A Randomized, Placebo-Controlled Trial of Transdiscal Radiofrequency, Biacuplasty for Treatment of Discogenic Lower Back Pain

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1 bs_bs_banner Pain Medicine 2012; *: ** ** Wiley Periodicals, Inc. A Randomized, Placebo-Controlled Trial of Transdiscal Radiofrequency, Biacuplasty for Treatment of Discogenic Lower Back Pain Leonardo Kapural, MD, PhD,* Bruce Vrooman, MD, Sheryar Sarwar, MD, Ljiljana Krizanac-Bengez, MD, PhD, Richard Rauck, MD,* Christopher Gilmore, MD,* James North, MD,* Girgis Girgis, DO, and Nagy Mekhail, MD, PhD *Carolinas Pain Institute and Center for Clinical Research, Winston-Salem, North Carolina; Pain Management Department, Cleveland Clinic, Cleveland, Ohio, USA Reprint requests to: Leonardo Kapural, MD, PhD, Carolinas Pain Institute at Brookstown, Wake Forest Baptist Health; Carolinas Pain Institute and Center for Clinical Research; Department of Anesthesiology, Wake Forest University, School of Medicine, 145 Kimel Park Drive, Suite 330, Winston-Salem, NC 27103, USA. Tel: ; Fax: ; lkapural@wakehealth.edu. Disclosure/Conflict of Interest Information: Financial support for the study was provided by Baylis Medical to cover coordinator time, administrative costs, and study treatments. Study equipment was provided at no cost. Treatments were provided to patients at no cost. No direct compensation was given to the physicians or staff who performed these procedures. No conflicts of interest are noted by participating study physicians or staff. Abstract Objective. The aim was to compare the efficacy of intradiscal biacuplasty (IDB) with that of placebo treatment for discogenic low back pain. Design. This is a randomized, placebo-controlled trial. Subjects were randomized on a 1:1 basis to IDB and sham groups. Follow-ups were conducted at 1, 3, and 6 months. Subjects and coordinators were blinded to randomization until 6 months. Of the 1,894 subjects screened, 64 subjects were enrolled, and 59 were treated: 29 randomized to IDB and 30 to sham. All subjects had a history of chronic low back pain for longer than 6 months. Interventions. Two cooled radiofrequency (RF) electrodes placed in a bipolar manner in affected discs to lesion the nociceptive fibers of the annulus fibrosus. The sham procedure was identical to the active treatment except that probes were not directly inserted into the disc space, and RF energy was not actively delivered. Results. The principal outcome measures were physical function, pain, disability, and opioid usage. Patients in the IDB group exhibited statistically significant improvements in physical function (P = 0.029), pain (P = 0.006), and disability (P = 0.037) at 6-month follow-up as compared to patients who received sham treatment. Treatment patients reported a reduction of 16 mg daily intake of opioids at 6 months; however, the results were not statistically different from sham patients. Conclusions. The results suggest that the clinical benefits observed in this study are the result of non-placebo treatment effects afforded by IDB. IDB should be recommended to select the patients with chronic discogenic low back pain. (Clinicaltrials.gov number, NCT ) Key Words. Discogenic; Pain; Radiofrequency; Transdiscal; Biacuplasty; IDB Introduction Low back pain (LBP) is one of the most common disabilities in Western civilization, with epidemic proportions affecting approximately 80% of Americans at some point in their lifetimes and a point prevalence of 28% [1 3]. Pain persistence lasting longer than 3 months is defined as chronic; and if left untreated, can be debilitating, unrelenting, and impacts quality of life severely. Socioeconomic consequences of LBP are massive and are estimated to cost between $100 and $200 billion per year either through direct medical costs or indirectly through decreased workplace productivity and lost work days [4]. Interestingly, chronic LBP patients, accounting for approximately 5% of the LBP patient population, consumes upward of 75% to 90% of all LBP associated health care costs [4 6]. Discogenic pain, arising from the intervertebral discs, accounts for the majority of chronic LBP cases [7]. The lumbar intervertebral disc is comprised of three sections: a central nucleus pulposus, a surrounding annulus fibrosis, and endplates. The annulus is composed of ordered 1

