Thursday, August 2, 2012

Group Petitions FDA to Change Opioid Label

Guest AuthorBy guest author, Bob Twillman, PhD, FAPM

On July 25 2012, Physicians for Responsible Opioid Prescribing (PROP) submitted a petition to the US Food and Drug Administration (FDA) on behalf of its members, several other individual healthcare provider signatories, and the advocacy group Public Citizen, requesting changes to the currently approved label for opioid analgesics. [The petition document is available here.]

I have a number of concerns about this petition and about the quality of the stated scientific basis for it. I believe the changes requested could severely impede the provision of the kind of high-quality, individualized, integrated biopsychosocial care for chronic pain called for by the 2011 Institute of Medicine report on chronic pain.

In their letter, the petitioners explain that the current FDA-approved indication for nearly all opioid analgesics on the market is for treatment of “moderate to severe pain,” with the addition of “when a continuous, around-the-clock analgesic is needed for an extended period of time” for extended-release opioids. They assert that many clinicians mistakenly believe that this indication means that long-term opioid therapy is appropriate for chronic non-cancer pain, leading to overprescribing and harm to patients.

They further assert that the current label for opioid analgesics is noncompliant with the Federal Food, Drug, and Cosmetic Act’s requirement that “a drug intended to treat a condition must be proven safe and effective for use as labeled.” The petition then asks FDA to change the approved indications for opioid analgesics when they are used in the context of noncancer pain. Specifically, the petition requests three changes to opioid analgesic labels:

  1. “Strike the term ‘moderate’ from the indication for noncancer pain” [so that only “severe” pain remains on the label];

  2. “Add a maximum allowable daily dose, equivalent to 100 milligrams of morphine for noncancer pain”; and

  3. “Add a maximum duration of 90 days for continuous (daily) use for noncancer pain.”

The document then includes 9 “statements of scientific basis for petition,” each of which will be described in some detail further below.

Suggested Dosing & Time Limits

The petitioners request that FDA limit the label indication for opioids for noncancer pain, NCP (note this is not just chronic NCP, but all NCP, including acute NCP) as outlined above, and they state that this would enable FDA “to reinforce adherence to dosing limits that have been recommended by the United States Centers for Disease Control [CDC], the state of Washington, and the New York City Department of Health and Mental Hygiene [NYC].”

Interestingly, a review of these 3 cited sources reveals a suggested threshold of 120 mg morphine-equivalent dose (MED) per day in two cases (CDC and Washington), and 100 mg MED in the NYC guideline. But these are not absolute limits that are not to be exceeded; in fact, each of these guidelines suggests that patients at or above these dosage levels either be considered for referral to a specialist for consultation (again, CDC and Washington) or for “reassessment of the patient’s pain status and treatment plan, and reconsideration of other approaches to pain management” (NYC); not that patients be automatically tapered off the medication.

The shifting nature of the target dose supports the assertion by many that these thresholds are arbitrarily chosen, and could just as easily be set at the 200 mg MED mark suggested in the American Pain Society/American Academy of Pain Medicine guideline for treatment of NCP referenced in the petition (a document, incidentally, whose first author was Roger Chou; he and co-author Jane Ballantyne are both signatories of this petition).

Similarly, the 90-day limit on use of opioids for NCP is arbitrarily chosen, and could just as easily be set at 180 or 360 days. I am aware of no scientific data supporting the notion that something occurs at the 90-day mark that makes this threshold more significant than any other arbitrarily-chosen threshold, and the petitioners do not cite a source for this number.

It is possible that the omission of the word “chronic” from the petition’s requested actions was an oversight, given that further references in the document all focus on chronic noncancer pain. However, this is a significant omission, as many patients with severe acute NCP, such as those with severe multiple traumatic injuries, can easily require doses of opioids higher than 100 mg MED for extended periods of time. Further, many definitions of chronic pain specify a minimum duration of 90 days, meaning that the request for a 90-day maximum duration of opioid therapy implies that opioid therapy for chronic NCP is always inappropriate.

Does This Label Comply with the Law?

