Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-08-11
2002-05-28
Fay, Zorreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06395788
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to methods and compositions comprising very low doses of cyclobenzaprine. The methods and compositions are useful for treating or preventing sleep disturbances. Particularly, the methods and compositions of this invention are useful for treating patients suffering from fibromyalgia syndrome, prolonged fatigue, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders, chronic pain syndromes, autoimmune diseases and symptoms thereof.
BACKGROUND OF THE INVENTION
1.1 Cyclobenzaprine
Cyclobenzaprine or 3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, is represented by the chemical formula:
Cyclobenzaprine was first synthesized in 1961. [Villani, F. J., et al., “Dialkylaminoalkyl derivatives of 10,11-dihydro-511-dibenzo a,d cycloheptene and related compounds,”
J. Med. Pharm. Chem.
5:373-383 (1962)]. Cyclobenzaprine was approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of local origin. [Katz, W., et al., “Cyclobenzaprine in the Treatment of Acute Muscle Spasm: Review of a Decade of Clinical Experience,”
Clinical Therapeutics
10:216-228 (1988)]. Cyclobenzaprine is sold as a hydrochloride salt in a 10 mg non-scored tablet under the tradename Flexeril® (Merck and Co.) or as a generic (Genera, Warner-Chilcott, Duramed, Mylan, Endogenerics, and Watson) for use as a skeletal muscle relaxant. The pharmacokinetics of cyclobenzaprine metabolism have been well studied (e.g., Katz, et al., page 219, supra).
No indications of organ toxicity were found in cyclobenzaprine-treated patients at recommended doses. Toxic effects were reported, however, for three individuals who ingested between 260 to 900 mg of cyclobenzaprine. [Katz, et al.,“Cyclobenzaprine in the Treatment of Acute Muscle Spasm: Review of a Decade of Clinical Experience,”
Clinical Therapeutics
10:216-228 (1988)]
The principal side effects of cyclobenzaprine treatment are drowsiness, dry mouth or tongue, dizziness and bad taste. [Katz, W. A., et al.,supra.] Other less common side effects include nausea, tiredness, constipation, blurred vision, nervousness, confusion, abdominal pain and discomfort. Although cyclobenzaprine use has been reported to be associated with the side effects of drowsiness or tiredness, the utility of cyclobenzaprine as an agent for improving the quality of sleep, being a sleep deepener, or treating sleep disturbances when administered using a very low dosage regimen has not been recognized.
1.2 Sleep and Sleep Disturbance
Humans cycle repeatedly through four stages of sleep, each approximately 1½-2 hours long. Rapid eye movement (REM) sleep, associated with dreaming, occurs during Stage 1 sleep at the end of each cycle. Non-REM sleep occurs during Stage 3 and 4. When sleep quality is disturbed due to, for example, shallow sleep, frequent awakenings, or early awakenings, patients complain of “zombie”, “zonked”, “groggy”, or “spacey” feelings, tiredness, feelings of being “run down,” and having difficulty concentrating during waking hours. (The terms “zombie” and “spacey” are English slang words used to describe a state of mind wherein disconnected thoughts may be frequent and/or one may experience impaired short-term memory and/or concentration.)
1.3 Fibromyalgia Syndrome
Fibromyalgia syndrome (FMS), also known as fibrositis, is a chronic, non-inflammatory rheumatic disorder. The American College of Rheumatology (ACR) published a classification criteria for FMS in 1990. [Wolfe, F., et al., “The American College of Rheumatology 1990 criteria for the classification of Fibromyalgia: Report of the Multicenter Criteria Committee,”
Arthritis and Rheumatism
33:160-172 (1990)].
Some practitioners further classify fibromyalgia into two categories—primary or secondary-concomitant fibromyalgia. Generally, primary fibromyalgia syndrome can be considered fibromyalgia occurring in the absence of another significant condition whereas secondary-concomitant fibromyalgia can be considered fibromyalgia occurring in the presence of another significant rheumatic disorder, which may have been caused by or is merely associated with the patient's fibromyalgia. Secondary or concomitant fibromyalgia can include fibromyalgia in patients with classical or definite rheumatoid arthritis, osteoarthritis of the knee or hand, low back pain syndromes, cervical pain syndromes (or combinations thereof).
