Combining two or more drugs vs one drug for pain control in inflammatory arthritis

This summary of a Cochrane review presents what we know from research about the effect of a combination of two pain relieving drugs for pain control in inflammatory arthritis (IA).

We are uncertain if two pain relieving drugs such as paracetamol (also called acetaminophen) (e.g. Panadol® and Tylenol®) plus non-steroidal anti-inflammatory drugs (NSAIDs), or paracetamol plus aspirin compared with one drug improved pain, because only single studies of low quality evidence were available. For the same reason, we do not have precise information about side effects and complications.

What is IA, and what drugs are used to treat pain?

IA is a group of diseases that includes rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and other spondyloarthritis (SpA). When you have IA, your immune system, which normally fights infection, attacks your joints. This makes your joints swollen, stiff and painful. In RA, the small joints of your hands and feet are usually affected first. In contrast, in AS, the joints of the spine are the most affected. PsA is characterised by inflammation of the skin, psoriasis, and joints and, depending on the disease type, can affect the small joints of the hands and feet or more the spine. There is no cure for IA at present, so the treatments aim to relieve pain and stiffness and improve your ability to move. Patients are started on disease-modifying antirheumatic drugs (DMARDs) (e.g. methotrexate, sulphasalazine, hydroxychloroquine and leflunomide) as soon as possible in an attempt to control the inflammation and to prevent the progression of the disease. Many people continue to have pain despite optimal disease treatment and have the need for specific medication to control pain.

Several drugs can be used to treat pain in IA. Paracetamol/acetaminophen, is used to relieve pain but does not affect swelling; NSAIDs such as ibuprofen, diclofenac and COX-2s (e.g. celecoxib), are used to reduce pain and swelling; and opioids, such as codeine-containing Tylenol®, hydromorphone (Dilaudid), oxycodone (Percocet and Percodan), morphine and tramadol are powerful pain-relieving substances. Other drugs have some pain relieving properties and can therefore be used to mainly control pain. This is the case of the so-called neuromodulators, such as antidepressants (e.g. fluoxetine, paroxetine and amitriptyline), anticonvulsants (e.g. gabapentine and pregabaline) or muscle relaxants (e.g. diazepam). It is not clear if combining two of these drugs offers the best treatment and which drugs cause more side effects. It is known that, for instance, high doses of paracetamol/acetaminophen may cause stomach problems, such as ulcers, and NSAIDs may cause stomach, kidney or heart problems.

Best estimate of what happens to people with IA who take combination therapy for pain

There is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. We included 23 studies in this review, all at high risk of bias (i.e. high chance of giving invalid results). Twenty-two of the trials were in patients with RA and one in a mixed population (RA and osteoarthritis). There were no studies in patients with AS, PsA or SpA. Included studies were old (all but one were published before 1990) and patients were, in general, not on optimal disease-modifying antirheumatic drugs, as is standard current practice. Therefore, it is not possible to draw conclusions about the value of combination pain therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed studies are needed to address this question.

Authors' conclusions: 

Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed trials are needed to address this question.

Read the full abstract...
Background: 

Despite optimal therapy with disease-modifying antirheumatic drugs, many people with inflammatory arthritis (IA) continue to have persistent pain that may require additional therapy.

Objectives: 

To assess the benefits and safety of combination pain therapy for people with IA (rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and other spondyloarthritis (SpA)). We planned to assess differences in effects between patients on background disease-modifying antirheumatic drug (DMARD) therapy and patients on no background therapy in subgroup analyses.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; and EMBASE. We did not impose any date or language restrictions in the search. We also handsearched conference proceedings of the American College of Rheumatology and the European League against Rheumatism (2008-10).

Selection criteria: 

Randomised and controlled clinical trials (RCTs and CCTs) assessing combination therapy (at least two drugs from the following classes: analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, opioid-like drugs and neuromodulators (antidepressants, anticonvulsants and muscle relaxants)) compared with monotherapy, for adults with IA (RA, AS, PsA and other SpA). We speficically excluded studies that did not report pain or studies without a standardised pain scale as an outcome measure.

Data collection and analysis: 

Two review authors independently selected trials for inclusion, assessed risk of bias and extracted data.

Main results: 

Twenty-three trials (total of 912 patients) met the inclusion criteria (22 in RA; one in a mixed population of RA and osteoarthritis); all except one were published before 1990. Most study populations were not taking DMARDs (e.g. methotrexate, sulphasalazine, hydroxychloroquine and leflunomide) and all studies were performed prior to the introduction of biologic therapies (e.g. etanercept, infliximab and adalimumab). All trials were at high risk of bias, heterogeneity precluded meta-analysis, and we were only able to report a general description of results.

The majority (18 studies, 78%) found no differences between the combination and monotherapy treatments they studied, while five (22%) reported conflicting results, favouring either the combination or monotherapy arms.

From the 12 trials on NSAID + analgesic vs NSAID, nine reported no significant difference between the interventions, while three did: in two, the combination therapy achieved better pain control; and the third trial compared combination therapy with two different dosages of monotherapy (NSAID alone) and reported that a high dose phenylbutazone was superior to combination therapy (paracetamol + aspirin), which was superior to low dose phenylbutazone.

From the five studies on the combination of two NSAIDS vs one NSAID, four reported no significant differences between interventions, and one reported significantly better pain control with combination therapy.

The single trial comparing a combination of opioid + neuromodulator vs opioid reported better pain control with monotherapy.

The remaining trials (NSAID + neuromodulator vs NSAID (3 trials); opioid + NSAID vs NSAID (1 trial); and opioid + analgesic vs analgesic (1 trial)) found no significant difference between combination therapy and monotherapy.

Information regarding withdrawals due to inadequate analgesia and safety was incompletely reported, but in general there were no differences between combination therapy and monotherapy.

No data were available that addressed the value of combination pain therapy or monotherapy for people with IA who have optimal disease suppression. There were no studies that included patients with AS, PsA or SpA.

Share/Save