The world is full of unexplained pain, with many dozens of possible causes. 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 28 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.
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
- Pain with literally no specific cause
- Muscle spasm, tension, contracture
- Referred pain
- Spatial summation
- The pain of stuckness
- Stupid, stupid neutrophils
- Chronic low-grade inflammation and “inflammaging”
- Idiopathic 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)
- 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
- Early stages of …
- Drug related:
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
- poverty, the mightiest of all predictors of chronic stress in humans, is strong cause 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 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.
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.”1
Translation (and the important thing for desperate patients to understand):
Not pain that’s “all in your head” pain, but pain that is “aggravated by your head.” Sometimes the brain amplifies pain 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.2 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.
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 it overlaps substantially with sensitization — it’s basically saying that sensitization may be triggered by a bunch of different stresses — but it’s a different enough perspective to be worth considering separately. The idea of pain that truly has no specific cause is something more patients probably need to consider.
Pain without 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.
“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). Using just 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.
Fun fact: if your muscles are contracted for long enough, they will actually “freeze” like that: essentially scarred into place, a phenomenon called “contracture.”3
See Cramps, Spasms, Tremors & Twitches: The biology and treatment of unwanted muscle contractions.
Referred pain results in an amazing amount of medical barking up the wrong tree.
Anything that hurts inside the body — anything deeper than skin — is harder for the brain to locate. This is partly because we literally just don’t have enough nerve endings for it, and partly because the nervous system isn’t perfect and signals literally get “crossed.” The practical result of this is that internal pain with any cause may be felt somewhere completely different. Despite the fact that this phenomenon is well known, it still results in an amazing amount of medical barking up the wrong tree. Referred pain isn’t exactly a “cause” of pain, but it belongs in this list because it’s an important concept that can help to explain many pain problems that otherwise don’t make sense. For instance, both of the examples at the beginning of this article were cases where referred pain fooled doctors — in both cases, the pain was caused by a trigger point in a nearby muscle, not by vital organs. The doctors simply looked in the wrong place!
Spatial summation and why some body areas suffer more, like the neck and back
If five bees stung you all at once, in one small area on your back, you would probably think you had been stung by one super-bee (or maybe that you’d been poked with a cattle prod). Two sources of pain close together will be felt as one larger painful spot, a neurological effect called “spatial summation.” Pain perception is low resolution, and the brain can merge pains that are up to 20cm apart.4 This might explain why some areas of the body, like the neck and back, are more prone to pain: either the brain can “sum” more widely spaced sources of pain in some places than others, and/or some areas simply have more to sum up, more potential sources of pain. Just recently, research showed that we have roughly the same perceptual “resolution” for pain everywhere in the body,5 so the spine is probably not a common trouble spot because we cast a wider summation net there. This makes it even more likely that there’s just more to sum in the spine: lots and lots of tissues that often have minor problems, which get perceived as a smaller number of worse problems. This could also help to explain the chronicity of spinal pain: if you have “one” back pain problem that is actually coming from two nearby sources, you’re going to think you have same back pain problem until both sources are relieved, which is probably going to take longer.
The pain of stuckness
Here’s a simple experiment: assume an awkward posture and stay there. How long can you last? Within an hour you will probably be in severe pain. Why? You haven’t actually damaged anything! But we seem to be wired to avoid stagnancy, probably because every cell in our body depends on nearly constant movement to survive. The exact mechanism of pain is probably nerve endings that detect tension on cartilage, ligaments, and tendons, and which in turn is interpreted by the brain as a surprisingly serious threat. But here’s the kicker: this effect is potent enough that it can be triggered without an obviously awkward posture. It can be caused by surprisingly subtle postural stresses (like from poor ergonomics), or anything that deprives tissue of full movement. When a joint feels “stuck,” for instance, and there is no obvious way (and sometimes no anatomical way) of moving to get “unstuck,” the sensation can escalate to a screaming itch-you-can’t-scratch. This is may be the main causes of neck cricks, for instance, and scads of other miscellaneous aches and pains.
Stupid, stupid neutrophils
Neutrophils are defender cells that are supposed to destroy bacteria that invade wounds, a normal part of the inflammatory response to injury. Bizarrely, neutrophils go to work even when the wound is sterile, not open to the outside world. Like an overzealous police force with nothing better to do, they also attack a common cellular organ, mitochondria, whenever it is spilled from cells by injury. Mitochondria are actually honoured symbiotic guests that convert our food to energy for us. Normally we live out our lives in perfect harmony with mitochondria, biological BFFs. But when they get the chance, neutrophils target and hunt them like they are invaders6 because for millions of years they haven’t gotten the evolutionary memo that mitochondria should be left in peace.
Inflammation often seems excessive because it is, because
For more information, see Why Does Pain Hurt? How an evolutionary wrong turn led to a biological glitch that condemned the animal kingdom — you included — to much louder, longer pain.
Chronic low-grade inflammation and “inflammaging”
Chronic, subtle, systemic inflammation may be a factor in stubborn musculoskeletal pain. We get more inflamed as we age, a process quaintly known as “inflammaging” (for real). This may be the way that some of the other things discussed here actually cause trouble, or it may be an independent phenomenon. Inflammaging correlates with poor fitness and obesity, also known as metabolic syndrome, the biological precursor to diabetes and heart disease. And that, in turn is linked to chronic psychological stress, and of course biological stresses like smoking and sleep deprivation. Basically, the “harder” we live, the more likely inflammaging and metabolic syndrome get.
