Reprinted with the kind permission of Cort Johnson.
Fibromyalgia syndrome – Novel therapeutic agents. – J. Ablin and D. Buskila. Maturitas 2013
“The long term follow-up of FMS patients indicates…..that the degree of improvement achieved by many medications…is modest at best” – Ablin and Buskia
Affecting 2-3% of the population of the U.S., or about 8,000,000 people, fibromyalgia’s impact is huge; yet physician ignorance is high, with many doctors restricting their drug prescriptions to the three drugs the FDA has approved for fibromyalgia.
The Mayo Clinic – which appears to set the standard for brief, pithy and unrevealing treatment prescriptions for FM and chronic fatigue syndrome – lists just three categories of FM drugs: NSAID’s, anti-depressants and anti-seizure drugs. Adding muscle relaxants, pain relievers (tramadol, opioids) and benzodiazpines to the mix, WebMD does better, but that list, as a recent review article focusing on possible FM drugs indicated, is still far too short.
If Ablin and Buskila are right, many doctors are just scratching the surface of the drug possibilities for fibromyalgia. With all the misery present in FM, it’s not acceptable that doctors are not aware of the all drug possibilities present.
(In fact, with their emphasis on the central-nervous-system-affecting drugs, Ablin and Buskila are certainly underestimating the drug possibilities for FM as research uncovers problems in the periphery (e.g., muscles, skin, immune system) as well. The finding that small fiber neuropathy may be common in fibromyalgia, for example, shifts the treatment focus in an entirely different direction, to the immune system and intravenous gamma globulin (IVIG).)
The review article is called ‘novel therapeutic agents’ but many of the drugs in it received one or two studies in the past. These ‘novel agents’ are mostly promising drugs that need more study.
The ‘Novel’ Fibromyalgia Drugs
Norepinephrine Reuptake Inhibitors (NRI’s)
Esreboxetine – the dogma in FM ‘antidepressant’ use is that serotonin and norepinephrine reuptake inhibitors work better than serotonin or norepinephrine reuptake inhibitors, but two studies suggest that the NRI esreboxetine can be quite helpful. A large (n>1,000 people) randomized, placebo-controlled, blinded study found esreboxetine produced significant reductions in pain, fatigue and fibromyalgia impact scores. (Note that studies indicate antidepressants can reduce pain in people without depression.)
Dopamine Receptor Agonists
A neurotransmitter most known for its ‘reward enhancing’ factors (and the role it plays in drugs like cocaine and amphetamines), dopamine also opens up the blood vessels (a vasodilator), is an immune modulator (reduces activity of lymphocytes), reduces food flow through the gut (gut motility), reduces insulin secretion and more.
Attention deficit disorder, restless leg syndrome, Parkinson’s disease and schizophrenia have all been associated with dopamine dysfunction. Low dopamine levels are associated with many symptoms common to fibromyalgia and chronic fatigue syndrome including stiff, achy muscles, tremors, cognitive impairment, difficulty focusing, poor balance and coordination, a walking pattern characterized by talking small steps and impaired fine motor skills.
Substance P Antagonists
A neurotransmitter that increases pain, substance P levels are increased in fibromyalgia, making it (and its receptor) an intriguing drug target. (Receptors found on the outside of cells or soluble receptors in the bloodstream react with a substance (such as substance P) to initiate change (such as increase pain). Reducing substance P receptor levels would, therefore, reduce substance P’s effects on the body. Substance P antagonists have been investigated for their use in reducing nausea during chemotherapy, as antidepressants and in reducing pain. A safety review indicated they were generally safe and well tolerated.
Casiopitant (Rezonic) – knocks down the receptor for substance P (neurokinin-1). A Casiopitant FM trial ended in 2008 but the results have not been published.
Aprepitant – the review does not mention aprepitant, the only substance P antagonist used in clinical practice. New substance P inhibitors are under development.
“More extensive use of opioid antagonists as well as the introduction of novel microglial activation inhibitors (miRNA) pose exciting new possibilities for the treatment of FMS.” – Ablin and Buskila
It may seem strange to target drugs that knock down one of the main pain inhibiting systems in the body but the opioid receptors in many FM patients appear to filled and elevated opioid activity in the brain can cause increased, not decreased pain sensitivity.
Low Dose Naltrexone (LDN) – An opioid antagonist long used by people with fibromyalgia for relief, LDN finally got a clinical trial and it was successful. At the low doses used in the trial, Ablin and Busklin suggested LDN’s effectiveness in FM may have been more due to anti-inflammatory effects than to opioid antagonism.
One theory suggests the endocannabinoid system in the body is simply not up to snuff in fibromyalgia, chronic fatigue syndrome, IBS, migraine and other disorders. This major system, which is found throughout the peripheral and central nervous systems, plays a key role in pain reduction and has strong anti-inflammatory properties.
A review of cannabinoid use in non-cancer pain found that fifteen of eighteen trials “demonstrated a significant analgesic effect of cannabinoid as compared with placebo and several reported significant improvements in sleep. There were no serious adverse effects.” Cannabinoids were described as usually ‘modestly effective’ in treating neuropathic pain.
(On a personal note I’ve found medical marijuana to be effective in reducing pain, enhancing sleep and as a stress reducer.) Dr. Clauw has said he would readily swap out cannabinoid drugs/medical marijuana for opioids and other drugs if they were available. Different kinds of medical marijuana can have different effects.
Located in the dorsal horn of the spinal cord, the NMDA receptors are found in prime territory to regulate pain symptoms. Dorsal horn neurons receive and filter sensory information from all over the body and then transmit it to the brain. Over activation of these neurons has been shown to participate in producing hypersensitivity pain states (central sensitization). This suggests that toning down the NMDA receptors on these neurons could turn down pain levels, as well.
Dextromethorphan – A 2005 study indicated dextromorphan reduced a key part of the process (windup) believed to produce central sensitization in fibromyalgia. Thirty percent of FM patients responded ‘positively’ to dextromethorphan in another.
Ketamine – Several studies indicate Ketamine can reduce pain in fibromyalgia. (See “Ketamine and Fibromyalgia”)
Memantine (Axura, Akatinol) – Studies indicating raised levels of glutamate in the insula, hippocampus and posterior cingulate cortex regions of the brains of FM patients have ignited interest in Memantine. Memantine is a new class of drug that blocks glutamate from exciting the NMDA receptors believed to contribute to central sensization…Memantine also enhances dopamine activity. A fibromyalgia memantine trial should be getting underway soon.
R-HT3 (Serotonin) Receptor Antagonists
Depending on where it’s produced, serotonin either enhances pain or diminishes it. 5-HT3 receptor antagonists attempt to diminish serotonin’s pain facilitating properties. 5-HT3 receptor blockade may also be able to reduce several immune factors that may be important in ME/CFS/FM, including TNF-a, IL-1b, IL-6 and fatty acid derivatives called prostaglandins that may be increased in ME/CFS.
Dolasetron – Forty-two and 28% of FM patients in one trial had greater than 30% and 50% decreases in pain. Reductions in fibromyalgia impact, anxiety and depression were not significantly different.
Tropisetron – Tropisetron not only helped to normalize cardiac autonomic nervous system functioning but reduced ‘pain perception’ as well in a 2007 study. Forty-five percent of patients reported having ‘good’ to ‘very good’ results in a large 2004 retrospective study. Fifty percent of FM patients in a small trial reported Tropisetron had a good or very good influence on their pain. Serum substance P levels droped in the responders. Reduced activation of brain regions associated with pain production was found in another small Tropisetron study. Forty patients of FM patients reported a greater than 35% reduction of pain in a large 2001 Tropisetron trial. The number of tender points and sleep and dizziness were significantly improved. Tropisetron also has neuroprotective, autonomic nervous system, immune modulating and sensory gating properties.
Sodium oxybate (Xyrem) is so unusual the authors put it in a category all its own. Approved for the treatment of narcolepsy, Xyrem is horrendously expensive but targets a key sleep dysfunction in ME/CFS/FM. Two recent studies indicated Xyrem does reduce pain and improve sleep in FM, but the FDA, citing concerns with abuse (it’s the ‘date rape’ drug) and side effects, failed to approve it, making unavailable for most in the US.
A non-opioid, non-NSAID pain reliever, doctors have been using Flupirtine for over twenty years to fight pain in Europe, and it is approved in the US as an anticonvulsant. It’s not clear how Flupirtine does what it does but it appears to involve the NMDA receptors and the sympathetic nervous system. A 2010 review suggested Flupirtine may be a unique kind of analgesic agent and interest in the drug has increased recently. A study long, long ago suggested it might be helpful in fibromyalgia but no followup studies were ever done.
Ablin and Buskila ended the paper on this hopeful note.
“As the fibromyalgia saga continues to unfold, novel and unexpected targets are added to the spectrum of treatments…..Indeed, FMS diagnosis and management in a decade may prove to be very different from what we know today…” – Ablin and Buskila
Source: Health Rising, July 13, 2013. By Cort Johnson.