What is the definition of an opioid, beyond that it's something that stimulates opioid receptors?

What is the definition of an opioid, beyond that it's something that stimulates opioid receptors?

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At first glance, this looks like a circular definition.

Is there some way to definitively determine if a given molecule is or is not an opioid? (Medically or scientifically, not legally).

I'm hoping for something more scientific than "if it's on this list, it is; and if it's not, it isn't."

Wikipedia's article Opioid receptor:

Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, and are also found in the spinal cord and digestive tract. (emphasis added)

Wikipedia's article on Opioid:

Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, treating addiction, reversing opioid overdose, suppressing cough, and suppressing opioid induced constipation. Extremely strong opioids are approved only for veterinary use such as immobilizing large mammals. Opioids are also frequently used non-medically for their euphoric effects or to prevent withdrawal. (emphasis added)

First there was opium. Then the active components of opium (morphine etc.) were defined and called opiates. Then the receptors for opiates were discovered, along with their endogenous ligands (enkephalins etc.), and since those endogenous ligands were not derived from opium and indeed (being peptides) were not chemically related to opiates, a new term was needed. This term was opioid, and yes, the definition of an opioid is that it is something which binds to an opioid receptor.

The perceived circularity lies in the shift of emphasis from the drug to the receptor as the central player - when the first binding studies were being done in the early 1970s the search was for opiate receptors, not opioid receptors.


Opioids are a class of drugs that include the illegal drug heroin, synthetic opioids such as fentanyl, and pain relievers available legally by prescription, such as oxycodone (OxyContin ® ), hydrocodone (Vicodin ® ), codeine, morphine, and many others. Learn about the health effects of prescription opioids and read the DrugFacts on Fentanyl, Heroin, and Prescription Opioids.

Opioid-involved overdose deaths rose significantly from 46,802 deaths in 2018 to 49,860 in 2019.

The ABC’s of Addiction: There are two distinctly different types of addiction and it matters

Prologue: Understanding addiction facts is to understand how millions of pain refugees were created in the last three years since the voluntary CDC “Guideline”. Pain patients have been taken off their pain medicines without consent something we have never done before as healers. Left in agony and disgrace millions of pain refugees have been banned from our health care system. Why?

The answer i s Fear of Addiction Phobia. In order to rescue the estimated 5–7 million pain patients deprived of pain relief treatment without their permission we must first understand why we are so afraid of opiates to the point some terminal patients we hear from are denied end of life pain medicines to avoid “becoming addicted”.

Our paper focuses the idea that the word “addiction” is too broad of a concept to conduct studies or to development treatments or to understand why this country dehumanizes people who take opiates for their rare and uncommon long term painful diseases.

When we analyzed the literature and our clinical experiences and the experiences of others, there sorts out more than one type of addiction. This has help us to explain what had puzzled us: why has nothing worked to address addiction and attendant deaths on the streets. The “overdose deaths” we hear of every day are really 95% Heroin and fentanyl deaths on the streets not in communities as the CDC portrays.

We are proposing a division of the concept of “addiction” into two distinctly different sub-categories which we will call Type 1 and Type 2, similar but very different. A good parallel to understand this new concept is Diabetes. There are two distinctly different types, Type 1 occurring in children and type 2 occurring in adults. To understand diabetes you have to understand the distinctions. The same is true with Addiction. As you read this you will begin to see why mistakes have been made.

The biggest mistake we have made for over 100 years is failing to understand type 2 Addiction or the typical Heroin type addict cannot be controlled with substance restriction. This terrible error has lead to jailing of doctors, led to worse crime and murders, and worst of all the involuntary disenfranchisement of millions of people with uncommon painful diseases spreading like the plague to emergency rooms,post-operative recovery rooms, and inpatient services.

Which word grabs your attention in the title. You wouldn’t be reading this article if it didn’t. We were all taught the title of your paper is what will captivate your readers, grabbing their attention. The one word your mind focused on when you read the title, the one word an entire nation seems to fear: Addiction.

You hear it on the radio, see it on the television and parents everywhere grab their children in fear, as if they may catch it like the common cold. We have made an grave error. Ignorance is not having the facts. We will try to supply more facts to stop the lunacy promulgated by Physicians for Responsible Opioid Prescribing (PROP) and its allies at the CDC who are trying to delist 4000 years of successful use of opium products (opioids, opiates or narcotics). The have espoused a dangerous and harmful stance against opiate pain medicine based on the ignorance of the two separate types of addiction.

Thirty six state’s attorney generals recently wrote a plea to the federal government not to soften its stance on “drugs” since — “anyone can become addicted”. As we shall see, this is not true. To correct the misinformation that led us down a path of destruction of daily life and suicides in those having nothing to do with addiction we need to think and analyze what we have come up with for this paper. It is up to you. We at JATH present our research. What you do with it is up to you,

We were steering off the the tract of understanding at the turn of the century when opium opiates were deemed sinful and morally dangerous and worse brought to us by immigrants, the Chinese and the Mexicans. It began as combating immorality with Randolph Hearst leading the charge against “the Yellow Peril. They ran opium dens. White woman were seen there. It must be they are being seduced by Chinese men and ruining their virtue. Morality we see today even mentioned in DEA papers as one of their goals. Moralists making horrible medical decisions like Opiate Pain Medicine (OPM) is too dangerous to use, which of course it is not true. FDA considers it safe enough to not put maximum dose limits for the primary pain medicines.

Much of what we read, over and over, and throughout the years by scanning the New York Times articles on narcotics in the 1950’s looks like news stories today. Why has nothing change, why are we always in a “crisis”, “scourge” “epidemic”. Much of what we read and believe is factually correct but it is in the wrong context. Type one diabetes requires continuous insulin, therefore adult onset type 2 diabetes should require insulin also. Bad logic. Controlling substance can control cocaine and methamphetamine type 1 addictions but will not work for type 2 Heroin addictions.

Government estimates of Heroin addiction settle in around 500,000 to 750,000 with a high number of one million. We will stipulate the highest estimate of one million. This seemed like a lot to us until we divided the one million by the U.S. population of 320 million corrected to over age 12 (when Heroin addiction begins) of 256 million. The calculator said 0.4% or less than 1%.

We were curious about Heroin addiction rates in other years. We were surprised . The prevalence of Heroin addicts in 1925 was less than 1%. Why has not the number of “junkies” (as they call themselves) increased. With what we read every day you would think half the American population would be in the streets shooting up.

The rarity of type two opiate or Heroin addiction kept popping up with the same numbers, and nearly always the same percentages in the population with Heroin addiction looking over the years (see Medium paper by this group “Is addiction rare?” As we kept looking we began to realized that this type of addiction had to be genetic, an new realization that explains a lot. JATH will address the genetic argument in a separate paper soon to be released: “Is Heroin addiction genetic?”

Type I “addiction” but not correct for the genetically determined type 2 or Heroin type addiction, as we shall see .

What type of “addiction” are we talking about? It matters. There are two major sub-types of addiction quite different from one another: Type 1 and Type 2. It is possible “anyone” can become addicted but only to to Type 1 substances like methamphetamine, cocaine, marijuana, and most alcoholics. Many exhibit poor choice. Many have psycho-social problems and wish to feel better. Kelsey Grammer when asked “why to you take drugs” he replied “Because they make me feel good”

Opiate addiction to Heroin and other opiate pain medicine (opioids, narcotics) is impossible to addict 99% of the population. IV Heroin users returning from Vietnam had only a 2% addiction rate two years after begin tapered off by the VA.

How do we know Heroin Addiction is genetic? The details are in a companion JATH paper here in Medium entitled “ Opioid Addiction, is it rare?” Basically there is a large body of scientific papers that say it is. If you wish to read them google the “A118G Addiction” (the abnormal gene in Heroin addiction) and you will find the biochemical proof.

The epidemiological proof is the fact that the prevalence or percentage of people in the US, and in other countries, with Heroin addiction is less than 1%. It has been this way since statistics were available in 1920 and sampling over the years from 1950 on show the same exact prevalence rate of less than 1% (actually consistently 0.5%) Today the high estimate for Heroin Addiction is 1 million divided by our population of 320 million — about 1/2 of 1 percent. Should be much higher is what Thomas Frieden and PROP say that doctors prescribing too much have caused the “opioid” epidemic. Where are the numbers? No numbers, no truth.

A disease process that never changes in its occurrence, by our medical standards, has to be genetic. With all the wild accusations that doctors prescribe too much where are the additional heroin addicts? They are not increasing, a fact left out of reports of increasing overdose deaths. The overdose deaths are in the addiction population of Heroin addicts and have increased yearly since 1970. The only thing increasing is the fabricated new definition of Opioid Use Disorder (OUD) by the SAMHSA** federal agency. This is not heroin addiction . SAMHSA presents two statistics, heroin addiction and their new definition OUD, backhandedly proving Heroin addiction and OUD are different or there would not be two categories of “abuse”, a word found in the agencies name not found else where in the world. This is Government misinformation. SAMHSA, the “abuse” agency, has had its budget substantially increased over the years and is abusing definitions.

The only way to become addicted to opiates (Heroin, and all med-opiates pain medicine like morphine, Percocet, methadone, Vicodin) is to be in the type 2 addiction category. Since this type of addiction is genetically controlled, you either have the gene or you don’t. Less than 1% carry the gene, 99% don’t. The 99% percent will never become addicted to opiates. The 99% will never get “high” from any opiate, including Heroin (diamorphine). This is why the ten million people in the United States with the “monster” diseases of systemic inflammatory diseases such as Complex Regional Pain Disease, Trigeminal Neuralgia, Adhesive Arachnoiditis and Interstitial Cystitis, the big four suicide diseases due to pain that is so severe and intractable people cannot survive without pain medications for their painful diseases. “Chronic pain” is a misnomer sounding like something made up. I can tell you that the four diseases above plus another 25 or so, are not made up. Survival without high dose pain medications is impossible. It is no wonder the decision to escape life without life is commonplace in those tapered from their medications for no reason following the latest trend that opiate pain medicines don’t work for long term and cause overdoses deaths — no, false, they do work and those dying in the CDC report are all addicts, save 500 a year that die under a doctors care.

So “she takes drugs” is not a proper statement. We need to ask which type of drugs are taken and which type of addiction is occurring. The failure to understand there are medically defined sub groups of addiction has caused one hundred years of misunderstanding, fear, and 5 drug wars. The control of the practice of medicine has left both groups of opiate disease left out in the cold —Type two addiction disease and ten times as many people with long term painful disease we just alluded to. If we are reading the newspapers correctly we fail to see a successful outcome of any of the drug wars, only billions spent assuaging irrational phobic fears and getting no where with the various “crises” and “epidemics” since Eisenhower. The crisis today the epidemic today is indeed correct, but it is no different since data began to be collected in 1970 by the Bureau of Vital Statistics.

Disease is morally neutral. We blame people for their diseases. This helps no one and makes things worse, adding stress and grief to the medical treatment equation. “Poor choice” has nothing to do with the pathology of the disease process in Type 2 opiate addictions, but yes is a factor in type 1 addiction disease.

In three years since the biased CDC “Guideline” was published we have seen wholesale abandonment of traditional medical practice treating all the sick. This will go down in history as the worst medical tragedy in our history, because it involves millions of people and it was done on purpose fearing more dope fiends or opiate receptor disease type 2 addiction, the reason we are presenting our findings to you. To understand the cruelty of trying to prevent more addiction by removing vital medications is not only showing ignorance of the medical facts, it is cruelty beyond what is expected given the morals and ethics of our american culture.

This paper hopes to begin a new thought about these different diseases.

Understanding there are two types of drug addiction explains a lot. It explains the failure of the one trillion dollar, hundred year War on Drugs — five of them. The War has been conducted on the wrong drugs, for the wrong reasons, on the wrong people. We are afraid of the wrong drugs. Had we realized the obvious differences between the two addictions we could have spend the money building 75 more aircraft carriers or 20,000 new high schools. We could have directed the funds to the type one addictions where serious non theft crime is prevalent, where people can become “crazy” through toxic psychoses, not found in opiate or Heroin type 2 addiction.

The two types or subgroups of addiction are:

Type 1 Addiction. JATH defines this addiction sub-type as “Substance use negatively affecting daily life”. If daily life is not effected then there is no addiction disease. This is a medical issue not a moral issue. Medically to have a “disease” one must have interference with homeostasis or life equilibrium If you use too much of substance that interferes with your life — you have a disease

Type 1 addiction frequently starts with maladjustment to the psycho-social equilibrium — feeling bad but not to the point of clinical depression, just feeling lousy. It is a medical/behavioral/psychological illness. It is not “abuse” or “misuse”. These are politically inflammatory words, not medical words.

It is, indeed, making choices along the lines of eating too much, or the choice to drive without a seat belt. “Poor choice” is another political, moralistic adjective, not a proper medical term. It does not help to label people with distressing diseases. He is fat, because he makes poor eating choices. So what? Does this guide treatment or does it discourage treatment? The holier than thou principle of medical treatment is no longer appropriate. We are going to substitute “love the neighbor” as the guiding treatment principle for addictions, both of them. Shaming and blaming is not acceptable medical or psychological treatment. Nor is it acceptable for $1000 a day “drug rehab”.

Type 1 Addiction is soft-wired in the brain, but wired just the same. It is identified with operant conditioning or behaviorally acquired addiction pathways or as some would say “learned” pathways. This is not the case in Type 2 or Heroin addiction as we shall.

Type 1 addiction can be stopped by stopping the substance. Type 2 where it is biochemically impossible. Type 1 can more easily stop but do not wish to so. Type 1 addiction goes away when the substance is no longer involved to the point of ruining daily life.

Rehabilitation talk therapy usually helps in Type 1 addiction. Lives can return to what they were before the substance involvement. This is not true for Type 2 or “Heroin type” addiction, a lifelong biochemical disease.

