By MARTIN SAMUELS, MD

In order to understand the concept of pain and its relationship to the current opioid crisis, it is prudent to review the neurology of pain an why it exists.  Several concepts are important to integrate.

Nociception:  Nociception is the capacity to sense a potentially tissue damaging (noxious) stimulus.  To illustrate this one should place a forefinger in a glass of ice water and determine how long passes until an unpleasant sensation arises.  If one performs this experiment in a large group, one can recognize that, although the stimulus is the same (a glass of ice water), the sensation arises at different rates in different people. 

In fact, a bell shaped curve will describe the distribution in any population of people.  Within 30 seconds almost all will have perceived an unpleasant sensation that is known at pain.  Nociception is a very primitive sensation. 

It is present in virtually all animals, even those without a brain, such as Aplysia, the sea slug.  Though it lacks a brain, it has nerves  and ganglia that allow it to sense and move away from a noxious stimulus.  Nociception is absolutely essential to our survival and well-being.  Without it, one would suffer tissue damage and ultimately death.  The human disease, leprosy, is a salient example of an infection that destroys the nerves that are responsible for nociception.  That lack of nociception is what causes all of the disfigurement that is characteristic of leprosy.  Anyone who has had a dental anesthetic is aware that one can inadvertently bite one’s own lip until the anesthetic wears off.

Controlling Nociception:  Why is it that a noxious stimulus ‘”wears off?”  Why does the unpleasant sensation not go on forever?  A system has evolved that is designed to turn off the nociceptive system.  This signal arises in the brain and releases a chemical that turns off the nociceptive impulses just after they enter the central nervous system.  This chemical is one of two small peptides, known as enkephalins, which bind to opioid receptors.  Because these are made in one’s own nervous system they are known as endogenous opioids.  Thus opioids are natural substances that are critical for controlling nociception so that the pain does not last beyond its use, which is to signal the presence of noxious stimuli.  Opioids are widespread in nature.  Many centuries ago, human being learned that there was something in poppies that relieved pain.  That substance was an opioid.  All natural and synthetic opioids have a very similar chemical structure and they all work by turning off the nociceptive system.  Those that come from sources outisde of one’s own nervous system are termed exogenous opioids. 

Pain:  Pain is discomfort caused by injury.  It is a phenomenon that arises in a part of the brain known as the thalamus, a cluster of nuclei in the center of the head (the centrencephalon).  The thalamus is the way station for virtually all sensation coming from the outside world, whether noxious or not.  Examples of non-noxious stimuli would be sounds, visions, touch, and vibration sense; in other words anything that is not potentially tissue damaging.  The only exception is the sense of smell, a system so old and so primitive that it does not have a thalamic connection; rather it has direct access to the higher parts of the brain, the limbic cortex.  The thalamus is constantly weighing the amount of noxious vs non-noxious information coming from the surrounding world.  When noxious stimuli exceed non-noxious ones, pain is the sensation experienced.  Pain allows one to consciously recognize that there is a potentially tissue damaging stimulus in the environment.  As such it is critical to health and even survival.  Pain that lasts beyond the experience of nociception has sometimes been called chronic pain, though it is better to think of it as a form of suffering.

Suffering:  Suffering is the experience of undergoing pain, hardship or distress.  Note that pain is only one of the causes of suffering.  Some others might be: war, poverty, marital discord, mental illness, work dissatisfaction, anxiety and depression, just to name a few. Suffering is a complex phenomenon that requires a high level brain.  We believe, but cannot prove, that Aplysia does not suffer though it clearly has nociception.

Phenomena common to the use of many drugs:  Several phenomena occur with drug use.

Tachyphylaxis is said to occur when increasing doses of a drug no longer produce greater effects.  Amphetamines, such as the street drug methamphetamine or many diet drugs, have this characteristic.  Tachyphylaxis occurs when the mechanism of a drug is the release of a preformed substance (e.g. catecholamines) from nerve endings.  When that substance is depleted, additional drug can have no incremental effect.  In other words, tachyphylaxis is sudden tolerance that is not dose dependent. 

