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by Chad D. Kollas, MD, Beverly Schechtman and Carrie Judy

Introduction

In May 2021, Pallimed published our commentary that described the inappropriate and disproportionate influence given to the advocacy group, Physicians for Responsible Opioid Prescribing (PROP, also known as Health Professionals for Responsible Opioid Prescribing) during the creation process of the Centers for Disease Control and Prevention (CDC) 2016 Guideline for Prescribing Opioids for Chronic Pain, hereafter the 2016 Guideline (1-3). In September 2021, Pallimed published our second commentary, which focused on the astonishing disclosure of an important conflict-of-interest (COI) by Dr. Roger Chou (5), who co-authored the 2016 Guideline, calling its integrity into question (4, 5).

This commentary, the final in our trilogy, expands on these articles to quantify and clarify the extent of Chou’s COI. We also explore additional COIs from the 2016 Guideline’s creation group before the final release of the updated CDC 2022 Clinical Practice Guideline on Prescribing Opioids for pain, hereafter the 2022 Draft Guideline (6,7). Our results suggest that advocates for unfocused reductions in opioid prescribing propagated a false narrative that physician overprescribing drove increases in overdose deaths over the last two decades. Using this false narrative, these advocates facilitated a corresponding moral panic that produced flawed national opioid policy that has increased drug overdose deaths and harmed patients in pain but has also served the competing financial and intellectual interests of the CDC, health insurers, mass tort litigation attorneys, state attorneys general and anti-opioid stakeholders.

Background/Chronology

“Just because you're paranoid doesn't mean they aren't after you (8).”

In a moral panic, a group of people are portrayed as posing a threat to themselves or society, thereby “justify[ing] intolerance and unfair treatment” of that group, while the “evidentiary standard” for treating them that way is lowered (9, 10). A moral panic can effectively sway public opinion to force a shift in public policy (9-11). “Moral entrepreneurs… crusade for making and enforcing rules that benefit their own interests by bringing them to the attention of the public and those in positions of power and authority under the guise of righting a society [sic] evil ” created by those causing the threat (9, 11). Medicine is not immune to such moral panics, and in the case of opioid policy, patients using opioid analgesics - whether to treat pain or opioid use disorder - became the group posing a “threat to society (9),” while physician advocates for unfocused reductions in opioid prescribing became moral entrepreneurs (9, 10).

How Did the Media Contribute to this Moral Panic?

In November 2003, the Orlando Sentinel published a series of articles on OxyContin, exemplifying the media’s moral panic about opioids (12). The series garnered national attention and culminated in the scheduling of a Congressional hearing on the dangers of OxyContin, popularizing the concept of “The Opioid Crisis (13, 14).” Suspicions about the veracity of the articles’ sources triggered an internal investigation, which led to the author’s resignation (15-17), but the series had created a foundation for a false narrative: duped by pharmaceutical companies’ deceptive marketing, physicians allegedly overprescribed opioids to patients with mild pain inappropriately, who eventually died from overdoses after becoming addicted to prescription medications.

Moral Entrepreneurs Seize the Opportunity

Opioid prescribing increased during the mid-1990s after widespread calls to improve pain management, particularly at the end of life (18-21). This unexpectedly and undesirably increased health insurers’ medication costs, including Medicare and Medicaid (22). Responding to an underfunded Medicaid program in 2003, Washington State’s Prescription Drug Preferred Drug List “steered people with state-subsidized health care — Medicaid patients, injured workers and state employees — to methadone” as a money-saving choice versus other opioid analgesics (23-25). By 2007, the Washington State Agency Medical Directors Group (AMDG), which included several eventual PROP members (23), published an “Interagency Guideline on Opioid Dosing for Chronic Non-Cancer Pain (26) that introduced the concept of hard dosing thresholds for opioid analgesics, which was later incorporated into the 2016 Guideline (2, 3). Although this reduced Washington state’s Medicaid costs, it contributed “to the deaths of at least 2,173 people between 2003 and late 2011 (23, 25).”

Despite these deaths, the false narrative gained traction and clarity when it was advanced by Andrew Kolodny, who co-authored a 2011 article with Roger Chou which announced the formation of the physician advocacy group, Physicians for Responsible Opioid Prescribing or PROP (26). Kolodny further asserted that physicians “contributed to an epidemic of overdose deaths and addiction by overprescribing opioids (27, 28).” PROP and Chou petitioned the Food and Drug Administration (FDA) to change opioid labeling in July 2012 (29, 30), but FDA rejected PROP’s call for a maximum daily dose of opioid analgesia of 100 morphine milligram equivalents (MME) based on a lack of supporting data (31).

The 2016 Guideline, Its Misapplication and Patient Harms

In the CDC, PROP found a more willing collaborator than FDA during the formation of the 2016 Guideline, prompting numerous concerns about the transparency and flawed integrity of its creation process (1, 4, 32-34). For example, in late 2015, Washington Legal Foundation alleged that one of the members of CDC’s Core Expert Group (later identified as PROP member, Jane Ballantyne) had “served as a paid consultant to a law firm planning multi-district litigation against opioid manufacturers (4, 33, 34).” WLF’s complaint compelled the CDC to re-open a second open comment period for the public, lasting 30 days in duration, rather than the two-day period for comment which CDC had originally presented via a September 2015 webinar (4, 35).

Despite transparency concerns and worries about conflicted interests on the part of the Guideline’s creators by key stakeholders (36-39), CDC published its 2016 Guideline on March 18, 2016 (2-4). That same month, Kolodny – who had served as a Stakeholder Reviewer for the 2016 Guideline - deflected concerns about PROP members’ relationships with law firms suing opioid manufacturers (34) and instead characterized key stakeholders’ open comments to CDC as driven by “financial relationships with opioid manufacturers (40).”

By November 2018, misapplication of the 2016 Guideline had begun to cause serious patient harms, including diminished access to medically appropriate opioid analgesia (41). Moreover, a group of CDC scientists publicly questioned the accuracy of CDC data on drug overdose deaths, which had not accounted for deaths involving illicit fentanyl (42). In response, the American Medical Association (AMA) called against widespread misapplication of the 2016 Guideline, including its embrace of hard dosing thresholds (1, 43). Other stakeholders quickly joined AMA’s call against misapplying the 2016 Guideline (44-47), and in April 2019, the Guideline’s co-authors acknowledged its widespread, including “inflexible application of recommended dosage and duration thresholds and policies that encourage[d] hard limits and abrupt tapering of drug dosages, resulting in sudden opioid discontinuation or dismissal of patients from a physician’s practice (48, 49).” That same month, FDA posted a public safety announcement warning against sudden discontinuation of opioid medications (1, 50), supplemented by a podcast warning against rapid opioid tapers (51). CDC issued another public warning against misapplication of the 2016 Guideline on April 24, 2019 (52).

Moral Entrepreneurs Undermine a Call for Balanced Opioid Policy

Just a few months earlier, a new hope for balanced opioid policy had emerged via the U.S. Department of Health and Human Services (HHS) Inter-Agency Task Force Draft Report on Pain Management Best Practices (53, 54). Pain management experts felt that the HHS Draft Report would “improve the access to pain care and remove the stigma, providing patients and providers with appropriate education, training, risk assessment, and evaluation (55).”

Opposing that view, however, the National Association of Attorneys General (NAAG) sent comments to HHS Assistant Secretary for Health, Dr. Vanila Singh, encouraging HHS not to move away “from key components of the CDC Guideline for Prescribing Opioids for Chronic Pain,” citing concerns that doing so “would undermine ongoing legislative initiatives [and] refinements to standards of medical care (56).” PROP hypocritically criticized the HHS Draft Report, noting that “HHS should have excluded individuals and organizations with financial ties to opioid manufacturers from serving on the HHS Pain Management Task Force (57).” The HHS Draft Report on Pain Management Best Practices quietly faded into obscurity.

Reassessing the 2016 Guideline; Creating the 2022 Opioid Guideline

As part of a planned assessment process, CDC opened a docket for public comments on its 2016 Guideline in April 2020 (58). Key stakeholders again expressed concerns about growing patient harms arising from the Guideline’s misapplication, especially from nonconsensual opioid tapers and denials for pain care, which amplified calls to rescind hard dosing thresholds (59, 60). In contrast, PROP predicted “the downward trends in new starts of chronic opioid treatment achieved by the 2016 guideline should be seen as a positive development that will encourage people to find alternative means of controlling chronic pain, which… will ultimately result in better outcomes and less distress (61).” Despite PROP’s optimism, CDC observed that “age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, heroin, and prescription opioids during 2013–2019” increased 1,040%, largely as the result of illicit fentalogues (62-64). PROP deflected this news by criticizing AMA’s opioid policy as tainted by contributions from the pharmaceutical industry (65, 66).

When Roger Chou unexpectedly disclosed his conflict of interest (COI) from receiving “funding to conduct reviews on opioids (4, 5),” evidence of harms from misapplications of 2016 Guideline had become more apparent (67-73). In the wake of Chou’s admission, the CDC 2022 Opioid Work Group (OWG) expressed additional concerns about the 2022 Draft Guideline, including that it was “not balanced and missing key studies” about potential opioid benefits and contained a constant tension between “public health benefits [versus] patient benefits (74).” The OWG also cited concerns about “including specific opioid dose thresholds in the recommendations” in the 2022 Draft Guideline (74). In light of the OWG’s concerns, we explored the depth of Chou’s COI disclosure (4, 5) and sought to uncover any other relevant, unreported COIs by those who created the 2016 Guideline and shaped current U.S. opioid policy.

Methodology

We qualitatively explored undisclosed or omitted conflicts of interests (COIs) from journal articles authored by the group of physicians who had advocated publicly, mainly through their PROP-related activities, for reduced opioid prescribing before their selection into the creation group of the 2016 Guideline. We examined whether they excluded disclosures of relevant COIs in publications that could influence opioid policy, emphasizing articles that might have prejudiced the creation process for the 2022 Draft Guideline.