Type 2 Addiction, is defined here as “Intense seeking of substance without regard to consequence”, the definition developed with the help of those with type 2 addiction , or “junkies” as they tongue in cheek call themselves. This is a group rarely consulted. Why not? They are what this is all about. Aren’t they the stakeholders? Are they all untouchable? Are the god fearing? Are they mothers and husbands? Are they in the work force? Or are they no longer humans just sub human dope fiends terrorizing our neighborhoods and our children like some proverbial boogeyman?

You cannot stop the substance in Type 2 addiction (Chemical Receptor Disease is a more medically correct term -CRD). Many Heroin type addicted people wish to stop but the biochemistry makes it a herculean task.

“Why don’t you just stop?” is a fundamental misunderstanding about this type of lifelong addiction. It is same biochemistry that will not allow thirst or intense hunger to go without “seeking substance”.

Type 2 opiate addiction is due to at least 18 genetic errors (polymorphisms) in the brain in charge of building the mu opioid receptors found in the brain, peripheral nerves, GI tract, and inflammatory tissue. These receptors are the new biology of all the humors of the human body, it is how estrogen, and insulin act on the cell. They sit on the surface and cause the activity in the cell to change, like poking a air needle in a basketball.

The receptors have to be just right. In Heroin type addiction something goes wrong with the genes that build the mu opioid receptors. It is inherited. It runs in families and soon the genes could be detected with just a mouth swab.

As a result of these genetic changes opiates cause a rare and unusual side effect — extreme, uncontrollable euphoria, almost an ADR or adverse drug response. This side effect only occurs in those with the genetically altered mu receptors, about 1 in 250 people.

How do we know there are changes in the mu receptors? Science. Cell biology, genetics, and biochemistry. The gene involved with the Chemical Receptor Disease or CRD is A118G.

According to an ex-opiate addict who now serves as a Judge in a New York drug court, the euphoria is of the same nature as the euphoria of child birth for woman, of eating a good meal, sex, finishing a workout routine — but, a 1000 times higher.

For people with the genetic type 2 disease when the very first opiate is taken into the body, the adverse drug response takes place instantly. The normal response to an opiate for 99.6% of the population without the abnormality of the A118G gene is sedation, not euphoria. Only the 0.4% of the population will experience this intense side effect governed by the A118G gene.

Soon a genetic test for opiate or Heroin type addiction will be available. The FDA has fast tracked the application process. The test will tell us who will not addict and who will.

“High” is a word which has enslaved us fearing this feeling leads to unpredictable behavior and crime. We never use the word “high” for the disease actually associated with serious crime and the highest overdose death rate of all addiction diseases — alcohol. The lowest rates of serious state penitentiary type crime occur with Heroin, the highest alcohol followed by meth-amphetamines and cocaine.

Because Type 2 opiate addiction is really genetic, those with triggered opiate addiction represent a random cross section of society, not a limited psycho-social/environmental sociological status incorrectly assumed for all “addicts”. A history of psycho-social problems is frequently observed for “addiction” disease but these Studies are conducted without separating the two types. The averaged results hid the difference of type 2 addiction disease the smaller of the two types. It is a critical difference.

Type 1 disease responds to “talk therapy” and traditional “rehab”. Type 2 disease does not respond to residential treatment and lead to overdose deaths due to forced abstinence and the changed tolerance to opiates. Type 2 disease requires Medication Assisted Treatment or MAT. There are no other effective options for this type of addiction in spite of moralistic protestations: “What? Treat junkies with more dope?” But then those protesting are moralists not doctors.

Medical treatment is provided in the U.S. only under FDA supervision and DEA (federal drug police) licensing. In Canada, for example, it is legal and proper for any physician to treat any addiction. Canada has no federal drug police, as is the case with other countries around the world.

This negative, criminal model for real medical disease in Heroin type 2 addiction seems to be the reason. “Oh yes, heroin addiction is a disease, I am sure”, but then funding goes wanting, fear and prejudice intervene.

Currently in a hot spot for opiate addiction north of Raleigh N.C. only about 20% of Type 2 Receptor Disease addiction is being medically treated with substitution protocols. National figures are about the same. It was this way with methadone and residential treatment in the 1950’s. Articles retrieved from the New York Times in the 1950's could be pasted into today’s newspapers without a noticeable difference.

There is no question substitution treatment (MAT) stops crime, stops overdose deaths, stops expensive incarceration, and restores the lives of those with type 2 opiate disease.

The answer to why should we use opiates to treat opiate addiction is first an understanding that we have a difference disease here. In substitution treatment we doctors will use much less opiate medicine, given under our strict medical direction, and using medicines not made and sold by criminals. MAT works, and works so well that more enlightened countries in Europe have had crime evaporate. A prescription pad is a great competitor for the 1000% profit margin street drug enterprises.

To review the important differences between Type 1 and Type 2 addictions the table that follows illustrates the critical differences

Nearly everyone can get “high” or “buzz” from Type 1 substances, marijuana, amphetamines, cocaine and alcohol but only 1% of the population can get the intense “high” response from opiates, orally or IV, it does not matter. This surprising fact makes biological sense because in Type 2 “Opiate” addiction, you must first have the genetic foundation to experience the “magic carpet ride” or “going to the moon” noticed when taking the first opiate pills. This is why prescription limitations 3 or 7 days, or whatever, will not stop Heroin addiction since it starts with one or two pills.

We need to stop limiting substance since it will not prevent type 2 opiate addiction unless every single pill is removed from the planet. It is cheaper and more humane just to ask the critical question “have you ever had an opiate”.

So yes addiction can start with the first doctor’s prescription, but the doctor is not causing the addiction but unwittingly triggering it. Is the doctor at fault. Yes. The doctor, who understanding the genetics of the disease, should have asked, have you ever taken an opiate before? Do you know the euphoric danger symptoms?

If you prescribe “heroin pills”, a pejorative term, for pain medicine, to 1000 people only 3 or 4 will get “opiate high” and if left untreated then our definition of type 2 addiction prevails: “intense seeking without regard for consequence” sets in, street addiction starts, that carries a 2% per year mortality (this mortality is the actual CDC overdose death data, not due to prescription drugs but due to street drugs— a fact not revealed by CDC).

Okay, what if you are in the 99.5% population group that does not have the genetic abnormality? Is opiate use still a problem? No, it is not. Talk to Type 1 addiction people. Almost none use Heroin, no genes- no high. The failed efforts over the last one hundred years, the terrible waste of 1000 billions (1 trillion) of dollars, and the terrible and widespread damage done to non-addicted medical pain patients stems from lack of basic medical information about mu receptor addiction or Chemical Receptor Disease (CRD) — the “junkies”. The true addiction is controlled by genetic not by the abundance of opiates. Substance exposure philosophy sounds logical but it is not medically valid.

The Type 2 Addiction is reported to be between 500,000 and one million people in the United States. It is not the two million reported as Opioid Use Disorder (OUD). OUD is a new governmental disease created by SAMHSA by changing the real medical definition into a governmental funding definition.

The previous medical definition of OUD was a person who takes their medicine in a way not prescribed by their doctor. This is a fairly accurate portrayal of type 2 addiction at least as a place to start. SAMHSA , our federal 4 billion dollar a year federal “abuse” agency changed the definition a couple of years ago to “any one who takes an opiate other than what the doctor prescribed”. This is flim-flam. Government agencies do not have medical prerogatives to change the original American Psychiatric Society’s definition of OUD (opiate use disorder) or any medical practice interference for that matter (see federal law 42 USC 1395, section 1801)

If a person with painful medical disease has a flare of their pain and takes two percocet instead of one they now have SAMHSA “OUD” or “opioid use disorder”. Wrong. They are taking what is needed because the doctor had no idea of the character or intensity of their pain, did not and could not, accurately prescribe the proper range of doses. The newest “abuse crime” gets funding and gets attention. Look for OUD in your next newspaper article.

To show the fallacy of the federal government interfering with medical practice notice the federal agencies report two different statistics: 500,000 Heroin addicts and 1.5 million OUD proving the new government disease which of course needs corrective action and more funding the new OUD.

Changing the definition from the original medical definition would seem to increase the numbers of “abusers, misusers, and drug miscreants”, a surefire way for congressional funding requests to be filled, since drug abusers are classified on the “horrible scale” right next to espionage agents and human sex slave traffickers the self righteous set prison sentences for this medical disease are frequently longer than for spies and human traffickers.

In 1925, after first federal ban of Opium, there were 200,000 heroin addicts within the United States’ population of 114.3 million citizens, for a rate of 0.2% Type 2 Heroin addiction the same number percentage wise as today!

Why is this? Why has this not changed? Are we not awash in opioids “given out like candy”? One would surmise this figure should be much higher, substantially higher — not essentially the same.

There is only one scientific explanation for this inconsistency. Type 2 Addiction is not environmental, it is genetic. With enough opiate pain medicine “for every man woman and child”, where are the additional “addicts”? Government data does not show an increase addiction in spite of the assumptions by many claiming “increase in addiction”! “Run for cover dope fiends are on the loose and there are more, lots more”. This is not true. This is fear of addiction phobia, a disease highly prevalent in the U.S.

We have looked and looked. There is no CDC or other agency statistic showing more addiction just the phony OUD polemic.

Ninety percent of Type 2 opiate addiction occurs in teenage years due primarily to experimenting. Doctors providing the first opiate pills about 20% of Type 2 addictions. Why? Failure to ask the simple but critical question — is this your first opiate? If the answer is no, and the person is not an addict already, the person has passed the triggering threshold and will never addict lacking the gene running in families.

If the answer to the million dollar question is, “No, I have never had an opiate pain pill” then this person has a risk of 1 in 250 or so of having the sentinel symptom for Type 2 addiction of being energized or euphoric on the very first pill, not feeling drowsy like 99% of people.

If we asked this critically simple question deaths from street overdoses (the CDC data source) would begin to dwindle.

In addition to the simple, compelling observations opiate addiction must be genetic, the idea is bolstered by 600 papers in the cell and brain biology medical research field. This supports Type 2 opiate addiction as a tragic genetic mistake allowing opiate pain medicine to lead to an extreme over reaction of the pleasure and reward center. Sadly this leads to “intense seeking without regard to consequence”.

The biochemical drive compelling the organism to seek opiates is no less powerful than water seeking for someone with three days of water deprivation or from the disease of diabetes insipidus a disease of water balance where people would do anything to find water.

It’s not the amount of opiate that causes Type 2 addiction thus all attempts to control substance through harmful manufacturing reductions by the federal drug police, by limiting dose and amount, by arresting doctors, by pharmacists refusing to fill prescriptions has not and will not prevent one single case of Type 2 addiction nor one single overdose death. This is hard to believe but look at the perennial failures, look at the data going no where.

Jamie Lee Curtis’s recent disclosure of her Type 2 opiate addiction supports the model presented here. Curtis mentioned with the very first pill a 10-year addiction battle began. According to the article produced by People magazine about Curtis’s addiction, it also shows that Type 2 addiction was in her family. Her father Tony Curtis and half-brother Nicholas were among the family members who had Type 2 addiction a familial genetic disease. “Tony abused alcohol, heroin, and Nicholas died from a heroin overdose.”

These were real type 2 addictions. Positive family histories are frequent in type 2 addictions, but less in Type 1.

You can’t stop opiate addiction because it is genetic but we can certainly stop overdose deaths with early intervention. There needs not be a single new CDC street overdose statistic.

Ninety percent of opiate addiction is triggered in teen years. Why are we not warning teeenagers that any “wild, magic carpet ride” or
going to the moon” when taking the first opiate as one Heroin addict described the unusual phenomenon or symptom of the disease.

Education based on don’t take drugs has not worked, nor will it. Teenagers need information so they can spot the sentinel symptom of feeling too good taking an “oxy” or “percs” when it is supposed to make you drowsy. Danger! A serious life long disease is on the horizon.

Failing to understand the addiction disease types, spending time denying the medical facts, demonizing and shaming people with opiate addiction disease or the “junkies”— or any addiction, for that matter — along with refusing medical care show how little we care for addicted persons as real people is shameful.

Fear of Addiction Phobia is driving irrational solutions to problems we do not understand in the first place. Fear of addiction phobia has spilled over into the other diseases requiring opiate treatment — the 10 million people with rare painful diseases. None of these patients will addict but 2/3 have been forced off their pain medicines without consent, something we have never heard of.

Failing to understand the simple medical facts presented here has only harmed those with addiction disease and those with painful disease.

We need to look at who are and what we stand for — compassion is not just a word in Webster’s.

The Opioid Epidemic: How We Got Here and What We Can Do

More than two million Americans have an opioid use disorder. Each day, more than 130 people die from an opioid overdose. That's nearly 50,000 people per year, on par with the number of Americans who die each year from the flu and pneumonia combined. Researchers, legislators and the public are asking, "How did we get here? And what can we do to help stop this epidemic?"

In this episode of Population Healthy, listen in as experts from the University of Michigan School of Public Health, Michigan Medicine and the Kent County Health Department discuss the complex nature of the opioid epidemic in the United States, and explore possible ways to curb it, including safer and potentially more effective approaches to treating chronic pain, and policy considerations from prescription monitoring to medication-assisted treatment for people with opioid use disorders.

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Be sure to follow us at @umichsph on Twitter, Instagram, and Facebook, so you can share your perspectives on the issues we discussed, learn more from Michigan Public Health experts, and share episodes of the podcast with your friends on social media.

