How is pain felt in areas without tissue damage?

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Welcome back to the Forensic Chiropractor podcast.

The article I would like to review today is one of my favorites.  It is also one that is hard to take in all the information.  I have to review this study a lot.  This is one podcast I will listen to myself a lot to keep refreshed on.  I want to start this podcast a little backwards today.  I want to start with a real-world example of this week.

This is worker’s compensation patient I performed an IME on.  This is a 50-year-old lady that had a fall at work and injured her hip, shoulder and knee.  She had treatment for years including a hip labral surgery, shoulder tendon surgery and lots of pain management.  The doctors all were confused by her intense ongoing pain.  At one point one of her doctors ordered a brain MRI to assess for multiple sclerosis due to pain that was way beyond what was expected.  All of her doctors truly believed she was in pain, but were unable to help her with her pain and were unable to explain why she was having so much pain. 

My IME was simple to show objective evidence from MRI and surgical reports of injuries.  These injuries clearly came from her work place injury since she had no prior symptoms and degenerative findings on the imaging.  The impairment rating was easy to do.  The hard part was she didn’t just want an impairment rating, but wanted to know what to do.  She was way worse off than I would expect for the injuries she had.  The injuries I could show just did not seem to be explaining all of her symptoms.  She was worse off than anyone expected. 

What is the best approach for this type of patient?  She seemed genuine and honest about her injuries.  She did not seem to be malingering, but that is often what patients like this get accused of.  This case reminded me of one of my all-time favorite research articles.  I want to go over this research article and then come back to the real-world example. 

Today’s article is Evidence, mechanisms, and Clinical implications of Central Hypersensitivity in Chronic pain After Whiplash Injury.  This was published in The Clinical Journal in 2004 by Michele Curatolo et al. 

This study is a review of the evidence on central hypersensitivity in chronic pain after whiplash injuries.  What is central hypersensitivity?  They defined this as enhanced perception of painful stimuli at healthy areas that surround damaged tissues.  This enhanced perception of pain comes from quote “profound changes in the central nervous system” end quote.  These changes are responsible for enhanced neuronal excitability.  So central hypersensitivity is changes in the central nervous system (which is brain and spine). These changes increase the excitability of the central nervous system leading to enhanced pain perception.  These changes have been shown to come from damaged tissue including quote “minimally damaged tissues” end quote. 

Today’s study will cover 1. the mechanism of central hypersensitivity, 2. review the evidence showing that central hypersensitivity occurs after injuries, 3. discuss clinical relevance and 4. cover possible treatments. 

I’ll start with the hardest part of the study and that is the mechanism of central hypersensitivity. 

The first mechanism is peripheral sensitization.  This is when we have an injury to tissue that is not the central nervous system.  This could be any tissue damage.  The body’s first response to tissue damage is inflammation.  Inflammation will quote “release potassium ions, substance P, bradykinin (brady keenen), prostaglandins and other substances” end quote.  This study referred to inflammation as a release of sensitizing soup.  These sensitizing substances often induce peripheral receptors including normally inactive nociceptors which leads to pain.    This sensitizing soup will increase gene expression in the dorsal root ganglion resulting in an increased production of peripheral receptors which will increase the sensitivity of the nociceptor.  This is a change in central nervous system function.  Pain signals alter the central nervous system’s gene expression. 

If this inflammation is long lasting and the sensitizing substances remain there will be long lasting stimulation of the nociceptors.  Long term stimulation of the nociceptors may start a synthesis of receptors that changes A-beta fibers to c-fibers.   A-beta fibers do not carry painful sensation, but are mechanoreceptors.  A-beta fibers help inhibit pain.  These A-beta fibers are being replaced with C-fibers with long term pain stimulation.  C-fibers are free nerve ending pain carrying nerves that are responsible for ongoing pain.  This is another change made after chronic pain.  We lose nerves that help inhibit pain sensation and they are replaced with nerves that carry pain signals.  This process creates an increase in spinal cord input and an ability to have increased sensitivity to pain. 