2 Kapural et al. collagen fibers innervated by nerves found only in the peripheral few millimeters of the outer annulus [8]. With aging or injury, the disc can undergo degeneration and damage leading to delamination and fissuring of the posterior annular layers [9,10]. Empirical evidence suggests that responses to this injury include inflammatory cytokine release and development of increased sensory fiber innervations extending as far as into the nucleus pulposus [11 14]. These manifestations may correlate to the feeling of pain, as supported by pain provocation and imaging studies [11,15,16]. Multiple treatment options are currently available including: pharmacologic and noninterventional conservative treatments such as pain medication and physiotherapy; minimally invasive interventional treatments; and surgical treatments such as spinal fusion or artificial disc replacement. In most instances, the first line of treatment is to receive conservative therapy. When this is no longer effective, the minimally invasive intermediate approach may offer select patients an alternative to more controversial solutions such as surgical spinal fusion. A more recently developed minimally invasive procedure, referred to as intradiscal biacuplasty (IDB), involves the use of two cooled radiofrequency (RF) electrodes placed on the postereolateral sides of the intervertebral annulus fibrosus to lesion the neo-innervated area acting as a potential pain generator. Compared to other percutaneous treatment options, it currently presents the lowest rate of adverse events [17 19]. Although the available evidence for IDB is positive and suggests a benefit to patients with chronic discogenic back pain, these studies are limited to small, uncontrolled case series [20 25]. This article is the first to compare the effects of IDB treatment to that of placebo in a double-blinded randomized controlled trial. Methods This was a double-blinded, placebo controlled, parallel group study with balanced randomization [1:1 treatment to sham ratio] conducted at two sites in the United States: 1) the Department of Pain Management at the Cleveland Clinic, Cleveland, Ohio, and 2) the Center for Clinical Research at Carolina s Pain Institute, Winston-Salem, North Carolina. Ethics approval for this study was obtained from the Cleveland Clinic Institutional Review Board and Quorum Review IRB. Study Design Power calculations showed the requirement for 64 patients, randomized on a 1:1 basis, to detect a 15-point change from baseline difference in SF-36 PF between groups at 6 months (a =0.05 and b=0.1). This assumed a within-subject standard deviation of 18 points, based on previous data [26]. Sample size calculations were made using SAS statistical software s POWER procedure (Cary, NC, USA). Recruitment and Screening Patients were recruited between September 2007 and October 2011 from the practices of the authors and their colleagues. No financial inducements were provided for participating in the study. Individuals deemed appropriate for the study underwent in-person screening by study coordinators and/or physicians. The inclusion criteria were: patients aged 18 or greater; history of chronic low back pain unresponsive to nonoperative care (including physical therapy and anti-inflammatory medication) for longer than 6 months; no surgical interventions within the previous 3 months; back pain more than leg pain, which is commonly exacerbated by sitting; pain reproduction present on provocative discography (completed within 12 months prior to enrollment) in degenerated, suspected pain-generator disc but not in control discs; disc height at least 50% of adjacent control disc; evidence of single-level degenerative disc disease or two-level disease without evidence of additional degenerative changes in other disc spaces on magnetic resonance imaging (MRI) (completed within 12 months of enrollment). The exclusion criteria were as follows: prior lumbar surgery of any kind; nucleus pulposus herniation, disc bulges >5 mm, presence of free disc fragments, or more than two discs degenerated on MRI; evidence of structural abnormality at the symptomatic level, such as spondylolisthesis; evidence of compressive radiculopathy with predominant leg pain; presence of concordant cervical or thoracic pain; symptoms or signs of lumbar canal stenosis; chronic severe conditions such as rheumatoid arthritis and fibromyalgia; immunosuppression (e.g., AIDS, cancer, diabetes, other surgery within last 3 months); history of coagulopathy or unexplained bleeding; progressive neurological deficits; traumatic spinal fracture; pending workers compensation claims; litigation or disability income remuneration; psychological issues by exam or history; beck depression inventory (BDI) > 20; pregnancy; systemic infection or localized infection at the anticipated entry needle site; allergies to contrast media or to any medication to be used in the procedure; history of opioid abuse; smoking; body mass index (BMI) > 30 kg/m 2 ; subject unwilling to consent to the study; participation in another investigation within 30 days of signing informed consent. All consecutive patients who satisfied the eligibility criteria were invited to participate in the trial. Patients were considered enrolled upon consenting. Randomization and Primary Treatment At enrollment, a baseline evaluation of all the subjects was completed, and the subjects were randomly assigned in a 1:1 ratio to either the treatment or sham group using computer-generated codes maintained in sequentially numbered opaque envelopes. The envelopes remained sealed until the day of the procedure. Upon completion of the procedure, the envelopes were kept in a secure area until subsequent unblinding. 2