We identified relevant publications via a query of PubMed (via the website link, https://pubmed.ncbi.nlm.nih.gov/) using the authors’ names and the search terms “CDC,” “Tapers,” “MME,” “Opioid Treatment,” or “Opioid Epidemic” for the period between September 1, 2015 and June 30, 2022. This start date reflected the timing of CDC’s webinar for its intended release of its 2016 Guideline (2, 3), while the end date preceded a decision by CDC on the final form for its 2022 Revised Opioid Guideline (6, 7). We included articles that articulated policy positions or recommendations relevant to either the 2016 Guideline or 2022 Draft Guideline. These articles contained key themes arising from discourse about the Guidelines, including but not limited to opioid tapering, MME, dosing thresholds and/or opioid prescribing recommendations. We called articles that met these inclusion criteria, “qualifying policy articles (QPAs).” Articles that focused on opioid use disorder or its treatment, acute pain management, or that made no recommendations about opioid treatment or U.S. policy were excluded from the analysis.

We defined “conflict of interest” using the methodology used by CDC itself in its creation of the 2016 Guideline, which “asked potential experts to reveal possible conflicts of interest such as financial relationships with industry, intellectual preconceptions, or previously stated public positions (2).” This included financial and non-financial or intellectual conflicts or competing interests. It also called for the exclusion of any experts that had “conflicts that might have a direct and predictable effect on the recommendations (2, italics ours),” such as taking a public position (such as signing a petition) or making recommendations intended to affect opioid policy. Additionally, we defined the authors’ role within relevant advocacy organizations based on their own statements of membership, or by virtue of their authorship of, or signature on, a supporting a policy document advocating for an opioid policy position.

Results

Table 1 summarizes the undisclosed or omitted conflicts of interest of the study group physicians, who advocated for reduced opioid prescribing prior to their involvement in the creation of the 2016 Guideline (2, 3). In sixty-three of 87 QPAs (72%), these physicians omitted or failed to disclose conflicts of interest (COIs) as defined by the 2016 Guideline (5). Three of these physicians (GF, DT and LN) failed to disclose relevant COIs in all their QPAs, and one physician (JB), failed to disclose COIs in 84% of her QPAs. Only one physician (RC) fully disclosed all COIs in more than half of his QPAs.



Table 2 lists the physicians’ most frequently cited QPAs and relevant conflicts of interest. As a group, four of six physicians (67%) omitted or failed to disclose both financial and intellectual (non-financial) COIs, while two of six physicians had intellectual COIs only. At the time of their selection to the 2016 Guideline creation group, each of the six physicians had an existing intellectual COI (4, 27, 29, 33) and two (RC and JB) had existing financial COIs (3, 4, 33, 34), although these COIs were identified only after they had contributed to the Guideline’s creation process.



Discussion

Conflict Overview, Ethics and CDC’s Guiding Principles

The Institute of Medicine (IOM) has defined a conflict of interest as “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest (107).” IOM has noted that “expert judgment based on clinical experience remains a significant element in the development of evidence-based practice guidelines,” and recommended that “groups that develop clinical practice guidelines should generally exclude as panel members individuals with conflicts of interest (107).” The American College of Physicians (ACP) recently echoed this sentiment, noting, “One of the hallmarks of a trustworthy clinical guideline or guidance statement is a comprehensive process for disclosure of interests (DOI) and management of conflicts of interest (COIs) (108).” ACP also emphasized that participants creating clinical guidelines should “disclose all active and inactive financial and intellectual interests related to health care,” noting that intellectual COIs “may leave a clinical guideline vulnerable to cognitive biases and may result in indirect financial benefit related to career advancement (108, 109).” Additionally, a Guideline Panel Review working group commissioned by the British Medical Journal (BMJ) identified “red flags” to raise “substantial skepticism” about clinical guidelines’ credibility (110). These “red flags” include any financial conflict by the committee chair, multiple panel members with financial conflicts and “any suggestion of committee stacking that would pre-ordain a recommendation regarding a controversial topic (110).”

Taking these position statements into account, our results suggest that the physicians from this study group have undermined the integrity of both the 2016 Guideline and 2022 Draft Guideline through their PROP- and MDL-related undisclosed or omitted COIs. We have applied CDC’s own ethics and guiding principles to identify these COIs, beginning with its definition of COIs from rules for creating the 2016 Guideline (2, 3). CDC has asserted that “users of guidelines and recommendations need to feel confident that those participating in the development process were not unduly influenced by personal interests. Minimizing competing interests among members of steering committees and technical groups improves guideline acceptability, credibility, and scientific rigor (111).” CDC acknowledged that “a participant with a competing interest might be excluded from participating in the development of the final recommendation statement (111),” and that “guideline developers should make every effort to either eliminate or manage financial, intellectual, or professional interests that compete with the goals of producing an evidence-based guideline (111).” Furthermore, CDC policy states that “reviewers must provide written assurance that their reviews are free of real or perceived conflicts of interest (112)”, and “scientists having real or perceived conflicts of interest with the applications under review may not attend or participate in initial peer review or secondary review meetings (112; italics ours).” Since HHS ethical rules allow obtaining a waiver if an “individual’s services [to an advisory committee] outweigh the potential for a conflict of interest created by the particular financial interest involved (113),” we have submitted a Freedom of Information Act (FOIA) request to CDC to view the waivers of the members of study group (JB, RC, DJ and AK) with financial COIs (see Table 2), the outcome of which is pending at this time (114).

COI Overview and Key Individual Conflicts

All authors should disclose all relevant financial and non-financial or intellectual COIs when creating clinical guidelines intended to influence health policy. In a 2012 study of 114 clinical guidelines created by medical specialty societies (115), COIs were disclosed for 71% of committee chairpersons and 91% of co-chairpersons, which still led to criticism about their trustworthiness for falling short of complete disclosure (116). The physicians in this study group had an overall COI disclosure rate of just 28% in QPAs, which should raise serious concerns about their credibility in matters of health care policy.

While Roger Chou omitted COIs in just 40% of QPAs in this study, he omitted disqualifying financial and intellectual conflicts at the time of his co-authorship of both the 2016 Guideline and the 2022 Draft Guideline (3, 27, 29, 85-91). At the time of his authorship of the 2016 Guideline, Chou did not disclose his pending funding from the Agency for Healthcare Research and Quality (AHRQ) for writing systemic reviews on opioid prescribing, although the grant award was not announced publicly until after its publication (85-91). The National Foundation for the Centers for Disease Control and Prevention, also known as the CDC Foundation, “an independent, private, nonprofit organization chartered by Congress in 1995 and classified as a 501(c)(3) public charity (117),” and AHRQ have both received funding from Group Health that supported Chou’s systemic reviews of opioids (4, 23). Chou’s competing interests should have mandated restriction “from further involvement in development of the clinical guideline… [including] participation in discussions, voting on recommendations, and authorship, or he or she may resign from the committee (108).” Chou did not resign from either the 2016 Guideline or 2022 Draft Guideline creation groups, nor did he step away from authorship, even after disclosing his financial COI publicly (4,5). Several stakeholders commented on these disqualifying COIs during the Open Period for comments on the 2022 Draft Guideline (118-121), but CDC created confusion by redacting Chou’s identity from many of these comments (122) despite public knowledge of his co-authorship of both Guidelines (122).

In addition to Chou’s egregious funding omission, Jane Ballantyne failed to report COIs in 84% of QPAs, while serving as a section editor for a well-known medical journal (123). As an editor, she understood well the ethical principles for reporting competing interests in medical journals (123-125). Furthermore, Ballantyne’s PROP colleague and frequent co-author, Mark Sullivan, recently failed to report his opioid litigation expert witness work as a COI in articles about opioid tapering policies in the journal which she serves as an editor (81, 126), including an article on which she “provided comments on an earlier draft (127).” When notified about the COI in a submitted editorial letter, the journal’s editor-in-chief pledged to publish a correction, but rejected the letter for publication, avoiding publicization of Ballantyne’s ethical violation (128). This correction has not been posted to date (126, 127). Similarly, Sullivan failed to disclose the same conflict in a letter to a medical journal that he co-authored with Ballantyne in March 2021 (129). Rather than publishing an editorial letter identifying the undisclosed COI, however, the article was updated to include the previously unreported competing interest (130). To date, identifying Ballantyne’s failure to disclose these omitted COIs has not affected her status as a section editor for the journal (123).

By contrast, Andrew Kolodny has published three QPAs since September 2019 (131-133), after he corrected his COI disclosures for JAMA articles from 2017 and 2018 (102-105). In more recent QPAs, Kolodny has consistently disclosed COIs arising from his PROP membership and expert witness work for multidistrict litigation (MDL) against opioid manufacturers and distributors (131-133). Unlike Ballantyne’s case, Annals of Internal Medicine posted a comment that revealed that a co-author on one of Kolodny’s QPAs (99) failed to disclose a relevant COI in an opioid policy article (134-136). While Kolodny’s recent reappointment as the president of PROP suggests that disclosing his more recent COIs has not restricted his aggressive advocacy (137), it is unclear whether that has affected the outcome of two recent MDL cases in which he testified for the plaintiffs (138, 139).

Does Disclosing COIs Matter?

The lack of consequences for omitting relevant COIs from QPAs in our study and the failure of many clinical practice guidelines to conform to standards for disclosing COIs (107-117) begs the question of whether disclosing COIs in medical journal articles even matters. Again, the answer comes from the CDC itself: “Guidelines, unlike some types of policies, are not mandatory. In health care and public health, guidelines are not meant to enforce but rather to recommend programs or practices based on the best evidence available. Often, however, CDC and others’ guidelines become ‘the standards of practice,’ unintentionally acquiring the force of policy (111). Users of guidelines and recommendations need to feel confident that those participating in the development process were not unduly influenced by personal interests. Minimizing competing interests among members of steering committees and technical groups improves guideline acceptability, credibility, and scientific rigor (111). Each release of a new CDC guideline might have a lasting impact on clinical and public health practice. Guidelines may be converted to policy, implying widespread implementation by a broad range of groups. Guidelines may be even converted into law, entailing subsequent regulatory enforcement (111; italics ours).”

Ironically, Roger Chou lamented this conversion of the 2016 Guideline into law because of its misapplication in the very same article in which he failed to disclose his funding for writing the systemic reviews upon which he based the both the Guidelines (4, 5, 23, 48, 85, 86). Accurate disclosures of COIs matter because the “public trust in the scientific process and the credibility of published articles depend[s] in part on how transparently an author's relationships and activities, directly or topically related to a work, are handled during the planning, implementation, writing, peer review, editing, and publication of scientific work (125).”