As the authors note, the law allowing FDA to determine official indications for medications states that a drug must be proven safe and effective for use as labeled. Obviously, to make this determination, some standard for “safe and effective” must be established, and FDA is granted the statutory authority to determine the standard to be used. Historically, when considering opioid analgesics, FDA has used the standard of a 12-week trial of the medication. It has not required longer studies, and has acted on the basis of evidence from 12-week trials whenever it has considered an opioid analgesic. In so doing, FDA technically has been in compliance with the law.

The petitioners, it seems, really want to challenge the decision of FDA to establish a 12-week standard as adequate, rather than to accuse it of breaking the law. It might be determined, after further review, that long-term studies (6 months? 12 months?) are necessary, given knowledge that has accumulated since these medications were approved. However, that is a different question, and one that is not included in this petition.

Statements of Scientific Basis for Petition

The petitioners include 9 statements purporting to provide a scientific rationale and support for the requested label changes. These statements are based on scientific works that are as sparse as the bodies of evidence supporting long-term opioid therapy criticized by the petitioners as being insufficient. I will critically examine each in turn.

  1. “Over the past decade, a four-fold increase in prescribing of opioid analgesics has been associated with a four-fold increase in opioid related overdose deaths and a six-fold increase in individuals seeking treatment for addiction to opioid analgesics.”

    This statement references a November 1, 2011 report from the CDC, which I have critiqued in a previous Pain-Topics UPDATE [here]. The many methodological flaws aside, this report sheds little light on the relationship between long-term opioid use and risk of overdose death and addiction. It is not at all clear how many of the people dying of overdoses involving opioids were taking their medication as prescribed, how many were taking their own medication in ways other than as directed, and how many were taking someone else’s medication.

    For example, Hall et al. [2008, ref below at end] found that 79% of people dying from overdoses involving opioids tested positive for alcohol and other drugs, and that 56% of cases had no prescription for an opioid. The solutions for these problems differ greatly, depending on the mediating factors between prescription and overdose death.

    The sharper increase in admissions to substance abuse treatment could be seen as a positive factor, indicative of an increased recognition of need for treatment and of treatment program availability.

    To be completely clear, even one case of addiction and even one case of death from overdose is a tragedy. So, too, is one case of inadequately treated chronic pain. The fact that increased rates of prescribing are matched by increased rates of overdose death suggests that the adverse outcome is a phenomenon that occurs at a certain rate regardless of how many prescriptions are written. To prevent the tragedies, though, we need to know how you get from “Point A” prescribing to “Point B” overdose and/or “Point C” addiction.

    In short, the correlation between prescribing and these two outcomes represents a signal that there may be a relationship, but the proper solution can be determined only by gaining a full understanding of the intervening factors between the supposed cause and its seemingly-related outcome.

  2. “Prescribing of opioids increased over the past 15 years in response to a campaign that minimized risks of long-term use for CNCP [chronic noncancer pain] and exaggerated benefits.”

    Certainly, any campaign supporting the use of opioid analgesics should provide accurate information about both the risks and benefits of their long-term use. The FDA has taken corrective action in this area, as have the courts, punishing manufacturers who marketed their products wrongfully, as the petitioners’ references in support of this point indicate.

    It strikes me as interesting, though, that the petitioners imply that there is no real evidence of benefits of long-term high-dose opioid therapy (LTHDOT), yet they claim that manufacturers exaggerated such benefits that may not exist. As we will see below, the same may be said with respect to the accusation of minimizing risks.

  3. “Long-term safety and effectiveness of managing CNCP with opioids has not been established.”

    As mentioned above, the FDA’s standard for evidence of safety and efficacy (note the difference between efficacy and effectiveness; these studies address the former and not the latter, and this is a significant difference) requires a series of 12-week clinical trials. Longer studies have not been mandated by FDA.
    A recent FDA workshop found general agreement among experts that high-quality long-term data on both risks and benefits are lacking. However, a number of post-marketing studies have been conducted, demonstrating continuing pain relief efficacy in some patients. Other reports in the literature, including Ballantyne [2006], find that low-quality evidence sources, such as case studies, demonstrate that some patients can attain satisfactory analgesia by using opioids for up to 6 years.

    At least one systematic review of long-term opioid treatment for NCP has been published. Devulder et al. [2005] presented the results of 11 studies that evaluated long-term treatment with opioids in patients with chronic NCP and also assessed quality of life (QoL; n=2877). Six of the studies were randomized trials and the remaining 5 were observational studies.