3 Biacuplasty for Discogenic Lower Back Pain On the day of the procedure, both treatment and sham patients received local anesthesia and moderate sedation. Patients were given 1 4 mg of midazolam for relaxation before the procedure and, if needed, mcg of fentanyl IV during the procedure. Both treatment and sham procedures were performed in a fluoroscopy suite equipped with a C-arm with patients lying prone. The equipment in the fluoroscopy suite was arranged such that the patient was visually isolated from the RF generator, thereby preventing disclosure of group assignment. At this time, the randomization code was revealed to the treating physician and the nurse operating the generator, who was in control of RF delivery to the patient. The patients were awake and communicating with the physician throughout the procedure. For subjects randomized to the treatment group, two TransDiscal probes (Kimberly Clark Health Care, Roswell, GA, USA) were positioned under fluoroscopic guidance in the posterior annulus using a posterolateral, oblique approach. First, two electrically insulated 17G TransDiscal introducers were used to gain access to the disc space. Next, two RF probes were positioned through each of the introducers bilaterally to create a bipolar configuration. The internally cooled RF probes were attached to the BMC generator, and RF energy was delivered. In 13 patients, the RF energy was delivered at 45 C in bipolar configuration for 15 minutes; and, in 16 patients, the RF energy was delivered at 50 C in bipolar configuration for 15 minutes followed by monopolar lesioning around each electrode at 60 C for 2:30 minutes. Probes were not reposition prior to monopolar lesioning. In all cases, placement of the transdiscal probes within the disc annulus was confirmed using oblique, lateral, and anterior-posterior fluoroscopic images (Figure 1A and B). (A) (B) (C) (D) Figure 1 Fluoroscopic images of radiofrequency (RF) probe placement in treatment and sham patient intervertebral discs. After just piercing with trocars inside the posterior annulus, electrodes are introduced. (A) Anterior-posterior fluoroscopic view of the final position of electrodes. Note that the active tips of radiofrequency probes (shown as visible darker bands) are positioned medial to the medial border of bilateral pedicles. That allows an optimal distance between two probe tips and an effective bipolar configuration for denervation. (B) Electrode depth in the lateral fluoroscopic view in treatment patient. The final position of the electrode tips should be just inside posterior annulus. (C) Anterior-posterior fluoroscopic view in patients who received a sham procedure. Electrodes were positioned just outside the lumbar disc. (D) Electrode depth in the lateral fluoroscopic view in sham patient. 3

4 Kapural et al. Sham procedures mimicked active treatment procedures, except that the introducers and electrodes were positioned just outside of the disc (Figure 1C and D), and no RF energy was delivered through the electrodes. Thus, sham patients were provided similar tactile, auditory, and visual experiences as treatment patients, without receiving the active RF treatment. Patients in both groups therefore remained blinded to actual treatment. Following completion of the intervention, needle penetration sites were bandaged, and patients were transferred to recovery and were monitored for 45 minutes prior to discharge. All the patients were provided with lumbar back braces to be worn for the first 4 weeks of recovery and were given a recovery guide detailing activities and exercises that should be followed for 6 weeks post procedure. Prescriptions for analgesics and/or muscle relaxants were also offered to the patient. Outcome Measures, Follow-Ups, and Unblinding The outcome tools used to assess physical function, pain, and disability were the short form SF-36 (version 1), a numerical rating scale (NRS), and the Oswestry disability index (ODI), respectively. A health care utilization questionnaire (HUQ) was used to determine patient baseline characteristics. Blinded subjects in both groups completed these instruments at baseline, on the day of the procedure before treatment was given, and at 1-month, 3-month, and 6-month post-procedure. Opioid use was obtained from patient medical records at the time of follow-up and was converted to chronic morphine equivalents. Physicians involved in performing the procedures were aware of subject allocation, and were not involved in follow-up patient visits. Study coordinators, patients, and data analysts were kept blinded to subject allocation. All questionnaires were administered by a blinded study coordinator at each follow-up. Subjects were unblinded after 6-month follow-up data were collected. Patients who received sham treatment were then offered the real IDB treatment. Sham patients who chose to undergo IDB received the active procedure as described above. Statistical Measures and Study Endpoints For continuous data, means, and standard deviations were