Would Daily Opioid Dose Limits Prevent Overdose?
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LAS VEGAS — Key factors aside from opioid dose are associated with an increased risk for overdose, including younger age, the use of sedatives, and the lack of a recent opioid prescription, suggesting that proposed dose limitations of 100 mg of morphine equivalent per day or lower will likely not be effective in preventing overdoses, a new study suggests.
"These results suggest that attempts to reduce overdose risk by simply limiting prescriptions to less than 100 mg/day may have limited impact," the authors, with first author Angela DeVeaugh-Geiss, Purdue Pharma LP, write.
Their findings were presented here at PAINWeek 2013.
The study, funded by Purdue Pharma, was in response to a petition to the US Food and Drug Administration (FDA) from a group of pain and addiction specialists called Physicians for Rational Opioid Prescribing (PROP), calling for such measures as limiting the daily opioid dose to the equivalent of 100 mg of morphine per day for noncancer pain per day to prevent overdoses.
As reported by Medscape Medical News, the FDA announced just last week that it needed more data before taking action on the dose limit recommendation.
However, it did move to require drug manufacturers to change labels for extended-release opioid analgesics to remove "moderate to severe" from the pain indication on labels and to instead indicate that the drugs are only "for the management of pain severe enough to require daily, around-the-clock opioid treatment and for which alternative treatments are inadequate."
The FDA also required that extended-release opioid labels include a boxed warning stating that long-term maternal use of extended-release opioid pain relievers can result in potentially fatal neonatal opioid withdrawal syndrome.
No Opioid Prescription
To address the dose limitation proposal, researchers with Purdue Pharma evaluated an insurance claims database of 9.6 million individuals who were dispensed new opioids between January 2008 and March 2012.
They found that among those prescribed the drugs, there were 3224 cases of overdose (0.02 case per 100 person-years).
Nearly half of the overdose cases (44%) were among patients who were not prescribed opioids in the 30 days before the overdose, overall. Among patients aged 18 to 24 years, that rate was higher (59%), and the rate declined to 30% among those aged 55 to 64.
Among patients receiving higher doses of opioids (>100 mg/day), most had prescriptions for extended-release opioids, whereas lower doses were associated with prescriptions for immediate-release opioids.
Patients who also had prescriptions for sedative or hypnotic agents, such as benzodiazepines, showed a significantly greater dose-risk response.
The opioid dose categories above 100 mg and up to 200 mg had an unadjusted relative risk for overdose of 1.15 (95% confidence interval [CI], 0.97 - 1.38), whereas the risk in the 50 mg to <100 mg category was 1.61 (95% CI, 1.27 - 2.04).
However, after adjustment for opioid type, age, and sedative/hypnotic use, the relative risks declined to 0.87 (95% CI, 0.72 - 1.04) and 0.81 (95% CI, 0.63 - 1.04), respectively.
The highest dose category (>350 mg) compared with the lowest dose category (<50 mg) showed an adjusted relative risk of 1.17 (95% CI, 0.86 - 1.59).
"In 9 million opioid users (3224 overdoses), the relationship between opioid dose and overdose risk was diminished considerably after adjustment for opioid type, sedative/hypnotics, and age, suggesting that comparisons of overdose risk in patients prescribed high versus low opioid doses are confounded by different patient types in the groups," the authors write.
"After adjustment, opioid type, age, and sedative/hypnotic use remained significant, strong predictors of overdose risk," they conclude.
Diversion the Main Concern
Addiction specialist Stuart Gitlow, MD, president of the American Society of Addiction Medicine, commented that a main concern among policymakers in considering opioid restrictions is diversion of higher doses of drugs.
"[Diversion] not only leads to law enforcement issues, but also to risk of overdose by those who are opioid-naive, as well as to extra expense for state-funded insurers who are paying for drug that is not being utilized as prescribed," he said.
But the higher doses likely aren't associated with overdose, he added.
"I've never heard anyone say that prescribing high dosages leads to a higher risk of overdose in the patient to whom the dose is being prescribed," he told Medscape Medical News. "Tolerance develops quite quickly to opioids and this would be very unlikely."
The more common problem is the prescribing of benzodiazepines or sedatives along with the opioid, Dr. Gitlow said. "This is a terrible practice — it runs against all treatment guidelines, and yet doctors fall into this trap over and over again."
The study's findings echo those concerns, he said.
"I'm not saying that policymakers aren't right to restrict prescribing of higher doses as diversion issues are probably larger there and they are trying to cut back on diversion potential," he concluded. "But to restrict prescribing to reduce risk of opioid overdose probably makes little sense."
Jane C. Ballantyne, MD, a professor with the University of Washington's Department of Anesthesiology and Pain Medicine, in Seattle, was among physicians signing the PROP petition. She said that while she wasn't surprised by these findings, the associations don't show the whole picture.
