Introduction
Pain is an important health problem that causes substantial reduction in quality of life. Pain is categorized on the basis of clinical characteristics and underlying mechanisms into nociceptive pain (i.e., originating from tissue damage), neuropathic pain (i.e., resulting from nerve damage), and idiopathic pain, which has no identified cause. Understanding these differences is crucial when tailoring treatment to achieve optimal pain relief [
1]. Osteoarthritis (OA) is a major cause of chronic pain and disability in older adults and currently affects more than 500 million people worldwide [
2]. In the absence of a curative therapy, symptomatic drugs remain the mainstay for pain management in OA. However, acetaminophen provides inadequate relief and oral non-steroidal anti-inflammatory drugs (NSAIDs) are associated with significant gastrointestinal and cardiovascular adverse events, which limit their long-term use in the elderly [
3,
4]. On the other hand, even though opioids are widely used in clinical practice if other analgesics provide insufficient pain relief or are contraindicated, their efficacy in OA is controversial. In addition, long-term opioid use is associated with serious risk of addiction and overdose deaths [
5]. Therefore, an unmet need still exists for effective and well-tolerated treatments.
Mounting evidence suggests that when the pathophysiology of a medical condition is mediated by multiple pathways such as in OA pain, use of rational combinations of analgesic drugs acting through different mechanisms can provide effective pain relief at reduced individual doses while also minimizing side effects in the long term [
6]. The combination of analgesics is also recommended by major clinical practice guidelines for pain, including the World Health Organization and the American College of Rheumatology [
7].
Acetaminophen and topical diclofenac (AtopD) have complementary mechanism of action (MoA) and are therefore promising candidates for use in combination analgesia. Although acetaminophen MoA is not completely understood, prevailing evidence suggests it to mediate central analgesic effect by activating descending serotonergic pathways [
8]. By contrast, diclofenac, a non-selective cyclooxygenase inhibitor, alters peripheral pain transmission pathways by its anti-inflammatory mechanisms [
9‐
12]. Combining topical diclofenac with oral acetaminophen could also be a useful strategy to address the limitations of acetaminophen monotherapy, which has recently been shown to have insufficient efficacy as a single agent in the treatment of OA [
13]. It may also be suitable for patients averse to oral NSAIDs as a result of comorbidities [
4,
14]. Moreover, several clinical practice guidelines in OA recommend concomitant use of topical NSAIDs with acetaminophen in case of inadequate pain relief with acetaminophen monotherapy [
15,
16]. Therefore, it can be hypothesized that the AtopD combination may show greater efficacy than either acetaminophen or topical diclofenac alone in the management of OA pain. However, while ample clinical evidence exists on the monotherapies of acetaminophen or topical diclofenac in OA pain, there is a gap in clinical evidence supporting their use as a combination therapy [
17]. Consequently, further research is needed to assess the efficacy of the combination therapy in OA pain.
Model-based meta-analysis (MBMA) has become an increasingly important quantitative tool to inform drug development decisions and address clinical questions for which direct evidence is not available [
18‐
20]. In the absence of individual patient-level data, MBMA allows not only direct and indirect comparison of drug treatments, like network meta-analysis, but also represents a robust regression-based technique for the evaluation of various clinical pharmacology questions, including dose–response, drug interaction, covariates effects, and/or endpoint bridging. MBMA is increasingly being used to determine overall treatment effect, a drug–drug combination effect, or an optimal dose compared against comparator drug in a specific disease or indication [
18,
21‐
25]. It is one of the approaches available for the implementation of model-informed drug development (MIDD), a concept for evidence generation which has gained recognition across drug regulatory authorities [
26‐
28].
It is also worth acknowledging that a high degree of overlap exists between acute and chronic pain states, both with regard to their chronology and pathophysiology [
29,
30]. Moreover, various acute pain and mild-to-moderate OA pain are recognized as nociceptive in nature [
31‐
34]. Given the gap in clinical evidence in OA pain, here we have attempted to leverage published summary-level data on the combination therapy in acute pain indications identified through literature search. Hence, this study aimed to assess the effects of AtopD combination and compare its performance relative to acetaminophen or topical diclofenac monotherapy on pain score reduction and opioid-sparing effect using an MBMA.
