Home » Featured Content » Research Practitioner » Lack of clinical data overshadows opioid prescribing guidelines

Lack of clinical data overshadows opioid prescribing guidelines

Sunday, May 1, 2016

On March 18, 2016, the Centers for Disease Control (CDC) in Atlanta released its guidelines for prescribing opioids for chronic pain in outpatient settings outside of active cancer treatment, palliative care, and end-of-life care. The results were instantly controversial. While no one argues that opioid addiction has become a health crisis, critics claim that a scarcity of clinical trial data undermine the guidelines and could even lead to patients being harmed.

The CDC defines chronic pain in the guidance as pain that lasts more than 3 months or past the time of normal tissue healing.1 The agency says that an estimated 20% of patients who go to the doctor complaining of noncancer pain symptoms or pain-related diagnoses receive a prescription for an opioid pain medication. These prescriptions per capita have increased 7.3% from 2007 to 2012, the CDC says, resulting in health care providers writing 259 million prescriptions for opioid pain medication in 2012. The increase in the prescriptions has been accompanied by an increase in opioid overdose and opioid use disorder. The CDC says primary care doctors have reported concerns about opioid pain medication misuse. The doctors say they find managing patients with chronic pain “stressful,” they worry about patients becoming addicted to the medication, and they often feel they have had insufficient training in prescribing opioids.1 “These attitudes and beliefs, combined with increasing trends in opioid-related overdose, underscore the need for better clinician guidance on opioid prescribing,” the CDC says in the guidelines. “Clinical practice guidelines focused on prescribing can improve clinician knowledge, change prescribing practices, and ultimately benefit patient health.”

Details of the guidance

In the guidance, the CDC has 12 recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care. These recommendations are grouped into three areas for consideration, the CDC says:

  • Determining when to initiate or continue opioids for chronic pain.
  • Opioid selection, dosage, duration, follow-up, and discontinuation.
  • Assessing risk and addressing harms of opioid use.

Each recommendation is followed by a rationale for the recommendation, with considerations for implementation noted.1

Listed first in the recommendations is that nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. “Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate,” the guidance says. The complete recommendations are listed in Table 1.

Lack of clinical data

Even before the guidance was released, stakeholders were expressing concern that guidelines were being developed for areas with little clinical data to analyze. “As articulated in both our original letter to you and the post-meeting communication, the discovery that CDC was engaged in developing opioid prescribing guidelines has been a topic of great curiosity,” wrote 13 organizations in a letter to Sylvia Mathews Burwell, Secretary of the U.S. Department of Health and Human Services.2 The letter, dated September 8, 2015, had signers including the American Cancer Society and the American Academy of Pain Management. “How the guidelines were being developed, by whom, and what they would address given the woefully inadequate body of clinical evidence supporting prescribing decisions, has not been transparent to our stakeholder community. Since CDC has traditionally not involved itself in developing and disseminating medication-prescribing guidelines, these process questions have become less a curiosity and more a concern.”

A Special Communication that evaluated the guidance was published in the Journal of the American Medical Association on April 19, 2016.3 Under the heading of “evidence synthesis,” the authors say that evidence consisted of observational studies or randomized clinical trials “with notable limitations, characterized as low quality using GRADE [Grading of Recommendations, Assessment, Development and Evaluation] methodology. Meta-analysis was not attempted due to the limited number of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of studies. No study evaluated long-term (≥ 1 year) benefit of opioids for chronic pain.”3

On October 1, 2015, the American Cancer Society Cancer Action Network (ACS CAN) wrote a letter to the CDC expressing serious concern about then-proposed guidelines. First, the guidelines could have the potential to significantly limit cancer patient access to needed pain medicines, the network writes.4 ACS CAN also had concerns about the lack of evidence on which the “guidelines were based, the methodology used to develop the guidelines, and the transparency of the entire process.” Because of these concerns, ACS CAN said it cannot endorse the proposed guidelines in any way and suggested suspending the process until the methodology flaws are corrected.4

In more detail, ACS CAN said the GRADE framework is widely used for producing evidence-based recommendations. ACS CAN said the CDC appears to have “deviated significantly from the established methodology, calling into question the integrity and validity of the ensuing recommendations.”4 For example, seven of the 12 recommendations were  “very low quality evidence,” and five of the 12 were based on “low quality evidence,” yet six of the seven recommendations with evidence rated “very low” and all of the recommendations with “low” evidence ratings were designated as “strong” recommendations. “The GRADE process ordinarily permits this discordance only in exceptional circumstances, and this stark departure from GRADE methodology was done without associated justification. The rationale statements appeared to rely heavily on expert opinion, but this was not explicitly acknowledged,” ACS CAN says.

