By Mary Carpenter
The TV series “Dopesick” portrayed how Purdue Pharma shamelessly marketed its opioid drug OxyContin beginning in the mid-1990s—sales agents convinced physicians the formulation was non-addictive. The next 20 years brought an explosion in opioid prescribing and a crisis of opioid overdose-related deaths.
But 2016 CDC Guidelines created to respond to overprescribing opioids are now under revision–charged with causing an acceleration of opioid overdose-related deaths. In 2020, the American Medical Association stated: “It is clear that the CDC Guidelines [to limit, discontinue or taper patients’ opioids] has harmed many patients.”
Debate rages, however, about where to direct blame for opioid overdose-related deaths — more than 100,000 occurring in the 12 months that ended in April, 2021, an increase of 28.5% over the previous year —and specifically about how to explain the connection between the two events—the proliferation of opioid prescriptions spurred by Purdue Pharma and the restrictions on prescribing imposed by the 2016 guidelines.
With about 30% of opioid overdose-related deaths each year labeled as suicides, questions arise about how many occurred for reasons unconnected to prescription opioids, as in “deaths of despair,” or the numbers who overdosed in pursuit of the euphoria provided by opioids— in contrast to people for whom addiction or intolerable pain, created by restrictions on their prescribed opioids, drove them to seek cheap but deadly street drugs like fentanyl and heroin.
At the heart of the debate, however, are questions about the risk of addiction—officially, opioid use disorder—for the five to eight million Americans taking medically prescribed opioids for severe chronic pain. According to the National Institute on Drug Abuse (NIDA), “roughly 21 to 29 percent of patients prescribed opioids for chronic pain misuse them,” while 8 to 12% develop an opioid use disorder—although the latter number could be as low as 1%.
From 255 million opioid prescriptions written in 2012, the number decreased to 142 million in 2020 — in response to the restrictive CDC Guidelines but varying in different parts of the country. Even cancer patients, explicitly exempted from the guidelines, “seem to have been hurt,” writes Maia Szalavitz in the New York Times. In a study of 100,000 medical records of patient prescribed opioids for chronic pain, drastic reductions or cuts in dosage under the guidelines increased the risk of overdose by 28% and of mental health crises by 78%.
Tolerance and physical dependence occur naturally with prescription oxycodone—in Percoset and OxyContin— but “resolve rapidly after discontinuation of the opioid…in a few days to a few weeks,” according to a New England Journal of Medicine review by psychiatrist Nora Volkow, now director of NIDA, and psychologist Thomas McLellan, founder and director of Philadelphia’s Treatment Research Institute.
Addiction—characterized by compulsive drug-seeking and use despite negative consequences —on the other hand, “develops slowly, usually only after months of exposure” and works via different molecular processes than tolerance, which makes it is a “separate, often chronic medical illness,” according Volkow and McLellan.
Of patients prescribed opioids, “only a small percentage” will develop an addiction, they write —with genetic vulnerability accounting for up to 40% of risk, along with history of trauma —reported by 90% of women with opioid use disorder. Mental illness may also play a role along with geographical or social context. The risk of addiction is higher in Appalachia, for example, than in Southern California.
But the Mayo Clinic site states that “taking opioid medications for more than a few days increases your risk of long-term use. The odds you’ll still be on opioids a year after starting a short course increase after only five days on opioids.” And even without “opioid use disorder,” withdrawal symptoms—the “dopesickness” of the TV series—linked to dependence can drive patients to seek more opioids with a desperation that can lead to psychosis and death.
Among many of the 18 million Americans reporting severe to moderate pain, more than 16% of men and 20% of women experience pain most days or every day over a three-month period. Of 245 opioid prescriptions written in 2104, 3 to 4% (9.6. to 11.5 million people) received opioid therapy for longer than three weeks. And in one Medicaid study, over 50% of opioid prescriptions covered more than six months.
Accompanying the analgesic effects of opioids are those of euphoria—because opioids bind to mu-opioid receptors in brain regions that are involved in both. Opioids also depress respiration, an effect that increases over time and can cause overdose and death. In addition to oxycodone, opioids include hydrocodone (in Vicodin) and codeine, as well as fentanyl, methadone, tramadol along with others.
Questions also arise about which kinds of pain are best treated by opioid medications. Acute, so-called nociceptive, pain—caused by injury or following surgery—that originates in peripheral pain receptors may be the most responsive to opioids. But the severe chronic pain that affects 40% of Americans often originates with signals from the brain and involves over-sensitization of the nervous system. University of Michigan oral surgeon Elizabeth Hatfield makes the comparison to getting sunburned—after which pain can arise with “things that normally feel okay” like a warm shower or a sheet touching your skin.
Chronic pain involving inflammation may respond well to NSAIDs—with better results from combining ibuprofen (Advil) with acetaminophen (Tylenol) —or to non-drug treatments that can affect the brain component, such as CBT (cognitive behavior therapy). But many chronic pain sufferers find relief only with opioid drugs. And especially away from large urban areas, the family physicians most often responsible for treating pain have received very little specialized training—one reason Purdue Pharma agents most successfully convinced doctors in regions like Appalachia to prescribe and then continue upping doses of OxyContin.
Finding better ways to assess pain levels— as well as the best dosage for different individuals— are primary goals of the government’s HEAL (Helping to End Addiction Long-term) initiative. Sensory testing to accurately measure nerve pain is one possibility. Volkow and McLellan write about the advantages of “access to biomarkers of pain and analgesia” via neuroimaging or genetic analyses that could help tailor dosages for individuals.
In addition, investigations into alternative pain medications have led to cell-based therapies as well as to the semisynthetic opioid Naltrexone. Used as a nasal spray to reverse opioid drug overdoses, naltrexone in low doses has for years been an “off-label option,” according to Hatfield, “because of its reduction in pain intensity [as well as] in opioid use for patients with chronic pain.”
The advice I received about taking Percoset 10 years ago following surgery that left a temporary pin in my forearm was to “stay ahead of the pain.” At my two-week checkup, however, I learned that I had received a double prescription by mistake and needed to stop taking the drug. When I woke up the next morning, intense aching pain spread through my entire body and lasted until late in the night. Because I did not desperately seek more pills, I believe I must have been withdrawing from dependence—not addiction —but the experience gave me new respect and deep empathy for anyone trying to quit taking opioid drugs.
—Mary Carpenter regularly reports on topical issues in health and medicine.