Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-09-26
2003-04-08
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S211080, C514S211130, C514S217000, C514S254060, C514S459000, C514S649000, C514S653000
Reexamination Certificate
active
06545057
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the use of the tricyclic antidepressants to produce local long-acting relief of different varieties of pain.
BACKGROUND OF THE INVENTION
To provide a better understanding of the invention it is necessary to distinguish between the two terms analgesia and anesthesia. Analgesia is defined as a condition in which nociceptive stimuli are sensed but are not interpreted as pain. Anesthesia is a state characterized by total loss of sensation, the result of pharmacologic depression of nerve function. Thus, analgesia does not produce anesthesia whereas anesthesia produces analgesia.
In general, pain is associated with a known tissue pathology (e.g., cancer pain, arthritic pain), inflammation, or injury to a body tissue (e.g., surgery). Neuropathic pain is thought to be a consequence of damage to peripheral nerves or to regions of the central nervous system. Neuropathic pain can present as an acute pain but frequently occurs as a form of chronic pain.
The use of long-acting local anesthetics that elicit complete neural blockage for more than several hours is frequently desirable in the management of acute and chronic pain. Pain relief research during the last two decades has focused on the identification of new local anesthetics to produce analgesia of long duration with minimal impairment of autonomic function and low toxicity. One of the best known “long-acting” local anesthetics developed to date, bupivacaine, reportedly blocks major nerve block for three to twelve hours. Unfortunately, bupivacaine is also highly cardiotoxic. The development of alternative “long-acting” local anesthetics met limited success.
Pain relief research also has focussed on the identification of new neurolytic agents for the treatment of chronic pain and intractable cancer pain. Historically, spinal opiate administration, surgical intervention, or both have been used to alleviate chronic and intractable cancer pain. When these methods fail to provide insufficient pain relief, phenol or absolute alcohol reportedly have been used as neurolytic agents to destroy the pathogenic nerve regions that are responsible for pain manifestation. However, these agents exert only weak local anesthetic effects and, accordingly, have been difficult to administer to alert patients without inducing additional pain. To date, a long-acting local anesthetic with no major side effects has not been available for the treatment of acute and chronic pain.
In view of the foregoing limitations of the existing local anesthetics to prolong the duration of anesthesia, a need still exists for useful long-acting local anesthetics for pain management. Preferably such local long-acting anesthetics also will exhibit reversible effects. Such drugs would be useful and desirable, for example, in postoperative analgesia, and for treating acute and chronic pain. Preferably, such agents would have sufficient potency to permit administration of a single, relatively low dosage of the agent, thereby minimizing the likelihood of side effects that have been attributed to the existing local long-acting anesthetic agents.
Tricyclic antidepressants are frequently used as analgesics in pain management but only when administered systemically. Among them, amitriptyline has been used orally for the analgesic therapy of chronic pain. Amitriptyline's sites of action are both central and peripheral. Despite the numerous reports on amitriptyline's analgesic effect on reducing pain when administered systemically, the exact mechanism of this effect remains unknown. To our knowledge, tricyclic antidepressants have not been used as local analgesics. Likewise, they have not been used at all as anesthetics either locally or systemically.
SUMMARY OF THE INVENTION
The invention involves in one respect the surprising discovery that tricyclic antidepressants act as long-acting local anesthetics and analgesics that are useful for alleviating pain. These tricyclic antidepressants exhibit unexpected anesthetic and analgesic properties compared to related compounds that previously have been used for pain management. The availability of compounds with strong local long-acting anesthetic properties, such as that of tricyclic antidepressants described herein, are advantageous over the existing compounds for pain management because conventional neurolytic agents typically exert only weak local anesthetic effects which are of short duration and produce irreversible damage to the nerves.
According to one aspect of the invention, a method for inducing local anesthesia in a subject is provided. The method involves administering locally to a subject in need of such a treatment an effective amount of a tricyclic antidepressant in an amount effective to block sensory and motor functions of a nerve(s) at the site of administration of the tricyclic antidepressant. The tricyclic antidepressant is selected from those described in the formulas below.
In one embodiment, the tricyclic antidepressant is amitriptyline or one of its analogues. Analogues of amytripyline include quaternary and tertiary analogues. Examples of quaternary amytripyline analogues include but are not limited to N-phenyl-propyl amitriptyline bromide, N-phenyl-ethyl amitriptyline bromide, or N-phenyl-methyl amitriptyline bromide. Tertiary amitriptyline analogues include but are not limited to N-phenyl-propyl nortriptyline bromide, N-phenyl-ethyl nortriptyline bromide, or N-phenyl-methyl nortriptyline bromide. A preferred quaternary analogue is N-phenyl-ethyl amitriptyline bromide.
The tricyclic antidepressant is administered in a therapeutically effective amount sufficient to induce anesthesia in a subject at the site of administration for at least 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, or 96 hours.
The compounds of the invention are useful when administered locally in treating all categories of pain, whether acute or chronic, local or general. The subject according to the invention can be experiencing or at risk of experiencing any of the forgoing categories of pain. Examples of different kinds of pain are described in the Detailed Description.
The compounds of the invention can be administered to sites well known by those of ordinary skill in the art to be appropriate for interfering with the nerve(s) propagating such pain.
In one embodiment of the invention, the tricyclic antidepressant is administered in the lower back to alleviate pain. In another embodiment, the tricyclic antidepressant is administered to alleviate pain propagated by the sciatic nerve.
The preferred mode of administration is local administration such as by injection, intramuscularly, subcutaneously, dermally, or intradermally by inhalation or by local application topically such as in a lotion or a patch.
In yet another aspect of the invention, a method for inducing local analgesia in a subject is provided. The method involves administering locally to a subject in need of such a treatment an effective amount of a tricyclic antidepressant in an amount effective to block sensory function of a nerve(s) at the site of administration of the tricyclic antidepressant. The tricyclic antidepressant is selected from those described in the formulas below.
In one embodiment, the tricyclic antidepressant is amitriptyline or one of its analogues. Analogues of amytripyline are quaternary and tertiary analogues. Examples of quaternary amytripyline analogues include but are not limited to N-phenyl-propyl amitriptyline bromide, N-phenyl-ethyl amitriptyline bromide, or N-phenyl-methyl amitriptyline bromide. Tertiary amitriptyline analogues include but are not limited to N-phenyl -propyl nortriptyline bromide, N-phenyl-ethyl nortriptyline bromide, or N-phenyl-methyl nortriptyline bromide. A preferred analogue is N-phenyl-ethyl amitriptyline bromide.
The tricyclic antidepressant is administered in a therapeutically effective amount sufficient to induce analgesia in a subject at the site of administration for at least 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours,
Gerner Peter
Wang Ging Kuo
Reamer James H.
The Brigham and Women's Hospital Inc.
Wolf Greenfield & Sacks PC
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