Brian Webster

Chapter 2 – A Primer on the Opioid Crisis

Pain

Pain is important. It is a signal from the body something is wrong. Pain is a warning. You need only get burned once to know, at a primal level, never to put your hand in a fire. Pain is an alarm. Get to the hospital before your appendix burns. Call an ambulance before the chest pain becomes a fatal heart attack. Nobody likes pain, but it can be necessary and protective.

Not everyone experiences pain the same way. If you touch a hot flame, neurons from your finger, called nociceptors, will flash a signal through the spinal cord to the brain, which releases neurotransmitters that register the ‘ouch.’ There’s also an emotional component. For example, if a person steps on a sharp rock after fighting with her spouse, the nerve fibers in her foot will send a sensation to her brain, and she will shout an obscenity. If she steps on a sharp rock after winning the Powerball, the nerve fibers will send the same sensation from her foot to her brain, but she might shrug it off.

There’s also a difference between acute pain and chronic pain. Acute pain is the protective response to injury, the warning, the alarm siren of a serious problem. Chronic pain is persistent, prolonged misery. Dr. Mel Pohl, in his book "A Day Without Pain", describes it as a complex disorder that lasts longer than six months, and has outlived its usefulness. Chronic pain acts like a disease, with biological, mental, emotional, and spiritual components. Traditional medical treatment can be useless against it, but piling on the medications can become dangerous.

Opioids

Many people use words like ‘opioids,’ ‘opiates,’ and ‘narcotics’ interchangeably, but there are distinctions. Opiates are drugs made from the opium poppy, a natural plant. Synthetic andsemi-synthetics are non-natural chemicals designed to have the same effect as opiates.

Opioids is the term for the entire family of opiates that are natural, synthetic, and semi-synthetic.

Narcotic derives from the ancient Greek word ‘narkotikos’ meaning ‘to make numb.’ Narcotics can include opioids, cocaine and other drugs. It has a negative connotation.

Medications can be administered orally (by mouth), intravenously (into the vein), transdermally (as a patch through the skin), or rectally (‘where the sun don’t shine’).

Medications come in varying strengths and can either help or harm in various combinations with over-the-counter painkillers such as acetaminophen (Tylenol) and ibuprofen (Motrin/Advil). The effect of a medication depends on its dose, its route of administration, itscombination with other medications, and the person's genetics. Genetics determines whether someone is a fast metabolizer, who will see a minimal effect, or a slow metabolizer, who is more at risk for toxicity and death

The Table includes the various opioid medications and other medications that are commonly found on autopsy of people who die unintentionally from prescriptions. [TABLE]

Drug Schedules

The United States Drug Enforcement Administration (DEA), classifies drugs across five categories based on acceptable medical use and potential for abuse and addiction. [TABLE]

The classification came about as part of the Comprehensive Drug Abuse Prevention and Control Act of 1970, signed into law by President Richard Nixon. Schedule I drugs are never acceptable for medicinal use while Schedule V has the lowest addiction and abuse potential.

Schedule Definition

Schedule I: No acceptable medical use and high potential for abuse.

Schedule II: High potential for abuse

Schedule III: Moderate to Low potential for physical or psychological dependence

Schedule IV: Low potential for abuse and dependence

Schedule V: Lower potential for abuse than Schedule IV or combination with low milligrams of narcotic

Opioid Metabolism

Different pain medications have different effects on people, and individuals can react to pain medicines in a variety of ways. Some of these differences can be explained by how quickly a patient’s body breaks down the opioids. If the body metabolizes the medicine too fast, the patient won’t feel much pain relief, if any. If the body works too slowly on the medicine, the patient can experience a toxic effect, and be at higher risk of an overdose.

Opioids will break down in the liver by one of two pathways. Phase 1 metabolism is a modification reaction. This includes the cytochrome P450 family of enzymes (CYP) in the liver. Phase 2 metabolism is a conjugation reaction called glucuronidation, and involves the catalyst uridine diphosphate glucuronosyl transferase (UGT) and makes the molecules hydrophilic, meaning they are more easily excreted in the urine.