calculated, and comparisons were made using t-tests. For categorical data, Fisher s exact test was used to make comparisons. Statistical significance was defined as P < 0.05 for all analyses. The last-observation carriedforward method of data imputation was used for all the missing data. No interim analysis for efficacy or futility was conducted. The primary endpoint of this study was a comparison of mean physical functioning, as measured by the SF-36 questionnaire, between treatment and sham groups at 6-month post-procedure. Secondary endpoints were comparisons of pain, disability, and opioid use between treatment and sham groups at 6-month post-procedure. Results Demographics A total of 1,894 patients were screened in-clinic for inclusion in this study (Figure 2). Of those, 1,771 did not meet clinical inclusion criteria, 36 did not show up for enrollment appointment, and 23 declined to be randomized or to comply with the protocol. Sixty-four subjects were consented and enrolled in the study. Thirty-two subjects were allocated to the treatment group and 32 to the sham group. Among the 32 subjects allocated to the treatment group, three patients did not receive treatment: one patient declined the procedure, and two patients were deemed to be in violation of eligibility criteria due to more recent imaging findings. In total, 29 subjects received active treatment, however two patients were censored from analysis: one patient dropped out of the study immediately after the procedure, and no follow-up data were available for analysis, and the other patient admitted to be abusing a controlled substance and was removed from the study. The remaining 27 subjects participated in the study until unblinding at 6 months, and their data were analyzed. Among the 32 subjects allocated to the sham group, two patients did not receive treatment: both patients were in violation of eligibility criteria due to more recent imaging findings. In total, 30 subjects received sham treatment. Of those, two patients dropped out of the study after the 3-month follow up. The remaining 28 subjects participated in the study until unblinding at 6 months. One sham patient failed to report any NRS data and was not included in the NRS calculations. Upon unblinding, the offer to receive the real treatment was offered to all sham patients; three chose not to participate, while the remaining 25 were scheduled for active treatment. Demographic characteristics, relevant clinical features, and outcome measures revealed no statistical difference between treatment and sham group at baseline (Tables 1 and 2). Complications No procedure related complications were encountered during the 29 active biacuplasty procedures or the 30 sham procedures throughout the study. There were also no procedure-related complications encountered during the 25 active procedures for the sham patients who decided to receive the real treatment after blinding. Two patients reported complications that may have been related to the IDB procedure: one treatment patient experienced a change in pain characteristic shifting from the right side to the left side 1 month after the IDB procedure; and, one sham patient reported exacerbation of pain 3 months after the IDB procedure. Both complications resolved shortly thereafter on their own. 4

5 Biacuplasty for Discogenic Lower Back Pain 1894 inquiries 1830 Excluded 1771 did not meet clinical inclusion criteria 36 skipped enrollment appointment 23 declined to be randomized or comply with protocol Three excluded before treatment: One declined to undergo procedure Two breached eligibility criteria 64 enrolled Treatment Group Sham Group 32 allocated to receive IDB 32 allocated to receive Two excluded before treatment: Two breached eligibility criteria Two subjects censored from analysis: One early drop out (no follow-up data obtained) One breach of eligibility criteria 29 received IDB 1-month follow-up (N = 27) 3-month follow-up (N = 27) 6-month follow-up (N = 27) Unblinding 30 received sham treatment 1-month follow-up (N = 30) 3-month follow-up (N = 30) 6-month follow-up (N = 28) 25 subjects received active treatment Two dropped-out (included in analysis) Three subjects chose not to receive active Figure 2 Flow diagram of enrollment, intervention allocation, follow-up, and data analysis for a randomized, placebo controlled trial of intradiscal biacuplasty (IDB) for treatment of discogenic low back pain. Physical Function, Pain, and Disability The mean values for physical function, pain, and disability outcomes are reported in Table 2 for treatment and sham groups across all time points. The treatment group reported significantly better outcomes in physical function (P = 0.029), pain (P = 0.006), and disability (P = 0.037) at the 6-month time point as compared to patients in the sham group. The mean change from baseline in physical function, pain, and disability outcomes is reported in Table 3 for treatment and sham groups at all time points. At the 6-month time point, the mean improvements in the treatment