Chronic Pain

How Opioids Can Worsen Pain

The use of chronic opioids leads to either tolerance or sensitization.  This results in loss of efficacy either way and results in pronociception either way. The nociceptive system works to maintain responsiveness of the system. The longer you take opioids to blunt chronic pain, the more likely you are to experience enhanced pain as the body tries to restore normal sensory function.

Preclinical evidence. Thermal hyperalgesia has been recognized back to the 1980’s in the animal sciences. Hyperalgesia is defined as an exaggerated response to painful stimulation.  Hyperalgesia is manifested as an exaggerated response to hot temperatures.  The animals who experienced hyperalgesia could tolerate less heat than normal animals not suffering from hyperalgesia.  Hyperalgesia can be demonstrated following the injection of morphine into the spinal fluid of rats over several days. The duration of the hyperalgesic effect extended beyond the time that the morphine was discontinued which implied changes in the nervous system.  [Vanderah et al. J Neurosci. 2000 Sep 15;20(18):7074-9 ,  Mao J et al. J Neurosci. 2002 Sep 15;22(18):8312-23.] Other opiates such as Fentanyl and Heroin have the same effect. [Celerier et al, J Neurosci. 2001 Jun 1;21(11):4074-80.]

Clinical Implications: Repeated use of opioids can lead to a pathological pain state. Decreased analgesic efficacy can be seen as early as following a single dose. [ Cooper et al. 1997, Vinik and Kissin 1998, Guignard et al 2000.] Patients not given opioids interoperatively required fewer opioids post operatively.

When patients with low back pain were tested for hyperalgesia with a cold pressor test, it was found that patients with low back pain alone had much better pain tolerance than patients who had low back pain and had been treated with opioids. [Chu et al 2006.]

It appears that chronic back pain alone causes little wind up when compared to healthy individuals, but exposure to opioids resulted in dramatic thermal allodynia and temporal summation. The patients simply had more pain. They felt pain with less stimulation and their pain was more severe.

In an effort to relieve pain in these patients by treating them with opioid pain relievers, the patients developed worse pain and lowered pain tolerance in a short period of time.


Chronic Pain

fMRI’s Ability to Show Pain

We are learning a great deal about pain from fMRI.  fMRI is a technique that allows us to look at areas of the brain that are metabolically active.  In this way, we can peer into the mind and see what parts of the brain light up when we are thinking about someone we love, or something we dislike.  We can also see what it looks like to feel pain.  Since we can see pain in the brain, we are able to study painful conditions.  What we are learning is very interesting.  First, we are beginning to be able to identify pain severity by viewing which parts of the brain light up when pain is being experienced. What we are able to see is that patients who suffer from chronic pain have these areas of the brain light up at lower levels of stimulation than normal controls. In other words, it takes less stimulation to cause pain in people who suffer from chronic pain.  They are more susceptible to pain.

So, we know that when a person says they are in pain, we can see signs of it in their brain.  People who suffer from chronic pain, actually experience more pain than normal people and that is also visible on fMRI. With this information, it is possible to see when the pain goes away.  With proper treatment, changes on fMRI normalize. The pain can be seen to resolve.  Can you learn to control your brain activity and control brain processes and will it lead to a change in pain perception The answer is yes. [Decharmes RC, et al. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18626-31. Epub 2005 Dec 13.]Does it lead to durable changes? That is, changes that last?  Yes.[Presented by Mackey et al at IASP 2008.] Using real time fMRI training it is possible to teach people to control activation of areas of the brain associated with pain.  It seems to be similar to biofeedback or EEG feedback, but much more pronounced and effective.

Chronic Pain

Pain and Genetics

It is clear that our ability to experience pain is inherited from our parents.  Some are more susceptible to pain than others and this is directly related to our genes.  This fact is being exploited for the development of treatments for pain. It is helpful for both new drug discovery and target identification. This explains variability in response to therapy. Not everyone has the same genetic makeup, so not everyone will respond in the same way to a given treatment.  Using this information, we will be  better able to target responders to particular treatments, including surgery and other invasive treatments.

Most painful diseases and disorders do not follow Mendelian genetics. They appear to be induced by diverse environmental exposure and genetic factors. Penetrance is variable and is dependent in part on genetic code. Probably several genes interact to alter penetrance. In other words, we are not just the product of our genetics.  Not everyone with genes that make them susceptible to pain, or likely to develop painful conditions such as Fibromyalgia or CRPS actually go on to suffer from these conditions.