View Transcript

00:01 Rachel Jantz: In undergrad, I volunteered at a harm reduction organization in Grand Rapids called The Grand Rapids Red Project. The Grand Rapids Red Project is a syringe exchange program in Grand Rapids. They also are dedicated to testing for and reducing the prevalence of HIV and hepatitis C in our community. I remember somebody coming into the syringe exchange program, and they were feeling pretty downtrodden that day and they just wanted to be able to help themselves. And they said to me, "People think that we don't care about our health because we're injecting drugs. People think that we just don't care about our lives, we don't care about our families, we don't care about our friends, but it just happens that I have a disease that I am addicted to opioids."

00:51 RJ: It was that conversation that, while I had been volunteering there for a while, it really made me remember that these are all individuals too. And being on the epidemiological side of things, it can sometimes be easy to turn people into numbers and to look at people as percentages or to look at them as a line on a chart that just continues to increase, and we say, "That is so terrible, look what's happening." But we forget that all of those people who are making up the increase in that chart, those are people that we see everyday on the street, who we go to church with, who we go to school with, people that we know and should get to know.

01:34 Speaker 2: More than two million Americans have an opioid use disorder. Each day, more than 130 people die from an opioid overdose. That's nearly 50,000 people per year, on par with the number of Americans who die each year from the flu and pneumonia combined. Researchers are asking, "How did we get here? And what can we do to help stop this epidemic?"

02:00 S2: Hello and welcome to Population Healthy, a podcast from the University of Michigan School of Public Health. Join us as we dig into important public health topics, stuff that affects the health of all of us at a population level. From the microscopic to the macro-economic, the social to the environmental. From neighborhoods to cities, states to countries, and around the world.

02:22 RJ: My name is Rachel Jantz and I'm a public health epidemiologist at the Kent County Health Department. I specialize in the opioid epidemic there. I graduated from the University of Michigan School of Public Health with my Masters of Public Health degree in Epidemiology in 2014. Kent County and Michigan in general have not been immune to the opioid epidemic that we have seen nationally. We know that since 1999, the number of people who have died from an opioid overdose has increased, and we're seeing that same kind of increase in Michigan and in Kent County in general. Between 2016 and 2017, parts of the nation did see a decrease in the number of opioid-related overdose deaths, but the Midwest was one particular region that did continue to see an increase, and so Michigan and Kent County are looped in with that as well. Between 2016 and 2017, in Kent County in particular, there was a 60% increase in the rate of opioid-related drug overdose death, as well as particular increases in heroin and fentanyl that were also seen in the rest of the nation.

03:48 RJ: Opioids are a class of medication that are commonly known as pain relievers, prescription pain medication. They can be natural, synthetic, or semi-synthetic. And when we're talking about natural opioids, that's like our morphine and heroin. The semi-synthetic opioids would be something like oxycodone or hydrocodone. And then we have our fully synthetic opioids, which would be something like fentanyl. Opioids bind to the Mu opioid receptor in the brain, and these receptors are located in a pain-regulating region of the brain. So when opioids bind to these receptors, there is a release of endorphins and general sense of analgesia and well-being that the person experiences. So when an individual continues to use opioids over time, the body doesn't produce as many endorphins, so a greater dosage of opioid is necessary to continue to feel that same level of well-being. We know that opioids are safest when used as prescribed from a doctor, typically for acute pain that would be for a duration of three days or less. What we run into is when individuals are using prescription pain medication in a way that is not prescribed by their doctor, for example using a greater dosage of pain medication, snorting or injecting the pain medication, and this can lead to dependency, which could lead to addiction over time.

05:31 RJ: There have been three distinct waves of the opioid epidemic. In the early 1990s, there was an increase in prescribing practices of physicians due to marketing of prescription pain killers as not being addictive. So there was this sense that we were not treating pain well in this country, and so physicians started overprescribing pain medications. Likewise, we saw an increase in opioid overdose deaths involving prescription pain medication around 1999, early 2000s. And from 1999 until about 2010, the majority of those opioid overdose deaths involved prescription pain medication. At about 2010, we started seeing the increase in the rate of opioid overdose deaths involving heroin. And then as of about 2013-2014, we're now seeing that there has been an increase in fentanyl-related opioid overdose deaths, and this isn't necessarily fentanyl that is prescribed by a doctor, but illicitly-manufactured fentanyl.

06:44 RJ: Working at the local level, we know that collaboration is absolutely necessary when we're dealing with the opioid epidemic. And of course, not every strategy is going to work in every community because every community has its own local flavor of culture, of funding available, of resources that are already available with law enforcement and treatment centers and social service agencies, and in addition, momentum around the issue, so the way that people think and talk about the opioid epidemic. So when we get everyone at the table, we have these people all talking together: What are you seeing? What is working? What isn't working? What are some of the evidence-based strategies that we have seen nationally that we might be able to implement here locally?

07:36 RJ: We know that addiction to opioids can happen to anyone. Addiction to opioids can really cause a breakdown in family trust because of some of the behaviors that are associated with addiction, for example if somebody is lying or stealing as a way to continue to source their addiction. And sometimes behaviors related to addiction can cause financial stress on a family. It can be traumatizing for children. We know that trauma is associated with the propensity for becoming addicted to something, and so we see this cycle where there may be children who are traumatized, and then they're at greater risk for becoming addicted themselves in the future because of this trauma. Family members may also be at a loss for how to help an individual because of barriers due to financing treatment, insurance barriers to accessing treatment, and sometimes family members aren't receptive to that help. Somebody may feel that they wanna help somebody who is in crisis, but that individual isn't at a state of behavior change, isn't ready to accept that help, and so these negative behaviors continue.

09:00 S2: It's clear that this is a complex epidemic without a straightforward solution. That's got some researchers thinking about addressing one of the root causes of this epidemic, treating pain with prescription drugs. What if there were safer and even more effective options?

09:18 Mary Janevic: I'm Mary Janevic. I'm an Assistant Research Scientist in the Department of Health Behavior/Health Education at the University of Michigan School of Public Health. So I should preface this by saying that I'm not a neuroscientist, I'm a community health researcher, but just to describe things on a very basic level, scientists now know that pain is a very complex experience in the brain. From imaging studies, we know that a variety of brain regions are involved in pain, so not just the area in the brain that's responsible for sensation, but also the areas that process emotion and attention, so that's the feeling and the thinking parts of the brain. The emotion is the suffering part of pain, and that's really the part that makes us dislike pain so much. This also means that things that you think and things that you feel can affect your pain, and in a way that's really good news because those are things that we have some control over. So strategies like relaxation, distraction, changing how we think about pain, all of those things can help to reduce pain and suffering.

10:24 MJ: Because of the opioid epidemic, there's more interest than ever in these non-pharmacological treatments. Although cognitive behavioral approaches to pain management are not new and they've long been included in clinical practice guidelines, they've really been kind of bumped up recently in priority, and they're now recommended as first-line treatment for common painful conditions like chronic low back pain. I think it's really important to think about the differences between acute and chronic pain. Acute pain is something that we're all unfortunately familiar with. It comes on quickly we touch a hot cookie sheet, we have an infection, we stub our toe, and the pain can be pretty severe, but thankfully, it usually only lasts a short time. And I think a key point is that that type of pain has a purpose, it's a warning, it's an alert, a cue to action. We do something as a result of that pain, we take our hand off the cookie sheet, or if we have a pain in our lower abdomen, we get checked out for appendicitis.

11:22 MJ: For acute pain, the treatment goals are healing and complete relief of the pain, and medications usually work well for acute pain. Chronic pain is different. Chronic pain is usually defined as ongoing or recurrent pain that lasts beyond the usual course of acute illness or injury. And chronic pain has a few features that really make it distinct. First, it doesn't have any value in terms of warning that something is wrong in the way that acute pain does. In fact, for a lot of people with chronic pain, when they do imaging of the affected part of the body, it actually looks perfectly normal. It looks like it's been healed, and yet the person still feels pain. Then the second feature of chronic pain is that it often takes place in the context of changes in the central nervous system that make it more sensitive to pain, so the nervous system kinda gets revved up, it starts to amplify pain more. And I think the third feature of chronic pain is that it's a biopsychosocial phenomenon. And that's a long word, but it basically means that factors in all three of those categories, biological, psychological, and social, can affect the pain experience, as well as be affected by it. And this often unfortunately takes the form of a vicious cycle. So for example, having pain can lead to feelings of depression, which then can lead to poor sleep, and that can lead to increased pain. So it's a little bit of a downward spiral for some people.

12:49 MJ: I think a good example of a non-pharmacological therapy for chronic pain is cognitive behavioral therapy, or CBT. CBT really works on a person's thoughts, emotions, and behaviors. So for example, people are given skills that they can distract themselves and move their thoughts away from pain, because we know that the more people focus on pain, the greater pain sensation they'll feel. It also gives strategies and techniques for getting people to break this cycle of inactivity that often happens with chronic pain. What happens is that people who are in pain are afraid to move sometimes because it makes their pain worse, and then they become deconditioned, which leads to even more pain. And so cognitive behavioral therapy gives them some tools to break through that cycle, become more active again, which usually has positive repercussions in terms of their pain.

13:51 MJ: There are a huge number of non-pharmacological options for chronic pain. Some of them involve practitioners or formal treatments and others involve skills or behaviors that people can do on their own. I think the important thing to keep in mind is that there is no magic bullet when it comes to chronic pain, whether it's a drug treatment or a non-drug treatment. The effects of medication on chronic pain are actually not particularly impressive when they're actually studied in rigorous research. I think the most we can say, even about medications, is that they can help some people, but usually not that much and sometimes not at all. I think what's almost certainly going to turn out to be the case as more research continues to be done on non-pharmacological treatments for pain is that the effects are going to be fairly individualized. So that is to say what works for one person might not work for another person. And I think moreover, what sometimes people will say about exercise, that the best type of exercise is the one that you'll actually do, is also true of non-pharmacological pain management. So it's really also a matter of personal preference.

14:57 MJ: Well, talking about the risks of these approaches, I think they really are a strong contrast to opioids because opioids have side effects that can range from mild to devastating. So one of the wonderful things about most of the psychological or behavioral approaches to pain management is that they're very low risk. So maybe mindfulness or relaxation doesn't work as well for you as it does for another person, but it's not gonna hurt you either.

15:23 MJ: Unfortunately, there's many barriers to people actually using these approaches. For one thing, many of the cognitive and behavioral approaches to pain require more effort on the part of the patient than just taking a pill. So doing tai-chi or walking a lot or cognitive behavioral therapy, all require time and motivation, sometimes skills, sometimes money. And pills often don't require any of those things. The fact is that many people have busy stressful lives with all kinds of constraints, and a yoga class just isn't gonna happen. Sometimes even just finding a quiet place or time to do a mindfulness exercise is just not possible. And then I think also providers are often not aware of these treatments, or at least of how their patients can access them, so they might know that they exist, but they don't really have any idea where they would send a given patient to access training or other resources to engage in some of these therapies. And unlike medications, which are usually covered by insurance, few of these behavioral or so-called alternative treatments are covered by insurance.

16:35 MJ: Last, I think sometimes patients have a resistance to engaging in psychological or mind-body treatments for pain because they think that the implication is that their pain is somehow not real, when the reality is that they perceive it as a very physical thing in their body. The thing to keep in mind is that the mind-body dichotomy is really artificial, and treatments that work on your thoughts and your emotions are actually affecting your brain chemistry, just as drugs affect your brain chemistry. And there are behavioral ways of affecting those brain chemicals, like exercise, that are so much safer than drugs because they tap into the body's natural opioid systems.

17:22 S2: As of July of 2019, 33 states plus the District of Columbia have legalized marijuana for medical purposes. But that doesn't mean it's free from stigma, and it is still illegal at a federal level. But one researcher with a personal history of chronic pain is taking a look at whether cannabis could be a safer alternative to opioids for managing pain.

18:25 KB: The main thrust of my work at this point is focused on cannabis and cannabinoids in the chronic pain setting. So we do survey studies in which we interview or send online surveys to people who are using cannabis for chronic pain and we ask them if they found it effective, we ask them how they use it, we ask them how long they've been using it and how it's interacted with things like pain or anxiety, etcetera people who are experienced at using cannabis as well as people who are new to cannabis, and following those people who are new cannabis over time, so we can really see that trajectory in people who don't have this type of experience with it. We do more epidemiological studies in which we've looked at the medical cannabis registries that are put in place for each state with these laws to see why people are using cannabis, and indeed, we found that chronic pain is the most common reason that people say that they'll be using cannabis.

19:24 KB: So at this point there's not very good evidence in terms of clinical trials of people using cannabis as a opioid substitute, but that's in part because there's a big limitation on the type of evidence that has been allowed to be collected, because cannabis is a Schedule 1 substance under the Controlled Substances Act, which means that by definition, it has a high potential for abuse and no accepted medical use. That being said, at this point, there are numerous, numerous studies from states all over the US, from Canada, from Israel, where people using cannabis for pain or other conditions have said, "I have substituted cannabis for opioids and for other pain medications for that matter, and I've done so because it provides better symptom management and fewer negative side-effects."

20:13 KB: And so this is the type of thing that we obviously have a lot of interest in because if it's possible to have people using a substance that doesn't cause lethal overdose, then it's possible that we could leverage that to provide people with better and safer chronic management care. That being said, there's still a lot of science to be done, and at this point, because cannabis still remains Schedule 1, we are seeing a lot of that work going on in other countries.

20:48 KB: So at this point, there's still quite a bit of opposition to the use of cannabis in a therapeutic context. Some of the concerns are around the fact that it is possible to abuse. About 9% of people who get exposed to cannabis have a dependence or an addiction issue with it, and that's something that of course we wanna be concerned about. And then I think the biggest health concern besides changes in brain structure and respiratory issues from smoking, is people getting behind the wheel of a car, especially if they're mixing that with alcohol. With those things in mind, we really wanna be certain that cannabis is used in a responsible way.

