By Dr Geoffrey Modest
There was a recent systematic review in the journal Neurology on pharmacotherapy for diabetic peripheral neuropathy pain and its effect on quality of life (see doi. org/ 10. 1212/ WNL. 0000000000003882). This appeared right after the recent guidelines from the American Diabetes Association (see link below), but had several eye-opening differences.
— the researchers updated a 2014 systematic review of 57 studies (see Griebeler ML. Ann Intern Med 2014; 161:639, and prior blog on this here) with 24 additional published studies and 25 unpublished studies. All trials were published between 1990 and 2015. The number of participants range from 20 to 804. They referenced the website clinical trials.gov on March 9, 2016 to get data on unpublished studies.
Results, from placebo-controlled RCTs (those with moderate or large effect are highlighted):
— for anticonvulsants:
— pregabalin, 16 RCTs, small effect, with low strength of evidence (SOE)
— gabapentin, 5 RCTs, not effective, low SOE
— serotonin-norepinephrine reuptake inhibitors/antidepressants:
— duloxetine, 7 RCTs, large effect, moderate SOE
— venlafaxine, 2 RCTs, large effect, moderate SOE
— tricyclic antidepressants, 4 RCTs, moderate effect, low SOE
— typical opioids (eg, oxycodone), 4 RCTs, not effective, low SOE
— atypical opioids (tramadol, tapentadol), 5 RCTs, moderate effect, low SOE
— topical agents
— capsaicin cream 0.075%, 5 RCTs, not effective, low SOE
— other agents
— dextromethorphan, 3 RCTs, not effective, low SOE
— mexiletine, 5 RCTs, not effective, low SOE
— botulinum toxin, 2 RCTs, moderate to large effect, low SOE
–there were not enough data to evaluate the effect of these medications on quality-of-life.
–adverse effects: varied by agent. Dropout rates in the studies varied from 2.5% to 70% for oral agents, very low for topicals
— Unfortunately, few of the studies extended beyond 3 months (mean follow-up was 8.8 weeks with a maximum of 22 weeks), limiting their clinical utility some.
— The presumptive difference between the typical and atypical opioids as above is that the atypical ones have activity as norepinephrine reuptake inhibitors as well as mu agonists, with moderate effectiveness (vs oxycodone, a mu agonist, which was no more effective than placebo)
— I was a little surprised that capsaicin cream had no benefit, given the initial studies. And I have had patients do pretty well, with essentially no adverse effects. But, even if this is mostly a placebo effect, it is a pretty harmless med and if it works…
— The American Diabetes Association review gave primary billing to pregabalin and duloxetine (see here )
— The ADA review also did find a small benefit for oxcarbazepine, with low SOE, but not for other anticonvulsants such as topiramate, valproic acid, or lamotrigine.
— So, why are the above conclusions so different from those of the American Diabetes Association? Of the 25 additional studies in clinicaltrials.gov which were unpublished, 18 were actually completed. The researchers were able to include 7 of these 18 completed studies. Of note, though pregabalin seemed to be effective, with a moderate reported effect size, when the 6 additional unpublished studies were included (all with negative results), the effect size decreased to “small”. In fact an analysis which included these negative clinicaltrials.gov studies found that the number of patients who would need to be treated with pregabalin for one patient to achieve a 50% pain relief was 7.7, so pretty few patients seem to benefit from pregabalin (Finnerup NB. Lancet Neurol 2015; 14:162)
–I suspect that the reason that gabapentin was considered ineffective but pregabalin not is mostly related to the serendipity of the studies done. Their anticipated physiologic effect is essentially the same, though gabapentin may be more slowly and erratically absorbed. In both cases there have been published studies suggesting positive efficacy of the medications, but on digging a tad under the surface, there are several large unpublished studies for each finding no benefit. My guess is that they really do have similar and probably low levels of effectiveness. As with most drugs, some patients may benefit more than others. Is this from genetic differences in receptors or other drug mechanism? Or maybe placebos work better in some people when they have mild to moderate adverse effects, and these meds both certainly do…(I have never seen anything written on this, but I suspect that meds with more systemic adverse effects may have more placebo effect as well, since some patients may internalize that meds with adverse effects must be stronger meds???…).The recent negative study of pregabalin in sciatica does also raise the question of its overall utility (see here ). So, I’m not convinced that we should use pregabalin (only available as an expensive brand-name drug) over gabapentin (widely available generic), if we decide to use one of these types of drugs.
— One important finding in the current Neurology review was that venlafaxine, available as an inexpensive generic, was found to have a large effect size, with moderate SOE. This was also found for tricyclic antidepressants, though with moderate effect size. I am a bit hesitant to endorse venlafaxine as the single best agent (largest effect size of meds, somewhat larger than duloxetine which has no generic), since there were only 2 studies published on it. But I will add it to my short list of initial meds to try, along with tricyclics.
–so, bottom line here: the American Diabetes Association’s top 2 drugs, pregabalin and duloxetine, have both been knocked down by this more extensive Neurology review….. and, I think all systematic reviews should include looking at clinicaltrials.gov to find potentially pivotal negative studies which have not been published.
But, I think there are a few pervasive generic issues that this systematic review brings up:
–one of the biggest issues raised by this systematic review is: what should we trust in the medical literature? Clearly meta-analyses and systematic reviews can come to different conclusions based on their study inclusion criteria (see here for some of my thoughts on this). But additionally, we have moved to a place where the majority of large-scale medical studies are industry-funded. And they have a very clear bias to publishing the most positive results and putting the most positive spin on their results. And negative results are often not reported (this was the reason the feds required new studies to be logged into clinicaltrials.gov when they are initially approved, a law enacted in 1997). And the finding above about pregabalin is a case in point (a similar issue prevailed in the initial gabapentin studies, where there were also large, unpublished negative studies). So, though pregabalin was highlighted in the recent Am Diabetic Assn recommendations 2 weeks ago, when the unreported negative studies are included, it really does not look so good…
–And, as per here companies often do not conform to government regulation/requirements, including rarely providing post-marketing data as required by the feds (their compliance rate was on the order of 15%!!!!!). And, and, and, this whole situation is very likely to get whole lots worse with Trump, as the FDA moves to earlier licensing of drugs and medical devices, with less rigorous attention paid to their actual clinical benefit. So, the really difficult challenge is “what should I believe in the medical literature??” I’m not sure how to answer that. But we need to be diligent, skeptical, and even less ready to jump on the bandwagon for new meds and medical devices. (One of my real purposes in writing these blogs is to critique studies or guidelines, and to assess their real generalizability and utility in the context of primary care clinical practice. And I hope they provide some context to help assess applicability of the studies/guidelines…..)