Discussion
Pain in osteoarthritis is a complex phenomenon that encompasses both inflammatory and non-inflammatory pain signaling pathways at peripheral and central levels of the nervous system [
37,
38]. Thus, it is not surprising that no single drug provides adequate pain relief while demonstrating optimal risk–benefit ratio in the long term. Consequently, successful approaches may require targeting several pathways at the same time [
39,
40]. In this context, combination therapy of AtopD can be a promising strategy to achieve effective analgesia with an adequate safety profile considering that, at the recommended therapeutic doses, both drugs are devoid of any major risk of serious adverse events in the subset of the population most prone to OA.
Acetaminophen, included in the World Health Organization’s List of Essential Medicines, is one of the most widely used analgesic and antipyretic medications globally owing to its high tolerability profile when compared with other analgesics, particularly in high-risk populations such as adults with comorbidities [
41,
42]. It was historically the first-line pain medication for OA [
43] before a few recent publications reported doubts over its efficacy in OA pain [
3]. Although acetaminophen rarely causes adverse effects in healthy individuals when used episodically at ≤ 4 g/day, doses exceeding the recommended daily maximum can result in liver toxicity [
42]. Topical NSAIDs, including diclofenac, have become valuable treatment options for the OA population, to whom oral NSAIDs are contraindicated [
44]. Topical NSAIDs have shown comparable efficacy to oral NSAIDs but exhibit better safety profile due to their considerably lower systemic exposure. Therefore, they are nowadays recommended as first-line medication by most OA clinical practice guidelines before resorting to oral NSAIDs. The most common adverse effects of topical NSAIDs are local site reactions [
45].
A multi-mechanistic therapeutic approach has greater potential to provide optimal analgesia in OA which involves multiple pain pathways [
6]. Acetaminophen plus topical diclofenac is a rational combination that is based on the complementary pharmacodynamics (i.e., different mechanisms of action) of the two drugs. In general, both drugs act by suppressing nociceptive signaling via inhibition of cyclooxygenase (COX), an enzyme involved in the conversion of arachidonic acid to prostaglandins, which mediate inflammation and pain. However, each drug acts via a slightly different mechanism. While topical diclofenac acts peripherally to inhibit prostaglandin synthesis at the site of nociception, acetaminophen inhibits prostaglandin synthesis mainly in the central nervous system [
46,
47]. As a result, the combination might work by blocking pain transmission at peripheral and central nervous system and thus provide greater analgesia than each drug alone [
47].
Although the combination treatment is commonly used, i.e., with more than one-quarter of patients using topical NSAIDs with oral non-opioid analgesics such as acetaminophen in real-world settings [
48], there is limited literature available on the combination of acetaminophen and topical NSAIDs [
17]. Only one RCT of 4-week duration was found that showed significantly greater pain reduction with the combination versus acetaminophen or placebo [
49]. Moreover, a qualitative systematic review focused on pain intensity scores and supplemental analgesic requirements in acute postoperative pain in adults showed the combination of acetaminophen and NSAIDs to be more effective than acetaminophen or NSAIDs alone in more than 60% of studies [
50]. In addition, a pharmacokinetic–pharmacodynamic study in children with acute postoperative pain also found combination treatment with lower doses of acetaminophen and diclofenac to provide comparable analgesia to monotherapies [
36]. Furthermore, several previous studies have investigated the effect of combining oral NSAIDs and acetaminophen in OA and have shown the combinations provide additional pain-relieving activity, thereby leading to a dose-sparing effect and improved safety versus monotherapies [
51‐
53]. These findings seem to support the recommendations of several prominent OA clinical guidelines, which endorse the use of topical NSAIDs concomitantly with acetaminophen [
15,
16]. However, there are no previous studies on the AtopD combination in OA pain. Our study represents therefore an attempt to integrate existing data and extrapolate findings from acute to chronic pain.
