Directions: After students have had a chance to review the article “Fatal fix,” lead a classroom discussion based on the questions that follow.

CHEMICAL AND BIOLOGICAL SCIENCES

Discussion questions:

1. Name some opioids that are made by the body and describe what they do.

Endogenous opioids are made by the body and are generally peptides or very small proteins. They include:

• Dynorphins: Several types of peptides in the brain and spinal cord that are involved in maintaining body temperature, appetite, circadian rhythms, mood and other functions.
• Endomorphins: At least two types of peptides in the brainstem and hypothalamus that may act in a similar way to the opioid morphine to control pain, but without being addictive or suppressing breathing, studies in mice suggest.
• Endorphins: At least three different types of hormones that are produced in the central and peripheral nervous system and that inhibit the transmission of pain signals. They are also involved in creating a runner’s high, or feeling of euphoria, among other phenomena.
• Enkephalins: At least two different types of peptides that are involved in regulating pain perception in the sensory nervous system.
• Nociceptin: One currently known type of peptide that is produced in the brain and spinal cord and is involved in pain perception but also apparently other functions, such as mood and learning.

2. What are the differences between natural, semisynthetic and synthetic opioids? What are the molecular structures of natural opioids and opioid drugs?

Almost all natural opioids are purified from poppy plants (Papaver somniferum); they include heroin, morphine and codeine. A few other plants such as kratom also produce some opioids. These natural opioids’ structures typically have several interconnected carbon rings. (Most endogenous opioids are a very long string of amino acids.)

Semisynthetic opioids are chemically modified from natural opioids; they include hydrocodone, hydromorphone, oxycodone and oxymorphone. The chemical modifications usually change one or more chemical groups that are hanging off of the carbon rings of the opioid.

Synthetic opioids are synthesized chemically in labs and behave like natural opioids in the body. Synthetic include fentanyl, carfentanil, methadone and loperamide. They also have carbon rings, but usually in a dramatically different arrangement than the carbon rings in natural or semisynthetic opioids.

Please note: If you have Molymod or similar molecular modeling components and enough class time, have students build models of some natural, semisynthetic or synthetic opioids. (Most endogenous opioids, being a string of amino acids, are too large for students to easily build models.) Use an online resource such as PubChem to find diagrams of the molecular structures of many opioids.

3. What are opioid receptors and their agonists and antagonists?

Receptors are proteins often found on the surface of cells that sense hormones, neurotransmitters or other molecules. When the appropriate molecule binds to a receptor, the receptor sends a signal inside the cell. Different cells in the body have different types of receptors for different molecules, and activation of those receptors can either excite or inhibit a wide variety of responses in the cells.

Agonists bind to receptors and activate the receptor. Opioid receptors are found on many cell types in the brain, spinal cord, peripheral nerves and gastrointestinal tract. When bound by natural opioids produced by the body, activated opioid receptors help to regulate levels of consciousness, breathing, pain sensation and digestion. But when bound by powerful opioid drugs in large quantities, the same activity can contribute to the inhibition of consciousness in the brain, breathing signals in the brain stem, pain signals in the spinal cord and peripheral nerves, and digestive muscle movements in the gastrointestinal tract.

Antagonists are chemical molecules that bind to the receptor but do not activate it. By taking the place of an agonist molecule that would activate the receptor, antagonists block (or antagonize) the agonist. Often an antagonist molecule is similar enough to the agonist in shape to bind to the receptor, but has enough chemical differences not to activate the receptor. Naloxone, better known by the brand name Narcan, is an opioid receptor antagonist. If someone overdoses on opioids and has difficulty breathing, administering naloxone intranasally or by injection can reverse the overdose and restore normal breathing. By antagonizing the binding of opioids to opioid receptors, naloxone also reverses the high feeling produced by the opioids and instead can lead to symptoms of opioid withdrawal.

Extension prompts:

4. What are the medical uses of opioids and other substances that bind to opioid receptors?

Codeine is a weak opioid and has been used in a wide variety of medicines to provide moderate pain relief. Though natural codeine exists, most is made from morphine via a semisynthetic route. Stronger opioids can provide much more pain relief, though with the risk of addiction and other side effects. Some pills combine an opioid pain reliever with a non-opioid pain reliever such as acetaminophen or ibuprofen in order to limit the dose of the opioid.

Methadone is a somewhat mild synthetic opioid that can be administered as a substitute for stronger opioids to try to wean an addicted person off of opioids.

Cold remedies have often included an opioid as a cough suppressant, with the intention that the opioid would partially inhibit some of the sensory signals and/or muscles involved in coughing. Codeine was used for that purpose for many years. More recent cold remedies use mild synthetic opioids such as dextromethorphan.

Loperamide is a synthetic opioid used to treat diarrhea. It works by inhibiting smooth muscles that normally move digestion along in the gastrointestinal tract, allowing more time for water in the intestines to be absorbed into the bloodstream. Thus, it can also cause constipation like other opioids. Loperamide does not readily cross the blood-brain barrier, so it generally does not act on the brain.

Naloxone or Narcan is an opioid antagonist that binds to opioid receptors throughout the body and can reverse an opioid overdose to restore breathing.

Naloxegol is also an opioid antagonist, but it cannot penetrate the blood-brain barrier. Therefore, its effects are mainly limited to the gastrointestinal tract.

5. What is opioid tolerance?

The longer a person takes opioids, the higher the dose the person’s body learns to tolerate. Consequently, the person needs to take higher and higher doses in order to relieve pain and/or satisfy an opioid addiction. The biological mechanisms that produce opioid tolerance currently are not well understood. There appear to be several ways in which opioid receptors decrease their sensitivity and their numbers in response to prolonged opioid exposure. Microbes in the gastrointestinal tract may be affected directly by opioids or indirectly by opioid-induced constipation, and in turn those microbes may metabolize opioids differently or induce the body to metabolize opioids differently. Like other drugs, opioids are metabolized by enzymes in the liver and secreted into urine by the kidneys; those processes (especially metabolism by the liver enzymes) may change with prolonged opioid exposure.

ENGINEERING AND EXPERIMENTAL DESIGN

Discussion questions:

1. How would you reconcile the graph “Deadly direction” in this issue’s article and the accompanying description that roughly 64,000 people died in the United States from a drug overdose in 2016?

The graph shows that roughly 42,000 Americans died from opioid overdoses in 2016. That means that around 22,000 must have died from overdosing on non-opioid drugs. Those other drugs could include benzodiazepines (prescription tranquilizers), cocaine and methamphetamine.  

2. What biochemical methods might be useful to prevent or reverse opioid addiction?

Biochemical methods could include using less addictive opioids (see the Science News article, “The opioid epidemic spurs search for new, safer painkillers”), using drugs that increase the body’s own production of natural opioids, modulating the number or sensitivity of opioid receptors in the body, controlling opioid metabolism in the gastrointestinal tract, controlling opioid metabolism in the liver and kidneys, and adjusting the potency and time response of opioid receptor antagonists.

3. What non-biochemical methods might be useful to prevent or reverse opioid addiction?

Non-biochemical methods might include social programs and media campaigns to discourage addictive behavior and promote recovery from addiction, minimizing opioid prescriptions, holding pharmaceutical companies and prescribing doctors legally accountable for opioid addiction and/or removing profit incentives, developing electronic sensors to monitor opioid levels in the body or signs of potential addiction or developing devices to release optimized amounts of opioids over time in the body.