Topics in PAIN MANAGEMENT Vol. 33, No. 4 Current Concepts and Treatment Strategies November 2017 CONTINUING EDUCATION ACTIVITY Should Radiofrequency Denervation Be Dropped From the Clinical Arsenal for Chronic Back Pain? Mark L. Schoene Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to: 1. Identify the effect of radiofrequency denervation (RFDN) on the nerves supplying the spinal joints. 2. Determine whether existing evidence supports the use of RFDN as a treatment for low back pain. 3. Outline the Dutch program designed to expedite research while also determining the cost-effectiveness of a treatment. Key Words: Chronic back pain, MINT, Radiofrequency denervation T hree randomized controlled trials (RCTs) from the Netherlands have concluded that a common treatment for chronic low back pain—radiofrequency denervation (RFDN) of nerves supplying spinal joints—does not have any clinically significant impact on pain and disability and should be dropped from the standard clinical arsenal. The studies are the product of a promising new model for evaluating the effectiveness and cost-effectiveness of treatments new and old. This innovative approach may speed the introduction of new treatments into clinical practice and weed out many marginal treatments that do not deserve continuing reimbursement. In This Issue CE Article: Should Radiofrequency Denervation Be Dropped From the Clinical Arsenal for Chronic Back Pain? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Autologous Stem Cells From Adipose Tissue Could Treat Nonresolving Inflammation and Chronic Pain . . . 8 Good and Bad News on the Opioid Front . . . . . . . . . . 9 CE Quiz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 ICYMI: In Case You Missed It . . . . . . . . . . . . . . . . . . 12 Mr. Schoene is the Editor of The BackLetter, 25 Storey Ave, Ste 154, Newburyport, MA 01950; E-mail: firstname.lastname@example.org. The author, faculty, and staff in a position to control the content of this CME activity have disclosed that they and their spouses/life partners (if any) have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. This article was published originally in The BackLetter, 2017;32(9): 97-107. CME Accreditation Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Lippincott Continuing Medical Education Institute, Inc., designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation assessment survey on the enclosed form, answering at least 70% of the quiz questions correctly. This CME activity expires on October 31, 2018. CNE Accreditation Lippincott Professional Development is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Lippincott Professional Development will award 1.0 contact hours for this continuing nursing education activity. Instructions for earning ANCC contact hours are included on page 12 of the newsletter. This CNE activity expires on November 30, 2019. 1 Topics in Pain Management CO-EDITORS Elizabeth A.M. Frost, MD Professor of Anesthesiology Icahn School of Medicine at Mount Sinai New York, NY Angela Starkweather, PhD, ACNP-BC, CNRN, FAAN Professor of Nursing University of Connecticut School of Nursing Storrs, CT ASSOCIATE EDITOR Anne Haddad Baltimore, MD EDITORIAL BOARD November 2017 These are the largest RCTs ever conducted in this area and are likely to impress governments, insurance companies, other third-party payers, and guideline architects. Tens of thousands of procedures performed annually—and millions of dollars in treatment costs—hang in the balance. Based on these results, the government of the Netherlands elected to stop reimbursing RFDN in the treatment of chronic pain attributed to the facet joints, sacroiliac (SI) joints, intervertebral discs—and/or combinations of these potential pain generators. Other payers around the world will certainly consider following suit. The Netherlands elected to stop reimbursing RFDN in the treatment of chronic pain attributed to the facet joints, sacroiliac joints, and intervertebral discs. Jennifer Bolen, JD The Legal Side of Pain, Knoxville, TN C. Alan Lyles, ScD, MPH, RPh University of Baltimore, Baltimore, MD Stephen Silberstein, MD Jefferson Headache Center, Philadelphia, PA Steven Silverman, MD Michigan Head Pain and Neurological Institute, Ann Arbor, MI Sahar Swidan, PharmD, BCPS Pharmacy Solutions, Ann Arbor, MI P. Sebastian Thomas, MD Syracuse, NY Emily Wakefield, PsyD Connecticut Children’s Medical Center, University of Connecticut School of Medicine, Hartford, CT Marjorie Winters, BS, RN Michigan Head Pain and Neurological Institute, Ann Arbor, MI Steven Yarows, MD Chelsea Internal Medicine, Chelsea, MI Lonnie Zeltzer, MD UCLA School of Medicine, Los Angeles, CA 2 RFDN is a procedure that delivers high-frequency electrical energy through a needle-like probe. The goal is to heat and damage nerve fibers supplying spinal joints and other anatomy— and in theory prevent these nerves from transmitting pain signals to the spinal cord and brain. Potential treatment targets are generally identified with anesthetic blocks—to see whether anesthetizing a particular nerve or joint will relieve offending symptoms. The continuing education activity in Topics in Pain Management is intended for clinical and academic physicians from the specialties of anesthesiology, neurology, psychiatry, physical and rehabilitative medicine, and neurosurgery as well as residents in those fields and other practitioners interested in pain management. Topics in Pain Management (ISSN 0882-5646) is published monthly by Wolters Kluwer Health, Inc. at 14700 Citicorp Drive, Bldg 3, Hagerstown, MD 21742. Customer Service: Phone (800) 638-3030, Fax (301) 223-2400, or Email email@example.com. Visit our website at lww.com. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Priority postage paid at Hagerstown, MD, and at additional mailing offices. GST registration number: 895524239. POSTMASTER: Send address changes to Topics in Pain Management, PO Box 1610, Hagerstown, MD 21740. Publisher: Randi Davis Subscription rates: Individual: US $339, international: $467. Institutional: US $768, international $894. 