The American Society of Pain and Neuroscience (ASPN) Evidence-Based Clinical Guideline of Interventional Treatments for Low Back Pain

IntroductionObjectives, Scope, and Goals

The objective of the American Society of Pain and Neuroscience (ASPN) Evidence-Based Clinical Guideline for Interventional Treatments of low back pain (LBP) is to provide evidence-based recommendations to address the appropriate utilization of interventional treatments for LBP. This guideline is intended to represent a comprehensive review of the spectrum of interventional treatments for LBP. The guideline is based upon the highest quality of clinical evidence available at the time of publication. The goals of the guideline are to assist clinicians in delivering the highest quality evidenced back interventional treatments, as well as understanding the known risks and complications of interventional treatments. The ASPN Back Guideline is intended to be updated periodically to maintain relevance with the current treatment landscape and empirical literature. Although the guideline represents a comprehensive review of the majority of the interventional treatments for LBP, it is important to note that not all interventional techniques were included. Exclusion of any particular technique does not necessarily suggest that the omitted therapies are inappropriate clinical use. The ASPN Back Guideline does not represent a standard of care. Treatment should be based on an individual patient’s need and the physician’s professional judgement and experience. This guideline is not intended to be used as the sole reason for denial or approval of treatment or services.

ASPN Back Guideline Clinical Committee and Multidisciplinary Collaboration

The ASPN clinical guideline committee is comprised of a diverse group of physicians representing the specialties most commonly involved in the provision of interventional treatments of LBP. This includes physicians from the core specialties of anesthesiology, neurosurgery, physical medicine and rehabilitation, and radiology, as well as a pain psychologist/medical ethicist with many years of experience in consulting with interventional physicians. Committee members were selected based on clinical experience, research, and previous publication history.

Disclosures of Potential Conflicts of Interests

All participants involved in the guideline development have been required to disclose all potential conflicts of interest. All evidence grading was reviewed and validated by committee members with no potential conflict of interest for any particular therapy. Authors with conflicts of interest on subjects with grading criteria were recused from those particular items.

Methods for Literature Search, Evidence Ranking and Consensus Development

The world literature in English from 2000-present was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for lower back interventional therapies for the treatment of pain. Search words were created specific to the topics for each major section pertaining to injection therapy, minimally invasive spine procedures and ablative procedures. Identified peer-reviewed literature was critiqued using the United States Preventive Services Task Force (USPSTF) criteria for quality of evidence,1 with modifications for interventional pain studies (Table 1). The hierarchy of evidence for the project considered RCT as the preeminent classification, followed by prospective observational studies, case series and finally expert opinion. Per the methodology, the process identified RCT and prospective observational studies of STROBE criteria quality in the creation of guidelines. Interventions with more than one RCT were considered to have sufficient evidence to create conclusions, and observational studies were not considered. Interventions with no RCTs or only one RCT then also utilized prospective observational studies in the creation of guideline recommendations. Should an intervention be found to have no RCTs or observational studies, case series were used. These are clearly denoted by the taxonomy of the recommendation that the predominant quality of evidence is of a classification less than RCT. For interventions where RCT and prospective observational studies are of requisite quality (STROBE) are not available, case series and/or expert opinion may be used in the creation of guidelines to fill in the current literature gap to assist the clinician in selecting care pathways. These designations follow a modified USPSTF process used previously by ASPN and NANS in the creation of guidelines. The details are listed in Table 1. After USPSTF letter grading was assigned, the working subgroup then assigned the “level of certainty regarding benefit” as described in Table 2.

Table 1 Quality of Evidence Ranking Using United States Preventative Services Task Force Criteria Modified for Interventional Spine Procedures

Table 2 Levels of Certainty Regarding Net Benefit

For each major section or topic, the ASPN Back Group formulated consensus points. Consensus points should not be confused with recommendations based on consensus alone, which were rendered as clinical guidance due to the lack of evidence-based literature (such as randomized controlled trials [RCTs], prospective observational studies, retrospective cohort/case series).

Injection TherapyEpidural Steroid Injections

LBP has consistently been one of the most common causes of functional limitation and absence from work, as it impacts over 80% of the general population around the world.2,3 A common diagnosis of LBP is lumbar radiculopathy, with a prevalence between 9.9% and 25%.4 Lumbar radiculopathy is generally defined as LBP that radiates down below the knees to the foot and toes and can be associated with neurological findings such as paresthesia and weakness. Radiculopathy is not only secondary to mechanical compression but may also be due to the release of inflammatory mediators at the site of pathology.5 When comparing to LBP without radicular symptoms, lumbar radiculopathy is associated with more disability and pain, and thus causes decreased quality of life and increased utilization of health resources.6 Per current guidelines around the world, treatment for lumbar radiculopathy includes spinal injections, specifically lumbar epidural steroid injections.

Epidural steroid injections are generally performed with three different approaches: interlaminar (midline or parasagittal), transforaminal or caudal. The interlaminar approach is widely used, but limitations can include lack of target specificity and the injectate being distributed to the dorsal epidural space, as opposed to the ventrolateral space.7 The transforaminal approach, however, is considered to be more specific as this injection localizes the injectate into the ventrolateral epidural space, which is anatomically located in close proximity to the nerve root.7 The caudal approach can be specifically utilized and may be advantageous in patients with previous spine surgeries, such as a lumbar fusion or laminectomy, in which cases it may be unsafe or anatomically impossible to utilize the interlaminar or transforaminal approach.

