2022 review: Amitriptyline compared with pregabalin, duloxetine and milnacipran. 2012-2019: Gabapentin NO evidence!

In this 2022 review, amitriptyline (‘Elavil’, ‘Endep’) was compared to pregabalin (‘Lyrica’), duloxetine (‘Cymbalta’) and milnacipran (‘Savella’). It finds amitriptyline compares favourably to them. Also, the results help a bit to decide which is best for a certain combination of main symptoms.
(Amitriptyline is off-label, whilst pregabalin, duloxetine, and milnacipran are the only on-label ones for FM, since only these were approved by the FDA - 2007, 2008 and 2009 respectively.) 36 studies, almost 12000 fibromyalgia patients.
Farag et al. 2022. Comparison of Amitriptyline and Food and Drug Administration–Approved Treatments for Fibromyalgia

A few of many interesting points are:

  • amitriptyline was associated with large improvement in sleep and QoL, a moderate improvement in fatigue, a small improvement in pain, and was not associated with improvement in depression compared with placebo. Duloxetine 120 mg was associated with improvement in all effectiveness outcomes, with the greatest improvements in pain and depression.”
  • "Although pregabalin 600 mg was associated with improved QoL, pregabalin generally showed only a small improvements in the other measured symptoms. Milnacipran 100 mg was associated with small improvements in all outcomes except QoL; milnacipran 200 mg was associated with small reductions in pain, depression, and fatigue, but did not improve sleep and QoL outcomes. Pregabalin, duloxetine, and milnacipran were associated with worse acceptability than placebo, while the acceptability outcomes associated with amitriptyline did not significantly differ from placebo.
    (= acceptability (defined as discontinuation of treatment owing to adverse drug reactions)
  • “Considering the dose-dependent adverse effects of all drugs, it is recommended to start at a low dose and increase slowly, if necessary.”
  • “Unfortunately, pharmacological treatments will provide a modest effect for most patients. For that reason, nonpharmacological approaches that promote physical activity and coping skills should be recommended to all patients.1 Cognitive behavioral therapy, aerobic exercise, tai chi, hydrotherapy, mindfulness-based stress reduction, and multicomponent therapies have been associated with reducing fibromyalgia symptoms and can be recommended either alone or in conjunction with pharmacological treatment.”

Some of the bottom lines:

  • amitriptyline generally showed less side effects than the others, and was one of the most effective, except for depression - where duloxetine was best (altho amitriptyline helps with “real” depression as opposed to fibro’s depression, probably caused by the pain).
  • But meds don’t help much so physical activity and coping skills are very important: CBT, exercise, tai chi, hydrotherapy, mindfulness…

Remember studies and reviews are generally about averages, whilst we are all different, have many different co-morbidities and it may turn out that we also belong to fibro-subgroups. So that’s even more reason to try changing meds.
Another thing is that docs tend to think they are in the know and we aren’t, but recent studies are admonishing them to listen to us patients more, since their diagnoses and opinions have a quite high proportion of error. It’s good to choose or train your docs to realize we’re in the know, and to make sure we are by listening to our bodies and reading up (like here [image] ).
I’m never going back on these meds again, only trying pain killers and amitriptyline, but with severe side effects.


Now I’m mind-blown :exploding_head:: It’s not possible to compare pregabalin to its precursor gabapentin, as there is NO real evidence for gabapentin helping fibromyalgia at all :bangbang:
I always thought gabapentin never got an FDA-approval just because pregabalin was later, but turns out gabapentin has no evidence for FM, but has been hyped by the industry, and unknowing docs are now frantically = wrongly using it even more all the same, as an alternative to opioids - that’s what several reviews are saying.

https://www.tandfonline.com/doi/full/10.3111/13696998.2012.660254, LLoyd et al., 2012, 682 patients.

  • “Over 12 weeks, total cost per patient was $229 higher with pregabalin 150 mg BID than placebo, whereas pregabalin 225 mg BID was $866 less costly than placebo. At 1 year, pregabalin was cost saving and more effective than placebo, duloxetine, tramadol, milnacipran, and gabapentin. Compared with amitriptyline, pregabalin was not cost-effective at both dosages, although when excluding old and methodologically weak studies of clinical effectiveness of amitriptyline, pregabalin 225 mg BID became cost saving and pregabalin 150 mg BID was cost-effective.”
  • “In this model, pregabalin 225 mg BID was consistently more cost-effective than pregabalin 150 mg BID. This was due to the equivalence in price between the two doses and slightly superior efficacy of the 225 mg BID dosage. Pregabalin 225 mg BID was also cost-saving when compared against placebo, duloxetine, tramadol, milnacipran, and gabapentin if direct and indirect costs were taken into account.”
  • “…this is the first study to estimate the cost-effectiveness of FM treatments in the US. Another study conducted in the UK found that pregabalin was cost-effective to the UK National Health Service…”
  • “Overall, the cost-effectiveness results reflect an improvement in quality-of-life consistent with other studies that used clinical data from pregabalin trials, particularly in patients with severe FM.”
  • " Studies have shown that the cost of illness associated with FM is substantial9. This is reflected in the high cost per patient estimated here and in the recent cost of illness study52, where a strong relationship was found between FIQ scores and direct medical costs and between the days patients missed work in the FIQ and indirect medical costs."
  • "found pregabalin to be a cost-effective treatment option relative to duloxetine, milnacipran, gabapentin, and tramadol, but not amitriptyline"