Following the Money

Advocates for reduced opioid prescribing have enjoyed an advantage from the failure of regulatory agencies and medical journals to identify and publicize relevant COIs, thereby propagating moral panic and the false narrative that overprescribing drives the opioid overdose deaths (27, 28). These deaths arose from an epidemic of poisonings from multiple illicit substances, including counterfeit drugs and ethanol, rather than from prescription opioids (42, 140-145). Knowing this, why have federal regulatory agencies and advocates for reduced opioid prescribing cling to a demonstrably false narrative about overprescribing?

As the saying goes, “Follow the money (146).” We described above how changes in opioid policy aimed at reducing Washington State’s Medicaid and Workers Compensation costs contributed to an increase in methadone deaths between 2003 and late 2014 (23-25). Focusing on similar cost reductions, the Centers for Medicare and Medicaid Services (CMS) proposed rules for 2019 including several directives intended to reduce "Opioid Overutilization,” including adoption of the “90 morphine milligram equivalent (MME) threshold cited by the 2016 CDC Opioid Guideline (147, 148). Simply put, reduced prescribing reduces costs for prescribed medications.

Chou received research funding to write systemic reviews of opioid analgesics that shaped both Guidelines, but largely ignored opioids’ potential benefits; he again failed to cite that funding when writing an article bemoaning early harms from the 2016 Guideline’s misapplication (3-5, 48, 74, 85-91). Employing a model created by the tobacco settlements of the 1990s (149), state, federal and local governments have successfully used the 2016 Guideline to justify their legal arguments in settlements of multidistrict litigation (MDL) suits against opioid manufacturers and distributors (150-153). Legal experts’ concerns about Ballantyne’s and Kolodny’s participation in the Guideline’s creation, during which they received financial compensation for MDL-related expert witness work (4, 23, 33, 34, 81-84, 99-105), proved correct when plaintiffs used the 2016 Guideline as a tool to support MDL lawsuits (37, 38, 154).). Andrew Kolodny openly anticipated making $500,000 from his expert witness work on Oklahoma’s lawsuit against opioid manufacturers and distributors (137, 155), while Ballantyne has never disclosed the amount of her personal fees from Motley Rice LLP, “one of the Nation's Largest Plaintiffs' Litigation Firms” and an MDL litigant (156, 157).

As of July 31, 2022, awards from opioid MDL lawsuits settlements had totaled more than $36 billion, with more suits still pending nationwide (158). Many policymakers have called for this settlement money to be spent fortifying public health (159), but tensions have emerged about “what interventions and treatments should be funded (160).” While it remains unclear how much the public will benefit from these settlements, it is very clear that plaintiff expert witnesses from our study group comprise one of the major financial beneficiaries of the MDL lawsuits.

Limitations and Criticisms

When creating our methodology, we purposely borrowed from Kolodny’s methodology (40) to disarm anticipated criticism by PROP and its allies. Similarly, when seeking publication, we received confidential criticism that we self-referenced our prior works in the same way that the study group’s references one another’s work to justify their opioid policy positions. To this we reply, “Turnabout is fair play (161).” Our study examines only physician advocates who served a role in creating the 2016 Guideline. Many more physicians have advocated for open-ended reductions in opioid prescribing and have omitted COIs in journal articles involving opioid policies (126-130, 132, 135), but have not been included in this commentary, because of our intentional limitation on its scope. Finally, we did not identify any participants in the creation process of the 2016 Guideline who possessed “conflicts that might have a direct and predictable effect on the recommendations” related to policy positions supporting medically appropriate opioid prescribing.

Concluding Recommendations

Our results strongly suggest that CDC disregarded or disobeyed its own rules and ethical guidelines (111-113) by allowing PROP members and allies to help create the 2016 Guideline, thereby compromising its ethical integrity (1, 4, 23, 34, 36, 119-123). Those physicians acted entrepreneurially to facilitate a moral panic (9-11) about opioid-involved overdose deaths, using a false narrative about overprescribing that successfully changed opioid policy nationally. These policies have unacceptably increased risks of harm for patients in pain (43-45, 48-52, 67-73). Unfortunately, abolishing or repealing the 2016 Guideline and 2022 Draft Guideline, while ethically justifiable, now seems like an impossible task. The federal government has invested too much time and too many resources into the Guidelines to abandon them, especially while MDL suits against opioid manufacturers and distributers are still pending.

What can be done to undo the harms created by the 2016 Guideline and prevent further harm from the 2022 Draft Guideline? We strongly recommend abolishing hard dosing thresholds from the 2022 Draft Guideline, because their misapplication has emboldened involuntary and/or rapid opioid tapers, contributing to patient harms (43-45, 48-52, 67-73). These hard dosing thresholds have been improperly translated into “mandatory policies and laws throughout the country, becoming, in effect a standard of care used by states, payers, pharmacy benefit plans, health care systems and providers (162).” Next, while the 2022 Draft Guideline offers some improved language toward that goal, CDC must unequivocally denounce the false narrative that overprescribing still drives the opioid crisis, as “the particular focus around reduced opioid prescribing has met with limited success and contributed to subsequent waves of the crisis (163).” CDC’s Opioid Workgroup for the 2022 Draft Guideline cited similar concerns about hard dosing thresholds, but also acknowledged the inherent tension between patient versus public or societal health benefits (74). In addition, we call on policymakers to correct the current policy imbalance between patients’ medical autonomy and society’s benefit, acknowledging that physicians have an individualized, fiduciary duty to act in their patients’ best interests which may sometimes reasonably conflicts with public health goals (164). Patients are not monoliths, and physicians cannot treat them individually using a broad policy brush. Physicians’ primary responsibility is to attend the individualized needs of the patients they are treating. Thus, we envision creating an ethics-based, education-focused informed consent process that allows patients to weigh treatment risks versus potential benefits collaboratively to enhance opioid prescribing safety (165).

Furthermore, we identified a 72% rate of nondisclosure of COIs in our study group, which we find ethically unacceptable, considering the purported importance of transparency when creating clinical guidelines (107-110). CDC itself has acknowledged this moral imperative, but hasn’t adhered to its own ethical rules (111-113). Given the apparent inability of the study group authors and the CDC to transparently self-regulate the conflict disclosure process, we encourage medical journals to become more vigilant about identifying authors’ financial and intellectual COIs in submitted manuscripts about opioid policies. This includes holding editors accountable when they deliberately ignore relevant competing interests (123, 126-128).

Finally, if these recommendations fail to restore balanced U.S. opioid policy, we call upon the U.S. House Committee on Oversight and Government Reform to convene a hearing to scrutinize CDC’s use of a Core Expert Group to write its opioid guidelines instead of complying with the supervisory requirements of Federal Advisory Committee Act (166). Alternatively, we would invite the U.S. Department of Justice to investigate why CDC has repeatedly violated internal rules and ethical policies while creating the 2016 Guideline and 2022 Draft Guideline (111-113). Permitting ongoing patients harms from these Guidelines desecrates the sacred trust between prescribing physicians and patients afflicted by chronic pain.

Dedication:

This commentary is dedicated to the memory of Dr. Terri Lewis, a beloved colleague and tireless advocate for patients with disabilities and chronic pain.

About the Authors:

Lead author, Chad Kollas, serves as the Medical Director for Palliative and Supportive Care at the Orlando Health Cancer Institute in Orlando, FL. He can be reached by e-mail at chad.kollas@orlandohealth.com or via Twitter at @ChadKollasMD.

Bev Schechtman is a patient with chronic illness and pain who has spent the last five years volunteering as a patient advocate. She is currently the Vice-president of The Doctor Patient Forum, and she has been with the volunteer organization, Don't Punish Pain, since its inception in 2017. She is a passionate researcher and advocate who hopes to give a voice to those in pain.

Carrie Judy is an unpaid contributor and researcher at The Doctor Patient Forum.

Competing Interests: Dr. Kollas recently served as Secretary on the Board of Directors of the American Academy of Hospice and Palliative Medicine (AAHPM). He also serves as the AAHPM Delegate to the American Medical Association (AMA) House of Delegates, where he is the Chair of the AMA Pain and Palliative Medicine Specialty Section Council and a member of the AMA Substance Use and Pain Care Task Force. Dr. Kollas provided testimony at a 2004 Congressional Hearing on OxyContin. Dr. Kollas has served as a medical expert witness in cases involving opinions regarding the standard of care in internal medicine and hospice and palliative medicine. He has received educational research grants from the AMA Education and Research Foundation, Geisinger Clinic and M. D. Anderson Cancer Center Orlando. He serves as the editor for the Advocacy section of AAHPM Quarterly and is a member of the Editorial Advisory Board and review for the Journal of Pain and Symptoms Management. He has also served as a reviewer for the Journal of Palliative Medicine, Annals of Internal Medicine, Journal of General Internal Medicine, Journal of Graduate Medical Education, and the Educational Clearinghouse for Internal Medicine.

Ms. Schechtman serves as the Vice-president of The Patient Doctor Forum, which accepts donations as a registered 501(c)(3) non-profit organization.

Ms. Judy serves as a volunteer researchist for The Doctor Patient Forum.

For more Pallimed posts about opioids.
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References

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by Chad Kollas, MD (@ChadDKollas)

Introduction

A recent study by the Centers for Disease Control (CDC) has captured the attention of the palliative care and chronic pain communities (1). Published on February 12, 2021, in Morbidity and Mortality Weekly Report (MMWR), it observed that the “age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, heroin, and prescription opioids during 2013–2019” have increased a whopping 1,040% (1). Several critics have attributed this increase in overdose mortality to failed federal opioid policy, particularly the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain and their misapplication (2-4). This criticism has generated recent flurry of activity on social media by the anti-opioid advocacy group (5), Physicians for Responsible Opioid Prescribing (PROP). This commentary will explore how PROP’s flawed policy approach over the last decade has reduced legitimate access to opioid medications and contributed to harms from increases in overdose deaths in the United States (US).