It is likely that about 25-60% of pain response is probably genetic. Phenotypes can sometimes be linked. That is, the characteristic of blond hair and the propensity to sunburn are linked phenotypes.  Phenotypes that are often linked together are the development of anxiety and depression and the development of chronic pain.  It is likely that the phenotype of high degree of psychological stress is associated with genes that are also associated with heightened experience of pain. By understanding this linking of phenotypes, it is possible to develop treatments that are more effective for these specific characteristics. It is also possible to develop treatment protocols that can be implemented early in the course of an illness to reduce the likelihood of developing other linked conditions.  As an example, if I treat my patient who is suffering with pain for anxiety and depression as well, I may get a better result than if I treat them for pain alone.

Pain sensitivity is associated with high sympathetic tone as well. High sympathetic tone is associated with low heart rate variability. Recall that a decrease in heart rate variability is associated with low vagal tone and is also associated with the presence of, or the risk of developing pain from a chronic inflammatory condition.

As you can see, it is possible to see pain in a variety of different ways. We know that the risk of developing chronic pain is inherited.  It is linked to the genes you get from your parents.  We also know that the risk of developing chronic pain is linked to the risk of developing anxiety and depression.  The genes that carry the risk for pain and the genes that carry the risk for depression and anxiety probably reside very close together in our chromosomes.  The more conditions we can link to the pain genes, the more likely we are to be able to identify these genes. If we can identify them, we will be able to develop treatments aimed specifically at these genes. The hope is to identify clusters of genetics that will be targets for treatments for specific syndromes. Genes for Fibromyalgia, Tempo= Mandibular Joint disease, Irritable Bowel Syndrome, etc will eventually be identified and we will be able to manufacture treatments aimed at turning these genes off, or blocking them so they never turn on and result in the condition at all.

In the mean time, we can to simple things to check to see if you are more likely to develop chronic pain.  One is to look at your heart rate variability.  If you have little or no heart rate variability, you may be at risk for developing chronic pain, or you may already be suffering from chronic pain. If you have low heart rate variability, there are things you can do.  Get on a strict regimen of diet and exercise, learn things like meditation and yoga. Change your life, before it gets the better of you.

Chronic Pain

Inflammation and Pain

An inflammatory reflex develops following cell damage or an infectious inflammation (virus, bacteria, toxin).  This results in the release of cytokines and inflammatory mediators.  These inflammatory mediators cause a sickness syndrome- the fever, anorexia, fatigue, and withdrawal from activity that we all feel when we come down with the flu.  People with other inflammatory conditions can feel the same sickness syndrome.  People who suffer from conditions as varied as irritable bowel syndrome and gulf war syndrome often report similar symptoms which are part of this inflammatory response to their condition.

It is felt that much of this inflammation is mediated both afferently and efferently via the vagus nerve. The vagus nerve is the 10th cranial nerve.  It is responsible for a number of actions in the body from coordination of breathing, speech, sweating and regulating heart beat to aiding in digestion to name a few. The principal neurotransmitter involved is Acetylcholine. [Thayer JF, Cleve Clin J Med. 2009 Apr;76 Suppl 2:S23-6. doi: 10.3949/ccjm.76.s2.05. Review.]

The vagus nerve is responsible for turning off inflammation in inflammatory cells in spleen, liver and periphery. There is a setpoint for triggering this inflammatory cascade.  Individuals who are susceptible have poor Vagal tone-evidenced by reduced heart rate variability. In fact, you can check your heart rate variability by feeling your pulse and seeing how it changes when you inhale and take a deep breath and when you exhale fully. Try it.  Feel the pulse at your wrist just below your thumb and note how your heart rate changes with deep breathing.  High vagal tone is felt to indicate that there is little central inflammation.  Low vagal tone is just the opposite. If your heart rate varies from beat to beat with breathing, you have good vagal tone and probably don’t have much systemic inflammation.  If your heart rate doesn’t vary much, the opposite may be true. Since it is known that the vagus is the nerve that most frequently activated in central inflammation, this is a good test for whether your are suffering from, or susceptible to chronic inflammation and central sensitization.

With effective treatment, Vagal tone can be restored.  Meditation and exercise are two activities proven to improve vagal tone.  Not surprisingly, these are also known to improve the symptoms associated with conditions of chronic inflammation and central sensitization ranging from Fibromyalgia to Chronic Fatigue syndrome to Gulf War Syndrome and TMJ. It is important to include exercise and psychological techniques for managing pain such as meditation and cognitive behavioral therapy in your pain management program.

Chronic Pain

Sleep, Exercise and Pain

Taking healthy college students and restricting sleep and exercise will result in chronic pain. [Clauw DJ, et al. Best Pract Res Clin Rheumatol. 2003 Aug;17(4):685-701.]