    Of the 4 randomized studies in which baseline QoL was reported, 3 showed an improvement in QoL. Similarly, of the 5 observational studies, a significant improvement in QoL was reported in 4 of them. The authors found that there is ample evidence suggesting that long-term treatment with opioids can lead to significant improvements in functional outcomes and QoL in patients with chronic NCP. However, the authors suggest, further investigations will help to confirm the long-term QoL benefit of opioid therapy in such patients, and to clarify any effects of physical tolerance, opioid withdrawal syndrome, and/or addiction — all potentially associated with long-term use of opioids — on patients' continued functional status.

    This is not intended to endorse long-term opioid therapy; however, it is necessary to remember that the absence of evidence for long-term opioid safety and efficacy does not equal evidence of absence of long-term opioid safety and efficacy. The simple truth is that we just do not know with much certainty how many, or which, individuals with chronic NCP benefit from, or are harmed by, LTHDOT. Unless and until FDA changes the standard on which it bases its labeling decisions, and adequate data are collected to demonstrate the contrary, the current labeling should stand, based on the absence of evidence to the contrary.

  4. “Recent surveys of CNCP patients receiving COT [chronic opioid therapy] have shown that many continue to experience significant chronic pain and dysfunction.”

    The use of the word “many” here is vexing. How many is “many”? What does it mean if “many” continue to experience significant pain and dysfunction?
    Given the current state of the science of pain management and therapeutics, it is unreasonable to expect anyone with chronic pain to find complete relief and return of normal functioning through the use of medication alone. Chronic pain represents a broad spectrum of conditions; all of these conditions are complex (as are all chronic conditions); some may respond well to pharmacologic intervention with opioids, and others may not.

    This depends on the particular nature of the condition and the person. In most cases, optimal treatment for chronic pain conditions require a host of other biological, psychological, social, and spiritual interventions as well. Successful treatment also depends largely on the willingness of people with chronic pain to become active participants in their care and make lifestyle changes (ie, eating well, exercising, employing stress reducing techniques, etc.).

    The fact that opioids do not alleviate all pain and dysfunction is, in fact, an expected outcome. Few, if any, medications on the market are 100% efficacious in treating any condition, especially medications whose effects are primarily mediated through the central nervous system (eg, opioids, antipsychotic medications, antidepressants, and benzodiazepines).

  5. “Recent surveys using DSM criteria found high rates of addiction in CNCP patients receiving COT.”

    The two studies referenced by the petitioners to support this point do find a high percentage of people using long-term opioid therapy for chronic NCP meeting criteria for diagnoses of opioid dependence and opioid use disorder. Boscarino et al. [2010] administered a standard structured interview to patients using opioids to treat chronic noncancer pain, and determined if they met the diagnostic criteria for a DSM-IV-TR diagnosis of opioid dependence. Later, the researchers used the same data set, but retrospectively applied the proposed DSM-5 criteria for opioid use disorder [Boscarino et al. 2011].

    Neither DSM-IV-TR nor DSM-5 has diagnostic criteria specifying the term “addiction,” leaving the diagnoses of opioid dependence and opioid use disorder the closest approximation. The 2010 study found 26% of subjects meeting criteria for current opioid dependence and 36% for lifetime opioid dependence, while the 2011 study reports a 35% lifetime rate of opioid use disorder. Curiously, the 2011 study does not report current opioid use disorder rates.

    Boscarino and colleagues note that both DSM-IV-TR and DSM-5 criteria for these disorders include tolerance and withdrawal, which, as signs of physical dependence, are normal expected consequences of long-term opioid therapy. Other diagnostic criteria also could be benignly endorsed by many long-term opioid therapy patients, including use of the medication in higher amounts or over a longer term than intended, and a persistent desire or unsuccessful efforts to cut down or control use of the medication.

    Many patients in clinical pain management settings report that they never wanted to use opioids for as long as they have, or at the doses they have used, and many try to exert control by stopping or curtailing their use without medical advice to do so — only to discover that withdrawal occurs, as we would expect. This, I submit, is not evidence of addiction, but rather of a normal desire of the patient to achieve pain relief without having to rely on opioids.

