Pain is one of the most common reasons that people end up in the doctor's office. And yet, until 1983, the field of pain management did not have its own medical society; today, the specialty still isn't widely taught in medical schools. For centuries, doctors even debated whether eliminating pain was morally acceptable: would it, for instance, defeat God's purpose in condemning Eve's daughters to suffer in childbirth?
Decisions about a patient's pain treatment are now made much more collaboratively, but even in modern times, the process is fraught with moral judgment, stemming largely from the nature of available pain treatments and an incomplete understanding of how to use them. Patients who ask for more pain drugs are eyed as potential addicts; doctors who prescribe pain medications too frequently fear being arrested for it.
But with about 10% to 15% of Americans, mostly middle-aged or older, suffering from chronic pain severe enough to interfere with daily life, figuring out which pain medications work best — and which are safest — is of crucial interest. That's why researchers have recently been taking a closer look at the class of drugs called opioids, which includes codeine, morphine and methadone — medicine's oldest and most powerful pain medications.
Although opioids are extremely valuable painkillers, particularly for patients at the end of life, drugs like Oxycontin (oxycodone) and Vicodin (hydrocodone and acetaminophen) are unfortunately better known for being addictive. While new studies have sharpened the understanding of how opioids work, and clarified their harms, the general question of safety remains complicated. Differences in the age and health of patients, their history of substance misuse, the nature of the pain and patients' sensitivity to certain drugs mean that a miracle drug for one person may be harmful to another.
Who Gets Addicted?
Psychiatrists are careful to distinguish between addiction and dependence. The latter occurs in almost all people who take opioids long-term; over time, they develop a tolerance to the drug, and suffer withdrawal if the drug is abruptly stopped. The point is, they are able to stop taking it eventually. Addiction, however, is defined as the compulsive use of a substance in spite of negative consequences: addicted patients whose pain symptoms have been resolved still can't quit taking the drug.
Although opioids have a reputation for being instantly addictive, studies find that the average patient does not enjoy the feeling of being on the drug; even among recreational users, most who try it don't get hooked. Patients who are prone to addiction are typically those who have histories of emotional trauma, mental illness or prior substance misuse.
In a review published in the Jan. 20 issue of the Cochrane Database of Systematic Reviews, a leading evidence-based-medicine journal, researchers found that only one-third of 1% of chronic-pain patients without a history of substance problems became addicted to opioids during treatment. The review included 4,893 mostly middle-aged chronic-pain patients, who were treated with opioids for between six months and four years. "This suggests that people who do not have a history of drug abuse or addiction are not highly like to develop [addiction] under physician care," says Meredith Noble, lead author of the review and senior research analyst at the ECRI Institute, a health care research and consulting group near Philadelphia.
Dr. Nora Volkow, director of the National Institute on Drug Abuse, takes a more sober view of the findings, pointing out that 18 of the 26 studies in Noble's review failed to mention addiction. The review authors say they assumed the omissions meant that those studies did not find any cases of addiction, but Volkow says it could mean that they simply didn't look for it.
Still, Volkow does not deny that age and prior addiction are key risk factors for drug problems; addiction is primarily a disorder of youth. Based on this review and other research involving middle-aged or older people screened for pre-existing drug problems, Volkow says, "Under those conditions, you can say that the risk [of addiction] is less than 3% [in people with no history of drug abuse]."
In some cases, however, undertreated pain may contribute to a situation that looks like addiction; patients ask for higher and higher doses and appear to be drug-seeking, when in fact they are looking for effective pain relief.
The Overdose Problem
For the most recent study of overdose risk, researchers examined the medical records of nearly 10,000 chronic-pain patients being treated within a Washington State health plan between 1997 and 2005. Published in the Annals of Internal Medicine in January, the study found that 51 patients had experienced overdose — six of them fatal. The overall risk of overdose was small, but it was clearly associated with the dose of the medication originally prescribed: patients receiving the highest doses were nearly nine times more likely to overdose than patients on the lowest doses. "The overall risk among people who continued to use opioids was 0.25% per year [or two overdoses per 1,000 people]," says Michael Von Korff, a co-author of the study and senior investigator at the Group Health Research Institute in Seattle, adding that most people involved in the study were on low doses.
Some of the overdose cases involved known drug misuse or suicide attempts, while others were due to patient error, but the study could not identify exactly what went wrong in all of the cases. Was it the high-prescribed dose alone, or were there other risk factors like illness, escalation of pain or undiagnosed addiction? While Von Korff and Volkow agree that prescription dose is a major contributor to overdose risk, they say better studies are needed to determine the precise causes and consequences. "One would hope that for a treatment regimen that millions of people are using, we'd have large, long-term, well-designed randomized controlled trials, and we don't," says Von Korff.
Which Painkiller Is Right?
One opioid is associated with a significantly higher risk of overdose than other drugs: methadone, which is being used increasingly to treat chronic pain because it is cheaper and draws less scrutiny than other strong, long-acting opioids like Oxycontin.
According to a review presented in February at the American Academy of Pain Medicine's annual meeting, methadone accounted for 5% of opioid prescriptions in the U.S. between 1999 and 2009 but was involved in 30% of opioid overdose deaths, as reported in malpractice cases, medical literature and federal and state databases. Some of these deaths occurred in heroin users being treated with methadone for addiction, but the overwhelming number of cases were in people who were prescribed the drug for chronic pain.
