Therapeutics

Review: In neuropathy, fibromyalgia, or chronic pain, duloxetine reduces pain but increases adverse events

Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115.

Clinical impact ratings: F ★★★★★★✩ e ★★★★★✩✩ N ★★★★★★✩ R ★★★★★✩✩ Question What are the efficacy and safety of duloxetine for painful neuropathy, fibromyalgia, and chronic pain in adults?

Review scope Included studies compared duloxetine, given for ≥ 8 weeks, with placebo or another control in adults with painful peripheral neuropathy, chronic pain with neuropathic or unidentified cause, or fibromyalgia. Outcomes included short-term (≤ 12 wk) pain reduction (≥ 50% from baseline on continuous measures or ≥ moderate on categorical measures) assessed using validated scales, long-term (> 12 wk) pain reduction, and adverse events.

Review methods MEDLINE, EMBASE/Excerpta Medica, and CENTRAL to Nov 2013; Cochrane Specialized Registers (Neuromuscular Disease Group and Pain, Palliative and Supportive Care Group); ClinicalTrials.gov to Apr 2013; Eli Lilly trials database (www.lillytrials.com); and reference lists were searched for double-blind, randomized, controlled trials (RCTs) or quasi-RCTs. Investigators and Eli Lilly were contacted. 18 RCTs (n = 6407, 16 with placebo control) were included: 17 met all selection criteria, and 1 had treatment duration < 8 weeks. Duloxetine dose ranged from 20 mg/d to 120 mg/d: 16 RCTs used 60 mg/d in 1 group or as starting dose, and 9 used 120 mg/d in 1 group or as final dose. 8 RCTS were done in painful diabetic peripheral neuropathy, 6 in fibromyalgia, 3 in patients with depression and painful physical symptoms, and 1 in central neuropathic pain. Reports of the results of 5 potentially eligible, completed trials identified in ClincalTrials.gov were not found. 9 studies had low risk for bias in allocation concealment, 12 in blinding, and 11 in completeness of outcome data. 17 studies were funded by the drug manufacturer.

Main results Compared with placebo, duloxetine reduced pain at ≤ 12 weeks in all pain conditions reviewed, and at ≥ 12 weeks in fibromyalgia (Table). Compared with pregabalin, duloxetine reduced pain at ≤ 12 weeks in painful diabetic neuropathy (1 RCT, n = 804, Duloxetine (dulox) vs placebo in patients with painful neuropathy, fibromyalgia, or chronic pain* Conditions

Painful diabetic neuropathy Fibromyalgia Physical pain in depression

≥ 50% pain reduction Follow-up

Number of trials (n)

Weighted event rates Dulox Placebo

8 to 12 wk

5 (1655)

46%

relative risk reduction [RRR] 46%, 95% CI 19 to 80). Compared with placebo or active control, duloxetine increased risk for adverse events at ≤ 12 weeks in all pain conditions reviewed (14 RCTs; n = 5258; 72% vs 62%; RR increase 15%, CI 11 to 20; number needed to harm 10, CI 9 to 15).

Conclusion In painful neuropathy, fibromyalgia, or physical pain associated with depression, duloxetine reduces pain compared with placebo but increases adverse events. Source of funding: No external funding. For correspondence: Dr. M.P. Lunn, National Hospital for Neurology and Neurosurgery, London, England, UK. E-mail michael.lunn@ uclh.nhs.uk. ■

Commentary Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor licensed in the USA, UK, and Europe for ≥ 1 of the following: treatment of major depression, urinary stress incontinence, and peripheral neuropathic pain. Published RCTs have found that duloxetine may be effective for painful physical symptoms in the context of depression and for fibromyalgia and painful neuropathies. Lunn and colleagues updated a metaanalysis on this topic, including 12 newer trials along with the 6 trials summarized in the original 2009 Cochrane review. The updated results, viewed in light of US-based economic analyses discussed in the review, suggest that duloxetine, 60 or 120 mg/d, is a reasonably cost-effective and well-tolerated potential first-line therapy for these chronic pain conditions. To better inform clinicians and patients, more evidence is needed about the comparative efficacy of duloxetine and other potential first-line therapies. Future RCTs should compare duloxetine with such agents as tricyclic antidepressants (e.g., imipramine, amitriptyline), pregabalin, and gabapentin in patients with specific, homogeneous chronic pain conditions and have follow-up > 28 weeks. An important concern was the inability of Lunn and colleagues to find or obtain results of 5 potentially eligible completed trials, all of which were sponsored by drug companies. Studies not sponsored by drug manufacturers are needed to bolster confidence in the validity of existing evidence.

RBI (95% CI)

NNT (CI)

30%

53% (19 to 96)†

7 (5 to 10)

8 to 12 wk

5 (1887)

36%

24%

50% (29 to 75)

9 (7 to 13)

27 to 28 wk

2 (845)

32%

23%

40% (9 to 79)

12 (7 to 34)

8 wk

2 (1023)

49%

36%

37% (19 to 59)

8 (6 to 15)

*Abbreviations defined in Glossary. Weighted event rates, RBI, NNT, and CI calculated from relative risks, risk differences, and control event rates in article using a fixed-effect model unless otherwise indicated. NNTs were rounded up.

In the meantime, Lunn and colleagues offer systematic evidence supporting the efficacy and safety of duloxetine for painful physical symptoms associated with depression and for fibromyalgia and painful peripheral neuropathies. The results incrementally improve our clinical options, although we must balance patient preferences and overall medical status with the most relevant scientific evidence. Charles C. Engel, MD, MPH RAND Corporation and Uniformed Services University Arlington, Virginia, USA

†Heterogeneity P < 0.05 and I2 > 50%. Data were pooled using a random-effects model.

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© 2014 American College of Physicians

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15 April 2014 | ACP Journal Club | Volume 160 • Number 8

ACP Journal Club. Review: In neuropathy, fibromyalgia, or chronic pain, duloxetine reduces pain but increases adverse events.

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