Is Saline Injection a True Sham/Placebo Treatment in Randomized Controlled Trials? A Systematic Review

Objective: To explore whether saline is a real sham/placebo agent, or it has potential therapeutic effects when used as control treatment in randomized controlled trials for the management of discogenic low back pain.
Methods: A comprehensive literature search was conducted investigating the effects of saline as a placebo in the treatment of chronic pain when administered into the intervertebral disc. Following stepwise filtering, selected articles were assessed for their levels of evidence, followed by a discussion of their contribution to the understanding of the role of saline in chronic pain management.
Results: Out of 95 articles that described the administration of intradiscal saline solution used as a placebo for chronic pain management, 8 articles met all of the inclusion criteria. Their levels of evidence ranged from 1a to 4 (Oxford Centre CEBM). Intradiscal administration of saline solution was found to have measurable therapeutic benefits. In some studies, the pain relief was similar to that provided by local anaesthetics and steroids.
Conclusion: Although the exact mechanism of the analgesic effects of saline is not clear, yet the use of intradiscal saline appears to have some analgesic benefits like local anaesthetics and steroids when used individually. Researchers should practice caution when designing RCTs using intradiscal saline injection as a sham/placebo treatment for the control arm or maybe, when possible, avoid the use of intradiscal saline injection as a sham treatment.



Introduction
Randomized controlled trials (RCTs) are considered the gold standard methodology in clinical research. It is commonly used to evaluate the therapeutic effects of a new treatment or intervention [1]. In order to eliminate or minimize the placebo effect, research subjects need to be blinded to which treatment arm they were randomized to. By doing so, the quality and reliability of the research outcomes improve significantly [2]. To further minimize the potential bias, researchers expand blinding to include the study evaluation team and sometimes the investigator(s) administering the therapy and biostatisticians analysing the data to further increase the reliability and validity of the results. When evaluating the safety and efficacy of an interventional procedure, the only way to blind participants is to randomize subjects to receive either the study intervention or a sham treatment that is administered in a way that simulates the study intervention. For example, the sham treatment is performed using the same or at least a very similar technique to the active treatment with the exception of substituting the active agent/treatment with an inactive agent. Saline solution is used in many clinical trials as the inactive or sham treatment agent without clear data to support the notion that it is, in reality, an inactive agent. One cannot ignore or underestimate the importance of the placebo/sham treatment arm in RCT and how it significantly strengthens the level of evidence a specific clinical trial provides. Although the positive results in the control arm could be explained by the placebo effect, we should not ignore the unknown potential therapeutic effect of injecting saline or other inactive formulation at the treatment target. In a well-designed RCT published in New England Journal of Medicine (NEJM), Friedly et al. compared epidural injections of glucocorticoids plus lidocaine or lidocaine alone for symptom control in patients with spinal canal stenosis. At 6 weeks, there was no statistically significant difference in Roland-Morris Disability Questionnaire (RMDQ) scores between the 2 groups, albeit both groups showed some improvement in their pain scores. On the Swiss Spinal Stenosis Questionnaire (SSSQ) satisfaction scale, 67% of patients who received glucocorticoids plus lidocaine reported being very or somewhat satisfied with their treatment, as compared with 54% of those who received only lidocaine (P=0.01) [3]. The authors did not provide an explanation for the long-term improvement in the lidocaine group. It is well-established, that lidocaine is a short-acting local anaesthetic; therefore, the prolonged pain relief and improved disability at 6 weeks must have a different mechanism than local anaesthesia. In another literature review conducted by Bar-Or et al., it was assumed that intra-articular saline injection that is used as placebo for knee osteoarthritis clinical trial has some analgesic effect since its effects were always better than no treatment [4]. The fundamental question became; is it all placebo effects? Or is there a longterm benefit of lidocaine beyond its duration of action as a local anaesthetic? Or is it possible that control treatment agent (lidocaine or saline) has potential unknown therapeutic effects [5]?
To our knowledge, there are no available systematic reviews to elucidate whether the saline solution is a really inactive agent, or it might have some therapeutic effects when used to evaluate interventional treatment of discogenic pain. Therefore, our goal is to review the world literature of the published randomized controlled trials to treat discogenic pain involving the use of intradiscal injection of saline as a sham treatment arm. The hope is to clarify if saline is a real inactive/sham treatment, or does it have some therapeutic benefits that investigators should be aware of or even not to use saline as a sham treatment arm.

I Research Question
"Is intradiscal saline injection a real sham treatment?" A literature review was performed using Ovid EMBASE MEDLINE INFO from 1974 to July 17, 2020.

II Data Collection
Inclusion criteria: Intradiscal electrothermal therapy, intradiscal drug administration, saline, and sodium chloride. All study designs limited to the English language were included. These studies were reviewed with regard to clinical application, dosage and route of administration, efficacy and potential side effects and complications. The level of evidence for each article selected for inclusion was determined based on the concept outlined by the Oxford Centre for Evidence-Based Medicine (CEBM) (Appendix 1). Results were filtered using the stepwise approach, as shown in the flowchart in (Figure 1).

