With the FDA clamping down on a major class of opioid drugs used for pain relief by fibromyalgia  patients, we’re taking a look at other alternatives.

In the first of a  two blog series, we’re checking out ongoing or recruiting (or in some cases, recently completed) fibromyalgia clinical trials to see what the future may hold. There’s no telling how effective these treatments will be, but we do know some big bucks have been committed to see if these treatments work, and that says something. The trials are found in a clinical trials database run by the NIH called clinicaltrials.gov (which includes trials done outside the US , as well. )

We want to emphasize that many helpful  treatments will never show up in clinicaltrials.gov because a certain level of funding – either from private sources (usually drug companies) or the federal government –  is required that the backers of  many drugs, supplements and techniques simply don’t have.

With that proviso, let’s see what drug companies, medical device makers, the federal government and a few others have come up with to better treat fibromyalgia.  These are the drugs/treatments that have the best chance of making their way to your doctor’s office in the next couple of years.

Trials of all sorts – from anticonvulsants to dopamine enhancers to muscle relaxants to brain stimulators – are underway. A couple of drugs – one from Japan – and another from the U.S. are new. The big money maker, Lyrica, continues to be the focus of several studies (not reported here), and medical product manufacturers are showing a major interest in developing electrical brain stimulation products to alter brain activity. Some supplements as well as a gluten-free diet are also being tested.

This overview will not include the many  mind/body/relaxation studies underway in fibromyalgia.

CENTRAL NERVOUS SYSTEM – DRUGS

Drugs that affect the central nervous system – the site of the central sensitization (pain amplification) – that’s been documented in FM are a major focus. (Studies have shown that pain amplification pathways are over-active and pain inhibition pathways are under-activated in FM. )

Lyrica is one such drug, but we’ll not be covering the ongoing Lyrica trials in this blog.

DROXIDOPA AND DROXIDOPA/CARBIDOPA 

•  Study Completed
• Sponsor: Chelsea Therapeutics

Droxidopa increases  central nervous system levels of norepinephrine.  Some studies suggest that increased norepinephine levels could result in decreased pain in fibromyalgia.

Norepinephrine (NE) demonstrates how complex our systems are.  A hormone produced by the adrenal glands, when NE hits the bloodstream it excites the sympathetic nervous system – already believed to be over-active in ME/CFS/FM – increasing muscle tension, reducing oxygen flows to the muscles, reducing lactic acid removal – and causing pain!

Within the spinal cord and central nervous system, however, NE can reduce pain through its effects on the dorsal horn of the spinal cord, the amygdala, hypothalamus and other ’emotional modulating’ centers of the brain. Doxepin and amytriptyline both reduce neuropathic pain by increasing NE availability in the CNS.

This study is complete….

• http://clinicaltrials.gov/ct2/show/NCT01323374?term=fibromyalgia&rank=8

A JAPANESE DRUG, NEUROTROPIN, GETS ITS SHOT AT FM (COURTESY OF THE NATIONAL INSTITUTES OF HEALTH )

• This study is currently recruiting participants.
• Sponsor: National Institute of Nursing Research (NINR)

This National Institute of Nursing Research (NINR) is examining the effectiveness of neurotropin, an experimental drug used in Japan  to treat pain, in a placebo-controlled, double-blinded, crossover fibromyalgia study.

A published 2005 case report suggests the drug may be helpful in chronic fatigue syndrome as well. A 28 year old male suffering from fatigue,  body-wide pain, difficulty concentrating, memory problems, frequent urination, etc. quickly  received significant help with fatigue, pain, sleep, concentration and memory from Neurotropin. Three months later he was symptom free and had discontinued treatment. Five months later he was still symptom free.

Neurotropin has been called an ‘anti-allodynia’ and anti-pain medication. It is- get this -an  extract from inflamed skin of rabbits inoculated with vaccinia virus :).  It’s believed to enhanced the pain inhibiting aspects of the monaminergic system in the brain. This system  terminates in the dorsal horn of the spinal cord which may be the site of central sensitization in FM/ME/CFS.

Neurotropin has beenreceiving significant  animal study recently.  It reduced mouse dorsal horn neuronal activity , reduced, in  combination with Lyrica, allodynia in mice and neuropathic pain in a rat model. It also significantly  reduced neuronal toxicity in chemotherapy patients.

