In the previous post, I reviewed evidence presented in Bar-Or, et al. concerning the potential analgesic activity of saline used as a placebo in clinical studies. The authors provided evidence that saline didn’t act as an “inert” material in clinical studies. I will cover the authors thoughts on possible mechanisms for the saline’s analgesic activity in this post.
The authors explored several roles played by the sodium ion in knee physiology. For example, the sodium ion frequently acts as a counter-ion to the negative charges associated with proteoglycans, like aggrecans, which are an integral part of articular cartilage. But when these components are degraded in OA the sodium ions are released. Thus, the authors argue that the released sodium ions can alter the osmolality of synovial fluid. If that is true, an obvious question is what does an injection of 0.9% saline do to the osteoarthritic knee, when there already is excess sodium floating around? One possibility is that it might push the synovial fluid to a higher osmolality, which paradoxically might offer some protection to the chondrocytes present in the pathologic articular cartilage. Bar-Or, et al. reported on a study in which explants of bovine articular cartilage were physically stressed, resulting in swelling and loss of viability of chondrocytes in the explanted tissue. However, chondrocytes in “post-impact” cartilage explants showed reduced swelling and increased viability if the explant was incubated in a hypertonic saline solution following the stress. Thus, hypertonicity it would seem can play subtle and not so subtle roles in the OA environment. Protecting chondrocytes would diminish the pro-inflammatory cascade, which in turn might mean a reduction in pain associated with saline used as a placebo.
As an example of another physiological role for sodium, the authors noted a potential impact of the sodium ion on voltage-gated Na channels known to be present in the knee, which are thought to control afferent fiber action potentials to the brain. In addition, Bar-Or, et al. reviewed one type of pain in OA knees, called nociceptive pain, which is associated with the pro-inflammatory environment in an osteoarthritic knee that stimulates pain transmissions. Saline is known to mitigate these painful sensations. However, as OA progresses, it is believed that the pain profile changes from local (nociceptive) pain to include peripheral and central nerve sensitization, producing what is called neuropathic pain (i.e., centralized pain). Thus, there really are two types of pain found in knee OA: nociceptive pain and neuropathic pain, the latter being associated with more advanced OA with symptoms of burning, numbness, tingling and pins and needles sensations (e.g., KL grades 3-4).
Since each type of pain responds to different drug treatments, the authors argue that perhaps saline is only a good placebo when used for advanced OA, since patients with advanced OA showed the biggest therapeutic benefits of drugs when compared to saline used as a placebo. From which the authors concluded that saline is less effective at dealing with neuropathic pain and more effective with local or nociceptive pain found in early-stage OA. This assertion was reinforced by a study the authors cited in which intradermal injection of lidocaine (a drug shown to be effective at reducing severe pain associated with OA when used IV) in patients waiting for a total knee replacement provided no better pain relief than an injection of saline. The implication being that localized pain could be reduced by injecting saline, since some pain relief was recorded.
The authors also cited literature in which up-regulation of specific biochemical factors contributing to a pro-inflammatory environment occurred in an invitro study when tissues were exposed to a hypertonic saline solution. But how would elevated pro-inflammatory factors in the OA knee lead to reduced pain? Bar-Or, et al. reasoned that a local increase in inflammation would elicit a host anti-inflammatory response. This proposed mechanism is exactly the rationale used by physicians who treat patients with prolotherapy, including the use of hypertonic saline solutions. It is thought that prolotherapy “works” due to localized irritation of the injected tissues, which in turn elicits an enhanced host response. However, not all patients respond favorably with prolotherapy. What I find most intriguing is the possibility that these physiological feedback loops operate at different levels of sensitivity, by which I mean some patients exposed to just a little more hypertonic solution might set this pro-inflammatory sequence in action, whereas other patients would need to have a lot more salt to initiate the pro-inflammatory sequence. If this is true, an obvious consequence is that the impact of a saline injection and its potential therapeutic benefit could vary widely between patients. A review of the PRP clinical studies literature certainly attests to the variability in response to PRP treatments among study subjects versus saline used as a placebo.
The authors recommended that it might be appropriate to use another material as a placebo, but offered no candidates to take the place of saline. There is a study published on the use of autologous stromal vascular fraction (SVF) preparations to treat OA-associated lameness in dogs (Black, et al., 2007), which was a randomized, double-blinded, placebo-controlled clinical evaluation. The placebo was phosphate-buffered saline (PBS). The authors indicated that there was a placebo effect of 20-30% depending on the outcome being assessed (there were five outcomes used to create a single composite pain score). However, neither the buffering nor the presence of phosphate ion seemed to make a difference in minimizing the analgesic impact of the saline being injected intraarticularly into the joint. Despite the large placebo effect due to PBS, the authors stated that there was a statistically significant reduction in pain for the subjects receiving freshly prepared SVF compared to the control subjects, which was durable out to three months.
All of which suggests that clinical researchers probably need to look for other fluids to use as a placebo, since it would appear that saline used as a placebo isn’t as inert as generally believed. The trick is to find a fluid that doesn’t rely on the use of saline to create a balanced osmolality that is physiologically appropriate. Good luck.