21:28 KB: Some of the other opposition to cannabis is cultural. Not only do we have this situation where it's a banned Schedule 1 substance for 50 years, which has totally influenced the education system, what doctors and other medical practitioners are taught about cannabis, there is also the fact that it's been culturally stigmatized through the escalation of the war on drugs and the way that that has really targeted a lot of communities of color and underrepresented communities in the US. So we have this really ugly situation where we have a substance that we're not allowed to research very effectively, we demonize its use, often for racist or xenophobic issues, and we punish people, typically people of color and people who are of low socioeconomic status for using this, and we don't teach physicians on how to safely and effectively use it.

22:25 KB: So the confluence of all these factors means that we're really in a difficult situation culturally and countrywide of how to deal with this, and this is now in opposition to many advocates and people who have used cannabis successfully for these different therapeutic indications saying, "Wait a second, there is actually a body of literature about this. Also, it's been effective for me, and I might be dead now if I wasn't using this." Obviously, there's different interpretations that people have of those personal anecdotes and stories, but they've been very effective in driving policy, and one of the reasons that we have over 30 states that have legal medical cannabis now.

23:15 S2: Of course, alternative pain treatments are not the only way to address this crisis. From databases that monitor drug prescribing to laws governing medication-assisted addiction treatment, there are many policy considerations that can play a role in curbing this epidemic.

23:31 Rebecca Haffajee: My name is Rebecca Haffajee. I'm an Assistant Professor of Health Management and Policy at the University of Michigan School of Public Health. Our rates of prescribing of opioids vastly dwarf those in other countries. And even since we've seen reductions nationally and in most states at this point in opioid prescribing, we're still at levels that are in multiples of what we see in other countries. Prescription drug monitoring programs are electronic databases that store, monitor, and analyze controlled substance dispensing information. Prescribers, pharmacists, law enforcement officers, and state medical boards typically can get access to these data. They will have an aggregate view of what a patient is being prescribed within a state. Sometimes states share their data as well. You also can see a prescriber, so you could look at a particular prescriber and see what their pattern of prescribing is as well.

24:28 RH: The idea is to flag high risk prescribing. This might be high dosages of opioids you're getting that are particularly risky for overdose. This might be polypharmacy, so using multiple opioids at the same time, or opioids and benzodiazepines for example. This might be patterns of patient behavior, so frequenting different pharmacies or different prescribers within a short period of time. So it's trying to track that risky behavior and provide that information to a clinician so that they can make the best informed decision when they're making the decision whether to prescribe a patient an opioid. They're particularly helpful for emergency department physicians or physicians that might not know the patient as well, but they're still helpful to a primary care physician, for example if they aren't getting the full information or having a long enough conversation to get all this information from a patient.

25:20 RH: So some of the controversy is who should have access to these data and under what circumstances, and that varies from state to state, so what those circumstances are. But typically, yeah, law enforcement and medical boards would be using the data more as an enforcement tool and a surveillance tool, so trying to see which prescribers or which patients are exhibiting risky behavior, and to help, in the law enforcement side, their investigations of that behavior and potentially making a case or shutting down a pain clinic or something like that. For medical boards, it would be more on the prescriber side. Maybe they're trying to monitor, "Who are outlier prescribers that we might need to look into and eventually perhaps sanction?" In my view, the goals of the program should be to reduce this high-risk prescribing. I also think another goal of the program, from a clinical side, is to provide the best care to patients, and if they are exhibiting some of these misuse, addiction types of characteristics, to use that information to actually refer patients to treatment.

26:34 RH: Treatment for opioid addiction is an incredibly important element. We're in a situation where we created this big population that had a dependence and/or addiction to opioids, and now how do we help those people? And it's important to remember that addiction is a chronic health condition, it's not something that is going to be cured in a month or two or three months' time. We're looking at a year, perhaps your whole lifetime. It could be along the lines of diabetes and having regular treatment for the rest of your life. There's more evidence for the effectiveness of medications. We think that behavioral health therapy is an important component and coupling with that, but in my mind, if we're gonna do anything, we need to provide the medications for addiction treatment. If we can provide the counseling and therapy on top of that, that's great, but if we can't, it doesn't mean that we shouldn't do the medications, because those alone are very effective.

27:27 RH: Buprenorphine is one of the dominant forms of medications for medication-assisted treatment therapy, and it's really promising approach in my view because it can be provided in primary care offices and by non-addiction specialists. The most restricted is methadone, and that's highly effective but it's only provided in opioid treatment programs, and we have a severe shortage of those. A last component is insurers actually have a lot of barriers to covering those medications for addiction treatment as well. Recent studies have shown even if all Medicaid programs cover them, there are a lot of additional hurdles, so prior authorization, those sorts of things. A lot of these kind of policies related to access to these treatments need to change to try to get more providers providing the treatment and then get more patients access and then on the treatments.

28:28 RH: Naloxone is the opioid overdose reversal agent. It's basically an antidote to an overdose and can reverse it if it's administered very quickly after the substance is ingested. It's in the hands of first responders but needs to be even more so, but also family and friends. One policy that I favor is potentially making naloxone an over-the-counter medication. Right now it is only by prescription. There are a few standing orders and things where you can prescribe to either friends or family members or somebody who meets certain criteria instead of the actual individual. But being over-the-counter, so just like your ibuprofen that you can get at the pharmacy, would open up access, I think, to a lot more people.

29:19 S2: Thank you for listening to this episode of Population Healthy from the University of Michigan School of Public Health. We're glad you decided to join us and hope you learned something that will help you improve your own health or make the world a healthier place. If you enjoyed the show, please subscribe or follow this podcast on iTunes, Apple Podcast, Google Play, Stitcher, Spotify, or wherever you listen to podcasts. Be sure to follow us @UMICHSPH on Twitter, Instagram, and Facebook, so you can share your perspectives on the issues we discuss, learn more from Michigan Public Health experts, and share episodes of the podcast with your friends on social media. You can also check out the show notes on our website, for more resources on the topics discussed in this episode. We hope you join us for next week's episode where we'll dig further into public health topics that affect all of us at a population level.

Related Links

  • Bridging Interests in Law and Public Health, Researcher Studies Opioids Crisis
  • Opioids Study Shows High-Risk Counties Across the Country
  • What Drives Patients to Use Medical Marijuana
  • Growing Life Expectancy Inequality in US Cannot Be Blamed on Opioids Alone
  • Responses To The Opioid Epidemic Vary Across The Country

In This Episode

Rachel Jantz

Public Health Epidemiologist - Opioids at Kent County Health Department

Rachel Jantz currently focuses on the opioid epidemic as an epidemiologist for the Kent County Health Department in Grand Rapids, Michigan. She works to enhance opioid-related surveillance in Kent County and serves as co-chair of the Kent County Opioid Task Force. Jantz received a Master of Public Health degree from the University of Michigan School of Public Health in 2014. Learn more.

Mary Janevic

Associate Research Scientist, Health Behavior & Health Education

Mary Janevic is a faculty member of the University of Michigan's Center for Managing Chronic Disease. Her work focuses on interventions to promote self-care among individuals with chronic pain and other chronic illness, particularly older adults and women. Learn more.

Kevin Boehnke

Research Investigator, University of Michigan Department of Anesthesiology and the Chronic Pain and Fatigue Research Center

Kevin Boehnke’s current research interests include medical cannabis as an analgesic and opioid substitute in chronic pain, and self-management strategies for pain, such as yoga. Boehnke received a PhD in Environmental Health Sciences from the University of Michigan School of Public Health. Learn more.

Rebecca Haffajee

Assistant Professor of Health Management and Policy, University of Michigan School of Public Health

Rebecca Haffajee’s research combines detailed legal analyses with empirical investigations of the relationships between law and health. She substantively focuses in the behavioral health and pharmaceutical policy areas, evaluating policies such as mental health/substance abuse parity and laws intended to curb opioid addiction and misuse, such as prescription drug monitoring programs. Learn more.

Analgesia and relief of pain

Elaine M Aldred BSc (Hons), DC, Lic Ac, Dip Herb Med, Dip CHM , . Kenneth Vall , in Pharmacology , 2009

All pain receptors are free nerve endings and are called nociceptors. These are part of the process that transmits the pain to the brain (the process of nociception). Various sensory receptors found throughout the body react to a variety of stimuli, such as hot, cold, pressure and chemical, all of which can give the patient the subjective experience of pain. Different types of neuron carry the pain signal to the central nervous system (CNS):

First-order neurons: transmit pain impulses. There are two subtypes: •

rapidly conducting (12–30 m/s), myelinated A fibres

slow conducting (0.5–2 m/s) non-myelinated C fibres.

These terminate in the dorsal (posterior) columns of the spinal cord ( Figure 32.1 ).

Second-order neurons: carry the pain stimuli to the thalamus ( Figure 32.2 ) via the lateral spinothalamic tracts.


Signs and symptoms include: [4] [5]

  • Drug seeking behavior
  • Increased use over time
  • Legal or social ramifications secondary to drug use
  • Multiple prescriptions from different providers
  • Multiple medical complications from drug use (HIV/AIDS, hospitalizations, abscesses)
  • Opioid cravings
  • Withdrawal symptoms

Addiction and dependence are components of a substance use disorder and addiction represents the more severe form. [13] Opioid dependence can occur as physical dependence, psychological dependence, or both. [21]

Withdrawal Edit

Opioid withdrawal can occur with a sudden decrease in, or the cessation of opioids after prolonged use. [22] [23] Onset of withdrawal depends on which opioid was used last. [24] With heroin this typically occurs five hours after use, while with methadone it might not occur until two days later. [24] The length of time that major symptoms occur also depends on the opioid used. [24] For heroin withdrawal, symptoms are typically greatest at two to four days, and can last for up to two weeks. [25] [24] Less significant symptoms may remain for an even longer period, in which case the withdrawal is known as post-acute-withdrawal syndrome. [24]

  • Agitation [4]
  • Anxiety [4]
  • Muscle pains [4]
  • Increased tearing[4][4]
  • Runny nose [4]
  • Sweating [4]
  • Yawning [4][4][4]
  • Diarrhea [4]
  • Fast heart rate [24]
  • High blood pressure [24]
  • Abdominal cramps [24]
  • Shakiness [24]
  • Cravings [24]
  • Sneezing [24]

Treatment of withdrawal may include methadone and buprenorphine. Medications for nausea or diarrhea may also be used. [23]

Opioid intoxication Edit

Signs and symptoms of opioid intoxication include: [5] [26]

  • Decreased perception of pain
  • Confusion
  • Nausea (slowed movement)
  • Head nodding
  • Slurred speech

Opioid overdose Edit

Signs and symptoms of opioid overdose include, but are not limited to: [28]

    may occur. Patient presenting with dilated pupils may still be suffering an opioid overdose. . People may be unresponsive or unconscious. (fluid accumulation in the lungs)

Opioid use disorder can develop as a result of self-medication. [29] Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients. [30] Prescription opioids are the source of nearly half of misused opioids and the majority of these are initiated for trauma or surgery pain management. [18] Further to this, healthcare practitioners have long been aware that despite the effective use of opioids for managing pain, the empirical evidence that supports the use of opioids long term is minimal [31] [32] [33] . [34] [35] In addition to this, many studies that involved patients with chronic pain have failed to show any sustained improvement in their pain or ability to function with long term opioid use. [36] [37] [38] [39] [40]

According to position papers on the treatment of opioid dependence published by the United Nations Office on Drugs and Crime and the World Health Organization, care providers should not treat opioid use disorder as the result of a weak moral character or will but as a medical condition. [16] [41] [42] Some evidence suggests the possibility that opioid use disorders occur due to genetic or other chemical mechanisms which may be difficult to identify or change, such as dysregulation of brain circuitry involving reward and volition. However, the exact mechanisms involved are unclear, leading to debate regarding the influence of biology and free will. [43] [44]

Addiction Edit

Addiction is a brain disorder characterized by compulsive drug use despite adverse consequences. [13] [45] [46] [47] Addiction is a component of a substance use disorder and represents the most severe form of the disorder. [13]

Overexpression of the gene transcription factor ΔFosB in the nucleus accumbens plays a crucial role in the development of an addiction to opioids and other addictive drugs by sensitizing drug reward and amplifying compulsive drug-seeking behavior. [45] [48] [49] [50] Like other addictive drugs, overuse of opioids leads to increased ΔFosB expression in the nucleus accumbens. [48] [49] [50] [51] Opioids affect dopamine neurotransmission in the nucleus accumbens via the disinhibition of dopaminergic pathways as a result of inhibiting the GABA-based projections to the ventral tegmental area (VTA) from the rostromedial tegmental nucleus (RMTg), which negatively modulate dopamine neurotransmission. [52] [53] In other words, opioids inhibit the projections from the RMTg to the VTA, which in turn disinhibits the dopaminergic pathways that project from the VTA to the nucleus accumbens and elsewhere in the brain. [52] [53]

Neuroimaging has shown functional and structural alterations in the brain. [54] A 2017 study showed that chronic intake of opioids, such as heroin, may cause long-term effects in the orbitofrontal area (OFC), which is essential for regulating reward-related behaviors, emotional responses, and anxiety. [55] Moreover, neuroimaging and neuropsychological studies demonstrated dysregulation of circuits associated with emotion, stress and high impulsivity. [56]

Dependence Edit

Drug dependence is an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake). [45] [46] [47] Dependence is a component of a substance use disorder. [13] [57] Opioid dependence can manifest as physical dependence, psychological dependence, or both. [21] [46] [57]

Increased brain-derived neurotrophic factor (BDNF) signaling in the ventral tegmental area (VTA) has been shown to mediate opioid-induced withdrawal symptoms via downregulation of insulin receptor substrate 2 (IRS2), protein kinase B (AKT), and mechanistic target of rapamycin complex 2 (mTORC2). [45] [58] As a result of downregulated signaling through these proteins, opiates cause VTA neuronal hyperexcitability and shrinkage (specifically, the size of the neuronal soma is reduced). [45] It has been shown that when an opiate-naive person begins using opiates in concentrations that induce euphoria, BDNF signaling increases in the VTA. [59]

