Use of Saline as a Placebo in Intra-articular Injections in Osteoarthritis: Potential Contributions to Nociceptive Pain Relief

David Bar-Or1, 2, 3, 4, 5, *, Leonard T. Rael1, 2, 3, 4, 5, Edward N. Brody6
1 Swedish Medical Center, Trauma Research, Englewood, CO 80133, USA
2 St. Anthony Hospital, Lakewood, CO 80228, USA
3 The Medical Center of Plano, Plano, TX 75075, USA
4 Penrose Hospital, Colorado Springs, CO 80907, USA
5 Ampio Pharmaceuticals Inc., Englewood, CO 80112, USA
6 SomaLogic Inc., Boulder, CO 80301, USA

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© Bar-Or et al.; Licensee Bentham Open

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Swedish Medical Center/Trauma Research Department, 501 E. Hampden Ave., Room 4-454, Englewood, CO 80113 USA; Tel: (303) 788-4089; Fax: (303) 788-4064; E-mail:



Osteoarthritis of the knee (OAK) is a severe debilitating condition characterized by joint pain, stiffness, and resultant limited mobility. In recent years, intra-articular (IA) injections have been used to relieve symptoms and have succeeded to varying degrees either with sodium hyaluronate preparations or with a biologic.


The objective of this review is to evaluate multiple studies that demonstrate some relief from the symptoms of OAK in the saline arm of various clinical trials.


A thorough literature search (PubMed) was performed assessing the pain efficacy of various compounds compared to saline injections in clinical trials. A total of 73 studies were identified in the literature search including a total of 5,816 patients. These clinical trials all involved the IA injection of a viscosupplement (hyaluronate, platelet rich plasma (PRP), etc.) or a biologic (the low molecular weight fraction (< 5kDa) of human serum albumin (LMWF-5A)). For all of these studies, the control arm was injection of sterile physiological saline that approximates the salt concentration and total solute concentration of blood and most tissues.


Based on our review of the current literature, the tested compounds performed with mixed results when compared to saline injections. Moreover, OAK is a variable disease, with severity measured on the Kellgren and Lawrence (KL) scale where various hyaluronate preparations have a therapeutic effect mostly on KL 2-3 patients while a biologic works best on KL 3-4 patients.


Since the effect of saline injection is always greater than no treatment, the evaluations of these treatments can be confounded in clinical trials. Therefore, the question of whether there are known therapeutic effects of saline injections might explain these results.

Keywords: Biologicals, Clinical trial, Osteoarthritis, Neuropathic pain, Nociceptive pain, Pain relief.