    Finally, these diagnoses in both DSM-IV-TR and DSM-5 require a determination that the patient is experiencing significant dysfunction and/or distress as a result of their substance use. Many people with chronic pain experience significant dysfunction and distress resulting from their chronic pain, and it is not clear to what extent Boscarino et al. determined whether it was the pain or the medication causing the observed dysfunction and distress.

    Other studies have produced very different findings about the prevalence of addiction in people on long-term opioid therapy. The issue of normal sequelae of long-term opioid use clouding the diagnosis of addiction was addressed by Elander et al. [2003]. Using DSM-IV criteria, they found that 31% of a sample of sickle cell disease patients taking opioids for pain met criteria for substance dependence — remarkably similar to the results of Boscarino et al. — however, when the assessment excluded pain-related symptoms, the rate fell to only 2%. More recently, Fleming et al. [2007] studied a sample of patients receiving daily opioid therapy from primary care physicians, and found a 3.1% point prevalence of DSM-IV opioid dependence.

    Evidence regarding the rate of addiction among patients with chronic pain using opioids long-term is, at best, equivocal. The extreme range of prevalence estimates, from 2% to 26% for current diagnoses, suggests that there may be methodological issues that need to be resolved in order to determine the true prevalence of addiction, as it is unlikely that samples with similar characteristics, drawn from similar medical settings, would differ to this high degree purely because of sampling error. This body of evidence does not support a change in opioid analgesic labeling.

  6. “A large sample of medical and pharmacy claims records found that two-thirds of patients who took opioids on a daily basis for 90 days were still taking opioids five years later.”

    It is hard to know what the petitioners intended to prove by including this finding. In essence, it says that patients who use opioids long-term do, in fact, often continue to use opioids longer-term. Is that a bad thing, a good thing, or some of both?

    Without knowing why these patients continue to use opioids, it is impossible to interpret the meaning of this finding. The patients may be continuing to use (prescribed) opioids because they are experiencing improved pain and functioning. They may be continuing to use opioids because they are addicted. They may be continuing to use opioids because they provide some degree of pain relief and improved function and they have not been offered other options by their providers. Unfortunately, in the case of the latter, this is all too prevalent because too few providers have the knowledge and skills to provide patients with optimal care and too few insurance companies reimburse for the full range of effective treatments.

    In any event, this claim by the petitioners contradicts some criticisms of long-term opioid treatment that high rates of patients discontinue the therapy because of inadequate pain relief or intolerable adverse effects. Without the necessary context to explain these findings, it provides no useful information with respect to labeling.

  7. “Patients with mental health and substance abuse co-morbidities are more likely to receive COT than patients who lack these risk factors, a phenomenon referred to as adverse selection.”

    There is considerable evidence that this is true, and I’m not going to dispute it. However, this is irrelevant to the discussion at hand; it says nothing about the long-term safety and efficacy of opioids. The solution to so-called “adverse selection” is to train prescribers to be more effective in their assessment practices, so that they detect these co-morbidities and treat them appropriately. Changing the label on opioid analgesics will not accomplish this, and it will not stop patients with these co-morbidities from receiving long-term opioid therapy at higher rates than those without them.

  8. “Three large observational studies published in 2010 and 2011 found dose-related overdose risk in CNCP patients on COT.”

    The 3 studies cited by the petitioners in support of this point have been thoroughly critiqued in previous Pain-Topics UPDATES: the Dunn et al. (2010) study [here], the Bohnert et al. (2011) study [here], and the Gomes et al. (2011) study [here].

    These large observational studies are retrospective exercises in data mining, involving initial sample sizes running well over 100,000 in two cases, with opioid-related fatality rates well under 1%. The studies do not control for a variety of potential confounding factors, such as the concomitant use of other central nervous system depressant medications, population factors that may increase the risk of overdose and death, and determination of the extent to which decedents used their medications in ways other than as prescribed.

    The elevated risk of death is cited in relative terms based on arbitrary dosage ranges (eg, patients using <20 mg morphine equivalent per day had a death rate of X, while those using 21-90 mg per day had a death rate of 2X). What gets lost in the shuffle is the fact that ‘X’ is very small in absolute terms. Twice (or 3 times, or 5 times) a very small number is STILL a very small number.