"What it comes down to is what you see clinically over the years, and that is that patients who stay on these drugs for long periods of time get higher and higher doses, they don't get good pain relief, and they do get all of the adverse events," she told Medscape Medical News.
"Yet in the literature there are only these epidemiological studies that try to poke holes and say you can't prove causation, and this is just another one."
She suggested that the 100 mg per day limit recommendation isn't so much a specific tipping point for the risk for overdose as a place to stop and consider the risks of higher dosing.
"There is not really anything specific about 100 mg, but the principle behind it is that when you get to the higher doses you see less and less efficacy and more adverse effects."
Dr. Ballantyne added that overdose and death may be some of the worst outcomes with opioid overuse, but they aren't the only ones of concern.
"There is also addiction, which we're seeing is much more common than people realized, as well as things like falls and fractures, cognitive impairment, the failure to get back to work, the continued pain, loss of libido, pregnancy issues, and a host of other problems."
The study was funded by Purdue Pharma LP. Dr. Gitlow is medical director at Orexo, a company that makes Zubsolv, a buprenorphine/naloxone product. Dr. Ballantyne has disclosed no relevant financial relationships.
PAINWeek 2013. Abstract 28. Presented September 4, 2013.
Pain Experts Confront the 'Great Divide' on Chronic Opioids
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LAS VEGAS — The contentious issues surrounding the long-term prescribing of opioids for chronic pain — and the pressure to tighten restrictions in a climate of widespread misuse and abuse — were confronted head-on by a panel of pain specialists and other experts here at PAINWeek 2013.
In the standing-room-only session, aptly titled "The Great Divide," moderator Daniel B. Carr, MD, laid out the conflicting crises: On one side is the pervasive public health issue of chronic pain, in which patients are "stigmatized, marginalized, and blamed," for conditions such as lower back pain, that are beyond their control and for which they desperately need effective treatment.
On the other side is a full-blown epidemic — the misuse and abuse of the very same prescription painkillers needed to treat the chronic pain, which, as detailed in one alarming report after another, is taking a heavy toll on society.
"These statistics are sobering, to put it mildly," said Dr. Carr, a professor of Public Health and Community Medicine at Tufts University in Boston, Massachusetts.
"One in 20 people in the US age 12 and older used prescription painkillers nonmedically in 2010. In 2008 there were 15,000 deaths due to opioids — triple the amount of a decade earlier, and there were a half million emergency department visits due to prescription painkiller abuse in 2009."
"This is an enormous problem with enormous costs," he said.
The crisis prompted a pivotal call to action, as reported by Medscape Medical News last year, in the form of a group of pain and addiction specialists and other clinicians uniting as Physicians for Rational Opioid Prescribing (PROP).
The group filed a petition with the US Food and Drug Administration, requesting that the agency take measures, including striking the term "moderate" from the prescribing of opioids for noncancer pain, leaving "severe pain" as the only indication; limiting the daily opioid dose to the equivalent of 100 mg of morphine for noncancer pain; and limiting the maximum duration of continuous daily opioid use for noncancer pain to 90 days.
Evidence Underscores Opioid Concerns
Panel member Jane C. Ballantyne, MD, who signed the petition but was not speaking on behalf of the group at the session, described evidence that sums up some of the key concerns and questions surrounding opioid treatment, noting observational and randomized controlled trials that collectively fall short in terms of addressing issues of addiction risk, while showing that many patients choose to discontinue opioids because of adverse effects or inadequate analgesia.
"What's missing from the observational data and randomized controlled studies is whether the analgesia lasts, and whether it improves function and quality of life," said Dr. Ballantyne, a professor with the University of Washington's Department of Anesthesiology and Pain Medicine in Seattle.
"These studies really cannot assess the risk of addiction."
Epidemiologic data on chronic opioid users was even more troubling. Dr. Ballantyne cited a large studyfrom Denmark comparing 228 opioid users with 1678 non–opioid users (Pain. 2006;125:172-179).
"The opioid users reported more severe pain than non–opioid users, worse self-rated health, higher levels of inactivity, higher unemployment, higher health utilization, and poorer quality of life," she said.
"This was extraordinary — to see that the opioid-treated patients actually seemed to be worse than the nontreated patients."
Whereas opioids are used with the hopes of helping patients return to normal function and to work, several large epidemiologic studies show opioids in fact delay the return to work, while higher doses and a longer duration of treatment appear to be a recipe for increasing the difficulty in getting patients off of the drugs.
"It's not that it can't be done, but it is not easy and is especially hard for the average primary care physician who cannot use all of the tools we have in a pain clinic," she said.
Finally, heavy chronic opioid use can lead to tolerances to opioids that block the effects of the drugs in more acute situations.
"There is evidence that when people present for surgery, if they have been taking high doses of opioids for years, they become so tolerant that it's very difficult to control their pain in the acute setting and at the end of life," Dr. Ballantyne said.
