Molecular Biology of Opioid Receptors in Skin and Muscle Tissue of FMS Patients
Principal Investigator: Haiko Sprott, M.D.
Award: $49,947 - June 1999
Fibromyalgia affects approximately 3% of Americans and Europeans. The chronic pain is so severe that it adversely impacts both the quality of life and the productivity of individuals in their prime of life. The treatments that are currently available are largely ineffective, claims the principal investigator of this study, Haiko Sprott, M.D. He explains that this is due in part to the relatively recent recognition of this disease and in part to its complexity. In response to this predicament, Sprott proposes that the recent introduction of novel molecular biology techniques be employed. These types of techniques have provided new insights into the mechanisms underlying other disease processes and offers the means necessary to test novel hypotheses that may form the basis for more effective therapies.
Sprott and coworkers propose that patients with FMS undergo a change in the expression of the receptors that recognize opioid molecules in their muscle tissue; that is, in the peripheral nervous system. Opioids are a group of analgesic molecules that are produced by the body, as well as being used in pain therapy. Upon interacting with their specific receptors, opioids modify the ability to perceive pain.
According to our hypothesis, says Sprott, the receptors for opioids are down-regulated in the skin and/or muscle tissue of patients with FMS, leading to the pain of the disease and interfering with the ability of opioid-type medications to fully alleviate the pain of FMS. (By “down-regulated”, Sprott means that the opioid receptors are either not present in the tissues or that they are not functioning properly. In fact, he presented preliminary data at the 1998 American College of Rheumatology meeting to imply that this is very likely the case, at least in the skin of many patients with FMS.)
Sprott proposes to test the above hypothesis by characterizing the expression of the opioid receptors in the skin and muscle biopsy tissue from patients with fibromyalgia and comparing the quantities of the specific types of receptors (Delta, Kappa and Mu) with those in a group of control patients. The level of opioids produced by the body and secreted into the plasma will also be measured as another indicator of the body’s pain regulating dynamics. These analyses will shed light on the biology of the disease and then serve as a basis for designing therapeutic interventions.
In a small scale study by Sprott, he found that the Kappa and Mu opioid receptors in the skin of FMS patients were down-regulated (a significantly smaller quantity was found in patients when compared to healthy controls). However, the Delta receptors seemed to be present in normal quantities and may be the target for future therapies. If Sprott’s data can be duplicated in this expanded study, he suggests that a topical cream that works on the Delta receptors could be developed and tested to determine if it will help minimize FMS pain. No commercially available opioid medication specifically targets the Delta receptor. Those most commonly prescribed work at the Mu receptor which may not be present in sufficient quantities in FMS patients to provide adequate pain relief. This can lead to a situation in which the higher opioid dose required for analgesia (if it is attainable) may create unmanageable side effects for patients.
Dr. Sprott has extensive experience in both the clinical care of patients with fibromyalgia and the use of molecular biology tools. He has been involved in FMS research since 1991 and has collaborated with investigators world-wide to help advance the science of this condition.
Autoantibodies to Neuropeptides in Fibromyalgia
Principal Investigator: Thomas Fasy, M.D., Ph.D.
Mount Sinai School of Medicine, New York
Award: $40,000 - June 1999
FMS, as well as CFS, is often characterized by various immunologic abnormalities such as allergies and/or evidence of autoimmune (anti-self) responsiveness. In this project, Thomas Fasy, M.D. is going to search for autoantibodies which bind to various neuropeptides (neurotransmitters and hormones) that are suspected to be malfunctioning in people with FMS. This binding process, if detected, could interfere with the ability of neuropeptides to function properly. Many experts now believe that a key feature of FMS is a disruption of the normal processing of pain and sensory stimuli in the brain, apparently due, at least in part, to neuroendocrine disturbances. The nature and location of these disturbances remain to be identified and clarified.
This research project is designed to test an autoimmune hypothesis for the suspected neuroendocrine disturbances in the pain processing centers in the central nervous system; namely, that patients with FMS, as well as some autoimmune mice, produce autoantibodies which specifically bind to one or more neuropeptides or hormonal factors relevant to the pathogenesis of FMS. Say for example, that people with FMS produce antibodies that bind to a substance that is crucial in the regulation of pain. Then identifying such an antibody would be vital for understanding FMS and developing therapeutic interventions.
Fasy proposes to search for antibodies to more than a dozen neuropeptides that might plausibly be involved in generating the symptoms of FMS. He will be analyzing both the serum and spinal fluid of well-characterized patients with FMS. Fasy will also be screening the sera from eleven strains of mice that already exhibit autoimmune diseases. If neuropeptide-binding autoantibodies are found in a given strain of mice, then this could assist in understanding the physiological effects of the autoantibodies and potentially hasten new treatment approaches.