    Additionally, even if the numbers are meaningful and significant, the lack of important contextual information makes this nothing more than a signal that there is a problem. It does not tell us the nature of the problem, leaving us with only one possible solution; ie, removing the one known factor — opioid analgesics. Data mining studies are useful for generating hypotheses but not for testing or proving those hypotheses.

  9. “COT at high doses is associated with increased risk of overdose death, emergency room visits and fractures in the elderly.”

    This statement is misleading in a number of ways; although, this concern does not endorse the safety of high-dose opioids. First, the Gomes et al. article is cited again in support of overdose risk, just as it was in the previous statement; there is no need to review and dispute it again here.

    Second, the petition cites  a report by Braden et al. [2010, ref below] on risk factors associated with emergency room (ER) visits among people using opioids long-term. The subjects come from two different populations; Arkansas Medicaid (n = 10,159) and a private insurance plan covering parts of 14 states (n = 38,491). Among other things, the study determines average daily opioid dose in mg MED per day, and then divides the sample into three categories: a) those taking less than the median dose (35 mg and 32 mg MED in the two samples, respectively); b) those taking between the median dose and 120 mg MED; and c) those taking more than 120 mg MED.

    The authors note that a cut point of 120 mg MED was arbitrarily chosen because it is the threshold recommended in dosing guidelines issued by authorities in Washington state. Data analyses determined that the two higher-dose groups had an elevated risk of ER visits in the Arkansas Medicaid sample (RR = 1.30 and 1.08, respectively), but not in the private insurance sample (RR = 1.03 and 0.97). Note that, despite the modest relative risk elevation in absolute terms, the Arkansas Medicaid findings reach statistical significance because of the very large sample size.

    However, given that the private insurance sample is nearly 4 times as large, the failure to find significant results in that group suggests that there really is no difference to be found, and there may be something specific about the Arkansas Medicaid sample that changes the findings. Methodologically, one also wonders what the findings would have been if a more traditional analysis comparing only groups above and below the median had been conducted.

    Third, a study by Saunders et al. [2010] is cited in the petition as examining the occurrence of bone fracture in people 60 years of age and older who had previously been prescribed opioids 3 or more times in a 90-day period. They examined risk of fracture as a function of current dose, including in one group that had discontinued opioid use and thus served as a no-current-opioid control.

    In a sample of 2,341 subjects followed for 6,379 person-years, 320 fractures were confirmed. Median daily dose of opioids was 7.6 mg MED. Groups based on opioid dose were arbitrarily established as: 0 mg MED; 1 – <20 mg MED; 20 – <50 mg MED; and 50+ mg MED.

    Compared to patients no longer taking opioids, patients currently taking any dose of opioids did not display a significantly elevated risk of fracture; although, there was a clear trend in the direction of more fractures (hazard ratio = 1.28, CI 0.99-1.64). Within the dosage levels, only the group taking 50+ mg MED displayed a significantly elevated fracture risk (hazard ratio = 2.00, CI 1.24-3.24); although, the confidence interval here overlapped with the overall, nonsignificant results for those taking any opioids.

    So, in order to display an elevated risk of fracture, patients needed to be taking an average opioid dose roughly 6 times the median dose for the population. The authors control for a number of confounding factors, but exclude perhaps the most obvious one: the patients’ underlying diagnoses.

    Those patients who continue to take opioids at elevated doses, compared to those who started opioids but were able to discontinue them, might well have painful conditions that necessitate the use of opioids. Those painful conditions themselves might create or mark an elevated risk of fractures. In any case, even if these findings hold up in subsequent studies, they represent valuable information about risks that are to some degree manageable through patient education and the provision of adequate assistive devices, they are not absolute contraindications.

The Problem of Defining “Noncancer Pain”

Even if the petitioners had an ironclad case supporting their assertions about the risks of long-term high-dose opioid therapy, I believe they would still have a significant problem with their requests of the FDA. That problem lies in their specification of proposed labeling changes applying to “noncancer” pain.

“Noncancer” pain is not, I submit, a solitary diagnostic entity. It is a category subsuming a large number and wide variety of conditions, some of which most pain management clinicians would agree may benefit from LTHDOT, and some of which clearly do not. The proposed label changes might be perfectly reasonable if the condition being treated is fibromyalgia, but they might be totally unreasonable for a person with severe rheumatoid or osteoarthritis that is not helped by other treatments.