Boston’s National Public Radio news station WBUR asked for the CDC to respond to these statements. An unnamed CDC spokesperson responded in an email, “Clinical guidelines are always based on best available evidence, including low-quality evidence. This does not mean ‘bad’ evidence, it means that not enough randomized controlled trials were conducted.”5

When the final CDC guidance was released in March, ACS CAN issued a stern statement. “We are disappointed that the CDC guideline released today did not address our previously stated concern about needed access to opioid analgesics for cancer survivors who experience severe pain that limits their quality of life.”6

A look at long-term opioid therapy

A study first published online in January 2015 on the website of the Annals of Internal Medicine aimed to evaluate evidence on the effectiveness and harms of long-term (> 3 months) opioid therapy for chronic pain in adults. They planned to focus on randomized trials and observational studies that involved “adults with chronic pain who were prescribed long-term opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies.”7 The researchers identified no studies of long-term opioid therapy for chronic pain versus no opioid therapy or nonopioid therapies that evaluated effects on pain, function, or quality of life at 1 year or longer. Most placebo-controlled, randomized trials were shorter than 6 weeks, and almost all were shorter than 16 weeks.7

The review had limitations, such as the researchers excluding non-English-language articles and they did not attempt meta-analysis. Despite these and other limitations, the evaluation was remarkable in that it identified no unpublished randomized trials that met its inclusion criteria.

“[T]he lack of scientific evidence on effectiveness and harms of long-term opioid therapy for chronic pain is clear and is in striking contrast to its widespread use for this condition and the large increase in prescription opioid–related overdoses,” the authors write.7 “Although it has been asserted that long-term opioid therapy may be more appropriate for certain types of pain problems or for patients assessed as being at lower risk for overdose or misuse, there was insufficient evidence (as detailed in the full report) to determine how benefits and harms vary in patient subgroups defined by demographic, pain, or other clinical characteristics. Studies generally restricted inclusion to persons with noncancer pain or were excluded because it was not possible to determine whether patients with cancer were at the end of life.”

Well-designed studies are urgently needed to address the key questions of this review, the authors continue. “Randomized trials evaluating benefits and harms of long-term opioid therapy are challenging to conduct, but more flexible, large pragmatic studies or well-designed controlled observational studies, with assessment of and control for potential confounders, could advance scientific knowledge in this area. Studies that include patients who are potentially at higher risk for adverse outcomes are needed because such patients are commonly prescribed long-term opioid therapy. Additional research is needed to develop and validate accurate risk prediction instruments and to determine how using them and other risk mitigation strategies affect patient outcomes. More research is needed on the comparative benefits and harms of different opioids, formulations, and dosing protocols and on comparative benefits and harms of long-term opioid therapy in patient subgroups characterized by type of pain problem and other potentially important characteristics. Greater standardization of methods for defining and identifying abuse-related outcomes is also needed.”7

The authors’ conclusion mirror what critics have said about the CDC guidance: “In summary, reliable conclusions about the effectiveness of long-term opioid therapy for chronic pain are not possible due to the paucity of research to date. Accumulating evidence supports the increased risk for serious harms associated with long-term opioid therapy, including overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction; for some harms, the risk seems to be dose-dependent. Research is needed to understand long-term patient outcomes, the risks for opioid abuse and related problems, and the effects of different opioid prescription methods and risk mitigation strategies.”7


  1. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. Centers for Disease Control Docket ID CDC-2015-0112. Posted March 23, 2016. Available at https://www.regulations.gov/#!docketDetail;D=CDC-2015-0112.
  2. Controversial CDC Opioid Guidelines – ICA Responds. Interstitial Cystitis Association website. Available at http://www.ichelp.org/controversial-cdc-opioid-guidelines-ica-responds/#sthash.WOFyQdiI.dpuf. Accessed April 30, 2016.
  3. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. JAMA 2016;315:1624-1645.
  4. Comment letter about the Centers for Disease Control and Prevention’s (CDC’s) Draft Guideline for Prescribing Opioids for Chronic Pain, 2016. American Cancer Society Cancer Action Network October 1, 2015 Available athttp://www.acscan.org/content/wp-content/uploads/2015/10/ACSCAN_Comments_CDC_Opioid_Guidelines_Final.pdf. Accessed April 30, 2016.
  5. Foreman J. Analysis: Controversy Over CDC’s Proposed Opioid Prescribing Guidelines. Wbur’s Common Health Reform and Reality January 9, 2016 Available at http://commonhealth.wbur.org/2016/01/analysis-controversy-over-cdcs-proposed-opioid-prescribing-guidelines. Accessed April 30, 2016.Hansen C.
  6. Final CDC opioid prescribing guideline could have unintended consequences for cancer survivors living with chronic pain. American Cancer Society Cancer Action Network March 15,2016 Available at http://www.acscan.org/content/media-center/final-cdc-opioid-prescribing-guideline-could-have-unintended-consequences-for-cancer-survivors-living-with-chronic-pain/. Accessed April 30, 2016.
  7. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: A system review for a National Institutes of Health Pathways to Prevention Workshop Ann Intern Med 2015;162:276-286.


By Sue Coons, MA

This article was reprinted from Research Practitioner, Volume 17, Number 2, May-June 2016.

Looking for more news, check out the new FREE CenterWatch Weekly!

The new FREE CenterWatch Weekly is your source of critical news, emerging trends, and business issues around everything in the rapidly changing clinical research marketplace. Check out our new CWWeekly page! Sign up today for your free email newsletter, update your bookmarks and check us out regularly! We look forward to bringing you the best news and information about clinical research in 2018!