PROP Appears on the Opioid Policy Scene

In 2011, a group of internists, including Michael Van Korff, Andrew Kolodny and Roger Chou, co-authored an article that modern palliative care physicians would recognize as a “warning shot (6)” in the world of opioid policy (7). They announced the creation of Physicians for Responsible Opioid Prescribing (PROP), a “nonprofit organization with no pharmaceutical industry funding or ties,” that would “identify practical approaches to more cautious opioid prescribing in community practice (7).” They declared that “Guidelines for long-term opioid therapy should not be developed by the field of pain medicine alone. Rather, experts from general medicine, addiction medicine, and pain medicine should jointly reconsider how to increase the margin of safety (7).”

PROP Petition to the FDA on Opioid Labeling

The Petition is Filed
In its first effort to influence national opioid policy, in July 2012, PROP submitted a Petition to the Food and Drug Administration (FDA) calling for a change in labeling of opioid analgesics (8). Signatories to the Petition included PROP President, Andrew Kolodny, PROP Vice-president, Michael Van Korff, and PROP Board Members, Jane Ballantyne, Roger Chou, Stephen Gelfand, and Gary Franklin, among other medical specialists, including American Society of Addiction Medicine (ASAM) President, Stu Gitlow (8). In its petition, PROP requested that the FDA to make three main changes to the labeling process for opioid analgesics:

    1) Strike the term “moderate” from the indication for non-cancer pain (the only clinical indication for using an opioid analgesic would be for severe cancer pain).
    2) Add a maximum daily dose of opioid analgesia, equivalent to 100 milligrams of oral morphine, for treatment of all non-cancer pain.
    3) Add a maximum duration of 90-days for continuous (daily) opioid analgesia use for non-cancer pain, after which opioid analgesia would be discontinued (8).

The FDA acknowledged receipt of the PROP Petition on July 26, 2012 (9), and it simultaneously received a letter of support for its petition on the same date, led by Congress member, Representative Mary Bono Mack from California (10).

The Backlash to the PROP Petition Begins
This unity within the supporters of the petitioning group was short-lived. A representative from within the palliative care community alerted PROP FDA Petition signatory and American Society for Addiction Medicine (ASAM) President, Stu Gitlow, about substantial concerns from the pain management and palliative medicine communities about the potential reduced access to opioid therapy for many patients. In response to concerns that the PROP Petition might have a chilling effect on medically-legitimate opioid prescribing, ASAM released a statement by Gitlow clarifying its position that “the relabeling proposals [were] not intended, in any way, to limit a chronic pain patient’s access to clinically appropriate opioid pain therapy or to impinge upon a pain specialist’s ability to make individual decisions regarding the most effective therapy for their legitimate pain patient (11).”

Several prominent pain management experts echoed important concerns about over-restricting patients’ medically legitimate access to opioid analgesics. Bob Twillman, a pain psychologist and Director of Policy and Advocacy for the American Academy of Pain Management (AAPM), pointed out that “the 90-day limit on use of opioid for [non-cancer pain was] arbitrarily chosen (12).” Because PROP’s Petition had criticized the use of long-term opioid therapy by citing a lack of evidence for opioids’ long-term effectiveness, Twillman also pointed out that “when considering opioid analgesics, FDA has used the standard of a 12-week trial of the medication[;] it has not required longer studies (12).” Similarly, co-chair the New York State Palliative Care Education and Training Council and palliative medicine physician, Russell Portenoy, wrote that in light of “the stunning disconnect between the label changes demanded in the petition and the ‘scientific basis’ presented to justify them, I am concerned that all of the signatories possess an incomplete understanding of opioid pharmacology and pain medicine, and as a result, may pursue regulatory changes that are not in the best interest of public health (13).”

Other PROP critics included several medical professional organizations, like the American Society of Anesthesiologists (ASA), who challenged the clarity of a definition of cancer pain, asking rhetorically, “Who will decide whether the persistent pain, for example, of nerve damage incurred during an otherwise curative course of chemo- and radiation therapy is or is not cancer-related? (14).” Likewise, the American Academy of Pain Medicine (AAPM) stated “we have serious concerns about the petition and believe the rationale for the requested changes is seriously flawed, potentially harmful to patients with debilitating pain conditions for whom opioid therapy is indicated, and without substantive scientific foundation (15).”

The American Pain Society (APS) cited similar concerns about the Petition’s “insufficient scientific evidence base to support [its] recommendations. Further, we are concerned that implementation of these labeling changes which would dictate indications, dosing and duration of opioid treatment will not accomplish the intended goals, but instead have unintended negative consequences for patients including but not limited to untreated pain and loss of access to individualized care (16).”

FDA Response to the PROP Petition

On September 10, 2013, the FDA provided its response to the PROP Petition to change opioid labeling, which was granted in part and denied in part (17, 18). The FDA agreed with PROP that “more data are needed about the safety of long-term use of opioids,” and, to this end, they required “all new drug application (NDA) sponsors of ER/LA opioids to conduct postapproval studies and clinical trials… to assess certain known serious risks of ER/LA opioid use: misuse, abuse, hyperalgesia, addiction overdose and death (17).” Additionally, based on stakeholder input, the FDA determined that “safety labeling changes to the labeling of ER/LA opioid analgesics [were] needed to more effectively communicate to prescribers the serious risks associated with [those] drugs, and to more clearly describe the population in whom these drugs should be used be used in light of these serious risks – thus encouraging better prescribing, monitoring and patient counseling practices involving these drugs (17).” This included a new box warning to disclose risks from ER/LA opioid analgesics and the addition of the phrase, “indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time (17).”

Despite calling for these changes, the FDA disagreed with the most important requests from the PROP Petition. It rejected PROP’s separation of non-cancer pain from cancer pain, noting “a patient without cancer, like a patient with cancer, may suffer from chronic pain, and PROP has not provided scientific support for why labeling should recommend different treatment for such patients (17).” The FDA also rejected PROP’s call for a 100 mg/day maximum morphine equivalent (MME) daily dose limitation, noting “the scientific literature does not support establishing a maximum recommended dose of 100 mg MED (17).” Furthermore, the FDA noted that creating a maximum dose of 100 mg MED “could imply a superior opioid safety profile under that set threshold, when there is no data to support that conclusion (17).” Finally, the FDA determined that PROP’s request to limit the maximum duration of treatment with opioid analgesia to 90 days was “not supportable” based on the evidence presented in the Petition (17).

PROP’s Influences the CDC Guidelines

A New Federal Regulatory Target
Although the FDA had rejected the most important changes which PROP had requested, based on a lack of scientific evidence, PROP publicly framed its FDA Opioid Labeling Petition as successful, then repeated its calls for a 100 mg/day MME (19). PROP had also explored other avenues to influence opioid policy and reduce opioid prescribing, reaching out for example to the Federation of State Medical Board (FSMB) to encourage it to make changes in its Revised Model Policy on the Appropriate Use of Opioid Analgesics in the Treatment of Pain (20). Ultimately, PROP identified a more accommodating regulatory agency than the FDA, the Centers for Disease Control and Prevention (CDC), which revealed via engagement webinars on September 16 and 17, 2015, that it had been drafting its own Opioid Prescribing Guidelines (21).

Another PROP Backlash
In the days following these engagement webinars, critics expressed concerns about a lack of transparency in the drafting of the Opioid Prescribing Guidelines, because CDC had failed “to disclose what outside advisors it consulted with during the drafting of its controversial opioid prescribing guidelines for physicians (22).” Additional concerns involved an unusually short, 48-hour period for stakeholders to submit comments about the CDC Pain Guidelines upon their originally planned release in September 2015 (23). Moreover, revelations that at least five PROP Board Members - including PROP President Jane Ballantyne, PROP Vice-President Gary Franklin, PROP Founder Andrew Kolodny, PROP Board Member David Tauben and PROP Board Member David Juurlink – had served on the panels that helped develop the CDC Guidelines, stirred deeper concerns (23, 24). Jane Ballantyne MD, who had succeeded Andrew Kolodny as PROP President, served as the sole clinician from the pain management community to be included in the CDC Core Expert Group (25).

Medical professional organizations joined in criticism of the CDC for a lack of transparency in its policy review process and the scarcity of pain management experts represented in the Core Expert Group (26). The American Medical Association (AMA) wrote that the “review process used to date by CDC, especially the public engagement webinars, [had] generated concern about lack of transparency (26),” and that the “process may have been better served by constructing a more balanced panel that included clinicians from various medical specialty and practice settings (26).” The Patient Quality of Life Coalition (PQLC), an advocacy group that included the American Academy of Hospice and Palliative Medicine (AAHPM), AAPM, the Center to Advance Palliative Care (CAPC), and the Hospice & Palliative Nurses association (HPNA), among others, wrote that “the Guideline in its current form is focused on curbing inappropriate [opioid] use, but seems devoid of empathy for patients who need legally‐prescribed opioid medications for relief from serious and long‐lasting pain that compromises their quality of life and independence (27).”

Following this outcry for transparency and expanded clinical representation regarding content, the CDC announced a second, 30-day open-comment period on its proposed 2016 Pain Guidelines, effective December 14, 2015 (28, 29). This delayed the roll out of the CDC Pain Guidelines past its originally anticipated implementation in January 2016, and prompted PROP founder, Andrew Kolodny to complain, “Opening a docket will tack months on to the process [and also] increases the likelihood that the guideline may never be released. This is an enormous win for the opioid lobby (30)." Interestingly, Kolodny co-authored a subsequent article examining the role of pharma funding and support of the CDC Pain Guidelines, and found that “of the 158 organizations that commented on the CDC’s draft guidelines, approximately 80% supported them either with or without recommendations, including many that received funding from opioid manufacturers (31).”