group in physical function (P = 0.012), pain (P = 0.014), and disability (P = 0.005) were significantly greater than the respective mean improvements in the sham group. Number of Treatment Levels A comparison of the results between single-level vs twolevel treatments is provided in Table 4. While the results do not yield statistically significant differences, the single-level treatment group had greater improvements in all the outcome measures. Opioid Usage Although daily opioid use in treatment patients decreased by 15.6 mg of chronic morphine equivalents, the change was not statistically different from that reported by sham patients at 6 months who reported 0 mg decrease (Table 5). Discussion This is the first double-blinded randomized controlled trial (RCT) to compare the effects of IDB treatment to those of a placebo intervention. Previous open-label prospective case series demonstrated clinical benefits of the procedure but, due to study design limitations, could not account for placebo effects [20 25]. Our patient group treated with IDB achieved a significantly greater improvement in physical function, pain, and disability at 6 months, as compared to patients who received sham treatment (Tables 2 and 3). These results provide evidence that IDB affords nonplacebo treatment effects and help validate those results seen in earlier noncontrolled studies. Additionally, no severe adverse events such as nerve damage or discitis were seen in the current study, and there were no reports of postprocedural flare-ups or exacerbation of pain following active IDB treatment. This safety profile is in accord with the results of earlier nonrandomized studies [22,23]. In the current study, randomization succeeded in generating two groups that were demographically and clinically equivalent. Furthermore, much care was taken to ensure that subjects remained unaware of treatment assignment. Sham procedures were performed in an uncompromising and systematic manner, replicating the idiosyncrasies of the active treatment; the exceptions, however, being that the probes were not inserted directly into the disc space, and RF energy was not actively delivered. Furthermore, extensive measures and methodologic precautions were taken to mask group assignment, such as blinding the follow-up assessors and post-procedure treating physicians. 5

6 Kapural et al. Table 1 Baseline demographic characteristics and clinical features of patients randomized to IDB or sham study groups IDB (N = 27) Sham (N = 30) Feature N % N % P Value Male 12 44% 15 50% Female 15 56% 15 50% Age (mean SD), years Work status: Unemployed because of back pain 5 19% 5 17% Unemployed not because of back pain 2 7% 4 13% Working 20 74% 21 70% Work class: Manual 3 15% 4 19% Sedentary 7 35% 6 29% Mixed 10 50% 11 52% Duration of pain: months 0 0% 1 3% months 2 7% 3 10% >24 months 25 93% 26 87% Previous treatment Physiotherapy 2 7% 3 10% Bed rest 12 44% 5 17% Anti-inflammatory drugs 17 63% 13 43% Opioids 14 52% 15 50% Injections 8 30% 7 23% Chiropractics 2 7% 8 27% Referred pain In buttock 18 67% 19 63% In thigh 9 33% 13 43% In leg 9 33% 15 50% Painful and treated discs L5-S1 7 26% 8 27% L4-L5 6 22% 7 23% L3-L4 3 11% 1 3% L4-L5, L5-S1 6 22% 8 27% L3-L4, L4-L5 3 11% 3 10% L3-L4, L5-S1 2 8% 3 10% IDB = intradiscal biacuplasty. When validating data of any interventional procedure, it is important to assess the clinical relevance of the study results. Clinically significant improvements in physical functioning, pain, and disability have been defined previously as 15-point increase in SF-36 PF, a 2-point decrease in NRS, and a 10-point decrease in ODI, respectively [8,9]. IDB patients in our study reported clinically significant improvements in SF-36 PF (mean increase of 15 points) and NRS (mean decrease of 2.2 points) at 6 months. Treatment patients did not, however, reach a clinically significant mean change in ODI at 6 months. Despite this finding, a subgroup analysis based on subject age demonstrated that younger patients (under the age of 40) did experience a clinically significant decrease of 11 points in ODI (data not shown). A separate subgroup analysis looked at the association between the number of discs treated and achievement of clinically significant results. This analysis demonstrated that only patients with singlelevel disc disease (and not those with two-level disc disease) achieved clinically significant mean improvements in all the three outcomes (Table 4). Taken together, these various analyses of clinical significance suggest that IDB can produce clinically significant improvements in patients with discogenic back pain and that younger patients suffering from single-level disc disease may attain the highest level of clinical benefit from IDB treatment. To gauge further the clinical relevance of the current results, an analysis was done to examine the proportion of patients meeting a binary definition of clinical significance, hereafter referred to as clinical success. Clinical success was defined as a 15-point increase in physical function coupled with a greater than 2-point drop in pain. Eight of the 27 treatment patients and one of the 30 sham patients 6

