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.


  • Ballantyne JC. Opioids for chronic noncancer pain. Southern Med J. 2006;99(11):1245-1255.
  • Bohnert AS, Valenstein M, Bair MJ, et al. (2011). Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA, 305:1315-21.
  • Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. J Addict Dis. 2011;30:185-194.
  • Boscarino JA, Rutstalis M, Hoffman SN, Han JJ, Erlich PM, Gerhard GS, Stewart WF. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system Addiction 2010; 105:1776-1782.
  • Braden JB, Russo J, Fan MY, et al. Emergency department visits among recipients of chronic opioid therapy. Arch Intern Med 2010;170:1425-32.
  • Devulder J, Richarz U, Nataraja SH. Impact of long-term use of opioids on quality of life in patients with chronic, non-malignant pain. Curr Med Res Opin. 2005(Oct);21(10):1555-1568.
  • Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, Weisner CM, Silverberg MJ, Campbell CI, Psaty BM, Von Korff M. Opioid prescriptions for chronic pain and overdose: a cohort study. Annals of Internal Medicine 2010;152:85-92.
  • Elander J, Lusher J, Bevan D, Telfer P. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci & Med 2003;57:1683-1696.
  • Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain 2007;8(7):573-582.
  • Gomes T, Mamdani MM, Dhalla IA, et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011;171: 686–91.
  • Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300(22):2613-2620.
  • Saunders KW, Dunn KM, Merrill JO, et al. Relationship of opioid use and dosage levels to fractures in older chronic pain patients. J Gen Intern Med 2010;25:310-5.


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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Anonymous said...

Thank you so much for this. It makes me think that maybe someone at the FDA is going to see the same things you have. Otherwise, well, a lot of us folks with chronic non-cancer pain are going to get our opiates for 90 days and then suffer.

Anonymous said...

I would like to point out something interesting about point 3 in the paper. We don't know the long term effects of a lot of medicines. There are non-narcotic medicines that get approved and have disastrous consequences. Look at Accutane or Cipro for example. It is almost a straw man argument to suggest we don't know the long term effects of opiates. We don't know the long term effects of a majority of medicines. And I would also like to point out that since all opiates are derived from the opium poppy plant, we have thousands of years of evidence to draw from.
2 minutes ago · Like

SB. Leavitt, MA, PhD said...

On July 26, 2012, Congresswoman Mary Bono Mack and 5 fellow members of the Congressional Caucus on Prescription Drug Abuse sent a public letter [PDF available here] to Margaret Hamburg, MD, FDA Commissioner, essentially endorsing the Petition and all of its recommended labeling changes. The letter concludes:

“We believe that if a labeling change were made to opioid analgesics to reflect the uncertainty and lack of evidence surrounding safety and effectiveness of these drugs for treatment of chronic non-cancer pain, physicians would think twice before prescribing these highly addictive narcotics for ‘moderate’ pain such as a toothache or sore knee. While those who seek treatment for cancer pain and other diseases that cause ‘severe’ pain would not be affected, the number of individuals prescribed opiate painkillers without evidence of the long-term safety and effectiveness may decrease and limit those susceptible to developing opioid dependence.”

This letter commands that the FDA pay serious attention to this issue, since the Caucus closes with, “we request an expedited review of the Citizen Petition submitted to FDA, and look forward to a timely response.”

SB. Leavitt, MA, PhD said...

So readers will know, we have extended an invitation to Dr. Andrew Kolodny, president of PROP, to respond to Dr. Twillman’s remarks (above), which we will publish as a separate UPDATES article. We do hope he takes us up on the offer, as it is important to examine all sides of these very important issues and we believe Dr. Kolodny has some vital perspectives to share.

Steven Passik, PhD said...

I think this letter is a symbolic gesture and seeing as I know a lot of the MDs who signed it, I know they know it. Question is why and why now? Not one of them, I am willing to bet, really thinks that unless a paractitioner trained on Mars, practices medicine straight from the Merck Manual or writes for oxycodone every time someone stubs their toe (to quote Hal Rogers, R-KY, years ago at an FDA hearing) that this has real clinical meaning? I think it is a political statement and very much at the wrong time.
The wrong time, why? The nature of people coming to pain experts has utterly changed. It used to be that I saw patients (because of my interest in pain and addiction) who were escalated to grams per day of opioids, not benefiting, overusing, and one wondered why they were escalated that high to begin with. Nowadays, I see salt of the earth people with terrible injuries- no one thought they were a kook when they had their 5th back surgery or their 20th epidural steroid injection. But they have been on the same 4 hydrocodone/apap for 5 years and no one is willing to give them anything resembling a real trial of sophisticated, tailored opioid therapy. Now is the time to advocate for patients again. They are already losing access to opioids. Many patients do not and I would argue have never had access to real, safe, individualized, sophisticated opioid therapy. 8.8 million people are on opioids for chronic pain in this country, 5.5 million are on hydrocodone. Never mind the fact that we have been teaching that short actings opioids are not necessarily right for every patient along the risk spectrum, but if we were really individualizing therapy would 63% of people be on the same drug? Limiting the indication will do nothing to help anyone learn sophisticated opioid therapy and will likely have them focused on the wrong variable anyway.