While a trend for beneficial effect was observed for the combination on pain score reduction compared to either drug alone, the combination effect was confounded by use of opioid PCA in the studies. Our MBMA of RCTs identified in acute postoperative pain revealed further reduction of opioid use in studies allowing PCA with the combination treatment versus acetaminophen monotherapy. Despite several reports showing opioids to exhibit minimal efficacy in chronic OA pain [
54,
55], opioid prescribing in clinical practice continues unabated [
56]. In this context, the beneficial potential of the combination therapy to reduce opioid consumption by 32% vs. acetaminophen monotherapy cannot be underemphasized when considering the substantial health risks of adverse outcomes associated with opioid usage, including the development of opioid use disorder (dependency and addiction), overdose fatalities, respiratory depression, falls, and their negative effects on gastrointestinal (nausea, constipation), endocrine, immune, and nervous systems (dizziness, somnolence, and fatigue) [
57]. In addition, opioid use is associated with significantly greater structural damage and faster progression of degenerative changes when compared with controls. In fact, opioid users also exhibited significantly greater pain, worse symptoms, and lower quality of life than controls, which suggests inadequate pain control by opioids [
58].
Whilst our findings indicate that combination therapy has a greater opioid-sparing effect when compared with diclofenac monotherapy, the beneficial effect was lesser in magnitude when compared with acetaminophen. This finding is in agreement with a previous clinical study which reported the combination of paracetamol and ibuprofen to exhibit significant efficacy vs. acetaminophen but not against ibuprofen monotherapy in chronic knee pain [
53].
To our knowledge, this is the first MBMA to evaluate and synthesize clinical evidence on the efficacy of the combination of acetaminophen and topical diclofenac in acute pain. Inferences from the results are made on the basis of extrapolation principles, which suggest the potential therapeutic value of the combined use of these two commonly recommended analgesics in mild-to-moderate OA pain. Furthermore, extrapolation of the findings appears to be supported by clinical practice. The majority of trials in OA pain, which included topical or oral diclofenac in one of their treatment arms, allowed acetaminophen as rescue therapy [
59,
60], suggesting that the combination is generally perceived to be beneficial and well tolerated.
Adding topical diclofenac to acetaminophen could also be a potential approach to mitigate safety concerns with acetaminophen by allowing its use at lower dosages. Eventually, it could also delay the progression to oral NSAIDs and opioids in clinical settings. Undoubtedly, insights from this MBMA open the door for a potential treatment option for the ever-increasing aging population suffering from OA, especially those who have cardiovascular and gastrointestinal comorbidities and hence may not transition to stronger analgesics such as oral NSAIDs and opioids.
We acknowledge the limitation of our analysis, which is based on summary-level data only. In this regard, it was not possible to fully assess the combination effect. We also recognize the implications of the restricted inclusion criteria, based on studies having acetaminophen or diclofenac in one of their treatment arms. Inclusion of studies on other NSAIDs could have provided further insight into the anti-inflammatory effect and possibly helped in understanding whether the observed differences are a class effect. From a technical perspective, it should be noted that the combination effect was estimated by adding treatment effect onto the non-parametric placebo response. As there was only one placebo-controlled trial to inform placebo response on the opioid-sparing effect in acute pain [
61], this may have introduced some degree of estimation bias. This limitation may be further compounded by the few studies available, and relatively small sample size. Consequently, we cannot rule out the impact of study-level variation on model precision, as suggested by the wide range of simulated confidence intervals. From a clinical perspective, the severity of acute pain caused by different types of surgery should not be overlooked, as it may drive large variation in the consumption of opioids (e.g., cesarean pain required higher dose of PCA vs. tonsillectomy). This effect could not be fully accounted for in the current parsimonious model because of the limited number of clinical studies. Lastly, our analysis might be subject to publication bias. However, considering acetaminophen and diclofenac have a long history of use, we believe that the chance of publication bias is low.