Much of the blame may fall on the Food and Drug Administration (FDA) and physician ignorance. Until 2006, FDA guidelines, which have since been revised, suggested starting pain patients on 80 mg of methadone a day — a dose that could kill people who haven't developed tolerance to this class of medications. The current recommendations call for 30 mg to start.
"I happen to think that methadone is an extraordinarily valuable drug," says longtime opioid researcher Gavril Pasternak, head of molecular pharmacology at Memorial Sloan-Kettering Cancer Center in New York City. "It works in many patients who don't respond to other agents, but it is more dangerous in the sense that it's more difficult to prescribe appropriately. We have to do better in terms of educating physicians."
That's true also for the use of over-the-counter painkillers like ibuprofen and naproxen, and other non-steroidal anti-inflammatory drugs (NSAIDs) like Celebrex (celecoxib). Guidelines written and published by the American Geriatrics Society warned against using these drugs chronically and at moderate-to-high doses in patients age 75 or older with persistent pain. Citing the many risks of long-term NSAID use, including fatal ulcers and gastrointestinal bleeding, increased risk of heart attack and stroke and dangerous interactions with other drugs commonly prescribed to the elderly, the American Geriatrics Society suggested that seniors try acetaminophen instead. If that doesn't ease pain, older patients are advised to use opioids like codeine or morphine, which don't have the same risks.
"We're not saying opioids are innocuous. They are dangerous drugs," says Dr. Bruce Ferrell, who chaired the panel that authored the guidelines. "We are saying that there is a substantial proportion of the population for which opioids might be a better choice than NSAIDs."
But while the risk of opioid addiction in the elderly is low, there are other cautions. A study published in January by Von Korff and colleagues linked high-dose opioid use to a doubling of the risk of broken bones in the elderly. "One-third of these were hip and pelvic fractures," Von Korff says. "These can really be debilitating." The authors speculate that the patients may have been prone to falls caused by dizziness or sedation, side effects of drug treatment that tend to occur early in a new drug regimen or when dosage changes.
The American Geriatrics Society says it took these considerations into account before writing its new guidelines. "There have been older studies that suggested that opioids may be associated with an increased risk for falls, and that's obviously a risk that physicians and patients should know about," says Ferrell.
Potential to Treat Psychological Pain
One of the most intriguing new findings regarding opioid use came out of a study including 696 Navy and Marine troops who were injured in combat in Iraq between 2004 and 2006. Published in the New England Journal of Medicine in January, the study found that soldiers who were given morphine during resuscitation and treatment for physical trauma were half as likely to develop posttraumatic stress disorder (PTSD) as those who did not get the drug.
Since the most severely injured troops were the most likely to receive morphine — and since this same group would be at a higher risk for developing PTSD — the finding is particularly striking. "It's incredibly exciting," says Dr. Glenn Saxe, associate professor of psychiatry at Harvard Medical School, who has conducted similar research in pediatric burn victims. "You could potentially be able to [reduce] the likelihood of getting a bad disorder like PTSD."
Saxe's research suggests a mechanism by which opioids may affect PTSD risk. Trauma researchers have long known that social support is critical for recovery from PTSD, and that the brain's natural opioids are involved in feelings of nurture and bonding. Saxe found that the pediatric patients in the hospital who had the most anxiety about being away from their families were also the most likely to develop PTSD, but in those treated with opioids for pain, the risk was reduced. "The pathway was opioid dose reducing separation anxiety, and reduced separation anxiety reducing PTSD," says Saxe.
Paradoxically, the findings suggest that the use of opioids could even help prevent addiction by reducing the risk of a psychological condition that is known to lead to substance misuse. "PTSD is so devastating, and it increases the likelihood of addiction," says Volkow. "I think it's definitely worth investigating."
Better Treatment Regimens Needed
Over the past few decades, researchers have made strides in understanding the treatment of certain kinds of pain. Relieving acute pain from trauma or surgery, for instance, reduces immediate suffering, but also speeds healing and reduces complications; the short-term use of opioids in the hospital is known to be safe and effective.
But because the how-tos in the treatment of chronic pain are much murkier, research suggests that still only a fraction of such patients receive the medication they need. While in some cases, doctors are using these powerful drugs too often, in others, concerns about misuse may have caused pain patients to suffer unnecessarily. "There is both overprescribing and underprescribing," says Volkow, who notes that, for instance, many dentists give opioids like Percoset too freely to teenagers after surgical procedures; in contrast, "you have individuals with very severe pain who are not given opioids or who are given doses that are [too low to treat the pain], and that in and of itself can put them at risk."
Doctors are often afraid to dispense high doses, sometimes at the expense of patients' daily functioning. "Those are the kinds of doses that get doctors arrested," says Siobhan Reynolds, founder of patient-advocacy group the Pain Relief Network. But as researchers figure out the best way to use their most powerful pain relievers, patients are beginning to benefit, Reynolds says. "More people are getting a very little bit of opioids, and that's good," she says. "But those who need high doses are still being put through hell. These drugs are a miracle for the right people: they're not good or bad; they're just what is."