Review by Tzellos et al. 2010 comparing pregabalin with gabapentin only found one good study about gabapentin, so couldn’t really compare. https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2710.2009.01144.x

Similar a review by Cooper et al. 2017 Gabapentin for fibromyalgia pain in adults - PubMed
which starts “Gabapentin is an antiepileptic drug widely licensed for treatment of neuropathic pain. It is not licensed for the treatment of fibromyalgia, but is commonly used because fibromyalgia can respond to the same medicines as neuropathic pain.” but concludes “We have only very low quality evidence and are very uncertain about estimates of benefit and harm because of a small amount of data from a single trial. There is insufficient evidence to support or refute the suggestion that gabapentin reduces pain in fibromyalgia.” (FM is not just pain, but if gabapentin is mainly for pain, then that’s a “striking” conclusion.)

Again in a a review by Moore et al 2014 Gabapentin for chronic neuropathic pain and fibromyalgia in adults - PubMed
“Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in neuropathic pain conditions except postherpetic neuralgia and painful diabetic neuropathy, and in fibromyalgia, is very limited.”
I had to read this sentence carefully: The comma before “and in fibromyalgia” shows that you can put parentheses around (except postherpetic neuralgia and painful diabetic neuropathy), so again that means “the amount of evidence for gabapentin… in fibromyalgia, is very limited.”

Strangely different though in this review by Calandre et al, 2016 Unfortunately the full article is behind a paywall, so I can’t find out where the mistake is. Alpha 2 delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use - PubMed
“Expert commentary: GBP and PGB are effective for the treatment neuropathic pain, fibromyalgia and epilepsy; in addition, they may be useful for the reduction of postoperative pain. PGB is also effective for the treatment of generalized anxiety disorder and GBP for the treatment of restless legs syndrome.”
“Mirogabalin (MGB), recently developed, is being investigated for the treatment of peripheral neuropathic pain and fibromyalgia…”

A review by Goodman et al. 2019 (full article behind paywall) A Clinical Overview of Off-label Use of Gabapentinoid Drugs - PubMed says:
“Despite these limited indications, gabapentin and pregabalin are widely prescribed off-label for various other pain syndromes. Such use is growing, possibly because clinicians are searching increasingly for alternatives to opioids.”
“notes how review articles and guidelines tend to overstate gabapentinoid effectiveness”
“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses.”
Two docs in the comments argue controversially,

  • the first in line with the article “lack of efficacy and adverse effects of gabapentinoids, even in FDA approved conditions. . They are essentially useless for somatic pain and infrequently beneficial for neuropathic pain, with significant adverse effects. This can be easily gleaned by listening to patients with an open mind.
    Cheaper and probably more efficacious , are older drugs including tricyclic antidepressants and possibly the SNRIs. They are cheaper and the side effects are more easily managed. As discussed in the review, gabapentinoids have been “hyped” and, in my opinion, should largely disappear from clinical practice.”
  • The other “The TCAs can be very sedating, anticholinergic of course increasing the risk of dementia, etc., pro-dysrhythmic, and come with all sorts of P450 interaction concerns. Gabapentin and pregabalin lack both of the latter two risks, not to mention the risk of hyper-serotonergism that is rampant these days with patients on multiple antidepressants, triptans, cyclobenzaprine, etc. In the course of nearly twenty years of anesthesia and pain medicine, my experience (and that of many of my colleagues) is that the gabapentinoids have tremendous efficacy, safety and utility, especially in the era of looking for opioid alternatives. Do they carry risk? Of course. Good risk stratification is essential. But to castigate the class like this is irresponsible. That’s like saying NSAIDs “should largely disappear from clinical practice” because they can be overused and confer risks.”

A review by Peckham et al., 2018 echoes the results of Cooper et al. above https://pubmfed.ncbi.nlm.nih.gov/30262984/, saying

  • “Increasing evidence has emerged suggesting that gabapentin may not be as benign as once thought and may be associated with substance abuse in concert with opioids.”
  • “Reviews on off-label indications such as migraine, fibromyalgia, mental illness, and substance dependence have found modest to no effect on relevant clinical outcomes. This high-quality evidence has often been overshadowed by uncontrolled studies and limited case reports.”

OK I should now have a look at mirogabalin, but a quick look reveals only 9 studies, 2 of them animals and “mirogabalin is still in its infancy”.
Merante 2020 The mirogabalin ALDAY phase 3 program in pain associated with fibromyalgia: the lessons learned - PubMed to me implies that a program with a negative result wasn’t patient-specific enough… – ah, clever, that.
Arnold et al. 2019 Efficacy and safety of mirogabalin for the treatment of fibromyalgia: results from three 13-week randomized, double-blind, placebo- and active-controlled, parallel-group studies and a 52-week open-label extension study - PubMed found
“While both mirogabalin doses were well tolerated by most patients and showed potential for reducing pain associated with FM, the primary endpoint of significant pain reduction in patients on mirogabalin compared with placebo was not achieved in any of the three randomized controlled studies.”

So - if anyone’s ever heard of mirogabalin as next in line, but “in infancy”: first results 2019/2020 are disappointing.