Tolerance means that, over time, increasing doses of the drug are required to produce a equivalent effect.  Opioids (eg codeine, morphine, oxycodone), alcohol and benzodiazepines (eg diazepam, lorazepam) have this characteristic.  When there is tolerance, the person will experience symptoms and signs of withdrawal when the dose of the drug is reduced or it is discontinued.  Tolerance is due to reduced number or sensitivity of drug receptors effected by exposure to the drug.  Everyone who uses a drug of this type will develop some degree of tolerance and withdrawal.

Addiction implies a craving or obsession.  Everyone is familiar with the obsession phenomenon as we all occasionally experience an “ear worm” meaning a tune that one cannot get out of one’s mind.  Obsessions, which are thoughts, may lead to acts (compulsions) that relieve the obsession, though often only temporarily.  Addictions do not only refer to drugs, but can be seen in other forms such as sex addictions or gambling addictions.  Drug addiction means that the person becomes obsessed with the drug and spends inordinate amount of effort and time in attempts to obtain it, even including illegal and dangerous activities.  The system in the brain that leads to addiction uses a different chemical, dopamine, the substance that is depleted in Parkinson Disease.  In the course of replacing dopamine to treat Parkinson Disease, some patients acquire obsessions, such as gambling problems.  Thus it is important to realize that addiction can be due to tolerance and withdrawal but not necessarily so.  People vary with respect to how susceptible they are to obsessiveness and addiction.  Just as we can demonstrate the variation in the experience of pain after putting one’s finger in a glass of ice water, one can prove that a bell shaped curve describes the tendency in a population of people to develop addictions.  This tendency is probably at least partially genetically determined and thus tends to run in families, though common experience also is a characteristic of familial relationships.  It is likely that genetic and epigenetic factors are at play.

The essential problem:  The essential problem underlying the opioid societal issue is that various forms of suffering are being routinely treated as if they were pain due to nociception.  It is important to remember that opioids are meant to reduce pain due to noxious stimuli; not for the relief of suffering caused by any number of other factors.  When we became physicians we all took an oath to reduce suffering.  We did not promise to remove pain and nociception, both of which are critical to good health and indeed survival.  Opioids have their very important place, but it is their side-effects that cause the deaths in people who are using them to treat their suffering, including suffering caused by chronic pain.  Recall the scene from the Wizard of Oz where Dorothy and her friends come across a field of poppies, which put them to sleep.  As a side effect, opioids can cause coma and stop breathing, thus causing death.  They also may stimulate the dopamine reward system, leading to addiction. 

It is thus critically important for the medical and lay communities to understand the proper place for opioids.  Put simply, exogenous opioids are needed when the noxious stimulus is sufficiently intense that endogenous opioids are not adequate.  A long bone fracture would be a good example.  Bone metastates might be another.  In both circumstances the longevity of the pain will be time-limited.  In the case of the fracture, immobilization and healing will be the end point.  In the case of bone metastases, radiotherapy or the end of life might mark the end point.   When endogenous opioids are not adequate to relieve a time-limited pain, exogenous opioids are the treatment and doctors must prescribe them.   Simply legislating limits on opioid prescribing does not address the essential problem.   It is more important to acknowledge and deal with the causes of human suffering (i.e. pain, hardship and distress) from poverty, war, abuse, depression, and anxiety with techniques that are meant for this purpose; not with the use of a class of drugs that is only meant for reducing pain from noxious stimuli.  Reducing suffering is much more complex and challenging than relieving pain.  It requires time, empathy and wisdom.  Machines do not possess the necessary attributes to relieve suffering.  Only people have those attributes.  The opioid epidemic is a symptom of our society’s overreliance on machines and drugs.  Staring at a computer and prescribing drugs, no matter how electronically sophisticated, is not medicine.  The word patient is derived from the Greek meaning one who suffers.  Medicine is all about relief of suffering.  Only people can provide that poultice.