Understanding Pain

By Michael Jorrin, "Doc Gumshoe", June 30, 2021

What started me down this path was a promotional piece for a new drug that was purported to suppress pain through a novel mechanism that prevented the nerve signal that conveyed to the brain a sensation that would usually be experienced as painful from actually being painful. In other words, while mincing an onion, you accidentally sliced into your left index finger. You felt the slicing sensation, you saw the blood, but it didn’t hurt. That’s not like an anaesthetic, which totally blocks the slicing sensation. With an anaesthetic, you feel nothing. But with this new drug (if you believe the hype) you do not lose sensation, but you do not feel pain. (Note, I definitely do not believe the hype – it came from a source that daily clogs my spam filter with a couple of dozen over-the-top claims. The phrase was something like “this little pill will end your pain.” The only little pill that I could think of that would “end your pain” was cyanide, so I took a look.)

What that hype ignored is that pain is actually highly useful. (I had thought of titling this piece “Praising Pain,” but then it seemed to me that it sounded too much like “Raising Cain,” and Doc Gumshoe does not want to be identified as a raiser of Cain.)

But, for the usefulness of pain, let me give an example. I was cooking a turkey for Thanksgiving a couple of years ago, and I took the gigantic stainless steel casserole out of the oven, carefully holding the two handles of the casserole with my hands encased in those padded mittens that protect the hands from hot objects. I set the casserole on the kitchen counter, which happens to be limestone and thus heat resistant. I took the lid off the casserole, and got a large ladle to scoop some of the turkey juices and pour them over the turkey. I then picked up one of the handles of the casserole in order to tip it and let the juices run to the other end of the casserole. Only I had taken the mitten off the wrong hand. I had the ladle in my left hand, which was protected by the mitten, and I picked up the casserole with my bare right hand.

It hurt like the dickens, or the deuce, whatever the demon of pain is named. I quickly put the casserole down, and ran to the sink to pour cold water on my burnt hand. The burn was not severe enough to require an emergency run to urgent care, and in any case there were things to be done before our dinner guests arrived, so I cursed myself for being a half-witted dunce and got back to work.

The burn kept hurting for days, of course. But imagine if, when I picked up that casserole with my bare hand, the instant message to my brain had not been that I had to put that casserole down and let go of the handle really, really quickly. If I had held on, it would have required more than a visit to urgent care.

So, of course, pain is an exceedingly valuable warning that something is going on that needs attention. The more excruciating the pain is, the more immediate the attention needs to be. Pain that comes on gradually can be a signal of a different kind; for instance, some migraineurs experience persistent headaches after being exposed to certain stimuli – red wine, certain foods, piercing or flashing lights. The signal to the migraineur is, avoid those stimuli whenever possible.

And then there are the pains and aches that tell us that something in our bodies is not working right. I had knee pains, growing in severity, for several years before it was decided that the best course would be to swap my natural bone knee joints for nice new ones made of titanium and plastic. This happened in a couple of installments, which Doc Gumshoe has described in some detail. My knee pain basically stopped. Except, of course, for the pain I experienced during the rehab period. The rehab was absolutely essential if I was to regain normal use of my legs, but the pain that came along with it was inescapable.

The pain during the rehab sessions taught me, I think, a valuable lesson. For several weeks after the surgery, the pain in the knee was fairly constant, and I was able to keep it under control by using various analgesics – oxycodone for the first few days after the surgery, followed by NSAIDS. But the rehab sessions were something else entirely.

What rehabilitation therapy is trying to accomplish is a return to normal. That means that I needed to bend my leg as much as I had been able to before the knee joint became arthritic, and I also needed to straighten my leg completely, locking the knee joint and getting the leg as straight as an arrow.

I could – and did – try to do that on my own, but there were limits to what I could manage. So the physical therapist steps in, to add his (or her) own muscle to mine. That meant that as I was lying on the table trying to straighten my leg, the Cruel Cristina would get up on the table and use all her weight to press down so as to get my leg really, really straight. The goal (never quite reached) was to have the back of my knee so snug against the table that she could not slip her fingers between the back of my knee and the table.

As she pressed down, she would say, “Tell me when it just hurts too much.”

When the pain became excruciating I would gasp something like “Enough!” And then Cristina would keep pressing down five more seconds or so.

She used the same procedure to bend my leg, eventually employing all her strength to get my knee joint to the desired acute angle, and again she would ask me to tell her when it hurt too much and then continue pushing for another few seconds.