Upregulation of the cyclic adenosine monophosphate (cAMP) signal transduction pathway by cAMP response element binding protein (CREB), a gene transcription factor, in the nucleus accumbens is a common mechanism of psychological dependence among several classes of drugs of abuse. [21] [45] Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid-induced physical dependence. [21] [45]

Opioid receptors Edit

A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for several specific variations however, the evidence for clinical differences in opioid effects is ambiguous. The pharmacogenomics of the opioid receptors and their endogenous ligands have been the subject of intensive activity in association studies. These studies test broadly for a number of phenotypes, including opioid dependence, cocaine dependence, alcohol dependence, methamphetamine dependence/psychosis, response to naltrexone treatment, personality traits, and others. Major and minor variants have been reported for every receptor and ligand coding gene in both coding sequences, as well as regulatory regions. Newer approaches shift away from analysis of specific genes and regions, and are based on an unbiased screen of genes across the entire genome, which have no apparent relationship to the phenotype in question. These GWAS studies yield a number of implicated genes, although many of them code for seemingly unrelated proteins in processes such as cell adhesion, transcriptional regulation, cell structure determination, and RNA, DNA, and protein handling/modifying. [60]

118A>G variant Edit

While over 100 variants have been identified for the opioid mu-receptor, the most studied mu-receptor variant is the non-synonymous 118A>G variant, which results in functional changes to the receptor, including lower binding site availability, reduced mRNA levels, altered signal transduction, and increased affinity for beta-endorphin. In theory, all of these functional changes would reduce the impact of exogenous opioids, requiring a higher dose to achieve the same therapeutic effect. This points to a potential for greater addictive capacity in these individuals who require higher dosages to achieve pain control. However, evidence linking the 118A>G variant to opioid dependence is mixed, with associations shown in a number of study groups, but negative results in other groups. One explanation for the mixed results is the possibility of other variants which are in linkage disequilibrium with the 118A>G variant and thus contribute to different haplotype patterns that more specifically associated with opioid dependence. [61]

Non-opioid receptor genes Edit

The preproenkephalin gene, PENK, encodes for the endogenous opiates that modulate pain perception, and are implicated in reward and addiction. (CA) repeats in the 3' flanking sequence of the PENK gene was associated with greater likelihood of opiate dependence in repeated studies. Variability in the MCR2 gene, encoding melanocortin receptor type 2 has been associated with both protective effects and increased susceptibility to heroin addiction. The CYP2B6 gene of the cytochrome P450 family also mediates breakdown of opioids and thus may play a role in dependence and overdose. [62]

The DSM-5 guidelines for the diagnosis of opioid use disorder require that the individual has a significant impairment or distress related to opioid uses. [4] To make the diagnosis two or more of eleven criteria must be present in a given year: [4]

  1. More opioids are taken than intended
  2. The individual is unable to decrease the number of opioids used
  3. Large amounts of time are spent trying to obtain opioids, use opioids, or recover from taking them
  4. The individual has cravings for opioids
  5. Difficulty fulfilling professional duties at work or school
  6. Continued use of opioids leading to social and interpersonal consequences
  7. Decreased social or recreational activities
  8. Using opioids despite being in physically dangerous settings
  9. Continued use despite opioids worsening physical or psychological health (i.e. depression, constipation)

The severity can be classified as mild, moderate, or severe based on the number of criteria present. [6]

The CDC gives specific recommendations for prescribers regarding initiation of opioids, clinically appropriate use of opioids, and assessing possible risks associated with opioid therapy. [63] Large retail pharmacy chains in the US are implementing protocols, guidelines, and initiatives to take back unused opioids, providing naloxone kits, and being vigilant for suspicious prescriptions. [64] [65] Insurance programs can help limit opioid use by setting quantity limits on prescriptions or requiring prior authorizations for certain medications. [66]

Opioid related deaths Edit

Naloxone is used for the emergency treatment of an overdose. [67] It can be given by many routes (e.g., intramuscular, intravenous, subcutaneous, intranasal, and inhalation) and acts quickly by displacing opioids from opioid receptors and preventing activation of these receptors by opioids. [68] Naloxone kits are recommended for laypersons who may witness an opioid overdose, for individuals with large prescriptions for opioids, those in substance use treatment programs, or who have been recently released from incarceration. [69] Since this is a life-saving medication, many areas of the United States have implemented standing orders for law enforcement to carry and give naloxone as needed. [70] [71] In addition, naloxone could be used to challenge a person's opioid abstinence status prior to starting a medication such as naltrexone, which is used in the management of opioid addiction. [72]

Good Samaritan laws typically protect bystanders that administer naloxone. In the United States, at least 40 states have Good Samaritan laws to encourage bystanders to take action without fear of prosecution. [73] As of 2019, 48 states allow for a pharmacist to have the authority to distribute naloxone without an individual prescription. [74]

Opioid use disorders typically require long-term treatment and care with the goal of reducing risks for the individual, reducing criminal behaviour, and improving the long-term physical and psychological condition of the person. [42] Some strategies aim to reduce drug use and lead to abstinence from opioids, while others attempt to stabilize on prescribed methadone or buprenorphine with continued replacement therapy indefinitely. [42] No single treatment works for everyone, so several strategies have been developed including therapy and drugs. [42] [75] '

As of 2013 in the US, there was a significant increase of prescription opioid abuse compared to illegal opiates like heroin. [76] This development has also implications for the prevention, treatment and therapy of opioid dependence. [77] Though treatment reduces mortality rates, the period during the first four weeks after treatment begins and the four weeks after treatment ceases are the times that carry the highest risk for drug-related deaths. These periods of increased vulnerability are significant because many of those in treatment leave programs during these critical periods. [7]

Medications Edit

Opioid replacement therapy (ORT) involves replacing an opioid, such as heroin, with a longer acting but less euphoric opioid. [78] [79] Commonly used drugs for ORT are methadone or buprenorphine which are taken under medical supervision. [79] As of 2018 [update] , buprenorphine/naloxone is preferentially recommended, as the addition of the opioid antagonist naloxone is believed to reduce the risk of abuse via injection or insufflation without causing impairment. [80] [81]

The driving principle behind ORT is the program's capacity to facilitate a resumption of stability in the user's life, while the patient experiences reduced symptoms of drug withdrawal and less intense drug cravings a strong euphoric effect is not experienced as a result of the treatment drug. [79] In some countries (not the US, or Australia), [79] regulations enforce a limited time for people on ORT programs that conclude when a stable economic and psychosocial situation is achieved. (People with HIV/AIDS or hepatitis C are usually excluded from this requirement.) In practice, 40–65% of patients maintain abstinence from additional opioids while receiving opioid replacement therapy and 70–95% can reduce their use significantly. [79] Along with this is a concurrent elimination or reduction in medical (improper diluents, non-sterile injecting equipment), psychosocial (mental health, relationships), and legal (arrest and imprisonment) issues that can arise from the use of illegal opioids. [79] Clonidine or lofexidine can help treat the symptoms of withdrawal. [82]

Participation in methadone and buprenorphine treatment reduces the risk of mortality due to overdose. [7] The starting of methadone and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies. [7] ORT has proven to be the most effective treatment for improving the health and living condition of people experiencing illegal opiate use or dependence, including mortality reduction [79] [83] [7] and overall societal costs, such as the economic loss from drug-related crime and healthcare expenditure. [79] ORT is endorsed by the World Health Organization, United Nations Office on Drugs and Crime and UNAIDS as being effective at reducing injection, lowering risk for HIV/AIDS, and promoting adherence to antiretroviral therapy. [7]

Buprenorphine and methadone work by reducing opioid cravings, easing withdrawal symptoms, and blocking the euphoric effects of opioids via cross-tolerance, [84] and in the case of buprenorphine, a high-affinity partial agonist, also due to opioid receptor saturation. [85] It is this property of buprenorphine that can induce acute withdrawal when administered before other opioids have left the body. Naltrexone, a μ-opioid receptor antagonist, also blocks the euphoric effects of opioids by occupying the opioid receptor, but it does not activate it, so it does not produce sedation, analgesia, or euphoria, and thus it has no potential for abuse or diversion. [86] [87]

In the United States, since March 2020 as a result of the COVID-19 pandemic, buprenorphine may be dispensed via telemedicine. [88]

The ultimate aim of methadone maintenance is for the individual to return to a more normal life. They could be eligible for drug dependency care, career counseling, and educational assistance once they start taking methadone under medical supervision. They can self-refer to social service providers as they continue to feel better and want to get back on their feet. Methadone may even be able to assist these individuals in avoiding relapse. Methadone is a long-acting drug, which means it sticks to the same opioid receptors in the brain as opium and prescription painkillers. As a result, patients who are taking methadone as part of an overdose treatment procedure will not feel opioid cravings or the severe withdrawal effects that come with it. This will encourage people in rehab to concentrate more on medication, laying a solid foundation for healing, rather than constantly fighting cravings and relapse impulses. Methadone is a long-acting drug that can last up to 56 hours in the body. This means it fits better as a preventive drug so it doesn't require regular dosing during the day. Methadone users in detox also find more luck in therapy because they don't have to deal with constant opioid cravings or the severity of acute withdrawal symptoms. Advantages of methadone include:

• Reduction in infectious disease due to the cessation of opiate misuse, especially injection drug abuse • Reduction in illegal crime due to the cessation in illicit drug usage • Overall increase in quality of life • Improved social functioning • More attendance in alcohol therapy since withdrawal symptoms aren't a diversion

Methadone replacement therapy will also help people achieve stabilization early on in their rehabilitation. People should devote 100% of their time to recovery, helping them to solve the underlying problems that lead to their opiate addiction. They will get a career and start to find a better balance in their lives. It also enables parents to continue raising their children in a safe home environment.

When their conditions improve and they want to refrain from taking methadone, they must be properly weaned off the medication, which must be done under medical observation.

Although other medication-assisted therapies for opiate addiction, such as buprenorphine, are available, methadone is often seen as the most promising alternative for people who are heavily addicted to opiates. Methadone has a number of serious side effects, including:

• Slowed breathing • Sexual dysfunction • Nausea • Vomiting • Restlessness • Itchy eyes

Dosages can be adjusted after 1-2 days, or another medication may be recommended for your situation if you experience side effects. Lung and breathing complications are possible long-term side effects of methadone use. Methadone, as an opiate, has the potential to be addictive. Any opponents believe that replacement drugs only substitute one addiction with another, and that methadone can be manipulated and exploited in some cases. Long-term usage has the ability to cause brain changes. Methadone causes changes in thought, cognitive performance, and memory by influencing nerve cells in the brain. An initial review is performed during alcohol therapy. The person will be evaluated and interviewed during this evaluation, and then the treatment team will then devise the optimal treatment plan for that individual.

Buprenorphine Edit

Buprenorphine is a partial opioid receptor agonist. Unlike methadone and other full opioid receptor agonists, buprenorphine is less likely to cause respiratory depression due to its ceiling effect. [86] Treatment with buprenorphine may be associated with reduced mortality. [7] Buprenorphine under the tongue is often used to manage opioid dependence. Preparations were approved for this use in the United States in 2002. [89] Some formulations of buprenorphine incorporate the opiate antagonist naloxone during the production of the pill form to prevent people from crushing the tablets and injecting them, instead of using the sublingual (under the tongue) route of administration. [79]

Other opioids Edit

Evidence of effects of heroin maintenance compared to methadone are unclear as of 2010. [90] A Cochrane review found some evidence in opioid users who had not improved with other treatments. [91] In Switzerland, Germany, the Netherlands, and the United Kingdom, long-term injecting drug users who do not benefit from methadone and other medication options may be treated with injectable heroin that is administered under the supervision of medical staff. [92] Other countries where it is available include Spain, Denmark, Belgium, Canada, and Luxembourg. [93]

Dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries. [94] Dihydrocodeine is an opioid agonist. [95] It may be used as a second line treatment. [96] A 2020 systematic review found low quality evidence that dihydrocodeine may be no more effective than other routinely used medication interventions in reducing illicit opiate use. [97]

An extended-release morphine confers a possible reduction of opioid use and with fewer depressive symptoms but overall more adverse effects when compared to other forms of long-acting opioids. Retention in treatment was not found to be significantly different. [98] It is used in Switzerland and more recently in Canada. [99]

Naltrexone Edit

Naltrexone is an opioid receptor antagonist used for the treatment of opioid addiction. [100] [101] Naltrexone is not as widely used as buprenorphine or methadone for OUD due to low rates of patient acceptance, non-adherence due to daily dosing, and difficulty achieving abstinence from opioids before beginning treatment. Additionally, dosing naltrexone after recent opioid use could lead to precipitated withdrawal. Conversely, naltrexone antagonism at the opioid receptor can be overcome with higher doses of opioids. [102] Naltrexone monthly IM injections received FDA approval in 2010, for the treatment of opioid dependence in abstinent opioid users. [100] [103]

Behavioral therapy Edit

Cognitive behavioral therapy Edit

Cognitive behavioral therapy (CBT), a form of psychosocial intervention that is used to improve mental health, may not be as effective as other forms of treatment. [104] CBT primarily focuses on an individual's coping strategies to help change their cognition, behaviors and emotions about the problem. This intervention has demonstrated success in many psychiatric conditions (e.g., depression) and substance use disorders (e.g., tobacco). [105] However, the use of CBT alone in opioid dependence has declined due to the lack of efficacy, and many are relying on medication therapy or medication therapy with CBT, since both were found to be more efficacious than CBT alone. A form of CBT therapy known as motivational interviewing (MI) is often used opioid use disorder. MI leverages a person intrinsic motivation to recover through education, formulation of relapse prevention strategies, reward for adherence to treatment guidelines, and positive thinking to keep motivation high—which are based on a person's socioeconomic status, gender, race, ethnicity, sexual orientation, and their readiness to recover. [106] [107] [108]

Twelve-step programs Edit

While medical treatment may help with the initial symptoms of opioid withdrawal, once the first stages of withdrawal are through, a method for long-term preventative care is attendance at 12-step groups such as Narcotics Anonymous. [109] Narcotics Anonymous is a global service that provides multilingual recovery information and public meetings free of charge. [110] Some evidence supports the use of these programs in adolescents as well. [111]

The 12-step program is an adapted form of the Alcoholics Anonymous program. The program strives to help create behavioural change by fostering peer-support and self-help programs. The model helps assert the gravity of addiction by enforcing the idea that addicts must surrender to the fact that they are addicted and be able to recognize the problem. It also helps maintain self-control and restraint to help promote one's capabilities. [112]

Digital care programs Edit

Digital care programs (see telehealth or digital health) have increased in number since the Coronavirus pandemic mandated the increased usage of remote healthcare options. These programs offer treatment and continuing care remotely, via smartphone and desktop applications. This often includes remote substance testing, access to peer support meetings, recovery coaching or therapy, and self-guided learning modules. Examples of digital care programs for opioid use disorder include: Chess, Pear Therapeutics, DynamiCare Health, Kaden Health and WeConnect.