Finally and this gets my goat, "PHYSICIANS" for safe opioid prescribing - how colleagial. Well I guess PHDs, NPs, PharmDs, and PAs dont get a vote. Very colleagial. I know more people in these disciplines who have done more to try to make opioid therapy safer and more individualized and tailored than many of the MDs in the world who are regular writers of these medications; so I guess you can discount my opionions above. Bob, you and I, and Steve Butler, and Simon Budman, and David Brushwood, and John Coleman, and Ken Kirsh and Peggy Compton and on and on.....we dont get a vote.

SB. Leavitt, MA, PhD said...

Thank you, Dr. Passik for your additional and very important perspectives. Points that I, for one, hadn't thought of. I hope that Dr. Kolodny or other signers of the petition will chime-in with their viewpoints -- we need an open dialogue on these issues.

SB. Leavitt, MA, PhD said...

As noted in the Addendum to the above article: - 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.

This is an opportunity to let your voice be heard by the FDA, pro or con, regarding this proposed label change for opioids.

Anonymous said...

Congress people who have no expertise in medicine should not force the FDA to do anything. That is the craziest idea I have ever heard. What the heck do congress people know about medicine? I think that total number of congress people who even have a background in any field of science is five.

Also, maybe we can form a counter group or something. Something like Physicians With Compassion For Pain Patients. Don't forget we can have political clout too if we can unite all the factions of pain patients including the elderly and handicapped.

Anonymous said...

Good luck with getting the PROP physicians to talk. They rely on manipulated data, anecdotal evidence, and straw man arguments. The evidence they are trying to pass off on congress is so bad that if a person tried to use it in a a dissertation for a PHD they would fail and have to start over.

Also, why are the pain patients being ignored? Even if opiates were proven unsafe for long term use, I would still use them. I would rather pass away ten or fifteen maybe even twenty years instead of living to eighty or ninety in severe pain. In other words, I don't believe opiates are dangerous for long term use, but even if they were I would still take them.

For me, it is about quality of life , not quantity of life.

Why can't a pain patient like me make my own choices? I know there are different methods to treat pain, but opiates work the best for me. I should be able to choose how I want to treat my pain. I would suggest these draconian pain rules are unconstitutional. They really would interfere with my right to pursue happiness.

Anonymous said...

So on the PROP website, under "Educational Materials," there is a PDF document titled " Cautious, Evidence-Based Opioid Prescribing." This document uses a table as its main source of evidence. Well, actually the evidence is cited at the bottom of the document, but the propaganda experts at PROP organized it in a neat myth-fact table.

I would like to take the time to systematically dismantle all of these ludicrous "facts." I am going to list all of the counter arguments, so be sure to read the document.

1. This "fact," is bizarre because it contradicts itself. It is essentially an oxymoron. It states that the long term efficacy of opioids is limited and long term use has not been proven safe. It also says the evidence is of poor quality. It is absurd to say we don't have enough long term evidence and then say long term use is dangerous. Basically, this point states we don't have enough evidence for anything, but we have enough evidence to show harm. It is strange that so many "scientists," and doctors did not notice that glaring mistake. Its also strange how they admit the evidence is of low quality and then attempt to use it.

2. This fact states that opioid tolerance and dependence can develop in weeks. Uh, duh? Why is that a problem? That is just the nature of the medicine. They don't explain why this is problem. This reason is why patients switch opiates or go on medicine breaks. This is not a big deal and definitely not ground breaking. I fail to see why that would be so bad as to warrant changing prescribing rules.

3. This basically says that it is hard to taper patients off of opiates. This may be true, but I have seen no good evidence. Its also hard to taper off of antidepressants and sleeping medicines. Why are they not attacking these medications?