Tissue damage sends pain or nociceptive input to the central sensory neurons in the spinal cord.  Overtime this pain or nociceptive input induces an increase in the excitability of these central sensory neurons.  This excitability is mediated by N-methyl D-aspartate aka NMDA receptors.  Increased NMDA receptors increase the enzyme COX-2.  The COX-2 enzyme involves the whole spinal cord and not just the area related to the pain or nociceptive signals.  This leads to a higher number of receptive fields in the dorsal horn neuron.  This leads to hyperalgesia in areas outside the injured area.       

Additional this leads to destruction of inhibitory neurons leading to increased pain sensations.  This process changes the location of the A-beta and C-fiber nerves.  With altered location of nerve’s this can cause pain with mechanical stimulation that do not produce pain under normal conditions such as touch.

When the brain experiences pain, we have natural opioid peptides called encephalin that inhibit the pain transmissions in the brain.  With chronic pain this process with reorganize how the brain works.  These changes are quote “long lasting plastic changes with a memory of nociceptive experiences” end quote.  This ultimately reshapes the brain for hyperexcitability. 

Thus far I have covered very important information about how pain changes the body.  This can be difficult to grasp and I would like to summarize a little.  Tissue damage creates inflammation.  This inflammation creates a substance that leads to sensitization.  These sensitization substances increase nerve receptors and nerves that normally do not feel pain and send pain signals.  This gets worse for ongoing chronic pain.   Overtime chronic pain alters the spinal cord and causes the neurons in the spinal cord to have excitability in the neurons throughout the spinal cord and not just the areas of pain leading to increased pain outside of the injured area.  Long term pain then has the ability to change the brain and increases the pain experience.  This study showed that this process is responsible quote “at least in part for persisting pain after injury” end quote.   They also showed that this sensitization of the nervous system to pain also decreased the threshold to activate pain neurons throughout the body and not just the level of damage. 

The first part of this article I am going over was a review of different studies showing how the body reacts to pain and the ongoing and amplified pain sensations.  The next part of this study covers specific research showing that this indeed does happen to people with injuries. 

The first study they reviewed was a group of whiplash injured patients and healthy volunteers.  They measured the detection of pain and tolerance to pain with painful electrical stimulation to the neck.  They found that the healthy volunteers had less pain while patients with tissue damage felt pain sooner.  This study showed an increase of pain with prior damaged tissues. 

The second study they reviewed was a group of whiplash injured patients and healthy patients.  They injected hypertonic saline that created pain at the site of injection and areas away for the injection in all participants.  Whiplash patients had higher levels of pain, longer duration of pain and larger areas of local and referred pain compared to healthy volunteers.  A lot of whiplash group patients had pain in the whole leg and even the leg opposite side of the injection.  The healthy group did not have pain in the entire leg or opposite side leg.  This study showed that hypersensitivity is not limited to the injured and surrounding areas, but is more general to the whole central nervous system. 

The third study they reviewed was a group of whiplash injured patients and healthy participants.  They measured pain thresholds to electrical stimulation and heat.  Pain was measured and then a local anesthetic was injected into the painful muscles and then pain was measured again.  The whiplash group had more pain with electrical stimulation, but did not have more pain with heat.  They then injected the local anesthetic at the area of the electrical stimulation and the pain was reduced, but the pain the electrical stimulation caused in the neck did not decrease for the whiplash group.  This means that the electrical stimulation in the whiplash group’s areas besides the neck caused an increase in neck pain, but once the local anesthetic was injected in these areas the neck pain did not decrease.  This showed that there is a central hypersensitivity causing an increase in neck pain.   

The fourth study they reviewed took a group of whiplash injured patients and patients with acute ankle injuries.  They applied pressure stimulation to the neck and hand to induce pain.  Pain in the neck was worse of whiplash patients in the first 90 days.  After 90 days the pain was similar between both groups.  This shows that over time the central hypersensitivity plays a role in pain.  Pain levels were the same in the neck for both groups after enough time passes. 