There are several other unproven but plausible reasons why inflammation escalates as we age. Each of these deserves its own discussion as yet another way that we may end up in pain, but they are also quite speculative, so for now I’ll just lump them together as “possible causes of inflammaging.” For more thorough discussion of these possibilities, see Chronic, Subtle, Systemic Inflammation.
- the accumulation of permanent minor infections
- lasting collateral damage from past infections (essentially causing minor autoimmune disease are too subtle or nonspecific to diagnose, and also allergies)
- environmental pollutants
Idiopathic neuropathy, especially channelopathy
“Neuropathic” pain is the ultimate false alarm: pain caused by trouble with the nervous system itself. It’s the difference between engine trouble and trouble with that light on your dashboard that says there’s engine trouble. There are some quite blatant neuropathic pain problems, such as spinal cord impingement (discussed below), but humans also suffer from a surprisingly high rate of unexplained and/or subtle neuropathies, where the pain-reporting system is just kinda a bit wonky.
Specifically, a lot of this trouble may be driven by channelopathy, which is a poorly understood type of neurological trouble related to “dysfunction of ion channels located in the membranes of all cells and many cellular organelles.”7 In other words, poorly understood glitchiness at the very tiniest scale of biology. What it boils down to is that sometimes nerves “fire” for no apparent reason, causing all kinds of trouble, including false alarm pain.
This is probably not one disease. It’s likely that unexplained neuropathy has many pathological explanations, if only we could see them. “Channelopathy” will probably never be its own diagnosis: it’s just a likely but hypothetical type of problem that’s basically still beyond the power of medicine to deal with.
Non-obvious nerve entrapment
Usually when you have a pinched nerve, the symptoms are obvious: zinging “electrical” pain, tingling, and numbness are the signatures of a distressed nerve, or peripheral neuropathy. Unfortunately, peripheral neuropathy does not always announce itself so clearly. Sometimes all you get is pain.8 This predicament almost invariably leads to a wild goose chase for more “mechanical” causes of pain. Consider this remarkable case study of cluneal nerve entrapment…
The cluneal nerve pass from the low back and sacrum into the buttocks, just under the skin, and they can get tangled up with ligaments and connective tissue on their way, potentially causing chronic low back pain. In 2016, Aota reported on “a case of severe low back pain, which was completely treated by release of the middle cluneal nerve.”9 Exploratory surgery identified nerves “entrapped in adhesions.” They cut them free … and that was the ticket. The patient was decisively cured. Which is pretty cool. But that was after years of suffering, and a pointless surgery on her intervertebral discs.
As straightforward as that example is, it is also possible that her problem was not the nerve “snag” per se but a biological vulnerability to feeling it. It’s likely that nerve entrapments only cause trouble when combined with other hard-to-diagnose problems… like some of the other things in this article. No one really knows.
Social isolation and loneliness
Social isolation — “loneliness” if you’re unhappy about it — is a major general health suppressor in the same league as other major vulnerabilities like sleep deprivation or smoking.10 It almost certainly involves increased vulnerability to chronic pain as part of the deal.11 We do know that sensitization and pain chronicity are driven by catastrophization and social factors, and injury and disability are going to seem more threatening — more “catastrophic” — to people without good social support, all other things being equal.
Most of us have some unexplained sore sports, which mainly feel like sensitive muscle tissue, but also tendons and ligaments. And some of us have a lot of them.
These are often called muscle knots informally, or “myofascial trigger points” more formally these days (and lots of other names through history). They seem to be involved in a lot of the world’s aches and pains.
There’s good news: as common and vexing as these sore spots are, many seem to be relieved by a bit of simple stimulation, by a little rubbing, like scratching an itch. For a basic primer, see Basic Self-Massage Tips for Myofascial Trigger Points. For an insane amount of information, see my book on this topic: Trigger Points & Myofascial Pain Syndrome.
Complex regional pain syndrome (CRPS)
Most pain sensitization is simply a reaction to pain itself, a more-or-less normal, common, and reversible reaction to chronic pain. But it’s also possible for the pain system to spin out of control and severely over-react to stimuli because it’s “sick,” a disease in its own right. The example of this is complex regional pain syndrome, which causes extreme pain, usually in a limb, and usually following some relatively minor tissue insult like an insect bite, a minor cut, or a small fracture.
When it’s full-blown, the severity of this problem is impossible to understate (suicide is common), and yet there probably are milder variations of it. Many times in my career I have become quite convinced that a patient had to be suffering from some lesser form of CRPS, awful but not enough to clinch a CRPS diagnosis.
Myelopathy and dysautonomia
An irritated spinal cord — usually irritated by being slightly pinched by a narrow spinal canal — can cause an astonishing variety of problems, including pain, without ever clearly giving itself away. Symptoms can be in virtually any location in the body, if the location of the trouble is high in the spine. This can go on for years, bad enough to cause pain but never bad enough to be easily diagnosable.
Worse, there’s some intriguing evidence that “minor” irritation of the upper spinal cord may be uniquely problematic, causing “dysautonomia” — excessive sympathetic arousal, causing you to react as if stressed.12 This weird low-grade crazy-making effect is new and still uncertain, but it is nicely consistent with the much firmer, recent discovery that the autonomic nervous system is very disturbed in the aftermath of major spinal cord injuries, causing organ failure13 — a clinical reality historically overshadowed by the seriousness of paralysis. Subtle dysautonomia from chronic mechanical irritation of the spinal cord is definitely a plausible, sinister, and thoroughly obscure explanation for some chronic pain and anxiety.
