Chronic pain

Approximately 100 million people live with chronic pain in US and for half of them pain is really impacting their life. The mechanisms of chronic pain are much more complicated than most people realize. This is just a general diagram of the pain network. Everybody has a personal pain experience because of the individual variations at so many levels.

Currently, our medical system is focused on medications and procedures. The success is not that great since these treatments do not address the underlying problems. I think a better way is to address the whole person and try to calm down these vicious cycles started by acute pain (increased muscle tone, hyper-reactivity of the autonomic nervous system/endocrine system, increased inflammation) and change the processing of information in the central nervous system (spinal cord and brain). For each potential pain treatment we should look at how it influences the following four final goals:
- decrease sensitization in the central nervous system
- decrease inflammation in the periphery and central nervous system
- improve self healing/homeostasis
- improve muscle activity and decrease joint load
Current medications and procedures almost do not accomplish any of these goals. What actually works is the good old wellness measures. The four areas essential for our well being are: nutrition (fasting seems to be a very potent treatment), physical exercise, sleep (really undervalued today) and mental health/spirituality. Just think about fasting and sleep. Both are free resources and both work on all the four goals above. If you are suffering from chronic pain and consider fasting please discuss this with your medical provider since it can affect other medical conditions.

Animal pain research

Over the last 15 years I have been involved in the pain field initially in research and then in clinical practice. I regularly attend scientific meetings. It continues to amaze me the amount of pain research done on mice/rats. Honestly, I do not think the findings in mice/rats are transferable to complex conditions like human pain. For a very simplistic and partial view please see my section about pain mechanisms. The result of so many billions of dollars spent on animal pain research is very lacking. Not much in terms of treatments came out of this research.

At recent scientific meetings the hype was about how male mice and female mice are different. Some researchers seem to believe that because most research was done on male mice, the results were not suitable for translational (treatment finding) research. Following this reasoning I am baffled that they do not realize that the difference between female mice and male mice is much much smaller than the difference between humans and mice. Humans are very different creatures. Recently I saw an article in the journal Nature describing the significant differences between the brain neurons in humans and mice: Hodge RD et al. Nature. 2019 Sep;573(7772):61-68. One of the conclusions of this paper is: “Notably, serotonin receptors are the second-most-divergent gene family, challenging the use of mouse models for many neuropsychiatric disorders that involve serotonin signalling.” Pain circuits are intimately connected to the the brain areas involved in various psychiatric diseases (e.g. anxiety, depression). Earlier this year one article that was very hyped on the internet talked about the areas of amygdala in mouse that seem to be important for the “unpleasantness of pain”: Corder G et al. Science. 2019 Jan 18;363(6424):276-281. I find it hard to believe that the findings of the Corder G et al. paper will have any importance for the human pain.

I think we should focus on animal research only to understand the fundamental mechanisms of biology (e.g cell biology, molecular biology) and use human research to understand complex diseases like pain. Even the fundamental mechanisms at the cellular level do not always translate from mice to humans. There are a few studies looking at functional knockouts in humans that were not predicted from studies in mice: Saleheen D et al. Nature. 2017 Apr 12; 544(7649): 235–239 and Narasimhan VM et al. Science. 2016 Apr 22; 352(6284): 474–477.

How to improve your sleep

One of the popular beliefs is that you have enough time to sleep when you are dead. I have to admit that until recently I did not pay attention to my sleep. But over the last year I taught a wellness class for my resident physicians and sleep is an essential part of a healthy living. I felt I had to read more about sleep. One book that I really enjoyed was: “Why We Sleep: Unlocking the Power of Sleep and Dreams” by Matthew Walker.

Matthew Walker makes a great case for sleep. Sleep is pretty much the Swiss army knife for health and it is free. Poor sleep has been correlated in studies with all the diseases you can imagine from heart disease, obesity, diabetes, degenerative brain diseases (Alzheimer’s) to cancer. The obesity connection is really interesting. Humans are the only animal who voluntarily deprives itself of sleep. The other animals decrease sleep only when they don’t have enough food. This connection sleep/food is likely preserved in us. When we don’t get enough sleep our brains/bodies are guessing that we are food deprived and we feel like eating a lot of food high in calories (junk food).