In this article, it was found that symptoms of central sensitization, similar to Fibromyalgia, could be induced simply by restricting sleep and limiting activity in students who had previously never experienced symptoms before.

In a similar experiment, a physician named Jose Ochoa found that he could reproduce signs and symptoms of RSD simply by immobilizing a limb in a cast for a few days.  Both fibromyalgia and RSD are felt to be central sensitization syndromes.

Anyone who has had for prolonged periods of sleep has probably had a similar experience of developing aching, stiff muscles and joints, having difficulty concentrating and thinking, and a general feeling of malaise.  I lived my life for years feeling like that when I was a medical student and resident physician suffering from chronic sleep deprivation and lack of exercise due to long work hours.  I remember it being hard to tell if I was coming down with flu, or if I just needed sleep.

In a study of patients who were septic, it was found that they suffered from cognitive impairment and functional limitation after they recovered from their infection.  [Iwashyna TJ, et al. JAMA. 2010 Oct 27;304(16):1787-94]. Their ability to live independently was limited as well.

What each of these examples has in common is the effects of central sensitization and inflammation. Studies are ongoing to try to find a way to reverse these effects.  In the mild cases such as the sleep deprived students or those who had a limb casted for a period of time, exercise and proper rest seem to be all that is required to completely heal.  The same can be said for many patients who have other central sensitization syndromes. The trick is being able to overcome the functional limitations brought on by the condition and being able to perform meaningful exercise and get good restorative sleep.


Chronic Pain

Glial Cells and Opioids

Glial cells play an important role in producing and maintaining pain. They also play an important role in influencing how well opioid pain relievers function.

It has been noted that taking opioids daily often results in very similar symptoms to how someone might feel with the flu. At first the opioids improve pain control, but soon they seem to become ineffective for most people, so they have to be increased. If you have been taking opioids for pain, think back to the time that you first began taking them. Are you taking the same dose and the same quantity now? Or are you taking more? Do they give you the same pain relief they did when you first started? What happens when you miss a dose? Have you noticed that things seem to hurt more? Before you answer, think about a time when you may have stubbed your toe, or burned your hand since you’ve been taking opioids.  Probably, it caused quite a bit more pain than it did before you started taking these medications. When someone takes opioids over a prolonged period of time, they begin to experience the same hypersensitivity to pain that occurs from injury or illness as was described in the previous post. This similarity led to the evaluation of glial cell function in the face of opiate use and what has been found is that glial cells activate in the same fashion in response to opioids as they do to stress from other causes. (Watkins LR, Hutchinson MR, Johnston IN, Maier SF. Glia: novel counter-regulators of opioid analgesia. Trends Neurosci 2005;28:661–9.).

As a person takes opioids, microglia and astrocytes activate and begin to produce cytokines and take other actions to sensitize the nervous system. The effects of sensitization are most apparent during withdrawal when increased pain is experienced if you miss a dose of opioid. Therefore, the glia inhibit the pain relieving effects of opioids. It is also being learned that in some cases, the addition of a glial cell inhibitor can enhance the activity of opioids and reduce the development of pain hypersensitivity associated with the use of opioids. We are beginning to explore the administration of ultra low dose naltrexone or naloxone with opioids and it appears that this may enhance the benefits of opioids. This was first noted with a couple of opioids that were formulated with naloxone and it was found that this combination worked better than just administering the opioid alone


Chronic Pain

How do Glial Cells Effect Pain?

We know that glial cells ramp up their effects in response to pain. We know that they can be responsible for enhancing pain via direct actions on the nervous system as well as indirect actions, such as the production of chemical inflammatory compounds such as cytokines. It is known that these inflammatory cytokines enhance the transmission of pain via nerves.  They serve to turn up the volume on the pain signals being transmitted to the brain. We also know that we can reduce pain by suppressing glial cells. Two medications that I work with to treat pain have direct action at the glial cell. The first is naltrexone.  Naltrexone is a drug that is primarily used to inhibit the effects of opioids (morphine and morphine like medications). Minocycline is an antibiotic.  Both of these drugs are known to suppress the activity of glial cells and both are effective at reducing certain types of pain.

Putting all of this together makes it much more clear what is happening. Glial cells such as astrocytes and microglia act to maintain normal central nervous system function. If a person is suddenly exposed to pain or illness, the glial cells will react and change their function. They begin to participate in the pain or illness by increasing their numbers and changing their function from a support role to an enhancing role. They enlarge and they form more glial cells and they begin to enhance the pain transmission abilities of the nervous system. They sensitize the nervous system to stimulation.