Claudication: the pain of impaired blood flow
Sometimes an artery gets narrowed or pinched off and causes serious pain. Although simple in principle, it tends to get missed in younger people, where it’s a relatively rare problem, and so the suspicion falls on other things. It also gets missed because “musculoskeletal” is a realm of medicine where circulatory function is rarely considered at all. But it should be an easy diagnosis: claudication tends to cause a deep aching pain exclusively with exertion (when tissues are demanding oxygen), which isn’t how most musculoskeletal problems behave. Here’s a good story about this kind of pain and its misdiagnosis …
A patient had sciatica-like leg pain for thirty-five years and was misdiagnosed many times until finally getting not only a definitive diagnosis but a cure.14 He had a narrowed artery (arterial stenosis causing “claudication,” the pain of impaired circulation). That’s it! Not even a difficult a diagnosis in the end, really. There were some pretty glaring clues there that got ignored by a lot of people who should have known better.
But not only was he misdiagnosed many times over more than three decades, he was misdiagnosed fashionably: that is, each misdiagnosis neatly fit a paradigm in physical therapy (better than it fit his symptoms). This carried on right up to and including the present day fascination with psychosocial factors and sensitization (which served him no better than any of the other paradigms had). Taylor and Kerry:
Interestingly, the patient’s belief that something ‘was actually wrong’ had remained with him throughout the journey. This, of course, had been explained away to him (more recently) by current research and evidence-based thinking on central sensitization and pain.
Just fascinating. The authors thoughtfully explore the implications of this rather shameful episode. The bottom line? Good diagnostic skills are never out of fashion. Or shouldn’t be, anyway!15
Hypermobility spectrum disorders and Ehlers–Danlos syndrome
Hypermobile patients get hurt easily and have a lot of chronic body body pain.16 There are many types of hypermobility, with a wide range of severity, from trivial party trick flexibility in one or two joints (“double-jointed”) with no apparent consequences — especially early in life — all the way to full-blown genetic disorders of the connective tissue with many serious medical consequences. There’s a huge gray zone in the middle of under-diagnosed and under-treated people, who are definitely having problems but may never figure out why or what to do about it.
Hypermobility spectrum disorders (HSD) are a group of conditions defined by joint hypermobility — unexplained joint looseness. HSD is a bucket diagnosis for people with symptomatic hypermobility, but without a connective tissue disorder that explains it, like Ehlers–Danlos syndrome or Marfan syndrome. Most connective tissue disorders are relatively obvious, but EDS can easily evade diagnosis, making it a prime suspect in many cases of chronic pain…
Ehlers–Danlos syndrome (EDS) is a group of conditions that includes hypermobility along with fragile tissues that injure easily and heal poorly (especially skin), with many consequences. The most common form of EDS is hypermobile EDS (hEDS). It’s tricky to distinguish hEDS from HSD.17 However, hEDS is probably associated with serious rheumatic diseases (i.e. psoriasis, ankylosing spondylitis, rheumatoid arthritis)… and this is fresh science and very likely to be missed, “perhaps due to a lack of gravitas surrounding the HEDS diagnosis.”18
Given the musculoskeletal troubles that we know hEDS can cause, it is reasonable to guess that less severe hypermobility (HSD) may also be both clinically important and yet even less obvious.
So, hEDS/HSD is serious … but it’s not taken seriously. Even doctors who know about hEDS/HSD usually assume that it’s mostly a minor condition, and would definitely not refer patients on to a rheumatologist.
Vitamin D and magnesium deficiencies
There is not a single supplement or anti-inflammatory superfood that is clearly beneficial for any common kind of pain, but there are a couple nutritional deficiencies that stand out as significant, legitimate suspects in many chronic pain cases. Pain may be the only clear symptom of either one.
Vitamin D deficiency is on the firmest ground. It is probably more common than once suspected — at least 1 in 20 people in the lowest estimates,19 and possibly many more.20 It can cause subtle widespread pain that may be misdiagnosed as fibromyalgia and/or chronic fatigue syndrome, including symptoms like muscle and bone aching,21 fatigue and weakness, lower pain threshold, and more acute soreness after exercise that is slower to resolve. For more information, see Vitamin D for Pain.
Magnesium deficiency is also a suspected factor in chronic pain, especially migraines.22 Some people are aware that magnesium supplementation is the specific rationale for Epsom salts: a form of getting the stuff into your body that is of very dubious value (especially compared to straightforward oral supplementation). Ironically, magnesium (in a clinical setting) is known to induce cramping and severe muscular pain, so none of this biology straightforward!
The first sign of syphilis is a lesion that is often minor and easily missed: usually painless, often inaccessible, nearly identical to a canker sore when it’s in the mouth. The second stage consists a few weeks of malaise and rashes. If the rashes aren’t clear enough, this stage is often mistaken for the flu or just an inexplicable phase of the blahs. The disease then goes dormant to some degree, for years, or forever, but in some people it will develop into the final stage, which is where the chronic aches and pains may develop (just one of a great variety of possible symptoms). It’s a slow disease that can affect many organ systems, so diagnosis often takes a long time, despite frank pathology that can be easily diagnosed with the right tests. Some patients with unexplained chronic widespread pain (fibromyalgia) probably have syphilis.