Corticosteroid injectable agents are divided into two groups: non-particulate and particulate. Non-particulate corticosteroids are faster in onset but have much shorter acting anti-inflammatory properties. On the other hand, particulate corticosteroids have a slower onset with a longer anti-inflammatory effect. Particulate corticosteroids include triamcinolone, methylprednisolone and betamethasone acetate and are insoluble in saline, local anesthetic and iodinated contrast agents,8 whereas non-particulate corticosteroids such as betamethasone sodium phosphate and dexamethasone are soluble in all agents.8 Of the corticosteroids, methylprednisolone is the largest in size while betamethasone is the smallest.8

The evidence for the three types of epidural steroid injections and analysis of the literature will serve as the foundation to provide recommendations and guidelines for each type of injection. There have been 48 systematic reviews and 42 RCTs examining the efficacy of epidural steroid injections in the management of chronic spinal pain.9 These studies have suggested that epidural steroid injections have clear but often not long-lasting reduction in chronic spinal pain.9 The most recent and authoritative of these systematic reviews was performed by Manchikanti et al. This review outlined the efficacy and the evidence-based recommendations for conditions treated with epidural injection therapy. Additionally, this review comprehensively evaluated the efficacy of each epidural treatment approach (caudal, interlaminar, transforaminal) for given spinal indications (disc herniation, lumbar spinal stenosis, etc.). Given the comprehensive nature and recency of that review, we will briefly summarize the results from that manuscript as: 1) no new studies were identified in our search process and 2) there have been numerous authoritative reviews of this modality.

Interlaminar Epidural Steroid Injection

The Manchikanti review identified 13 high-quality RCTs evaluating the efficacy of interlaminar steroid injections. Ten studies were rated as high quality. The review concluded that there is Level I evidence treatment of lumbar disc herniation with interlaminar epidural steroid injections and Level II evidence for the treatment of lumbar spinal stenosis and axial/discogenic pain. The manuscript also suggests that overall the treatment effect has been rated as significant with the exception of systematic reviews with methodological flaws. These reviews were not specified. No new or additional studies were identified in our review process in the interval between publication of the Manchikanti study and the preparation of this manuscript.

Transforaminal Epidural Steroid Injection

In the Manchikanti review, there were 13 high-quality RCTs evaluating the efficacy of transforaminal epidural steroid injections. The majority of the studies examined the efficacy of transforaminal approaches in the setting of disc herniation. The evidence synthesis suggested Level I evidence for transforaminal injections in the setting of disc herniation and Level II evidence in the setting of lumbar spinal stenosis.

Caudal Epidural Steroid Injection

In the Manchikanti review, there were ten high-quality RCTs meeting inclusion criteria. Two compared caudal epidural injections to interlaminar and transforaminal injections in the management of disc herniation, while one study compared transforaminal injections to caudal injections in the management of lumbar disc prolapse. The remaining studies evaluated treatment of spinal stenosis, axial back pain or post-surgery syndrome. None of the RCTs were placebo controlled. Using the criteria methodology from that review the following conclusions were drawn concerning caudal epidural steroid injections: Level III evidence that caudal and interlaminar approaches are equivalent, Level II–III evidence for treatment of lumbar spinal stenosis with caudal approaches, Level II in post-surgery syndrome, Level III evidence that transforaminal approaches are superior to caudal approaches.9

Evidence Summary

For epidural interventions, RCTs and observational studies with functional status improvement measures were included. Short-term relief was defined as less than six months whereas greater than six months was considered long-term relief. The ASPN consensus guideline committee reviewed the 36 RCTs mentioned above as being of high quality. No additional studies were identified in our search process. For epidural interventions, there was sufficient evidence in the form of RCTs (Table 3), for the committee to make recommendations. Table 4 summarizes those recommendations.

Table 3 Evidence Summary for Epidural Steroid Injections

Table 4 ASPN Back Consensus Group Recommendations for Epidural Steroid Injections

Trigger Point Injections

For trigger point interventions, there was sufficient evidence in the form of RCTs for the committee to make recommendations. A review of RCTs regarding TPIs has revealed 25 studies investigating the efficacy of these injections for myofascial pain syndrome (MPS) with diverse medications. Over 40 RCTs were found through a PubMed literature search for “trigger point injection” that studied trigger point injections (technical variations, adjuncts for MPS treatment, and in comparison to other treatments for MPS). Given the volume of RCTs available, a focus was placed on literature published within the past five years with a focus on further studies outside this time frame to evaluate and clarify points made.

MPS is a soft tissue pain condition, characterized by a localized taut band of muscle that can cause acute or chronic pain.10 This condition is clinically diagnosed by identification of the characteristic taut bands on physical exam and a history indicative of myofascial pain, although objective means for diagnosis are often costly and not widely available. Diagnostic criteria defined by Simons et al are often referenced when describing the features of trigger points including the presence of taut bands, tenderness from taut bands, reproducibility of pain, local twitch response, restricted range of motion, autonomic symptoms, and referred pain.11 Palpation of an active trigger point can cause referred pain through activation of the central nervous system along with the distribution of the nerve innervating the muscle that is activated.12 Once diagnosed, MPS is treated by a variety of modalities including pharmacologic therapies (namely nonsteroidal anti-inflammatory drugs), therapy (including dry needling and acupuncture), and trigger point injections (TPIs).

