Opioids on Trial – Part 2

This past week the U.S. Food and Drug Administration (FDA) held a hearing titled “Impact of Approved Drug Labeling on Chronic Opioid Therapy.” Ostensibly, the purpose was to obtain testimony on issues pertaining to the safe use of opioid drugs in treating chronic pain, but unofficially the meeting was a response to a petition last summer from PROP, or Physicians for Responsible Opioid Prescribing, requesting changes to the labeling of opioid analgesics. As much as anything, it seems that these pain relievers are on trial and the outcome judgments could severely impact the fates of all persons with pain in the United States and other parts of the world.

FDA Information Gathering

The public hearing on February 7-8, 2013, hosted by the FDA in Bethesda, Maryland, had the stated purpose of obtaining “information, particularly scientific evidence, such as study data or peer-reviewed analyses, on issues pertaining to the use of opioid drugs in the treatment of chronic pain. These issues include: diagnosis and understanding of patient pain, understanding and adhering to the labels of pain-treating products, limiting opioid prescriptions and use, and abuse and misuse of opioid medicines.”

It is widely assumed that the hearing was motivated by a citizen petition to the FDA last summer by PROP and the advocacy group, Public Citizen. What is generally referred to as the “PROP petition” has sparked heated debates among healthcare professionals and considerable fear among patients with pain.

The petition requests 3 changes by the FDA to opioid-product labeling: (1) strike the term “moderate” from the indication of opioid analgesics for noncancer pain (leaving “severe pain” as the only indication); (2) add a maximum daily opioid dose, equivalent to 100 milligrams of morphine for noncancer pain; and (3) add a maximum duration of 90 days for continuous (daily) opioid use for noncancer pain.

In response to the PROP petition, which had been posted at the U.S. Government Regulations website, there were 1,740 comments submitted as of February 5, 2013 (of which 688 were posted for public viewing). In fact, further comments may still be submitted by any interested persons to the docket (#FDA-2012-P-0818) until April 8, 2013 [access here].

The recent 2-day hearing was conducted by a 5-member panel of FDA officials under the leadership of Douglas Throckmorton, MD, deputy director of the FDA’s Center for Drug Evaluation and Research (CDER). The agenda listed 55 speakers who had registered in advance — anyone could request a time slot — and each was afforded 7 minutes for a presentation.

The FDA had stated that the hearing would be informal and the rules of evidence did not apply. Curiously, a number of speakers submitted audiovisual presentations of their testimony and were not physically present at the meeting, which was not stated as being permissible in the official notice of the hearing.

One presenter, a concerned parent, gave his own presentation and then also filled-in for several other parents who had time slots but did not appear at the meeting. During an open comment period at the end, two additional persons came forward. So, the FDA exhibited considerable flexibility in conducting the hearing and, surprisingly, few presentations required the full 7 minutes and the meetings ended early on both days. The agenda and webcast archives of the hearing presentations are available for viewing [here].

Opioids on Trial: Who has the Onus Probandi?

During the 2 days of testimony, there were fervent claims and pleas by patients, family members, advocates, healthcare providers, and researchers on both sides — for and against the PROP petition. It was obvious that this is a highly polarizing issue, with vastly different perspectives on the problems and disparate interpretations of the available scientific evidence.

Excellent first-hand observations and commentary regarding specific presentations on days 1 and 2 are available from Jeffrey Fudin, PharmD [here] and [here], and Kristina Fiore of MedPageToday [here] and [here].

All of the speakers expressed concerns about the problems of prescription opioid misuse, abuse, addiction, overdose, and deaths. Whether or not the changes requested in the PROP petition would resolve those problems, while assuring that persons with pain would still have access to much needed medication, was hotly contested.

Foremost among the more science-oriented presentations were disagreements over current best evidence for arriving at judgments regarding the necessity and validity of the recommended labeling changes. Along these lines, parallels of law and medicine, particularly when it comes to assessing evidence as proof in arriving at sound judgments affecting patient care, were discussed in a prior UPDATE [here].