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Topics in Pain Management is independent and not affiliated with any organization, vendor or company. Opinions expressed do not necessarily reflect the views of the Publisher, Editor, or Editorial Board. A mention of products or services does not constitute endorsement. All comments are for general guidance only; professional counsel should be sought for specific situations. Editorial matters should be addressed to Anne Haddad, Associate Editor, Topics in Pain Management, 204 E. Lake Avenue, Baltimore, MD, 21212; E-mail: email@example.com. Topics in Pain Management is indexed by SIIC HINARI and Google Scholar. ©2017 Wolters Kluwer Health, Inc. All rights reserved. Topics in Pain Management November 2017 What Are Some Potential Shortcomings of the Innovative MINT Studies? What are some potential limitations of the new randomized controlled trials (RCTs) on radiofrequency denervation (RFDN) for chronic low back pain? Roger Chou, MD, suggested that critics might be key on the fact that the study employed single rather than double anesthetic blocks to select patients for the facet joint and sacroiliac (SI) joint wings of these RCTs. “Patients were selected for facet joint and SI joint RFDN with a single diagnostic block and did not require a positive block at all in the combination pain trial. Some might suggest that failure to use dual blocks could have resulted in inappropriate selection of patients for RFDN and could explain the negative results,” Chou observed. There is evidence that single diagnostic blocks result in an elevated false-positive rate. In other words, some patients may report pain relief that does not stem from the anesthetic employed in the block. Some other aspect of the injection or clinical encounter might lead to the pain relief. (See Bogduk7 for a discussion of this issue.) However, Chou noted that scientific studies have not identified a single “best” method of selecting patients for RFDN in realworld practice, pointing to a widely cited RCT by Steven Cohen, MD, and colleagues, which compared no blocks, single blocks, and double blocks in the selection of patients for RFDN of the facet joints.8 There are complex trade-offs with all these approaches. The authors of the MINT (Minimal Interventional Procedures for Patients with Chronic Low Back Pain) RCTs acknowledged that the use of double anesthetic blocks might have reduced the false-positive rate—at the expense of increasing the rate of false-negative blocks. So with double blocks, some patients with pain from the facet or SI joints might have been denied a potentially effective treatment. Using double blocks also increases the costs of RFDN treatment, reducing its potential cost-effectiveness. And double blocks increase the treatment burden for patients—because of extra visits and extra interventions. But the main reason for employing single diagnostic blocks in the MINT studies was the consensus of the investigators and stakeholders in favor of this approach in real-world practice settings. “The project team and the Dutch Society of Anesthesiology had extensive consultations with a representative group of Dutch anesthesiologists, after which we agreed that performing a single diagnostic block represents [standard] daily practice,” according to lead author Esther Maas, PhD. She also noted that the Dutch guideline “Vertebral Column-Related Low Back Pain” recommended a single diagnostic block. Readers can find an airing of other potential limitations of the MINT RCTs in the discussion section of the study in JAMA.1 What About the Generalizability of the MINT RCTs? However, one key issue going forward is the extent to which the results of the MINT RCTs might apply in other countries and other clinical settings. Some will argue that the results of these RCTs might not apply outside of the Netherlands, because these studies were designed and developed for a specific multidisciplinary treatment program within the Dutch health care system. However, a recent Cochrane review of RFDN by Maas and colleagues could not find high-quality evidence supporting RFDN. And it found that the evidence was heterogeneous. There were differences in the inclusion criteria, diagnostic and treatment methods, and other aspects of care in almost all the clinical trials. This heterogeneity is a problem that extends across this body of evidence.2 Raymond Ostelo, PhD, of Vrije University in the Netherlands coauthored both the Cochrane review and the new Dutch RCTs. “I find it hard to see why the results [of the new RCTs] would not be generalizable to other countries and settings. Certainly there were some differences among the studies in the Cochrane review [e.g. inclusion criteria and treatment protocols for example], and between those studies and the MINT RCTs, but these differences were marginal,” he commented via e-mail. And the MINT studies would seem to reflect something approaching standard practice in many venues and appear to be relevant beyond the Netherlands. Maas pointed out in a recent e-mail that there is enough information in the new RCTs to allow researchers, clinicians, and policy makers to make up their own minds on this question. “We have been transparent in the description of these procedures (diagnosis and treatment). Researchers/clinicians in other countries or settings can therefore evaluate whether these procedures reflect daily practice in their setting,” she said. ©2017 Wolters Kluwer Health, Inc. All rights reserved. 