The CDC Guidelines are Published, Despite Ongoing Concerns

Notwithstanding PROP-founder Kolodny’s fears that the guidelines “may never be released (30),” the CDC Pain Guidelines were published via MMWR on March 18, 2016 (4). While most pain experts generally felt that the Pain Guidelines would be useful for those prescribing opioids in primary care settings, many expressed concerns that the Guidelines could be misapplied and affect a much broader group of patients than intended. For example, AMA board chair-elect, Patrice Harris, said that while the AMA shared the goal of reducing harm from opioid abuse, it remained concerned “about the evidence base informing some of the recommendations, conflicts with existing state laws and product labeling, and possible unintended consequences” including insurance coverage limitations for non-pharmacotherapeutic options for chronic pain (30). Similarly, Bob Twillman, executive director of the AAPM, said the CDC guidance “leaves much to be desired,” particularly regarding the limitations on dose, duration of treatment and arbitrary dosing threshold (32, 32). “Our concern is that, based on experience when states have implemented similar guidelines, some clinicians will interpret these ‘soft limits’ and thresholds as absolute ceiling doses, and that people with pain will suffer needlessly as a result,” Twillman said (32).

On August 29, 2016, a group of scientists from the CDC itself expressed integrity concerns about the agency’s data and its “the current state of ethics,” noting that “[i]t appears that our mission is being influenced and shaped by outside parties and rogue interests (34),” without specifically identifying PROP as one of those forces. Calling themselves the “CDC Spider Group (CDC Scientists Preserving Integrity, Diligence and Ethics in Research),” they reached out to Carmen S. Villar, MSW Chief of Staff, Office of the Director for the CDC, plainly stating that CDC “data were clearly manipulated in irregular ways” for political purposes (34). In October 2016, an article echoed similar concerns regarding CDC’s manipulation of data in a variety of projects, again alleging that the CDC was being influenced by corporate and political interests in a way that compromised its data collection (34). Despite these warnings, the 2016 CDC Opioid Prescribing Guidelines were implemented as planned.

Unintended Harms and the Backlash Against Misapplication of the CDC Guidelines

Just two years later, yet another article authored by CDC scientists was published in April 2018, again calling into question the methodology used by CDC to estimate opioid overdose deaths (35). The authors alleged that the CDC traditional method for calculating opioid overdose deaths overestimated deaths due to prescription opioids because the CDC failed to account for the emergence of illegally-manufactured fentanyl (IMF) as a cause of overdoses in its methodology (35). The authors proposed a method that would exclude IMF-related deaths for a more accurate estimate of total opioid overdose deaths (35). Using its traditional method, the CDC “estimated 32,445 prescription opioid–involved deaths occur[ing] in 2016.” Using these authors’ proposed “more conservative method, 17,087 prescription opioid–involved deaths occurred in 2016.” The concerned scientists concluded that “obtaining an accurate count of the true burden and differentiating between prescription and illicit opioid-involved deaths [was] essential to implement and evaluate public health and public safety efforts (35).”

In addition to concerns about the accuracy of CDC’s overdose data, by 2018 it had become clear that misapplication of its Pain Guidelines had begun to contribute to deaths from “suicides within and outside of the Veterans Affairs Healthcare System in the United States” from forced or involuntary tapers off of opioid analgesics (36). Although the CDC had designed the Guidelines “as non-mandatory guidance for primary care physicians[,] legislators, pharmacy chains, insurers, and others [had] seized on certain parts of its dosage and supply recommendations and translated them into blanket limits in law[s] and mandatory policy (37).” These misapplications and unintended consequences prompted the passage of an AMA Resolution against ongoing, widespread misapplication of the CDC Pain Guidelines in November 2018 (38). Adopted by the AMA House of Delegates at its November 2018 Interim Meeting, the new AMA policy affirmed that:

    1) “Some patients with acute or chronic pain [may] benefit from taking opioid pain medications at doses greater than generally recommended in the CDC Guideline for Prescribing Opioids for Chronic Pain and that such care may be medically necessary and appropriate,”

    2) The “AMA advocate against misapplication of the CDC Guideline for Prescribing Opioids by pharmacists, health insurers, pharmacy benefit managers, legislatures, and governmental and private regulatory bodies in ways that prevent or limit patients’ medical access to opioid analgesia,” and,

    3) “No entity should use MME (morphine milligram equivalents) thresholds as anything more than guidance, and physicians should not be subject to professional discipline, loss of board certification, loss of clinical privileges, criminal prosecution, civil liability, or other penalties or practice limitations solely for prescribing opioids at a quantitative level above the MME thresholds found in the CDC Guideline for Prescribing Opioids (38).”

In the months after adoption of this AMA policy change, more clinical professionals and medical societies would actively seek to reverse the harms of the CDC Pain Guidelines’ misapplication.

In December 2018, a group of clinical leaders and international stakeholders in the pain management community signed an open letter calling for urgent action against forced tapering of opioids (36). On February 13, 2019, the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) sent a joint letter to Debra Dowell, Chef Medical Officer of the CDC Opioid Response Coordinating Unit, to follow up on a stakeholder meeting that was held on November 8, 2018, during which those professional organizations called for CDC “to address unintended implementation and reimbursement consequences that have been occurring in practice” because of the misapplication of CDC’s Pain Guidelines (39). On February 19, 2019, Dowell answered back in a letter that stated, “The Guideline is not intended to deny any patients who suffer from chronic pain from opioid therapy as an option for pain management (40).” She also wrote, “CDC encourages physicians to continue to use their clinical judgment and base treatment on what they know about their patients, including the use of opioids if determined to be the best course of treatment (40).” This response letter was embargoed for release until April 9, 2019 (40), to coincide with other anticipated press releases related to federal actions regarding misapplication of the Pain Guidelines (see below).

Similarly, on March 6, 2019, a group identified as Health Professionals for Patients in Pain (HP3) called upon “the CDC to follow through with its commitment to evaluate the impact by consulting directly with a wide range of patients and caregivers, and by engaging epidemiologic experts to investigate reported suicides, increases in illicit opioid use and, to the extent possible, expressions of suicidal ideation following involuntary opioid taper or discontinuation (41).” HP3 also urged “the CDC to issue a bold clarification about the 2016 Guideline – what it says and what it does not say, particularly on the matters of opioid taper and discontinuation (41).” The CDC responded on April 10, 2019, noting that “the Guideline does not endorse mandated or abrupt dose reduction or discontinuation, as these actions can result in patient harm (42).”

FDA Warning and CDC Clarification About the Pain Guidelines

FDA Warning Against Rapid Tapers
One day prior to the CDC response letter to HP3 (42), on April 9, 2019, the FDA posted a safety announcement warning against sudden discontinuation of opioid pain medications (43). In the announcement, the FDA noted that it had “received reports of serious harm in patients who are physically dependent on opioid pain medicines suddenly having these medicines discontinued or the dose rapidly decreased. These include serious withdrawal symptoms, uncontrolled pain, psychological distress, and suicide (43).” This information was also released via a special FDA podcast on 4/17/2019 (44).

CDC Warns Against Misapplication of its Pain Guidelines; PROP Gets Defensive

In view of the embargo for release of the CDC response to the NCCN-ASCO-ASH, which occurred on April 9, 2019 (40), and the CDC response to HP3 (42) on April 10, 2019, it seems likely that the FDA and CDC coordinated their communications to response to the Pain Guideline backlash. CDC then released another embargoed statement on April 24, 2019, in which it advised against the misapplication of its Guideline for Prescribing Opioids for Chronic Pain (45). More explicitly, CDC sought to raise “awareness about the following issues that could put patients at risk:

     - Misapplication of recommendations to populations outside of the Guideline’s scope.
     - Misapplication of the Guideline’s dosage recommendation that results in hard limits or ‘cutting off’ opioids.
     - The Guideline does not support abrupt tapering or sudden discontinuation of opioids.
     - Misapplication of the Guideline’s dosage recommendation to patients receiving or starting medication-assisted treatment for opioid use disorder (45).”

On the heels of this media release, the CDC referenced a companion article published in New England Journal of Medicine (NEJM), co-authored by PROP member and CDC Core Group member, Roger Chou, which was available online on April 24, 2019, and in print on June 13, 2019 (46). Those authors also admitted that “some policies and practices purportedly derived from the guideline have in fact been inconsistent with, and often go beyond, its recommendations (46).” But in contrast to the contrite note struck by the CDC media release, the NEJM article vigorously defended the Pain Guidelines, noting that “the medical and health policy communities [had] largely embraced its recommendations” and that “the guideline was rated as high quality by the ECRI Guidelines Trust Scorecard (46).” The NEJM article also dismissed allegations about the lack of transparency in the Guideline creation, noting that the CDC had “engaged clinicians, health systems leaders, payers, and other decision makers in discussions of the guideline’s intent and provided clinical tools, including a mobile application and training, to facilitate appropriate implementation (46).” Notably, the article ended with this disclaimer: “The views expressed in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (46).”

Undeclared Conflicts of Interest

Less than a month after the printed publication of the Chou’s NEJM article defending the Pain Guidelines, the US Department of Justice (DOJ) announced obtaining a record-setting $1.4 billion settlement against Reckitt Benckiser, the manufacturer of Suboxone, an opioid addiction treatment drug (47). For years, critics had alleged financial connections between PROP members and Reckitt Benckiser, with suspicions driven by comments by PROP’s Kolodny, who in 2005 - when asked about his financial relationship with the company - replied, “They are not a pharmaceutical company. They make Lysol (48)." In 2015, Reckitt Benckiser had spun off its Suboxone manufacturing to a subsidiary that it named Indivior (49), more commonly identified as its manufacturer currently. Additionally, in recorded testimony during government hearings, Kolodny had encouraged the use of Suboxone as a measure to combat the opioid crisis. In 2011, at a New York State Senate Hearing, then-PROP President Kolodny testified, ““If we want to see a decline in overdose deaths, you have to [sic] provide effective treatment for people who are opioid-addicted. And for this epidemic, that’s probably going to mean buprenorphine (50).” Likewise, during a US Senate Hearing in 2018, Kolodny testified, “The first-line treatment for opioid addiction is buprenorphine, also called ‘’Suboxone.’ Access to this treatment is not sufficient (51).”