Indications and Contraindications

TPIs should be considered in patients after thorough evaluation has ruled out other causes of back pain including muscle strain, facetogenic back pain, discogenic back pain, vertebrogenic back pain, spinal cord stenotic disease, vertebral body disease (including fracture), and radicular back pain. Once MPS has been diagnosed with the criteria outlined by Simons et al,11 patients can be trialed with conservative management, including pharmacologic therapy and physical therapy. If MPS persists and taut bands are identified, it is reasonable to perform TPIs. Contraindications for the procedure include patient refusal, infection overlying the site of injection and concurrent use of specific anticoagulants and anti-platelet medications.13

Safety/Complications

Though relatively safe as TPIs are generally performed with large gauge short needles by anatomic technique through identification of taut bands by physical examination, they are occasionally associated with complications specific to the region at which the injections are performed, namely the cervical and thoracic region. A 2004 study by Fitzgibbon et al characterized 5475 claims from the American Society of Anesthesiologists Closed Claims Project between 1970 and 1999 for chronic pain, with the authors determining that 284 pain management-specific claims (5.1%) were made with 276 of these claims (5.0% of total claims, 97.1% of pain management claims) were for invasive procedures.14 Of those claims, 138 (50%) involved injections (50%), including 17 claims for TPIs (6.1% of pain management claims, 12.3% of injection-specific claims). Interestingly, when assessed for complication type, 18 incidences of pneumothorax were reported with injections out of 59 total from all of the pain management associated claims (30.5%), of which 15 were associated with TPIs (83.3% of all injection associated pneumothoraxes; 88.2% of all TPI-associated claims).14

A review of the literature regarding complications of TPIs reveals a general dearth of publications, although a number of reports of complications associated with dry needling and acupuncture have been published. One of the first articles addressing TPI-associated complications of pneumothorax was published by Shafer in 1970.15 Subsequently, several additional case reports have been published, including one by Ahiskalioglu et al, in which a patient developed pneumothorax following cervical and thoracic TPIs.16 In their report, a 25-year-old 45 kg female received TPIs to her trapezii, supraspinatus, levator scapulae, and rhomboideus muscles with subsequent development of pneumothorax.16 Fortunately, this episode was self-resolving through conservative care and close follow-up. Paik et al published a case report in which a CT-guided aspiration was required for a 25-year-old female who developed a right-sided pneumothorax following a right trapezius TPI.17

Local anesthetics are often used for TPIs, and there is also a risk of reversible myotoxicity. In a review by Zink et al examining reports of histologic changes of skeletal muscle upon exposure to various local anesthetics (procaine, carbocaine, lidocaine tetracaine, chloroprocaine, bupivacaine) suggested that all local anesthetics studied resulted in some degree of reversible myotoxic effects in experimental models. However, few reports of clinical myotoxic reports have been published.18 No incidences of bowel perforation or pneumoperitoneum associated with TPIs were found through a thorough literature review. TPIs are considered a low-risk procedure and one should abide by the multi-specialty, multi-organizational guideline publication on peri-procedural antiplatelet and anticoagulant management for interventional spine and pain procedure when performing these injections.13

Evidence Summary

A review of RCTs regarding TPIs has revealed several studies investigating the efficacy of these injections for MPS with diverse medications. Over 40 RCTs were found through a PubMed literature search for “trigger point injection” that studied trigger point injections (technical variations, adjuncts for MPS treatment, and in comparison to other treatments for MPS). A focus was placed on literature published within the past 5 years with a focus on further studies outside this time frame to further evaluate and clarify points made by recent studies (Tables 5 and 6).

Table 5 Evidence Summary for Trigger Point Injections

Table 6 ASPN Back Consensus Group Recommendations for Trigger Point Injections

Facet Interventions

Facet interventions have a long history of clinical effectiveness, and there are multiple systematic reviews examining the efficacy of the technique. The current section will review recent efficacy studies with an eye toward answering several relevant clinical questions concerning facet intervention such as the role of articular injections vs RFA, facet intervention and medical management, risk mitigation for intra-arterial injection and prognostic value of diagnostic blocks.

Lumbar facet joint pain is one of the most common types of axial back pain. Its prevalence varies greatly in the literature, with estimates of prevalence ranging from as low as 4.8% to over 50%.19–22 Many of the studies investigating prevalence have been methodologically flawed. The wide disparity in reported prevalence demonstrates the need for standardized criteria on how to properly diagnose lumbar facet pain. In addition, there is a poor correlation between lumbar facet joint pathology on imaging and LBP.23 Numerous questions have been raised regarding the ideal cutoff for determining whether a diagnostic block is positive, how many blocks should be performed before considering radiofrequency ablation (RFA) and the volume of local anesthetic that should be injected.24–29 Lumbar facet interventions are the second most commonly performed procedures for chronic pain, yet there is still controversy regarding their effectiveness.30,31 While most reviews concluded that RFA is effective for lumbar facet joint pain,32–35 some studies dispute this.31,35 Facet blocks, including intra-articular and medial branch blocks, are frequently used prior to radiofrequency ablation. Cohen et al36 in the FACTS, RCT discussed effectiveness of lumbar facet joint blocks and predictive value prior to the procedure. This randomized study established the lack of long-term therapeutic benefit for intra-articular and medial branch facet blocks but suggested the possibility that when used as prognostic tools, these injections may provide superior outcomes prior to RFA on some measures compared to control blocks. For intra-articular injections, most reviews have concluded that the injections are ineffective,31,32,34,37,38 although some studies indicate they may provide some benefit compared to sham and conservative treatment.39–41

