neurological mechanism, and that treating the emotional component is not a soft supplement to the real treatment. It is one of the most impactful biological interventions available.

Mind-body counseling, pain reprocessing therapy, and even general talk therapy that explicitly connects emotional states to the physiological pain mechanisms produce measurable improvements in pain outcomes. Not because they talk the pain away. But because they interrupt the bidirectional mechanism in which pain drives fear and anxiety, and fear and anxiety drive more pain.

This piece of the treatment plan should not need to be argued for, justified, or treated as an add-on by any provider who understands the physiology. It is standard of care. And if you are not receiving it alongside your physical and biochemical treatment, that is a gap that deserves to be closed.

The Thread Running Through All Eight

A 4 out of 100 and a 100 out of 100 in response to the same 118-degree probe. The 2017 study does not just demonstrate that pain varies between individuals. It demonstrates that there are specific biological systems whose state at any given moment determines where on that spectrum any individual lands.

COMT gene variants and opioid receptor expression. Sex hormone fluctuation and its effect on neurotransmitter-driven descending inhibition. Chronic inflammation elevating the pain baseline. Gut microbiome composition delivering calming or threatening signals to the brain. NMDA receptor sensitization trained to keep the gate open. Vagal tone shaped by cardiovascular, respiratory, and gastrointestinal health. Mitochondrial function determining whether the energy required for healing and regulation is available. And the emotional state of the periaqueductal gray, shaped by the ongoing experience of living in pain.

None of these are fixed. All of them are addressable. And a treatment plan that evaluates and targets all eight is a fundamentally different proposition from one that manages the pain signal while leaving every one of its drivers intact.

The Bottom Line

You are not more sensitive to pain because you are weak, anxious, or imagining things.

You are more sensitive to pain because specific biological mechanisms are amplifying the signal, and virtually none of them are being addressed by the treatments you have likely already tried.

Understanding what is actually driving your pain is not the end of the conversation. It is the beginning of the one that can actually change it.

Written By:

Dr. Jason Winkelmann

Naturopathic doctor, Chiropractor, Chronic Pain Specialist, and Educator

Frequently Asked Questions

If the same stimulus caused wildly different pain ratings in the study, does that mean some of those people were exaggerating?

No. The study's design controlled for the stimulus precisely so that the variable being measured was biological pain sensitivity, not exaggeration or tolerance. The differences in response reflect real differences in how each participant's nervous system processed an identical input. The mechanisms responsible, including COMT gene variants, chronic inflammation levels, gut microbiome composition, NMDA receptor sensitivity, and vagal tone, all produce measurable physiological effects on pain processing. A person rating the stimulus at 100 out of 100 is not dramatizing. Their nervous system is genuinely producing that level of pain signal in response.

I have been told my pain is psychological. Is that what this article is saying?

No. This article is describing documented physiological mechanisms. The emotional component, mechanism eight, operates through a specific brain structure called the periaqueductal gray, which physically modulates the descending inhibition system. The effect of emotions on pain is biological, not metaphorical. The distinction between physical and psychological pain is not a useful one in chronic pain, because the mechanisms overlap completely. Fear and anxiety produce neurological changes that alter pain processing the same way inflammation does. Both require treatment. Neither invalidates the other.

Why does my pain vary so much from day to day if my underlying condition has not changed?

Several of the eight mechanisms are dynamic rather than static. Gut microbiome composition, blood glucose stability, hormonal fluctuation, and the state of the NLRP3 inflammasome all change from day to day based on diet, sleep, stress levels, and activity. Any of these can shift the pain baseline significantly within a 24-hour period. This also means that targeted interventions in these areas can produce relatively rapid results in both directions: the same speed that worsens pain when inputs deteriorate is the speed at which pain can improve when the right inputs are consistently applied.

Is it possible to influence the COMT gene variant if I have it?

The genetic variant itself cannot be changed. What can be influenced is the epigenetic environment around it: the nutritional, hormonal, and lifestyle factors that determine how strongly the variant expresses and how its downstream effects manifest. Addressing chronic inflammation, supporting serotonin and norepinephrine production through adequate precursor amino acids and cofactors, improving gut health, and optimizing mitochondrial function all reduce the impact of the sluggish COMT variant on pain sensitivity, even though the gene itself remains unchanged. Genetics in this context sets a predisposition. Epigenetics determines how strongly that predisposition is expressed.

What is the most important of the eight mechanisms to address first?

They are all interconnected, and in most chronic pain patients, multiple mechanisms are active simultaneously. That said, chronic inflammation is the one that feeds most directly into all of the others. It sensitizes the NMDA receptor, impairs gut health, degrades mitochondrial function, disrupts hormonal balance, and activates the periaqueductal gray. Addressing the four inflammatory pathways comprehensively, through nutrition, gut health, and targeted supplementation rather than anti-inflammatory medications alone, creates the most favorable downstream conditions for the other mechanisms to respond to treatment. The appropriate starting point is a comprehensive evaluation that identifies which of the eight are most active in your specific case.