Effect of Milnacipran on Pain in Patients with Rheumatoid Arthritis with Widespread Pain: A Randomized Blinded Crossover Trial

Abstract

Objective Clinical trials have shown that serotonin norepinephrine reuptake inhibitors, such as milnacipran, decrease pain in non-inflammatory pain conditions like fibromyalgia and osteoarthritis. We examined the effect of milnacipran on self-reported pain intensity and experimental pain sensitivity among rheumatoid arthritis (RA) patients with widespread pain and stable RA disease activity. Methods In this double-blind, crossover study, RA patients with widespread pain, on a stable treatment regimen, were randomized (via a random number generator) to receive milnacipran 50 mg twice daily or placebo for 6 weeks, followed by a 3-week washout and crossed over to the other arm for the remaining 6 weeks. The primary outcome was change in average pain intensity, assessed by the Brief Pain Inventory short form. The sample size was calculated to detect a 30% improvement in pain with power = 0.80 and alpha = 0.05. Results Of the 43 randomized subjects, 41 received study drug, and 32 completed the 15-week study per protocol. On a 0–10 scale, average pain intensity decreased by 0.39 (95% CI −1.27, 0.49; P = 0.37) more points during 6 weeks of milnacipran treatment compared to placebo. In the subgroup of subjects with swollen joint count ≤ 1, average pain intensity decreased by 1.14 (95% CI −2.26, −0.01; P= 0.04) more points during 6 weeks of milnacipran compared to placebo. Common adverse events included nausea (26.8%) and loss of appetite (9.7%). Conclusion Compared to placebo, milnacipran did not improve overall, self-reported pain intensity among subjects with widespread pain taking stable RA medications. Trial registration: ClinicalTrials.gov NCT01207453

Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study

“…Similarly, no significant analgesic effect of milnacipran compared with placebo was observed on global pain, and pain diminished similarly in both groups, stressing the lack of efficacy of milnacipran and the strong placebo effect. This lack of analgesic effect is, however, contradictory to previous studies with milnacipran and duloxetine that showed 40 – 43 , 56 a pain diminution of 30% in 40% patients, a value higher than that in our study (30% diminution in 29% milnacipran group and 25% placebo group, p =0.745). The strong placebo effect observed in FM patients confirms, however, the literature on milnacipran 60 and was also shown for duloxetine and gabapentin.…”

“…Chronic pain and FM are known to have a deleterious influence on cognitivo-emotional domains, affecting emotion, concentration, and memory. 44 , 56 , 63 Our FM sample was cognitively impaired regarding vigilance and memory when compared with non-FM healthy volunteers from a previous study (Corriger et al, unpublished data, 2017). After 1-month treatment with milnacipran, no difference was, however, highlighted between both groups.…”

“…If these pathways were functional, the second series of stimuli would be less painful than the first series because of the inhibitory effect on pain as described in a number of chronic pain situations including FM. 53 , 55 , 56 CPM is calculated as the difference (for 10- and 30-second stimulation [CPM 10 and CPM 30 , respectively]) between the NRS pain scores rated after and before immersion of the nondominant hand in the water bath at 46.5°C. Delta CPM is the CPM difference between M1 and inclusion.…”

Discordant inflammation and pain in early and established rheumatoid arthritis: Latent Class Analysis of Early Rheumatoid Arthritis Network and British Society for Rheumatology Biologics Register data

“…However, using widespread pain alone for selective recruitment of participants was not adequate in a clinical trial of the centrally acting analgesic milnacipran in people with RA, although the number of participants might be small and secondary analysis implicated a confounding effect of synovitis on the pain measurements [42]. Clustering algorithms based on studies such as ours and others [19] represent an alternative tool for determining recruitment criteria for personalised medicine trials.…”

Non‐specific analgesia during a clinical trial in fibromyalgia

“…29 Finally, in a double-blind RCT of milnacipran in patients with rheumatoid arthritis and widespread pain, changes in pressure pain threshold in the placebo group did not correlate with changes in pain intensity at the 6th week of treatment. 30 FM is also associated with impairment of cognitive and executive functions, which is worse in the case of accompanying depressive disorders. 31,32 There are few data about cognitive improvement during therapeutic challenges, and none about the relationship with non-specific pain relief.…”