Cochrane Clinical Answers - Fulltext - How does gabapentin compare with placebo in improving outcomes among people with amyotrophic lateral sclerosis/motor neuron disease?

Question:How does gabapentin compare with placebo in improving outcomes among people with amyotrophic lateral sclerosis/motor neuron disease?

Clinical Answer:

In people with amyotrophic lateral sclerosis/motor neuron disease, gabapentin does not provide added benefit over placebo and is commonly associated with adverse events.

High-quality evidence shows that gabapentin is no more effective than placebo in improving survival, rate of decline in arm strength (measured by maximum voluntary isometric contraction), or rate of decline in respiratory function (measured by forced vital capacity) among people with amyotrophic lateral sclerosis/motor neuron disease. Furthermore, moderate-quality evidence shows no greater effect of gabapentin over placebo on rate of decline on the functional rating scale or on quality of life.

Adverse events such as light-headedness, drowsiness, falls, limb swelling, and probably fatigue were more commonly associated with gabapentin.

Full outcome data is detailed below:

1.Gabapentin versus placebo

  • Population, Intervention, Comparator

    Population:

    Adults (aged 21-85 years; gender mix not reported) with a clinical and laboratory supported diagnosis of amyotrophic lateral sclerosis (ALS)/motor neuron disease with symptoms for no more than 3 years

    Intervention:

    Oral gabapentin 800-1200 mg 3 times daily for 6-9 months

    Comparator:

    Placebo

  • OUTCOME 1.1: Survival at 6 to 9 months

    Quality of the evidence:

    The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

    Narrative result:

    Two RCTS with 355 participants reported this outcome; neither of them reported any statistically significant difference between groups.

    Relative effect or mean difference:

    Estimated survival was 78% (95% CI 68% to 86%) with gabapentin versus 77%(95% CI 66% to 85%) with placebo, P = 0.63. Results not depicted in a forest plot.

    Reference:
    Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
    • OUTCOME 1.2: Rate of decline in maximum voluntary isometric contraction (MVIC) at 6 to 9 months

      Quality of the evidence:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

      Narrative result:

      Two RCTS with 345 participants found no statistically significant difference between groups. This outcome was assessed using the arm megascore that assesses the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population.

      Relative effect or mean difference:

      The mean rate difference in megascore decline with gabapentin versus placebo was: 0.005 arm megascore (-0.002 to 0.013) in one RCT and -0.004 (-0.010 to 0.003 in the other RCT. Results not depicted in a forest plot.

      Reference:
      Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
      • OUTCOME 1.3: Rate of decline of % predicted forced vital capacity (FVC) at 6 to 9 months

        Quality of the evidence:

        The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

        Narrative result:

        Two RCTS with 274 participants found no statistically significant difference between groups.

        Relative effect or mean difference:

        The mean difference in FVC decline between gabapentin and placebo was -0.057 (-0.21 to 0.09). Results not depicted in a forest plot.

        Reference:
        Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
        • OUTCOME 1.4: Rate of decline (per month) of functional rating scale (ALSFRS-R) at 9 months

          Quality of the evidence:

          The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

          Narrative result:

          One RCT with 128 participants found no statistically significant difference between groups.

          Relative effect or mean difference:

          The mean difference in monthly ALSFRS-R decline between gabapentin and placebo was 0.015 (-0.34 to 0.05). Results not depicted in a forest plot.

          Reference:
          Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
          • OUTCOME 1.5: Health-related quality of life at 9 months

            Quality of the evidence:

            The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

            Narrative result:

            One RCT with 128 participants reported no statistically significant difference between groups. This outcome was assessed with the Short Form 12 Health Survey (SF-12).

            Relative effect or mean difference:

            Results on the SF-12 (Physical) were: mean change (± SD) of -0.03 (± 0.7) on gabapentin and -0.2 (± 0.5) on placebo (P = 0.19). Results not depicted in a forest plot.

            Reference:
            Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
            • OUTCOME 1.6: Adverse events

              Narrative result:

              Some adverse events were more common with gabapentin than with placebo (light-headedness, drowsiness, falls, limb swelling and fatigue (although only one trial contributed to the analysis of this outcome)). Some other adverse events showed no statistically significant difference between groups: headache, weakness, diarrhea, cramps, shortness of breath, depression and nausea. Click below for full details.

