How an opioid drug called tapentadol (Nucynta) told us something about the small fiber neuropathy in fibromyalgia

Given the concerns about the use of opioid prescription drugs, the fact that one not called Tramadol worked in fibromyalgia may not elicit much interest. One the other hand, it may have told us something about a subject of great interest in FM – small fiber neuropathy (SFN).

Nucynta and tramadol attach to the μ-opioid receptors in the brain.

Tapentadol (Nucynta) is an opioid drug with some similarities to tramadol – the most widely used opioid drug in FM. Both attach to the μ-opioid receptor and increase norepinephrine levels. Unlike tramadol, though, Nucynta does not affect serotonin levels, and with its potency lying somewhere between tramadol and morphine, it’s a much stronger drug, and can produce more side effects.

I don’t believe tapentadol (Nucynta) is widely used in FM, but a fascinating FM tapentadol study has cropped up which sheds light on a seemingly entirely unrelated issue – small nerve fiber neuropathy (or polyneuropathy) – which is also found in chronic fatigue syndrome (ME/CFS) as well.

Earlier, the Dutch researchers had shown that tapentadol relieved pain in diabetes patients by enhancing the inhibitory pain pathways that run down from the brain and essentially turns off or reduces pain levels. Those same pathways – which are referred to as “conditioned pain modulation (CPM)” – have been shown many times to be impaired in FM.

In general, “pain should inhibit pain”; i.e. the same amount of heat applied twice in a row should result in a reduced sensation of pain the second time.

The Gist

  • Nucynta is an opioid painkiller similar to Tramadol in some ways, but stronger (and with more side effects).
  • The controlled pain modulation system is a descending pain inhibition process which reduces pain levels. It has repeatedly been shown in fibromyalgia to be balky.
  • After a study showed that Nucynta was able to reduce pain levels in diabetes by enhancing the controlled pain modulation system, the drug was tried in fibromyalgia.
  • The researchers found that Nucynta worked very consistently (85%!) in FM patients who did not have small fiber neuropathy (SFN) – a condition in which the small nerves in the skin or the eyes are damaged or lost. Nucynta both improved their controlled pain modulation process and reduced their pain levels.
  • While Nucynta did improve the pain inhibition process in FM patients with SFN, it did not, however, improve their pain levels.
  • It was not clear what was happening, but the authors posed two reasons: the FM patients with SFN were simply too sick to benefit or they had a different kind of FM entirely.
  • There’s evidence for both answers: studies indicate that FM patients with SFN have more severe symptoms than those without it. Plus, the study suggested that the neuropathic pain the patients with both FM and SFN experience is not due to problems with pain inhibition. Dr. Oaklander believes that FM patients with SFN don’t have FM – they have small fiber neuropathy.
  • The cause of the SFN in FM is still unclear, and basic processes that govern the small nerves may need to be elucidated before that becomes clear. Some believe that central sensitization causes SFN while others believe SFN may cause central sensitization.
  • A recent study that found reduced small nerve fibers near the blood vessels suggested nerve damage could be impairing the microcirculation.
  • On the bright side, more study into the SFN problems in FM is occurring than ever before, and SFN is being found in more diseases than before including post-COVID-19, post-treatment Lyme disease, ME/CFS and diseases like Parkinson’s Disease, ALS and Ehlers Danlos Syndrome.
  • The treatment picture of SFN is complicated with a variety of drugs used which are helpful for some, but not in others. IVIG is an emerging possibility for FM, with one recent but small study finding it effective.

A balky pain inhibition response isn’t the only game in town in FM – other factors play a role – but it could play a significant role in some patients. The strength of the “conditioned pain modulation” response has even been used to predict which drugs might be helpful.

Diabetic patients, for instance, with more impaired CPM or pain inhibition pathways, benefitted more from Cymbalta (duloxetine) than those with intact pain inhibition pathways.

Since Nucynta is able to perk up the pain inhibition response, it made some sense to try it in FM.

The twist was small fiber neuropathy (SFN). SFN refers to the damage or destruction of small nerve fibers in the skin or eyes that carry sensory and/or autonomic nerve signals to the brain. No one knows why this is happening in FM, but it appears to show  up in from 40-50% of FM patients, and about the same number of ME/CFS patients.

For some reason, these researchers took it upon themselves to also assess whether or not the 34 FM patients in this placebo-controlled trial had reduced numbers of small nerve fibers in the corneas of their eyes. It was a good thing they did.

The Study

The 34 patients in the randomized, double-blinded trial were started off on 50 mg of tapentadol twice daily. Each week, the dose was increased by 50–100 mg per day, to a maximum of 250 mg, two times a day.

During each of the five visits they made to the clinic during the 4 month trial, their pain inhibition pathways were assessed using heat and cold tests.


Tapentadol did improve the pain inhibition response and significantly improved pain levels, but only in one group – the fibromyalgia patients without small nerve fiber damage. In fact, a remarkable 85% of the FM patients without SFN reported a significant improvement in pain. (While the authors reported that Nucynta or tapentadol is safer than drugs like oxycodone, they recommended that it be used for 3 months or less.)

