How Effective are Non-Steroidal Anti-Inflammatory Drugs and Opioids for the Treatment of Osteoarthritis?

How Effective are Non-Steroidal Anti-Inflammatory Drugs and Opioids for the Treatment of Osteoarthritis?

Osteoarthritis is an inflammatory condition that most commonly affects the knees and hip joints in older people. It can cause significant pain and result in reduced physical function and quality of life as well as an increased risk of all-cause mortality. The routine pharmacology treatment for osteoarthritis includes the prescription of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. In the UK, 84% of all patients diagnosed with osteoarthritis between 2000 and 2015 were prescribed opioids.

Evidence shows that improvements in pain and physical function could be similar for opioids and NSAIDs, but opioids carry a substantially higher risk of adverse events (e.g., nausea, vomiting, and drowsiness), addiction, and abuse. Furthermore, 7 of the 10 recommendations made in a recent guideline for opioid treatment in chronic non-cancer pain are focused on harm reduction due to these substantial risks. Nonetheless, opioids remain among the most prescribed drugs for osteoarthritis, despite the availability of safer treatments with stronger analgesic (pain-relieving) effects.

A recent systematic review aimed to assess the effectiveness and safety of different preparations and doses of NSAIDs, opioids, and paracetamol for knee and hip osteoarthritis pain and physical function.

Design and Methods of the Study

The researchers considered for inclusion large, randomised trials of patients with knee or hip osteoarthritis that compared either NSAIDs, opioids or paracetamol with placebo. They also included trials that included other types of osteoarthritis if 75% or more of the participants had confirmed knee or hip osteoarthritis. To reduce small study bias, only trials with at least 100 participants randomised per arm were included for review.

In total, data from 192 trials were included, for a combined patient sample of 102,829 patients: 147 of which assessed the effectiveness and safety of NSAIDs only, 29 assessed opioids only, 9 NSAIDs v paracetamol, 5 paracetamol only, and 2 NSAIDs v opioids.

The researchers’ prespecified primary outcome was pain, as measured by several scales, including the global osteoarthritis pain assessed using visual analogue or numerical rating scales, pain on walking, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore, and composite pain scores other than WOMAC.

Physical function was also measured as a secondary outcome, again measured using a number of scales, including global osteoarthritis function score, walking disability, WOMAC physical function subscore, and composite physical function scores other than WOMAC.

Results of the Study

Pain Outcomes

Diclofenac 150 mg/day (NSAIDs) and etoricoxib 60 mg/day (NSAIDs) appeared to be the most effective treatments for pain management. Etoricoxib 60 mg/day (NSAIDs) seemed to have a lower risk of patients experiencing a serious adverse event than diclofenac 150 mg/day; however, the authors note that effect estimates were imprecise. Patients treated with etoricoxib 60 mg/day also appeared to be less likely to stop treatment due to adverse events.

On the other hand, among topical treatments, diclofenac, at any dose, was seen to have the largest effect on pain. At the lowest dose, topical diclofenac had a 92% probability of having a minimum clinically relevant improvement on pain, with a better safety profile than oral diclofenac.

None of the opioid interventions, regardless of dose, seemed to have a clinically relevant effect on pain.

Physical Function

The results of past studies indicate that all interventions improved physical function when compared with placebo, except for two: nabumetone 1000 mg/day (NSAID) and paracetamol <2000 mg/day. None of the opioid interventions, regardless of dose, seemed to have a clinically relevant effect on physical function.


Among the NSAIDs that are commonly prescribed in the US, meloxicam and diclofenac were more effective and had similar safety outcomes compared with ibuprofen and naproxen at their respective recommended daily doses. The safety outcomes of opioids, in general, were significantly worse than the other interventions assessed. Furthermore, higher doses of opioids also led to higher a higher risk of harm.


The authors note that the findings of this review can be used to identify the lowest doses of different drug preparations that are effective and safe when first prescribing treatment for hip and knee osteoarthritis. Treatments should preferably be prescribed on an as-needed basis, to improve efficacy and reduce the risk of adverse events.

The evidence shows that even when patients receive lower doses of non-tramadol opioids, they are up to 13 times more likely to interrupt treatment due to adverse events, and up to 10 times more likely to experience any type of adverse events compared with oral placebo. These findings indicate that the low effects of opioids on pain and physical function do not outweigh the harm they may cause in patients with osteoarthritis.

The results from this network meta-analysis indicate that lower doses of oral NSAIDs, such as oral diclofenac 100-105 mg/day and etoricoxib 30 mg/day, or topical diclofenac 70-81 mg/day, have more favourable safety profiles than the maximum recommended daily doses. High dose diclofenac (150 mg/day) and etoricoxib (60 mg/day) appeared to be the most effective for pain and function in the setting of lower limb osteoarthritis. However, the increased risk of adverse events, likely means that these treatments may not be appropriate for those with comorbidities or requiring long-term treatment. Consequently, the authors recommend topical diclofenac (70-81 mg/day) as the first line pharmacological treatment for knee osteoarthritis.

In light of the paucity of pharmacological options for those with osteoarthritis, it is important to develop new and novel options for pain control for these patients. This is particularly true in light of the growing backlog of routine surgery in the NHS following the Covid-19 pandemic limiting the access to joint replacements.