What causes chronic pain – or – how does pain become chronic?

Pain, as terrible as it can be when it outlasts its stay, is actually a vital protective function of our nervous system. The body detects pain through a subgroup of primary sensory neurons, called nociceptors, that innervate the entire body and which normally respond only to high-threshold stimuli such as extreme heat or strong mechanical stimulation. This nociceptive response to potentially tissue damaging stimuli is critical for reflexes and coordinated responses to the stimulus which generally result in a protective reaction (such as withdrawing your hand from a hot stove). Hence, the activation of peripheral nociceptors by pain-inducing stimulation serves a crucial teaching function insofar as it is the signal that protects us from further damage. This fact is best exemplified by studies of rare cases where individuals have a genetic mutation that makes them insensitive to pain. For instance, a family was recently discovered in Pakistan wherein mutations in a voltage-gated sodium channel (called Nav1.7) involved in generating pain signals in nociceptors led to a total lack of pain sensation. Members of this family were working as street entertainers, performing incredible feats such as placing daggers through their arms. Horrifically, one of these young men died after jumping off a roof during one such performance. As tragic as this story is, it serves as an excellent example of how we depend on pain signals to keep us safe from potentially life-threatening injuries.

This story also leads into another crucial factor for how we perceive pain. The expectation of pain is a strongly motivating feature of our endogenous pain system. The mere thought of the pain of landing after jumping from a roof is enough to motivate almost any person to come down safely by a ladder; however, in the absence of prior pain experiences, it is not clear that such a motivation is even possible. Hence, while the stimulation of nociceptors serves a major protective function, other systems that reside within higher brain centers are paramount for how we perceive pain. Clinical studies in human volunteers have shown that context, mood, memories, hypnosis, expectation and even the prior administration of a placebo can have profound influences on how we process incoming pain signals. Importantly, these processes appear to play a major role when pain transitions from acute to chronic.

Pain that might be experienced as a result of daily living (e.g. stubbing one’s toe) is actually quite different from clinically significant pain. Whereas the pain transmission system is normally only activated by high threshold stimuli, in clinical pain conditions the pain transmission system can be stimulated by low threshold stimulation. This may manifest as normally innocuous stimuli becoming painful, referred to clinically as allodynia. Moreover, there is frequently a mismatch between the duration of the stimulus and the duration of the pain. For example, stubbing a toe may cause pain for 5 minutes in a normal person whereas it may precipitate a day-long episode of extreme pain in someone with fibromyalgia. Such an increased response to a noxious stimulus is termed hyperalgesia. Clearly such changes are maladaptive and current research into the neurobiology of chronic pain is starting to unravel these mechanisms.

Chronic pain is characterized by plasticity within the nervous system leading to “sensitization” in how the pain system responds to noxious or innocuous stimulation. First, peripheral nociceptors themselves can become strongly sensitized to circulating or local hormones or inflammatory mediators. This process may make nociceptors responsive to much lower concentrations of these pain-promoting agents than they would under normal circumstances. In addition to the sensitization of peripheral nociceptors, neurons within the spinal cord that send pain signals onto higher brain centers, where pain perception occurs, can also become sensitized. Remarkably, these spinal cord neurons show a particular type of plasticity, called long-term potentiation, that is molecularly similar to processes that are thought to be involved in the formation of memories within the brain. Sensitization of the pain system is not limited to peripheral nociceptors or spinal cord neurons. Neurons in the “nociceptive amygdala (the amygdala is a brain area strongly linked to emotion and fear) and neurons in the anterior cingulated cortex (ACC, a brain area involved in the affective component of pain) are also sensitized in chronic pain conditions such that they show enhanced responses to painful stimuli and they acquire novel low threshold inputs (a neural correlate of allodynia). Thus far, our discussion of pain amplification in the setting of chronic pain has been limited to evoked stimuli; however, it is also clear that stimulation of peripheral structures (e.g. the skin) is not a requisite for the precipitation of pain in people that suffer from chronic pain. In fact, spontaneous pain, especially the dull ache that characterizes so many chronic pain conditions, is often the primary complaint of chronic pain patients and is the most difficult feature to treat. Persistent questions in pain neurobiology are: why does this type of pain arise, what are its origins and how can it be treated or reversed?