Facioscapulohumeral Muscular Dystrophy [early stages]
I have a good friend, someone I’ve known for most of my life, who has this common and usually fairly mild form of muscular dystrophy. It was undiagnosed for decades because the symptoms were subtle and he wasn’t even trying to figure it out. By his late 30s, his upper trapezius wasting away, he finally got the diagnosis — and then he started to see how the disease explained an awful lot about his life, many experiences and personal “quirks”… like a lifelong tendency to excessive soreness after exercise!23
Even his father’s life made more sense: the disease is genetic, and he obviously struggled with it, stoically, undiagnosed from cradle to grave.
Biology is destiny, and this condition is a really good example of it. How many people out there are in that multi-decade period of wondering why they get so sore so easily, before finally being diagnosed with FSHD?
Autoimmune diseases [early stages]
The autoimmune diseases are a huge class of pathologies that can cause essentially any non-specific symptoms for a long time before diagnosis. These are conditions like lupus, rheumatoid arthritis, celiac disease, inflammatory back pain (spondyloarthritis, a common cause of the phenomenon of morning back pain), and many, many more. Lupus is one of the most common and notoriously unpredictable and slow to develop. Some people with a variety of weird aches and pains and other symptoms are going to end up getting diagnosed with lupus eventually, but it can take literally years for the situation to clarify. It’s a classic hypochondriac’s diagnosis, because of its many possible vague symptoms that overlap with anxiety symptoms.
And then there’s multiple sclerosis …
Multiple sclerosis [early stages]
Another classic hypochondriac’s diagnosis, multiple sclerosis is all too real, and the most common autoimmune disorder of the central nervous system. So it's another autoimmune disease, but it's one that is particularly common, serious, and prone to causing pain before diagnosis. It definitely does not cause primarily pain in every patient; the classic onset of multiple sclerosis is more blatantly neurological in character (tingling, numbness, and sensory disturbances). But some patients definitely start with pain, and spasm is the primary mechanism. One particularly good and sinister example: the “MS hug,” which feels like a painfully tight band around the chest. Although the feeling of constriction is the classic symptom, many patients also just experience widespread and erratic pain in the chest wall, probably from erratic, isolated painful contractions.
A diagnosis of multiple sclerosis usually isn’t anywhere near as slow to come as, say, a lupus diagnosis. It will probably reveal itself sooner rather than later. But there is definitely potential for a period of unexplained pain.
Lymphoma (cancer of the lymphatic system, lymph nodes)
Lymphoma is a cancer of the infection-fighting cells of the immune system, cells in the lymph nodes, spleen, thymus, bone marrow, and other parts of the body. These cells grow out of control. Although relatively easy to treat, as cancers go, it’s also notorious for causing extremely unpredictable symptoms for long period before diagnosis. There is a classic, obvious first sign — badly swollen lymph nodes — but many cases are clinically subtle, mainly just various forms of “the blahs” and a couple distinctive symptoms like night sweats and itching. The swollen nodes are not painful, and pain is not a classic symptom … but it is a possible, depending on where tumours are forming and what they are pressing on, and possibly because of increased systemic inflammation.
Drug side effects
Some drugs are notorious for causing joint and/or muscle pain as a side effect. Other kinds of pain are possible too, but those are usually more distinctive and readily identified as a drug side effect. Joint and muscle pain are easily mistaken for the ordinary aches and pains of aging, removing suspicion from the drugs that are actually causing them. Some of the usual suspects are:
- statins (for lowering cholesterol)
- bisphosphonates (for osteoporosis and Paget’s disease)
- fluoroquinolones (a class of antibiotics)
- retinoids (for skin conditions, like Accutane for acne)
- Trintellix (an antidepressant)
Some of these may actually be innocent, others almost certainly do cause trouble: it’s surprisingly unclear, like most of medicine. Here’s some more detail about statins and bisphosphonates …
Actonel (risedronate) is one of the more popular bisphosphonate drugs, any of which may cause severe musculoskeletal pain years after first exposure.
The bisphosphonates — On January 7, 2008, the U.S. Food and Drug Administration alerted health care professionals and consumers to the unusual severe side effects of a popular class of drugs for osteoporosis and Paget’s disease, the bisphosphonate (Wikipedia). They can cause “severe and sometimes incapacitating bone, joint, and/or muscle pain” which “may occur within days, months, or years” after first taking the medication. This medication has almost certainly explained some otherwise inexplicable pain in some of my patients over the years! Alendronate and risedronate (Actonel) are the two most popular bisphosphonates, and they are usually prescribed for osteoporosis or for a bone-deforming condition called Paget’s disease. If you are 40+ and grappling with a mysterious pain problem, check your medicine cabinet for bisphosphonates in particular, but of course any other medication that could cause pain as a side effect.
The statins — The drugs that lower our blood cholesterol, like Lipitor and Crestor, may also cause pain. Statins are important and widely used drugs, and their deleterious effect on muscle is widely considered a diagnosable condition: statin myalgia, or statin-associated muscle symptoms (SAMS).24 A few patients, about 1 in 10,000, get a more obvious, serious case of muscle poisoning, rhabdomyolysis,25 and an even rarer and more serious condition afflicts 1 in 100,000: statin-associated autoimmune myopathy.2627
And yet there is also confusion and controversy about the prevalence of statin myalgia.28 There’s even clear evidence that it could be some kind of illusion or misunderstanding: in one head-scratcher of a study, taking statins only increased pain when patients knew they were taking statins.29 So that’s weird! The truth is probably “all of the above” and “it’s complicated” — it seems likely that some patients are genuinely intolerant of statins, while others are suffering from fear of statins and/or some other cause of musculoskeletal pain (of which there many). There might also be some tricky X-factors, like vitamin D deficiency, which seems to be linked to statin myalgia.30
Fortunately, for the genuinely statin intolerant — and you probably do exist! — it’s easy to solve by lowering the dose or switching to another statin.