7 Biacuplasty for Discogenic Lower Back Pain Table 2 Mean physical function, pain, and disability outcomes of subjects who received IDB or sham procedures at all time points IDB Sham Outcome measure Mean SD Mean SD P Value SF-36 Physical functioning (0 100) N = 27 N = 30 Baseline month months months NRS for pain (0 10) N = 27 N = 29 Baseline month months months Oswestry disability scale (0 100) N = 27 N = 30 Baseline month months months IDB = intradiscal biacuplasty; SF = short form; NRS = numerical rating scale; SD = standard deviation. met this definition at 6-month follow-up, which corresponds to a number needed to treat of four (data not shown) to obtain clinical success. Typically, an number needed to treat of 4 or less is considered to be indicative of an effective treatment [27]. It is worth noting that all the treatment patients who met the definition of clinical success also reported a decrease in disability, albeit two were not clinically significant (mean ODI decrease of 16 points; range 2 to 28 points); conversely, the sham patient who met the definition of clinical success reported an increase in disability of 12 points. Opioid use was currently tracked as an auxiliary marker of patient improvement. Opioids are commonly prescribed for chronic back pain either alone or in conjunction with other therapies and aberrant medication-taking behaviors, Table 3 Change in physical function, pain, and disability outcomes of subjects who received IDB or sham procedures at all time points IDB Sham Outcome measure Mean SD Mean SD P Value SF-36 physical functioning (0 100) N = 27 N = 30 Baseline month change month change month change NRS for pain (0 10) N = 27 N = 29 Baseline month change month change month change Oswestry disability scale (0 100) N = 27 N = 30 Baseline month change month change month change IDB = intradiscal biacuplasty; SF = short form; NRS = numerical rating scale; SD = standard deviation. 7

8 Kapural et al. Table 4 Physical function, pain, and disability scores in patients who received IDB treatment in 1 and 2 disc levels 1 Level (N = 16) 2 Levels (N = 11) Outcome measure Mean SD Mean SD P Value SF-36 physical functioning (0 100) Baseline months month change NRS for pain (0 10) Baseline months month change Oswestry disability scale (0 100) Baseline months month change IDB = intradiscal biacuplasty; SF = short form; NRS = numerical rating scale; SD = standard deviation. suggestive of substance abuse or dependency, occur in 24% of cases [28]. Due to the highly addictive properties of prescription pain medication, it is axiomatic that any therapy which can decrease the use of opioid analgesics is highly sought. Although the reduction was not statistically significant, treatment patients in the current study reported a decrease from 52 mg to 36 mg daily opioid use between baseline and 6-months (P = 0.211). Further, of the 23/27 treatment patients and 19/30 sham patients who were taking opioids at baseline, 26% of treatment and 16% of sham reported a complete cessation. Contrarily, two sham patients, who were initially free of opioid use at baseline, resorted to opioid utilization at 6 months; whereas this behavior was not exhibited in treatment patients. While the current results are not statistically significant, they do suggest that IDB may allow some patients to decrease or discontinue opioid use. Perhaps with a larger sample size, or with subjects more heavily afflicted with opioid use, statistical significance could be detected. The positive effects of IDB may, for some patients, delay or prevent the need for extensive or aggressive spinal surgery which is invasive, costly, and can propagate adjacent segment degeneration [29,30]. Patients who have received IDB, however, are not prohibited from undergoing surgery later should their symptoms worsen or if degeneration progresses beyond that indicated for percutaneous treatment. This was exemplified in this trial by a patient who decided to pursue spinal fusion after 6 months of trial participation. The proposed mechanism of action for IDB is the coagulation of nociceptors within the posterior aspect of the disc. In order to coagulate nociceptive fibers, the tissue needs to reach a minimum temperature of 45 C [31,32]. A temperature distribution study of IDB in human cadavers found that the posterior longitudinal ligament (PLL) and the anterior disc reached temperatures of 40 3 C and 41 3 C, respectively; the outer layer and the inner twothirds of the posterior annulus fibrosus, however, heated Table 5 Daily opioid use in treatment and sham patients IDB (N = 27) Sham (N = 30) Mean* SD Mean* SD P Value Daily opioid use (mg) Baseline month months months month change month change month change * Opioid use expressed in chronic morphine equivalent dose. IDB = intradiscal biacuplasty; SD = standard deviation. 8