Globally, the number of people with opioid dependence increased from 10.4 million in 1990 to 15.5 million in 2010. [7] In 2016, the numbers rose to 27 million people who experienced this disorder. [11] Opioid use disorders resulted in 122,000 deaths worldwide in 2015, [12] up from 18,000 deaths in 1990. [19] Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013. [19] [12]

United States Edit

The current epidemic of opioid abuse is the most lethal drug epidemic in American history. [15] In 2008, there were four times as many deaths due to overdose than there were in 1999. [114] In 2017, in the US, "the age-adjusted drug poisoning death rate involving opioid analgesics increased from 1.4 to 5.4 deaths per 100,000 population between 1999 and 2010, decreased to 5.1 in 2012 and 2013, then increased to 5.9 in 2014, and to 7.0 in 2015. The age-adjusted drug poisoning death rate involving heroin doubled from 0.7 to 1.4 deaths per 100,000 resident population between 1999 and 2011 and then continued to increase to 4.1 in 2015." [115]

In 2017, the U.S. Department of Health and Human Services (HHS) announced a public health emergency due to an increase in the misuse of opioids. [116] The administration introduced a strategic framework called the Five-Point Opioid Strategy, which includes providing access recovery services, increasing the availability of reversing agents for overdose, funding opioid misuse and pain research, changing treatments of people managing pain, and updating public health reports related to combating opioid drug misuse. [116] [117]

The US epidemic in the 2000s is related to a number of factors. [16] Rates of opioid use and dependency vary by age, sex, race, and socioeconomic status. [16] With respect to race the discrepancy in deaths is thought to be due to an interplay between physician prescribing and lack of access to healthcare and certain prescription drugs. [16] Men are at higher risk for opioid use and dependency than women, [118] [119] and men also account for more opioid overdoses than women, although this gap is closing. [118] Women are more likely to be prescribed pain relievers, be given higher doses, use them for longer durations, and may become dependent upon them faster. [120]

Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs. [119] [121] [122] This does not reflect opioid use as a whole, which includes individuals in younger age demographics. Overdoses from opioids are highest among individuals who are between the ages of 40 and 50, [122] in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30. [121] 21- to 35-year-olds represent 77% of individuals who enter treatment for opioid use disorder, [123] however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013. [124] Among the middle class means of acquiring funds have included Elder financial abuse through a vulnerability of financial transactions of selling items and international dealers noticing a lack of enforcement in their transaction scams throughout the Caribbean. [125]

In 2018, the Massachusetts Supreme Judicial Court found that a probationer with opioid use disorder could be detained for a parole violation after she tested positive for fentanyl. [126] [127]

US yearly deaths from all opioid drugs. Included in this number are opioid analgesics, along with heroin and illicit synthetic opioids. [128]


The possibility that fish and other non-human animals may experience pain has a long history. Initially, this was based around theoretical and philosophical argument, but more recently has turned to scientific investigation.

Philosophy Edit

The idea that non-human animals might not feel pain goes back to the 17th-century French philosopher, René Descartes, who argued that animals do not experience pain and suffering because they lack consciousness. [3] [4] [5] In 1789, the British philosopher and social reformist, Jeremy Bentham, addressed in his book An Introduction to the Principles of Morals and Legislation the issue of our treatment of animals with the following often quoted words: "The question is not, Can they reason? nor, Can they talk? but, Can they suffer?" [6]

Peter Singer, a bioethicist and author of Animal Liberation published in 1975, suggested that consciousness is not necessarily the key issue: just because animals have smaller brains, or are 'less conscious' than humans, does not mean that they are not capable of feeling pain. He goes on further to argue that we do not assume newborn infants, people suffering from neurodegenerative brain diseases or people with learning disabilities experience less pain than we would. [7]

Bernard Rollin, the principal author of two U.S. federal laws regulating pain relief for animals, writes that researchers remained unsure into the 1980s as to whether animals experience pain, and veterinarians trained in the U.S. before 1989 were taught to simply ignore animal pain. [8] In his interactions with scientists and other veterinarians, Rollin was regularly asked to "prove" that animals are conscious, and to provide "scientifically acceptable" grounds for claiming that they feel pain. [8]

Continuing into the 1990s, discussions were further developed on the roles that philosophy and science had in understanding animal cognition and mentality. [9] In subsequent years, it was argued there was strong support for the suggestion that some animals (most likely amniotes) have at least simple conscious thoughts and feelings [10] and that the view animals feel pain differently to humans is now a minority view. [3]

Scientific investigation Edit

In the 20th and 21st centuries, there were many scientific investigations of pain in non-human animals.

Mammals Edit

In 2001 studies were published showing that arthritic rats self-select analgesic opiates. [12] In 2014, the veterinary Journal of Small Animal Practice published an article on the recognition of pain which started – "The ability to experience pain is universally shared by all mammals. " [13] and in 2015, it was reported in the science journal Pain, that several mammalian species (rat, mouse, rabbit, cat and horse) adopt a facial expression in response to a noxious stimulus that is consistent with the expression of pain in humans. [14]

Birds Edit

At the same time as the investigations using arthritic rats, studies were published showing that birds with gait abnormalities self-select for a diet that contains carprofen, a human analgesic. [15] In 2005, it was written "Avian pain is likely analogous to pain experienced by most mammals" [16] and in 2014, ". it is accepted that birds perceive and respond to noxious stimuli and that birds feel pain" [17]

Reptiles and amphibians Edit

Veterinary articles have been published stating both reptiles [18] [19] [20] and amphibians [21] [22] [23] experience pain in a way analogous to humans, and that analgesics are effective in these two classes of vertebrates.

Argument by analogy Edit

In 2012 the American philosopher Gary Varner reviewed the research literature on pain in animals. His findings are summarised in the following table. [24]

Argument by analogy [24]
Fish Amphibians Reptiles Birds Mammals
Has nociceptors Y Y Y Y Y
Has brain Y Y Y Y Y
Nociceptors and brain linked Y ? [a] / Y ? [b] / Y ? / Y Y
Has endogenous opioids Y Y Y Y Y
Analgesics affect responses Y ? [c] ? [d] Y Y
Response to damaging stimuli similar to humans Y Y Y Y Y

Notes Edit

Arguing by analogy, Varner claims that any animal which exhibits the properties listed in the table could be said to experience pain. On that basis, he concludes that all vertebrates, including fish, probably experience pain, but invertebrates apart from cephalopods probably do not experience pain. [24] [29]

Some studies however find crustaceans do show responses consistent with signs of pain and distress. [30]

Although there are numerous definitions of pain, almost all involve two key components.

First, nociception is required. [31] This is the ability to detect noxious stimuli which evoke a reflex response that rapidly moves the entire animal, or the affected part of its body, away from the source of the stimulus. The concept of nociception does not imply any adverse, subjective "feeling" – it is a reflex action. An example in humans would be the rapid withdrawal of a finger that has touched something hot – the withdrawal occurs before any sensation of pain is actually experienced.

The second component is the experience of "pain" itself, or suffering – the internal, emotional interpretation of the nociceptive experience. Again in humans, this is when the withdrawn finger begins to hurt, moments after the withdrawal. Pain is therefore a private, emotional experience. Pain cannot be directly measured in other animals, including other humans responses to putatively painful stimuli can be measured, but not the experience itself. To address this problem when assessing the capacity of other species to experience pain, argument-by-analogy is used. This is based on the principle that if an animal responds to a stimulus in a similar way to ourselves, it is likely to have had an analogous experience.

Nociception Edit

Nociception usually involves the transmission of a signal along a chain of nerve fibers from the site of a noxious stimulus at the periphery to the spinal cord and brain. This process evokes a reflex arc response generated at the spinal cord and not involving the brain, such as flinching or withdrawal of a limb. Nociception is found, in one form or another, across all major animal taxa. [31] Nociception can be observed using modern imaging techniques and a physiological and behavioral response to nociception can often be detected. However, nociceptive responses can be so subtle in prey animals that trained (human) observers cannot perceive them, whereas natural predators can and subsequently target injured individuals. [32]

Emotional pain Edit

Sometimes a distinction is made between "physical pain" and "emotional" or "psychological pain". Emotional pain is the pain experienced in the absence of physical trauma, for example, the pain experienced by humans after the loss of a loved one, or the break-up of a relationship. It has been argued that only primates and humans can feel "emotional pain", because they are the only animals that have a neocortex – a part of the brain's cortex considered to be the "thinking area". However, research has provided evidence that monkeys, dogs, cats and birds can show signs of emotional pain and display behaviours associated with depression during or after a painful experience, specifically, a lack of motivation, lethargy, anorexia, and unresponsiveness to other animals. [7]

Physical pain Edit

The nerve impulses of the nociception response may be conducted to the brain thereby registering the location, intensity, quality and unpleasantness of the stimulus. This subjective component of pain involves conscious awareness of both the sensation and the unpleasantness (the aversive, negative affect). The brain processes underlying conscious awareness of the unpleasantness (suffering), are not well understood.

There have been several published lists of criteria for establishing whether non-human animals experience pain, e.g. [33] [34] Some criteria that may indicate the potential of another species, including fishes, to feel pain include: [34]

  1. Has a suitable nervous system and sensory receptors
  2. Has opioid receptors and shows reduced responses to noxious stimuli when given analgesics and local anaesthetics
  3. Physiological changes to noxious stimuli
  4. Displays protective motor reactions that might include reduced use of an affected area such as limping, rubbing, holding or autotomy
  5. Shows avoidance learning
  6. Shows trade-offs between noxious stimulus avoidance and other motivational requirements
  7. High cognitive ability and sentience

The adaptive value of nociception is obvious an organism detecting a noxious stimulus immediately withdraws the limb, appendage or entire body from the noxious stimulus and thereby avoids further (potential) injury. However, a characteristic of pain (in mammals at least) is that pain can result in hyperalgesia (a heightened sensitivity to noxious stimuli) and allodynia (a heightened sensitivity to non-noxious stimuli). When this heightened sensitisation occurs, the adaptive value is less clear. First, the pain arising from the heightened sensitisation can be disproportionate to the actual tissue damage caused. Second, the heightened sensitisation may also become chronic, persisting well beyond the tissues healing. This can mean that rather than the actual tissue damage causing pain, it is the pain due to the heightened sensitisation that becomes the concern. This means the sensitisation process is sometimes termed maladaptive. It is often suggested hyperalgesia and allodynia assist organisms to protect themselves during healing, but experimental evidence to support this has been lacking. [35] [36]

In 2014, the adaptive value of sensitisation due to injury was tested using the predatory interactions between longfin inshore squid (Doryteuthis pealeii) and black sea bass (Centropristis striata) which are natural predators of this squid. If injured squid are targeted by a bass, they began their defensive behaviours sooner (indicated by greater alert distances and longer flight initiation distances) than uninjured squid. If anaesthetic (1% ethanol and MgCl2) is administered prior to the injury, this prevents the sensitisation and blocks the behavioural effect. The authors claim this study is the first experimental evidence to support the argument that nociceptive sensitisation is actually an adaptive response to injuries. [32]

The question has been asked, "If fish cannot feel pain, why do stingrays have purely defensive tail spines that deliver venom? Stingrays' ancestral predators are fish. And why do many fishes possess defensive fin spines, some also with venom that produces pain in humans?" [37]

Peripheral nervous system Edit

Receptors Edit

Primitive fish such as lampreys (Petromyzon marinus) have free nerve endings in the skin that respond to heat and mechanical pressure. However, behavioural reactions associated with nociception have not been recorded, and it is also difficult to determine whether the mechanoreceptors in lamprey are truly nociceptive-specific or simply pressure-specific. [38]

Rainbow trout (Oncorhynchus mykiss) have polymodal nociceptors on the face and snout that respond to mechanical pressure, temperatures in the noxious range (> 40 °C), and 1% acetic acid (a chemical irritant). [39] [40] [41] [42] Further studies found nociceptors to be more widely distributed over the bodies of rainbow trout, as well as those of cod and carp. The most sensitive areas of the body are around the eyes, nostrils, fleshy parts of the tail, and pectoral and dorsal fins. [43]

Rainbow trout also have corneal nociceptors. Out of 27 receptors investigated in one study, seven were polymodal nociceptors and six were mechanothermal nociceptors. Mechanical and thermal thresholds were lower than those of cutaneous receptors, indicating greater sensitivity in the cornea. [44]

Bony fish possess nociceptors that are similar in function to those in mammals. [45] [46]

Nerve fibres Edit

There are two types of nerve fibre relevant to pain in fish. Group C nerve fibres are a type of sensory nerve fibre which lack a myelin sheath and have a small diameter, meaning they have a low nerve conduction velocity. The suffering that humans associate with burns, toothaches, or crushing injury are caused by C fibre activity. A typical human cutaneous nerve contains 83% Group C nerve fibres. [47] A-delta fibres are another type of sensory nerve fibre, however, these are myelinated and therefore transmit impulses faster than non-myelinated C fibres. A-delta fibres carry cold, pressure and some pain signals, and are associated with acute pain that results in "pulling away" from noxious stimuli.