This is basically the mother of all side effects, with a generous dose of tragic irony.
Opioids are, of course, the cause of an enormous amount of misery and controversy right now. Most people assume opioids are “powerful medicine,” and of course they are in some ways, but what few people realize is that they are surprisingly ineffective for many kinds of chronic pain, completely ineffective for a fairly high percentage of the population with a certain gene … and they can backfire in anyone. “Opioid induced hyperalgesia” is a nasty fate in which opioids actually cause pain instead of relieving it.31 It’s so counter-intuitive that many people on opioids take a long time to figure out that their “pain medication” is causing pain.
This almost counts as a drug side-effect, but it’s an important enough phenomenon in its own right that it deserves separate description. When you take a lot of analgesics — pain-killers — it’s possible to pre-empt the production of your body’s own pain-fighting molecules. Endorphin production, for instance, will drop. This can have disastrous consequences when you stop taking the drugs, resulting in worse pain than ever. This is part of the phenomenon of the well-known serious withdrawal symptoms from some drugs; it is a less well-known problem with over-the-counter pain-killers. Although this phenomenon isn’t particularly mysterious or difficult to identify, it does show us something important about how pain works: we aren’t entirely without our own defenses, and those defenses can actually be undermined by artificial help. And there are scenarios where analgesic rebound may be difficult to detect. Given how extremely common analgesic usage is, it’s likely that people with recurrent headaches may be suffering primarily from bouts of rebound pain, occurring in the occasional gaps between erratic but generally intensive self-prescribing of pain killers.
I have a good story about a terrible withdrawal-induced headache: see my headache tutorial.
Benzodiazapene withdrawal syndrome
The benzos, Valium and many others, are potent tranquilizers, which sedate us by simulating a flood of an important neurotransmitter that is one of the body’s built-in sedatives. We can quickly develop powerful physical dependence on benzos, and rushed withdrawal is notoriously brutal. Withdrawal symptoms can even develop while we are still taking the drug, going a little bit into withdrawal before the next dose, which basically causes erratic and minor but frequent withdrawal symptoms.
In benzo withdrawal, you are the opposite of tranquilized: you’re anti-tranquilized. Huge chunks of your biology are way too excitable. The list of potential side effects is endless — benzo withdrawal is notorious for the freakish variety of symptoms it causes — but they all revolve around a strong theme of jittery misery, like being over-caffeinated but more extreme. Sensory distortion in general is the rule, and everything hurts more than it should.
And, in some people, for unknown reasons, withdrawal symptoms are long-term. It’s unclear what the mechanism for this persistence is, but it’s likely that the ferocity of withdrawal results in a poorly calibrated pain system (central sensitization), which is a tough neurological tailspin to pull out of. Another way of putting it is that withdrawal is basically so surreal and traumatic that it can permanently disrupt our nervous system’s ability to interpret stimuli, especially threatening stimuli, leading to long-term erratic false alarms.
Chronic pain as a destiny: many causes for many years!
Nothing’s ever simple and chronic pain least of all: it’s usually caused by a sinister stew of factors that eat away at people for a long time. Chronic pain may be “destiny” with roots going back many years, even decades.32 Trying to solve it by fixing one thing — like vitamin D, say — may be about as feasible as trying to fix a broken engine with just one tool. It can be an impossible puzzle to even understand, let alone treat. Elisa Arnaudo:
Medically unexplained symptoms (MUS) represent a major challenge for healthcare systems in industrialised countries. These symptoms are so prevalent that they are assessed in up to 50% of consultations in primary care.
Probably almost all MUS involve chronic pain, and Arnaudo’s post seems to be mostly about fibromyalgia. She proposes MUS patients are a stumper because of “an inadequate explanatory framework of disease.” In other words, we’re not just missing some pieces from a puzzle; it’s that we probably don’t even know what kind of puzzle we’re looking at.
And … not necessarily such a puzzle.
Ending with a ray of hope
It’s also possible that many of the explanations we need are really hovering just out of our current reach, and really not so tricky after all — just too subtle to be easy. They get missed not because the problem requires godlike medical insight, but because most doctors just don’t know that much about chronic pain and economics keeps appointments relatively short and so even some pretty straightforward things just get missed.
That possibility is the inspiration for this article. Some of the ways to hurt described above may be the main factors, or even the only factors, for some people.
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About Paul Ingraham
I am a science writer, former massage therapist, and I was the assistant editor at ScienceBasedMedicine.org for several years. I have had my share of injuries and pain challenges as a runner and ultimate player. My wife and I live in downtown Vancouver, Canada. See my full bio and qualifications, or my blog, Writerly. You might run into me on Facebook or Twitter.
Appendix: Two stories of diagnosing mysterious pain
Some extraordinarily desperate people came to see me when I was working as a massage therapist. Two memorable examples:
- A woman spends three days in the hospital with severe abdominal pain, but is cleared of every possible ominous medical cause … and then comes to see me?! A massage therapist!
- A man gets a ride in an ambulance with severe chest and left shoulder and arm pain, but doctors cannot find anything wrong with him … and then he comes to see me.
I got lucky with both of these cases, and I was able to treat both of them quickly and easily. There are many ways to hurt, and success was hardly guaranteed. I saw many patients with strange pains I was never able to diagnose. But both of these cases involved surprisingly clear and and treatable trigger points: hypersensitive spots in muscle tissue, causing more pain than anyone thought possible.