The fifth study they reviewed took a group of whiplash injured patients and healthy uninjured participants.  They applied different nonpainful stimuli to both groups at nondamaged areas.  65% of whiplash injured patients had pain with vibration and none of the healthy uninjured participants had pain with vibration.    The injured patients had more pain with heat and cold than did the healthy uninjured participants.  This study quote “confirms the presence of central hypersensitivity in patients with whiplash” end quote. 

The sixth study they reviewed is unique.  The prior 5 studies relied on the patient’s subjective reports of pain.  The sixth study used electrophysiological method of nociceptive withdrawal reflex.   An electrical stimuli was applied to the innervation area of the sural nerve and the withdrawal reflex of the biceps femoris muscle was measured by electromyography.  The latency must be below 150 milliseconds to  define the muscle contraction as a spinal reflex.  If whiplash injured patients have a lower threshold for pain their spinal reflexes for pain should have a lower threshold.  This study did confirm that whiplash injured patients have a lower threshold or ability to feel pain compared to the healthy uninjured population.  This study is objective evidence of central hypersensitivity with injured patients. 

They summarized the 6 research articles they covered by saying quote “Taken together, the evidence shows that patients with chronic pain after whiplash injury display pain hypersensitivity after sensory stimulation of healthy tissues, most likely resulting from an alteration of the central processing of sensory input. The central hypersensitivity is not confined to the areas of the central nervous system that are connected to the painful region, but is probably generalized” end quote. 

They went on to say quote “ It is important to recognize that central hypersensitivity is not specific for whiplash, but has been observed in other chronic pain syndromes, such as fibromyalgia, osteoarthritis,  tension-type headache,  temporomandibular joint pain,  and postmastectomy pain” end quote. 

The study just covered some evidence showing that central hypersensitivity occurs in patients with injuries.  Now the study changes gears and discusses the mechanism of central hypersensitivity.  They discuss that when tissue is damaged the central nervous system can become sensitized.  This sensitization makes the central nervous system more sensitive to stimulation both painful and nonpainful. 

If tissue damage can cause a sensitized central nervous system lowering the threshold for pain with both painful and nonpainful stimulation, will the sensitization resolve with resolution of the tissue damage?  This is a difficult aspect of this study to address since it can be very difficult to know for certain that all tissue damage has resolved.  They showed that it is likely that central hypersensitivity likely disappears or looses clinical relevance when the pain signals from the damaged tissues is blocked.  This hypothesis is based on radiofrequency ablation of the facet joints.  The radiofrequency ablation is burning the nerves to block pain signals.  This often leads to complete pain relief in patients with facet mediated pain. 

Another study they looked into was a study on painful osteoarthritis of the hip.  These patients had a low pain threshold that normalized after surgery.  This is another indication that the central nervous system hypersensitivity may become clinically irrelevant after the pain signals are blocked or resolved.  They concluded that it is likely that patients with ongoing central nervous system hypersensitivity likely continue to have pain signals from the damaged tissue.  They reported that even with advanced diagnostic tools we often miss tissue damage.  They caution that quote “hyperexcitability may vary from patient to patient” end quote.  

They reported that there are some animal studies that show central hypersensitivity may be the result of irreversible structural changes in the spinal cord.  Either way it appears that some patient will have quote “peripheral lesions that may heal after whiplash injury, but irreversible changes take place in the spinal cord that maintain a state of hyperexcitability” end quote. 

Side note from the study.  I would like to give some of my thoughts here.  Lots of injuries in a MVC are permanent including disc damage and ligament damage.  I have covered a lot of this in my prior podcasts.  These permanent injuries can be managed with ongoing care as discussed in prior podcasts.  Often patient stop managing care at MMI.  The pain then comes back and often spreads to other areas.  I see this a lot at the end of active care.

 Treatment appears to manage the damage and the pain signals decrease or resolve.  This lowers the central sensitization and the patient feels good.  They stop care and the permanent injuries again start sending pain signals and the central nervous system becomes hypersensitive again. 

I see this a lot with patient that have the radiofrequency ablations or steroid injections.  The ablation or steroid blocks the pain signals and the pain all around decrease.  Then after a few months the pain slowly increases and after a few more months they seem to have lots of pain all over. 