And while “noncancer” pain is not a solitary entity, neither is “cancer” pain. In fact, with an ever-increasing number of long-term cancer survivors who have chronic pain as a result of their treatment, applying the label “cancer” pain starts to strain credulity. Yet, under the petitioners’ proposal, it would be deemed acceptable to use LTHDOT to treat, for instance, phantom limb pain resulting from a below-the-knee amputation due to osteosarcoma, but it would not be acceptable to treat the same condition resulting from a traumatic amputation. That’s just not logical, and it exposes how inadequate and inappropriate the false dichotomy of “cancer” versus “noncancer” pain can be.

To those unfortunate individuals who have moderate to severe pain unrelated to cancer, and relieved by LTHDOT, what are we to say? “I’m sorry, but even though you achieved greater pain relief with each opioid dose increase up to 100 MED, I am not allowed to go any higher, so you’ll just have to live with the pain that you have.” Or, “I’m sorry, I realize that the opioids I have prescribed for you have given you relief for the past 3 months, but now I have to stop giving them to you; good luck finding something else that works.” Neither of these seems either reasonable or consistent with the moral obligations of the medical profession.

Summing Up: No Simple Solutions for Complex Issues

In considering all of this, it appears that the petitioners are asking for changes to the indications for LTHDOT for noncancer pain based on a small number of studies with significant methodological shortcomings and findings that are not conclusive. In short, they are basing their request for label changes on the same kind of evidence that they, themselves, criticize as being insufficient to support the safety and efficacy of LTHDOT for noncancer pain.

Evidence is not conclusive until there is a sufficient accumulation of high-quality studies with consistent findings, something that has not been demonstrated by the evidence proposed as supporting this petition. For its part, the FDA sponsored a 1½ day workshop last May at which it considered these issues at length. Having attended that workshop, I have to say that I left with the conclusion that, based on the large body of solid scientific studies presented, we do not know much at all about either the risks or the benefits of LTHDOT. [A transcript of that workshop is available here.]

What we DO know about this therapy is primarily derived from anecdotal clinical observation. That source of information tells us that there are, indeed, some patients who benefit from this type of therapy, while there are others who are harmed by it. The question, it seems to me, is not the simple “Why should we ever do this?” but rather the more complex “When should we do this, in which patients, using what clinical protocols, and with which safeguards?”

The petitioners’ proposal is a blunt instrument solution based on the faulty premise that this problem will be solved if we only restrict the supply of opioid analgesics to a sufficient degree. Unfortunately, such “supply-side” solutions threaten the ability of people with chronic pain to obtain safe and effective relief when opioids are responsibly prescribed, in conjunction with other treatments, by skilled clinicians.

Chronic pain is not simple, it is complex; addiction is not simple, it is complex; the solution to the problem of prescription drug abuse also is not simple, but complex. Having reasonable discussions about the nature of the problems and their solutions, with a willingness to move away from the extremes of either hard-and-fast prohibitionist or “opioids-for-everyone” stances is what will be required to find the complex answers that we need. It is time to invest our efforts in that productive pursuit and balanced dialogue, rather than in a constant tug-of-war over which extreme position is right.


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Bob Twillman, PhDAbout the Author: Bob Twillman, PhD, FAPM, is the Director of Policy and Advocacy for the American Academy of Pain Management. A 2011-2012 Mayday Pain & Society Fellow, he is also a Clinical Associate Professor of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine. Dr. Twillman practiced as a clinical psychologist in academic medical centers for 20 years, primarily in the areas of psycho-oncology and pain management.

Proviso: All observations, opinions, advice, or facts expressed above are those of the guest author, and do not necessarily reflect the positions of Pain Treatment Topics, our staff and advisors, or our educational supporters/sponsors. Opposing views, opinions, or clarifications regarding this UPDATE article are welcomed in comments below or by separate submission for consideration of publication.

There now is a site for the petition at “Physicians for Responsible Opioid Prescribing - Citizen Petition; Docket ID: FDA-2012-P-0818” [click here].  The petition document is available there as a PDF. Also, there is a “Comment Now!” button at that site [or click here], so those interested can type-in comments or submit documents with comments directly to the FDA.

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