Basically the recommendations I found so far are:
- Allocate enough time for sleep - at least 8 hours per night
- Use dim lights in the evening (or red lights if you have them), no screen time, turn your devices to night mode (reddish color of the screen)
- Cold room: 65-68 degrees F (use socks if needed, obviously this temperature is much easier to achieve in the winter)
- Decrease worry/anxiety: best is meditation, another option is to do journaling one hour before bed and end the journaling with a couple of things for which you are grateful that day
- No food/exercise for 2-3 hours before bed
- No alcohol in the afternoon/evening
- Limit/give up coffee (including decaf) or caffeinated beverage (i.e tea, Coke, Pepsi). If you sleep enough you might not need any of these
- Create the connection between bed and sleep, go to bed only when sleepy, don’t do anything else in bed (like reading or watching TV). If you don’t fall asleep get up and do something else
- Avoid sleeping pills, they do not induce normal sleep

And even more recommendations:
- If you snore discuss with your doctor about a sleep study, maybe you have sleep apnea
- If your sleep partner interferes with your sleep, consider sleeping in different beds/rooms

Matthew Walker appeared on a few podcast shows that I follow. You can listen to him on Peter Attia podcast: episode 1, episode 2 and episode 3.

The tight integration of the immune and nervous systems

Years ago, in the medical school I learned about various parts/systems in our body. But nobody spent much time in putting everything together. Nowadays I think the situation is still the same and most doctors end up looking at our bodies as a piece here and there. Of course having so many specialized doctors does not help the integration cause.

Over the last year I spent some time reading about the interactions between the immune system and the nervous systems. Depending where we draw the line I would argue that the immune system and the nervous system are basically one thing. The immune system can be seen as part of the sensory system with a role to inform the brain about potential bacteria/viruses present around the body. Nervous system also modulates the immune system. An interesting presentation by Kevin Tracey (TEDMED talk) describes how the vagus nerve changes the immune response. Another lecture by him goes even in more details: the academy of medical sciences talk. Currently there are efforts to use vagus nerve stimulation to treat autoimmune diseases like Crohn’s disease and rheumatoid arthritis (one article here).

The central nervous system (brain and spinal cord) has a significant amount of immune cells in the form of microglia. It is estimated that microglia are 10-15% of all glial cells in the brain. Microglia are tightly integrated with neurons and have a role in the maintenance and regulation of the synapses between neurons. Things can go wrong. There are theories that some forms of depression are caused by inflammation. Charles Raison is one physician researcher who is working on depression and immunity (this interview with Rhonda Patrick is really good). The other day I read an article in the New York Times where cases of schizophrenia seemed to be related to the immune system. In this article one patient developed what appeared to be schizophrenia, then developed leukemia and had stem cell transplant. His schizophrenia resolved after the stem cell transplant. Another patient had leukemia and got stem cell transplant from his brother who had schizophrenia. Strangely enough this second patient developed schizophrenia himself.

The connection between the immune system and the nervous system has been used for thousands of years in yoga and practices of breathing exercises. One recent version is the Wim Hof method which is a combination of cold exposure, meditation and breathing exercises. For a perspective about Wim Hof, the man, this is a good documentary by Vice. Luckily some researchers got involved and they showed that the practitioners of Wim Hof method had a different response when they were injected with Escherichia coli endotoxin. You can read the article published in PNAS for free: here. Anecdotal evidence from the followers of Wim Hof method suggests an improvement of the autoimmune diseases. There is a book by Scott Carney that discusses more on this topic: link here.

This post is just a little introduction on the this topic. My interest is in chronic pain and I think inflammation and pain create a vicious cycle that maintains both of them. We have to start looking at the bigger picture when we treat complex diseases like chronic pain.

Slow medicine vs fast medicine

We live in a fast-paced society. It seems that new technological advances happen every day. We see commercials for better cars, new TV sets, super fast phones (which are pretty much computers in our pockets). I think some of the expectations are transferring to the medical care. Patients expect a fast fix for most diseases. They ask: doctor, do you have a pill to fix this or that? Or an injection, or maybe a surgery?

I think it is worth trying to look at the bigger picture. The time scale in biology is very different than in technology. Little changes happen in our bodies every second and some times these little changes accumulate over many years to cause a disease. Furthermore, we do not live suspended in a vacuum. We interact with our environment; we are part of the environment. During history different trends in medicine tried to make sense of the bigger picture. In 1960 George Engel published “A Unified Concept of Health and Disease”, a paper that I would recommend to everybody (it was recommended to me in a book by Lorimer Moseley and David Butler). George Engel promoted the biopsychoscial model of disease. He criticized the medical practice at that time, medical practice which is still the same today. A few key paragraphs from his paper:

“To be able to think of disease as an entity, separate from man and caused by an identifiable substance, apparently has great appeal to the human mind. Perhaps the persistence of such views in medicine reflects the operation of psychological processes to protect the physician from the emotional implications of the material with which he deals.”

