Thursday, July 26, 2012

Injections for Knee Pain: Ineffective, Harmful?

InjectionOsteoarthritis (OA) of the knee is an increasing problem in an aging population and many patients turn to various types of injection therapies to avoid surgery or strong medications. While interventional pain specialists claim the injections help to relieve pain and disability associated with knee OA, current evidence suggests that these therapies may be largely ineffective, somewhat costly, and possibly even cause harm in some cases.

Writing in the Annals of Internal Medicine, Anne Rutjes, PhD, of the University of Bern in Switzerland, and colleagues report conducting a systematic review and meta-analysis of studies examining viscosupplementation — the intra-articular injection of hyaluronic acid — for symptomatic relief of painful knee OA in adults [Rutjes et al. 2012]. Hyaluronic acid is a lubricant in joint fluid that acts like a shock absorber, but declines with the wear-and-tear of osteoarthritis. An improved form, cross-linked hyaluronic acid, has higher molecular weight that enhances its elastoviscous properties and provides a longer period of residence in the joint space (ie, slower resorption).

The literature search by Rutjes et al. uncovered 89 randomized controlled trials involving roughly 12,700 patients aged 50 to 72 with knee OA who received either viscosupplementation or a sham injection, or served as nonintervention control subjects. Pain intensity and flare-ups were the primary outcomes; function and serious adverse events were secondary outcomes. Of those 89 studies, 40 had a followup of 3 months or longer and 22 used cross-linked forms of hyaluronic acid. Overall quality of the trials was low, there was a high degree of heterogeneity (ie, differences in trial conduct and measurements), and safety data often were not reported.

A total of 71 trials (nearly 10,000 patients) showed a moderate reduction in pain scores; however, even the small effect size (0.37) was biased by trial size, blinded outcome assessment, and publication status. The remaining 18 trials, all large in size, demonstrated a clinically irrelevant effect size (0.11), plus there were another 5 trials that were unpublished and showed a trivial effect size of only 0.03

Furthermore, 6 trials found that viscosupplementation increased the risk for flare-ups in pain and swelling, although this was not statistically significant (relative risk [RR], 1.51; 95% CI, 0.84 to 2.72), and 14 trials showed a significant 41% increased risk for serious adverse events (RR, 1.41; 95% CI, 1.02 to 1.97). Therefore, the authors conclude from their meta-analysis that viscosupplementation with hyaluronic acid for knee OA affords only minimal reduction in pain while potentially increasing the risk for flare-ups and serious adverse events — “the administration of these preparations should be discouraged,” they write.

In a separate study reported recently, Canadian researchers assessed the effectiveness of another type of injection therapy — regenerative injection therapy, or RIT — to relieve pain and restore function in 36 patients with knee OA [Dumais et al. 2012]. In an open-label crossover design participants were randomly assigned to one of two groups: Group A (N=18) received exercise therapy for 32 weeks plus RIT on weeks 0, 4, 8, and 12; Group B (N=18) received exercise therapy for 32 weeks plus RIT on weeks 20, 24, 28, and 32.

The RIT intervention consisted of injections of 1cc of dextrose (15%) and lidocaine (0.6%) in the collateral ligaments and a 5cc injection of dextrose (20%) and lidocaine (0.5%) inside the knee joint. The primary outcome was change on the Western Ontario and McMaster Universities Osteoarthritis Index of severity of osteoarthrosis symptoms (WOMAC) score.

Writing in the journal Pain Medicine, the researchers report that after 4 months (16 weeks) participants in Group A, receiving RIT, experienced a significant reduction of their OA symptoms according to WOMAC scores, which persisted during the last 16 weeks of follow-up, when the participants received exercise therapy only. In Group B, WOMAC scores in the first 16 weeks when participants were receiving only exercise therapy did not change significantly, but there was a significant decrease in this groups' WOMAC scores during the last 16 weeks when they received RIT.

Overall, after 36 weeks, WOMAC scores improved in both Group A and B by 47% and 36%, respectively, and the decreases attributable to RIT alone corresponded to roughly a 30% improvement in WOMAC scores. The researchers conclude that this first randomized controlled trial to assess pain and function outcomes following RIT for knee OA demonstrated a meaningful improvement with RIT alone and further improvements with a combination of RIT and exercise. They believe these results, combined with the low risk, low price, and accessibility of dextrose makes RIT of the knee a viable alternative for the management of knee OA. However, there is some question as to whether the result of this single trial can be trusted as valid and clinically important.

