Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-02-27
2001-06-19
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S434000, C424S435000, C424S436000, C424S449000
Reexamination Certificate
active
06248789
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the management of chronic pain without requiring administration of narcotics, or by synergizing with narcotics to allow for a lower effective narcotic dose. The invention also relates to self-management of pain on an outpatient basis.
BACKGROUND OF THE INVENTION
Ketamine ((2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) is a general anesthetic used by anesthesiologists, veterinarians, and researchers. Usually, ketamine is administered intramuscularly (i.m.) or intravenously (i.v.) for induction of anesthesia. Presently, only ketamine for injection is available for administration (
Physician's Desk Reference
). Nasal administration of ketamine, in one instance with midazolam, for an ophthalmic procedure, and prior to elective surgery in healthy children, has been reported (Louon et al., 1993, Br. J. Ophthalmol. 77:529-530; Weksler et al., 1993, Can. J. Anaesthesia 40:119-121).
Ketamine has also been known to have analgesic properties (Domino et al., 1965, Clin. Pharmacol. Ther. 6:279); analgesia can be achieved with subanesthetic doses of ketamine (Bovill, 1971, Br. J. Anaesth. 43:496; Sadove et al., 1971, Anesth. Analg. 50:452-457). The drug is administered by various routes, including i.v., i.m., caudal, intrathecal, and subcutaneous (s.c.). Subcutaneous administration of ketamine has been used to treat pain following surgery and associated with terminal cancer (see, e.g., Oshima et al., 1990, Can. J. Anaesth. 37:385-386). Ketamine hydrochloride administered via a subcutaneous cannula was reported to successfully treat phantom limb pain (Stannard and Porter, 1993, Pain 54:227-230).
Management of pain, and particularly chronic pain, is complex and frequently unsuccessful. The first line of treatment usually involves administration of &mgr;-opioid agonists, e.g., narcotics such as morphine (see, e.g., Anderson and Brill, 1992, Semin. Anesth. 11:158-171). However, rarely do physicians engage in aggressive pain management. Undertreatment for pain frequently leads to conditions where patients are forced to suffer pain up to the point of tolerability before receiving medication, and the medication is usually only partially effective. Ineffective pain management is a consequence of lack of training, and of fear of narcotics on the part of patients, the medical personnel, and society in general. Children, because of their natural reticence and budding communication skills combined with a greater fear of over-administering “dangerous” narcotics particularly suffer from under treatment for pain.
Moreover, rapid tolerance and marked resistance to narcotics frequently develop, thus rendering these agents ineffective (see, e.g., Abram, 1993, Reg. Anesth. 18(SUPPL):406-413). Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, have been reported to interfere with the development of tolerance to the analgesic effects of morphine, possibly through blockade of the NMDA receptor rather than from “side-effects” of the antagonist, since the antagonists were not found to reverse tolerance (Trujillo and Akil, 1994, Brain Res. 633:178-188).
Often, pain management involves administration of a plethora of drugs, such as narcotics, agonist-antagonist agents, butorphanols, benzodiazepines, GABA stimulators, barbiturates, barbiturate-like drugs, orally, e.g., in a pill or liquid formulation, or by i.v. or i.m. injection. Opioid agonists and antagonists may be combined. Thus, a combination of drugs can have offsetting effects. More problematic is the possibility of adverse side effects, particularly gastric distress that accompanies oral administration, or the fear that injections can inspire.
Frequently, a patient suffering from chronic pain will require medication to control stomach and other gastric problems as a result of oral administration of drugs. Alternatives to oral self-administration for most of the analgesic and sedative medications for the treatment of chronic pain are not common, can be cumbersome (e.g., i.v. or s.c. administration requires use of a cannula or needle), and generally require medical training.
U.S. Pat. No. 4,671,953 describes the administration of sedative, analgesic or sedative drugs in a candy matrix, such that the drug enters the bloodstream through the oral mucosal membranes. However, this method suffers from the disadvantage that a sedated patient may fall asleep with the candy remaining in his or her mouth, which can result in choking. Furthermore, because the total dose of the drug in the candy may exceed the desired dose, administration of the candy must be medically supervised. Finally, the candy is simply unsuitable for everyday use, as sucking on a lollipop is an unseemly practice for an employee or business person.
Moreover, when administration is under the control of the patient suffering from pain, i.e., on an outpatient basis, the potential for overdosing or abuse exists, particularly with respect to narcotics.
Thus, there is a need in the art for self-management of pain using non-opioid drugs.
There is a further need in the art for a rapid method for reducing or eliminating breakthrough pain that is refractory to standard treatment regimens.
There is a further need in the art to avoid injection administration of pain medication.
There is a need in the art for a fast, convenient, and socially acceptable method for patient self-administration of medication to manage or control pain.
There is yet a further need in the art to avoid overdose and abuse of self-administered medication, and to enhance the effectiveness of pain medications, particularly narcotic pain medication.
These and other needs in the art have been addressed by the instant invention, which is based on the inventor's discovery that ketamine can surprisingly be administered nasally to alleviate pain safely and effectively, in conjunction with or independently of other pain management regimens.
The citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.
SUMMARY OF THE INVENTION
The present invention is broadly directed to a method for treating pain in a subject comprising administering via a transmucosal route a dose of ketamine effective to alleviate pain to a subject suffering from pain. In specific embodiments, administration of ketamine can be via transbuccal, sublingual, vaginal, and rectal routes. Alternatively, the pain-relieving effects of the present invention can be accomplished by administration via oral administration (via the gastrointestinal tract, rather than the oral-pharyngeal mucosa). In a further embodiment, the present invention provides for pulmonary administration of ketamine by inhalation. In a specific aspect, the invention provides an effective pain-relieving dose of ketamine by transdermal administration. Administration of an analgesic dose of ketamine advantageously allows for patient self administration of the drug, which provides for pain management on an outpatient basis. Moreover, ketamine administration via transmucosal and transdermal delivery are generally socially acceptable.
Transmucosal administration of ketamine is rapid, allowing for fast action of the drug. In addition, both transmucosal and transdermal administration are easily accomplished by a non-medically trained patient. The present invention is based, in part, on the discovery that high levels of analgesia can be achieved with small doses of ketamine, particularly ketamine administered by a transmucosal route (e.g., transbuccal, sublingual, vaginal, and rectal), or by a transdermal route. It has further been discovered that effective pain treatment is better achieved by establishing small doses via transdermal or transmucosal delivery, and that these routes of administration avoid side effects associated with a bolus dose of ketamine delivered i.v. or i.m. administration. Furthermore, a small transmucosal or transdermal dose of ketamine can be administered more frequently, which achie
Darby & Darby
Spivack Phyllis G.
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