“Patients, certainly, regardless of their level of education and sophistication, prefer to blame their illness on something they "caught" or ate or that happened to them and to think of disease as something apart.”

“A disease, then, has substantive qualities, and the patient can be cured if the diseased ("bad") part is removed. That this often proves to be the case, as attested to by the successes of surgery, is actually not evidence for the validity of such a point of view”

In more recent times the trendy terms are mind-body medicine and integrative medicine. I would argue that both of these new terms are trying to accomplish the same thing as the biopsychosocial model, take the patient as a whole person interacting with the environment. Diseases are caused by a combination of genetic factors, lifestyle and environment. At this point we cannot control most genetic factors, but we have the power to change the lifestyle and the environment. However, changes come through education and with effort. Last national program with meaningful results was the campaign against smoking. Since then other issues took over, one of the most important being the obesity.

Once a disease develops I think it is worth looking again at the cause of the disease and work very hard to change the contributing factors. Also we have to be cognizant that it will take time to reverse biological processes. Usually a disease does not develop overnight and the solution takes time too. This is what I would call slow medicine. Of course, there are medications we can give to patients in the meantime, but the medications should be only a short term solution for most conditions. Medications have many predictable and unpredictable side effects: see my blog post (Side effects of medications). Small incremental positive changes for long term benefit are not that appealing in the current culture. I think we really need a change in culture. In my case I treat chronic pain conditions. I have many patients who come to me and say they had pain for over 10 years. At this point their whole nervous system is changed, their social lives are different, their psychological status is different. One medication or injection is not going to change everything. I tell them that there are things I can do for them (e.g medications, procedures, referral to physical therapy/psychology) and there are things they can do for themselves (e.g. lifestyle changes, weight loss, healthy diet, quit smoking, participate in physical therapy/psychology). We will work together as a team and manage their pain.

The other type of medicine I would call fast medicine. This is very dramatic and appealing to the doctors/patients/general public. Fast medicine includes surgeries, treatment of cancer, curing of possibly deadly infectious diseases. There is definitely a place for fast medicine, we need it. I love fast medicine myself. I am an anesthesiologist and enjoy practicing fast medicine in the OR, fixing things fast. It is very rewarding. Every now and then I am blown away by what fast medicine can accomplish. Recently I read this article in the journal Nature: “Regeneration of the entire human epidermis using transgenic stem cells” (Nature volume 551, pages 327–332, for a general public version of the story here). Basically they had this kid with a genetic disease (Junctional epidermolysis bullosa) that involves the skin (superficial layer called epidermis) and mucosa. His skin had a lot of wounds (60% of his epidermis was lost). They took biopsies from his skin, engineered his skin stem cells to get rid of the genetic mutation, grew epidermis in the lab and transplanted it on the kid. In the end, they were successful in replacing 98% of his skin. It felt like reading a Sci-Fi short novel, truly remarkable stuff. But in the big picture if they stop here it will still be a failure. First, they did not fix his mucosa. Then, the kid likely has already tremendous psychological baggage and that is likely true about his parents. His social situation is also different after living with this disease.

In the big picture we have to understand when to use fast medicine approaches and when to use slow medicine approaches. I would argue that fast medicine needs slow medicine to take over afterwards and look at what caused the situation to occur in the first place, reverse what can be reversed and take care of the long term consequences.

Side effects of medications

It is pretty impressive to see how many medications patients take in the U.S. I looked at the official statistics from CDC and my anecdotal observations were confirmed. From 2011 to 2014 approximately 49% of population used at least one prescription drug in the last 30 days. In the same period approximately 12% of population used five or more prescription drugs in the last 30 days.  All this started with the antibiotics, the first real successful class of medications. Then, the medical system tried to apply the same principles to treat all human diseases. It was successful for some diseases (e.g. diabetes, high blood pressure, hypothyroidism) but for other diseases the success was not that great (e.g. cancer, pain). One major difference is that now patients are on medications for years compared with the short therapy with the antibiotics. Long term use of medications comes with side effects.