Consensus practice guidelines on interventions for lumbar facet joint pain developed by a multispecialty, international working group42 concluded that lumbar medial branch RFA may provide benefit to well-selected individuals, with medial branch blocks (MBB) being more predictive than intra-articular (IA) injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of more false-negatives,42 potentially missing many patients that could benefit from RFA procedures. Physical examination signs such as tenderness over the facet joints, lumbar paraspinal tenderness and increased pain with trunk extension can help improve diagnostic accuracy. However, most reviews and guidelines do not support positive physical examination requirements for a diagnosis of lumbar facet pain,43,44 but rather favor diagnostic injections as the only reliable means for diagnosing it. Physical examination such as palpation of the lumbar spine under fluoroscopy and recognizing pain referral patterns can help determine the levels at which a diagnostic block can be performed. Regarding imaging studies such as scintigraphy, magnetic resonance imaging (MRI) and CT, there is weak or no evidence supporting the use of these imaging modalities for identifying painful lumbar facet joints prior to MBB or IA facet joint injections.45,46 Although there is insufficient evidence regarding the optimal timing of facet joint blocks for chronic LBP, or the duration of conservative treatment prior to consideration of facet injections, 3 months of conservative therapy prior to considering facet interventions is typically considered acceptable Compared with saline controls, both IA and medial branch injections with a local anesthetic (LA) provide better predictive information for medial branch RFA.36 Despite the lack of large prospective studies comparing the prognostic value of MBB and intra-articular facet injections as a screening procedure prior to RFA, some studies32,47,48 concluded that medial branch blocks are superior to intra-articular facet injections in predicting the success of RFA and should be the preferred screening method. Intra-articular injections of corticosteroids may, however, be used as a therapeutic injection for certain patients with suspected inflammatory pain, and in those who want to avoid ablative therapies, such as young athletes.49,50

The volume of the injectate for MBB and IA facet injections remains a subject of debate. Injecting excessive volumes can lead to spread of the injectate to adjacent structures such as the epidural space, spinal nerves, musculature and ligaments, undermining the specificity and positive predictive value of RFA. In addition, injecting insufficient volumes can lead to capsule distension and rupture in cases of IA injections. There are no studies evaluating the prognostic effect of the injectate volume on RFA outcomes. For MBB, there are several studies evaluating the efficacy of lumbar facet MB RFA using different volumes36,51–53 such as 0.3 mL, 0.5 mL, 0.75 mL and 1 mL with no difference in outcomes based on injectate volume. For IA injections, the joint capsule volume ranges from 1mL to 2 mL.54 Different volumes have been used in different RCTs examining the prognostic value and efficacy of IA injections. Large injectate volumes may result in rupture of the joint capsule and inadvertent spread to other potential pain generators, thereby undermining specificity. On the other hand, insufficient volumes may fail to anesthetize the joint, leading to false-negative blocks. In short, the accepted consensus is to use a volume of 0.5 mL–1.0 mL for MBB to reduce spread to adjacent structures and a volume of less than 1.5 mL for IA injections to prevent capsular rupture and spread to adjacent structures. Adding steroids to the injectate for MBB and IA injections for diagnostic purposes should be avoided. Many studies provide evidence against the use of intra-articular steroids.36,55,56

In Phase I of a three-arm double-blind study that compared IA LA and steroid lumbar facet injections, MBB with LA and steroid, and saline control blocks, Cohen et al36 found no significant differences in any outcome measure at any time point in the 6-month follow-up. Based on a review of evidence, the routine use of therapeutic facet injections is not recommended. However, there are a few exceptions, such as patients who may be at risk of complications from RFA (young athletes, older individuals on anticoagulation therapy or with implantable cardiac devices). In those cases, it is reasonable to add steroids to a block for possible intermediate-term relief. The number of diagnostic MBBs before RFA remains a subject of controversy. The American Society of Interventional Pain Physicians (ASIPP) and the Spine Intervention Society (SIS) advocate for the use of two diagnostic blocks prior to RFA19,44 to minimize placebo effects and false-positive results. False-positive results can also be contributed to spilling of the injectate into surrounding structures, use of sedation, use of copious superficial anesthesia and resting while not performing normal activities following the block.32,57 There are several reasons for false-negative blocks, including intravenous uptake, failure to anesthetize the target nerve, inability to access the joint for IA injections, aberrant anatomy, procedure-related pain such as muscle soreness and spasm and opioid-induced hyperalgesia. The decision whether to perform a single block, double block or no blocks is based on weighing false-positive versus false-negative results. There exists evidence that the success rate for medial branch RFA will increase with the number of blocks, but this will occur at the expense of missing out on some patients with false-negative results who could have benefited from the RFA. The multispecialty, international working group42 advocates for the use of a single block prior to RFA. They concluded that dual blocks result in a higher subsequent success rate for medial branch RF, but that the use of no diagnostic MBB results in the highest overall number of patients with a positive response to the RFA, thereby making a single block the “middle ground” option. They concluded that the decision to either proceed straight to RFA, performing a single block or double blocks can be tailored to the clinical scenario. Another debatable subject is the cutoff that should be used to consider a block as successful. Several studies compared outcomes of RFA based on percentage of relief from MBB, using different cutoffs including 50%, 80% and 70%.24,48,58–63 A 50% or greater cutoff is generally the most accepted model. In addition, other parameters to measure functional improvement should be considered when assessing the success of a diagnostic block.

