A Blockbuster Drug

Lyrica truly merits the description ‘blockbuster drug’. FDA approved for seizures, neuropathic pain, fibromyalgia (2007), and generalized anxiety disorder (Europe), Lyrica (pregabalin) sales hit their peak in the last quarter in the US, bringing in over $550 million for Pfizer.

Lyrica’s enormous success despite its side effect and efficacy issues, highlights the needs for better pain relieving drugs.

Lyrica’s success – despite issues with side effects and efficacy in a significant number of fibromyalgia patients – highlights the tremendous need for drugs that relieve neuropathic pain.  Fifteen years in development, Lyrica was originally developed to reduce seizures by increasing GABA levels, but was later found to reduce glutamate, substance P and norepinephrine levels instead.

Researchers know the pharmacological effects Lyrica has, but they don’t know what parts of the brain it’s affecting. It’s great to have a drug that works (for some people) but finding out why and where a drug works can help us understand what went wrong in the first place. This type of reverse engineering is happening in ME/CFS with Drs. Fluge and Mella (rituximab), and Dr. Montoya and Dr. Kogelnik (antivirals).

PLoS One. 2013 Sep 6;8(9):e74099. doi: 10.1371/journal.pone.0074099. Evaluation of the effectiveness of pregabalin in alleviating pain associated with fibromyalgia: using functional magnetic resonance imaging study.

In this study as FM and healthy controls got their thumbnails pressed to induce pain, fMRIs were used to determine which parts of their brains became activated before and after they took Lyrica.  Reduced brain activation in concert with reduced pain should reveal which parts of a fibromyalgia patient’s brain were producing pain.


With their exquisite sense of pain, it perhaps wasn’t surprising to see almost 50% more brain regions light up in the presence of pain in the FM patients than in the healthy controls pre-Lyrica. Post-Lyrica things changed, at least for some.

The study showed that when Lyrica works, it really works. It was only effective in less than half those who tried it (9/21) but it cut the responders’ pain in half, dropped their ‘pain sensitivity’ down to normal levels, and their sleep and fatigue scores improved significantly.

Post-Lyrica the responders’ brains were very different as well. Now, the same number of brain regions as in healthy controls became activated during pain. It was as if a sort of “pain infection” that had infected neighboring brain regions had been stopped and reversed. Reductions in insula, somatosensory cortex, and thalamus activity suggested these regions, in particular, play an important role in pain in FM.

Focus on Mind/Body Integration in the Insula

insula in brain

A small slice of brain sitting not far from the brainstem, the insula affects both physiology and mood

One of the most interesting organs in the brain, the insula plays an important role in both physiology and emotion. One of the chief homeostatic organs in the brain, the insula is in charge of adjusting the body’s physiology (heart rate, temperature, blood sugar, etc., to maintain an even, healthy state. It helps determine how much pain you experience. It lights up in the presence of fear. It’s associated with awareness and cognitive issues. It’s involved in determining ‘anticipation’; i.e., if just the thought of doing something makes you feel ill, that could be your over-active insula talking.

Lyrica’s ability to reduce activity in two areas of the insula and the cingulate cortex suggested that the ‘motivational affective component of pain’, i.e., the part of pain that is so unpleasant that it makes you want to crawl out of your skin, is increased in FM.

Arousal and Sensory Integration in the Deep Brain: Focus on the Thalamus

The reduced level of thalamus and somatosensory cortex activity post-Lyrica suggested that the aberrant pain signaling process in FM may begin deep in the brain.  The thalamus, which sits right on top of the brainstem, relays sensory and motor signals from the spinal cord to the rest of the brain and regulates sleep and alertness. Long thought as a ‘switchboard’, it’s now clear that the thalamus processes and determines the flow of information to the rest of the brain.

Thalamus in the brain

Lyrica reduced activation of the thalamus – the main regulator on sensory input into the brain in fibromyalgia

An overactive thalamus could conceivably reflect breakdowns earlier in the sensory routing system (the Lights’ and Van Elzekker’s suggestion of over-active sensory neurons) that caused massive amounts of sensory information to smack the thalamus.

The thalamus’s regulation of arousal and alertness also suggests it could contribute to the wired and tired issues in ME/CFS/FM.  Lyrica’s ability to reduce pain and fatigue and improve sleep and reduce fatigue suggests pain and arousal may be two sides of the same coin in FM, something that certainly makes subjective sense.

This study and others suggest insula, thalamus, and somatosensory cortex over-activation is wreaking havoc with the pain levels, arousal, and possibly emotions in fibromyalgia, and perhaps in ME/CFS.

(A successful Lyrica chronic fatigue syndrome study currently under way could tell us more about Lyrica’s mode of action and the genetics of pain production in ME/CFS.  By charting gene expression levels in ME/CFS patients pre- and post-Lyrica, the Lights are hoping they can identify specific genes that are responsible for pain, arousal, sleep problems and other issues in ME/CFS.)

Sidebar – Why Cognitive Behavioral Therapy (CBT) May Not Work Well in Fibromyalgia/ME/CFS

A fascinating study used insula activity to determine whether people with depression do better with an antidepressant (Lexapro) or ‘talk therapy’ (Cognitive Behavioral Therapy). It turned out that while people with low insula activity responded well to CBT, those with high insula activity responded better to Lexapro. Given the increased insula activity generally found in FM/ME/CFS, this suggests that antidepressants or other agents might work better than CBT.

Turning Down Insula and Thalamic/Somatosensory Activity in FM and ME/CFS

If insula, thalamus, and somatosensory cortex activity is increasing your pain, upping your stress levels with negative anticipation, dysregulating your autonomic nervous system and physiology, and overall just giving you a bad time, what can you do about it?

Some treatments that can reduce insula, thalamus and somatosensory cortex are below:

  • Meditation – has been found to reduce somatosensory cortex activity and pain.
  • Lyrica – reduces insula and somatosensory cortex activity in some people with FM.
  • Tropisetron – Tropisetron, a serotonin 5-HT 3 receptor antagonist, reduced pain and blood flow in the somatosensory cortex, the insula, and the anterior cingulate cortex in fibromyalgia.
  • Deep brain stimulation and trans-cranial magnetic stimulation appears to be able to reduce activity in these areas.
  • Antidepressants – While the study noted earlier used Lexapro, a similar effect might be found with similar antidepressants.
  •  ???


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