PROP versus PROMPT
Panelist Jeffrey Fudin, PharmD, who is the chairman of a group formed in opposition to PROP's proposed label changes — Professionals for Rational Opioid Monitoring and Pharmacotherapy (PROMPT) — stated that he also was not speaking on behalf of the organization in the session but noted that the debate between the 2 groups has only helped to bring important issues to the forefront.
"I think we all owe PROP a debt of gratitude because if they hadn't done what they did, we wouldn't be having this debate, so I think they brought enough attention to this that these questions are being asked in a bigger way," said Dr. Fudin, who is with the Albany College of Pharmacy & Health Sciences in New York.
Another panelist, Nabarun Dasgupta, PhD, MPH, a quantitative epidemiologist with the University of North Carolina, Chapel Hill, described a different approach to 6 key dose-response pain trials in which he sought some definitive threshold for a risk for overdose, but again found that conclusions were hard to draw, largely because of differences between study criteria.
"There is a lot of heterogeneity and I think this is a big part of the problem in this field in general," he said. "For example, one study included suicides and the others did not, and some included noncancer pain while others did not."
In seeking to take a closer look at the role of benzodiazepines in the overdose rates, Dr. Dasgupta and his colleagues turned to prescription monitoring data from North Carolina for 2010.
"We know benzodiazepines and opioids together cause respiratory depression, and we wanted to see quantitatively how much of a difference this makes in the overdose rate because only 1 of the 6 pain studies looked at it," he said.
The researchers found rates of adverse incidents to be significantly higher among opioid users who were also taking benzodiazepines.
"Much of the dose-dependent effect of opioids on respiratory depression and overdose mortality is largely possibly explained by co-prescribed benzodiazepines," Dr. Dasgupta said.
"This is not shocking to clinicians. We know about this risk, and it's not shocking to drug users on the street — they know about it as well, but in the studies being often cited to move public policy, this stratification hasn't been done and I think that's an important thing to keep in mind as we go forward."
"The Road to Hell …"
The public policy involving opioid restrictions is already well under way in some states, however, and, without a full, clear comprehension of the true benefits and risks of such interventions, "there can be unintended consequences," said panel member Stephen J. Ziegler, PhD, JD, an attorney.
"Because of these 2 competing health care crises, the government has received a lot of pressure and the media has raised that attention, so they have to do something, but it wasn't until I worked for the government years ago that I truly understood that the road to hell is paved with good intentions," he said.
As an example of a potential problematic restriction, he pointed to restrictions in Washington State. "The intervention in Washington requires that a pain consultation is triggered if a patient reaches 120 mg of morphine equivalent dosage per day."
"One would think that would be good innovation — but there have been concerns expressed, particularly due to the fact that there are already well over 10,000 patients who exceed that dose."
The bottom line is that each patient a clinician treats represents a unique and often complex clinical challenge that simply may not fit the narrow profile defined in a clinical trial, said panelist Charles E. Argoff, MD, a neurologist with the Albany Medical Center in New York.
"You cannot, in my mind, take so-called evidence-based guidelines and apply them to the patient sitting in front of you," Dr. Argoff said.
"It's not valid or evidence-based. By the very notion that in a randomized controlled trial, most of the patients who are included are not the ones you see in your office, so how do you extrapolate?"
A good place to start, he emphasized, is to take a step back before even writing that opioid prescription.
"Why do we focus on opioids as the only clinical treatment that we use to take care of somebody? Let's remember that there are many other modalities that we can use, that we should use, and for which there are many lines of evidence to support."
That's not to say refraining from opioids altogether, he added, suggesting a broadened approach that is truly patient-centered.
"Let's be real about combining therapies and stop this dichotomy of pro- or anti-opioid. It's false and it doesn't serve healthcare professionals or patients or society well," he asserted.
"We should be pro-health and make treatment decisions in that context," he added. "We have to learn how to select patients as well as possible for all pain management therapies."
Dr. Ballantyne, Dr. Dasgupta, Dr. Ziegler, and Dr. Carr have disclosed no relevant financial relationships. Dr. Argoff is consultant and/or independent contractor for Collegium Pharmaceutical, Depomed Inc, Endo Pharmaceuticals Inc, Forest Laboratories Inc, Janssen Pharmaceuticals Inc, Lilly USA LLC, and Pfizer Inc. He has received grant/research support for Endo Pharmaceuticals, Forest Laboratories Inc, and Lilly USA LLC and honoraria from Depomed Inc, Endo Pharmaceuticals, Forest Laboratories Inc, and Lilly USA LLC. He is on speakers bureaus for Allergan Inc, Depomed Inc, Endo Pharmaceuticals, and Lilly USA LLC. He is a stock shareholder for Pfizer Inc. Dr. Fudin is a consultant for Practical Pain Management in the development of an online opioid conversion calculator and is on the speaker's bureaus for Janssen Pharmaceuticals and Purdue Pharma.
PAINWeek 2013. Presented September 6, 2013.