Patients may be experiencing placebo effect, but it’s still an effect, rheumatologist says

by John Gever, Managing Editor, MedPage Today
April 19, 2018

CHICAGO — In dealing with osteoarthritis, both patients and their physicians often have a hard time understanding what to make of novel “cures” such as platelet-rich plasma (PRP), stem cell treatments, and so-called prolotherapy.

Although these are typically marketed as halting or reversing joint degeneration in OA, there is virtually no evidence that they actually do. Yet it’s impossible to discount the countless reports from patients that the treatments helped them in terms of pain and function.

The explanation may very well lie in the placebo effect, said Joel Block, MD, a well-known osteoarthritis specialist at Rush University, speaking here at the American College of Rheumatology’s 2018 State of the Art Symposium.

But the thrust of Block’s 30-minute talk can be summed up in two words: So what?

The placebo effect is still an effect and a very important one, he argued repeatedly in addressing current knowledge about therapies, largely unregulated, now marketed nationwide in newspapers and online as “disease-modifying.”

It’s “extraordinarily strong” in osteoarthritis, Block said, for reasons that aren’t entirely clear. The experience from randomized trials is that one normally expects a 40% response rate with placebo with large effect sizes. Moreover, the improvements in patient-reported pain do not quickly disappear: the trial data indicates that placebo responses last beyond a year, he said.

“Placebo is active treatment,” Block said. Moreover, the effect size appears to be closely related to the treatment’s invasiveness. This is critically important for the new ostensibly disease-modifying treatments because they all involve injections, often given repeatedly, which in many patients’ minds can create the impression of something powerful.

And also of critical importance, Block reminded his audience, the physician’s main job is to make patients feel better — “regardless of whether it’s better than placebo, or is placebo.”

He struck the same theme in addressing three specific types of novel therapy.

Platelet-Rich Plasma

PRP is an autologous product, made in-clinic using little more than a standard centrifuge. The actual products vary widely between clinics, but in general they consist of (as the name suggests) plasma enriched with platelets with some white cells included as well. Lab analyses indicate that PRP provides a complex cocktail of growth factors, cytokines, and plasma proteins as well as whole live cells.

The idea is that this cocktail will stimulate restoration of joint components including bone and cartilage.

Studies that have looked for evidence of morphological benefit in the joint have pretty much universally failed to find it, Block said. In fact, his own search of studies registered on Clinicaltrials.gov involving PRP in OA did not find a single one with a joint structure measure as the primary outcome, and only one with such a measure as a secondary endpoint.

On the other hand, numerous studies have reported benefits in patient-reported pain and function. Of these, only 14 were prospective, randomized, and controlled — and these formed the basis for 81 systematic reviews, Block noted wryly. Most of these reviews lacked detail as well, omitting effect sizes and funnel plots, for example.

Block created his own funnel plot from the 14 randomized trials, which did show large effect sizes, although with high heterogeneity and various other inconsistencies.

The upshot, according to Block: “Many people will feel improvement after PRP treatment.” It may be a placebo effect, “but we must respect the placebo effect” — particularly in patients suffering OA pain despite conventional treatment.

Stem Cell Therapies

Essentially the same claims have been made for therapies using autologous stem cells. These treatments too are even more variable than PRP concoctions, and have been studied even less rigorously in randomized controlled trials. Although 34 trials are listed in Clinicaltrials.gov, Block said, all but one had pain and/or function as primary endpoints. The lone trial with a structural endpoint is comparing injections of hyaluronic acid injection versus mesenchymal stem cells with results not yet reported.

Still, as with PRP, “scientific data may not matter” to patients seeking pain relief.

For both PRP and stem cell treatments, the costs to patients can be substantial. They are not covered by insurance and, for stem cell therapies, patients are charged around $5,000 for a course, according to a published survey of clinics.

Block also noted that (in one of the seedier aspects of these treatments) marketing claims may include suggestions of FDA approval. In fact, no PRP or stem cell treatment has been submitted to the FDA for evaluation of efficacy and safety. But the equipment and processes used in preparing materials for injection are regulated by the FDA, typically through 510(k) clearance, providing a basis — however misleading — for claiming FDA approval.

Prolotherapy

Versions of this treatment have been around for many decades. The name is drawn from “proliferative,” the supposed effect of injecting small quantities of crystalloid (typically hypertonic glucose) into the joint to stimulate a healing response.

One hint that this is nonsense on a physiological level, Block suggested, is that some studies have shown benefit in pain and function even when injections are periarticular — that is, not even within the joint.

Prolotherapy is favored by a subset of osteopaths, who recommend it for a host of pain conditions including OA, as well as varicose veins. Prospective studies have been scarce: Block said he found just four on Clinicaltrials.gov, two controlled — and one of those had enrolled just two patients.

Nevertheless, as Block noted again as before, reports of patient-reported outcomes appear positive, despite lack of any evidence of structural benefit.

He emphasized that, because OA pain for many patients is medically intractable, they can’t be dissuaded from seeking “alternative” treatments including those that come at high cost and aren’t risk-free. Moreover, patients reporting improvement from such treatments typically indicate a very significant improvement.

And if the patient says a treatment worked, Block argued, then physicians must accept that it did.

Block reported relationships with pharmaceutical companies developing or marketing osteoarthritis drugs including Pfizer, GSK, Novartis, AbbVie, Janssen, and several others.