What I learned to do that helped a great deal was to put distance between myself and the pain. I felt the pain for sure, but it was down in my knee – not in any essential part of my body, not my heart, not my gut, not my head. It wasn’t going to kill me. Yes, it was painful, but it wasn’t terrifying.

My strategy of distancing the pain did not prevent my nervous system from transmitting the specific pain sensation to my brain. There was no doubt whatever that the impulse got there, and that the sensation hurt like blazes. What it did not do was create that sense of doom, where your heart rhythm goes wacky and you gasp for breath. In other words, my sympathetic nervous system did not go into the desperate fight for survival mode in response to the acute pain. And that made it possible for me to treat the torture of physical therapy as a more or less casual incident.

But what would happen if we did not feel pain?

Pain insensitivity

Believe it or not, there are human beings on Planet Earth who mostly do not feel pain. This phenomenon is real, and it has been labeled “pain insensitivity,” and has become the subject of considerable scientific inquiry. There are excellent reasons for investigating this subject. Not only would it provide insight into the mechanisms of pain – how is a sensation perceived as being painful? How is it that a gentle touch on the finger with the head of a pin is perceived as nothing more than that – a gentle touch, whereas if the pin penetrates the skin and enters the flesh, the gentle touch is transformed into an “ouch!” But also, might it be possible to find ways to preserve the sensation, but spare the actual “ouch?”

This would be particularly beneficial in cases of chronic pain – pain that is not a warning signal, but a constant reminder that something is wrong, and that you really can’t do anything about it, or at least, not quickly enough to alleviate the pain. Just recently, on May 27th, The Lancet published a three-part series on this type of pain, which I will attempt to digest for the benefit of the Gumshoe tribe later on in this piece. For now, let me quote the introductory words of The Lancet papers:

“Pain is the most common reason people seek health care and the leading cause of disability in the world. Chronic pain has been defined as pain that persists or recurs for longer than 3 months, and it exerts an enormous personal and economic burden, affecting more than 30% of people worldwide. Even controlling for higher rates of depression, suicide, and opioid use, chronic pain is associated with a lower life expectancy.” (Lancet 2021;397:2082-2097)

Returning to the subject of pain insensitivity, would it not be excellent if the root of this characteristic were found to be some genetic trait which could then be copied via CRISPR or some similar gene-editing tool, and then inserted into the genome of persons affected by chronic pain for which there was no available remedy? Aside from scientific curiosity, that is sufficient reason for the investigation of cases of pain insensitivity.

Scientists, philosophers, quacks, and ordinary people have been studying pain for as long as humans could be said to have “studied” anything. In spite of huge efforts to understand how pain works, it remains a puzzle. We know that neurons everywhere in our bodies send signals to the brain which translates all that information into perception. We know that certain centers in the brain are specific for the senses such as touch, taste, and smell. But there is no single brain region specific for the perception of pain. There may be many, as many as half a dozen. This has made treatment for pain a mostly crude exercise. Most pain treatments have emerged completely empirically, often from folk medicine; e.g., aspirin originating from willow bark and opiates from the wild poppy.

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It appeared intuitively likely that insensitivity to pain is a genetic trait – not learned, not acquired; I learned to tolerate my knee pain, but I definitely felt it. If pain insensitivity is genetic, it might present in families. A pair of researchers – John Woods of University College and Geoff Woods of Cambridge University, both in the UK, did some work on a Pakistani clan known as the Qureshi biradari. John Woods had done some research on a young boy from this clan who worked as a street performer, walking across burning coals and stabbing himself with knives. A few years later, Geoff Woods went in search of the boy, who by then had died from injuries he sustained when he did a stunt leap from a rooftop.

Other members of that clan exhibited similar degrees of pain insensitivity, although they did not exploit that characteristic as performers inflicting pain on themselves. Geoff Woods was able to collect blood samples from several members of that family, and it turned out that they possessed the same gene abnormality that John Woods had previously found in the young street performer. It was a subtle mutation in a gene regulating pain-sensing neurons, which disabled a key component named Nav 1.7, which in a typical healthy person helps notify the brain of pain or discomfort. When Nav 1.7 is absent or defective, the pain signal is not transmitted.