A major focus of work to understand why spontaneous pain arises has been on the peripheral sensory system. We now know that a peripheral nerve injury, metabolic neuropathy (e.g. diabetic neuropathy) or chronic inflammation can lead to persistent “ectopic” activity in injured sensory nerves that can persist even after an injury resolves. The current view on this activity, in the absence of any obvious stimulus, is that a redistribution or change in expression in voltage gated sodium channels causes injured nerves to become ectopically active leading to a persistent, low level peripheral input that drives spontaneous pain perception. Work from the laboratory of Marshal Devor has shown that changes in voltage gated sodium channel expression can lead to sub-threshold membrane oscillations and this mechanism may be a major cause of ectopic activity in sensory nerves after injury. Such sub-threshold membrane oscillations lead to fluctuations in membrane potential, which would otherwise be stable, changing the excitability of these nerves and leading to action potential generation in the absence of any other stimulus. While these recent electrophysiological and biophysical findings are a critical key to solving the mystery of why pain becomes chronic it is also true that this low level, pathological peripheral input is coupled with neural adaptations throughout the CNS that contribute strongly to changes in pain perception in chronic pain patients.

The first processing center for incoming pain information from the periphery is the dorsal horn of the spinal cord. Here peripheral nociceptors synapse onto CNS neurons that send projections onto the major areas of the brain that are involved in nearly all aspects of the pain experience. In the late 1990s Patrick Mantyh and colleagues discovered that a subset of these dorsal horn neurons that reside in the outermost layer of the spinal cord are critical for chronic pain. This group used a toxin coupled to a neurotransmitter to selectively ablate these neurons and found that when these neurons are absent most forms of chronic pain fail to develop. These experiments were powerful indicators that sensitization of the central nervous system is crucial for the development of chronic pain but the actually mechanisms of this plasticity remained to be fully elucidated. In the past five years at least one of these mechanisms have been discovered. Jurgen Sandkuhler’s group has demonstrated that long-term potentiation (LTP) can be established by low frequency stimulation in the same subset of neurons ablated by Mantyh and colleagues. As mentioned above, this LTP shares many of the same molecular mechanisms associated with LTP in learning and memory; however, whereas LTP in brain areas such as the hippocampus requires high frequency input, this spinal form of LTP can be evoked by low frequency input. Hence, LTP in spinal neurons known to be involved in spinal pain processing and the generation of chronic pain can be sensitized by an input frequency that matches the low level, pathological ectopic activity that arises in peripheral nerves after injury. Therefore, it is likely that ectopic activity in peripheral nerves couples to LTP in spinal neurons to create a powerful amplification mechanism to send pain signals onto the brain in the setting of chronic pain.

Unfortunately peripheral plasticity and spinal LTP are not the end of the story for amplification systems that drive chronic pain. It is also clear that descending pain modulatory systems exist and that these systems also play a key role in amplifying incoming pain information after chronic inflammation or nerve injury. This system, first described by Howard Fields and Allan Basbaum arises in the periaqueductal grey area (PAG) and connects to the rostral ventromedial medulla (RVM) which then sends outputs caudally down to the spinal dorsal horn creating a pain modulation circuit arising in the brain stem. This circuit is perhaps best known for its role in endogenous analgesia mechanisms wherein endogenous opioids released from PAG neurons engage a descending output from the RVM that promotes a powerful inhibition of spinal dorsal horn neuron activity leading to analgesia. On the other hand, work from Frank Porreca’s group has shown that the RVM can also mediate a prominent pain promoting effect called descending facilitation. After peripheral nerve injury or chronic inflammation blockade of RVM output or ablation of RVM neurons leads to an alleviation of chronic pain in animal models. These experiments have led to the view that the RVM is a critical switch for the emergence of chronic pain wherein the RVM transitions from a brainstem area that promotes endogenous analgesia to one that facilitates spinal amplification. While the mechanisms that lead to this switch have not been fully elucidated they are likely to be important future targets for chronic pain control. In support of this view are recent human functional MRI studies from the group of Irene Tracey which demonstrate that inhibition of RVM circuitry in a human pain model is a valuable predictor of analgesic efficacy. This finding supports the importance of the RVM for the amplification of pain perception and points to a potential screening mechanism for the efficacy of novel analgesic drugs.