CLINICAL COMMENTS: The first study, by Rutjes et al. [2012], was a very thorough review and meta-analysis of viscosupplementation with hyaluronic acid for knee OA, and it is surprising that there were was such an extensive evidence base to draw upon. Meta-analysis is a very powerful tool for examining a body of evidence to reach valid conclusions regarding the safety and efficacy of a therapeutic approach or intervention, and it is clearly apparent that examining individual studies (or even select groups of studies) in isolation could result in otherwise misleading perceptions. That is, for various reasons, there almost always are one or more studies demonstrating favorable outcomes even for ineffective therapies.

We have cautioned previously in these UPDATES that authors of research articles or commentary often selectively pick and choose the studies that they use as evidence in support of their claims. While there could be justifications for this in some cases, at least in the authors’ minds, it also can mislead readers along a path of faulty reasoning and acceptance of fallacious conclusions [discussed in an UPDATE here].

From the meta-analysis by Rutjes and colleagues, it seems evident that hyaluronic acid therapy for knee OA is not only ineffective but could cause exacerbations of pain symptoms or adverse events. According to a news report in conjunction with the study [Doheny 2012], the U.S. FDA approved the injections in 1997 and they are not inexpensive; in 2006 injections for a 6-month period ranged from $850 to $1,840, and they must be repeated for longer-term effect.

Our concern about this intervention was further piqued recently by a radio advertisement from a pain clinic in the Chicago, Illinois, area promoting this very therapy as an effective remedy for knee pain. We wondered if any listeners — patients or healthcare providers — would know of this meta-analysis that clearly disputes that claim. This, of course, leads us to wonder about the many other unproven and potentially harmful therapies for pain that are being widely promoted and foisted on unwary patients.

The second study — by Dumais et al. [2012] demonstrating benefits of regenerative injection therapy for knee pain, using dextrose as the active ingredient — might be faulted in several respects: 1) it is an isolated trial in a select group of patients, 2) there was no control group with or without exercise alone throughout the trial period to assess and compare the natural course of the pain condition, 3) there was no extended followup to determine longevity of treatment effects, and, most importantly, 4) the small number of only 36 subjects in an unblinded cross-over design of this sort would likely bias outcomes to erroneously favor therapeutic benefits.

For example, in an extensive analysis of therapies for osteoarthritis, Nüesch et al. [2010] observed that the predominance of small studies in the pain field — considered as <100 subjects in each arm — can distort results in favor of falsely demonstrating beneficial effects of a treatment. Even at 100 participants in each group, there is only 80% power to detect a small to moderate standardized effect size of 0.40 at a two-sided P=0.05; which corresponds to a difference of about 1cm between experimental and control groups on a 10cm visual analog scale. The implication is that, even if a statistically significant and beneficial effect size is found in a study with fewer participants, it is likely that this result may be skewed or biased by having too few subjects for a true clinical representation of the outcome. (Coincidentally, lead author of this analysis, Eveline Nüesch, was a coauthor of the recent meta-analysis by Rutjes et al. 2012 noted above.)

In their study of RIT for knee OA, Dumais et al. had somehow calculated in advance that only 18 subjects per group would be needed to provide 80% power for detecting a significant (P<0.05) 40% improvement of WOMAC scores due to RIT. Their outcome of 30% improvement attributable to RIT actually did not achieve even this modest effect size; so, until further confirming research is conducted, the outcomes of this trial should be considered tentative at most. (For interested readers, the concept of statistical power was discussed in a Pain-Topics UPDATE [here] and effect sizes were discussed [here].)

Interventional therapies for a variety of chronic pain conditions are being more widely promoted in the face of mounting controversies and concerns about analgesic pharmacotherapies — opioids in particular. Questions remain, however, as to the circumstances and patients in which these interventions are most applicable and whether they are ultimately cost effective. For example, we have previously written about concerns regarding epidural steroid injections [here], and the debate over procedural techniques that may be driven more by economics than better patient care in the ongoing turf wars between interventionists and medical practitioners was discussed [here].