Without getting too deeply into the weeds, what is Nav 1.7 anyway? It’s a channel in the cell membrane that permits the passage of sodium (Na) ions, which, in turn, signal an action potential, or, in other words, turn on a switch. There are several ion channels active in different parts of the body. Perhaps the best known are the calcium channels in the surface of arteries. Passage of calcium ions through those channels cause arterial constriction and therefore hypertension; calcium channel blockers are effective treatment for some types of hypertension. In the case of Nav 1.7, it’s a sodium channel that is specifically involved in the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability; thus, Nav 1.7 essentially facilitates and amplifies the transmission of the pain signal.

If calcium-channel blockers are effective hypertension drugs, one would think that sodium-channel blockers would be effective pain medications. Based on that reasoning, several drug companies have developed inhibitors of Nav 1.7, including Pfizer, Teva, Roche/Genentech, and Biogen as pain medications. Unfortunately, clinical trial results to date have not been promising. The Nav 1.7 inhibitors they developed do not pass the blood-brain barrier, and it is in the brain that Nav 1.7 performs its mischief.

The Italian “superwoman”

A few years after Geoff Woods’ work with the Pakistani clan, John Woods encountered another person with a remarkable degree of pain insensitivity. This was Letizia Marsili, who was the subject of an article in Smithsonian Magazine by Matthey Shaer (May 2019). Shaer recounts how Marsili was skiing with her sister in the Italian Alps when she lost her balance and crashed into the snow. She felt a jolt of pain, but then the pain subsided. She got up, brushed herself off, and skied another 18 miles. She felt fine, but later that day, having dinner, she found that she could not hold her fork. Next day, she saw a doctor who X-rayed her and told her that her shoulder was broken.

She was not surprised. That kind of thing had happened to her many times. When she was six years old, she impaled herself on a nail while climbing a pole. She just stopped the blood flow and kept on playing. Her friends were horrified. She would twist her ankle while rock climbing or burn her hands in hot oil. In each case, her reaction was the same: a brief shudder of discomfort, and nothing more.

As an adult, Marsili’s reactions were much the same. She didn’t bother to dress against the cold – she just didn’t feel it. Nor did she protect herself from sunburn. At the University of Sienna, where Marsili is a professor of marine ecology, her colleagues refer to her as “superwoman.”

In the late 1990s, Marsili was introduced to Anna Maria Aloisi, who was director of the University’s pain clinic. Aloisi had access to a new high-tech lab, and volunteered to help Marsili with research on contaminants in swordfish and tuna. When Aloisi found out about Marsili’s pain insensitivity, she performed some experiments on Marsili, including injecting capsaicin directly into her arm. Capsaicin is the chemical that gives chili peppers their fiery quality. Initially, Marsili flinched in response to the injection of liquid fire. But after about a minute the pain subsided and Marsili felt nothing.

John Woods met Marsili through Aloisi, who told him that not only did Letizia Marsili have an extraordinarily high tolerance for pain, but so did much of her family – her mother, her sister, her sister’s daughter, and Letizia’s sons. In other words, Letizia’s pain insensitivity was a genetic trait, and not a single accidental mutation.

Woods was able to get blood samples from Letizia Marsili and several of her relatives, which he sent back to his lab in London for analysis. After following a number of blind alleys, James Cox, who had been part of the research that identified Nav 1.7 as the source of the Pakistani family’s pain resistance, found a mutation in a gene known as ZFHX2, which affects neurons that play a role in transmitting pain signals to the brain. Experiments showed that the mutant gene behaved differently from its non-mutant (“wild”) counterpart.

Cox and his co-workers then procured mice whose genes had been altered such that the ZFHX2 gene had precisely the same mutation as the one in the Marsili genome. These poor mice were placed on hot plates and exhibited much less sensitivity to heat than would be expected.

Torturing those mice supported the premise that the mutation in the ZFHX2 gene was the underlying cause of Marsili’s pain insensitivity.

… and the Scottish superwoman…

She is Joanne Cameron, 73 years old, the subject of a long piece in The New Yorker by Ariel Levy (01/13/20). She not only does not feel pain – she doesn’t seem to have any negative emotions such as anger or fear. She and her husband have never had a fight. She feels “righteous indignation” when she hears of the misdeeds of a political figure. “But then,” she says, “you just go to a protest march, don’t you?”

As a child, she fell while roller skating and injured her arm. But she had no idea she had a broken arm until her mother noticed that it was dangling strangely.

When she was pregnant with her first child, her friends warned her not to do the “natural childbirth” thing, which they said was horribly painful. So, when she was ready to give birth she said to herself, “As soon as it gets painful I’ll ask for the drugs. But it was over before I knew it.’