In law, the burden of proof (onus probandi in Latin) refers to the obligation of a plaintiff or petitioner initiating an action or complaint to present evidence establishing their allegations or pleading at trial or a formal proceeding. This is adjudicated by a “trier of fact,” which may be a judge, jury, board of inquiry, or a select panel.

As for the PROP petition, the FDA is the trier of fact and the burden of proof rests foremost with the petitioners. There is no “defendant” in such cases, although, as noted above, it does seem here that opioids as a class of drugs have been put on trial. Also, there often is no “respondent” in petition cases, but a broad cross-section of advocates, healthcare providers, and concerned organizations came forward at the hearing (as well as in many submission to the docket) to contest the PROP petition.

A critical question is: Does the PROP petition satisfy the necessary onus probandi; that is, presenting sufficient evidence of adequate quality to serve as an acceptable level of proof favoring their requested opioid labeling changes?

The PROP petition initiative — led by Andrew Kolodny, MD, who is president of the organization — has been discussed and dissected in a previous UPDATE article [here] and Kolodny responded in a separate UPDATE [here]. The petition letter includes 9 points of evidence, which were critiqued in a Pain-Topics UPDATE by Bob Twillman, PhD [here].

Furthermore, the petition letter references 20 documents as evidence in support of the cosigners’ claims, and those citations are listed in Appendix A (see below). Most of that same evidence was referred to at the FDA hearing by various proponents of the petition in their presentations.

Much of the evidence has been critiqued in past UPDATES articles (as indicated after the respective citations below with links) and, for the most part, the evidence is of low-quality and questionable reliability or validity. Several of the evidence documents are secondary sources featuring the commentary or opinions of the respective authors or agencies, which probably would be considered in formal proceedings as being only hearsay evidence.

One recently-reported research study, introduced as evidence at the FDA hearing but not included in the petition itself, was a data-mining investigation from Canada that found an association of opioid analgesic dose and the risk of injurious automobile crashes among drivers taking those medications. However, as described in an UPDATE [here], there were significant limitations and biases in this study, and it provided only weak evidence that was largely unsupportive of the claimed increased risks of opioid therapy.

More could be said about some of the evidence cited in the petition that has not been previously critiqued in Pain-Topics UPDATES. As it is, PROP members no doubt would disagree with our unfavorable assessments of their evidence; however, the onus probandi is on them to demonstrate why and how their evidence is reliable and valid. Merely reiterating results and quoting data from government reports or articles in peer reviewed journals — with an assumption that those documents represent a suitable quality of evidence and should be uncritically accepted by the FDA and others as such — is presumptuous.

At best, the petition and its associated evidence raises “reasonable suspicion” that changes in opioid prescribing practices for chronic pain may be warranted, and some of the evidence suggests “probable cause” for further investigation. However, strictly from an evidence-based medicine perspective, the petition overall does not make a “clear and convincing” case to satisfy the burden of proof for accepting the requested labeling changes.

More Evidence to Consider

An important argument put forth by the PROP group — in their petition letter and in commentary at the FDA hearing — is that there is a lack of evidence supporting a favorable benefit-to-risk ratio for long-term opioid therapy in chronic noncancer pain. Similarly, one presenter at the hearing suggested that there is a lack of evidence that patients would suffer if there were less prescribing of opioids for chronic pain.

We have argued in various UPDATES that “an absence of evidence is not itself evidence” and that, if anything, further research is needed before passing judgment. However, we were wrong. There actually is much further research evidence available for consideration; but, of course, this was not included in the PROP petition or during the FDA hearing.

The 25 documents listed in Appendix B (below) present studies that examine opioid therapy of longer duration than the 90-day limit in the PROP petition. Many of the studies are prospective, randomized, controlled clinical trials of potentially reasonable quality. Various types of moderate-to-severe chronic noncancer pain are examined, using different opioid agents, and at widely-ranging doses.