Indications and Contraindications

Lumbar facet MBBs and intra-articular facet injections are indicated in the diagnosis and possible treatment of LBP due to lumbar facet joint pathophysiology. Chronic facet pain due to osteoarthritis (OA) has been associated with degenerative disc disease (DDD). DDD results in concomitant changes in the facet joints, and the reverse is also true: degeneration and motion abnormalities of the facet joints can accelerate disc degeneration. DDD usually precedes facet joint arthritis, and it is well noted that facet arthropathy is more prevalent at spinal levels with advanced DDD. Other conditions other than facet OA may cause facet-induced pain. Inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis and reactive arthritis can use lumbar facet pain. Other less common conditions such as pseudogout, synovitis, chondromalacia facetae and infection can also cause facet pain. Facet synovial pseudocysts can cause axial back pain as well as possible radicular pain due to compression of adjacent structures. Severe trauma such deceleration injuries and motor vehicle accidents can cause dislocation of the lumbar facet joints and lumbar facet pain following the trauma. Contraindications include patient refusal, ongoing active infection, and allergy to the medications used. Coagulopathy and patients on anticoagulants should be assessed prior to performing these interventions. Benefit versus risk analysis should be performed for those patients prior to proceeding with the injection.

Complications

The risks and complications from lumbar facet injections can be due to vascular penetration and injury, injection, procedure-related pain and injury to non-target neural structures. The incidence of vascular penetration and positioning of the needle intravascularly varies from 3.6% to 20%.64–69 A multispecialty, international working group42 and other societies such as SIS recommend checking for intravascular placement of the needle tip by aspirating and visualizing the spread of contrast on fluoroscopy in real-time prior to performing MBBs to reduce false-negative results. This should ideally be done in a manner such that the total injectate dose (LA and contrast) is kept as low as possible to minimize the effect on local anesthetic dispersion.42 Most societies recommend continuation of non-heparin anticoagulants prior to lumbar facet MBBs, as the risk of discontinuation of those medications such as development of thromboembolic events outweighs the benefits. Post-procedural pain can lead to false-negative results for the prognostic MBB, particularly in patients experiencing opioid-induced hyperalgesia. Manchikanti et al68 found that irritation of the nerve roots occurred in 0.1% of patients but found no long-term neural deficits out of 3162 MBBs performed. Proper use of fluoroscopic or CT guidance is recommended for MBBs and IA facet injections, although ultrasound guidance can be used by physicians highly skilled and experienced in ultrasound. Proper formal training in interventional pain procedures is recommended for physicians performing MBBs and IA facet injections to avoid complications and improve outcomes.

Evidence Summary

A review of RCTs for facet joint injections reveals several studies investigating the efficacy of these injections for LBP. A PubMed literature search yielded 11 RCTs evaluating lumbar facet injections and/or medial branch blocks for LBP during the literature review time period warranting inclusion. The focus was placed on literature published during this time period. Other landmark studies published outside of this time frame were also evaluated to clarify and support data from more recent studies. For facet interventions, there was sufficient evidence in the form of RCTs (Table 7), for the committee to make recommendations. Table 8 summarizes those recommendations.

Table 7 Evidence Summary for Intra-Articular Facet Joint Injections

Table 8 ASPN Back Consensus Group Recommendations for Intra-Articular Facet Injections

Two of the main questions regarding intra-articular facet joint injections are 1) do they replace radiofrequency ablation, and 2) do they delay the need for radiofrequency ablation.56,70 Most of the data suggests that intra-articular facet joint injections are not therapeutic, and they do not replace or delay the need for radiofrequency ablation.36,56,70 However, there are several studies that suggest otherwise. For example, Wu et al demonstrated that both autologous platelet-rich plasma and intra-articular steroid injections were effective for treating lumbar facet joint syndrome.71 In addition, Sae-Jung et al determined that methylprednisolone facet joint injections were effective for facet-mediated LBP but augmented with the addition of diclofenac.72

Intradiscal Regenerative Therapies

The intervertebral disc plays a crucial role in the health of the spine complex. Several pathologies of the disc itself, including internal disc disruption, tears, degeneration, and loss of height can all predispose patients to discogenic back pain and its sequelae. The disc is a central part of the interconnected biomechanical system of the spine, which allows for mobility and distribution of stress. Degeneration often correlates with loss of disc height that can lead to excess motion and instability. While this review will focus on treating pain originating from the disc itself, damage to the disc may lead to excess forces and subsequent damage throughout the spine.

The disc is a sensitive environment as it depends on diffusion for nutrients and waste movement due to its avascular nature at baseline. This diffusion capacity is relatively poor and worsens with both increasing age and pathology. In healthy discs, nerve endings are limited to the outer one-third of the disc and are not found in the inner annulus or nucleus pulposus region.73 In degenerated discs, nociceptive nerve fibers along with vasculature may migrate into the central disc regions.74 It is theorized that neurotransmitters together with changes within the extracellular matrix itself and the release of cytokines regulate this nerve ingrowth. In addition, pain-related peptides and proinflammatory cytokines are increased.