9 Biacuplasty for Discogenic Lower Back Pain to 54 6 C and 60 6 C, respectively [33]. This demonstrated that RF applied to the posterior disc can produce temperatures required to achieve neural ablation while maintaining a safe temperature in the PLL, equina and surrounding neural structures (Figure 3). The TransDiscal system has several technological characteristics intended to optimize the ability of the physician to ablate nociceptive fibers in the posterior annulus. First, internally cooled electrodes serve to maximize the treatment area without damaging effects on peridiscal neural structures [34,35]. Temperature profiles show that circulating coolant in the RF electrode will allow a greater volume of tissue to be treated while eliminating excessive heating close to electrodes which can otherwise cause tissue adherence [36]. Second, the bipolar configuration of the RF electrode placement increases the maximum volume of tissue ablation from that of a monopolar RF electrode [35]. This is particularly beneficial for patients with relatively large intervertebral discs. Together, the two bipolar cooled probes synergistically produce large barbell-shaped lesions that should encompass the known location of nociceptive nerve growth in the disc (Figure 3). As the anatomical basis of discogenic back pain is further elucidated, the treatment parameters of IDB continue to undergo optimization. The two previous prospective studies on IDB reported bipolar RF delivery at a set Figure 3 Schematic representations of heated area during intradiscal biacuplasty (IDB) with the Trans- Discal system in an intervertebral disc. Isotherm lines form dumbbell shape around and between radiofrequency (RF) probes to cover the posterior segment of the annulus fibrosus. Image adapted from data published by Petersohn et al. [34]. temperature of 55 C for 15 minutes or 45 C for 15 minutes [22,23]. Bipolar lesion duration for our study was 15 minutes at a set temperature of C. In addition to the bipolar treatment, two monopolar lesions (set temperature of 60 C for 2 minutes and 30 seconds duration) were applied to the latter 16 patients treated in this study. There was no significant difference observed in the patients that were treated within this range. It is conceivable that future advances in the understanding of the neural anatomy of the disc and pathogenesis of IDD could be translated into optimized IDB treatment parameters. As is true with any interventional spine procedure, properly selecting patients is key to obtaining successful outcomes. When discogenic pain is suspected, the primary tool used by many physicians to establish whether a particular disc is painful, is provocative discography [37]. However, some research has suggested limitations in its diagnostic accuracy [38 40]. Thus, one of the biggest challenges faced by physicians is to diagnose correctly the pathologic or anatomical entity causing LBP. Additionally, since discography results are incumbent upon patient reported pain response, issues of chronic pain confounded by social stressors, opioid use, or emotional troubles may all compensate. These factors have been shown to be associated with an increased risk for false positive discogram reports [41]. As diagnostic techniques for identifying patients with discogenic back pain improve, identifying the ideal candidates for IDB treatment will be further facilitated. The limitations of the current study included the lack of a formal assessment of blinding effectiveness. Patients were not queried as to which group they believed to be part of after the procedure, and future research should include such an assessment. A second limitation was the relatively short follow-up period. Our data suggested a trend of treatment patient outcomes improving with time. A lengthier follow-up period may be beneficial in determining the long-term benefits of IDB. Third, patients with both one and two-level disc diseases were eligible for trial participation. A subgroup analysis, however, suggested that patients with one-level disc disease may have a better treatment response as compared to patients with twolevel disc disease (Table 4). While this result was nonsignificant, the patient sample size was limited in this subgroup analysis. It remains possible that the true potential of IDB for treatment of single level disc disease was masked in the overall analysis. Future studies with a focus on one-level disc disease may be beneficial. Finally, this study had a large number of patients screened (N = 1,894) to arrive at the sample size dictated by the power calculation. There were two exclusion criteria that were particularly prohibitive with respect to enrollment: BMI > 30, and active smoking status. These two attributes have been shown to be strongly associated with LBP, and thus precluded inclusion of numerous patients that were otherwise eligible for treatment [42,43]. It is worth noting that these same attributes have been suggested to be associated with treatment resistance in some patients [19,44,45]. 9

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