Bony fish possess both Group C and A-delta fibres representing 38.7% (combined) of the fibres in the tail nerves of common carp and 36% of the trigeminal nerve of rainbow trout. However, only 5% and 4% of these are C fibres in the carp and rainbow trout, respectively. [47] [48]

Some species of cartilagenous fish possess A-delta fibres, however, C fibres are either absent or found in very low numbers. [47] [49] [50] The Agnatha (hagfishes and lamprey) primarily have Group C fibres. [51]

Central nervous system Edit

The central nervous system (CNS) of fish contains a spinal cord, medulla oblongata, and the brain, divided into telencephalon, diencephalon, mesencephalon and cerebellum.

In fish, similar to other vertebrates, nociception travels from the peripheral nerves along the spinal nerves and is relayed through the spinal cord to the thalamus. The thalamus is connected to the telencephalon by multiple connections through the grey matter pallium, which has been demonstrated to receive nerve relays for noxious and mechanical stimuli. [51]

The major tracts that convey pain information from the periphery to the brain are the spinothalamic tract (body) and the trigeminal tract (head). Both have been studied in agnathans, teleost, and elasmobranch fish (trigeminal in the common carp, spinothalamic tract in the sea robin, Prionotus carolinus). [52]

Brain Edit

If sensory responses in fish are limited to the spinal cord and hindbrain, they might be considered as simply reflexive. However, recordings from the spinal cord, cerebellum, tectum and telencephalon in both trout and goldfish (Carassius auratus) show these all respond to noxious stimuli. This indicates a nociceptive pathway from the periphery to the higher CNS of fish. [53]

Microarray analysis of gene expression shows the brain is active at the molecular level in the forebrain, midbrain and hindbrain of common carp and rainbow trout. Several genes involved in mammalian nociception, such as brain-derived neurotrophic factor (BDNF) and the cannabinoid CB1 receptor are regulated in the fish brain after a nociceptive event. [54] [55]

Somatosensory evoked potentials (SEPs) are weak electric responses in the CNS following stimulation of peripheral sensory nerves. These further indicate there is a pathway from the peripheral nociceptors to higher brain regions. In goldfish, rainbow trout, Atlantic salmon (Salmo salar) and Atlantic cod (Gadus morhua), it has been demonstrated that putatively non-noxious and noxious stimulation elicit SEPs in different brain regions, including the telencephalon [56] which may mediate the co-ordination of pain information. [46] Moreover, multiple functional magnetic resonance imaging (fMRI) studies with several species of fishes have shown that when suffering from putative pain, there is profound activity in the forebrain which is highly reminiscent of that observed in humans and would be taken as evidence of the experience of pain in mammals. [57] [58]

Therefore, "higher" brain areas are activated at the molecular, physiological, and functional levels in fish experiencing a potentially painful event. Sneddon stated "This gives much weight to the proposal that fish experience some form of pain rather than a nociceptive event". [59]

Opioid system and effects of analgesics Edit

Teleost fish have a functional opioid system which includes the presence of opioid receptors similar to those of mammals. [60] [61] All four of the main opioid receptor types (delta, kappa, mu, and NOP) are conserved in vertebrates, even in primitive jawless fishes (agnathastoma). [51]

The same analgesics and anaesthetics used in humans and other mammals, are often used for fish in veterinary medicine. These chemicals act on the nociceptive pathways, blocking signals to the brain where emotional responses to the signals are further processed by certain parts of the brain found in amniotes ("higher vertebrates"). [62] [63]

Effects of morphine Edit

Pre-treatment with morphine (an analgesic in humans and other mammals) has a dose-dependent anti-nociceptive effect [64] and mitigates the behavioural and ventilation rate responses of rainbow trout to noxious stimuli.

When acetic acid is injected into the lips of rainbow trout, they exhibit anomalous behaviours such as side-to-side rocking and rubbing their lips along the sides and floors of the tanks, and their ventilation rate increases. Injections of morphine reduce both the anomalous, noxious-stimulus related behaviours and the increase in ventilation rate. [65] When the same noxious stimulus is applied to zebrafish (Danio rerio), they respond by decreasing their activity. As with the rainbow trout, morphine injected prior to the acid injection attenuates the decrease in activity in a dose-dependent manner. [46]

Injection of acetic acid into the lips of rainbow trout causes a reduction in their natural neophobia (fear of novelty) this is reversed by the administration of morphine. [43]

In goldfish injected with morphine or saline and then exposed to unpleasant temperatures, fish injected with saline acted with defensive behaviours indicating anxiety, wariness and fear, whereas those given morphine did not. [66]

Effects of other analgesics Edit

The neurotransmitter, Substance P and the analgesic opioid enkephalins and β-endorphin, which act as endogenous analgesics in mammals, are present in fish. [67]

Different analgesics have different effects on fish. In a study on the efficacy of three types of analgesic, buprenorphine (an opioid), carprofen (a non-steroidal anti-inflammatory drug) and lidocaine (a local anaesthetic), ventilation rate and time to resume feeding were used as pain indicators. Buprenorphine had limited impact on the fish's response, carprofen ameliorated the effects of noxious stimulation on time to resume feeding, however, lidocaine reduced all the behavioural indicators. [68]

Tramadol also increases the nociceptive threshold in fish, providing further evidence of an anti-nociceptive opioid system in fish. [43] [69]

Effects of naloxone Edit

Naloxone is an μ-opioid receptor antagonist which, in mammals, negates the analgesic effects of opioids. Both adult and five-day-old zebrafish larvae show behavioural responses indicative of pain in response to injected or diluted acetic acid. The anti-nociceptive properties of morphine or buprenorphine are reversed if adults, [46] or larvae, [70] are co-treated with naloxone. Both naloxone and prolyl-leucyl-glycinamide (another opiate antagonist in mammals) reduced the analgesic effects of morphine to electric shocks received by goldfish, indicating they can act as an opiate antagonist in fish. [71] [72]

Physiological changes Edit

The physiological changes of fish in response to noxious stimuli include elevations of ventilation rate [54] [64] [65] [73] and cortisol levels. [69]

Protective responses Edit

Studies show that fish exhibit protective behavioural responses to putatively painful stimuli.

When acetic acid or bee venom is injected into the lips of rainbow trout, they exhibit an anomalous side-to-side rocking behaviour on their pectoral fins, rub their lips along the sides and floors of the tanks [74] and increase their ventilation rate. [73] When acetic acid is injected into the lips of zebrafish, they respond by decreasing their activity. The magnitude of this behavioural response depends on the concentration of the acetic acid. [46]

The behavioural responses to a noxious stimulus differ between species of fish. Noxiously stimulated common carp (Cyprinus carpio) show anomalous rocking behaviour and rub their lips against the tank walls, but do not change other behaviours or their ventilation rate. In contrast, zebrafish (Danio rerio) reduce their frequency of swimming and increase their ventilation rate but do not display anomalous behaviour. Rainbow trout, like the zebrafish, reduce their frequency of swimming and increase their ventilation rate. [75] Nile tilapia (Oreochromis niloticus), in response to a tail fin clip, increase their swimming activity and spend more time in the light area of their tank. [76]

Since this initial work, Sneddon and her co-workers have shown that rainbow trout, common carp and zebrafish experiencing a noxious stimulation exhibit rapid changes in physiology and behavior that persist for up to 6 hours and thus are not simple reflexes. [52]

Five-day old zebrafish larvae show a concentration dependent increase in locomotor activity in response to different concentrations of diluted acetic acid. This increase in locomotor activity is accompanied by an increase in cox-2 mRNA, demonstrating that nociceptive pathways are also activated. [70]

Fish show different responses to different noxious stimuli, even when these are apparently similar. This indicates the response is flexible and not simply a nociceptive reflex. Atlantic cod injected in the lip with acetic acid, capsaicin, or piercing the lip with a commercial fishing hook, showed different responses to these three types of noxious stimulation. Those cod treated with acetic acid and capsaicin displayed increased hovering close to the bottom of the tank and reduced use of shelter. However, hooked cod only showed brief episodes of head shaking. [73]

Avoidance learning Edit

Early experiments provided evidence that fish learn to respond to putatively noxious stimuli. For instance, toadfish (Batrachoididae) grunt when they are electrically shocked, but after repeated shocks, they grunt simply at the sight of the electrode. [77] [78] More recent studies show that both goldfish and trout learn to avoid locations in which they receive electric shocks. Furthermore, this avoidance learning is flexible and is related to the intensity of the stimulus. [69] [79] [80]

Trade-offs in motivation Edit

A painful experience may change the motivation for normal behavioural responses.

In a 2007 study, goldfish were trained to feed at a location of the aquarium where subsequently they would receive an electric shock. The number of feeding attempts and time spent in the feeding/shock zone decreased with increased shock intensity and with increased food deprivation the number and the duration of feeding attempts increased as did escape responses as this zone was entered. The researchers suggested that goldfish make a trade-off in their motivation to feed with their motivation to avoid an acute noxious stimulus. [80]

Rainbow trout naturally avoid novelty (i.e. they are neophobic). Victoria Braithwaite describes a study in which a brightly coloured Lego brick is placed in the tank of rainbow trout. Trout injected in the lip with a small amount of saline strongly avoided the Lego brick, however, trout injected with acetic acid spent considerably more time near the Lego block. When the study was repeated but with the fish also being given morphine, the avoidance response returned in those fish injected with acetic acid and could not be distinguished from the responses of saline injected fish. [43] [81]

To explore the possibility of a trade-off between responding to a noxious stimulus and predation, researchers presented rainbow trout with a competing stimulus, a predator cue. Noxiously stimulated fish cease showing anti-predator responses, indicating that pain becomes their primary motivation. The same study investigated the potential trade-off between responding to a noxious stimulus and social status. The responses of the noxiously treated trout varied depending on the familiarity of the fish they were placed with. The researchers suggested the findings of the motivational changes and trade-offs provide evidence for central processing of pain rather than merely showing a nociceptive reflex. [81] [82]

Paying a cost for analgesia Edit

Zebrafish given access to a barren, brightly lit chamber or an enriched chamber prefer the enriched area. When these fish are injected with acetic acid or saline as a control they still choose the same enriched chamber. However, if an analgesic is dissolved in the barren, less-preferred chamber, zebrafish injected with noxious acid lose their preference and spend over half their time in the previously less-favourable, barren chamber. This suggests a trade-off in motivation and furthermore, they are willing to pay a cost to enter a less preferred environment to access pain relief. [33]

Cognitive ability and sentience Edit

The learning abilities of fish demonstrated in a range of studies indicate sophisticated cognitive processes that are more complex than simple associative learning. Examples include the ability to recognise social companions, avoidance (for some months or years) of places where they encountered a predator or were caught on a hook and forming mental maps. [67]

It has been argued that although a high cognitive capacity may indicate a greater likelihood of experiencing pain, it also gives these animals a greater ability to deal with this, leaving animals with a lower cognitive ability a greater problem in coping with pain. [83]

Scientists have also proposed that in conjunction with argument-by-analogy, criteria of physiology or behavioural responses can be used to assess the possibility of non-human animals perceiving pain. The following is a table of criteria suggested by Sneddon et al. [33]

In the table, Y indicates positive evidence and ? denotes it has not been tested or there is insufficient evidence.

Given that some have interpreted the existing scientific information to suggest that fish may feel pain, [84] it has been suggested that precautionary principles should be applied to commercial fishing, which would likely have multiple consequences. [84]

Both scientists and animal protection advocates have raised concerns about the possible suffering (pain and fear) of fish caused by angling. [85] [86] [87]

Other societal implications of fish experiencing pain include acute and chronic exposure to pollutants, commercial and sporting fisheries (e.g. injury during trawling, tagging/fin clipping during stock assessment, tissue damage, physical exhaustion and severe oxygen deficit during capture, pain and stress during slaughter, use of live bait), aquaculture (e.g. tagging/fin clipping, high stocking densities resulting in increased aggression, food deprivation for disease treatment or before harvest, removal from water for routine husbandry, pain during slaughter), ornamental fish (e.g. capture by sub-lethal poisoning, permanent adverse physical states due to selective breeding), scientific research (e.g. genetic-modification) may have detrimental effects on welfare, deliberately-imposed adverse physical, physiological and behavioural states, electrofishing, tagging, fin clipping or otherwise marking fish, handling procedures which may cause injury. [38] [88]

Browman et al. [89] suggest that if the regulatory environment continues on its current trajectory (adding more aquatic animal taxa to those already regulated), activity in some sectors could be severely restricted, even banned. They further argue that extending legal protection to aquatic animals is a societal choice, but they emphasize that choice should not be ascribed to strong support from a body of research that does not yet exist, and may never exist, and the consequences of making that decision must be carefully weighed.

Legislation Edit

In the UK, the legislation protecting animals during scientific research, the "Animals (Scientific Procedures) Act 1986", protects fish from the moment they become capable of independent feeding. [90] The legislation protecting animals in most other circumstances in the UK is "The Animal Welfare Act, 2006" which states that in the Act, " "animal" means a vertebrate other than man", [91] clearly including fish.