Testimony from hearings encouraging the use of Suboxone and deflective comments, like Kolodny’s dismissal about his relationship with Reckitt Benckiser, were less suspicious as betraying conflicting interests before it was revealed that PROP members failed to disclose relevant conflicts of interest when authoring several articles printed in medical journals. Kolodny failed to disclose conflicts of interest pursuant to his executive directorship of PROP and provision of expert witness testimony in malpractice cases involving opioids when he published two articles in the Journal of the American Medical Association (JAMA) in October 2017 and April 2018 (52). Similarly, PROP President, Jane Ballantyne, failed to disclose her affiliation with PROP in an “Ideas and Opinions” article, co-authored with PROP members, Anna Lembke and Roger Chau, in Annals of Internal Medicine in 2019 (53, 54). Moreover, PROP’s Mark Sullivan failed to declare a conflict of interest regarding his work on a opioid tapering device, which occurred during his participation in the drafting of the CDC Pain Guidelines, until he was participating in a CDC-sponsored Clinical Outreach and Community Activity, after the Guidelines’ publication (55). More recently, the British Medical Journal (BMJ) updated a “Rapid Response” that accused the AMA of a pharmaceutical industry bias when creating opioid policy, written by several members of PROP, when it was revealed that one of the co-authors, PROP’s Sullivan, did not disclose his competing interest related to his work as an expert witness in cases in Maryland and Missouri (56).

Despite their collective tendency to under-report relevant conflicts of interest in publications, PROP members continued to place themselves successfully in key positions to enhance their ability to shape opioid policy. In early April 2020, the Agency for Healthcare Research and Quality (AHRQ) disclosed for the first time the identity of the authors of the controversial report, “Opioid Treatment for Chronic Pain,” which had concluded “opioids were no more effective in treating pain than nonopioid medication, and that long-term use of opioids increases the risk of abuse, addiction and overdose, especially at high doses (57).” The lead author of that report was revealed to be Roger Chou, a PROP member who has been described as “a vocal critic of opioid prescribing for years (58).” This revelation was especially concerning at the time, because CDC had announced its plans to review and possibly revise the 2016 CDC Pain Guidelines, which were co-authored by Chou, and because the AHRQ study had reaffirmed many of CDC’s still-disputed conclusions about opioid therapy (58).

CDC Begins a Reassessment of the 2016 CDC Pain Guidelines

Open Docket for Comments
On April 17, 2020, the CDC announced “the opening of a docket to obtain comment concerning perspectives on and experiences with pain and pain management, including but not limited to the benefits and harms of opioid use, from patients with acute or chronic pain, patients' family members and/or caregivers, and health care providers who care for patients with pain or conditions that can complicate pain management (59).” Eventually, it received 5,392 comments from patients, physicians, medical organizations, and other stakeholders with feedback about its 2016 Pain Guidelines (60).

The AAHPM did not mince words when commenting about its concerns of misapplication of the CDC Pain Guidelines: “The 2016 Guideline has been broadly misapplied, with devasting effect on patients and prescribers. Forced tapering of patients’ opioid prescriptions has been incentivized and/or mandated, violating ethical and evidentiary norms of medical practice. This has resulted in many patients’ medical deterioration, loss of care relationships, turning to illicit substances/alcohol, and suicidality. Swapping products and formulations to reduce opioid prescriptions where not medically necessary has also led to medical errors. At the same time, prescribers have faced professional discipline, loss of board certification, loss of clinical privileges, criminal prosecution, civil liability, or other penalties or practice limitations solely for prescribing opioids at a quantitative level above the morphine milligram equivalent (MME) thresholds included in the CDC Guideline (61).”

The AMA echoed these concerns, writing “It is clear that the CDC Guideline has harmed many patients—so much so that in 2019, the CDC authors and HHS issued long-overdue, but greatly appreciated, clarifications that states should not use the CDC Guideline to implement an arbitrary threshold (Italics mine, 62). It also noted that “the CDC Guideline has been misapplied as a hard policy threshold by states, health plans, pharmacy chains, and PBMs,” and that “these policies, moreover, have not withstood any meaningful evaluation or data analysis as to whether they have improved pain care or reduced opioid-related harms (62). There also are no data to suggest that payers have increased access to non-opioid pain care options. If one of the goals of the CDC Guideline was to increase access to non-opioid pain care, that has not been realized (62). Rather, there is evidence that payers continue to erect and support barriers to non-opioid pain care (62).” The AMA urged the CDC to rescind policies employed by “many health insurers, pharmacy chains, and PBMs” based on the concept of a hard MME threshold to avoid “harms done to patients as a result of inappropriate tapering or denials of care (62, 63).

In its comments, PROP conceded that reduced opioid prescribing was associated with downward trends in “prescription opioid related morbidity and mortality (64),” but did not acknowledge a concomitant, upward trend in total opioid-related morbidity and mortality from illicit drug, including illegally manufactured fentanyl. They further argued, “For some patients, continued opioid use is necessary not because it effectively manages the pain that prompted opioid prescribing initially, but because continued use averts the negative effects of opioid discontinuation (64),” a claim advocates for patients with chronic pain have labeled as a gaslighting strategy (65). Furthermore, as discussed later in the article, PROP also incorrectly predicted, “The downward trends in new starts of chronic opioid treatment achieved by the 2016 guideline should be seen as a positive development that will encourage people to find alternative means of controlling chronic pain, which though harder to employ than the prescription pad, will ultimately result in better outcomes and less distress (65).”

The BSC/NCIPC Workgroup
On July 6, 2020, the CDC announced the formation of a new Opioid Workgroup and the Board of Scientific Counselors, National Center for Injury Prevention and Control Centers for Disease Control and Prevention (The BSC/NCIPC Workgroup), which would “review the Opioid Workgroup’s report, discuss, deliberate, and provide advice and recommendations for CDC to consider as part of the potential update and/or expansion of the Guideline. The updated and/or expanded Guideline is anticipated to be released in 2022 (66).” This announcement was followed by the release of a PowerPoint Presentation entitled, “Update on the BSC/NCIPC Workgroup,” on July 22, 2020, which elaborated on the process of choosing the new Opioid Workgroup (67). An additional update from October 13, 2020, identified the membership of the Opioid Workgroup – NCIPC BSC Committee Members (68). The updated and/or expanded Pain Guideline was anticipated to be released in 2022 (66), but that timeframe was projected before the full impact of the COVID-19 Pandemic.

Increases in Overdose Deaths and CDC Data Flaws

The February 2021 MMWR Report

While the world anxiously awaited word on any new or revised CDC Pain Guidelines, on February 12, 2021, the MMWR Report (1) mentioned at the top of this commentary quickly captured the attention of those already hungry for news from the CDC, including patients with chronic pain and clinicians who manage that pain. In the setting of a 1,040% increase in “age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, heroin, and prescription opioids during 2013–2019 (1),” it seemed prudent to critically question PROP’s assertion that “The downward trends in new starts of chronic opioid treatment achieved by the 2016 guideline should be seen as a positive development that will encourage people to find alternative means of controlling chronic pain, which though harder to employ than the prescription pad, will ultimately result in better outcomes and less distress (64).”

On February 16, 2021, in what felt like an effort to draw attention away from the stark reality of the MMWR Report, PROP wrote a letter to AMA President, Susan R. Bailey, regarding “AMA’s Opposition to Dose & Duration Guidance for Opioid Prescribing (69),” based on AMA’s comments to Dr. Deborah Dowell in the CDC Open Docket (61). PROP concomitantly published this letter to the AMA as a “Rapid Response” to an article entitled, “UK recommendations on opioid stewardship (70, 71).” The letter alleged that AMA Opioid Policy was inappropriately influenced by donations from the pharmaceutical industry (69, 70). AMA President, Susan Bailey, quickly responded back to PROP, in a letter dated February 19, 2021, saying “With respect to the issue you raise in your letter, it might be helpful to point out that the CDC authors of the 2016 CDC Guideline themselves have recognized it has been misapplied (Italics mine; 72, 73).” Additionally, Bailey pointed out, “When policies or organizations focus only on the restriction of a legitimate pharmacologic option to help patients with pain, they miss the chance to address the complexity of policies needed to truly help patients with pain. That misguided focus also has led to harmful stigmatization and other stressors. That is why the AMA provided comprehensive recommendations on the 2016 CDC Guideline and why we continue to advocate for policies that support comprehensive, multidisciplinary, multimodal pain care, including opioid therapy when appropriate. If you choose to cite the AMA’s policies in the future, we encourage you to cite them in their entirety to ensure accurate context (72),” and Bailey provided the link for the AMA’s comments to Deborah Dowell to guide PROP when referencing AMA policy in the future (62).

Inaccurate CDC Data on Opioid Deaths

Just a few weeks later, PROP’s troubles worsened, with the publication of an article by John Peppin and John J. Coleman in Pain Therapy (74) that detailed fundamental methodological shortcomings in CDC’s data on prescription overdose deaths (35). The authors held that “CDC erroneously reported prescription opioid overdose deaths in 2016 and for more than a decade before (74)” in a way that overestimated overdose deaths due to prescribed opioids. They further assert that “the CDC ignored the problem until 2016 data showed serious inconsistencies with other, more reputable, data for prescribing volumes of opioids (74).” Furthermore, in “2018, the U.S. Congress mandated the CDC to ‘’modernize’’ its system for reporting drug overdose deaths but this has not yet occurred (74).” They concluded: “For more than a decade, millions of Americans were misled into believing that—as a White House report once characterized it— ‘opiate overdoses, once almost always due to heroin use, are now increasingly due to abuse of prescription painkillers.’ Little did they know or suspect that the CDC’s coding of prescription painkillers included non-prescribed illicitly manufactured fentanyl and fentanyl analogs and non-prescribed methadone administered or dispensed to patients being treated for opioid use disorder (74).”

This report again exposed PROP’s and CDC’s false narrative that overprescribing of opioid analgesics had driven the US overdose crisis (74). In a predictable response, Andrew Kolodny reacted quickly to soften the crushing blow and establish some semblance of plausible deniability for PROP’s culpability. On March 22, 2021, Kolodny produced a webinar during which he “refuted” several alleged “myths and false narratives” about the opioid crisis (75). This presentation was swiftly characterized as “a rambling dialogue by Kolodny that gaslighted pain sufferers, doctors, patient advocates and anyone else critical of the CDC guideline (76).” For example, in a clear example of a Straw Man Argument (77), Kolodny alleged a myth that the “CDC Guideline forced millions of patients off opioids resulting in an epidemic of suicides (75),” when in fact both the CDC and FDA had publicly acknowledged the potential harms of forced tapers, acknowledging that the extent of the harm was not yet known (Italics mine, 42-45). In response to legitimate concerns about harms from polices influenced by PROP’s advocacy, one of its individual members had responded with gaslighting (75), informal fallacies (77) and deflection, aimed apparently at creating plausible deniability for their contribution to those harms.