              Reference:
              Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
              • Subgroup analysis 1.6.1: Adverse events - [subgroup: Light-headedness]
                Quality of the evidence:

                The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

                Narrative result:

                Two RCTs with 353 participants found that more people had light-headedness with gabapentin compared with placebo.

                Relative effect or mean difference:

                There was a statistically significant difference between groups, in favor of placebo (RR 2.80, 95% CI 1.79 to 4.40).

                Forest plot from Cochrane Review

                Absolute effect:

                357 per 1000 people (95% CI 228 to 561) with gabapentin compared with 127 per 1000 people with placebo.

                Reference:
                Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
              • Subgroup analysis 1.6.2: Adverse events - [subgroup: Drowsiness]
                Quality of the evidence:

                The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

                Narrative result:

                Two RCTs with 353 participants found that more people had drowsiness with gabapentin compared with placebo.

                Relative effect or mean difference:

                There was a statistically significant difference between groups, in favor of placebo (RR 2.64, 95% CI 1.61 to 4.33).

                Forest plot from Cochrane Review

                Absolute effect:

                259 per 1000 people (95% CI 158 to 425) with gabapentin compared with 98 per 1000 people with placebo.

                Reference:
                Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
              • Subgroup analysis 1.6.3: Adverse events - [subgroup: Falls]
                Quality of the evidence:

                The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

                Narrative result:

                Two RCTs with 353 participants found that more people had falls with gabapentin compared with placebo.

                Relative effect or mean difference:

                There was a statistically significant difference between groups, in favor of placebo (RR 1.65, 95% CI 1.06 to 2.57).

                Forest plot from Cochrane Review

                Absolute effect:

                242 per 1000 people (95% CI 155 to 378) with gabapentin compared with 147 per 1000 people with placebo.

                Reference:
                Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
              • Subgroup analysis 1.6.4: Adverse events - [subgroup: Limb swelling]
                Quality of the evidence:

                The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

                Narrative result:

                Two RCTs with 353 participants found that more people had limb swelling with gabapentin compared with placebo.

                Relative effect or mean difference:

                There was a statistically significant difference between groups, in favor of placebo (RR 2.70, 95% CI 1.45 to 5.02).

                Forest plot from Cochrane Review

                Absolute effect:

                291 per 1000 people (95% CI 157 to 541) with gabapentin compared with 108 per 1000 people with placebo.

                Reference:
                Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]
              • Subgroup analysis 1.6.5: Adverse events - [subgroup: Fatigue]
                Quality of the evidence:

                The reviewers did not perform a GRADE assessment of the quality of the evidence. The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

                Narrative result:

                One RCT with 149 participants found that more people had fatigue with gabapentin compared with placebo.

                Relative effect or mean difference:

                There was a statistically significant difference between groups, in favor of placebo (RR 3.84, 95% CI 1.14 to 12.92).

                Forest plot from Cochrane Review

                Absolute effect:

                165 per 1000 people (95% CI 49 to 554) with gabapentin compared with 43 per 1000 people with placebo.

                Reference:
                Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]

            Additional Information:

            DOI

            10.1002/cca.1618

            Publication Dates

            1. Published Online: 19 MAY 2017

            CCA derived from

            Diana A, Pillai R, Bongioanni P, O'Keeffe AG, Miller RG, Moore DH. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD006049. DOI: 10.1002/14651858.CD006049.pub2. [Review search date: August 2016]

            How to Cite

            How does gabapentin compare with placebo in improving outcomes among people with amyotrophic lateral sclerosis/motor neuron disease? Sera Tort (MD) and Loredana La Mantia (MD) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2017. DOI: 10.1002/cca.1618.

            Further Information

            • CCA Associate editor: Sera Tort (MD), Clinical Editor, Cochrane Editorial Unit, London, UK.
            • CCA Associate editor: Loredana La Mantia (MD), Senior Consultant, I.R.C.C.S. Santa Maria Nascente Fondazione Don Gnocchi, Milano, Italy.
            • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.