THE PAIN IS IN YOUR BRAIN: Your Knees Know Next to Nothing

A “frozen shoulder” can be manipulated to move freely again under general anesthesia. The medications we use to put patients to sleep for such procedures work on the brain and don’t concentrate in the shoulder joints at all.

An ingrown toenail can be removed or an arthritic knee can be replaced by injecting a local anesthetic – at the base of the toe or into the spine – interrupting the connection between the body and the brain.

An arthritic knuckle can stop hurting and move more freely after a steroid injection that dramatically reduces inflammation, giving lasting relief long after any local anesthetic used for the injection has worn off.

The experience of pain involves a stimulus, nerve signaling and conscious interpretation.

Our brains not only register the neurological messages from our sore knees, shoulders, snake bites or whatever ails us. We also interpret the context or significance of these pain signals. Giving birth to a long awaited first baby has a very different emotional significance from passing a kidney stone, for example.

I have written before about how we introduce the topic of pain to our chronic pain patients in Bucksport. Professor Lorimer Moseley speaks entertainingly of he role of interpretation in acute pain and also explains the biochemical mechanisms behind chronic pain.


Even when we are awake, we can reduce orthopedic pains with medications that work on the brain and not really in our joints. A common type of arthritis, such as that of the knees, is often treated with acetaminophen (paracetamol), nonsteroidal anti-inflammatory drugs (NSAIDS) like ibuprofen or even opioids.

NSAIDS reduce inflammation, and reach the tissues inside our knees, but also have an effect on our nervous system’s signaling and perception of pain in the absence of serious inflammation. Their main action is inhibiting cyclooxygenase (COX) enzymes that are involved in prostaglandin release, which happens in the brain to a large extent. Prostaglandins do bad things like causing pain, swelling and fever, but they also do good things, like repair stomach ulcers.

Acetaminophen (paracetamol) also inhibits COX enzymes, but doesn’t reduce inflammation. By itself it does relatively little for pain, but when added to an NSAID, it can greatly improve pain control.

Opiates work mostly centrally for pain, helping our brains filter out the pain messages from different kinds of receptors throughout our bodies. The most well studied are Mu, Delta and Kappa receptors. Less well understood is the nociceptin opioid peptide receptor (NOP).

While Mu, Delta and Kappa receptor stimulation all decrease pain perception, there are other effects, too. Mu simulation contributes to addiction.

Mice without Mu receptors don’t get pain relief from opiates and also don’t get addicted to them. They do show increased pain sensitivity in general and are less likely to develop addictions to non-opioid drugs of abuse.

Mice without Delta receptors demonstrate more anxious and depressive behaviors than normal mice.

Kappa receptor stimulation in pain patients can cause depression and may have a primary role in depression, unrelated to pain, as well. Experimental drugs that stimulate or block only Kappa receptors interestingly have different effects in men and women. This may deepen our understanding of older opioid medications. New Kappa receptor blockers are on the horizon as possible antidepressants.


Chronic pain is like a self perpetuating bad habit: Nerve signals from damaged tissue can continue to fire, even if there is no further damage occurring. The frightening thing with treating chronic pain with opioid drugs is a phenomenon called opioid induced hyperalgesia. By blocking the usual nerve signaling in our modern, human, fast transmitting and precise nervous system, our bodies can rely more, an “up-regulation”, on a primitive system of nerve fibers I think of as a lizard system, that tells us something is wrong, as in tissue damage, but with less specificity about type and location. Physicians see this when a person with a bad back on oxycodone treatment winces when you pump up the cuff to take their blood pressure or reports they just plain hurt “everywhere”.

Non-opioid medications for chronic pain that are viewed as safer, like gabapentin, Lyrica (pregabalin) and duloxetine, have their own dependence potential.

Pregabalin produced a “buzz” in some of the patients who took it in early testing, and was therefore made a federally “controlled substance”. Gabapentin is classified as such in the UK and some US states. It is often misused and is more and more often mixed with opiates, benzodiazepines and alcohol by substance abusers.