A similar trial is underway to examine neurotropins effectiveness in treating complex regional pain syndrome (CRPS)

• http://clinicaltrials.gov/ct2/show/NCT00366535?term=fibromyalgia&rank=73

ANOTHER ANTI-CONVULSANT – LEVETIRACETAM (KEPPRA) – FOR FIBROMYALGIA 

• Sponsor: University of California, San Francisco

Anticonvulsants such as Lyrica and Neurontin are commonly used in ME/CFS/FM. This recently completed double-blinded, placebo-controlled study at the University of California, San Francisco, examined the effectiveness of Levetiracetam in reducing pain in fibromyalgia.

Keppra is mostly used to treat epilepsy but can reduce neuropathic pain and has also been used in autism, Alzheimer’s disease, anxiety and bi-polar disorder. According to Wikipedia it’s generally well tolerated.

• http://clinicaltrials.gov/ct2/show/NCT00254657?term=fibromyalgia&rank=43

A DOPAMINE ENHANCER- ROPINIROLE (REQUIP) IN FM 

GlaxoSmithKline’s large (160 subjects recruited from 9 European countries) double-blinded ropinirole study  has been underway since 2005, and has been completed.

A dopamine enhancer used in the treatment of restless leg syndrome and Parkinson’s disease, ropinirole or Requip can reduce muscle rigidity and stiffness.  Dopamine is abundant in the part of the brain which coordinates muscle movements, and reduced dopamine levels can  result in stiff and rigid muscles, which are common in Fibromyalgia.

Parkinson’s Disease, attention deficit disorder, schizophrenia and restless leg syndrome are believed to be associated with reduced dopamine levels in the brain. Decreased dopamine levels have been are associated with increased pain.

Dopamine also affects motivation, reward, arousal and cognition. (Ritalin is a dopamine activating stimulant.) Outside the nervous system dopamine also modulates blood flows – an area of concern in ME/CFS/FM.

• http://clinicaltrials.gov/ct2/show/NCT00256893?term=fibromyalgia&rank=75

MEMANTINE – A GLUTAMATE INHIBITOR

• This study is not yet open for participant recruitment.
• Verified July 2012 by Aragon Institute of Health Sciences”’

Raised levels of glutamate, the primary excitatory neurotransmitter in the brain, have been found in the insula, hippocampus and posterior cingulate regions of the brains of people with FM. Among other things, the insula regulates the autonomic nervous system and determines how to respond to sensory inputs such as pain.  An important part of the limbic system hippocampus is found in the deep brain and is particularly vulnerable to long-term stress. Several popular ME/CFS/FM drugs (Lyrica, Gabapentin, Klonopin) lower nervous system activity, and Lyrica and Gabapentin reduce glutamate levels.

Memantine is from a new class of drugs developed for Alzheimer’s that block NMDA-like glutamate receptors. Glutamate induced neurotransmission is believe to destroy neurons in Alzheimers.

This double-blinded,  randomized, control trial – which is probably already underway –  will assess pain thresholds, pain perception, cognitive state, anxiety and depression in FM patients.

• Dig Deeper: the glutamate/GABA hypothesis for ME/CFS/FM
• http://clinicaltrials.gov/ct2/show/NCT01653457?term=fibromyalgia&recr=Open&rank=39

AN ANTI-ANXIETY DRUG PAROXETINE-CR (PAXIL-CR) FOR FM PATIENTS…WITHOUT ANXIETY   

• This study has been completed.
• Sponsor: Duke University
• Collaborator: GlaxoSmithKline

This large randomized, double-blinded, placebo-controlled  trial (n=116)  determined if the anti-anxiety drug Paxil reduced pain, depression and anxiety, and improved sleep and increased functionality in FM patients without a current diagnosis of either depression or anxiety (!).

Citing the high rate of anxiety and depression in Fibromyalgia ,the researchers are hoping some overlap between pain and anxiety production is present. (They’re following past efforts that found anti-depressants can reduce pain in FM patients who do not have depression. 

Will Paxil do the same? This study was completed this year…

• http://clinicaltrials.gov/ct2/show/NCT00610610?term=fibromyalgia&rank=47

EFFECT OF LOW DOSE PROPRANOLOL ON THE AUTONOMIC NERVOUS SYSTEM AND MUSCLE PAIN 

• This study is currently recruiting participants.
• Verified March 2012 by University of Aarhus

This randomized, double-blinded, crossover study is on TMJ not Fibromyalgia, but it’s use of propranolol – a beta blocker- to reduce pain is intriguing.  Dr. Light found that low-dose propanolol  (1/5th – 1/10th normal) improved the ability  of ME/CFS patients to stand without symptoms, increased cortisol (often low in ME/CFS) and reduced pain in a small study. He believes low-dose propranolol reduces sensory receptor activity (and warns that normal doses may have the opposite effect. )

• Find out more about low-dose propanolol in ME/CFS here.
• http://clinicaltrials.gov/ct2/show/NCT01333150?term=fibromyalgia&recr=Recruiting&rank=97

Completely New

TD-9855 MASS BALANCE STUDY 

• This study is not yet open for participant recruitment.
• Verified August 2013 by Theravance, Inc.

