PDF: Duloxetine for Central Pain in MS
(2015)Objective
To evaluate the efficacy of duloxetine, a serotonin-norepinephrine reuptake inhibitor, for treating central pain in patients with multiple sclerosis
Study Summary
• Average daily pain was reduced by 39% with duloxetine compared to 10% with placebo (P=0.002)
• However, fewer patients tolerated duloxetine compared to placebo, with 22% discontinuation rate in duloxetine group versus 10% in placebo group due to adverse effects
Intervention
Duloxetine 30 mg daily for 1 week, then 60 mg daily for 5 weeks, then 30 mg daily for 1 week taper, versus matched placebo. Rescue medication (ibuprofen up to 2400 mg/day or acetaminophen up to 2000 mg/day) was allowed
Inclusion Criteria
MS diagnosis (McDonald or Poser criteria) ≥3 months prior, age >18 years, no MS exacerbation or disease-modifying therapy change for 90 days, daily pain attributed to MS present ≥2 months, worst pain score ≥4 on 0-10 Likert scale on majority of days, pain clearly differentiated from other non-MS causes
Study Design
Arms: Duloxetine (N=18) versus Placebo (N=20)
Patients per Arm: 18 duloxetine, 20 placebo (38 total randomized); 14 duloxetine and 18 placebo completed per protocol
Outcome
• Average pain reduced 38.5%±29.1% (duloxetine) vs 10.4%±18.9% (placebo), P=0.002
• 44% of duloxetine patients vs 5% of placebo patients achieved >30% reduction in average pain (P=0.007)
• No significant differences in sleep quality, depression scores, or SF-36 quality of life measures
Bottom Line
Among MS patients who completed 6 weeks of treatment, duloxetine 60 mg daily significantly reduced both worst pain (29% reduction vs 12% placebo, P=0.016) and average pain (39% reduction vs 10% placebo, P=0.002). However, tolerability was a significant issue with 22% of duloxetine patients discontinuing due to adverse effects versus 10% of placebo patients. The findings suggest duloxetine has a direct pain-relieving effect in MS and may be considered as a second-line therapeutic option, though not all patients will tolerate the medication.
Major Points
- First randomized controlled trial specifically examining duloxetine for MS-related central pain with detailed pain diary outcomes
- Significant reduction in both worst pain (29%) and average pain (39%) with duloxetine versus placebo at 6 weeks
- Pain relief evident as early as 2 weeks for average pain and 4 weeks for worst pain
- Clinically meaningful pain reduction (>30% improvement) achieved in 44% of duloxetine patients vs 5% of placebo for average pain
- Tolerability concerns limit clinical utility - 22% discontinuation rate in duloxetine group due to adverse effects
- No significant improvements in mood, sleep quality, or quality of life measures, suggesting direct analgesic effect rather than indirect effects through mood improvement
- Study supports duloxetine as second-line agent for MS pain, after anticonvulsants or tricyclic antidepressants
- Daily pain diaries used to capture real-time patient-reported outcomes
- Rescue medication (NSAIDs/acetaminophen) allowed and tracked
- Small sample size (38 patients) due to slow recruitment and funding limitations
Study Design
- Study Type
- Parallel-group, double-blind, randomized, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind. Treating physician and examining research coordinators blinded to treatment allocation until end of trial. Randomization performed at clinical research pharmacy
- Sample Size
- 38
- Follow-up
- 6 weeks acute therapy phase plus 1 week taper period (7 weeks total treatment), with follow-up phone call 2 weeks after final visit
- Centers
- 1
- Countries
- United States
Primary Outcome
Definition: Percent change in worst pain score from baseline to week 6, recorded daily on pain diary using 0-10 visual analogue scale in per-protocol population
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - (Not reported) | 0.016 |
Limitations & Criticisms
- Small sample size (38 patients) - less than target enrollment of 54 patients due to slow recruitment and funding limitations, reducing statistical power
- Short treatment duration (only 6 weeks of acute therapy) - may not be sufficient to assess longer-term efficacy or antidepressant effects which typically require 6-8 weeks
- High dropout rate in duloxetine group (22%) due to adverse effects limits clinical utility and affects intent-to-treat analysis
- Pain etiology verification challenging - efforts made to exclude non-neurogenic causes but cannot guarantee all pain was truly MS-related central neuropathic pain
- Missing data from early terminators affects robustness - worst pain outcome became non-significant with worst-case imputation
- Single-center study limits generalizability
- No active comparator - comparison only to placebo, not to other standard treatments like anticonvulsants or tricyclic antidepressants
- Excluded patients already on SSRIs, SNRIs, or MAO inhibitors - may have excluded clinically relevant population
- Study excluded patients with low baseline pain (<4/10) - benefit-to-risk ratio may be less favorable in milder pain
- No long-term follow-up to assess durability of pain relief or late-emerging adverse effects
- Lack of blinding for pain diary completion (patient-reported) - though outcome assessors were blinded
- Use of rescue medication allowed - may have confounded results, though usage was tracked
- No correction for multiple comparisons beyond primary outcome - secondary outcomes should be considered hypothesis-generating
Citation
Brown TR, Slee A. A Randomized Placebo-Controlled Trial of Duloxetine for Central Pain in Multiple Sclerosis. Int J MS Care. 2015;17:83-89. DOI: 10.7224/1537-2073.2014-001