Predictors of a placebo response in patients with hand osteoarthritis: post-hoc analysis of two randomized controlled trials

Osteoarthritis (OA) of the hands is common in middle-aged and elderly populations, especially women [1]. The marked disability and reduced quality of life caused by the disease are comparable with those caused by rheumatoid arthritis (RA) [2, 3]. Pain can be especially debilitating in patients with erosive hand OA, which is characterized by painful swelling, and joint inflammation as well as the subchondral bone erosions and marginal osteophyte formation on radiographic images. The main therapeutic approach to hand OA is to control symptoms by using a combination of non-pharmacological and pharmacological interventions [4]; this is because, unlike for RA, there are no effective disease-modifying osteoarthritis drugs (DMOADs). To date, oral non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or opioid-based analgesics constitute the mainstay of treatment targeting pain control. Inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α) may contribute to the degeneration of articular cartilage matrix [5]. Therefore, treatment targeting inflammation and pro-inflammatory cytokines were attempted. In a recent study, a short-term treatment with low dose corticosteroid improved pain and signs of inflammation in patients who experience a flare-up of hand OA [6]. However, they and other medications, including anti-tumor necrosis factor inhibitors and anti-interleukin-1 antibody, show only minimal to moderate effect sizes, emphasizing an unmet need for better treatment modalities for hand OA [7‐9].

A previous randomized clinical placebo-controlled trial (RCT) involving patients with hand OA reported that 30.2% of patients in the placebo group demonstrated a positive Outcome Measures in Rheumatology-OA Research Society International (OMERACT-OARSI) response at Week 4 [10], suggesting that placebo can have a significant therapeutic effect [11]. In one meta-analysis, the placebo response might account for about 75% of response to drugs commonly used in OA [12]. Boosting the intrinsic placebo response in OA treatment might improve clinical care. For this, it might be important to identify factors associated with a susceptibility to placebo effect [13]. However, it is unclear which patients with hand OA will benefit most from this placebo effect. In this post-hoc analysis of two RCTs, we aimed to identify factors associated with a clinically meaningful placebo response in patients with hand OA.

This post-hoc analysis of two prospective, double-blind, randomized, placebo-controlled studies shows that placebo yielded a clinically meaningful improvement in about one third of patients with hand OA. This placebo response was associated significantly with baseline pain, but not with structural changes such as joint swelling or osteophyte formation.

Hand OA is common, with a prevalence ranging from 29 to 76% [1, 18]. In half of patients, the disease will progress, leading to severe functional limitation and a serious disease burden [19]. In the absence of effective DMOADs, symptoms (i.e., pain, function and stiffness) are controlled by NSAIDs, tramadol, and opioid analgesics. However, the potential gastrointestinal and cardiovascular side effects of these drugs limit long-term use [20‐23].

Although pain associated with OA is caused by structural changes due to accelerated degeneration of articular cartilage and secondary bone remodeling, pain signals are ultimately perceived by the brain after intensive central pain processing at multiple levels [24]. Consistent with this, we found that pain at baseline was not associated with structural changes such as swollen joints, nor was it associated with osteophyte formation and joint deformity (Supplementary Table S1). Pain correlated with the tender joint count only in RCT 2. Rather, pain was more closely associated with subjective parameters such as the AUCAN stiffness and function scores. Similarly, improvements in AUSCAN stiffness and function scores correlated with baseline stiffness and function, respectively. Taken together, not only pain generation in joints, but also central pain processing, might ultimately determine the level of pain and functional impairment experienced by patients with hand OA.

Although the mean improvement in AUSCAN pain was low, pain responses to placebo varied markedly among the OA patients, ranging from − 76.4 - 33.2 from baseline. Strikingly, high baseline pain, but not the severity of structural joint changes, was associated with a better placebo response (Table 1) [25]. This is consistent with a prior observation demonstrating that neither structural damage observed on ultrasound nor clinical severity of OA are predictive of treatment response [26]; this further supports the dissociation between treatment response and structural joint changes in those with hand OA. Rather, we found that improvements in pain, function, and stiffness correlated significantly with their respective baseline levels (Fig. 1).

While baseline AUSCAN pain and function were associated with a clinically meaningful placebo response, the multivariable analysis identified only the baseline AUSCAN pain as the factor for the placebo response. Interestingly, women with hand OA were 10 fold more likely to have a positive placebo response (Table 3), consistent with sex difference in the placebo response [27]. While OA affects both men and women, women were dominant in both RCTs, consistent with female dominance in the recent trials with hand OA [6, 9]. This suggests that women might suffer more from hand OA than men and they, therefore, are more likely to seek medical attention. Whether women with hand OA are more susceptible to pain, placebo response or both needs further investigation.

Placebo effect is not limited to hand OA and it depends on the mode of delivery. In knee OA, intra-articular and topical placebo elicited a greater placebo response than oral placebo [28]. The placebo effect can vary among OA sites since it was greater in knee OA than in hip OA [29]. Taken together, all placebo are not equal. However, it is still important to identify additional factors associated with a treatment response to optimize clinical care of OA patients. As example, early radiographic features such as congruent articular reduction and tiabial plateau alignment were associated with a better pain improvement after surgical treatment of displaced tibial plateau fractures [30]. It is interesting that use of tramadol/AAP was also associated with a better placebo response, whereas NSAIDs and other medications were not. Tramadol acts on central pain processing; it is a weak agonist of the mu opiate receptor and inhibits both serotonin and norepinephrine reuptake, thereby exerting anti-nociceptive effects [31].

A previous study shows that in patients with chronic pain and associated pain sensitization (such as those with fibromyalgia), the retention rate for tramadol/AAP is higher than that for placebo [32, 33]. Therefore, OA patients with severe pain might have developed aberrant central pain processing over time, resulting in increased central sensitization [34]. OA patients who were taking tramadol/AAP at baseline might benefit from anti-nociceptive effects on central pain processing, making them more susceptible to placebo effects. Indeed, duloxetine, which modifies central pain sensitization, is an effective treatment for knee OA [35]. The mechanism underlying central pain processing in OA requires further investigation.

It might be unethical to prescribe a placebo in routine clinical practice. However, the inherent placebo effect of any pharmacological and non-pharmacological treatment could be optimized in routine clinical practice. This is of particular importance since the placebo response might account for about 75% of response to drugs that are commonly used in OA treatment [12]. To optimize this placebo effect, it might be crucial to identify patients who are more susceptible to a placebo response. In this study, female gender and high baseline pain were associated with a clinically significant placebo response (Table 3). The question of whether a warm and reassuring consultation, optimistic attitudes of healthcare providers, and positive relationships between patient and physician improve OA outcomes should be investigated in future.

This study has several limitations. First, the lack of a control group that did not receive any treatment (even placebo) makes estimating the placebo effect difficult. Second, we did not consider depressive mood disorders and/or emotional or physical stress, which might influence pain processing and so placebo responses. Third, RCT 2 (41 patients in the placebo arm) is too small to enable comparison of clinical parameters between clinical responders and non-responders. However, both RCT 1 and RCT 2 showed remarkably similar placebo responses (Supplementary Table S2). Further studies are needed to identify therapeutic and situational factors that improve placebo responses.

The placebo effect can be significant in patients with hand OA who have high pain levels at baseline. Further studies are needed to understand the pathophysiology and underlying mechanisms, and to optimize the placebo effect as an OA treatment in clinical practice.