4. This states that addiction and opiate use disorder are rampant among pain patients. I would say how do they know the patients that they studied were not faking being in pain? It is unfortunate, but part of the problem facing doctors are healthy ( people not in pain) drug abusers faking pain. Pain is a subjective experience that is difficult to prove. Physicians usually have to rely on the patient's testimony about the patient's pain. But even if real pain patients were abusing their medicines that does not indicate a serious problem. Some patients might need to abuse their medicines because they are severely under treated. How is someone with sciatica, five slipped discs, and some broken vertebrae suppose to get by on twenty milligrams of MS contin? Pain medicine abuse does not do anything to prove opioids are dangerous. This is just a feeble attempt to frighten people.

5. This point only points out the side effects of opiates. This point is ridiculous. What, are all other medicines side effect free? All medicines have side effects. This is not some big revelation. There are a lot of non-narcotic medicines with black box warnings. Again, antidepressants have caused people to commit suicide , but PROP is silent about that. I don't understand how a medicine's potential side effects would warrant banning those medicines. Does prop want the FDA to change the warning that is place on all medicine bottles? Every time I purchase a medicine I get a list of possible side effects with the warning " some people have experienced some side effects with this medicine. They usually go away over time. If they persist as are bothersome talk to your doctor." This is another scare tactic attempt. This is also a straw man argument.

Anonymous said...

These points are continued from my above posting. I ran out of space and time earlier. Also, there is a limit on the length of comments.

6. This fact is so irrelevant to PROP that I'm unsure why they even listed it.

7. This point is just a rehash of point one with two more arguments. The same counter argument from point one can be used here. One new point states that higher doses of opiates can have more side effects. Is that suppose to be a surprise? Most medicines have dose dependent side effects. Is this suppose to be a ground breaking fact? The other point is that people who take higher doses of opiates are still in substantial pain. Well, maybe the people who are on higher doses have severe pain issues that can only be reduced with opiates. Again, the chances that a patient with slipped discs, broken vertebrae, and damaged nerves will receive substantial pain relief is low. Sometimes, you have to take the relief you can get. Anyone in pain would tell you a level 4 pain level is better than a level 6 . Some relief is better than no relief. Why is that so hard to comprehend?

8. This one states that patients can accidentally overdose and die. Accidental overdose in patients is rare. And as I mentioned above some patients abuse their medicine. This is a rehash of the side effect argument above.

In conclusion, this list really has only six "facts," to try to persuade people with. Two of the "facts," listed are just rehashes of previously listed "facts". None of these "facts," are even remotely close to being good reasons for banning the use of opiates to treat non-cancer chronic pain.

The "scientists," and "doctors," that wrote this paper should be required to take remedial science and philosophy classes. It is amazing that they passed their board examinations. I find it hard to believe any scientist or doctor would actually put their name on a paper with so many obvious flaws. Maybe this report was intended to be handed out to non-scientist in order to scare them into supporting PROP.

Scientists and doctors are suppose to be objective and base their hypotheses and theories on solid evidence. All the evidence listed is either anecdotal or of low quality. What kind of scientist would say "the evidence is of low quality, but I'm going to use it to construct my theory or hypothesis?" Have any of these "scientists," or "doctors," even had anything published by a reputable journal? I would be horrified if they had articles published given their inclination to use poor evidence to build a hypothesis. Especially, a hypothesis built on fear and terrible logic.

This hit piece report is an embarrassment to the scientific community. That is probably why it is self published and supported by only forty doctors.

SB. Leavitt, MA, PhD said...

As a courtesy to readers, here is the link to the document discussed in the above 2 comments, Cautious, Evidence-Based Opioid Prescribing: (Clicking the link may take you away from this site; if so, press the back arrow in your browser to return.)

Anonymous said...

Because some people abuse their medication and OD the rest of us need to suffer? What happened to the Hippocratic Oath?

It is common knowledge that individuals with chronic pain can gradually increase opioid dosages to large levels safely. The key is gradual increments. This can and does occur over a period of many years or decades.

I know of many individuals with chronic severe pain who would decide not to continue to live if he or she could no longer access opioids at required levels.These patients are following doctor's medication directives.

It is imperative that any effort to reduce opioid overdoses not adversely effect chronic pain patients under the direction of a physician who require large dosages beyond the equivalent of 100 mg of morphine. Don't punish innocent chronic pain patients in order to save a different group that uses too much and ODs.

Pain With Dignity said...

First Thank You Dr. Twillman for an excellent review!

Second, based on the number of the petition's sources based on insurance claims data, could the source of funding for this petition be largely from the insurance companies themselves?