Notices of these research studies have been variously submitted to the FDA docket and they merit closer examination and assessment from quality-of-evidence perspectives. Each has its limitations; however, at a minimum the studies generally suggest there is “some credible evidence” (as a level of proof) that at least subsets of patients with moderate or severe chronic noncancer pain may benefit from opioid analgesia during many months of treatment. And, these patients may experience prolonged significant pain relief with tolerable side effects, improvements in important quality of life measures, and modest needs for dose escalations, if any, over time.

The studies listed in Appendix B are probably not inclusive of all that may be available, and there is a need for more thorough systematic reviews and data meta-analyses of all the evidence. Several observations are worth noting…

1. In many of the studies, there often are sizable numbers of patients discontinuing opioid therapy. However, this seems to be a proverbial question of “is the glass half empty or half full?” During the FDA hearing, one presenter pointed to discontinuation rates as evidence of opioid inefficacy and adverse effects. Meanwhile, another speaker, looking at the same type of data, was impressed by the significant proportions of patients who do continue long-term on opioid therapy and find it of benefit for chronic noncancer pain. Same data — very different perspectives and interpretations.
   
   
2. While there have been anecdotal claims and small cases series of select patients with chronic pain who actually improve after discontinuation of long-term opioid therapy, there do not appear to be good quality studies involving substantial numbers of patients that broadly support this contention.
   
   
3. Also, there do not appear to be high-quality studies of extremely long-term opioid therapy for chronic noncancer pain, largely due to problems with followup over so many years. Yet, in 2010, there was a reported case series of 100 patients (ages 30-85 years, 61% male) who had been taking opioid medications for 10 to 35 years for a variety of noncancer pain conditions [see UPDATE here]. All had benefitted from this therapy and achieved better quality of life. Dosing in most patients remained stable during long periods of time and adverse effects were readily manageable medically. It must be conceded, however, that case series such as this are low-quality evidence, and further research is needed.

Challenges Ahead for FDA

It seems uncertain just how the FDA will proceed, but they no doubt face a daunting challenge ahead. As the trier of fact and adjudicating body the FDA must distinguish fact from hearsay opinion, separate science from pseudoscience, and distinguish poor-quality evidence from the good.

Clearly — based on the 2 days of hearings, the many submissions to the petition docket, and the abundance of other evidence — the problems surrounding opioid analgesics are serious, complex, and multifaceted. Action is needed, but there is great potential for doing harm rather than good.

The PROP petition has raised many important questions for consideration, along with some confusion and apprehension. In clarification of the petition’s intent, Kolodny suggested during the FDA hearing that the purpose is to prohibit drug companies from promoting long-term use of their opioid products for conditions where use has not been proven safe and effective. He stipulated that the petitioners are not claiming that long-term use of opioids for chronic pain or higher-dose opioids are always inappropriate, for all patients.

Furthermore, he affirmed that if the labeling changes are approved, practitioners still would be able to prescribe opioids “off-label” for any type of pain, at necessary doses, and for adequate periods of time. In fact, Kolodny suggested that “off-label” prescribing is often considered appropriate medical practice and even necessary in some cases, and that insurance carriers usually recognize this as such.

At the same time, others during the FDA hearing expressed concerns about the prudence of such practices. There were observations that off-label prescribing is discouraged in current medical education, and it would be a deterrent to conscientious practitioners who strive to rigorously adhere to rules as well as to those concerned about regulatory compliance and liability. And, off-label prescribing might be used by insurance carriers as justification for denying payment; an example of this already happening based merely on evidence in the unapproved petition was noted by one speaker.

Still, it seems that off-label opioid prescribing is the solution proposed by PROP for assuring adequate opioid availability for patients with chronic pain. Given that, an important question is: If the FDA were to approve the requested labeling changes in the PROP petition, would this also be a tacit and de facto endorsement by the FDA of off-label prescribing for meeting individual patient needs?