Duloxetine is related to the serotonergic antidepressants, SSRIs, but also has an effect on norepinephrine. Just like the SSRIs, it is associated with a sometimes severe withdrawal syndrome. I had one new patient who was on duloxetine for fibromyalgia suffer severe symptoms when she tapered herself off duloxetine. She went through a year of seizure-like phenomena, causing a neurologist to put her on anti-seizure drugs to control her twitching muscles and electric shock sensation in her limbs. There are now doctors and clinics specializing in helping people get off SSRIs. There is a growing concern, perhaps especially in Sweden, about the permanent brain changes these drugs can cause and how they can actually prevent full recovery from depression.

Given all this, it seems as if we need to move further and further away from the old pharmacocentric (Hey, I think I just made up a new word!) view that pain is a vital sign and something that deserves and always should be treated with medications.

But if drugs can change the brain’s perception of pain, are there non-drug options for doing the same? The context of pain can be altered: We are hardwired to associate pain with danger, tissue damage. But that isn’t always the case. If we know that use of a joint won’t change how fast our arthritis will progress, perhaps we will still choose to do some of the things we enjoy. We know that poor sleep doubles self-reported pain levels. Stress can increase pain perception as well as cause muscle spasm and a host of other health issues. We also know that hypnosis can change our pain experience. And, let’s not forget that we have naturally occurring opiate-like endorphins that work on same of the same receptors as the opiate drugs. Endorphins are naturally released in response to pain or stress. They can also be released in response to exercise, sex, dark chocolate, chili peppers and acupuncture.


There is research that holds the promise of safer centrally acting drugs, but we don’t know just how safe they will be. There are interesting studies on peripherally acting opioids, injected into joints, that actually have both pain relieving and anti-inflammatory properties. But will they be safe? How long will it take to find out and know for sure?

There is some hope for the future but a great deal to worry about today when it comes to treating pain. For too long, pain has been viewed too simplistically as easily and objectively quantifiable and treatable with drugs. Now we know that opiates can ultimately cause more pain and prevent us from releasing our own endorphins. As so often in medicine, a seemingly brilliant shortcut can lead us astray, down a treacherous road, where more pain, addiction and depression affects so many patients.

A holistic, multimodal approach to pain may sound like a lot of work, but since such a strategy boosts our natural biochemical abilities to overcome both acute and chronic pain, it is worth the effort.

Doxepin, a Little Known Super Drug in My Personal Black Bag of Tricks

A while back I was able to completely stop my mastocytosis patient’s chronic hives, which the allergist had been unable to control.

I did it with a drug that has been on the market since 1969 and is taken once a day at a cost of 40 cents per capsule at Walmart pharmacies.

Hives are usually treated with antihistamines like diphenhydramine (Benadryl). My super drug has a 24 hour duration of effect and is about 800 times more potent than diphenhydramine, which has to be taken every fours hours around the clock.

Histamine is involved in allergic reactions, but it also plays a role in stomach acid production. The allergic response happens mostly through stimulation of Histamine 1 receptors and the stomach acid output is regulated mostly via Histamine 2 receptors. Typical antihistamines are blockers of the H1 receptor, or binding site; they don’t do anything except sit there and prevent the real histamine from attaching and starting the allergic chain reaction. While diphenhydramine sits there for 4 hours, loratadine and the other modern, nonsedating (and less itch-decreasing) antihistamines work for 24 hours. Because there is some overlap between H1 and H2 blocking effects, H2 blockers like famotidine can boost the antiallergy effect of the typical H1 blockers. My mastocytosis patient still had hives on diphenhydramine, loratadine and famotidine combined.

But, wait, there’s more…

A much less well known effect of H1 receptor stimulation happens in the central nervous system. An interesting 2013 article explains:

Histamine is an excitatory neurotransmitter in [the] central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressants with sleep-promoting effects, for example, doxepin, promote sleep not through a sedative action but through resynchronisation of [the] circadian cycle. The stimulation of the H1 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the H1 receptor, making it a selective H1 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressants, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients.

American Family Physician writesControlled-release melatonin and doxepin are recommended as first-line agents in older adults.” Yet, at least in this country, trazodone is much more commonly used, even though it is less specific in how it helps people sleep.

Doxepin definitely deserves more attention than it is getting.

Osler said “Listen to your patient, he is telling you the diagnosis”. Duvefelt says “Listen to your patient, he is telling you what kind of doctor he needs you to be”.


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