When you take a medication the goal is for the active chemical to get to a target in the body (usually a receptor or enzyme) and alter an intracellular pathway. The reality is much messier than the textbooks. Nature used the same building blocks many times to create different receptors in the body. Medications are very rarely (maybe never) specific to just one target.  One interesting website that shows possible interactions for medications is: http://stitch.embl.de/. Human receptors and the intracellular pathways can also have genetic variations and result in different effects for certain patients. Also, the medications are usually prescribed for one organ disease, but the molecular targets are present in other organs. One example of effects on other organs is the side effects of NSAIDs (nonsteroidal anti-inflammatory drugs) on gastrointestinal tract, cardiovascular system and kidneys.

The side effects to medications range from something quantifiable (e.g. changes in blood glucose, white blood cell count) to something very vague (e.g. feeling tired). One website that lists side effect to medication is:  http://sideeffects.embl.de/. The problem with the vague side effects is that although they can be very bothersome, sometimes they are not caused by the medication. Most people heard about placebo effect. However, there is the opposite effect, the nocebo effect. Basically, you give a "sugar" pill to somebody and the subject complains of random side effects. Normal people on no medication walk around feeling tired, sleepy, maybe slightly nauseated once in a while. When we give them a pill (active or inactive) they start to attribute their usual feelings to the pill. This is actually a big problem, there are clinical studies showing that 1 in 5 people receiving inactive pills complain of side effects (Barsky et al 2002).

When patients take more than one medication, the interactions are very unpredictable. I watched an intriguing TED talk by Russ Altman. He describes how they found that pravastatin and paroxetine when taken together increase blood glucose. Innovatively, they used a bioinformatics approach and a side effect database. Knowing the mechanism of action of pravastatin (a cholesterol lowering drug) and paroxetine (an antidepressant) the blood glucose effect is very surprising.

What can we do better in the future? We should think twice before prescribing medications long term. Sometimes there are other options, like healthy diet for weight loss (which helps diabetes, high blood pressure) or relaxation/meditation techniques for anxiety and sleep. Only if everything fails we should rely on medications.  Or we can use medications only short term while implementing the other methods. Our society is looking for a quick easy fix for every health problem, but the long lasting fix usually takes time and requires effort.

Opioid therapy

In the December 2017 issue of the Pain journal I read an excellent article about opioids by Jane Ballantyne and Mark Sullivan: "Discovery of endogenous opioid systems: what it has meant for the clinician’s understanding of pain and its treatment" (full article here).  In the same issue there is also a commentary by Daniel Clauw: "Hijacking the endogenous opioid system to treat pain: who thought it would be so complicated?" (full article here). Both articles describe how opioid receptors in the human body are there to interact with chemicals made in the human body. This innate opioid system is important for many functions in the body (some examples include mood, metabolism) and social functions. Basically, a therapy with high dose opioids alters all these innate mechanisms. Another issues is that a high dose opioid therapy may interfere with other nonpharmacological therapies for pain that likely use the endogenous opioid system: exercise, acupuncture and mind body therapies.

Currently, the U.S. is going through an opioid epidemic and opioids are frequently discussed in the news. I think it is important to look at the bigger picture. Humankind has a long history with opioids. There are some theories that even Neanderthals used poppy seeds. A good timeline is presented here by PBS. There were even opium wars between the British Empire and China with the British Empire promoting opium trade. It is a fascinating read about the first opium war and then the second opium war. At that time people had all kind of ideas about how drugs work. A quote from the first article above: "during the many centuries that opium and its derivatives were used for pain, the efficacy of opiates was often attributed to divine benevolence. Thomas Sydenham, the 17th-century “English Hippocrates,” wrote “Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.” Sir William Osler called opium, “God’sOwn Medicine.”

Our last excessive use of opioids started in the lat 20 years with a significant increase in deaths. CDC estimates that from 1999 to 2015, more than 183,000 people have died in the U.S. from overdoses related to prescription opioids. This does not include the deaths related to illegal opioids. More statistics are available on the CDC website. In March 2016 CDC came up with guidelines about opioid prescription: long version and short version. Basically, the recommendation is to be very cautious when prescribing more than 50 mg Morphine equivalents daily and have a very good reason to prescribe more than 90 mg Morphine equivalents daily. Most people nowadays are prescribed hydrocodone and oxycodone as outpatient opioid medication. Hydrocodone dosage is equivalent to morphine dosage, so 10 mg hydrocodone is equivalent to 10 mg morphine. Oxycodone is one and a half time more potent than morphine, so 10 mg oxycodone is equivalent to 15 mg morphine. Oxycontin is the slow release version of oxycodone and the same conversion as for oxycodone applies.