Studies exploring the relationship between sleep disturbances and fibromyalgia have been conducted. For example, Moldofsky et al. observed that seven fibromyalgia patients had alpha rhythm contamination in stage 4 sleep (non-REM sleep) and three fibromyalgia patients had an entire absence of delta waves (a hallmark of stage 4 sleep). [Moldofsky, H., et al., “Musculoskeletal symptoms and non-REM sleep disturbance in patients with ‘fibrositis syndrome’ and healthy subjects,”
Psychosom. Med.
37:341-51 (1975)] In another study, selected individuals who were not suffering from fibromyalgia prior to commencement of the study, were subjected to noise that artificially disrupted their slow-wave sleep. They experienced a similar alpha EEG sleep anomaly and complained of nonrefreshing sleep and diffuse myalgia/fatigue (Moldofsky, H. and P. Scarisbrick, “Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation,”
Psychosom. Med.
38:35-44 (1976)). The subjects did not show any increased muscle tenderness when deprived of REM sleep (Moldofsky, et al., 1976, supra).
Various drugs including analgesics, anti-inflammatory agents, psychotropic drugs, such as tricyclic antidepressants (TCAs), or high doses of cyclobenzaprine have been used with some success to treat some fibromyalgia patients.
TCAs have been typically administered in a dosage range of tens of milligrams/day with increasing dosages as needed. [Wysenbeek, J. et al. “Imipramine for the treatment of fibrositis: a therapeutic trial”,
Ann. Rheum.
44:752-753 (1985); Carette, S. et al. “Evaluation of amitriptyline in primary fibrositis”,
Arthritis Rheum,
29: 655-659 (1986); Goldenberg, D. L., “A Review of the Role of Tricyclic Medications in the Treatment of Fibromyalgia Syndrome,”
J. Rheumatology
16:137-139, 139 (1989); Bryson, H. M. et al., “Amitriptyline: A Review of its Pharmacological Properties and Therapeutic Use in Chronic Pain States,”
Drugs & Aging
8:459-476, 461 (1996)].
Cyclobenzaprine has been administered to fibromyalgia patients typically in a dosage range of tens of milligrams per day. For example, several studies reported treatments of fibromyalgia or fibrositis using 10 to 40 mgs of cyclobenzaprine per day. [Bennett, R. et al. “A comparison of cyclobenzaprine and placebo in the management of fibrositis,”
Arthritis Rheum.,
31:1535-1542 (1988); Hamaty, Daniel et al., “The plasma endorphin, prostaglandin, and catecholamine profile of patients with fibrositis treated with cyclobenzaprine and placebo: a 5-month study,”
J. Rheumatol.,
16:140-143 (1989); Quimby, Lucy G. et al., “A randomized trial of cyclobenzaprine for the treatment of Fibromyalgia”,
J. Rheumatol.,
16:140-143 (1989)]
In another study, twelve fibromyalgia patients treated with twenty to forty mgs of cyclobenzaprine per day did not experience decreased pain, as monitored by tender point count and dolorimetry measurements. (Reynolds, W. J., et al., “The effects of cyclobenzaprine on sleep physiology and symptoms in patients with Fibromyalgia,”
J. Rheumat.
18:452-4 (1991)). Furthermore, the cyclobenzaprine did not favorably change the alpha non-REM EEG sleep anomaly (stage IV sleep) and mood ratings of the fibromyalgia patients. Thus, no specific effect of cyclobenzaprine in that dosage range on sleep physiology was documented.
Santandrea et al. compared two groups of fibromyalgia patients treated with either 10 mg/day or 30 mg/day of cyclobenzaprine. [Santandrea, S., et al., “A Double-Blind Crossover Study of Two
Fay Zorreh
Haley Jr. James F.
Joslyn Kristin M.
Kwon Brian-Yong
Vela Pharmaceuticals, Inc.
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