Nucynta pain inhibition small fiber neuropathy fibromyalgia

Nucynta strengthened their pain inhibition pathways, but the FM patients with SFN didn’t experience any pain relief.

While Nucynta was able to improve the pain inhibition response in the FM patients with small nerve fiber damage, they did not experience any pain relief.

A recent study that found high levels of impaired pain inhibition in FM patients with SFN gave no reason to expect anything other than a positive result from a drug like Nucynta. It just didn’t happen – leaving us with a new medical mystery.

The authors suggested that FM patients with SFN may simply be sicker and less responsive to treatment. A large SFN study coming out of the Uceyler group in Germany suggests that FM patients with SFN do tend to be quite a bit sicker. They had more severe symptoms (higher pain intensity, were more impaired by pain, had higher disease, experienced more stabbing pain sensations and numbness and, not surprisingly, more anxiety) than FM patients without SFN.

If that’s true, then Nucynta just didn’t impact enough of whatever is causing their pain to make a difference. A drug like Nucynta could be helpful, but only in conjunction with other approaches.

The authors of the study also suggested that two distinct types of FM may exist – one type with SFN – and one without. The fact that the neuropathic pain scores in the SFN group were not correlated with pain inhibition scores suggested that a different component (like SFN) was causing their neuropathic pain.

The study was small and needs to be replicated before we can have confidence in its results – but it suggests, like the studies noted above, that SFN is not, as some researchers have believed, an add-on issue of little consequence. It’s either indicative of a more severe pain inducing process overall or of a different pain inducing process.

Causes of SFN

Unfortunately we don’t know what’s causing SFN. We do know that the SFN in FM appears to be different from the small fiber problems in diabetes, but tracking down the cause has not been easy. In a recent video presentation, Dr. Uceyler, a prominent SFN and FM researcher, asserted that we need to learn a lot more about small nerve fibers in general to understand what’s happening in FM.

Daniel Clauw has suggested a kind of brain-body merger. He believes the central sensitization in the brain may actually be causing the small nerve fiber problems in the body. The tapentadol study suggested we have a chicken and egg problem: they proposed that the opposite could be happening as well – that the small nerve problems in the body could be causing central sensitization.

Is the Brain Causing the Small Fiber Neuropathy in Fibromyalgia (and ME/CFS?)

All this goes to show is that while SFN is found in FM (and allied diseases like ME/CFS, interstitial cystitis, irritable bowel syndrome, and Ehlers Danlos Syndrome), the bad news is that we still don’t know why it (or central sensitization) is occurring.

The good news is that interest in SFN in FM is at an all-time high with studies emerging regularly. Recently, for instance, the Uceyler group dug a little deeper into the skin to find a reduction of small nerve fibers near the blood vessels. Cautiously interpreting the finding, Ucelyer noted that the finding fit with past FM findings suggesting that the microcirculation may be affected in FM.

Low Energy Production and Pain in Fibromyalgia – Is Your Microcirculation To Blame?

That’s a very intriguing possibility given Systrom’s findings suggesting that impaired microcirculation may be contributing to the energy production problems in chronic fatigue syndrome (ME/CFS). (We clearly need more SFN research in ME/CFS).

Plus, SFN is popping up in more and more diseases. It turns out that the more you look for it, the more it’s there. It’s not so surprising SFN might pop up in diseases which share similarities with FM and ME/CFS such as irritable bowel syndrome and interstitial cystitis, or that it’s also shown up in post-COVID syndrome and post-treatment Lyme syndrome. It’s also showing up in diseases like Parkinson’s, amyotrophic lateral sclerosis (ALS) and inflammatory neuropathies.


Effective treatment is, of course, the ultimate goal. The most common treatments (antidepressants, antiseizure and/or opioid drugs, lidocaine creams) may be helpful for some but clearly aren’t getting at the heart of the problem. Some drugs that are not commonly used (flupirtine, Infliximab, adalimumab, lacosamide) may be helpful in some cases. Of the fibromyalgia drugs duloxetine (Cymbalta) and pregabalin (Lyrica) can sometimes be helpful. (If you respond to Cymbalta, it may be because you have a problem with your pain inhibition pathways.)

IVIG is an intriguing possibility, but is expensive and hard to get. It is, however, commonly used to treat SFN in immune diseases like sarcoidosis. Fibromyalgia is not usually considered an immune disease, but Oaklander believes FM is misdiagnosed in patients with SFN: she believes that FM is SFN – and has some proof that it is immune mediated.

Oaklander has reported on IVIG’s success in children with SFN. Plus, a recent small case-report series found that IVIG improved both symptoms and small nerve fiber density in people with fibromyalgia. It will take more studies, but if they are done and that trend continues, at some point insurance companies will be more likely to pay for IVIG.

IVIG – Intravenous Gamma Globulin Therapy for Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia and POTS

While we don’t know what’s causing the SFN in FM, ME/CFS, post-treatment Lyme disease and post-COVID 19 syndrome and the treatment options aren’t exactly exciting, it’s good to interest in SFN catch on. It’s also good to know that given the right opportunity those small nerve fibers can grow back. Hopefully we’ll get more answers in the not too distant future.

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