Rational, Balanced Solutions are Needed

A decision to accept or reject the PROP petition will leave one side or the other dissatisfied. However, the FDA may be in a position to propose balanced and rational compromise solutions that will address the important issues raised by the petition and help to assuage at least some of the current problems associated with opioid prescribing. For example,

• It seems evident from the various presentations at the FDA hearing that more evidence-based understandings are needed regarding the concepts of opioid tolerance, hyperalgesia, withdrawal, dependence, addiction, drug interactions, and the pharmacogenomics of metabolism in different patients. Also, distinctions between cancer and noncancer pain, as well as moderate and severe pain need better clarification. The FDA could exert a leadership role in gathering the research and expert opinion necessary to further our understandings of those issues as they relate to safe and effective opioid prescribing for chronic pain.
  
  
• Rather than changing labeling, the FDA does have the mechanism of “black box warnings,” which can be added to product information as necessary to highlight areas of particular concern, such as the need for prudent patient selection and monitoring, the necessity of periodic reevaluation for analgesic effectiveness and safety, and other concerns brought forward during the hearing and in comments to the docket. It seems that healthcare providers do attend to such warnings, even when they are less familiar with subtleties of product indications and many other details in the labeling. 
  
  
• Certainly, more and better prescriber education is needed, and the FDA mandated Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioid analgesics, as well as for select other opioid products, were an important step in that direction. Education programs and other actions associated with the REMS are just beginning to go into effect, so their impact is still undetermined. If necessary, the FDA has reserved the right to strengthen those efforts and, as many in the pain field have requested all along, the REMS could be extended to all opioid analgesics whether long- or short-acting.
  
  
• Patient and public education on opioid safety are clearly inadequate, and effective approaches for minimizing fatal overdose risks are being neglected. FDA REMS initiatives stress the importance of patient education as a component of due diligence, but this often appears to be a secondary objective. Meanwhile, assertive and effective community-based programs like Project Lazarus [discussed in UPDATE here] have not gained nationwide traction, our own dedicated educational website for patients and caregivers — Opioids911-Safety [here] — has been underutilized, and the widespread distribution of the overdose antidote, naloxone, has been considered by the FDA and other government agencies, but has been languishing for unknown reasons.

These are but several possibilities for constructive action; others could no doubt be added to the list. Rather than adamantly pursuing their label-changing agenda, it might be more practical and beneficial if the PROP group were to partner with the FDA and the rest of the pain community to (a) gather better research evidence and objectively evaluate it, (b) develop appropriate protocols for identifying patients who would or would not benefit from opioid therapy for chronic pain, and (c) strengthen existing educational efforts and develop new programs as necessary.

As one speaker suggested during the FDA hearing, heading off in the wrong direction at this time could result in millions of patients getting hurt. And, that is not what PROP members or anyone else wants to happen.

As always… reader comments are welcomed.

 

APPENDIX A
Evidence cited in the PROP petition to the FDA, July 25, 2012 (alphabetical sort):

· Agency Medical Directors’ Group. Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain. Washington State Agency Medical Directors’ Group: 2010 [available here; to a significant extent, this document relies on studies below as evidence for its recommendations].

· Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-1321 [critiqued in UPDATE here].

· Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. J Addict Dis. 2011;30:185-194 [critiqued in UPDATE here].

· Boscarino JA, Rutstalis M, Hoffman SN, et al. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. Addiction. 2010; 105:1776-1782 [discussed in UPDATE here].

· Braden JB, Russo J, Fan MY, et al. Emergency department visits among recipients of chronic opioid therapy. Arch Intern Med. 2010;170:1425-32.

· Centers for Disease Control and Prevention (CDC). Poison Issue Brief: Unintentional Drug Poisoning in the United States, 2007 [available here].

· Centers for Disease Control and Prevention (CDC). Vital signs: overdoses of prescription opioid pain relievers — United States, 1999-2008. Morbidity and Mortality Weekly Report. 2011(Nov 1); 60:1-6 [critiqued in UPDATE here].

· Chou R, Fanciullo GJ, Fine PG, et al. American Pain Society – American Academy of Pain Medicine (APS/AAPM) Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain. 2009; 10:113-130 [critiqued in Pain-Topics e-Briefing here].

· Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Annals of Internal Medicine. 2010;152:85-92 [critiqued in UPDATE here].

· Edlund MJ, Fan MY, DeVries A, Braden JB, Martin BC, Sullivan MD. Trends in use of opioids for chronic non-cancer pain among individuals with mental health and substance use disorders: the TROUP Study. Clin J Pain 2010;26:1-8.

· Eriksen J, Sjogren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on opioids in chronic non-cancer pain. An epidemiological study. Pain. 2006;125:172-9.

· Gomes T, Mamdani MM, Dhalla IA, et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171: 686–691 [critiqued in UPDATE here].

· Hamburg MA. Innovation, regulation, and the FDA. N Engl J Med. 2010;363:2228-2232.

· Martin BC, Fan MY, Edlund MJ, Devries A, Braden JB, Sullivan MD. Long-term chronic opioid therapy discontinuation rates from the TROUP study. J Gen Intern Med. 2011;26(12):1450-1457.

· Paone D, Dowell D, Heller D. Preventing misuse of prescription opioid drugs. City Health Information. 2011;30(4):23-30 [available here].

· Saunders KW, Dunn KM, Merrill JO, et al. Relationship of opioid use and dosage levels to fractures in older chronic pain patients. J Gen Intern Med. 2010;25:310-315 [critiqued in UPDATE here].

· Suffolk County Supreme Court Special Grand Jury. Grand Jury Report: CPL 190.85(1)(C): April 2012 [available here].

· Sullivan MD, Von Korff M, Banta-Green C, Merrill JO, Saunders K. Problems and concerns of patients receiving chronic opioid therapy for chronic non-cancer pain. Pain. 2010 May;149(2):345-53.

· U.S. General Accounting Office: Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the Problem (GAO-04–110), Washington, DC, U.S. General Accounting Office, 2004.

· Van Zee A. The promotion and marketing of OxyContin: commercial triumph, public health tragedy. Am J Public Health. 2009;99:221–227.

 

APPENDIX B
Trials of longer-term opioid therapy (>90 days), with various agents at varying doses for moderate and/or severe chronic noncancer pain.

· Allan L, Richarz U, Simpson K, Slappendel R. Transdermal fentanyl versus sustained release oral morphine in strong-opioid naive patients with chronic low back pain. Spine. 2005;30(22):2484-2490. [Duration: 13 months.]

· Bettoni L. Transdermal fentanyl in rheumatology: two years' efficacy and safety in the treatment of chronic pain. Recenti Progressi in Medicina. 2006;97(6):308-310. [Duration: 2 years.]

· Breivik H, Ljosaa TM, Stengaard-Pedersen K, et al. A 6-month, randomized, placebo controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids. Scand J Pain. 2010;1(3):122-141. [Duration: 6 months.]

· Caldwell JR, Rapoport RJ, Davis JC, et al. Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage. 2002;23(4):278-291. [Duration: 30 weeks.]

· Collado F, Torres LM. Association of transdermal fentanyl and oral transmucosal fentanyl citrate in the treatment of opioid naive patients with severe chronic noncancer pain. J Opioid Manag. 2008;4(2):111-115. [Duration: 6 months.]

· Devulder J, Richarz U, Nataraja SH. Impact of long-term use of opioids on quality of life in patients with chronic, non-malignant pain. Curr Med Res Opin. 2005(Oct);21(10):1555-1568.

· Fredheim OM, Kaasa S, Dale 0, Klepstad P, Landro Nl, Borchgrevink PC. Opioid switching from oral slow release morphine to oral methadone may improve pain control in chronic non-malignant pain: a nine-month follow-up study. Palliat Med. 2006;20(1):35-41. [Duration: 9 months.]

· Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ. 2006 May 23;174(11):1589-1594. [41 RCTs, but most were short-term and data were not suitable for meta-analysis in all trials.]