3 Topics in Pain Management In a study with 2 lead authors, Johan N. S. Juch, MD, Esther Maas, PhD, and colleagues from universities and health centers across the Netherlands conducted RCTs of participants with chronic low back pain attributed to these spinal structures.1 RFDN did not fare well in these large clinical trials—collectively known as the MINT RCTs (Minimal Interventional Procedures for Patients with Chronic Low Back Pain—see sidebar on page 3). According to Juch et al., “Radiofrequency denervation combined with a standardized exercise program resulted in either no improvement or no clinically important improvement in chronic low back pain compared with a standardized exercise program alone. The findings do not support the use of radiofrequency denervation to treat chronic low back pain from these sources.”1 Based on this study, radiofrequency denervation is not recommended and should be performed only in a research setting. “Based on this study, radiofrequency denervation is not recommended and should be performed only in a research setting,” according to these investigators.1 Lead author Maas conducted this research project when she was at Vrije University in Amsterdam. She is now at the University of British Columbia in Vancouver. Maas said the results of the MINT RCTs are not a surprise, based on previous reviews of the literature in this area—such as the 2015 systematic review from the Cochrane Collaboration.2 “Multiple international studies (as published in our Cochrane review) have shown similarly small effects of radiofrequency denervation,” said Maas via e-mail. So the MINT RCTs are not outliers in their characterization of RFDN. In fact, they amplify the results of some previous studies with RCTs of greater size and methodological rigor. Additional Evidence of Ineffectiveness? Roger Chou, MD, Professor of Medicine and Director of the Pacific Northwest Evidence-Based Practice Center at Oregon Health & Science University, has followed the evidence in this area closely. He and his colleagues performed a systematic review of the evidence on RFDN for the American Pain Society (APS) guideline in 2009. That review found no conclusive evidence supporting the use of RFDN.3 “The 2009 APS review that I led found that the evidence on RFDN was weak and inconsistent, and the APS guideline did not recommend its use,” said Chou in a recent e-mail. He said he is not aware of RCTs performed since then that would alter that conclusion. 4 November 2017 The new studies from the Netherlands further question the effectiveness of RFDN for these indications. “These trials indicate that RFDN is not an effective treatment for back pain attributed to the facet joints, discs, or SI joints and do not provide support for their use. In fact, they provide additional evidence of ineffectiveness,” according to Chou et al.3 For both facet joint pain and combination pain, there was a nonstatistically significant trend towards worse pain at 12 months. For both facet joint pain and combination pain, there was a non-statistically significant trend towards worse pain at 12 months. “For pain attributed to the facet joint, which appears to be the indication for which RFDN is most commonly performed, there was no benefit on pain or function at any time point. For SI joint and combination pain, effects favored RFDN at 3 months but were below the threshold for clinically important differences, and were no longer present at longer follow-up. In fact, for both facet joint pain and combination pain, there was a non-statistically significant trend towards worse pain at 12 months.” “Effects on function also favored the control group at 9–12 months. These findings are especially striking because patients were not blinded—which would normally be expected to bias results in favor of the active intervention (RFDN),” according to Chou et al.3 An Appealing But Controversial Treatment RFDN is an appealing treatment that can be performed on an outpatient basis. There is broad consensus among pain interventionists that this nerve ablation technique can provide effective relief of pain attributed to the facet joints, the SI joints, and the intervertebral discs—or combinations of these—at least in some patients. However, these are also controversial treatments. There are no validated diagnostic methods—including physical testing, imaging, or invasive procedures—that can definitively link back pain to any of these structures. So there is always an uncomfortable level of guesswork in diagnosing and treating these putative abnormalities and in determining whether treatments specifically targeting these structures are safe and effective. The previous evidence supporting RFDN is of low quality and difficult to interpret. Background of the MINT RCTs Researcher Raymond Ostelo, PT, PhD, of Vrije University, a coauthor of the new RCTs, described the background of the MINT trials on RFDN in a presentation to the International Back and Neck Pain Forum in 2016. ©2017 Wolters Kluwer Health, Inc. All rights reserved. Topics in Pain Management He explained that the government of the Netherlands had sponsored systematic reviews on the evidence for RFDN—and could not find a single acceptable study proving its effectiveness and cost-effectiveness for any spinal indication. Most of the existing trials had methodological problems and/or insufficient sample size. “The Minister of Health suggested that in order to be reimbursed we needed trials of this intervention compared against usual care. We did not find those trials in our review of the literature,” said Ostelo et al.4 So the Netherlands Organization for Health Research Development commissioned a 4-year research project involving multiple RCTs on RFDN for spinal indications. The researchers worked extensively with all the stakeholders to come up with treatment and clinical trial protocols that would be acceptable to all parties.5 The research group originally intended to perform 4 RCTs: one on RFDN for pain attributed to the disc, one on pain attributed to the facet joints, another on symptoms attributed to the SI joints, and one on pain attributed to multiple sources among these structures.6 Ostelo et al1 explained that the researchers could not recruit enough candidates for the RCT on pain attributed to the disc and quickly abandoned that trial. The research team went ahead with the other 3 trials, which were all published in JAMA in July 2017. Details of the 3 RCTs Here are skeletal details of the RCTs (see Juch et al1 for further details): Juch and colleagues performed 3 multicenter RCTs of unblinded patients conducted at 16 pain clinics across the Netherlands. The reason that participants were not blinded to their assigned treatment was because the study aimed to duplicate the usual RFDN treatment protocols in the Dutch health care system—which do not involve blinding patients to their treatment choices. “The Dutch Ministry of Health, Welfare and Sport requested a pragmatic trial in which existing, common applied treatment options would be compared. We also included an economic evaluation with these trials. Blinding patients is not suitable for this type of research,” explained Maas via e-mail. The study aimed to duplicate usual RFDN treatment protocols in the Netherlands— which do not involve blinding patients to their treatment choices. Standardized Radiofrequency Protocol To enter the trial, patients from 16 to 70 years of age had to have chronic back pain that failed to improve with at least 3 months of conservative care. The study used a standard guideline protocol on “diagnosing” chronic back pain related ©2017 Wolters Kluwer Health, Inc. All rights reserved. November 2017 What About Further Research on RFDN for Chronic Back Pain? Where would researchers involved in the MINT trials on RFDN like to see research go from here? “As far as it concerns low back pain as a result of facet joint, sacroiliac joint, and discogenic [problems], and the treatment of these entities with radiofrequency denervation, a better understanding of the underlying pathophysiology, diagnosis, and different treatment techniques is necessary,” commented Esther Maas, PhD, joint lead author of the trials. “Worldwide, several initiatives are under [development]. Until results from these studies are available, it is our advice to perform these procedures in research settings only,” she added. Coauthor Raymond Ostelo, PhD, agreed via e-mail that a better understanding of chronic back pain is key to moving forward. “Indeed, diagnostic studies to determine whether it is possible to validly identify the source of back pain has high priority,” said Ostelo. Without better knowledge, he suggested, further clinical trials would have limited usefulness. “Further clinical trials should only be performed if there is improvement in diagnosis, patient selection, and/ or the pain intervention.” Roger Chou, MD, of Oregon Health & Science University, said he has limited confidence that further clinical trials in this area will be useful, given current levels of knowledge. “I am not sure that this is an area that warrants additional clinical trials,” said Chou. “As noted previously, some might argue that patients should have been selected using dual blocks, but we have randomized controlled trial evidence showing that dual blocks are no better than single blocks for selecting patients for RFDN,” Chou commented. “Results seemed best for patients with ‘combination’ pain, so perhaps this is a group that deserves additional study—though this diagnosis was pretty vague and it is hard to get excited about doing multiple interventional procedures for ill-defined pain, especially when patients received intradiscal electrothermal therapy (a procedure that has been abandoned by many) or biacuplasty (I am not aware of any sham-controlled studies of this treatment) for the discogenic pain component,” Chou explained. “One potential area to investigate in further detail is whether the degree of central sensitization predicts responsiveness to RFDN. Some evidence suggests that patients with more central sensitization tend to respond better to things like cognitive behavioral therapy, exercise, certain meds (serotonin–norepinephrine reuptake inhibitors/gabapentin/pregabalin) rather than to procedures like this,” Chou added. Many RFDN providers believe there is a subgroup of patients—with a distinctive phenotype or phenotypes— that can have superior results. However, those potential subgroups have not been clearly identified. 5 Topics in Pain Management to facet joints, SI joints, or combination of facet joints, SI joints, and discs. All relevant stakeholders, including RFDN practitioners, agreed on this protocol before the study. Patients first had to undergo a history and physical examination to see whether they qualified. To be considered for a diagnostic SI block, patients had to have positive results on 3 of the 6 physical examinations: compression test; distraction test; flexion, abduction, and external rotation test; Gaenslen test; thigh thrust test; and Gillett test. November 2017 If patients were suspected of having isolated pain stemming from the facet joint or SI joint, they then underwent a single diagnostic block (ie, an injection of local anesthetic) to see whether this relieved their usual pain. (“Patients must answer ‘yes’ on the question ‘is there a 50% or more reduction in pain?’ 30 minutes after the test block,” according to the study protocol.) If patients met this criterion, they qualified for either the facet joint RCT or the SI joint RCT. Bold Quest to Identify Effective and Cost-effective Treatments for Low Back Pain There is a subplot to the 3 innovative MINT (Minimal Interventional Procedures for Patients with Chronic Low Back Pain) randomized controlled trials (RCTs) from the Netherlands—one that is just as interesting as the studies themselves. And it has caught the attention of back pain researchers and policy makers around the world. Over the past several years, the health care system of the Netherlands has been working on a program to introduce innovative treatments into standard clinical practice in a more timely manner. Developing and testing new treatments and technologies can be a long, arduous process. It can take years or even decades for treatments to wend their way—in unplanned fashion—through case studies, case series, controlled cohort studies, safety studies, RCTs, cost-effectiveness studies, and systematic reviews. But what if a government agency or health care system worked to speed up this process, by getting all relevant stakeholders (patients, providers, insurers, and policy makers) onside and then funding definitive research to determine whether treatments are effective and cost-effective—and deserving of reimbursement? The government of the Netherlands and the Netherlands Organization for Health Research and Development recently decided to do just that. They elected to fund scientific studies in areas where definitive cost-effectiveness research was lacking. “With a rising demand for care and increasing costs, the Dutch health care [system] faces a shortage of resources,” the latter organization noted at its website. “Decision-makers in policy and practice need to carefully weigh the benefits of interventions against costs. [Costeffectiveness studies] provide the evidence base to make decisions about the introduction of innovative interventions while discouraging the use of inefficient interventions.”9 The new program developed by this agency will allow the introduction of new treatments into clinical practice even if there is no definitive evidence of their effectiveness—provided that all relevant stakeholders agree to support and complete rigorous cost-effectiveness research in a prespecified period. Normally, all treatments included in the Netherlands basic health insurance package would have to meet a high evidence standard, documenting that they are “state-of-the-art in terms of scientific knowledge and practice,” according to this research agency. However, under the new program, “An intervention may be granted a temporary exemption from this criterion, and be conditionally included in the basic package for a period of 4 years. Any missing data must be gathered over this four-year period,” the agency noted. Or as Maas explained via e-mail, “The idea … is to bring new treatments to patients at an earlier stage of development. For a temporary time period, a new treatment is reimbursed in combination with a study investigating the cost-effectiveness of that treatment. At the end of the project, it is decided [whether] to continue or discontinue reimbursement,” she added. The Same Process Can Be Applied to Existing Treatments This same approach can be applied to existing treatments in the clinical marketplace, for interventions that are already receiving reimbursement but lack solid evidence of cost-effectiveness. Many therapies for low back pain have been grandfathered into clinical practice—and reimbursement—based on consensus along with evidence of dubious quality. And once they become established in the clinical marketplace, they often continue to receive reimbursement from third-party payers for years and decades. To make progress in addressing the low back pain and disability crisis, this pattern clearly needs to change. If soaring back pain costs around the world are to be brought under control, governments and other payers should only support cost-effective treatments. So the Netherlands Organization for Health Research and Development chose radiofrequency denervation—a long-established treatment in the Dutch system—as the first treatment approach to be investigated under the new program. 6 ©2017 Wolters Kluwer Health, Inc. All rights reserved. Topics in Pain Management November 2017 If patients were suspected of having multiple sources of pain (facet and/or SI joint and/or disc), they did not receive diagnostic blocks initially. joints, or intervertebral disks showed a statistically significant but not clinically important improvement in pain intensity 3 months after the intervention. No clinically important or statistically significant differences between the groups were shown in the trial assessing The two trials assessing RFDN for the sacroiliac joints and a radiofrequency denervation combination of the facet joints, sacroiliac joints, or intervertebral for facet joint pain. Only small or no effects were found disks showed a statistically significant but not clinically important for all secondary outcomes,” improvement in pain intensity 3 months after the intervention. according to Juch et al.1 The research team also performed cost-effectiveness “Participants with a suspected combination of sources of studies of RFDN for these indications. Those have yet to be pain were randomized based on participant history and physipublished. However, the fact that the Dutch health care system cal examination prior to receiving the diagnostic blocks. This elected to stop funding RFDN based on these studies suggests choice was made for ethical reasons. It would be unethical to that these treatments did not achieve adequate cost give participants in the study multiple diagnostic blocks (i.e. a effectiveness. ■ facet joint diagnostic block, a sacroiliac joint diagnostic References block, and a provocative discography [for suspected disc1. Juch JNS, Maas E, Ostelo RWJG, et al. Effect of radiofrequency related pain]) before treatment,” according to Juch et al.1 denervation on pain intensity among patients with chronic low All Study Subjects Completed a 3-Month Exercise Program In all 3 RCTs, all study subjects underwent a 3-month exercise program based on the Dutch physical therapy guidelines (with optional psychological support, if necessary). (See Juch et al1 for a description of the exercise approach.) Patients randomized to receive RFDN received 1 to 3 RFDN procedures, starting within a week of the exercise program. Those in the facet trial and those in the SI joint RCT were assigned to RFDN of nerves supplying these joints. Those in the combination group were assigned to RFDN of the facet joints and/or SI joints—and/or intradiscal electrothermal therapy (IDET) or biacuplasty of the disc. Both of the latter are thermal procedures intended to interrupt pain transmission from the disc. Readers can find details of the RFDN protocols in supplement number 2 of the study in JAMA.1 An impressive 251 subjects entered the facet joint RCT, 228 took part in the SI joint trial, and 202 participated in the combination study. 2. 3. 4. 5. 6. 7. 8. Disappointing Results As mentioned earlier, the results of the RFDN interventions were disappointing. “The two trials assessing radiofrequency denervation for the sacroiliac joints and a combination of the facet joints, sacroiliac ©2017 Wolters Kluwer Health, Inc. All rights reserved. 9. back pain: the MINT randomized clinical trials. JAMA. 2017;318(1):68-81. doi:10.1001/jama.2017.7918. Maas E, Ostelo RW, Niemisto L, et al. Radiofrequency denervation for chronic low back pain. Cochrane Database Syst Rev. 2015;(10):CD008572. doi:10.1002/14651858.CD008572.pub2. Chou R, Loeser JD, Owens DK, et al. Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society. Spine. 2009;34(10):1066-1077. Ostelo R, et al. Effectiveness and cost-effectiveness of radiofrequency denervation for chronic low back pain originating from the facet joints. Paper presented at: the International Forum for Back and Neck Pain Research in Primary Care; Buxton, UK, 2017. ZonMw. Netherlands Organization for Healthcare Research and Development, Efficiency Studies. www.zonmw.nl/en/researchandresults/efficiency-studies. Nederlands Trial Register. Trial Info, Cost-effectiveness of minimal interventional procedures for patients with chronic low back pain. www.trialregister.nl/trialreg/admin/rctview.asp? TC=3531. Bogduk N. On diagnostic blocks for lumbar zygapophysial joint pain, F1000 Reports. Medicine. 2010;2(57). https://www.ncbi.nlm. nih.gov/pmc/articles/PMC2990543. Cohen SP, Williams KA, Kurihara C, et al. Multicenter, randomized, comparative cost-effectiveness study comparing 0, 1, and 2 diagnostic medial branch (facet joint nerve) block treatment paradigms before lumbar facet radiofrequency denervation. Anesthesiology. 2010;113(8):395-405. doi:10.1097/ALN.0b013 e3181e33ae5. Netherlands Organization for Healthcare Research and Development. Efficiency Studies. www.zonmw.nl/en/researchandresults/efficiency-studies. 7 Topics in Pain Management November 2017 Autologous Stem Cells From Adipose Tissue Could Treat Nonresolving Inflammation and Chronic Pain R egenerative medicine—in particular, autologous stem cell therapy—could be one way to treat the nonresolving inflammation cycle, and thus the chronic pain that it can lead to, according to a physician chief executive officer (CEO) who said he uses it to treat his own patients.1 Regenerative medicine deals with use of stem cells and other processes to replace or repair tissue and function, such as by growing ex vitro cells, tissues, or even organs that can be transplanted into the body. In a presentation at PAINWeek 2017, held in Las Vegas in early September, Jay Joshi, MD, chief executive officer, and medical director of the National Pain Centers in Vernon Hills, Illinois, gave an overview of stem cell therapies used in regenerative medicine to treat a number of pain conditions.2 As reported in Clinical Pain Advisor, Joshi2 told attendees that he has treated pain patients with autologous stem cell therapy, in which adult multipotent mesenchymal stem cells (MSCs) are collected from a patient’s adipose tissue and transplanted back into damaged tissue.1 The MSCs have the potential to differentiate into osteoblasts, chondrocytes, myocytes, and neural progenitors. Trials are also ongoing across the country using allogenic MSCs, particularly those collected from umbilical cord tissue. Joshi2 said a search on ClinicalTrials.gov using the term “umbilical cord MSCs” indicates that 145 clinical studies are ongoing. Joshi said he believes the field of regenerative medicine will grow in scope and refinement.1 nonresolving inflammation cycle. Nonresolving inflammation cycles are thought to be one factor that can lead to chronic pain.3 Nonresolving inflammation cycles are thought to be one factor that can lead to chronic pain. Diagnosing the cause of nonresolving inflammation and determining whether it is due to a suboptimal or prolonged response is essential, Joshi2 said. For example, certain food allergies or substances that contribute to the process are underdiagnosed, in his opinion. Other factors contributing to this perpetuating inflammation include autoimmune conditions, irritable bowel syndrome, and obesity.1 Stem cell therapy can also use allogenic (nonautologous) stem cells, which yield much higher concentrations of MSCs (approximately 2 million/mL of umbilical cord tissue, compared with 1 million from 60 mL of adipose tissue). These umbilical cord stem cells are epigenetically young, and do not require surgery, although they are associated with a risk for viral and bacterial infection and need to be stored in liquid nitrogen. Allogenic MSCs are generally derived from umbilical cord tissue, the matrix of which can also be used in regenerative medicine as it is rich in hyaluronic acid, cytokines, and growth factors. Amniotic membrane and amniotic liquid suspension are another source of material used to treat burns and Collected marrow stromal cells are already indicated for joint wounds and repair soft tissue. MSCs can also be repair. It is not yet clear which of the stem cells or growth factors derived from Wharton’s jelly, the umbilical cord conprovide the most beneficial outcomes. nective tissue, and are used to prevent inflammation.1 ■ Autologous stem cells—those obtained from the patient’s References own body—can be obtained from adipose tissue and bone 1. Chavernoff F. Stem cell therapy for pain management. Clinical marrow aspirate concentrates. Collected marrow stromal cells Pain Advisor website (clinicalpainadvisor.com), September 8, 2017. Accessed September 11, 2017. Coverage from PAINWeek are already indicated for joint repair; they are injected back 2017 meeting in Las Vegas, Nevada. into the patient with a combination of growth factors. It is not 2. Joshi J. Stem cells and regenerative medicine. Presented at: yet clear which of the stem cells or growth factors provide the PainWeek 2017, September 5-9, 2017, Las Vegas, Nevada. 2 most beneficial outcomes. 3. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140(6): Joshi2 emphasized the link between pain and inflammation. 871-882. http://www.clinicalpainadvisor.com/painweek-2017/ Although inflammation is a mechanism meant to protect and many-different-options-are-available-for-the-use-of-stem-cell-therapies-in-regenerative-medicine/article/687612/ heal the body, it can also delay healing and become a 8 ©2017 Wolters Kluwer Health, Inc. All rights reserved. Topics in Pain Management November 2017 Good and Bad News on the Opioid Front T here is good news and bad news on the opioid front, according to the latest update from the US Centers for Disease Control and Prevention (CDC).1 On the positive side, the report documented a gradual decline in the rate of opioid prescription in the United States in the second decade of the new millennium. Opioid prescription rates rose precipitously in the first decade of this century and then began to level off. Prescribing rates increased from 72.4 prescriptions per 100 people in 2006 to 81.2 in 2010. They stayed level from 2010 to 2012 and then declined to 70.6 per 100 people from 2012 to 2015, a 13.1% drop. US physicians continue to prescribe opioids at dramatically elevated rates, and the average duration of opioid use seems to be increasing. Yet, despite the decline, US physicians continue to prescribe opioids at dramatically elevated rates. The amount of opioids prescribed in the United States in 2015 was 3 times higher than that prescribed in 1999. US physicians prescribed 4 times the amount of opioids as European physicians in 2015. On the positive side, high-dose opioid prescription has also declined. High-dose opioid prescription (daily dose of 90 morphine equivalents or more per day) stayed level from ©2017 Wolters Kluwer Health, Inc. All rights reserved. 2006 to 2010, and then declined from 11.4 per 100 people to 6.7 in 2015. However, the average duration of prescription opioid use seems to be increasing. “From 2006 to 2015, the average duration of opioid prescriptions increased by a third, from 13.3 to 17.7 days,” according to an article by Anne Schuchat, MD, of the CDC, and colleagues and published by the Journal of the American Medical Association. “The new data suggest that fewer patients may be initiating prescription opioid use, whereas patients already prescribed opioids may be continuing long-term use. Taking opioids for longer periods increases the risk of opioid use disorder, overdose, and death,” Schuchat and her coauthors added. And opioid overdose death rates continue to spike upwards— largely driven by increases in overdoses of illicit opioids such as heroin and fentanyl. However, according to a variety of data from US states, medically prescribed opioids are still playing a role in the opioid mortality epidemic. For example, more than a third of people who died from an illicit fentanyl overdose in Rhode Island over a 27-month period had filled an opioid prescription within 90 days of death. ■ This article was published originally in The BackLetter, 2017;32(9):101. Reference 1. Schuchat A, Houry D, Guy GP Jr, et al. New data on opioid use and prescribing in the United States [published online ahead of print July 6, 2017]. JAMA. doi:10.1001/jama.2017.8913. 9 Topics in Pain Management November 2017 Topics in Pain Management CE Quiz To earn CME credit using the enclosed form, you must read the CME article and complete the quiz and evaluation assessment survey on the enclosed form, answering at least 70% of the quiz questions correctly. Select the best answer and use a blue or black pen to completely fill in the corresponding box on the enclosed answer form. Please indicate any name and address changes directly on the answer form. If your name and address do not appear on the answer form, please print that information in the blank space at the top left of the page. Make a photocopy of the completed answer form for your own files and mail the original answer form in the enclosed postage-paid business reply envelope. Your answer form must be received by Lippincott CME Institute by October 31, 2018. Only two entries will be considered for credit. Online CME quiz instructions: Go to http://cme.lww.com and click on “Newsletters,” then select Topics in Pain Management. Enter your username and password. First-time users must register. After log-in, follow the instructions on the quiz site. You may print your official certificate immediately. Please note: Lippincott CME Institute, Inc., will not mail certificates to online participants. Online quizzes expire on the due date. To earn nursing CNE credit, you must take the quiz online. Go to www.nursingcenter.com, click on CE Connection on the toolbar at the top, select Browse Newsletters, and select Topics in Pain Management. Log-in (upper right hand corner) to enter your username and password. First-time users must register. As a subscriber benefit, nurses can earn contact hours when taking CE activities from Topics in Pain Management for free. You must enter your subscription number in your registration profile where there is a field for Link to my subscription. The 100% discount is applied when payment is requested. Non-subscribers pay a $49.00 fee to earn ANCC contact hours for this activity. After log-in, locate and click on the CE activity in which you are interested. There is only one correct answer for each question. A passing score for this test is 7 correct answers. If you fail, you have the option of taking the test again. When you pass, you can print your certificate of earned contact hours and access the answer key. For questions, contact Lippincott Professional Development: 1-800-787-8985. The registration deadline for CNE credit is November 30, 2019. 1. Conclusions from RCTs on RFDN of nerves supplying the spinal joints as a treatment for low back pain can be summarized by which one of the following statements? A. RFDN should be considered as a first-line treatment for low back pain. B. Only patients with a herniated disc should receive RFDN therapy. C. RFDN should be dropped from the standard clinical arsenal for low back pain. D. It is premature to drop RFDN as a viable modality for treatment of low back pain. 2. Based on results of 3 recent studies on RFDN, the government of the Netherlands elected to A. start reimbursing RFDN in the treatment of chronic pain attributed to the facet joints, sacroiliac joints, intervertebral discs—and/or combinations of these potential pain generators B. make no change in reimbursement for RFDN for chronic low back pain C. increase reimbursement for RFDN for chronic low back pain D. stop reimbursing RFDN in the treatment of chronic pain attributed to the facet joints, sacroiliac joints, intervertebral discs—and/or combinations of these potential pain generators 3. Which one of the following statements regarding RFDN is true? A. RFDN delivers high-frequency electrical energy through a needle-like probe. B. RFDN heats and damages nerve fibers supplying spinal joints and other anatomy and, in theory, prevents nerves from transmitting pain signals to the spinal cord and brain. C. RFDN involves identifying treatment targets with the use of anesthetic blocks to determine whether anesthetizing a particular nerve or joint will relieve pain. D. All of the above 4. Which one of the following statements regarding how new studies from the Netherlands compare with the 2009 APS guideline on RFDN is true? A. The APS guideline found strong and consistent evidence supporting RFDN in 2009. B. The authors of the APS guideline have challenged the 3 new studies on RFDN. C. The Netherlands studies directly conflict with the 2009 guideline from the APS. D. The APS guideline reported weak and inconsistent evidence of RFDN for back pain. 5. RFDN has been used by spine interventionists A. in the outpatient setting B. primarily for pain attributed to the facet joints, the sacroiliac joints, and intervertebral discs C. only after definitive diagnostic images indicate exactly which structures are the cause of the pain D. A and B 10 ©2017 Wolters Kluwer Health, Inc. All rights reserved. Topics in Pain Management 6. In looking for trials of RFDN compared with usual care, the authors of the study at Vrije University found A. only 1 study showing a moderate increase in effectiveness from RFDN B. only 3 studies in the Netherlands showing a moderate increase in effectiveness from RFDN C. no acceptable studies proving effectiveness of RFDN for any spinal indication D. several studies worldwide showing effectiveness of RFDN 7. One of the potential shortcomings of the RCTs on RFDN for chronic low back pain is that A. patients were selected based on single rather than double anesthetic blocks B. the use of double anesthetic blocks may have resulted in an elevated false-positive rate C. cost-effectiveness and patient burden may have been influenced by using double blocks D. a single diagnostic block does not represent standard clinical practice for selection of RFDN November 2017 9. In the study by Juch et al, the investigators performed 3 multicenter trials with unblinded patients because A. it was technically impossible to do so B. it was impossible to recruit participants under those circumstances C. the study aimed to duplicate the usual RFDN treatment protocols in the Dutch health care system—which do not involve blinding patients to their treatment choices D. time constraints imposed by the Netherlands Minister of Health prevented it 10. In all 3 of the recent trials on RFDN, the study subjects A. did not undergo any exercise program, to remove that variable B. were required not to receive psychological support, to remove that variable C. underwent different exercise programs of their own choosing D. underwent a 3-month exercise program based on the Dutch physical therapy guidelines (with optional psychological support, if necessary) 8. A program in the Netherlands to introduce innovative treatment into standard practice in a more timely manner is based on A. ensuring that all treatments included in basic health insurance meet high evidence standards B. funding scientific studies in areas where definitive cost-effectiveness is lacking C. offering expensive therapies only to patients with significant functional impairments D. providing coverage for a wide range of therapies, including those that are not effective ©2017 Wolters Kluwer Health, Inc. All rights reserved. 11 Topics in Pain Management November 2017 ICYMI: IN CASE YOU MISSED IT Notes from recent studies related to pain management, compiled by Elizabeth A.M. Frost, MD Can Adherence to Long-Term Opioid Therapy Guidelines Reduce Opioid Misuse? A cluster-randomized clinical trial among 53 primary care clinicians (PCCs) and their 985 patients receiving long-term opioid therapy for pain was conducted between January 2014 and March 2016 in 4 safety-net primary care practices. Study PCCs received nurse care management, an electronic registry, one-on-one academic detailing, and electronic decision tools for safe opioid prescribing. Control PCCs received electronic decision tools only. Primary outcomes included documentation of guidelineconcordant care (both a patient-PCC agreement in the electronic health record and at least 1 urine drug test) over 12 months and 2 or more early opioid refills. Secondary outcomes included opioid dose reduction [ie, 10% decrease in morphine-equivalent daily dose (MEDD) at trial end] and opioid treatment discontinuation. Adjusted outcomes controlled for differing baseline patient characteristics: substance use diagnosis, mental health diagnoses, and language. The 985 participating patients included 519 men and 466 women (mean patient age, 54.7 years). Patients received a mean (standard deviation) MEDD of 57.8 (78.5) mg. At 1 year, intervention patients were more likely than controls to receive guideline-concordant care (65.9% vs 37.8%). The authors concluded that a multicomponent intervention improved guideline-concordant care but did not decrease early opioid refills. Trial Registration: clinicaltrials.gov identifier: NCT01909076. (See: Liebschutz JM, Xuan Z, Shanahan CW, et al. Improving adherence to long-term opioid therapy guidelines to reduce opioid misuse in primary care: a cluster-randomized clinical trial. JAMA Intern Med. 2017. doi:10.1001/jamainternmed.2017.2468.) Guidelines for Prevention and Treatment of GlucocorticoidInduced Osteoporosis The authors conducted a systematic review to synthesize the evidence for the benefits and harms of options to prevent and treat glucocorticoid-induced osteoporosis, using Grading of Recommendations Assessment, Development and Evaluation methodology. Final recommendations and gradation of strength were determined by group consensus. The American College of Rheumatology guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in patients receiving long-term GC treatment, and in special populations of long-term GC users. Limited evidence regarding the benefits and harms of interventions in GC users make most recommendations conditional (uncertain balance between benefits and harms). Recommendations include: • Treating only with calcium and vitamin D in adults at low fracture risk; • Treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk; • Continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate; and • Continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen while continuing to receive GC treatment. Special populations include children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment. Conclusions made require that clinicians and patients use a shared decision-making process that accounts for patients’ values, preferences, and comorbid conditions. Recommendations should not limit or deny access to therapies. (See: Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2017;69(8):1095-1110. doi: 10.1002/acr.23279.) Coming Soon: • Emotion Regulation and Pain Management • The Evidence on Prehab: Optimizing Function Before Surgery 12 ©2017 Wolters Kluwer Health, Inc. All rights reserved.