A common cause of disc failure is overloading in which forces may lead to desiccation of the disc and annular tears. The disc itself has a limited compression capacity which worsens with decreasing fluid content. To improve disc failure, the premise is to regain or maintain disc height to reduce the axial nerve compression and to restore the tissue dynamics (fluid content) of the annulus. A second goal is to possibly reconstitute the central nucleus with a matrix environment that can hold fluid and improve nutritional flow. Using regenerative medicine, the hope is to improve the damaged internal environment of the disc by reconstituting a matrix that may improve and return disc function.75

Indications

Intradiscal regenerative medicine has primarily been studied in patients with intractable chronic LBP for at least 3–6 months despite failure of a multi-modal treatment approach including indicated medications, physical therapy, and other interventional procedures as per recommendation guidelines. Patients should have history, physical exam, and radiologic findings consistent with their symptomatic lumbar intervertebral discogenic pain. Provocative discography can further specify the source of pain and the precise level(s) to treat.

Safety and Complications

The overall safety profile of regenerative therapies is excellent and comparable to standard intradiscal procedures. Rare adverse events may include LBP, muscle spasms, and discitis. Standard intradiscal precautions should be taken with an emphasis on sterile technique in both the preparation of the injectate and the intradiscal procedure itself. To further illustrate this significance, a case of spondylodiscitis with positive Cutibacterium acnes culture has been reported subsequent to platelet-rich plasma (PRP) intradiscal injections. The authors stressed the importance of appropriate sterile technique and risk-stratification of patients with high infection potential, as well as better understanding of intradiscal biologic therapies and the intradiscal environment.76 Traditional antibiotic therapy protocols for intradiscal interventions may benefit from further review specifically regarding regenerative medicine.

Evidence Review with Evidence Level Designation: Intradiscal Regenerative Therapies

It is important to understand that not all biologics used in regenerative medicine are equivalent. For instance, factors at a minimum that can affect the final PRP product include volume of blood aspirated, baseline platelet count, patient health status and comorbidities, patient medications, anticoagulant of choice, centrifugation parameters, and inclusion/exclusion of leukocytes. Similarly, mesenchymal stem cells (MSCs) are found in most tissues of the human body but primarily sourced for reimplantation from the bone marrow and adipose due to ease of access. Volume of aspirate, patient health status and comorbidities, patient medications, harvesting protocol parameters and technique can all affect the final MSC product. Not distinguishing this heterogeneity, we have summarized the gross clinical evidence evaluating regenerative medicine for LBP from discogenic pathology, including prolotherapy, protein-rich plasma (PRP), cellular therapy, and other intradiscal injectates (Table 9).

Table 9 Evidence Summary for Intradiscal Regenerative Therapies

Evidence Review with Evidence Level Designation: Prolotherapy and Platelet Rich Plasma

Prolotherapy is among the earliest studied regenerative medicines. There have been several prospective and retrospective trials and case reports studying PRP, although only one published RCT. A prospective, double-blind, randomized controlled trial by Tuakli-Wosornu et al in 2016 investigated intradiscal PRP for treatment of chronic moderate to severe lumbar discogenic pain unresponsive to conservative treatment and confirmed with discography. Twenty-nine patients received intradiscal PRP with the control group consisting of 18 patients who received only intradiscal contrast. Over 8 weeks of follow-up, there were significant improvements in participants who received the intradiscal PRP with regard to pain, function, and patient satisfaction compared with the controls.77 Furthermore, those who received PRP were able to maintain significant improvements in the Functional Rating Index for at least 1-year follow-up. In 2019, Cheng et al performed a 5-to-9-year follow-up on the same patients from the aforementioned RCT by Tuakli-Wosornu et al. From the PRP intervention group, 21 of the 29 original patients were able to be included in this follow-up study. Seventy-one percent were classified as successes as they demonstrated both clinical and significant improvements in pain and function. The remaining 29% of patients required spinal surgery and were classified as failures. This study further supports improvements in pain and function post-intradiscal injection of PRP sustained for follow-up periods of 5–9 years following intradiscal PRP treatment for moderate-severe lumbar discogenic pain.78

Cellular Therapy

Several case series and prospective studies have investigated the use of intradiscal autologous stem cells for lumbar discogenic pain. Overall, there is moderate evidence, including that from two relatively small size RCTs, supporting intradiscal allogeneic mesenchymal stem cells in the treatment of discogenic LBP. Regarding human umbilical cord tissue-derived mesenchymal stem cells, there is a single study of small sample size producing low evidence in its support.