Third, it is disappointing to see the rebuttal of the data on falls and medications neglect a much more serious problem: the fact that pain itself, regardless of medication, is associated with falls at least in the elderly. They also happen in younger adults as well, and these are discussed by patients if the door is opened. Patients are embarrassed by the falls until asked to discuss them.

Leveille's articles are here:

1. Musculoskeletal pain and risk for falls in older disabled women living in the community.
J Am Geriatr Soc. 2002; 50(4):671-8 (ISSN: 0002-8614)
2. Chronic Musculoskeletal Pain and the Occurrence of Falls in an Older Population; JAMA. 2009;302(20):2214-2221

SB. Leavitt, MA, PhD said...

Hmmm... seems to me that we mentioned someplace in an UPDATE that unrelieved pain can contribute to falls -- in persons of any age. But, thanks for the references (above). --SBL

Bob Twillman, Ph.D. said...

Thank you for the references. I did mention this, although in a less detailed fashion: "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."

Anonymous said...

Dear Dr. Leavitt:

Thanks a lot for keeping We Sufferers, with Intractable non-cancer Pain who rely on Dr. Forest Tennant's Pioneering LEGAL & ETHICAL daily "High Dose Opioids Program" for our very Lives, informed of another attempt by "Big Brother-Oriented Doctors" to weaken California's Intractable Pain Laws!

I am one of those Californians who is a Patient of Dr. Tennant. I have been in His "Intractable Pain Clinic" Program for 21 consecutive years, and would be 100% Disabled from having #10, 24/7/365 Pain, if I wasn't in his Program!

I hope this doesn't start ANOTHER War against California's "Intractable Pain Laws"!!

If Dr. Kolodny {whom I am acquainted}, and all the other Intruders into the Lives of People whom they don't know and People whom they have no Interest in, could spend any-random-24 consecutive Hours in my Shoes, they would be ashamed of & appalled at their attempt to (again) Imprison me and destroy the Life that High Dose Opioids have made possible for 21 years.

Again, Dr. Leavitt You are a Personal Hero of mine and I thank You so very much for your Purpose in Life and for Your WebSite!!

Anonymous said...

First smart reply I read on this comment page today. Can anyone please be for the patient? I have severe Degenerative Arthritis of the Spine since 2005. I was then put on a low dose of Ocycontins (30 mg 1x day) and oxycodone 10/325 for breakthrough. That work pretty well and just as my Dr. was going to raise me up due to increase in pain; he died. He was the only Dr. in his office. My husband was transferred to another state and ever since then I have been unable to get back on my pills. Every Dr. I have gone to says they do not prescribe Opioids. I now use large amounts of Motrin, asprin, Bengay, pool therapy, walking with a cane, and in sooooo very much pain. Unfortunately, I am now in Orlando, FL and I will probably die before I get any opioid medication for my severe back pain in this state. Doctors have gone too far in the opposite direction and people in REAL SEVERE PAIN are suffering terribly! Thank you for this opportunity to respond.

Dr. Jeffrey Fudin said...

I posted comments on my blog at on this very subject. It would be worthwhile visiting our blog, as Dr. Leavitt and I have been in constant communication over this! Please note that Dr. Kolodny reached out to me today and we had a very productive conversation. I am hopeful there will be some communication to follow.

SB. Leavitt, MA, PhD said...

Yes… I recommend that readers visit Dr. Fudin’s blog for added perspectives on this issue. To make it easier, just Click Here

cushiegirl said...

As a chronic pain patient this very much scares me to death. Why are they punishing us for what the bad people do. Long term opioid therapy has saved my life. I was in so much pain I was housebound. I laid in the fetal position in bed all day long wishing to die. I got into pain management and it changed my life. I'm able to get my activities of daily living done. Please! Please! Don't punish us by telling the drs what and how much they can prescribe.

Anonymous said...

I have been in chronic pain from the complications of cushings disease and surgery. Nerve damage and severe arthritis from steroids. Without opioids, I would not be able to get out of bed and function. I sought many pain clinics and therapies before going on opioids and also have relied on pain management doctors to help get the dosage I need. I also do not have an addictive personality nor cancer but severe, debilitating pain. Please do not punish us by scaring the doctors into not prescribing opioids to those who need it. Would you take insulin away from a diabetic or blood pressure meds away from someone with hypertension? They could die. Chronic pain is horrible and has given me back some quality of life. Please do not punish us by saying those without cancer don't need pain meds as we do so we can have some quality of life.

Becky Roberts said...