In the woman’s case, the trigger point was in her iliopsoas muscle, a muscle deep in the abdomen and extending downward through the pelvic that is the subject of much hype and legitimate skepticism. However, it is possible to massage it in some patients. There’s very little to tell: I guessed that it might be the problem, found the trigger point, gently massaged it for a few minutes … and that was the end of her misery. Just like that!
The man’s case was even more straightforward: he had a trigger point in his pectoralis major muscle. It was easy to find, as the muscle twitched violently when I palpated it, the most robust example of a “jump sign” I ever saw. It was nasty, but in twenty minutes of massage we reduced the “heart attack” pain by 80%. The next day it was gone, and it stayed gone for as long as I knew him — years after that. I tell his story in more detail in my trigger points book.
- PS The 3 Basic Types of Pain — Nociceptive, neuropathic, and “other” (and then some more)
- PS Pain & Injury Survival Tips — Dozens of ideas (and links) for evidence-based rehabilitation and self-treatment for common pain problems and injuries
- PS Why Does Pain Hurt? — How an evolutionary wrong turn led to a biological glitch that condemned the animal kingdom — you included — to much louder, longer pain
- PS Insomnia Until it Hurts — The role of sleep deprivation in chronic pain, especially muscle pain
- PS Nerve Pain Is Overdiagnosed — A story about nerve pain that wasn’t really nerve pain
- PS A Rational Guide to Fibromyalgia — The science of the mysterious disease of pain, exhaustion, and mental fog
- PS Chronic, Subtle, Systemic Inflammation — One possible sneaky cause of puzzling chronic pain
What’s new in this article?
Sixteen updates have been logged for this article since publication (2007). All PainScience.com updates are logged to show a long term commitment to quality, accuracy, and currency. more
When’s the last time you read a blog post and found a list of many changes made to that page since publication? Like good footnotes, this sets PainScience.com apart from other health websites and blogs. Although footnotes are more useful, the update logs are important. They are “fine print,” but more meaningful than most of the comments that most Internet pages waste pixels on.
I log any change to articles that might be of interest to a keen reader. Complete update logging of all noteworthy improvements to all articles started in 2016. Prior to that, I only logged major updates for the most popular and controversial articles.
See the What’s New? page for updates to all recent site updates.
June — Added section about benzodiazepene (tranquilizer) withdrawal.
June — Added section about social isolation and loneliness, the first of a series that I will be adding about non-specific vulnerabilities to illness and chronic pain.
March — Added a listed other possibilities that I’m considering for future updates. I think the list itself has value, even without elaboration.
February — New section: “Spatial summation and why some body areas suffer more, like the neck and back.”
2018 — New section: “Non-obvious nerve entrapment.”
2018 — New section: “Claudication: the pain of impaired blood flow.”
2018 — New section: “Syphilis.”
2018 — New section: “Pain with literally no specific cause.”
2018 — Major reboot and expansion. This is now a much more comprehensive review of possible causes of pain. There’s more to do and suggestions and requests for additions are very welcome. I hope this will become one of the most useful articles on PainScience.com.
2018 — More information about other drugs with painful side effects.
2017 — Science udpate — Cited evidence that statin myalgia could be bogus, not actually a real problem.
2017 — Added a table of contents. A few minor edits.
2016 — New conclusion, with both discouraging and encouraging perspectives, taken from a recent blog post about the challenge of medically unexplained symptoms.
2016 — Added Vitamin D deficiency and chronic low-grade inflammation.
2016 — Minor addition: a sidebar about “the wilderness of the medically unexplained.”
2016 — Added sidebar about the basic types of pain, nociceptive and neurpathic. Added #10, about exaggerated inflammation.
2007 — Publication.
- Melzack R. Pain and the neuromatrix in the brain. J Dent Educ. 2001 Dec;65(12):1378–82. PubMed #11780656. ❐
The neuromatrix theory of pain proposes that pain is a multidimensional experience produced by characteristic "neurosignature" patterns of nerve impulses generated by a widely distributed neural network-the "body-self neuromatrix"-in the brain. These neurosignature patterns may be triggered by sensory inputs, but they may also be generated independently of them. Acute pains evoked by brief noxious inputs have been meticulously investigated by neuroscientists, and their sensory transmission mechanisms are generally well understood. In contrast, chronic pain syndromes, which are often characterized by severe pain associated with little or no discernible injury or pathology, remain a mystery. Furthermore, chronic psychological or physical stress is often associated with chronic pain, but the relationship is poorly understood. The neuromatrix theory of pain provides a new conceptual framework to examine these problems. It proposes that the output patterns of the body-self neuromatrix activate perceptual, homeostatic, and behavioral programs after injury, pathology, or chronic stress. Pain, then, is produced by the output of a widely distributed neural network in the brain rather than directly by sensory input evoked by injury, inflammation, or other pathology. The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain. Its output pattern is determined by multiple influences, of which the somatic sensory input is only a part, that converge on the neuromatrix.
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Weren’t ulcers proved to be caused by a bacteria? That they were. Helicobacter pylori was famously hunted down in 1983 by Australian scientists Barry Marshall and Robin Warren. Although its link with ulceration was initially met with much skepticism, science came around relatively quickly — convinced by evidence, just like it’s supposed to work. By the mid-90s it was widely accepted that H. pylori infection causes ulcers, and Marshall and Warren got a Nobel prize in 2005 (acceptance speech).