In 2021, Beall et al published one-year results of the VAST RCT investigating the clinical relevance of treating painful intervertebral disc tissue by supplementary transplantation of viable cellular allograft disc matrix. This structural allograft is prepared from human nucleus pulposus allograft that contains allogeneic viable cells. A minimum of 6 × 106 cells were suspended in each allograft matrix suspension. This prospective, randomized, parallel-arm, multicenter study enrolled a total of 218 subjects who demonstrated clinical disc degeneration of 1 or 2 vertebral levels from L1 to S1 and Pfirrmann levels 3 through 6 on MRI. The cellular allograft group was compared to saline placebo or continued treatment with nonsurgical management in a 3.5:1:1 randomization. At 12 months with a total of 182 subjects completing the study, clinically meaningful improvements in mean visual analog scale of pain intensity (VASPI) and ODI scores were achieved in both the investigational allograft and saline groups. A responder analysis demonstrated a clinically meaningful reduction in ODI of ≥15 points at 12 months that was statistically significant in favor of the allograft group (76.5%) compared to the saline group (56.7%). The supplementation of the disc with viable allograft was able to produce a marked reduction in pain, an improvement of function, and a safety profile similar to traditional discography. Although the saline control placebo group also was able to demonstrate improvements, as previously suggested in prior studies, intradiscal saline may have some therapeutic advantage in itself and thus likely is an active comparator rather than a neutral placebo control.79,80

Cellular Therapy: Other Intradiscal Injectates

Methylene blue has been studied by an RCT by Peng et al in 2010. Seventy-two subjects with discogenic LBP were randomized: 36 of whom received 1 mL of 1% methylene blue followed by 1 mL of 2% lidocaine, and 36 in the placebo group received 1 mL of isotonic saline followed by 1 mL of 2% lidocaine. The authors of this single study concluded that the injection of methylene blue into the painful disc is a safe effective and minimally invasive method for the treatment of intractable and incapacitating discogenic LBP.81

Fibrin is another injectate that has been trialed to treat discogenic pain. In 2014, Yin et al reported on 15 adults with confirmed discogenic pain who underwent intradiscal injection of a fibrin sealant. Eighty-seven percent of the subjects achieved at least a 30% reduction in low back pain VAS compared with baseline at the 26-week primary end point without significant adverse events. Although this was not an RCT and only evaluated 15 patients, fibrin may provide benefits in certain patients. Fibrin is composed of purified prothrombin and fibrinogen and reconstituted with aprotinin and calcium. When injected into the annular tears, it has the ability to form a matrix sealant that protects the nucleus pulposus.82

In an attempt to further define the evidence for intradiscal treatments, a post hoc comparison in 2020 by Ju et al aggregated single-site data from 4 separate multicenter RCTs [Study A: Growth factor BMP-7 (n = 15); Study B: active fibrin sealant (n = 10); Study C: Growth Factor rhGDF-5 (n = 3); Study D: cell-based stem cell treatment MPC-06-ID in HA (n = 10); and saline control group (n = 12)]. While there was both a significant decrease in VAS pain and an improvement in patient reported disability scores, the authors concluded there was no significant difference between the investigational group of biologics and the saline control group. The authors suggested that perhaps saline injection itself has a therapeutic effect, possibly by diluting pro-inflammatory mediators within the degenerated disk, decreasing intradiscal pressure, or a combination of the placebo effect. The small sample sizes and heterogeneity of combining multiple studies make it difficult to draw conclusions from this study83 (see Table 9 for evidence summary).

Therapy Grading

Intradiscal regenerative therapy is burgeoning area of research and intervention. Different than interventions in the previous sections that have established histories with decades of experience, this intervention category is relatively recently introduced into the lexicon of therapeutic intervention. As a result, there is one RCT and several observational studies and case series which are utilized to form recommendations. Table 9 summarizes the current literature on this family of interventions and Table 10 summarizes those recommendations. There is evidence for the use of intradiscal PRP in the form of a single RCT, and several prospective observational studies and case series for both autologous bone marrow and adipose tissue-derived mesenchymal stem cells, as well as allogeneic mesenchymal stem cells and cellular allograft disc matrix for the treatment of persistent lumbar discogenic back pain. It is important to discern that the primary patient populations studied have previously failed the multidisciplinary standard of care. Regenerative Medicine holds the potential to provide an alternative intervention for these patients whose pain persists despite the recommended conservative management. In these selected patients, intradiscal biologics may improve pain and function without the need for advanced surgical treatments that can impair the spine’s native biomechanics (Table 10).

Table 10 ASPN Back Consensus Group Recommendations for Regenerative Therapies

Sacroiliac Joint Injections

The sacroiliac joint (SIJ) is a diarthrodial synovial joint with abundant innervation from the lumbosacral nerve roots.84,85 The joint itself is approximately two-thirds synovial and one-third ligamentous, with the synovial portion extending anterior and inferiorly and reinforced at its posterior and superior aspect by syndesmotic ligament.86 The sacroiliac joint is accepted as a relatively common source of low back and/or buttock pain with or without lower extremity pain. The sacroiliac joint has been implicated as the primary pain generator in 10% to 27% of low back pain cases.87,88 SIJ dysfunction more commonly occurs with degenerative conditions or with an imbalance between the two SI joints; therefore, patients at increased risk for SIJ pain include those with leg length discrepancy, advanced age, inflammatory arthritis, pregnancy, trauma, and previous spine surgery.89

There are no definite historical, physical, or radiological features to provide a definite diagnosis of sacroiliac joint pain.90–92 A systematic review by Szadek et al evaluated the diagnostic validity of the International Association for the Study of Pain (IASP) criteria for sacroiliac joint pain and concluded that the thigh thrust test, the compression test, and 3 or more positive stressing tests contain sufficient discriminative power for diagnosing sacroiliac joint pain.93