With my understanding of this article and my clinical experience it appears that patient with permanent damage need future care to decrease pain signals from the damaged tissue to lower the central sensitization.  When management of the damage tissues is stopped the pain signals return as does the central sensitization. 

Now back to the research article.  The next topic they review is psychological factors.  They showed that quote “based on these data, the results of psychophysical studies showing exaggerated pain responses in patients with whiplash are very unlikely the result of personality disorders or malingering” end quote.  It is important that we take these patients serious and don’t just assume that they have a personality disorder or are malingering.  They reported that psychogenic causes of central hypersensitivity can not completely be ruled out, but there is almost no experimental support for this.  They said quote “   Attributing central hypersensitivity solely to psychologic factors would ignore the overwhelming and consistent evidence that injury and tissue damage induces hypersensitivity of the central nervous system” end quote.  Again, they reported that with all of our advanced diagnostic methods we do not always detect tissue damage. 

The authors of this study performed a study to assess mechanisms of central hypersensitivity.  They created painful pressure points and then measured pain thresholds 15 minutes after a local anesthetic.  They showed that pain levels decrease even in areas where the local anesthetic was not given.  Which hints at the thought of any pain signal reduction in the body may decrease pain in other areas of the body.       

The next topic is clinical implications of central hypersensitivity.  They reported that whiplash injury patients often have a lack of signs of tissue damage and likely have low intensity pain signals arising from minimally damaged tissue.  These low intensity pain signals are amplified by the central nervous hypersensitivity.  This can lead to an exaggerated pain response. 

Another side note, I have had patients who were in a MVC and did not make the progress I would have expected and the pain was much worse than I expected.  It seems like if I can find a way to offer some relief beyond my normal treatment with shockwave, massage therapy, acuputure or pain management then progress seems to go as expected with my normal treatments.  It is like I just have to have a break through moment where the pain is decreased and then they make expected progress. 

Central hypersensitivity can be treated by one of the 3 approaches.  First is block or reduce pain signals form the injured area.  This goes along with what I was just saying.  Find a way to block or reduce the pain signals to help with hypersensitivity.  Second is to use medications to decrease the spinal cord system hypersensitivity.  The third is using medication to act at the supraspinal level and descending modulation system. 

I already talked about the first treatment approach with my side note.  This is managing the damage.  There are of lot treatments I offer and a lot of available treatments I do not offer.  The second treatment approach they talk about is spinal cord modulation.  NMDA-antagonists may play a role in spinal cord hypersensitivity.  They discuss ketamine’s role in this approach but report that this is unfavorable due to side effects of ketamine.  Low intravenous doses have proven effective for acute pain.  Some studies  showed that this approach is most effective when ketamine and opioids are used in combination. 

The third approach to treat hypersensitivity is to alter the brain and descending pathways.  They reported that opioids, antidepressants and other medications can alter the brain.  They reported that they are not aware of studies covering this approach.  They reported that clinical studies are needed in this area. 

To summarize this article quickly: tissue damage leads to inflammation.  Inflammation has sensitizing substances that change gene regulation in the body and this increases pain receptors and increases the nerves in the body that transmit pain.  Overtime the chronic pain alters the spinal cord and brain allowing for hypersensitivity to pain even in areas without the tissue damage.  They covered multiple studies showing that this indeed takes place.  The showed a possible resolution for some with resolution of damaged tissue although it can be hard to know if the damaged tissue has resolved.  This whole process can lead to exaggerated pain responses that do not correlate with initial tissue damage.  This was shown to not be related to psychological factors or malingering.     

Back to my real-world example.  The patient I performed the IME on seems to fit this study very well.  She has been living with different injuries for years.  It took years to even perform some of her surgeries.  It is clear that she has had tissue damage for years that would have sent pain signals to the brain.  It appears likely that these pain signals over time have created central nervous system hypersensitivity.  This explains to some extent her ongoing pain levels and difficulty getting her pain under control.  However, just knowing this doesn’t help offer treatments.  It does explain why she may be having exaggerated pain from what everyone treating her would expect.  All of her providers over the years have not been able to block her pain signals and have not been able to decrease the hypersensitivity.