While the pain research community has made major strides in understanding pain amplification leading to chronic pain, a major question persists: what is the impact of this amplification on higher brain centers involved in the perception of pain and how does it manifest in other symptoms that are frequently found in chronic pain patients? Here it is useful to return to your imaginary patient. While his continuing pain is clearly problematic, other symptoms are arising such as inability to concentrate, depression and a general cognitive decline. Why are these symptoms common in chronic pain patients and how can we understand these processes mechanistically with a view toward better treatment? Until recently these co-morbid problems were largely unexplored from a basic science perspective but the advent of more sensitive human brain imaging techniques and the incorporation of behavioral tests in laboratory animals that assess the emotional or cognitive state of the animal have led to several major breakthroughs on this front.

Human fMRI studies from the groups of Vania Apkarian, Bud Craig, Cathy Bushnell, Irene Tracey, Karen Davis and others have pioneered the notion that a “pain axis” exists in the human brain that is activated by peripheral noxious input. Interestingly, pain not only stimulates sensory areas of the brain but is also a powerful activator of brain areas involved in emotion such as the anterior cingulated cortex (ACC), the insula and the amygdala. Moreover, these areas can become hyperactive in chronic pain conditions. For instance, fibromyalgia patients show an enhanced response to noxious stimulation in the ACC. In animal models, lesions of the ACC have no effect on nociceptive reflexes but strongly inhibit the aversive qualities of persistent pain and peripheral nerve injury and chronic inflammation lead to neural plasticity in the ACC. These findings suggest that the ACC may be a critical region for amplification of the aversive qualities of chronic pain. Interestingly, human imaging studies have shown that pain responses in the ACC are powerfully modulated by mood, placebo and hypnotic suggestion indicating that the ACC is likely to be an integrator of sensory input with emotional state likely leading to some of the affective disturbances associated with chronic pain. One such problem is known as pain catastrophizing, which is associated with the expectation or fear that pain will be intense and unmanageable. Pain catastrophizing is a particularly salient feature of many chronic pain disorders and several human imaging studies have shown that the ACC is also engaged during pain catastrophizing. As our understanding of the role of the ACC in chronic pain, expectation of pain and pain catastrophizing continues to emerge it is likely that therapeutic strategies that are capable of targeting these mechanisms will be discovered with the opportunity to treat these symptoms more efficaciously.