Conclusion

Despite being turned back from an effort to bluntly reduce opioid prescribing by the FDA in 2013 based on a lack of scientific evidence for its position (17,18), PROP has had a disproportionate effect on opioid policy in the Untied States for almost a decade. PROP found a willing federal regulatory partner in the CDC, and while PROP may not have “secretly written” the 2016 CDC Pain Guidelines (75), they certainly enjoyed disproportionate representation on CDC’s review panels and Core Expert Group (23-25) in a process that lacked transparency (22, 23, 26, 27). When the CDC admitted that its Pain Guideline had been widely misapplied (40) and joined the FDA in a call against forced opioid tapers (42, 43, 45), PROP doubled down on its rhetoric (46), dismissing legitimate concerns about potential harms in a performative manner (75) that encouraged their ongoing misapplication, while assailing PROP’s critics (76, 77). All of this has occurred as PROP members have repeatedly concealed relevant conflicts of interest, including key conflicts that should have been disclosed during the process of drafting the CDC Pain Guidelines (48-54).

Given this, at a minimum, PROP should no longer enjoy a prominent role in guiding future opioid policy in the United States. This is a particularly urgent concern, as Roger Chou has been linked to authorship of CDC’s New Pain Guidelines, which have not yet been released to the public (78). Chou’s involvement in yet another set of Guidelines and CDC’s recurrent lack of transparency (79) in identifying the new Guidelines’ authors should alarm all advocates who support access to pain medications for all patients with a medically legitimate indication for opioid therapy.

Beyond limiting PROP’s role in developing future, potentially harmful opioid policy, a reasonable individual would be justified in wondering to what extent PROP bears culpability for the harms that arose from misapplications of the 2016 CDC Pain Guidelines. In our country, civil suits – like class action lawsuits, for example – only require a preponderance of the evidence – that is something is “more likely than not” - as the burden of proof for liability. It is more likely than not that PROP’s efforts to affect opioid policy helped shape the CDC Guidelines, which CDC has admitted were misapplied harmfully (40). It is also more likely than not that PROP’s performative advocacy efforts contributed to misapplication of the CDC Guidelines. And it is more likely than not that widespread misapplication of the CDC Guidelines resulted in harms with attendant civil liability. This would expose PROP to civil liability with a potentially enormous settlement if a class action suit were to arise from those harmed by the misapplication of the CDC Guidelines. Perhaps that is why PROP member, Andrew Kolodny, and others have worked so hard recently to create plausibly deniability (75) in the wake of the damaging February 12, 2021, MMWR Report (2).

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Dr. Kollas is board certified in internal medicine and provides pallative and supportive care in Orlando, FL.. He first wrote about his personal experiences with chronic illness and pain in a 1997 article in the “On Being a Patient” series in Annals of Internal Medicine. You can find him on Twitter at @ChadDKollas.

To cite this article: Kollas C. Mandated PROP’s Disproportionate Influence on U.S. Opioid Policy: The Harms of Intended Consequences. Pallimed. May 2021. Available at: https://www.pallimed.org/2021/05/props-disproportionate-influence-on-us.html

Correction 5/4/2021: A date was incorrectly included in the original article as "April 9, 2021," which was incorrect. It was changed to the correct date of "April 9, 2019."

Addition 5/6/2021: A Twitter user was able to find the PDF link to Reference number 40. The reference was updated with this link.

Conflict of Interest (submitted upon publication, added here 5/4): Dr. Kollas had submitted a Conflict of Interest statement when submitting this article for publication. It was not originally included in error in the original article here due to editor error. You can find the conflict of interest statement here - https://twitter.com/ChadDKollas/status/1389616181762478080. We have a copy of the COI statement, if this link ever is removed or in error.

References

1. Mattson CL, et al. MMWR, February 12, 2021. 70(6):202-7 (or see https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7006-H.pdf).

2. See https://twitter.com/BethDarnall/status/1366901343642742784.

3. See https://twitter.com/ChadDKollas/status/1365661703191560192.

4. See the CDC Pain Guidelines at https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm.

5. See https://twitter.com/supportprop/status/1362043581544947712.

6. Old, JL. Fam Pract Manag. 2011 Nov-Dec;18(6):31-35 (or see https://www.aafp.org/fpm/2011/1100/p31.html.

7. Von Korff M, et al. Ann Intern Med. 2011 September 6; 155(5): 325–328; See https://www.acpjournals.org/doi/10.7326/0003-4819-155-5-201109060-00011?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed&.

8. PROP Petition to FDA, 2012, See https://www.citizen.org/wp-content/uploads/migration/2048.pdf.

9. See https://www.regulations.gov/document/FDA-2012-P-0818-0002.

10. See https://www.joepaduda.com/2012/08/14/responsible_opi/.

11. See food-and-drug-administration-follow-up-letter-to-relabeling-petition-clarification-of-asam-position-nbsp-september-13-2012.pdf.

12. Originally posted at http://updates.pain-topics.org/2012/08/group-petitions-fda-to-change-opioid.html, but that link is not operational; the article is currently referenced at https://painpolicy.wordpress.com/2012/08/03/why-the-fda-shouldnt-change-the-labeling-of-opioid-analgesics/.

13. Portenoy RK. Letter to Nirav R. Shah, MD, MPH, Commissioner, New York State Department of Health. August 16, 2012. (PDF copy available on request from this article’s author).

14. See https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwi8i4imqMzvAhU_TDABHQS7Cc4QFjAAegQIBRAD&url=https%3A%2F%2Fwww.asahq.org%2F-%2Fmedia%2Fsites%2Fasahq%2Ffiles%2Fpublic%2Fadvocacy%2Ffederal-activities%2Fregulatory-activities%2Fpain-medicine%2Fasa-letter-fda-prop-8-22-12.pdf%3Fla%3Den%26hash%3D09DC35AB25C0C8F30807578C2038EA0244B7D7C9&usg=AOvVaw1-eZoU2_-k4xbDsC4EYdjT.

15. Grabois M. Letter to Dockets Management Branch, Food and Drug Administration. August 12, 2012. (PDF copy available on request from this article’s author).

16. See https://www.acttion.org/static/docs/aps_letter.pdf; referenced at https://www.acttion.org/news/november-26-2013-american-pain-society-letter-to-fda-commissioner-hamburg-about-immpact-and-acttion).

17. See https://www.supportprop.org/wp-content/uploads/2014/12/FDA_CDER_Response_to_Physicians_for_Responsible_Opioid_Prescribing_Partial_Petition_Approval_and_Denial.pdf.

18. See http://www.fdalawblog.net/2013/09/fda-grants-prop-petition-in-part-proposes-new-labeling-and-requires-post-marketing-studies-for-erla/.

19. See http://www.supportprop.org/wp-content/uploads/2014/01/PROP_OpioidPrescribing.pdf.

20. See http://www.supportprop.org/wp-content/uploads/2014/12/PA_3_29_13_FSMB.pdf.

21. See https://www.cdc.gov/injury/pdfs/fundedprograms/Response_to_Constituent_Comment_CDC_Prescribing_Guideline.pdf.

22. Anson P. CDC Maintains Secrecy Over Opioid Guidelines. Pain News Network, September 18. 2015. See https://www.painnewsnetwork.org/stories/2015/9/18/cdc-maintains-secrecy-over-opioid-guidelines.

23. Anson P. Chronic Pain Groups Blast CDC for Opioid Guidelines. Pain News Network, September 22, 2015. See https://www.painnewsnetwork.org/stories/2015/9/22/chronic-pain-groups-blast-cdc-for-opioid-guidelines.

24. Anson P. Special Interest Groups Behind CDC Opioid Guidelines. Pain News Network, September 24, 2015. See https://www.painnewsnetwork.org/stories/2015/9/24/3xz1qq23yuilyeluz63kgwckplwh21.

25. Anson P. PROP Helped Draft the CDC Guidelines. Pain News Network, September 21, 2015. See https://www.painnewsnetwork.org/stories/2015/9/21/prop-helped-draft-cdc-opioid-guidelines.

26. Madara JL. Letter to Thomas Freiden, Director, Centers for Disease Control and Prevention. October 1, 2015. (PDF copy available on request from article’s author).

27. Patient Quality of Life Coalition. Letter to The Honorable Lamar Alexander, Chairman, Committee of Health, Education, Labor and Pensions, United States Senate. November 13, 2015. (PDF copy available on request from this article’s author).

28. See https://www.federalregister.gov/documents/2015/12/14/2015-31375/proposed-2016-guideline-for-prescribing-opioids-for-chronic-pain.

29. Samp R. CDC Bows To Demands For Transparency And Public Input On Draft Opioid-Prescribing Guidelines. Forbes, December 15, 2015. See http://www.forbes.com/sites/wlf/2015/12/15/cdc-bows-to-demands-for-transparency-and-public-input-on-draft-opioid-prescribing-guidelines/#36c587e1122a.

30. Norman B. POLITICO Pro: CDC opens opioid prescription guidelines to public comment. Politico, December 11, 2015. (PDF copy available on request from this article’s author).

31. Lin DH, et al. Financial Conflicts of Interest and the Centers for Disease Control and Prevention’s 2016 Guideline for Prescribing Opioids for Chronic Pain. JAMA Internal Medicine, March 2017; 177(3):427-8.

32. Fiore K. CDC Comes Down Hard on Opioids for Chronic Pain — Urges physicians not to use opioids first-line for chronic pain. MedPage Today, March 15, 2016. See https://www.medpagetoday.com/publichealthpolicy/publichealth/56745.

32. See http://blog.aapainmanage.org/academys-response-center-disease-controls-guideline-prescribing-opioids-chronic-pain/.

33. See https://usrtk.org/wp-content/uploads/2016/10/CDC_SPIDER_Letter-1.pdf.

34. Gillam C. The CDC is being influenced by corporate and political interests. The Hill, October 17, 2016. See https://thehill.com/blogs/pundits-blog/healthcare/301432-the-cdc-is-being-being-influenced-by-corporate-and-political .