Phase 1 metabolism is the primary path fentanyl, oxycodone, methadone, and tramadol take on their way out of a patient’s system. There are various CYP enzymes in this phase, namely CYP3A4 and CYP2D6. The CYP3A4 enzyme metabolizes more than 50% of all drugs. Because CYP3A4 is involved with so many medications, people who have abnormalities with this enzyme are more susceptible to adverse drug-vs-drug interactions. There are genetic variations of the CYP2D6 enzyme and an estimated 5% to 10% of white people have a genetic variation that makes them poor metabolizers and at risk for toxic dosages. They simply are unable to break down these medications. A different 1% to 7% of whites and 9% to 30% of African Americans are rapid metabolizers, meaning they break down a drug fast, and recieve less benefit of the drug.Phase 2 metabolism is seen in the use of morphine, oxymorphone, and hydromorphone. Since these drugs do not use the CYP system, they have less chance for drug-vs.-drug interactions. These drugs depend on the UGT system, and researchers have found two gene variants, UGT2B7-840G and -79 which have been associated with decreased breakdown, which leads to an accumulation of morphine in the body. Not good.

It gets even trickier. Some medicines, like codeine, are prodrugs, meaning the codeine has to be broken down into morphine before pain relief kicks in. Slow metabolizers can get codeine toxicity, and people who are rapid metabolizers can end up with morphine toxicity.

Complicating matters more, many painkilling medicines such as morphine, hydromorphone, codeine, and oxycodone, have active metabolites in them. This means their break down compounds can also further opioid effects.

Jeremy Adler, a pain specialist and former president of the California Academy of Physician Assistants, once gave a riveting case presentation on how the genetics of enzyme variations can adversely affect pain medication. A 61-year-old woman who managed well on 5 mg of oxycodone twice a day for many years, checked into the hospital with pneumonia. Her attending physician put her on the antibiotic azithromycin, a drug that alters the CYP system. It did not play well with the woman’s usual oxycodone dosage. She stopped breathing and had to be placed on a ventilator. This scared her physicians. They attributed her respiratory failure to her pain medication after noting how she improved with naloxone. Once she’d been discharged, her doctors decided against putting her back on her previous pain regimen. She left the hospital with her pneumonia treated, but her pain worsened. Genetic testing revealed she was a poor metabolizer of her CYP2D6 enzyme. Oxycodone, her usual pain regimen, requires both CYP2D6 and CYP3A4 to metabolize. The antibiotic she received in the hospital blocked the CYP3A4 enzyme, while her own CYP2D6 enzyme was defective. Her body could no longer break down oxycodone, which caused her to overdose in the hospital on her regular 5 mg pain medication. Her pain specialist had to switch her to oxymorphone (Opana), which is unaffected by her genetic anomaly and uses an alternate UGT breakdown process. The lesson here: factors like opioid metabolism and human genetics make prescribing medicine a much more complicated matter than schedules and dosages — and it’s often a matter of life or death.

Side Effects: Tolerance, Dependence and Withdrawal

All medications can have side effects. With opioids, those can include sedation, dizziness, nausea, vomiting, and constipation — and that’s from one dose. Longer term dangers can be physical dependence, tolerance and respiratory depression, but it’s better to think of those more as a death spiral than side effects. Tolerance occurs when the prescribed dosage becomes ineffective, and the patient needs more — and eventually even more — of the drug to achieve the desired effect. Dependence on a medication takes hold when a patient can’t function without his or her daily dose. Respiratory depression is most scary. At a certain dosage, which varies from patient to patient, and can occur under varying conditions, opioids will suppress the body’s natural, automatic impulse to breath. Even someone accustomed to high dosages can cross the danger line simply by taking over-the-counter cough medicine. Similarly, even a prescribed dose of an opioid can kill when combined with a seemingly innocuous sedating agent such as Benadryl, an anxiety pill, or marijuana. A person could fall asleep and never wake up.

The amount of tolerance for a drug depends on continued use. If a patient stops taking the medication for a while, tolerance will remain at a low or normal level. This is why fatal overdoses so often happen to patients who relapse afer a stint in a rehabilitation facility. They relapse to their habitual levels of the drug after their body has detoxified and returned to a normal state of tolerance. What used to get them high now can get them dead.

Opioid withdrawal is unpleasant. Symptoms of it include anxiety, muscle aches, tearing, insomnia, runny nose, sweating, and yawning. There also can be abdominal pain, vomiting,and diarrhea. The good news is, these symptoms are not deadly, and go away within a few days. The lone exception is Tramadol, an opioid that also works on the serotonin system and can cause seizures.