Results
We obtained 95 results after selecting the following keywords: intradiscal electrothermal therapy, intradiscal drug administration, saline, and sodium chloride. After title and abstract review, 39 studies were excluded. The remaining 55 studies were reviewed by two investigators. In case of disagreement, a third reviewer was used to break the tie. After full review, only 8 studies were included (see Figure 1 for inclusion and exclusion details). The level of evidence for each article selected for inclusion was determined based on the concept outlined by the Oxford Centre for Evidence-Based Medicine (CEBM), as shown in the (Appendix 1). Table 1 summarizes each of the studies meeting the inclusion criteria and the related level of evidence for each study according to Oxford CEBM.  [6,7]. The results did not support the findings of Peng et al. [6]. NRS between the groups was statistically insignificant after 6 months. Responders rate at 3 months, defined as >30% reduction in pain score, was 24.4% and 25% in placebo (saline) and treatment group, respectively. Patients' global impression of change was also evaluated. In the placebo group, 26.8 and 24.4% reported improved PGIC at 3 and 6 months, respectively compared to 20 and 25% in the treatment group.
In a prospective, blinded RCT by Khot et al., 120 patients with chronic low back pain of discogenic origin, confirmed by discography, were randomized to receive an intradiscal injection of either saline (1 mL) or methylprednisolone (40 mg in 1 mL) after a positive discography [8].
The primary outcome was a change in disability scores at 1 year followup. Interestingly, there was no significant difference in disability scores between the groups. Patients in the steroid group reported a mean change of 2.28 in percentage disability compared to 3.42 with intradiscal saline injection. Moreover, there was no difference in changes of VAS among the groups even though the patients reported achieving pain relief with the administration of saline and steroids, indicating that no superiority was demonstrated between the two.
In a recent prospective, multicenter RCT, Beall and collaborators analysed the results of 220 patients with discogenic pain due to disc degeneration using MRI scoring, physical examination and pain evaluation [9]. Patients were randomized to receive intradiscal active allograft, non-surgical management (NSM) or saline as a placebo. Interim analysis of the first 24 patients was examined and clinical improvement was achieved at 6 months. VAS for back pain improved from 54.81 to 16.0 (70% improvement) for the allograft group and from 55.25 to 41.0 (26% improvement) for the saline group. At 12 months, VAS continued to decrease to 12.27 (78% improvement) and 19.67 (64% improvement) in allograft and saline group, respectively. More interestingly, average pain score and percentage reduction in VAS at 3 months were lower in the intradiscal saline group compared to intradiscal allograft, while in NSM average VAS score increased at 3 months. The ODI at 6 and 12 months improved by 66 and 76% for the allograft group, respectively and improved by 42 and 81% in placebo group at 6 and 12 months, respectively. Similarly, at 3 months, ODI increased from baseline for the NSM group. All NSM patients elected to cross over to the allograft group at 3 months.
In another double-blinded RCT, Nguyen et al. randomized 135 patients with low back pain (LBP) secondary to disc pathology to receive a single injection of either 1 mL of iodixanol contrast plus 1 mL (25 mg) of prednisolone acetate (2 mL total) versus 1 mL of iodixanol contrast only. Although the percentage of responders "defined to have LBP <40 on 0-100 NRS at 1 month" were statistically significant between the treatment and placebo group, 55% and 33%, respectively. 54% of the placebo group reported improvement in LBP-related limitations in activities at 1 month. This is, in addition to 33% of the placebo group achieving primary endpoint. After 3 months, the pain score started to increase in the treatment group, even higher than in the control group and at 12 months, no differences were seen between the two groups.
Schwetschenau and collaborators in 1976 studied chymopapain to treat lumbar herniated disc [10,11]. 66 patients were enrolled in the doubleblinded RCT. 35 patients received placebo (contrast diluted in water only) and 31 patients received contrast diluted in water plus chymopapain. The subjects were followed in 6 weeks, 3 months, 6 months and 12 months. Bae and collaborators performed a post hoc comparison using data from the results of four clinical trials assessing intervertebral disc injections. All trials were randomized, controlled trials utilizing intradiscal saline as a placebo. At 12 months, patients injected with intradiscal saline experienced a 58% reduction in their VAS score compared to only 36.6% VAS reduction in the treatment group. There was a statistically significant decrease in VAS for both groups across the four studies. The authors concluded that an intervertebral injection of saline could offer patients pain relief, decreased disability, diminish substance reaction and injection trauma [12].
On the other hand, there are some studies that contradict the possible therapeutic mechanism of action of intradiscal saline injection. In a double-blinded RCT, Cao and collaborators assessed the outcomes of intradiscal steroid therapy in patients with chronic discogenic pain [13]. They compared the effect of intradiscal saline, diprospan and diprospan+songmeile in patients with type I or type II Modic changes. In his RCT, there was no improvement in outcome measures with intradiscal normal saline injection while diprospan either alone or with songmeile resulted in statistically significant improvement in VAS and ODI at 3 and 6 months.