She also had hip replacement without anaesthetic. A few years later, when she needed surgery to remove a small joint at the base of her thumb, she came to the attention of Devjit Srivastava, a consultant anesthetist at Raigmore Hospital in Inverness, Scotland, which serves the Scottish Highlands. Srivastava dismissed her claim that she would not need anaesthetic, attributing it to Scottish stoicism. He used anaesthetic during the surgery, but was surprised that after the surgery she took only the single paracetamol tablet that nurses automatically give all surgical patients. Looking into her charts, he saw that after her hip replacement she also took only the single mild analgesic. Srivastava at that point began to delve into Jo Cameron’s remarkable pain insensitivity. This brought him into contact with James Cox, who had (as mentioned above) worked on both the Pakistani family’s pain insensitivity and that of Letitzia Marsili.

Working together, Srivastava and Cox found that the factor accounting for Cameron’s pain insensitivity was a mutation in a gene that controls for fatty acid amide hydrolase (FAAH). Normally, FAAH breaks down endocannabinoids, which mitigate the stress response and the perception of pain. The mutated gene, labeled FAAH-OUT has less activity in the breakdown of endocannabinoids and also results in elevated concentrations of anandamide, which is involved in pleasure and feeding. The paper by Cox and Srivastava suggests that new routes to develop FAAH-based analgesia by targeting of FAAH-OUT could significantly improve the treatment of postoperative pain, and potentially chronic pain and anxiety disorders. (Br J Anaesth 2019 Aug;123(2):e249-e253)

The findings of Srivastava and Cox suggest that Joanne Cameron lives in a constant cannabis high. Pain specialists are dubious whether such a condition is desirable for everyone. It might be fun, but without question, it’s highly risky. Joanne’s mother noticed when Joanne’s arm was broken, therefore it was treated. Some moderation of Cameron’s total pain insensitivity might be a better option.

Evidently there are several possible targets in the quest to find ways of conferring at least a degree of pain resistance. The ones that have been identified are the sodium channel transporter Nav 1.7 and the gene mutations in ZFHX2 and FAAH. It seems highly likely that there are others.

What seems clear is that research on this front is highly tempting. It would be a singular accolade for a scientist to be recognized as the person who found a procedure that would make a person impervious to pain. But at the same time, the benefit of making a person impervious to pain needs to be seriously questioned, for the reasons discussed above.

In fact, Doc Gumshoe would definitely characterize the capacity to experience pain as a survival characteristic. As far as we know, this capacity is shared by all animal species. The reason pain insensitivity is so rare is that it is the opposite of a survival characteristic. Creatures that don’t experience pain, particularly in the wild, have a greatly reduced chance of surviving and passing their pain insensitivity to their offspring.

Pain that serves a purpose as an urgent warning, such as when we experience a burn or an injury is obviously the type of pain whose suppression could be a serious problem. But what about chronic pain – pain that is always present and does not point to an obvious cause? We’re not talking about pain that hangs on until a specific cause is identified and treated, like my knee pains until I had the joints replaced. Chronic pain can be of low intensity, and it can get better and worse, but it doesn’t entirely go away. The cause, whether it is musculo-skeletal, neuropathic, due to the progression of a disease that is resistant to treatment, or yet something else, is not easily addressed. The question is, how best to treat chronic pain?

Managing pain that has no immediate evident cause

That is the fundamental distinction between chronic pain and different types of acute pain. The target of treatment of acute pain is whatever it was that caused the pain. Sometimes identifying the specific cause of pain is a big clinical challenge, and sometimes clinicians fail to find it.

That doesn’t mean that the pain sensation has no cause. There’s a cause in there somewhere, but it may be elusive, or it may be the result of a condition that can’t directly be remedied.

A small anecdote. Quite a few years ago I found that I was going about with a stiff and painful neck. It was a major bother. But it totally went away when I got a new pair of glasses. Evidently, what had been causing my stiff neck is that, in order to read my computer screen, I would crane my neck to see under my glasses. Why I didn’t take them off I don’t know. But my new glasses were bifocals; I could see the screen just fine, and my neck stopped hurting.

My pain in the neck could be called chronic pain, until the cause was remedied. I know a woman who had been experiencing back pain which ceased when the arm rest of her office chair was adjusted. Some people have lower back pain resulting from a lifetime of hard physical labor. And of course many diseases are associated with persistent pain which continues unless the disease can be treated and resolved.

The three-part La