Cognitive decline and problems with concentration or attention have long been recognized as features of chronic pain but basic science has only recently begun to understand how this occurs. A major milestone in this line of research was the observation of cortical thinning in chronic back pain patients. Vania Apkarian’s group discovered that, compared to age matched controls, chronic back pain patients demonstrated a loss of cortical grey matter roughly equivalent to 10-20 years of ageing. This important finding has now been replicated in other groups of chronic pain patients, including fibromyalgia, and may represent a major mechanism through which cognitive decline can occur. Findings from animal models have suggested other mechanisms through which cognitive problems may be generated in the setting of chronic pain. Volker Neugebauer’s group has shown that chronic arthritic pain leads to neural adaptive changes in the amygdala that potentially exert a powerful inhibitory influence on the prefrontal cortex, an area involved in cognition and decision making. This circuit involves amplification of pain signaling in the “nociceptive amygdala” that then influences other amygdalar output regions that exert inhibitory control over the prefrontal cortex. A set of elegant behavioral experiments have demonstrated that this cortical inhibition leads to an impairment of decision making in a modified Iowa Gambling Task wherein rats with chronic pain are unable to detect changes in the game that would lead to better chances of their receiving a food pellet. Remarkably, these findings parallel similar experiments in the Iowa Gambling Task in chronic back pain patients where these patients also show impairments in decision-making. Hence, the combination of chronic pain-induced neurodegeneration and feed-forward inhibition of cortical circuits from areas of the brain that become hyperexcitable in chronic pain conditions (e.g. the nociceptive amygdala) may represent a neural basis for cognitive decline, depression and even pain catastrophizing when pain becomes chronic.

The view that emerges from the experimental and clinical findings discussed above is that chronic pain is a disease in and of itself that needs treatment as such to improve outcome and prevent or reverse structural changes. Disease modification may be possible, even with existing drugs that target mechanisms involved in the maintenance of chronic pain – e.g. tumor necrosis factor α, interleukin 6 or nerve growth factor sequestering treatments. Therapeutics targeting these mechanisms are either currently available or are in late stage clinical development and preclinical findings suggest that these treatments may be able to modify chronic pain by targeting molecules that are involved in its maintenance in the periphery. Another major focus is on biomarkers of chronic pain and early detection through better diagnostic tools may allow for improved treatment that reverses or limits pain amplification processes in the CNS before they become well established. Here it is important to recognize that while neurodegeneration as a result of chronic pain is likely to be difficult, if not impossible, to fully reverse, several recent discoveries in this area offer a high degree of confidence that the brain can cope with these problems given the proper opportunities. For instance, recent research in mouse neurodegeneration models indicates that environmental enrichment can enhance cognitive function and even restore certain types of memory deficits. Therefore, appropriate pain control medications coupled with physical and/or mental therapy (e.g. puzzle solving or other types of cognitive challenges) may hold considerable promise for patients experiencing cognitive decline as a result of chronic pain.

The past decade has seen an exponential growth in our understanding of the basic mechanisms which underlie the transition from acute to chronic pain. The molecular mechanisms of this transition share common features with the synaptic plasticity that underlies learning and memory and the recognition that chronic pain can lead to neurodegeneration has shed new light on the myriad of complications that frequently accompany chronic pain. As we continue to gain a firmer understanding of these processes and their respective potential therapeutic targets there is growing hope that we will be able to alleviate the suffering of the millions of people worldwide who experience chronic pain.

NB: Rather than linking to original research papers, I have tried to supply links to reviews throughout to make the information more accessible to readers that may not have direct experience in the pain neuroscience area.

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15 responses to “What causes chronic pain – or – how does pain become chronic?

  1. husband suffering with leg pain,that is so painful he can not get sleep even with drugs.he thrashes with legs and arms,but his legs are cold,and feet hotHe has to walk,hot showers,baths nothing helps He starts sneezing or coughing during the day,and feels weak but only has leg pain at night
    He feels tired,weak during the day but at night the pain starts.He has been to pain clinic,and had nerve blocks,andlarge dose of magnesium,HELP

  2. I was once diagnosed with fibromyalgia, but due to insurance had to change doctors to one who didn’t “believe” in it. I’ve been reluctant to mention that previous diagnosis to any doctor since. (I get shuffled to lots of different doctors.)

    Is it safe to ask about fibromyalgia now?

  3. Pingback: Wednesday Round Up #65 « Neuroanthropology

  4. hi juniorprof,

    about 10 mos ago i had a lower molar toothache which subsequently went bilateral after a week. it then spread to the rest of my face on both sides over the course of a month. no nerve injury, trauma, or illness. no dental caries. no MS, blood work normal, MRI thin slice neg. no lupus, sjogrens, scleroderma.

    i take lyrica and nortriptyline for pain at 150 and 50 mg respectively. i live in boston, yet no neurologist can explain what is happening to me.

    i am in constant daily pain which fluctuates from mild to moderately severe. teeth ache, forehead/scalp burns, cheeks ache. any ideas what happened to me?