But! Most people infected with the bacterium have no symptoms, and there are many variables that determine the severity of the infection and whether or not it leads to ulcer. Stress is one of those factors (see Guo et al. and Jia et al.). Thus ulcer is very likely both an H. pylori infection and a “stress-sensitive” condition.BACK TO TEXT
- Csapo R, Maganaris CN, Seynnes OR, Narici MV. On muscle, tendon and high heels. J Exp Biol. 2010 Aug;213(Pt 15):2582–8. PubMed #20639419. ❐ PainSci #55265. ❐
Chronic heel wearers, for instance, do have shortened calf muscles, stiffer Achilles tendons, and a smaller ankle range of motion. It doesn’t actually seem to cause much of a problem, but the tissue does shorten.
(See more detailed commentary on this paper.)BACK TO TEXT
- This depends on many other factors. For instance, if you can clearly see that you’ve been struck by two paintballs, 15cm apart, you’re brain is probably not going to experience one mighty paintball sting — brains are not idiots, and they can use lots of data sources to generate higher fidelity perception. BACK TO TEXT
- Holbert MD, Pedler A, Camfermann D, Harvie DS. Comparison of spatial summation properties at different body sites. Scand J Pain. 2017 Oct;17:126–131. PubMed #28850365. ❐ These researchers compared summation in the neck and back to the extremities, and found that it works about the same way: in any region, painful sites separated by as much as 15-20cm will be “summed” by the brain, making the entire area feel painful. BACK TO TEXT
- McDonald B, Pittman K, Menezes GB, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010 Oct;330mcd(6002):362–6. PubMed #20947763. ❐ BACK TO TEXT
- Kim JB. Channelopathies. Korean J Pediatr. 2014 Jan;57(1):1–18. PubMed #24578711. ❐ PainSci #53026. ❐ “Channelopathies that primarily affect neurons include certain types of epilepsy, ataxia, migraine, hyperekplexia, blindness, deafness, and peripheral pain syndromes.” BACK TO TEXT
- It might accompanied by subtle signs of neuropathy, such as a slight buzzing quality to the pain, but not enough to raise clinical suspicion of a nerve pinch. There’s clearly a range, but at least some significant percentage of cases are not obviously nerve-y. BACK TO TEXT
- Aota Y. Entrapment of middle cluneal nerves as an unknown cause of low back pain. World J Orthop. 2016 Mar;7(3):167–70. PubMed #27004164. ❐ PainSci #53097. ❐ BACK TO TEXT
- Sapolsky RM. Why Zebras Don’t Get Ulcers. 3rd ed ed. New York: Times Books; 2004. p. 164. “…the fewer social relationships a person has, the shorter his or her life expectancy, and the worse the impact of various infectious diseases. Relationships that are medically protective can take the form of marriage, contact with friends and extended family, church membership, or other group affiliations. This is a fairly consistent pattern that cuts across a lot of different settings. Moreover, these general findings are based on some careful prospective studies and are seen in both sexes and in different races, in American and European populations living in both urban and rural areas. Most important, this effect is big. The impact of social relationships on life expectancy appears to be at least as large as that of variables such as cigarette smoking, hypertension, obesity, and level of physical activity.” BACK TO TEXT
- Smith TO, Dainty JR, Williamson E, Martin KR. Association between musculoskeletal pain with social isolation and loneliness: analysis of the English Longitudinal Study of Ageing. Br J Pain. 2019 May;13(2):82–90. PubMed #31019689. ❐ PainSci #52275. ❐
This study looked for a link between chronic musculoskeletal pain, and loneliness and social isolation in several thousand older adults. They found that subject in pain were actually less likely to be socially isolated, but more likely to be lonely, an interesting apparent contradiction. However, loneliness is probably what matters: that is, social isolation isn’t a problem if you don’t feel socially isolated (lonely).BACK TO TEXT
- Holman AJ. Fibromyalgia and Positional Cervical Cord Compression Differ Only By Autonomic Nervous System Consequences: A Double-Blinded, Prospective Study. Arthritis Rheumatol. 2015;67(suppl 10).
This paper presents evidence “minor” irritation of the upper spinal cord may cause “potent sympathetic arousal in humans” — firing up the same branch of our nervous system that handles emergencies. Thirty-one of fifty-four patients with fibromyalgia and positional cervical cord compression showed clear signs of sympathatic arousal.BACK TO TEXT
- See Sezer, Hagen, Hou, Stein. BACK TO TEXT
- Taylor AJ, Kerry R. When Chronic Pain Is Not "Chronic Pain": Lessons From 3 Decades of Pain. J Orthop Sports Phys Ther. 2017 Aug;47(8):515–517. PubMed #28760092. ❐ BACK TO TEXT
- There are good criticisms of this paper from a couple of my favourite experts and writers, pointing out in a letter to the journal that one of the “fashionable” paradigms impugned here, the biopsyschosocial model, “includes the considerations [the “bio” part] that eventually cured the patient’s pain.” I like the criticism and I like the authors’ response — I see only healthy debate here. BACK TO TEXT
- Scheper MC, de Vries JE, Verbunt J, Engelbert RH. Chronic pain in hypermobility syndrome and Ehlers-Danlos syndrome (hypermobility type): it is a challenge. J Pain Res. 2015;8:591–601. PubMed #26316810. ❐ PainSci #52758. ❐ Hypermobility is “highly prevalent among patients diagnosed with chronic pain.” BACK TO TEXT
- “The essential difference between HSD and hEDS lies in the stricter criteria for hEDS compared to the HSD.” But it’s very tricky, and those criteria all very new (see the 2017 EDS International Classification). BACK TO TEXT
- Rodgers KR, Gui J, Dinulos MB, Chou RC. Ehlers-Danlos syndrome hypermobility type is associated with rheumatic diseases. Sci Rep. 2017 Jan;7:39636. PubMed #28051109. ❐ PainSci #52757. ❐
hEDS patients may see multiple subspecialists without realizing a connection between their joint symptoms and multi-systemic involvement of the disease; they are often dismissed as hypochrondriacs, and report feelings of isolation from the lack of diagnosis.