In the US, the legislation protecting animals during scientific research is "The Animal Welfare Act". [92] This excludes protection of "cold-blooded" animals, including fish. [93]

The 1974 Norwegian Animal Rights Law states it relates to mammals, birds, frogs, salamander, reptiles, fish, and crustaceans. [94]

A 2018 article by Howard Browman and colleagues provides an overview of what different perspectives regarding fish pain and welfare mean to in the context of aquaculture, commercial fisheries, recreational fisheries, and research. [89]

Nervous system Edit

Receptors and nerve fibres Edit

It has been argued that fish can not feel pain because they do not have a sufficient density of appropriate nerve fibres. A typical human cutaneous nerve contains 83% Group C nerve fibres, [47] however, the same nerves in humans with congenital insensitivity to pain have only 24–28% C-type fibres. [47] Based on this, James Rose, from the University of Wyoming, has argued that the absence of C-type fibres in cartilagenous sharks and rays indicates that signalling leading to pain perception is likely to be impossible, and the low numbers for bony fish (e.g. 5% for carp and trout) indicate this is also highly unlikely for these fish. [47] Rose concludes there is little evidence that sharks and rays possess the nociceptors required to initiate pain detection in the brain, and that, while bony fish are able to unconsciously learn to avoid injurious stimuli, they are little more likely to experience conscious pain than sharks. [ citation needed ]

A-delta-type fibres, believed to trigger avoidance reactions, are common in bony fish, although they have not been found in sharks or rays. [47]

Rose concludes that fish have survived well in an evolutionary sense without the full range of nociception typical of humans or other mammals. [47]

Brain Edit

In 2002, Rose published reviews arguing that fish cannot feel pain because they lack a neocortex in the brain. [95] [96] This argument would also rule out pain perception in most mammals, and all birds and reptiles. [57] However, in 2003, a research team led by Lynne Sneddon concluded that the brains of rainbow trout fire neurons in the same way human brains do when experiencing pain. [97] [98] Rose criticized the study, claiming it was flawed, mainly because it did not provide proof that fish possess "conscious awareness, particularly a kind of awareness that is meaningfully like ours". [99]

Rose, and more recently Brian Key [2] [100] from The University of Queensland, argue that because the fish brain is very different to humans, fish are probably not conscious in the manner humans are, and while fish may react in a way similar to the way humans react to pain, the reactions in the case of fish have other causes. Studies indicating that fish can feel pain were confusing nociception with feeling pain, says Rose. "Pain is predicated on awareness. The key issue is the distinction between nociception and pain. A person who is anaesthetised in an operating theatre will still respond physically to an external stimulus, but he or she will not feel pain." [101] According to Rose and Key, the literature relating to the question of consciousness in fish is prone to anthropomorphisms and care is needed to avoid erroneously attributing human-like capabilities to fish. [102] Sneddon suggests it is entirely possible that a species with a different evolutionary path could evolve different neural systems to perform the same functions (i.e. convergent evolution), as studies on the brains of birds have shown. [103] Key agrees that phenomenal consciousness is likely to occur in mammals and birds, but not in fish. [2] Animal behaviouralist Temple Grandin argues that fish could still have consciousness without a neocortex because "different species can use different brain structures and systems to handle the same functions." [98] Sneddon proposes that to suggest a function suddenly arises without a primitive form defies the laws of evolution. [ citation needed ]

Other researchers also believe that animal consciousness does not require a neocortex, but can arise from homologous subcortical brain networks. [11] It has been suggested that brainstem circuits can generate pain. This includes research with anencephalic children who, despite missing large portions of their cortex, express emotions. There is also evidence from activation studies showing brainstem mediated feelings in normal humans and foetal withdrawal responses to noxious stimulation but prior to development of the cortex. [104]

In papers published in 2017 and 2018, Michael Woodruff [105] [106] summarized a significant number of research articles that, in contradiction to the conclusions of Rose and Key, strongly support the hypothesis that the neuroanatomical organization of the fish pallium and its connections with subpallial structures, especially those with the preglomerular nucleus and the tectum, are complex enough to be analogous to the circuitry of the cortex and thalamus assumed to underlie sentience in mammals. He added neurophysiological and behavioral data to these anatomical observations that also support the hypothesis that the pallium is an important part of the hierarchical network proposed by Feinberg and Mallatt to underlie consciousness in fishes. [107]

Protective responses Edit

Initial work by Sneddon and her co-workers characterised behavioural responses in rainbow trout, common carp and zebrafish. [52] However, when these experiments were repeated by Newby and Stevens without anaesthetic, rocking and rubbing behaviour was not observed, suggesting that some of the alleged pain responses observed by Sneddon and co-workers were likely to be due to recovery of the fish from anaesthesia. [108] [109] [110]

Several researchers argue about the definition of pain used in behavioural studies, as the observations recorded were contradictory, non-validated and non-repeatable by other researchers. [39] [47] In 2012, Rose argued that fishes resume "normal feeding and activity immediately or soon after surgery". [47]

Nordgreen said that the behavioural differences they found in response to uncomfortable temperatures showed that fish feel both reflexive and cognitive pain. [111] "The experiment shows that fish do not only respond to painful stimuli with reflexes, but change their behavior also after the event," Nordgreen said. "Together with what we know from experiments carried out by other groups, this indicates that the fish consciously perceive the test situation as painful and switch to behaviors indicative of having been through an aversive experience." [111] In 2012, Rose and others reviewed this and further studies which concluded that pain had been found in fish. They concluded that the results from such research are due to poor design and misinterpretation, and that the researchers were unable to distinguish unconscious detection of injurious stimuli (nociception) from conscious pain. [47]

Endorphins: Effects and how to increase levels

Endorphins are chemicals produced naturally by the nervous system to cope with pain or stress. They are often called “feel-good” chemicals because they can act as a pain reliever and happiness booster.

Endorphins are primarily made in the hypothalamus and pituitary glands, though they may come from other parts of the body as well. The well-known “runner’s high” that is felt after lengthy, vigorous exercise is due to an increase in endorphin levels.

The level of endorphins in the human body varies from person to person. People who have lower levels may be more likely to have depression or fibromyalgia, but more research is needed in this area.

Share on Pinterest Endorphins are chemicals that help to relieve pain or stress, and boost happiness.

Endorphins are chemicals produced by the body to relieve stress and pain. They work similarly to a class of drugs called opioids.

Opioids relieve pain and can produce a feeling of euphoria. They are sometimes prescribed for short-term use after surgery or for pain-relief.

In the 1980s, scientists were studying how and why opioids worked. They found that the body has special receptors that bind to opioids to block pain signals.

The scientists then realized that some chemicals in the body acted similarly to natural opioid medications, binding to these same receptors. These chemicals were endorphins.

The name endorphin comes from the words “endogenous,” which means “from the body,” and “morphine,” which is an opioid pain reliever.

Some of the more common opioid drugs include:

Some illegal drugs, such as heroin, are also opioids. Both legal and illegal opioid medications have a high risk of causing addiction, overdose, and death.

The National Institute on Drug Abuse state that 90 people die each day in the United States from an opioid overdose. Many of these are a result of overdosing or misusing prescription opioids.

Opioid abuse and overdose have become such a serious problem that the National Institutes of Health have declared it a crisis. Medical experts are now looking into safe and effective pain relievers without opioids.

Natural endorphins work similarly to opioid pain relievers, but their results may not be as dramatic. However, endorphins can produce a “high” that is both healthy and safe, without the risk of addiction and overdose.

Body’s 'Natural Opioids' Affect Brain Cells Much Differently than Morphine

A new study led by UC San Francisco scientists shows that brain cells, or neurons, react differently to opioid substances created inside the body – the endorphins responsible for the “natural high” that can be produced by exercise, for example – than they do to morphine and heroin, or to purely synthetic opioid drugs, such as fentanyl. The researchers say their findings may help explain why the use of synthetic opioids can lead to addiction.

UCSF scientists developed a "biosensor" that reports where and when opioids bind to a matching receptor. When morphine was applied to a nerve cell membrane (seen in purple in left panel), the drug rapidly crossed the membrane, and within 20 seconds had bound to receptors in an internal cell structure called the Golgi apparatus (bright yellow and white in right panel). Image courtesy of Von Zastrow lab/UCSF

Since both synthetic opioids and the natural, “endogenous” opioids produced in the brain bind to and activate opioid receptors on the surface of nerve cells, scientists have long assumed that both types of molecules target the same cellular systems. But the new research reveals that these molecules also activate opioid receptors inside cells, and that the locations of these activated intracellular receptors differ between natural and synthetic opioids.

In the new study, published in the May 10 issue of Neuron, the researchers report that this difference could help explain why the effects of synthetic opioid drugs are more rewarding than those produced by endogenous opioids.

“There has been no evidence so far that opioid drugs do anything other than what natural opioids do, so it’s been hard to reconcile the experiences that drug users describe – that opioid drugs are more intensely pleasurable than any naturally rewarding experience that they’ve ever had,” said Mark von Zastrow, MD, PhD, a professor of psychiatry at UCSF and senior author on the new paper. “The possibility that these opioid drugs cause effects that natural opioids cannot is very intriguing because it seems to parallel this extremely rewarding effect that users describe.”

Researchers in von Zastrow’s lab collaborated with Aashish Manglik, MD, PhD, assistant professor of pharmaceutical chemistry, to create a “biosensor” that binds to the opioid receptors along with an opioid drug or natural opioid. The tool allowed the scientists to see what’s happening inside cells, giving them a closer look than ever before at opioids’ effects. “It's a way of sniffing out where these receptors are active in the particular types of neurons in which opioids work,” explained von Zastrow, a member of the UCSF Weill Institute for Neurosciences.

It has generally been thought that all opioid molecules, natural or synthetic, impart their signal only from receptors on the surface of the cell. Opioid-bound receptors are then taken inside the cell to compartments called endosomes, but receptors were thought not to signal from this location. Overturning this long-held view, the research team discovered that receptors actually remain active in endosomes and they use the endosome to sustain the signal within cells.

But in the most intriguing twist, the research team discovered that morphine and synthetic opioids activate receptors in yet another internal location called the Golgi apparatus, where endogenous opioids are unable to produce any activation at all.

“It really surprised us that there was a separate location of activation for drugs in the Golgi apparatus that could not be accessed by endogenous opioids,” said first author Miriam Stoeber, PhD, a postdoctoral researcher in von Zastrow’s lab. “Drugs, which we generally thought of as mimics of endogenous opioids, actually produce different effects by activating receptors in a place that natural molecules cannot access.”

Moreover, morphine and synthetic opioids crossed cell membranes without binding receptors or entering endosomes. They traveled directly to the Golgi apparatus, reaching their target much more quickly than endogenous opioids got into endosomes, taking only 20 seconds compared to over a minute. This time difference could be important in the development of addiction, the researchers said, because typically the faster a drug takes effect, the higher its addictive potential.

The scientists hope to apply their findings to create new types of opioid-based pain medications that have a lower risk for addiction. They also plan to screen other existing medications to see if they act more like natural or synthetic opioids.

“We're very excited about the possibility of leveraging these principles to develop better or more selective drugs that have the ability to get into the brain, but then differ in their activities at internal locations within individual neurons,” says von Zastrow. “This is an area that hasn't been explored in drug development because people haven’t been thinking about it, but the potential is there.”

Other authors on the study were Damien Jullie and Braden Lobingier of UCSF Toon Laeremans and Jan Steyaert of Vrije Universiteit Brussel, in Brussels, Belgium and Peter Schiller of the Clinical Research Institute of Montreal, in Canada.

The research was supported in part by funding from the National Institute of Drug Abuse (DA10711, DA012864, DA004443, and DP5 OD 02304801), the Canadian Institutes of Health Research (MOP-89716), and the Swiss National Science Foundation (P2EZP3_152173 and P300PA_164712).

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top ranked graduate schools of dentistry, medicine, nursing and pharmacy a graduate division with nationally renowned programs in basic, biomedical, transitional and population sciences and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.

The Effect of Substance Use Disorders on Children and Adolescents

HOOVER ADGER JR. , HAROLYN M.E. BELCHER , in Developmental-Behavioral Pediatrics , 2008


Cocaine, an alkaloid extracted from the leaves of the South American Erythroxylon coca, is supplied as the hydrochloride salt in crystalline form. It is rapidly absorbed from the nasal mucosa, detoxified by the liver, and excreted in the urine as benzoyl ecgonine. Its half-life is slightly more than 1 hour. The perceived effect of “snorting” cocaine may be influenced by some of the many diluents now being added to or actually substituted for the drug (heroin, amphetamines, phencyclidine, or fillers such as mannitol or quinine). Smoking the cocaine alkaloid (“freebasing”) in pipes or cigarettes, mixed with tobacco, marijuana, or parsley, or as a paste, has become a popular method of use.

Accidental burns are potential complications of this practice. With crack cocaine, the smoker feels “high” almost immediately. The risk of addiction with this drug is higher, and the addiction more rapidly progressive, than from snorting cocaine. Tolerance develops, and the user must increase the dose or change the route of administration, or both, to achieve the same effect.

Clinical Manifestations

Cocaine produces euphoria , increased motor activity, decreased fatigability, and, occasionally, paranoid ideation. Its sympathomimetic properties are responsible for pupillary dilatation, tachycardia, hypertension, and hyperthermia. Binge patterns of use are common. Neurological effects such as dizziness, paresthesia, and seizures can occur. Use in group settings has been associated with sexual promiscuity and increased risks of acquiring sexually transmitted infections. Lethal effects are possible, especially when cocaine is used in combination with other drugs, such as heroin, in an injectable form known as a “speedball.” Pregnant women who use cocaine place their fetus at risk for premature delivery, complications of low birth weight, and possibly congenital malformations and developmental disorders.