  5. hi juniorprof,

    about 10 mos ago i had a lower molar toothache which subsequently went bilateral after a week. it then spread to the rest of my face on both sides over the course of a month. no nerve injury, trauma, or illness. no dental caries. no MS, blood work normal, MRI thin slice neg. no lupus, sjogrens, scleroderma.

    i take lyrica and nortriptyline for pain at 150 and 50 mg respectively. i live in boston, yet no neurologist can explain what is happening to me.

    i am in constant daily pain which fluctuates from mild to moderately severe. teeth ache, forehead/scalp burns, cheeks ache. any ideas what happened to me?


  6. KBD,
    I am not a physician and I really cannot fathom a guess at what has happened to you but it certainly sounds terrible. Does the lyrica and nortriptyline help? Have they ruled out trigeminal neuralgia? No signs of TMD?

  7. yes, it is difficult not getting answers. i am not sure how well the meds help, the only way to know is to come off them, and i am a bit concerned in doing that. it is better now than last august, that is for sure.

    TN is ruled out. i just had another thin slice mri which showed nothing remarkable including the 5th nerves.

    my bite changed during this time from a retainer i wore for grinding. i am not sure how it plays into the pain, but i would not posit a guess as to how my forehead and scalp became involved.

    i wanted to write to you as i read you research pain. i guess i was curious if you knew how it went bilateral.



  8. Dear juniorprof,
    very nice comprehensive articles.
    gud luck with ur research :-)
    keep writing.

  9. Josep Vilaplana

    Hi. Juniorprof
    I am Anesthesiologist that works in a pain clinic and I woud give congratulations for your great job in your blog

  10. Hi,

    This is Vicky Silvers, I am an editor for Hospital.com. We are a medical publication whose focus is geared towards promoting awareness on hospitals, including information, news, and reviews on them. We would like to have our site included within your blog and offer our information to your readers, of course we would be more than happy to list your website within our directory as well.

    vicky silvers

  11. work is magical. I have suffered pervasive pain since 1962 as a result of back injury,wrong diagnoses and wrong treatment etc Only in the last 10 years has any sense been spoken on the subject which is hardly surprising in view of the emergent complexity. The sense of relief is huge just to know that the work is being done and we will stop being told “its’all in your mind” reading this site I can already see possible explanations for my case which has been unexplained for nearly 50 years. My heartfelt thanks to all the researchers’

  12. Thanks Kevin! I hope you’ve been able to find something that helps to relieve your pain after all these years.

  13. Pingback: #painresearchmatters campaign « JUNIORPROF

  14. Thank you so much for the work you are doing! It could save my life some day. I was diagnosed with Central Sensitization that started in 2004 and have suffered bad pain every minute of every day since then with terrible skin aching/burning from the base of my skull to the tips of my toes, with no end in sight. This all started with advanced degeneration of my cervical and lumbar spine, a case of shingles that became PHN, and manifested when I went through a traumatic experience (a hurricane that almost killed me).

    I take drugs for the pain (Lyrica, Amytriptyline, narcotics) but they don’t make much of a dent. I’ve been to many doctors and have even tried 2 spine surgeries, and tried all sorts of non-invasive therapies, including hypnosis. I’m just treading water, waiting for someone like you and your research associates to come up with something that works. Until then, I have no choice but to remain a virtual hermit — a prisoner in my house.

    I do have one question: what kind of pain is it that hurts with no stimulation of any kind? It doesn’t seem to fit the definition of either hyperalgesia or allodynia.


  15. Super news it is without doubt. My girlfriend has been seeking for this content.

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