Discussion
Discogenic pain refers to pain originating from within the intervertebral disc due to derangement of the disc structure and the development of nociceptors as part of the degeneration that occurs with the aging process. Although it is an aging process, it is mistakenly called degenerative disc disease (DDD). Discogenic pain is a major cause of chronic low back pain in the United States. Degenerative changes of the disc include loss of water and proteoglycans and structural changes leading to imbalances between synthesis and degenerations favouring catabolism and disc degradation. Based on the degenerative process, one could conclude that the addition of an isotonic fluid e.g., normal saline solution, would aid the homeostasis maintenance of the structure hence decreasing the pain of such origin. If so, should we continue to use intradiscal saline injection as a sham treatment?
The potential therapeutic effect of saline injection has been studied previously in different interventions. In 1980, Frost and his colleagues randomized patients with myofascial trigger point pain into 2 groups to receive trigger point injections with local anaesthetics versus saline. It was surprising when they found that the group who received saline injection tended to have better pain relief in an experimental animal study, where authors injected rabbits with intradiscal hypertonic saline for the purpose of decreasing intradiscal pressure and relieving the pain generated by lumbar disc herniation through chemonucleolysis [14]. Intradiscal injections were administered in rabbits at 1, 4, 8, and 12 months. The authors concluded that 0.02 ml 10% hypertonic saline has the potential for reducing intradiscal pressure. Furthermore, an injection of a higher amount and concentration could be effective clinically [15].
An interesting, randomized control study conducted by Karppinen and his colleagues comparing transforaminal epidural methylprednisolone bupivacaine combination or saline found significant leg pain relief in favour of the steroid group but there was statistically significant more improvement in back pain in the saline group at 3 and 6 months [16].
Similarly, the use of intradiscal saline injection was found to have a positive effect in 6 out of 8 studies, demonstrating some improvement in pain and disability scores with sham treatment or at least no significant difference between sham and investigational treatment. One study showed no significant improvement in pain scores or functionality with intradiscal saline injection compared to methylene blue, while subjects who received intradiscal methylene blue reported statistically significant improvement in pain scores. Nonetheless, when the study was replicated by Kallewaard in 2019, it did not show a significant difference between intradiscal saline injections and intradiscal methylene blue [7]. Among subjects who received intradiscal saline injection, the responder rates were 17, 24.4 and 26.7 at 6 weeks, 3 and 6 months, respectively.
In animal models, the expression of pro-inflammatory mediators has been studied and compared between healthy versus degenerated intervertebral discs. It was found that induction of degenerative disc changes increases expression of Interleukin (IL) 1, 8 10 and Tumor necrosis factor α (TNF-α), with a more exaggerated response with repeated and prolonged injury [17,18]. Similarly, in humans, IL-1β and TNF-α were elevated in degenerated and herniated intervertebral discs [19,20]. Although the exact etiology for intervertebral disks (IVDs) degeneration is unclear, there are multiple hypotheses explaining potential mechanisms of IVDs degenerations. It includes up-regulation of proteolytic enzymes e.g., aggrecanases, alkaline phosphatase and inflammatory cytokines e.g., interleukin 1β (IL-1β) [21]. In another interesting study that was published in nature, Gilbert et al. found that acidic intervertebral disc media promotes disc degeneration. Another possible explanation of the therapeutic effect of intradiscal saline is neutralizing IVD acidic media which will slow down disc degeneration [22].
Although the mechanism of pain and disability improvement with intradiscal saline injection is yet unclear, there is some speculation that saline injection can potentially dilute/wash out inflammatory mediators, proteolytic enzymes and cytokines that in turn ameliorate nerve endings irritations or by neutralizing IVD acidic media [5]. A study investigating the effects of local anaesthetics in degenerated rabbit IVDs showed interesting results [23]. During the in vivo analysis, the number of cells in the nucleus pulposus was significantly decreased among the saline and local anaesthetics groups compared with the control and puncture-only groups. The results were confirmed with histologic analysis with no difference between the saline, puncture-only, bupivacaine, and lidocaine groups. In a prospective study, 20 out of 25 patients with low back pain due to disk herniation achieved tearing of the thinned posterior longitudinal ligament after undergoing a high-pressure injection of saline. These patients received a single high-pressure injection of 5-10 mL of normal saline into the nucleus of the disk. Even though patients experience immediate pain relief, long-term follow-up is pending [24]. In a double-blinded RCT comparing biacuplasty to sham treatment, there was no statistical significance in VAS scores and ODI at 8 weeks between the 2 groups. Nonetheless, VAS and ODI showed similarities and even showed slightly more improvement in the sham group. However, it might be a placebo effect. One cannot exclude a possible mechanical mechanism or similar mechanism of action to trigger point injection (TPI) which, in addition to local anaesthetic effect, could be secondary to mechanical disruption of muscle pain and release of local mediators [25]. On the other hand, there are some studies that contradict the possible therapeutic mechanical mechanism of action of intradiscal saline injection.

Conclusion
The use of saline possibly represents the result of a type II statistical error when used as in the control group vs active treatment for the management of chronic pain. Having pain relief in a control group is detrimental to the objectivity of the study and this error could pass unnoticed by investigators. On the other hand, the use of saline could be useful, pending further trials, as a treatment in the management of chronic pain.