The procedure examined in the study above by Dumais et al. falls under the concept of “regenerative medicine” (RM), which dates back to the 1930s and is described in an excellent review by DeChellis and Cortazzo [2011, see ref below]. Currently, RM is an umbrella term encompassing several therapies used to treat painful musculoskeletal conditions: prolotherapy, platelet-rich plasma therapy (PRP), and stem cell therapy. Although the specific treatments are based on similar concepts, the mechanisms behind their alleged reparative properties differ; however, it also should be noted that the exact mechanisms and their scientific underpinnings are still largely undetermined. And, fairly recently, the use of ultrasound has been added to RM therapies as a way of guiding the injected solutions to the exact site of injury.

The RIT, or regenerative injection therapy, procedure studied by Dumais et al. is within the prolotherapy category, which has been traditionally used to treat tendon and ligament injuries. Prolotherapy is a technique that involves the injection of an irritant, usually a hyperosmolar dextrose solution (as in the Dumais et al. study) or another solution, into a joint space, ligament, or tendon-insertion site as a complementary medical therapy — the most immediate goal usually being pain relief.

Mechanisms of how prolotherapy, or RIT, might benefit osteoarthritis in the knee are still speculative. Dumais and colleagues propose that RIT might help by increasing ligament mass, thickness, and cross-sectional strength to improve stabilization of the knee. Or, the intervention might play a role in tissue repair and reduced inflammation in ligaments and tendons. Although their study demonstrated some benefits of RIT, it really did not answer the question of whether special exercise alone or other physical rehabilitation might be equally or more effective and safe over time.

The most frequently published indication of prolotherapy is in the treatment of chronic low back pain, but some studies have examined its use in the management of refractory tendinopathies — particularly lateral epicondylitis and Achilles tendinopathy — and now this present study in osteoarthritis. In a thorough and informative review of prolotherapy, Distel and Best [2011, see ref below] observe that, “despite its long history and widespread use as a form of complementary therapy, there still are disparities over its optimal indications and injection preparations.” Furthermore, large, randomized controlled trials are still needed in order to make specific recommendations regarding optimum protocols and indications.


  • DeChellis DM, Cortazzo MH. Regenerative medicine in the field of pain medicine: Prolotherapy, platelet-rich plasma therapy, and stem cell therapy—Theory and evidence. Tech Reg Anesth Pain Manag. 2011;15(2):74-80 [access here].
  • Distel LM, Best TM. Prolotherapy: A Clinical Review of Its Role in Treating Chronic Musculoskeletal Pain. PM&R. 2011;3(6 Suppl 1):S78-S81 [access here].
  • Doherty K. Knee Injections for Arthritis? Save Your Money, Study Says. Healthday. 2012(Jun 11) [available here].
  • Dumais R, Benoit C, Dumais A, et al. Effect of Regenerative Injection Therapy on Function and Pain in Patients with Knee Osteoarthritis: A Randomized Crossover Study. Pain Med. 2012(Jul); online ahead of print [abstract here].
  • Nüesch E, Trelle S, Reichenback S, et al. Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study. BMJ. 2010;341:c3515 [access here].
  • Rutjes AWS, Jüni P, da Costa BR, et al. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med. 2012(Jun); online ahead of print [access here].

Fair Balance Addendum 7/29/2012 — Shortly after posting this UPDATE, we came across a recent literature review broadly examining evidence for intraarticular knee injections in the management of arthritic knee pain. The results are presented here without our further analysis or critique.

The authors conclude that the evidence supports the use of intraarticular corticosteroid injections for rheumatoid arthritis, osteoarthritis, and juvenile idiopathic arthritis. Pain relief and functional improvement are significant for months up to 1 year after the injection. Intraarticular injection of hyaluronate may provide longer pain relief than steroid injection in osteoarthritis and can also be effective for rheumatoid arthritis knee pain; however, it is only recommended for patients with significant surgical risk factors and for patients with mild radiographic disease in whom conservative treatment has failed. Botulinum toxin type A injection is effective in reducing arthritic knee pain, and so is tropisetron and tanezumab. New agents, such as rAAV2-TNFR:Fc, SB-210396/CE 9.1, and various radioisotopes have provided various degrees of success, but their long-term safety and efficacy remain to be determined. Source: Cheng OT, Souzdalnitski D, Vrooman B, Cheng J. Evidence-Based Knee Injections for the Management of Arthritis. Pain Med. 2012;13:740–753 [abstract here].

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