35. Seth P, et al. Quantifying the Epidemic of Prescription Opioid Overdose Deaths. AJPH, April 2018; 108(4):500-2. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844400/pdf/AJPH.2017.304265.pdf.

36. Darnall BD, et al (including Kollas CD). International Stakeholder Community of Pain Experts and Leaders Call for an Urgent Action on Forced Opioid Tapering. Pain Medicine, 2018; 0:1-4. See https://pubmed.ncbi.nlm.nih.gov/30496540/.

37. Nicholson KM, Hoffman DE, Kollas CD. Overzealous use of the CDC’s opioid prescribing guideline is harming pain patients. Stat News, December 6, 2018. See https://www.statnews.com/2018/12/06/overzealous-use-cdc-opioid-prescribing-guideline/.

38. See Resolution 235 at https://www.ama-assn.org/system/files/2018-11/i18-refcomm-b-annotated.pdf.

39. Carlson RW, et al. Letter to Deborah Dowell, Chief Medical Officer, Opioid Response Coordinating Unit, CDC National Center for Injury Prevention and Control. February 13, 2019. See https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/documents/2019-NCCN-ASCO-ASH-Letter-CDC.pdf.

40. Dowell D. Centers for Disease Control and Prevention. Letter to NCCN, ASCO, ASH, February 28, 2019. https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/documents/2019-CDC-Opioid-Guideline-Clarification-Letter-to-ASCO-ASH-NCCN.pdf

41. Health Professionals for Patients in Pain (HP3), led by Alford DP (and including Kollas CD). Professionals Call on the CDC to Address Misapplication of its Guideline on Opioids for Chronic Pain through Public Clarification and Impact Evaluation. March 6, 2019. See https://healthprofessionalsforpatientsinpain.org/the-letter-1.

42. Centers for Disease Control and Prevention. Letter to Daniel P. Alford MD MPH, Professor of Medicine, Brown University Medical Campus. April 10, 2019. (PDF copy available on request from this article’s author).

43. FDA Drug Safety Communications. FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering. April 9, 2019. See https://www.fda.gov/media/122935/download.

44. FDA Drug Safety Podcast. FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering. April 17, 2019. See https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-identifies-harm-reported-sudden-discontinuation-opioid-pain-medicines-and-requires-label-changes#:~:text=On%20April%209%2C%202019%20FDA,%2C%20psychological%20distress%2C%20and%20suicide.

45. CDC Media Relations. CDC Advises Against Misapplication of the Guideline for Prescribing Opioids for Chronic Pain. Embargoed Until: Wednesday, April 24, 2019, 5 PM, EDT. See https://www.cdc.gov/media/releases/2019/s0424-advises-misapplication-guideline-prescribing-opioids.html.

46. Dowell D, Haegerich T, Chou R. No Safecuts to Safer Opioid Prescribing. N Engl J Med 2019; 380:2285-2287. https://www.nejm.org/doi/full/10.1056/NEJMp1904190.

47. Department of Justice, Office of Public Affairs. Justice Department Obtains $1.4 Billion from Reckitt Benckiser Group in Largest Recovery in a Case Concerning an Opioid Drug in United States History. July 11, 2019. See https://www.justice.gov/opa/pr/justice-department-obtains-14-billion-reckitt-benckiser-group-largest-recovery-case.

48. McGray D. The Bitter Pill. Wired, April 1, 2005. See https://www.wired.com/2005/04/bupe/.

49. See https://web.archive.org/web/20150329132943/http://www.rb.com/rb-complete-demerger-of-indivior.

50. See https://medium.com/@jmkillingworth/grandmas-on-smack-and-other-unsavory-tactics-from-prop-benefactor-reckitt-benckiser-group-fb5ee76a3ed5.

51. See https://www.govinfo.gov/content/pkg/CHRG-115shrg31264/pdf/CHRG-115shrg31264.pdf.

52. JAMA. 2019 Sep 4 : e1914523. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727681/?report=printable.

53. Chou R, et al. Rethinking Opioid Dose Tapering, Prescription Opioid Dependence, and Indications for Buprenorphine. Ann Internal Med, Sept 17, 2019;171(6):427-430. See https://www.acpjournals.org/doi/pdf/10.7326/M19-1488.

54. Anson P. PROP President Discloses Conflicts of Interest. Pain News Network, November 19, 2019. See https://www.painnewsnetwork.org/stories/2019/11/12/prop-president-discloses-conflicts.

55 See https://emergency.cdc.gov/coca/transcripts/2016/call-transcript-080316.asp.

56. Personal communication with Sharon Davies, Letter Editor, British Medical Journal. March 15, 2021, at 2:05 PM ET. (Copy of e-mail available on request from this article’s author).

57. Agency for Healthcare Research and Quality, US Department of Health and Human Services. Opioid Treatment for Chronic Pain. AHRQ Publication No. 20-EHC011, April 2020. See https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/opioids-chronic-pain.pdf.

58. Anson P. PROP Linked to New Federal Opioid Study. Pain News Network, April 20, 2020. https://www.painnewsnetwork.org/stories/tag/Roger+Chou

59. See https://www.regulations.gov/document/CDC-2020-0029-0001.

60. See https://www.regulations.gov/docket/CDC-2020-0029.

61. American Academy of Hospice & Palliative Medicine. Letter to Robert R. Redfield, MD, Director, Centers for Disease Control and Prevention. RE: Management of Acute and Chronic Pain: Request for Comment; Docket No. CDC–2020– 0029. June 16, 2020. (PDF copy available on request from this article’s author).

62. Madara JL. Letter to Deborah Dowell, MD, MPH. Chief Medical Officer, National Center for Injury Prevention and Control, U.S. Centers for Disease Control and Prevention. Re: Docket No. CDC-2020-0029. June 16, 2020. See https://searchlf.ama-assn.org/undefined/documentDownload?uri=%2Funstructured%2Fbinary%2Fletter%2FLETTERS%2F2020-6-16-Letter-to-Dowell-re-Opioid-Rx-Guideline.pdf.

63. AMA urges CDC to revise opioid prescribing guideline (Press Release). June 18, 2020. See https://www.ama-assn.org/press-center/press-releases/ama-urges-cdc-revise-opioid-prescribing-guideline.

64. Ballantyne JC et al. Letter to Robert R. Redfield, MD, Director, Centers for Disease Control and Prevention. Re: Docket No. CDC-2020-0029- Management of Acute and Chronic Pain. See http://www.supportprop.org/wp-content/uploads/2020/06/PROP-Comment-CDC-Docket-2020.pdf?fbclid=IwAR2SCNj6MTLhYml9TbthlEm8nfzXQpEQX4tmCGSKFAkptZk42p-OOsKZHZc.

65. Fudin J. Chronic Opioid Patients Speak Out Against PROP. PainDr, August 12, 2012. See https://paindr.com/chronic-opioid-patients-speak-out-against-prop/ in Comments.

66. See https://www.cdc.gov/injury/pdfs/bsc/OWG_Terms-of-Ref_FINAL-7-6-2020-r.pdf.

67. Ross M. Update on the BSC/NCIPC Opioid Workgroup Formation. Board of Scientific Counselors Meeting, July 22, 2020. See https://www.cdc.gov/injury/pdfs/bsc/Ross_OWG-Update-7-7-2020-508.pdf.

68. See https://www.cdc.gov/injury/pdfs/bsc/OWG-Roster-External-10-13-2020-FINAL-a.pdf.

69. Ballantyne JC, et al. Letter to Susan R. Bailey, MD, President, American Medical Association. RE: AMA’s Opposition to Dose & Duration Guidance for Opioid Prescribing. February 16, 2021. (PDF copy available on request from this article’s author).

70. Ballantyne JC, et al. Rapid Response: Letter from Physicians for Responsible Opioid Prescribing (PROP) to the American Medical Association (AMA) -- RE: AMA’s Opposition to Dose & Duration Guidance for Opioid Prescribing. BMJ 2021;372:m4901. See https://www.bmj.com/content/372/bmj.m4901/rr-1.

71. Levy N, et al. UK recommendations on opioid stewardship. BMJ 2021 Jan 5;372:m4901. See also https://pubmed.ncbi.nlm.nih.gov/33402365/.

72. Bailey SR. Letter to Physicians for Responsible Opioid Prescribing (PROP). February 19, 2021. https://static1.squarespace.com/static/54d50ceee4b05797b34869cf/t/6036d35738d4d95a0458ab65/1614205783776/AMA+letter+to+PROP.pdf.

73. Anson P. AMA Scolded for Seeking Changes in CDC Opioid Guideline. Pain Network News, February 17, 2021. See https://www.painnewsnetwork.org/stories/2021/2/17/prop-attacks-ama-for-seeking-changes-in-cdc-opioid-guideline-nbsp.

74. Pepin JF and Coleman JJ. CDC’s Efforts to Quantify Prescription Opioid Overdose Deaths Fall Short. Pain Ther 2021 Mar 24;1-14. Published online ahead of print on March 24, 2021. See https://pubmed.ncbi.nlm.nih.gov/33761120/ or https://link.springer.com/content/pdf/10.1007/s40122-021-00254-z.pdf.

75. See screen capture by Carrie Judy at https://twitter.com/life_is_art___/status/1374453671136616448/photo/1.

76. Anson P. Kolodny: Critics of CDC Opioid Guideline ‘Twisting the Facts’. Pain News Network, March 24, 2021. See https://www.painnewsnetwork.org/stories/2021/3/24/kolodny-critics-of-cdc-opioid-guideline-twisting-the-facts.

77. See, for example https://en.wikipedia.org/wiki/Straw_man.

78. Anson P. PROP Linked to New Federal Opioid Study. Pain News Network, April 20, 2020. See https://www.painnewsnetwork.org/stories/2020/4/20/prop-linked-to-new-federal-opioid-study.

79. Anson P. CDC Won’t Say Who is Writing Update of Opioid Guideline. Pain News Network, April 5, 2021. See https://www.painnewsnetwork.org/stories/2021/4/4/cdc-wont-say-who-is-writing-update-of-opioid-guideline.