There are many therapies for SIJ dysfunction, with the most common and often first step in therapy algorithms being SIJ intra-articular injections, which can be utilized both diagnostically and therapeutically.94

Indications and Contraindications

Diagnostic intra-articular SIJ blocks and therapeutic intra-articular SIJ blocks have their own specific roles in the diagnosis and therapy of SIJ-mediated pain. A thorough history and physical examination including provocative tests are performed for an accurate diagnosis. Typically, if a patient has a positive response to 3 or more SI joint provocative tests, a positive outcome of a diagnostic SI joint block can be predicted.93 However, SIJ diagnostic injection is then indicated, as it is a true confirmatory test.95,96 In diagnostic blocks, an anesthetic is injected into the posterior SIJ under fluoroscopic guidance, and if there is a certain degree of pre-defined pain relief following the diagnostic injection for the duration of the anesthetic, then the diagnosis of SI joint dysfunction can be established.97,98

Therapeutically, a local anesthetic is combined with a corticosteroid medication to provide pain relief in the SI joint. Therapeutic SI joint injections can be intra-articular or periarticular, and a growing body of research suggests that intra-articular therapeutic injections are superior to periarticular injections.98,99 Absolute contraindications of SI joint injections include patient history of allergy to cortisone injections, and local malignancy. Relative contraindications include coagulopathy, current, uninterrupted use of blood thinning agents, pregnancy, systemic infection, septic joint, osteomyelitis, and poorly controlled diabetes.100–102

Safety and Complications

The largest study to date on SIJ adverse events indicated that there were very low numbers of adverse effects secondary to SIJ injections, with 3% (5/191) of patients experiencing immediate transient reactions and 24% (32/132) with delayed adverse reactions, the most common being increased pain.103 There are rarer but more serious complications reported in the literature including trauma to the nerves, accidental intervertebral foraminal injection, hematoma, sciatic palsy, meningitis, abscess, and systematic infection.104–106 Another study determined that 2.5% of 525 SIJ injection resulted in a vasovagal reaction, and there have been case studies illustrating very rare complications such as herpes reactivation or pyogenic sacroiliitis.107–109 Temporary sciatic palsy was reported in two studies, with 3/67 cases in one and 5/60 in the other.110,111 One of the major complications of the procedure is that many were technically unsuccessful, with rates of 10–20%.112

The most recent data on SIJ blocks, both diagnostic and therapeutic, was compiled to guide the below best practice guidelines. Image guidance for SIJ injections has been found to be very important in multiple studies.113–116 A study determined that in patients who underwent SIJ injections without image guidance, intra-articular needle placement was confirmed in only 22% in subsequent computed tomography (CT) scans.113 In another study of “blind” injections, only five of 60 needles closely approximated the joint, and none had proper intra-articular placement.114 Ultrasound and CT can also be used for image guidance.115 However, ultrasound cannot verify intra-articular placement of the injectate, and was found to be inferior to fluoroscopic guidance in a prospective, randomized, single-blinded study.116 CT guidance can also be utilized but has been found to be less effective than fluoroscopy at capturing the escape of injectate from the joint to adjacent structures, and neither ultrasound nor CT guidance can rule out concurrent intravascular flow.113

Diagnostic intra-articular SIJ blocks remain the gold standard for establishing a diagnosis of SIJ pain.114 The positive response of intra-articular diagnostic injections is a complete or near complete relief of pain. Various studies have set different levels of pain relief as the threshold needed for a positive test, ranging from >70% pain relief to >50% pain relief from the diagnostic block.93,115,117,118 The studies that utilized >70% pain relief as the threshold for an accurate diagnostic block had a smaller number of subjects and therefore were more specific for diagnosis for SIJ-mediated pain.119 The most important criteria, however, found across multiple studies, was the use of a single positive, diagnostic block versus dual positive, diagnostic blocks.109,120–126 Utilizing dual controlled blocks significantly decreases the positive response rate, with dual blocks reporting rates of positive SIJ pain diagnosis from 10 to 40% whereas single control blocks produced 29–63% positivity rates of SIJ pain.109,120–126 Therefore, it has been demonstrated that diagnostic accuracy is at Level II for dual diagnostic blocks, with at least 70% pain relief as the criterion standard and Level III for single diagnostic blocks, with at least 75% pain relief as the criterion standard.109,120–126

There have been only two randomized controlled trials, one in which therapeutic SIJ injection was completed utilizing a steroid versus utilizing saline in patients with ankylosing spondyloarthropathy. Those receiving a steroid experienced a mean VAS score decrease from 6.8 to 1.3 compared to the decrease in saline VAS score from 7.0 to 5.2, with a 50% decrease in NSAID use in the steroid group and 14% relief in the saline group, as well as 1 month pain relief sustained in 5/6 patients in the steroid group and 1/6 in the saline group.110 While of small sample size, these data demonstrated statistically and clinically significant improvements with steroid injection versus placebo. However, Kim et al, who compared prolotherapy to therapeutic SIJ injection, found that 27.2% of subjects achieved 50% pain relief in the steroid group at 6 months and 63.6% of those in the prolotherapy group achieved 50% pain relief. This was repeated at 15 months, with 10.2% in the steroid group achieving significant pain relief compared to the prolotherapy group, in which 58.7% of patients experienced sustained pain relief.127 However, the study is significantly flawed, and confounded in that many subjects received varying numbers of in

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