Period of Abstinence—Then Overdose: We often hear about people succumbing from an overdose after a period of rehabilitation. This was the case in the recent deaths of Hollywood actor Phillip Seymour Hoffman, former Glee star Cory Monteith and thousands of other overdose deaths that get reported in local obituary sections instead of the national entertainment press.

Opioids dull the pain by causing neurotransmitter receptors to function at an artificially low level. Once a person has stopped taking the drug(s) for a while, their neurotransmitter receptors return to a normal level. Therefore, a dose of opioids that had been tolerated previously can now overwhelm the system. This is the case whether it’s a medically prescribed pain killer or a drug purchased illegally on the street. This is also why a doctor should never refill a high-dose opioid to an unfamiliar patient, not even if the person swears he or she has been on oxycodone 40 (also known as oxycontin) for years.

A good physician refers to the Prescription Drug Monitoring Program (PDMP) system if it’s available. If the doctor finds a prescription from two weeks earlier for a four-month supply of oxycodone 40, then the patient’s story makes sense. If the PDMP scan shows no prescription, or the patient is from out of town and there is no PDMP record, the safe response is to write either no prescription, or one for a small quantity of hydrocodone.

My pain specialist colleagues have educated me on the best way to handle these types.

They delay prescription refills for at least two weeks until they have gathered the medical data.

If patients can wait two weeks for the pain specialists, then the internal medicine and emergency physicians can wait as well. True, withdrawal for opioids is uncomfortable — often even miserable — for the patient. Withdrawal is not deadly, though. The wrong prescription of an opioid can be.

Opioid-Induced Hyperalgesia

Opioid Induced Hyperalgesia is a strange side effect that can occur after a year of opioid use. In this condition, a patient experiences pain far out of proportion to what is expected. Hyper (too much) and algesia (pain). I recall a time I gently touched my stethoscope on a patient and she began screaming in pain. I’d barely touched her. How could she be screaming? I became annoyed with her, certain she was faking. It turned out she wasn’t. Her pain pathways had been corroded by years of taking strong pain killers. Now more medication made it worse. The strongest opioids were designed to ease the suffering of terminal cancer patients waiting to die. They weren’t meant to be ingested for years on end. Treating hyperalgesia involves weaning the patient off pain medication long enough for their pathways to normalize. It is a difficult process, one requiring much trust between patient and doctor.

Addiction vs Dependence

Believe it or not, part of today’s opioid epidemic arose from a myth that people suffering real pain can’t get addicted, because they’re not seeking pleasure, but a reprieve from suffering. Unfortunately, it took millions of victims for the medical community to understand people in legitimate pain also become addicted. Ah, but there’s a slight distinction between dependence and addiction — and undue recognition of it has hindered some efforts to meet the crisis head on.

The National Institute of Drug Addiction has this to say: “Addiction—or compulsive drug use despite harmful consequences—is characterized by an inability to stop using a drug; failure to meet work, social, or family obligations; and, sometimes (depending on the drug), tolerance and withdrawal. The latter reflect physical dependence in which the body adapts to the drug, requiring more of it to achieve a certain effect (tolerance) and eliciting drug-specific physical or mental symptoms if drug use is abruptly ceased (withdrawal). Physical dependence can happen with the chronic use of many drugs—including many prescription drugs, even if taken as instructed. Thus, physical dependence in and of itself does not constitute addiction, but it often accompanies addiction.”

In other words, every addict is physically dependent on the drug of choice. But not all people with a physical dependence are addicts. The distinction between these terms is merely academic. The medical examiner’s office can’t tell the difference between addiction and dependence. When a person dies after ingesting one too many drugs, it happens regardless of their brain chemistry, which can’t be posthumously analyzed.

In the emergency department, I can’t tell the difference between a dependent patient and an addicted one. I don’t have time to even try. I can, however, tell if a patient is on a dosage that might kill him, and if that’s a risk, it’s all that matters to me. The CDC recommends opioid pain pills should not reach higher than 90 MME (morphine milligram equivalents) per day. At such a high dosage, which is definitely up in the danger zone, the distinction between dependence and addiction is truly irrelevant. Death doesn’t care.