Perhaps due to a lack of gravitas surrounding the hEDS diagnosis, management of the disease varies among practitioners, and clinical workup does not often extend beyond the joint and skin examination.BACK TO TEXT
- Manson JE, Patsy M B, Rosen CJ, Taylor CL. Vitamin D Deficiency — Is There Really a Pandemic? N Engl J Med. 2016 Nov 10;375(19):1817–1820. PubMed #27959647. ❐
The claim that large proportions of North American and other populations are deficient in vitamin D is based on misinterpretation and misapplication of the Institute of Medicine reference values for nutrients — misunderstandings that can adversely affect patient care.
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- Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S–6S. PubMed #18400738. ❐ PainSci #55028. ❐ BACK TO TEXT
- Bone aching is caused by osteomalacia, which is bone weakening specifically caused by malfunctioning bone building biology. The Mayo Clinic describes osteomalacia symptoms like so: “The dull, aching pain associated with osteomalacia most commonly affects the lower back, pelvis, hips, legs and ribs. The pain may be worse at night, or when you’re putting weight on affected bones.” BACK TO TEXT
- Mauskop A, Varughese J. Why all migraine patients should be treated with magnesium. J Neural Transm (Vienna). 2012 May;119(5):575–9. PubMed #22426836. ❐ Treating migraines with magnesium is hardly a sure thing, and some object to it, but conservative magnesium supplementation is about as low-risk an intervention as they get — far better than any any migraine drug. BACK TO TEXT
- We know that FSHD causes excessive delayed-onset muscle soreness, often for many years before diagnosis, and without any other symptoms. This is a well-described genetic pathology. There is nothing squishy or uncertain about the diagnosis. And yet the mechanism by which FSHD causes soreness in the absence of any other symptoms is simply unknown. No one knows how FSHD does that. If a disease like FSHD can do it without anyone knowing how, there are surely other pathological ways to be sore without a diagnosis. BACK TO TEXT
- Di Stasi SL, Macleod TD, Winters JD, Binder-Macleod SA. Effects of Statins on Skeletal Muscle: A Perspective for Physical Therapists. Phys Ther. 2010 Aug. PubMed #20688875. ❐ BACK TO TEXT
- “Rhabdo” is a nasty but also very interesting condition. I discuss it in detail in Poisoned by Massage. BACK TO TEXT
- Mammen AL. Statin-Associated Autoimmune Myopathy. N Engl J Med. 2016 Feb;374(7):664–9. PubMed #26886523. ❐ BACK TO TEXT
- Regarding classification, professionals should take a look at a great 2004 interview with Eliot A. Brinton, MD: “There are 4 interrelated terms for muscle problems that can occur with statins. Unfortunately, they are often confused even by healthcare professionals … .” (Technical note: this document is freely available, but direct linking will hit a paywall. Medscape only reveals the whole thing to people arriving from a Google search. Simply search for do a Google search for it to get around the paywall.) BACK TO TEXT
- Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J. 2014 Jul;168(1):6–15. PubMed #24952854. ❐
In this review of several statin trials, only slightly more patients had pain on statins than without (placebo): just 12.7%, compared to 12.4%. You could conclude from this data that there actually is no such thing as statin mylagia! But it probably probably is a real phenomenon, which is highly plausible based on the existence of rarer but very severe side effects on muscle (see Mammen or Statin Therapy). We don’t have very good data about it, it’s mostly not severe, and it’s hard to distinguish from the “background noise” of many other common causes of musculoskeletal pain.BACK TO TEXT
- Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017 Jun;389(10088):2473–2481. PubMed #28476288. ❐
This study was designed to test the existence of the phenomenon of statin myalgia. Taking statins did not increase pain in patients when they were unaware that they were taking them. This suggests that statin myalgia is something people get because they are afraid of it, not because it’s a real side effect. As the authors concluded:
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These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins arenot causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects.
- Michalska-Kasiczak M, Sahebkar A, Mikhailidis DP, et al. Analysis of vitamin D levels in patients with and without statin-associated myalgia - a systematic review and meta-analysis of 7 studies with 2420 patients. Int J Cardiol. 2015 Jan;178:111–6. PubMed #25464233. ❐ BACK TO TEXT
- Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011;14(2):145–61. PubMed #21412369. ❐
Opioid-induced hyperalgesia (OIH) is defied as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli.
Clinicians should suspect OIH when opioid treatment's effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain, and increased levels of pain with increasing dosages.”
- Burke NN, Finn DP, McGuire BE, Roche M. Psychological stress in early life as a predisposing factor for the development of chronic pain: Clinical and preclinical evidence and neurobiological mechanisms. J Neurosci Res. 2016 Jul. PubMed #27402412. ❐ “Early-life adversity increases the risk of developing a number of disorders, such as chronic pain, fibromyalgia, and irritable bowel syndrome.” BACK TO TEXT