Gabapentinoids: still not help low back or radicular pain

A recent systematic review/meta-analysis found that gabapentinoids (gabapentin and pregabalin) were ineffective in treating either low back or lumbar radicular pain (see lbp gabapent not help cmaj2018 in dropbox, or doi: 10.1503/cmaj.171333).

Details:

-- 9 trials comparing the anticonvulsants topiramate, gabapentin, or pregabalin vs placebo, in 859 people

-- average age of participants 51 years (38-71)

-- all but one trial had low risk of bias.

-- Mean treatment duration was 6.7 weeks

Results:

-- 14 of the 15 comparisons found anticonvulsants were not effective in reducing pain or disability in patients with either low back pain or lumbar radicular pain

    -- all 6 short-term (2 weeks-3 months)and intermediate term (3-12 months) studies with gabapentin showed no effect for low back pain with or without radicular leg pain

    -- 7 studies specifically on lumbar radicular pain (6 with pregabalin, one with gabapentin) found no benefit of any in the short-term, intermediate-term, and long-term (>12 months), except for one short-term study with gabapentin, which only had 23 people in the gabapentin group, and did show benefit with a dose of 3600 mg per day

    -- only 2 studies used topiramate, one short-term study of 48 patients found that low back pain with or without radiating pain did find some benefit for pain (considered small benefit but clinically worthwhile) in the short-term but no effect on short-term disability; another on lumbar radicular pain by itself found no effect on pain or disability

-- none of the studies found benefit for disability either in the short, intermediate, or long-term, as measured by the Oswentry Disability Index or the Roland-Morris Disability Questionnaire 

-- adverse events (7 studies, 2 did not report adverse events): there was high quality evidence that gabapentinoids were associated with a 40% increased risk of adverse events, RR 1.4 (1.2-1.7). The most common adverse events were drowsiness/somnolence, dizziness, nausea. The data on topiramate was more difficult to interpret: one study reported no adverse events though the placebo group was given diphenhydramine (which also causes drowsiness/somnolence). The 2^nd study did show 21 adverse events in 41 patients on topiramate vs 10 on placebo, but did not report the total number of people who experienced an adverse event

Commentary:

-- the study’s conclusions:

    -- for chronic low back pain:

        -- there was high-quality evidence showing that gabapentinoids did not reduce pain or disability in the short-term, and similarly but with low-quality evidence in the intermediate-term

        -- there was moderate-quality evidence that topiramate provided a small clinically worthwhile effect for pain in the short-term but no effect on disability

    -- for lumbar radicular pain:

        -- there was generally moderate-to-high quality evidence showing that the anticonvulsants had no effect on pain or disability at all time points

    -- for adverse events:

        -- there was high-quality of evidence showing that gabapentinoids were associated with increased adverse events

    --in sum: “there is moderate-to-high quality evidence that anticonvulsants are ineffective for treatment of low back pain or lumbar radicular pain. There is high-quality evidence that gabapentinoids have a higher risk for adverse events”

--use of gabapentinoids for back pain is concerning not just because of their ineffectiveness but also  because of evidence of:

    -- dramatic increases of anticonvulsant prescriptions in primary care for back and neck pain, including radicular pain, increasing 535% in the past 10 years

    -- potentially severe adverse reactions such as increased suicidality. See https://www.nejm.org/doi/10.1056/NEJMoa0909801?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov ), an article that assessed suicidality of patients on antiepileptic drugs, finding a 65% increased risk, though this increased risk was limited to patients with depression. They did not provide very specific data on the use of gabapentinoids in particular. But a major concern is that many patients with low back pain with or without radiculopathy are depressed.

    -- though they have low addictive potential, gabapentinoids can lead to euphoric and dissociative effects similar to recreational drugs (eg, see gabapentin misuse. addiction2016 in dropbox, or doi:10.1111/add.13408). and they can augment the effects in those on the recreational drugs

-- prior meta-analyses have found that gabapentinoids are ineffective in treating chronic low back pain but have lots of adverse effects  (seehttp://gmodestmedblogs.blogspot.com/2017/08/gabapentinoids-not-indicated-for.html). the current study extended this conclusion to low back pain with radicular symptoms, ie neuropathic pain where in theory gabapentinoids are supposed to work better. Even with diabetic neuropathy, which seems to me like perhaps the last stand for gabapentinoids for neuropathy, there was a systematic review in the journal Neurology that found no benefit with gabapentin and a small one with pregabalin but with low strength-of-evidence. Venlafaxine and duloxetine were the big winners, showing significant benefit (see http://gmodestmedblogs.blogspot.com/2017/04/diabetic-peripheral-neuropathy-and-more.html  ). Topiramate was not evaluated in the systematic review, though the American Diabetes Association review did not find evidence of effectiveness (see http://gmodestmedblogs.blogspot.com/2017/03/diabetic-neuropathy-guidelines.html )

    --as mentioned in the blog http://gmodestmedblogs.blogspot.com/2017/03/diabetic-neuropathy-guidelines.html ,  there have been drug company manipulations in the original studies for both gabapentin and pregabalin, where even large negative studies were not published, significantly skewing the overall analyses to suggest benefit, and reinforcing in us that these are useful drugs.

-- both the US and United Kingdom guidelines for low back pain therapy do not recommend the use of anticonvulsants.  

     --The NICE guidelines from the UK: “do not offer anticonvulsants for managing low back pain”

    -- 2017 US clinical guidelines: “the evidence is insufficient to determine the effect of antiseizure medications on radicular low back pain” ​​

-- one comment on the small study of high-dose gabapentin for lumbar radicular pain that found some benefit: it is really hard to have a "placebo-controlled" RCT when one group of patients is getting a high dose of meds with lots of adverse events. ie, those really lethargic on 3600 mg of gabapentin (probably a fair % of the 23 people in the study) more likely knew they were on an active med, and that might have enhanced the drugs perceived effect/benefit vs those on placebo

so, this all adds to the pretty consistent literature that gabapentinoids are not very effective meds.  However, many patients are on them and think there is real benefit. (sort of like many patients on opiates are convinced that they are the only drugs to work, though there is an increasing literature suggesting that nonopiates may work as well as opiates for chronic pain: see http://gmodestmedblogs.blogspot.com/2018/03/opioids-not-better-for-chronic.html​ ).  i have had some success in convincing some patients on gabapentinoids to try venlafaxine or duloxetine, with reported benefit. And, these SNRIs have the added ability to help treat the underlying depression that so often goes along with chronic pain.

geoff​

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