The last post asked whether we should feed sick people less, which would make sense if sickness behaviors are adaptive. This post asks whether we make infection worse when we block pain. Pain is a central feature of several sickness behaviors including myalgias, hyperalgesia, and headache. While technically these are sickness symptoms, I am going to stick with “sickness behaviors” for consistency, and also because they change behavior. These changes were noted by Julie Lasselin who has studied the role of pain in sickness behavior. She noted that sick people undergo characteristic changes in gait, caused by restricted movements. Gait is highly visible to others, and might perform a signal role that elicits caregiving behavior.

Whether or not altered gait prompts caregiving, Lasselin suggests also that pain promotes energy conservation. In sickness, myalgias affect large muscle groups in the thighs and back during illness. Pain in those muscles discourages movement and promotes energy conservation. (Even if sick people wanted to run a marathon, they couldn’t, because muscles are temporarily unable to take up glucose energy, a phenomenon called insulin resistance.) Indeed people experiencing pain and myalgias increase time at rest and reduce energy expenditure. This rest is useful when activated immune cells slurp up all available energy.

Pain during sickness is widespread in the animal kingdom, implying an evolutionarily conserved function. Increased sensitivity to pain, or hyperalgesia, is common during and after infection and injury, seen in squid, fruit flies, rodents, and people. During bacterial infection, genes associated with pain sensing are upregulated in fruit flies. Infected mice show hyperalgesia, as do humans. These evolutionarily conserved pain responses appear to be functional, albeit highly unpleasant, and they are a leading reason why patients visit a doctor.

Should an evolutionary medicine approach to pain involve treating less of it? Maybe. I suspect we have a lot of room for improvement in how we treat pain. Shared decision making with patients is a must. The goal is to relieve suffering, while taking into consideration the tradeoffs of treatments used to treat pain. The problem is that the tradeoffs are considerable.

I have written papers on why we should not treat fever in most cases. In some ways, pain follows the same logic as fever. In part this is because we use some of the same medications for both. There is one problem: fever is different from pain. Most patients do not seek treatment for fever per se; they come in because they are miserable and want their pain to go away. Accepting the side effects of pain relievers is a tradeoff many patients might accept. It is the job of a physician to help patients weigh short term benefits against the costs of various pain treatments.

Most people would accept a small increased risk of kidney injury, gastrointestinal bleeding, or cardiovascular disease from a short term course of a non-steroidal anti-inflammatory drug (NSAID). Some would accept the risks of constipation, addiction, respiratory depression, and increased overall mortality that comes with an opioid prescription*.

Another underappreciated harm is that analgesics might actually increase future pain, not just rebound pain, but chronic ongoing pain. This is a common problem in those taking opioids. Pain sensitivity is upregulated after chronic opioid use. This effect is called tachyphylaxis, and it contributes to dangerous drug escalation. Chronic pain can be a adverse effect of NSAIDS too. In 2022, Parisien and colleagues published a study in Science Translational Medicine that got my attention, by way of Randy Nesse who pointed it out to me. Nesse is the author of Why We get Sick – the new science of Darwinian Medicine, and a founder of ISEMPH, the International Society for Evolution Medicine and Public Health. We both understood that inflammation can be a host defense, and he had urged me to look into potential harms of blocking inflammation after an injury. This particular study was very informative, joining prior work showing that NSAID use might interfere with tendon healing and bone repair after injury. Parisien’s study showed that NSAIDS prolong pain in mice and in people with back pain. The problem is that NSAIDS inhibit neutrophils, a subset of white blood cells. Neutrophils were shown in this study to cause short term inflammation that prevented long term pain. In other words, post injury inflammation and inflammatory pain might be the price one has to pay to be free of more chronic pain. This study highlighted an unintended effect of anti-inflammatory drugs. NSAID use produced prolonged pain in experimental mice, and also in people. Pain persistence was likelier in humans who took NSAIDS after an acute back injury.

Most of my medical coworkers and their patients are likewise unaware that treating pain can worsen the risk of infection. Although causality is uncertain, opioids are shown in observational studies to increase invasive Pneumococcal disease and severe infection in those with rheumatoid arthritis. Compared to opioids, NSAIDs appear safer, but they make mice more vulnerable to severe Streptococcal infections. Finally, opioid use disrupts the microbiota, causing a pathogen enriched dysbiosis that exacerbates infections and increases chronic pain. At the 2022 ISEMPH meeting in Portugal, Kevin Lozo, Athena Aktipis, and I presented a model of conflict over pain between hosts and microbes. We argued that hosts and microbes engage in a tug of war around the defensive function of pain, somewhat akin to the tug of war over iron discussed previously. The bottom line is that pain has an unappreciated defensive role – see more about our model here.

Armed with most of the information I cited above, I vowed to minimize my use of NSAIDs and opioid pain relievers when I underwent shoulder surgery about a year ago. Was I successful? Not really. My rotator cuff surgery was the most painful thing I have experienced. I ended up taking every pill that was prescribed. My experience highlights the conundrum embedded in modern medical care – sometimes the need to relieve intense immediate suffering justifies treatments that carry risk. On the other hand, a prescriber who is alert to these risks might opt for alternative treatments, including topical analgesics, ice and physical therapy that reduce long term pain and dysfunction. I did all of those too. However, ice and physical therapy are more often prescribed for injury, not infection. Further, exercise and physical therapy are difficult when sick. Why? Because myalgias, fatigue, and headache reinforce rest that is probably protective during an acute infection. When you are sick, it is probably better to be a couch potato, at least a temporary one. While you are lying on the couch and your pain can be managed without NSAIDS or opioids, it might be a small consolation to know that painful sickness behavior is doing you some good – defending you from further harm and speeding your recovery from infection.

*Note: Here in New Mexico, we routinely prescribe naloxone (Narcan) for patients going home with opioids so that their family or friends can treat life threatening respiratory depression. Aware of these serious side effects, some of my patients will elect to forgo opioids for painful diagnoses, like long bone fractures. Even though these medications are commonly prescribed for broken bones here in North America, this is not at all the norm in some countries, notably, Japan.

Post script: Could treatment of inflammatory pain predispose a patient to chronic post-infectious pain in long COVID? We really don’t know, but Bernie Crespi and I are researching whether sickness behavior can explain some of the mysteries of Long Covid. Stay tuned.

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine