I. Background and Objectives for the Systematic Review

Background

Pain is nearly universal, contributing substantially to morbidity, mortality, disability, and healthcare system burdens.¹ Acute pain usually lasts for less than 7 days but often extends up to 30 days, and may recur periodically. Acute pain is ubiquitous following surgery, is the most common reason for emergency department visits, and is commonly encountered in outpatient and inpatient settings. Although acute pain usually resolves rapidly, in some cases it can persist to become chronic. Chronic pain, often conceptualized as pain that persists past normal healing time (e.g., >3 months),¹ is a serious public health issue in the United States, affecting approximately 50 million people and resulting in $635 billion in costs.^2,3 Chronic pain substantially impacts physical and mental functioning, reducing productivity and quality of life. It is the leading cause of disability in the United States and often difficult to treat.

Persons eligible for Medicare due to age or disability are highly impacted by pain. Musculoskeletal conditions such as back pain are the most common Social Security Disability Insurance qualifying diagnosis, accounting for 34 percent of program participants in 2011 (up from 20% in 1996).⁴ In 2016, approximately 13.6 million Americans 65 years of age or older were estimated to have chronic pain and 5.4 million had high-impact chronic pain.³ The prevalence of chronic pain was 27.6 percent among those 65 to 84 years of age and 33.6 percent among those 85 years of age or older, the latter prevalence exceeding any other age group. In older adults, management of pain is often complicated by medical comorbidities, polypharmacy, increased susceptibility to treatment harms, and assessment challenges due to impaired cognition, often resulting in untreated or under treatment of pain.^5,6

Opioids, traditionally considered the most potent analgesic, are frequently prescribed for acute or chronic pain, including in older adults and those with disabilities.^4,7,8 Therefore, pain management must be considered within the context of the current opioid crisis. Opioid prescribing quadrupled from 1999 to 2010; concurrently, the number of opioid analgesic deaths and opioid use disorder (OUD) cases similarly rose sharply.⁹ In 2018, an estimated 46,802 Americans died from opioid overdose (approximately 15,000 from prescription opioids)—both representing declines from 2017, but well above pre-2010 levels. Opioid prescribing is highest among persons over 65 years of age, and studies indicate recent increases in admissions and emergency department visits related to OUD in this age group.^10-12 Further, people successfully treated for OUD are becoming Medicare beneficiaries, with increases in both survival and acute and chronic pain that can accompany aging. Therefore, there is a need to identify effective and safe interventions that could augment or replace opioids for pain treatment in this population.

The key decisional dilemma for pain management in Medicare beneficiaries is providing adequate pain relief, in order to improve quality of life and improve function, while minimizing harms, including those related to opioid use or withdrawal. Given concerns regarding opioids, non-opioid pharmacologic and non-pharmacologic therapies hold promise and have become increasingly accepted as first-line therapies. The 2016 CDC Guideline for Prescribing Opioids for Chronic Pain provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care.  It recommends non-opioid therapy as preferred for treatment of chronic pain,^13-15 though opioids remain an option for appropriately selected and monitored patients. In the aging population, the Pain Management Best Practices Inter-Agency Task Force report recommended consideration of a multidisciplinary approach with nonpharmacologic emphasis, given the increased risk of medication side effects.¹⁶ Interventional approaches were also specifically highlighted by the Task Force as an important nonpharmacologic option. Data indicate that interventional procedures are frequently used in this population (~5 million procedures annually in Medicare fee-for-service).¹⁷

The term “interventional procedure” has been applied to a myriad of procedures, ranging from soft tissue injections to minimally invasive surgeries, but in this report it will be used to refer to non-surgical interventional procedures (i.e., excluding minimally invasive surgical procedures). A myriad of interventional procedures and techniques are available for pain. The Inter-Agency Task Force report suggested that a number of interventional procedures be considered for acute or chronic pain, including epidural steroidal infections, facet joint nerve block and denervation procedures, cryoneuroablation, radiofrequency ablation, peripheral nerve injections, sympathetic nerve blocks, neuromodulation, intrathecal medication pumps, vertebral augmentation procedures, trigger point injections, joint injections, and regenerative adult autologous stem cell therapy.¹⁶ The Task Force did not specifically make recommendations for use of these procedures in Medicare populations, in whom optimal management of pain must consider factors such as medical comorbidities, polypharmacy, presence of disability, falls risk, and cognitive issues.¹⁸ Therefore, a systematic review focusing on the benefits and harms of selected interventional therapies of uncertain utility in this population is warranted. 

Purpose of the Review

This systematic review will evaluate the effectiveness and harms of selected interventional procedures in the Medicare population. The review will focus on procedures which are not currently covered for by the Centers for Medicare & Medicaid Services (CMS) but are relevant for and have potential utility for use in the Medicare population, or procedures that are covered by CMS but for which there is important uncertainty or controversy regarding use. The intended audiences for this review are CMS and other stakeholders including clinicians, policymakers, patients and researchers. This review is part of the Dr. Todd Graham Pain Management Study and is sponsored by CMS. The Dr. Todd Graham Pain Management Study also includes three complementary topic briefs on pain topics in Medicare populations as well as a separate systematic review¹⁹ on integrated pain management and multidisciplinary multi-modal treatment models.

II. Key Questions

The draft Key Questions and scope were developed by the Evidence-based Practice Center with input from the Agency for Healthcare Research and Quality (AHRQ) and CMS and was revised based on input from a Technical Expert Panel (TEP) prior to finalization. The interventional therapies were selected based on the following factors: (1) available in the United States but not currently covered by CMS; (2) relevance and potentially utility in the Medicare population (i.e., use in Medicare-eligible persons or for pain conditions commonly encountered in this population); and (3) uncertainty or controversy regarding use.

Key Question 1: What are the effectiveness and harms of selected interventional procedures (vertebral augmentation procedures, piriformis injection, sphenopalatine block, occipital nerve stimulation, cooled or pulsed radiofrequency ablation, intradiscal and facet joint platelet rich plasma, intradiscal methylene blue, intradiscal ozone, and peripheral nerve stimulation) versus placebo, a sham procedure, or no interventional procedure for Medicare beneficiaries with pain?

1. How do the effectiveness and harms vary according to demographic (age, sex, race/ethnicity), clinical (type of pain, severity of pain, prior treatments, medical and psychiatric co-morbidities), and technical factors (variations in techniques, intensity, frequency, dose, and number of treatments)?

The interventional procedures for this review are:

1. Vertebral augmentation procedures (vertebroplasty and kyphoplasty). These procedures are performed for vertebral compression fractures, which are common in the Medicare population and often are due to osteoporosis or metastatic disease. There is ongoing controversy about the role of vertebral augmentation procedures, due to conflicting trial results.^20,21
2. Piriformis injection. This procedure is performed for piriformis syndrome, which results from compression of the sciatic nerve by the piriformis muscle.^22,23 The injection may be performed using corticosteroids, local anesthetics, and/or botulinum toxin.
3. Sphenopalatine block. This procedure is performed for trigeminal neuralgia, migraine headaches, cluster headaches, and other headache syndrome.²⁴ It involves injection of the sphenopalatine ganglion with a local anesthetic; the U.S. Food and Drug Administration (FDA) has approved three devices for this procedure.
4. Occipital nerve stimulator. This procedure is performed for various headache disorders. It involves electrical stimulation of the occipital nerve.²⁵
5. Cooled radiofrequency ablation for degenerative low back or hip pain and pulsed radiofrequency ablation for degenerative low back pain. Like standard radiofrequency ablation, the cooled radiofrequency procedure ablates nerve tissue thought to be the cause of pain using high frequency electrical current. It differs from standard radiofrequency ablation by using a larger, "cooled" radiofrequency probe that keeps the tip cool, potentially resulting in a larger and more effective lesion.^26,27 The Coolief cooled radiofrequency ablation probe was approved by the FDA for treatment of knee pain. However, it has also been proposed as an alternative to standard radiofrequency ablation for other indications, including degenerative back and hip pain. Pulsed radiofrequency differs from standard (continuous) radiofrequency by delivering a smaller current in brief bursts. Unlike continuous radiofrequency, it is not intended to destroy nerve tissue; rather, it is thought to reduce pain through neuromodulatory effects.²⁸
6. Intradiscal and facet joint platelet rich plasma. This procedure involves the injection of autologous platelet rich plasma, which is rich in growth factors, into the intervertebral disc for low back pain of presumed discogenic origin²⁹ or into the lumbar facet joint for low back pain of presumed facet joint origin.³⁰
7. Intradiscal stem cells. This procedure involves the injection of stem cells, which have potential regenerative potential, into degenerative intervertebral discs for low back pain of presumed discogenic origin.³¹
8. Intradiscal methylene blue. This procedure involves the injection of methylene blue, a dye that may prevent fibrosis or ablate sensory endings, into the intervertebral disc for low back pain of presumed discogenic origin.³²
9. Intradiscal ozone injection. This procedure involves the injection of ozone, a gas with potential anti-inflammatory or other effects, into the intervertebral disc for radicular low back pain or non-radicular low back pain of presumed discogenic origin.³²
10. Peripheral nerve stimulation. This procedure involves stimulation of peripheral nerves using a mild electrical current, in patients with chronic neuropathic pain. It is most commonly used for ulnar, median, and radial neuropathy.³³

This review does not address minimally invasive surgical procedures. It also does not address orthopedic procedures such as intra-articular or soft tissue corticosteroid, hyaluronic acid, or soft tissue or non-spinal intra-articular platelet rich plasma injections. It also does not address soft tissue injections with local anesthetic, corticosteroid, and/or other medications (e.g., botulinum toxin) that are commonly performed in primary care settings and do not require specialized training or expertise. It also does not address interventional procedures conducted in the Medicare population that are covered by CMS, are recommended in clinical practice guidelines, and/or have been addressed in other recent and comprehensive systematic reviews (e.g., epidural steroid injection, perioperative peripheral and central regional anesthetic techniques, and spinal cord stimulation).^32,34-39

III. Methods

All methods used for this systematic review will be conducting in accordance with AHRQ’s Methods Guide for Effectiveness and Comparative Effectiveness Review, developed for the Evidence-based Practice Centers.⁴⁰

Criteria for Inclusion/Exclusion of Studies in the Review: The criteria for inclusion and exclusion of studies for the systematic review will be based on the KQs and on the specific criteria for population, interventions, comparators, outcomes, timing, and settings (PICOTS), listed in the below Table.

Study Design: RCTs will be included. Given the anticipated small number of RCTs, we will also include cohort studies when RCTs are not available, focusing on studies that adjust for potential confounders. Large (n>500) case series will be included for evaluation of serious, rare harms that may not be identified in RCTs and cohort studies. Systematic reviews will be used to identify potentially eligible studies.

Non-English-Language Studies: We will restrict to English-language articles, given the focus on Medicare eligible patients within the U.S. healthcare system.

Literature Search Strategies To Identify Relevant Studies to Answer the Key Questions

Literature Databases: Ovid^® MEDLINE^®, PsycINFO^®, CINAHL^®, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews will be searched. We will also search clinicaltrials.gov for unpublished and in-progress studies. See Appendix A for Medline search strategies.

Publication Date Range: Searches will be conducted across all Key Questions, with study dates reaching back to 1990 for each database. This date corresponds to publication of the earliest clinical studies on the interventional procedures addressed in this review. Searches will be deduplicated and screened for inclusion. Searches will be updated while the draft report is open to public comment, to capture any new publications. Literature identified during the updated search will be assessed by following the same process of dual review as all other studies considered for inclusion in the report. If any pertinent new literature is identified for inclusion in the report, it will be incorporated before the final submission of the report.

Supplemental Evidence and Data for Systematic review (SEADS): Manufacturers and other stakeholders of included drugs and devices will be informed about submitting information relevant to this review using a Federal Register notification. A portal about the opportunity to submit information will be made available on the AHRQ Effective Health Care website.

Hand Searching: To supplement searches on literature databases, reference lists of included articles will be reviewed for includable studies.

Process for Selecting Studies: In accordance with the Methods Guide for Effectiveness and Comparative Effectiveness Review,⁴⁰ we will use the pre-established criteria above to screen citations (titles and abstracts) identified through our searches or Federal Register notification submissions to determine eligibility for full-text review. To ensure accuracy, any citation deemed not relevant for full-text review will be reviewed by a second researcher. All citations deemed potentially eligible for inclusion by at least one of the reviewers will be retrieved for full-text screening. Each full-text article will be independently reviewed for eligibility by two team members. Any disagreements will be resolved by consensus. A record of studies excluded at the full-text level with reasons for exclusion will be maintained.

Data Abstraction and Data Management: After studies are selected for inclusion, data from the studies will be entered into tables. Elements will include, but not be limited to: study design, year, setting, country, sample size, eligibility criteria, attrition, population and clinical characteristics (including age, sex, comorbidities such as medical or psychological disabilities), diagnostic classification/information, pain characteristics (e.g., degree of nociplasticity), sociodemographic factors, intervention component characteristics (including the type, number, intensity, duration of and adherence to treatments), processes of care (e.g., provider types, roles, coordination, decision support, sequence of care components, modifications to treatment), comparator characteristics, program/model characteristics (e.g., goals, emphasis, target population, staffing), and results (including harms). Information relevant for assessing applicability will be abstracted, including the characteristics of the population, interventions, and the number of patients enrolled relative to the number assessed for eligibility. All study data abstraction will be verified for accuracy and completeness by a second team member.

Assessment of Methodological Risk of Bias of Individual Studies: Methods from the Methods Guide for Effectiveness and Comparative Effectiveness Review will be used in concordance with the approach recommended in the chapter, Assessing the Risk of Bias of Individual Studies When Comparing Medical Interventions.^40,41 RCTs will be assessed based on criteria established in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8.5 Risk of Bias Tool),⁴² and instruments tailored to observational studies will be used for non-randomized studies.⁴³  Each study will be independently reviewed for risk of bias by two team members. Any disagreements will be resolved by consensus. Based on the risk of bias assessment, individual included studies will be rated as being "good," "fair," or "poor" quality as described below: 

Good

• Least risk of bias, results generally considered valid
• Employ valid methods for selection, inclusion, and allocation of patients to treatment; report similar baseline characteristics in different treatment groups; clearly describe attrition and have low attrition; use appropriate means for preventing bias (e.g., blinding of patients, care providers, and outcomes assessors); and use appropriate analytic methods (e.g., intention-to-treat analysis)

Fair

• Susceptible to some bias but not enough to necessarily invalidate results
• May not meet all criteria for good quality, but no flaw is likely to cause major bias; the study may be missing information making it difficult to assess limitations and potential problems
• Category is broad; studies with this rating will vary in strengths and weaknesses; some fair-quality studies are likely to be valid, while others may be only possibly valid

Poor

• Significant flaws that imply biases of various kinds that may invalidate results; "fatal flaws" in design, analysis or reporting; large amounts of missing information; discrepancies in reporting; or serious problems with intervention delivery
• Studies are at least as likely to reflect flaws in the study design or execution as the true difference between the compared interventions 
• Considered to be less reliable than higher quality studies when synthesizing the evidence, particularly if discrepancies between studies are present

Data Synthesis: Data will be qualitatively summarized in tables, using ranges and descriptive analysis and interpretation of the results. 

Outcomes will be assessed based on continuous measures (e.g., mean differences) as well as dichotomous measures (e.g., relative risks or odds ratios). Meta-analyses, using profile-likelihood random effects models, will be conducted to summarize data and obtain more precise estimates where there are at least three studies reporting outcomes that are homogeneous enough to provide a meaningful combined estimate.⁴⁴ Study designs will be pooled separately (RCTs vs. cohort studies). Sensitivity and subgroup analyses, including meta-regression, will be performed to explore statistical heterogeneity and differences by study quality, intervention differences, patient characteristics, and outcome measurement, data permitting (e.g. at least six to ten studies for continuous variables and four studies for categorical variables). We will classify the magnitude of effects for continuous measures of pain and function using the same system as in prior and in-progress AHRQ reviews on pain,^45-49 and where possible, will focus on the proportion of patients meeting thresholds for clinically important differences (e.g., >30% improvement in pain). Publication bias will be assessed using funnel plots and statistical methods when there are at least 10 RCTs that can be combined in meta-analysis.⁵⁰

Results will be presented as structured by the Key Questions, and primary outcomes will be presented first. 

Grading the Strength of Evidence (SOE) for Major Comparisons and Outcomes: Outcomes to be assessed for strength of evidence were classified as primary or secondary based on input from the Technical Expert Panel. The strength of evidence for comparison-outcome pairs within each KQ will be initially assessed by one researcher for each clinical outcome (see PICOTS) by using the approach described in the Methods Guide for Effectiveness and Comparative Effectiveness Review.⁴⁰ To ensure consistency and validity of the evaluation, the initial assessment will be independently reviewed by at least one other experienced investigator using the following criteria; disagreements will be resolved by consensus:

• Study limitations (low, medium, or high level of study limitations)
  • Rated as the degree to which studies for a given outcome are likely to reduce bias based on study design and conduct. The aggregate risk of bias across individual studies reporting an outcome is considered.
• Consistency (consistent, inconsistent, or unknown/not applicable)
  • Rated by degree to which studies find similar magnitude of effect (i.e., range sizes are similar) or same direction of effect (i.e., effect sizes have the same sign)
• Directness (direct or indirect)
  • Rated by degree to which the outcome is directly or indirectly related to health outcomes of interest. Patient centered outcomes are considered direct
• Precision (precise or imprecise) 
  • Describes the level of certainty of the estimate of effect for a particular outcome with a precise estimate being on that allows a clinically useful conclusion.  This may be based on sufficiency of sample size and number of events, and if these are adequate, the interpretation of the confidence interval.  When quantitative synthesis is not possible, sample size and assessment of variance within individual studies will be considered.
• Reporting bias (suspected or undetected)
  • Publication bias, selective outcome reporting, and selective analysis reporting are types of reporting bias. Reporting bias is difficult to assess as systematic identification of unpublished evidence is challenging. If sufficient numbers of RCTs (>10) are available, quantitative funnel plot analysis may be done.

The strength of evidence will be assigned an overall grade of high, moderate, low, or insufficient according to a four-level scale by evaluating and weighing the combined results of the above domains.

High: We are very confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has few or no deficiencies. We believe that the findings are stable, i.e., another study would not change the conclusions.

Moderate: We are moderately confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has some deficiencies. We believe that the findings are likely to be stable, but some doubt remains.

Low: We have limited confidence that the estimate of effect lies close to the true effect for this outcome. The body of evidence has major or numerous deficiencies (or both). We believe that additional evidence is needed before concluding either that the findings are stable or that the estimate of effect is close to the true effect.

Insufficient: We have no evidence, we are unable to estimate an effect, or we have no confidence in the estimate of effect for this outcome. No evidence is available, or the body of evidence has unacceptable deficiencies, precluding reaching a conclusion.

Bodies of evidence consisting of RCTs are initially considered as high strength while bodies of comparative observational studies begin as low-strength evidence. The strength of the evidence may be downgraded based on the limitations described above. There are also situations where the observational evidence may be upgraded (e.g., large magnitude of effect, presence of dose-response relationship or existence of plausible unmeasured confounders) as described in the AHRQ Methods Guide.^40,41  Where both RCTs and observational studies are included for a given intervention-outcome pair, we follow the additional guidance on weighting RCTs over observational studies, assessing consistency across the two bodies of evidence, and determining a final rating.⁴⁰ 

Assessing Applicability: Applicability to U.S. practice settings and the Medicare population (i.e., persons eligible for Medicare due to age ≥65 or disability [including ESRD]) will be assessed based on the EPC Methods Guide, using the PICOTS framework.⁴⁰ Applicability refers to the degree to which outcomes associated with the intervention are likely to be similar across patients and settings relevant to the care of the Medicare population based on the populations, interventions, comparisons, and outcomes synthesized across included studies. Factors that may affect applicability, which we have identified a priori include (1) patient factors (e.g., age and disability status, medical and psychiatric comorbidities, symptom severity, duration and underlying pain condition); (2) technical factors (e.g., medications used [for procedures that involve medications], intensity or dose, number of treatments, frequency of treatments, duration of treatment, use of imaging guidance, technique utilized, and clinical background of person performing the procedure [e.g., anesthesia pain medicine, interventional radiology, or other]); (3) comparators (e.g., sham procedure, no treatment, or usual care); (4) outcomes (e.g., use of nonstandardized or unvalidated outcomes); and (5) settings (e.g., country). We will use information regarding these factors to assess the extent to which interventions and results are likely most relevant to real-world clinical practice in typical U.S. settings that include the Medicare population. We will provide a qualitative summary of our assessment.

IV. References

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39. Chou R, Hashimoto R, Friedly J, et al. Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Sep 1;163(5):373-81. doi: 10.7326/m15-0934. PMID: 26302454.
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V. Definition of Terms

Not applicable. 

VI. Technical Experts

Technical Experts constitute a multi-disciplinary group of clinical, content, and methodological experts who provide input in defining populations, interventions, comparisons, or outcomes and identify particular studies or databases to search.  The Technical Expert Panel is selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicting opinions are common and perceived as healthy scientific discourse that fosters a thoughtful, relevant systematic review. Therefore, study questions, design, and methodological approaches do not necessarily represent the views of individual technical and content experts.

Technical Experts provide information to the EPC to identify literature search strategies and suggest approaches to specific issues as requested by the EPC. Technical Experts do not do analysis of any kind; neither do they contribute to the writing of the report. They do not review the report, except as given the opportunity to do so through the peer or public review mechanism.

Members of the TEP must disclose any financial conflicts of interest greater than $5,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as Technical Experts and those who present with potential conflicts may be retained. The AHRQ TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

VII. Peer Reviewers

Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodological expertise. The EPC considers all peer review comments on the draft report in preparing the final report. Peer reviewers do not participate in writing or editing of the final report or other products. The final report does not necessarily represent the views of individual reviewers.

The EPC will complete a disposition of all peer review comments. The disposition of comments for systematic reviews and technical briefs will be published 3 months after publication of the evidence report.

Potential peer reviewers must disclose any financial conflicts of interest greater than $5,000 and any other relevant business or professional conflicts of interest.  Invited peer reviewers with any financial conflict of interest greater than $5,000 will be disqualified from peer review. Peer reviewers who disclose potential business or professional conflicts of interest can submit comments on draft reports through the public comment mechanism.

VIII. EPC Team Disclosures

EPC core team members must disclose any financial conflicts of interest greater than $1,000 and any other relevant business or professional conflicts of interest. Direct financial conflicts of interest that cumulatively total more than $1,000 will usually disqualify an EPC core team investigator.

IX. Role of the Funder

This project was funded under Contract No. 75Q80120D00006 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The AHRQ Task Order Officer reviewed the EPC response to contract deliverables for adherence to contract requirements and quality. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by either the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

X. Registration

This protocol will be registered in the international prospective register of systematic reviews (PROSPERO).

Appendix A. MEDLINE Search Strategies

Database: Ovid MEDLINE(R) ALL 1946 to September 18, 2020

1. chronic pain/ or acute pain/ or exp arthralgia/ or exp back pain/ or exp headache/ or exp musculoskeletal pain/ or neck pain/ or exp neuralgia/ or exp nociceptive pain/ or pain, intractable/ or fibromyalgia/ or myalgia/ or exp peripheral nervous system diseases/ 
2. (((back or spine or spinal or vertebral or leg or musculoskeletal or neuropathic or nociceptive or radicular) adj1 pain) or headache or arthritis or fibromyalgia or osteoarthritis or neuralgia or neuropath*).ti,ab,kw. 
3. ((acute or chronic or persistent or intractable or refractory) adj3 pain).ti,ab,kw. 
4. or/1-3 
5. exp Cementoplasty/ 
6. exp Injections/ 
7. (anesthetic or anaesthetic or corticosteroid* or steroid* or botulinum).ti,ab,kf,sh. 
8. 6 and 7 
9. Denervation/ 
10. Sphenopalatine Ganglion Block/ 
11. Methylene Blue/ 
12. Ozone/ 
13. (("platelet rich plasma" or "methylene blue" or ozone) adj2 (intradiscal or disc*)).ti,ab,kf. 
14. (intradiscal or disc*).ti,ab,kf. 
15. (11 or 12) and 14 
16. (piriformis adj3 injection).ti,ab,kf. 
17. (vertebroplasty or kyphoplasty).ti,ab,kf.
18. "sphenopalatine block".ti,ab,kf. 
19. (sphenopalatine adj2 (block or injection*)).ti,ab,kf. 
20. ((cool* or cryo* or cold) adj3 denervation).ti,ab,kf. 
21. (occipital adj3 stimulat*).ti,ab,kf. 
22. 5 or 8 or 9 or 10 or 13 or 15 or 16 or 17 or 18 or 19 or 20 or 21 
23. 4 and 22 
24. limit 23 to randomized controlled trial 
25. (random* or control* or trial or cohort or prospective or retrospective).ti,ab,kf,sh. 
26. 23 and 25 
27. 24 or 26