This study is listed as safety study for  a new drug, TD-9855 simply consists of six people and should be done by the end of this year. The drug company involved, Theravance, however, stated here that the drug has been safely tested and a 375 person trial has begun.

Coming out of Theravances ‘Monamine Reuptake Inhibitor Program’, TD-9855 is a  norepinephrine and serotonin reuptake inhibitor (NSRI) being developed to treat chronic pain and ADHD.  The company states TD-9855 has shown anti-pain activity across a wide variety of inflammatory, neuropathic and osteoarthritis pain models, and that it, interestingly, enhances the pain reducing effects of morphine.  They believe it may help with fatigue as well.

• http://finance.yahoo.com/news/theravance-announces-initiation-phase-2-210500633.html

CENTRAL NERVOUS SYSTEM – ELECTRICAL STIMULATION

Much interest is being shown in developing electrical stimulation products that reduce the activity in brain regions believed to increase pain.

DIRECT TRANSCRANIAL (BRAIN) STIMULATION TO ALTER PAIN PROCESSING IN FIBROMYALGIA 

• Currently Recruiting

Previous results from this research team suggests that reducing the levels of excitatory neurotransmitters, altering patterns of brain activity (connectivity) and changing the ‘cortical thickness’ of central pain producing neurons using direct transcranial stimulation can produce ‘lasting therapeutic benefits’.

Delivering  low electrical currents to the brain, tDCS was orginally developed to treat brain injuries, but has been able to increase the cognitive abilities, as well, including memory and attention span, in health adults. The hope is that tDCS will be able to use the brains inherent plasticity to reduce activity in the over-active pain processing areas of the brain in fibromyalgia

This study, thankfully, will study the long-term effects of tDCS on ‘multiple central nervous system levels’ in fibromyalgia.

http://clinicaltrials.gov/ct2/show/NCT01745003?term=fibromyalgia&rank=22

See another tDCS study that is recruiting below

http://clinicaltrials.gov/ct2/show/NCT01745003?term=fibromyalgia&recr=Open&no_unk=Y&rank=5

LONG TERM EFFECTS OF rTMS IN FM

• This study is currently recruiting participants.
• Verified October 2013 by Centre Hospitalier Esquirol

This long term study will examine improvement after 15 sessions of rTMS  in 3 weeks, and then after a maintenance session done every 19 days for seven months.  It’ll be considered successful if a 30% reduction in pain occurs. An earlier study found a 40% reduction in pain which slowly dropped over time – hence the idea of doing maintenance doses every 3 weeks or so. This study should be finished by Feb. 2015.

• http://clinicaltrials.gov/ct2/show/NCT01942538?term=fibromyalgia&recr=Open&no_unk=Y&rank=16

RINCE  –“REDUCED IMPEDANCE NONINVASIVE CORTICAL STIMULATION” IN FM

• This study is ongoing, but not recruiting participants.
• Sponsor: Cerephex Corporation

Cerephex has developed an electrostimulation product called Neuropoint they state is  designed specifically to treat ‘central sensitivity’ by reaching into the deeper regions of the brain. Cerephex notes that over-activation of these deeper brain regions can generate pain even when no pain signals are being generated by the body

Cerephex’s earlier study had modest effects in FM.

OTHER DRUGS

TARGETING HERPESVIRUSES IN FM 

• This study is ongoing, but not recruiting participants.

This privately funded,  randomized, double-blind, placebo-controlled, 16-week study combines an antiviral and an antinflammatory to get at herpes viruses in Fibromyalgia. We’ll be covering this study in more detail in a future blog.

• http://clinicaltrials.gov/ct2/show/NCT01850420?term=fibromyalgia&rank=50

Flexeril

Two studies are looking at different forms of Flexeril, a muscle relaxant.

CYCLOBENZAPRINE ER FOR FM 

• This study is currently recruiting participants.
• State University of New York – Upstate Medical University

Cyclobenzaprine (flexeril) is a muscle relaxant and tricyclic antidepressant that is often used off-label to treat fibromyalgia. Cyclobenzaprines muscle relaxant capabilities may be able to reduce muscle spasms while its tricyclic antidepressent characteristics may reduce pain signaling in the spinal cord. This double-blinded, placebo-controlled study will evaluate the extended release form of cyclobenzaprine (Amrix), and besides pain reduction will also evaluate sleep and fatigue.

• http://clinicaltrials.gov/ct2/show/NCT01041495?term=fibromyalgia&rank=38

BEDTIME SUBLINGUAL TNX-102 SL (BESTFIT)

• This study is currently recruiting participants.
• Verified September 2013 by Tonix Pharmaceuticals, Inc.

Tonix Pharmaceuticals has begun a large (120 person) multi-center, randomized, double-blinded 12-week  trial to see if a new formulation of sublingual cyclobenzaprine taken at a  very low dose (VLD – 2.8 mgs.) at  bedtime will help with pain in FM.  This study was projected to begin in Sept of this year and end in Dec of next year.

• http://clinicaltrials.gov/ct2/show/NCT01903265?term=fibromyalgia&recr=Recruiting&rank=35

CYMBALTA TAKES A LOOK AT SMALL FIBER NEUROPATHY 

• This study is currently recruiting participants.
• Verified June 2012 by University of California, San Diego

This study is going to use skin biopsies (small nerve fiber neuropathy) to assess peripheral nerve functioning to see if patients with or without peripheral nerve issues respond better to Cymbalta (Duloexetine).

• http://clinicaltrials.gov/ct2/show/NCT01619566?term=fibromyalgia&recr=Open&no_unk=Y&rank=20

GUT AND SUPPLEMENTS

REDUCING GUT PERMEABILITY FOR LESS PAIN IN FM? 

• This study is currently recruiting participants.
• Verified January 2013 by Lescuyer Laboratory

The Permaprotect food supplement glutamine, curcumin and other substances purported to reduce intestinal permeability, and the low-grade, chronic inflammation associated with it.  This study will determine if gastrointestinal complaints in FM are reduced after using Permeaprotect, prebiotics, probiotics and grapefruit seed extract.

• http://ichgcp.net/clinical-trials-registry/research/index/NCT01469936

TRIALING A GLUTEN-FREE DIET IN FM 

• This study is currently recruiting participants.
• Sponsor: Universidad de Granada

A recent study finding that up to 10% of people with celiac disease go on to develop fibromyalgia suggests that some people with fibromyalga have undiagnosed celiac disease or non-celiac gluten intolerance. No studies yet have examined celiac disease or gluten intolerance in fibromyalgia or chronic fatigue syndrome in a comprehensive manner.

This study will compare the effect of a gluten-free diet with a hypocaloric (low calorie?) diet in patients with fibromyalgia and celiac-type symptoms.

• Dig Deeper – Check Niki Gratrix’s blogs to learn more about celiac disease and non-celiac gluten intolerance.
• http://clinicaltrials.gov/ct2/show/NCT01881360?term=fibromyalgia&rank=45

ORAL IRON THERAPY TO IMPROVE NEUROTRANSMITTER FUNCTIONING 

• This study is not yet open for participant recruitment.
• Verified March 2013 by Sanjay Gandhi Postgraduate Institute of Medical Sciences

Sponsor: Sanjay Gandhi Postgraduate Institute of Medical Sciences

We don’t hear much about oral iron but studies have shown fibromyalgia is more prevalent in patients who have iron-deficient anemia. Anemia is of interest because of the low blood volume present in chronic fatigue syndrome and possibly fibromyalgia.

These Indian researchers believe the synthesis of two important nervous system neurotransmitters, serotonin and dopamine, may be impaired by iron deficiency in FM. This three month double-blinded, randomized and placebo-controlled 120 person study will feature one group taking FM drugs (Lyrica, cymbalta, etc.) without iron and one group taking FM drugs with iron (230 mgs of elemental iron). It will be completed by December of next year.

Effect of Transdermal Magnesium Chloride on Quality of Life in Patients With Fibromyalgia

• This study is not yet open for participant recruitment.
• Verified October 2013 by Mayo Clinic

Sponsor: Mayo Clinic

Magnesium deficiency can send muscles into spasm, impair sleep, cause headaches and produce anxiety and magnesium supplementation is common in ME/CFS/FM. This  small pilot study (40 women) will gather preliminary data on whether applications of transdermal magnesium chloride over a month can improve quality of life in  fibromyalgia.

• http://clinicaltrials.gov/ct2/show/NCT01968772?term=fibromyalgia&rank=6