The world is full of unexplained pain, with many dozens of possible causes. By far the most important thing to understand about treating chronic pain is that it is difficult because it almost never has one cause: it is extremely multifactorial. It’s always a game of Whac-A-Mole with chronic pain — but some really strange moles (and well-camouflaged too).

I publish a busy website about pain, and so I get email like this more often than I change my socks:

I’ve been to every medical specialist you can imagine. They can’t find anything wrong with me. The psychiatrist says it’s not in my head, and the rheumatologist says it’s not in my body. But something is causing my pain. It’s not an infection or a fracture or a cancer. It’s not a sprain or a pinched nerve or a cattle prod. What else is there? What else is left?

What else indeed? When “obvious” and known causes of pain have been eliminated, what next? What else causes pain? How else can pain start, change, worsen? This article summarizes 34 of the not-so-obvious ways to hurt, the things that might help you understand pain that has defied diagnosis or explanation so far. There are a lot more possibilities, but it’s a start, and this article hopefully focusses on the most important.

A lot of pain is unexplained

A man hid a little wad of marijuana up his nose, and then lost it up there and then forgot it for almost twenty years — oops! — until it started causing severe headaches:

Through the years he suffered recurring sinus infections and had trouble breathing out of the right side of his nose. But he didn’t connect the problems to his lost cannabis. It wasn’t until 18 years later — when he was struggling with headaches and had a CT scan of his brain — that doctors finally discovered the petrified pot.

Doesn’t get much more surprising than that! There are countless other less bizarre possibilities. The “official” causes of all kinds of chronic pain break down into three roughly equally large categories, plus one small “other” category:1

injury (38%)
unknown (31%)
musculoskeletal (24%), a vague category dominated by arthritis, the rheumatic diseases, and headaches
other (7%), which is mostly cancer and abdominal pain plus “everything else” (mostly pain related to major physiological systems, and one-in-a-zillion cases like petrified pot up your nose)
Misdiagnosis is routine, of course. Arthritis and the rheumatic diseases should probably be in their own major category, and almost everything else filed under “unknown.” Pain after injury is surprisingly murky: sure, it might have started with an injury, but two years later is that still the “cause”? It has usually transmogrified into something else, and exactly how that works is much more about the “unknown” than “injury.” Many cases of chronic pain are hard to put in just one of these categories (or they only seem easy to place). As you browse around this article, you’ll notice that most causes of pain are hard to categorize.

Table of Contents

Basic mechanisms, processes, and concepts (potentially relevant to many injuries or illnesses, and a lot of these overlap partially or even completely):

Sensitization (somatic and visceral)
Chronic pain does not work like acute pain
Psychological amplification
All in your head: pure psychosomatic pain
Pain with literally no specific cause
Muscle spasm, tension, contracture
Referred pain
Spatial summation
The pain of stuckness
A genetic defect that exaggerates all sensation
Stupid, stupid neutrophils
Chronic subtle inflammation and “inflammaging”
Unexplained neuropathy (especially channelopathy)
Non-obvious nerve entrapment
Loneliness & social isolation
And some specific pathologies (things that can be diagnosed, and in some cases treated)…

Trigger points
Complex regional pain syndrome (CRPS)
Fibromyalgia? By definition, fibromyalgia is unexplained chronic widespread pain. It is not in itself a “cause” of pain. Read more about fibromyalgia.
Myelopathy (spinal cord impingement, especially and probably intermittent)
Claudication: the pain of impaired blood flow
Ehlers–Danlos syndrome and the hypermobility spectrum disorders
Nutritional deficiencies: vitamin D and magnesium
Mitochondrial disease
Chronic immune activation after infection
Early stages of …
Facioscapulohumeral Muscular Dystrophy (FSHD)
Autoimmune diseases
Multiple sclerosis
Drug related:
Side effects, especially statins, bisphosphonates, fluoroquinolones, retinoids
Opioid-induced hyperalgesia
Analgesic rebound
Benzodiazepene withdrawal (both erratic and chronic)
If I included every disease that causes aches and pains, this list would wrap around the Earth. I’ve narrowed it down to problems that are particularly notorious for both (a) evading diagnosis and (b) causing primarily aches and pains and other vague, non-specific symptoms (and not other symptoms that would easily lead to a diagnosis). Some of them are in a grey zone, of course.
Some more topics I’m considering for future updates to this article:

multiple level radiculopathy (similar in spirit to subtle/intermittent myelopathy)
painful anatomical oddities like os trignum syndrome (and there are quite a few of these actually)
Whipple’s disease can cause a bunch of joint pain (interesting but super rare)
fluoroquinolone toxicity
the acne drug Isotretinoin (Accutane) may cause joint pain and, in rare cases, symptoms that mimic rheumatoid arthritis and axial spondyloarthritis
mycotoxin poisoning from mold
chronic low-grade infections, probably a bigger deal than we realize (and also overlaps with some crankery)
autonomic neuropathy
exertional rhabdomyolysis (much more common in the era of CrossFit), and weirdly it’s possible that “deep tissue” massage is also causing a lot of rhabdo
inequality/injustice/poverty, the great predictors of chronic stress in humans, are strong causes of disease and all-cause mortality — which inevitably includes chronic pain — and this relationship remains strong even in places where access to health care is more egalitarian

Pain itself often modifies the way the central nervous system processes pain, so that a patient actually becomes more sensitive and gets more pain with less provocation. This is called “central sensitization.” (And there’s peripheral sensitization too.) Sensitized patients are not only more sensitive to things that should hurt, but also to ordinary touch and pressure as well. Their pain also “echoes,” fading more slowly than in other people. This phenomenon is usually superimposed over other problems, but it can also occur acutely and be the primary issue, as in complex regional pain syndrome, or amplified pain syndrome, which disporportionately affects girls and young women.

Importantly, sensitization can affect our guts more than skin, muscles, and joints. Visceral sensitization can be caused by stress, which may be one reason why stress is so closely linked with abdominal pain.

For more information, see Sensitization in Chronic Pain: Pain itself can change how pain works, resulting in more pain with less provocation.

Chronic pain does not work like acute pain

Chronic and acute pain are radically different. Chronic pain is not just acute pain that kept going. Over several weeks, the nature of pain changes. Unfortunately, we actually still don’t have a good understanding of how it changes. It probably involves a complex stew of the ideas in this article. For instance, sensitization (see above) is clearly a major factor. Emotional and physical stresses are strongly linked to chronic pain, but we’re not sure exactly how.

Chronic pain can become a kind of “neurological habit,” regardless of whether any tissue is still in trouble.Chronic pain can become a kind of “neurological habit,” regardless of whether any tissue is still in trouble.
The “neuromatrix” theory of pain suggests that pain is produced by “widely distributed neural network in the brain rather than directly by sensory input evoked by injury, inflammation, or other pathology.”2

Translation (and the important thing for desperate patients to understand): chronic pain rarely continues to be driven by tissue in trouble, and starts to become a kind of “neurological habit” — regardless of whether any tissue is still in trouble. In many cases, it’s not! The pain is a kind of ghost of the original, a tormenting poltergeist. The analogy to “phantom limb pain” is strong: it’s like phantom limb pain, but without losing a body part.

The 3 Basic Types of Pain: Nociceptive, neuropathic, and “other”

There are two main kinds of pain: nociceptive and neuropathic. Nociceptive pain is the most familiar because it arises from damaged tissue, like a cut or a burn. Neuropathic is more rare, because it is caused by damage to the damage-reporting system itself, the nervous system. Some pain, like fibromyalgia pain, doesn’t fit into either category, and was historically and poorly labelled “functional pain.” Pain is also either somatic (skin, muscle, joints) or visceral (organs). Read more …
Psychological amplification

Not pain that’s “all in your head” pain, but pain that is seriously “aggravated by your head.” Sometimes the brain amplifies pain substantially as a consequence of stress, anxiety, and fear. Like an ulcer, there can be a physical problem, but one that is also sensitive to your emotional state.3 Sometimes, the brain’s interpretation of a situation becomes a major part of the issue, or even the dominant factor — still not “all” in your head, but “a lot” in your head. Like picking at a scab, the brain can become excessively focused on a pain problem. For more information, see Pain is Weird: Pain science reveals a volatile, misleading sensation that is often more than just a symptom, and sometimes worse than whatever started it.