The project proposed by Fasy is extremely timely (see box below). Along with looking for autoantibodies to neuropeptides, such a substance P, he will also be searching for autoantibodies which bind to the two recently discovered opioid-like substances, nociceptin and nocistatin. The structures of these two functionally antagonistic neuropeptides were only recently determined and may turn out to be essential clues to understanding the neurobiology of FMS, CFS and other related pain syndromes.
All in all, Dr. Fasy’s search for neuropeptide-binding autoantibodies that correlate with FMS symptoms represents an important first step in clarifying the neuro-hormonal dysfunction that occurs in people with this condition.
Randomized Clinical Trial of Clonazepam versus Placebo in FMS/CFS
Principal Investigator: Don L. Goldenberg, M.D.
Newton-Wellesley Hospital, MA
Award: $24,450 - January 1999
At the American Association for CFS in October '98, several physicians stated that clonazepam (brand name Klonopin) was one of the more effective single agents that they used for patients with CFS and FMS. Clonazepam is an anti-seizure, benzodiazepine and it's one of the drugs of choice for treating two sleep disorders that tend to cluster in people with FMS/CFS: restless leg syndrome (RLS) and periodic limb movements during sleep (PLMS). Both conditions cause annoying, uncontrollable movements of the arms and legs, making it difficult for a person to achieve a good night's sleep. Living with a persistent sleep disruption of this serious nature may also lead to a breakdown in the body's rhythmic production of many essential hormones, chemical transmitters and immune system substances.
At the November '98 American College of Rheumatology meeting, a small pilot study using lorazepam (brand name Ativan) showed great promise. In fact, during the special meeting on FMS, Don Goldenberg, M.D., of Boston, MA, brought attention to this study, indicating that further investigation of agents in this class of benzodiazepines is warranted.
How do drugs such as clonazepam work in patients with FMS/CFS? Does it just improve sleep problems and reduce anxiety? Or, does this type of medication also lead to a reduction in pain? Benzodiazepines work at the body's GABA receptors. The GABA system is partially responsible for inhibiting pain signals traveling down the spinal cord from the brain and out to the tissues. So, it is possible that drugs like clonazepam not only work to reduce sleep disruption, but they may also play a significant role in FMS/CFS to minimize pain.
Goldenberg has been awarded an AFSA grant to evaluate the effectiveness of clonazepam in treating people with FMS and CFS. "Most FMS/CFS patients have sleep disturbances and medications that improve these sleep abnormalities and that also decrease pain perception have been of most therapeutic benefit in this condition," says Goldenberg.
"Our experience suggests that clonazepam is helpful in many FMS/CFS patients. We have also found it very safe and free of most adverse side effects. However, its efficacy has not been established in FMS/CFS. We will be evaluating a low dose of clonazepam in a randomized, double blind controlled study. Every patient will receive clonazepam for three months and a placebo for three months, in a cross-over study design."
Goldenberg's clinical experience and that of many other physicians, indicates that clonazepam works in a subgroup of patients, but this has to be proven in a placebo controlled study. Also, for patients who do respond well to clonazepam, there are other questions to be answered: What areas of improvement does the drug provide? And, can any predictions be made based on a patient's symptoms as to whether they will be a clonazepam responder? It's not good enough to show that a given drug works in "some" patients. It's important to know in whom the drug works best and why.
If the anecdotal experience of several physicians is that clonazepam works and that at low doses it is a safe drug, why bother with the study? Clonazepam is in the benzodiazepine class of medications and a large number of treating physicians have cast this category of drugs aside, claiming that they are all bad. As a result, patients are being denied the chance of even a trial prescription of clonazepam. And, if a patient does find that clonazepam works for them, they still face having the drug yanked away from them at a later date because many physicians view benzodiazepines as habit-forming. In other words, these drugs may be reserved for short-term use and this creates a serious dilemma when a person has a long-term illness.
A controlled trial of clonazepam by a prestigious clinician such as Dr. Goldenberg will go a long way to help calm the concerns of physicians who want to help their patients, but are afraid to prescribe a drug previously believed to be a potentially addictive agent. In many ways, a large number of physicians fear prescribing benzodiazepines almost as much as they fear prescribing opioids for chronic pain syndromes. Recent developments in researching both medications have shown that they can be prescribed safely and responsibly to people with chronic illnesses. Yet, without published studies to provide more concrete evidence that drugs--such as clonazepam--are safe and effective in FMS/CFS, patients will continue to be denied promising therapies based on the prescribing fears of their treating physician.