· Kalso E, Edwards JE, Moore RA, Mc-Quay HJ. Opioids in chronic non-cancer pain: Systematic review of efficacy and safety. Pain. 2004; 112:372-380. [15 trials examined, 6 with duration up to 24 months.]

· Manchikanti L, Ailinani H, Koyyalagunta D, et al. A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Physician. 2011;14(2):91-121. [Rigorous review, but included few studies with longer-term followup.]

· Martell BA, O’Connor PG, Kerns RD, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med. 2007:146(2):116-127. [38 studies, some up to 16 weeks, mostly low-quality evidence.]

· Mcilwain H, Ahdieh H. Safety, tolerability, and effectiveness of oxymorphone extended release for moderate to severe osteoarthritis pain: a one-year study. Am J Ther. 2005;12(2):106-112. [Duration 12 months.]

· Milligan K, Lanteri-Minet M, Borchert K, et al. Evaluation of long-term efficacy and safety of trans dermal fentanyl in the treatment of chronic noncancer pain.J Pain. 2001;2( 4):197-204. [Duration: up to 12 months.]

· Mystakidou K, Parpa E, Tsilika E, et al. Long-term management of noncancer pain with transdermal therapeutic system-fentanyl. Pain. 2003;4(6):298-306. [Duration: up to 48 months.]

· Nicholson B, RossE, Sasaki J, Weil A. Randomized trial comparing polymer-coated extended-release morphine sulfate to controlled-release oxycodone HCl in moderate to severe nonmalignant pain. Curr Med Res Opin. 2006;22(8):1503-1514. [Duration: 24 weeks.]

· Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database of Systematic Reviews. 2010;1(CD006605). [26 studies of long-term opioid treatment, only 1 RCT.]

· Portenoy RK, Farrar JT, Backonja MM, et al. Long-term use of controlled-release oxycodone for noncancer pain: results of a 3-year registry study. Clin J Pain. 2007;23( 4):287-299. [Duration up to 3 years.]

· Rauck R, MaT, Kerwin R, Ahdieh H. Titration with oxymorphone extended release to achieve effective long-term pain relief and improve tolerability in opioid-naive patients with moderate to severe pain. Pain Med. 2008;9(7):777-85. [Duration: 6 months.]

· Richarz U, Waechter S, Sabatowski R, et al. Sustained safety and efficacy of once-daily hydromorphone extended-release (OROS® hydromorphone ER) compared with twice daily oxycodone controlled-release over 52 weeks in patients with moderate to severe chronic noncancer pain. Pain Practice. 2013;13(1):30-40. [Duration: 52 weeks.]

· Roth SH, Fleischmann RM, Burch FX, et al. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation. Arch Intern Med. 2000;160:853-860. [Duration 18.5 months.]

· Steiner D, Munera C, Hale M, Ripa S, Landau C. Efficacy and safety of buprenorphine trans dermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study. J Pain. 2011;12(11):1163-1173. [Duration 17 weeks.]

· Wen W, Munera CL, Dain B, Ripa SR. Long-term use ofbuprenorphine transdermal system (BTDS) in patients with chronic pain. Poster presented at Pain Week, 2010 Sept 8-11; Las Vegas, NV. [Duration: up to 12 months.]

· Wild JE, Grond S, Kuperwasser B, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract. 2010;10(5):416-427. [Duration 52 weeks.]

· Zenz M, Strumpf M, Tryba M. Long-term oral opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Manage. 1992;7(2):69-77. [Duration: 32 weeks.]

Disclosure: Pain Treatment Topics — including Pain-Topics.org, Pain-Topics UPDATES, Opioids911.org — is independently produced and supported in part by medical education grants from pharmaceutical manufacturers. In accordance with the strictest standards, these organizations do not have any role in the inception, development, review, or approval of any Pain Treatment Topics contents; all facts are from the sources cited, all opinions are expressly those of the editor/author.

Addendum: This UPDATES article was submitted to the FDA docket on 2/10/2013; tracking# 1jx-83lx-lh2i.

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