Amplified pain exists near one end of a spectrum: acute pain with a clear cause is at one end, chronic pain driven entirely by the mind at the other. With a clear traumatic trigger, the diagnosis of “amplified” pain seems apt: there was a painful problem originally, it just got exaggerated by the power of the mind. The more disproportionate that amplification gets, the more like pure psychosomatic pain it gets…

All in your head: true psychosomatic pain

Pure “all in your head” chronic pain is probably quite rare. Unexplained chronic pain is routinely chalked up to psychology. “Patients often find themselves trapped in a zone between the worlds of medicine and psychiatry, with neither community taking full responsibility.” (O’Sullivan) But, in most cases, there’s a diagnosable cause that simply hasn’t been diagnosed yet, and that’s the main reason this article exists. Most pain patients need better diagnosis, not a psychiatrist.

But at least a few probably do need a psychiatrist. Pure psychosomatic pain probably does exist. Some tension headaches are probably good examples of how mental state can directly drive pain with no clear intermediate mechanism. Amplified pain is a much more extreme example, which makes it quite clear that psychological factors can dominate chronic pain. The phenomenon of functional neurological disorder (FND, formerly known as “conversion” disorder) makes it even clearer: seizures, paralysis, blindness, and other neurological symptoms in the absence of neurological disease.45 Strange but true! If we can paralyze ourselves with our minds, we can probably make ourselves hurt tooStrange but true! If we can paralyze ourselves with our minds, we can probably make ourselves hurt too, although this is surprisingly unclear. In fact, some chronic pain might actually be one of the members of the FND family, just undiagnosable — because pain can have so many other causes (whereas seizures, paralysis, and blindness have relatively short lists of possible causes to eliminate, leaving only the power of mind to explain the problem). No one really knows.

Even the most psychological of all cases of chronic pain likely still have a seed, something that originally inspired the pain, making them extreme cases of “amplified pain” (see previous section), and not technically “pure” psychosomatic pain. But if the trigger is subtle enough, relative to the psychosomatic consequences, then it’s psychosomatic for all intents and purposes, and the trigger no more defines the problem than a grain of sand defines a pearl.

Pain with literally no specific cause

Like other complicated things in life, pain may not have any specific cause at all. Although we often speak of pain being multifactorial, we still tend to assume that just one of those factors is the specific cause of pain, and the others — sleep loss, stress, etc — are only piling on, making a bad situation worse. That picture may be wrong: some chronic pain is probably an emergent property of a big mess of synergistic stresses, with literally no specific cause. It may crop up only with an unholy combination of many factors. This is a systems perspective on pain and malaise.

How does nothing in particular actually make us hurt? There are two major key neurobiological processes: sensitization and neuroinflammation lower our thresholds for pain and malaise. They can occur independently but are usually entangled. They are set in motion by major trauma and disease, but — and this is the systems perspective — potentially also just by a variety of stresses, none of which would be enough to cause trouble on its own.

The idea of pain that truly has no specific cause is something more patients probably need to consider. Pain with no one cause is a good news scenario in the sense that it might be treated by relieving enough of the contributing factors … but bad news in the sense that it may be like fighting a hydra.

For more information, see Vulnerability to Chronic Pain: Chronic pain often has more to do with general biological vulnerabilities than specific tissue problems.

“Spasms”: cramps, dystonia, spasticity, etc

Muscle tissue is everywhere — our most massive biological system — and its subtler hijinks can cause a lot of discomfort without giving itself away. No one has any doubt about the cause of pain when they get a massive calf or foot cramp, but not all cramps are so obvious, and there are other types of insidious, uncomfortable muscle contractions.

This is a broad category of trouble, which contains a number of specific examples, some of which are discussed below, like “trigger points” and the “multiple sclerosis hug” (spasticity of the ribcage), and vaginismus (spasticity of the vaginal and pelvic floor muscles). Using just a wide brush for now, the types of unwanted contractions that cause the most trouble without being easy to diagnose are cramps, dystonia, and spasticity. “Spasm” — as in a “back spasm” — is an informal and non-specific term that could be used to “explain” a lot of musculoskeletal pain, and could refer to any of the more specific types of pathological contractions.