Hi, I am a chronic pain sufferer, and I am totally against Prop and limiting Opiods to chronic Pain Patients..I have started a Petition on
If you are against this Prop petition..Please sign this petition and tell your story

SB. Leavitt, MA, PhD said...

As I noted above -- see Editor's Addendum to the full article above, with link -- the government has a place where anyone can enter their comments directly to the FDA. I would highly recommend that as the place where readers should voice their opinions on the Petition. The FDA really does read all of those entries and takes them seriously.

Anonymous said...

To Anonymous in Flordia, I have chronic pain and I use to take a mild perscribed pain "killer" (darvocet 64 I think) that had little effect, so I took large amounts of tyleonal which really did nothing except make me think I was doing something. Then my doctor did a blood test and found that my liver was about to give out on me (cirrhosis). When I told him I did not drink,nor use non-perscription drugs,except that I took several bottles of extra strength tyleonal in a month. He then knew what was wrong with my liver. He increased my perscription pain medicine and told me to avoid tyleonal as much as possible. I did not know that even the perscription medicine had large amounts of tyleonal in it. My liver got better otherwise I would not be writing this right now. I suggest you have your liver tested, unless you perfer to go due to liver failure, which is rather painless up until the end I am told?

Anonymous said...

I talked to my doctor several years ago aobut this issue and he said that the doctors on the review board in our state, that oversee pain medicine use, are almost all political appointees and except for their MD's, they have no special training in pain management and most are retired and out of touch with the latest research on anything.

Anonymous said...

I totally agree with you. But ask yourself does anyone want to do anything? If they had an objective machine that measured how much pain a person felt it would solve a lot of these problems. Then doctors would know for sure how much pain a person had and how much pain medicine they needed. If you try to find out if any devise exists or how much research is being done on the problem, you will find very little. Pain has been an issue since the first human got a thorn stuck in his/her foot. Right now the best actor gets the most pain medicine, just ask Rush Limbaugh among others. But no one really wants an objective measure of pain, just think of the money the medical industry would loose if doctors really knew how much pain a person was experiencing and only wrote what was needed. And don't forget the patients who are really awake during surgery, but paralized so they can not say anything, this type machine would help them also.
Do not forget organized crime that makes a bunch of money from pain suffers who can not get what they need legally. All of these groups pay large amounts of money to politicans to get the laws they want. Why are there not more enlighten laws regarding euthanasia, just consider the money being made taking care of the dying until their body finally gives out.
I am greatful for Dr. Twillman and the others who put humanity before their pocketbook, but they are to few and far between. Greed and money controls this country and will until some serious changes are made.

Anonymous said...

older people and those with injuries tend to fall more, whether they are on any medicine or not, it goes with the territory.

Anonymous said...

If we spent more money for research into a machine that would objectively measure pain it would help everyone, except the greedy rich. I know of too many who have commited suicide rather than go through the pain that they have seen others go through.
Next to the military-industrial complex, the medical industry is one of the most lucurtive, doctors come to this country from all over the world to make money. In my opinion that is why nothing will be done to measure pain or treat it effectively. Nor do they want anyone who can pay to die, so forget euthanasia laws, put aside the moral and ethical reasons, the greed reason is why people will be kept alive and suffering as long as possible. This petition is just a way of enriching those who support it. Think about it, if you are in pain you will continue to go to doctors paying office visit fees and ER fees and buying any kind of medicine that might help the pain no matter how useless it is. I had never taken anything stronger than asprin until I lost my leg in Vietnam. From that point until now I have probably spent enought money on just pain medicine to pay for a house and the pain continues. As said earlier if the pain goes from level 9 to level 6 you are willing to try it. For my part I would be glad if I never had to take another pill or shot again ever, if the pain would stop. Yet every time I see a new doctor they immediately want to stop my pain medicine, but they have no answer for the pain. Of course greed comes in again since I get a disability pension and if I die the greedy rich figure their taxes will go down. That is not an overstatement I have hear some of them talk when they don't realize I am disabled. No one here talked about the statistics of the suicide rate among handicapped, especially those with pain, it's higher than the average. Even this information is under stated since many commit suicide, but it is called an accident if no note is found.
If the FDA acts on this petition the result will be an increase in suicides, more arrests of pain patients getting drugs illegally and more money for the medical industry as pain patients go to more and different doctors and try all kinds of different medications either by perscription or over the counter as well as an increase in alternative treatments. From what I have seen and read nothing good can come from this petition, except that some greedy rich, will get richer and in this country, sadly, that is more the rule than the exception.