Think back to a time when you were ill with a bad cold or flu. Remember how your body ached? Remember how you didn’t want to be touched, or talk, or even read or look out the window? Your nervous system was hypersensitized and all these stimulation-sight, touch, sound-became painful. This is what glial cells do to worsen your pain. They do it via chemical mediators that signal them to switch their role from support to enhancement of suffering. This is important to help the body heal. It encourages you to go lie down, conserve your energy and allow the body to direct its efforts at healing you, rather than having to maintain the normal activities that result from your normal busy daily schedule.

If I give you a drug to block the activity of glial cells, I can reduce these symptoms, so I know the glial cells are responsible, at least in part, for how you feel when you are ill or injured.


Chronic Pain

Glial Cells and Pain

What is a Glial Cell?

Glial cells are non neuronal cells of the central nervous system. That is, they are cells that don’t transmit and receive electrical signals as do the neuronal cells in the brain and spinal cord. They have historically been considered support cells, or a type of scaffolding that holds up the neuronal “thinking” structures of the brain. They were thought to play the role of housekeepers. Cleaning up debris, and insulating the neuronal cells of the central nervous system. There are a variety of different glial cells, but for our interests in Pain Medicine, there are two that are very important; the microglial cells and the astrocytes. There are other non neuronal cells in the central nervous system that participate in the pain response, but these are the two that are the easiest to study, and hence two that are the most studied. There are far more glial cells than there are neurons in the central nervous system.

Under baseline conditions, glial cells have no influence on pain, but once activated, they have the ability to enhance the pain experience and response. As I have discussed before, glial cells can be activated by illness or injury not related to the brain. A simple case of the flu can result in the activation of glial cells and lead to the sickness response-the feeling of wanting to curl up in a ball and die. It is also known that pain can also activate this glial cell response and the subsequent production of pro inflammatory cytokines.



Microglia comprise around 10% of all glia in the central nervous system and make up about the same percentage of all the cells in the central nervous system. Most of the time, microglia function as immune cells in the central nervous system, but they can be activated by stimuli including infection, trauma and other stressors which causes them to change function. (Raivich G. Like cops on the beat: the active role of resting microglia. Trends Neurosci 2005;28:571–3) Microglia can then begin to migrate towards the cite of damage and release inflammatory mediators including cytokines. After the injury or insult resolves, they can revert back to normal, or they may enter a state where they are “primed” to respond again (Watkins LR, et al. Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun. 2007 February; 21(2): 131–146). Once they are primed, they may over respond to the next episode of pain. This is thought to be an explanation for why some people seem to be more sensitive to painful stimulation than others



There are more astrocytes than neurons in the central nervous system. They are found tightly wrapped around most synapses in the central nervous system and are felt to influence nerve to nerve communication at the synapse. They are believed to enhance function at the synapse and with repeated activation they contribute to memory at the level of the synapse. They also act to provide energy to the nerve cells and aid in the production of chemicals found in the synapse between nerve cells. Astrocytes can become activated by the same conditions that activate microglia. When activated, microglia and astrocytes serve to enhance each others function.

Chronic Pain

Reading Minds

If the study posted previously about fMRI being able to peer into your mind and determine not only if you are experiencing pain, but how much pain you are experiencing didn’t give you pause, these reports should.

Researchers are developing techniques using fMRI to see what you are thinking, or who you are thinking about. Soon it will be possible to read your mind, see your dreams and see what you are feeling. MRI technology is increasing in speed every day. Soon it may be possible to acquire one when you walk through a doorway. No longer will you have to lie still in a magnet for an hour.

Chronic Pain

Stems Cells and Low Back Pain

Two recent studies have been published evaluating treatment options for degenerative disc disease.  Discogenic low back pain is one of the most common conditions I treat. Almost half the patients who come to see me have symptoms including aching back, occasional radiating pain into the legs which often waxes and wanes or moves back and forth from leg to leg and pain in the back with prolonged sitting or standing, It is one of the hardest conditions to treat.  Surgery doesn’t work well, conventional injections don’t work well and medications generally don’t work well. The pain can be very debilitating.

Stem cells are showing promise in relieving this pain.  One study demonstrated that stem cells from human umbilical cord blood will start building collagen within the disc of a rabbit. Collagen is the primary material that makes up the disc and it is thought that the breakdown of collagen within the disc is responsible for the development of pain. By demonstrating that it is possible to heal collagen, there is hope that we may be able to some day restore the native disc to normal function and take away the pain. The other study demonstrates that injecting bone marrow, which is a rich source of stem cells, into the disc will ease pain in some patients. This pain relief can last longer than a year, at least in this pilot group. While neither of these two studies is conclusive, it is the best hope I have seen for treating discogenic pain in a long time.