Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists

Abstract

This invention relates to a method of selectively enhancing the analgesic potency of morphine and other clinically used bimodally-acting opioid agonists and simultaneously attenuating development of physical dependence, tolerance and other undesirable side effects caused by the chronic administration of said bimodally-acting opioid agonists comprising the co-administration of a bimodally-acting opioid agonist which activates both inhibitory and excitatory opioid receptor-mediated functions of neurons in the nociceptive (pain) pathways of the nervous system and an opioid receptor antagonist which selectively inactivates excitatory opioid receptor-mediated side effects. This invention also relates to a method of using excitatory opioid receptor antagonists alone to block the undesirable excitatory side effects of endogenous bimodally-acting opioid agonists which may be markedly elevated during chronic pain. This invention further relates to a method of long-term treatment of previously detoxified opiate, cocaine and alcohol addicts utilizing said excitatory opioid receptor antagonists, either alone or in combination with low-dose methadone, to prevent protracted physical dependence, and to compositions comprising an excitatory opioid receptor antagonist of the invention and a bimodally-acting opioid agonist.

Description

FIELD OF THE INVENTIONThis invention relates to a method of enhancing the analgesic (inhibitory) effects of bimodally-acting opioid agonists, including morphine, codeine and other clinically used opioid analgesics, while at the same time attenuating anti-analgesic effects, physical dependence, tolerance, hyperexcitability, hyperalgesia, and other undesirable (excitatory) side effects typically caused by chronic use of bimodally-acting (excitatory and inhibitory) opioid agonists. As used herein, the term "opioid" refers to compounds which bind to specific opioid receptors and have agonist (activation) or antagonist (inactivation) effects at these receptors, such as opioid alkaloids, including the agonist morphine and the antagonist naloxone, and opioid peptides, including enkephalins, dynorphins and endorphins. As used herein, the term "opiate" refers to drugs derived from opium or related analogs.In the instant invention, a very low dose of a selective excitatory opioid receptor ant...

AI Technical Summary

Benefits of technology

This invention is directed to a method of selectively enhancing the analgesic potency of morphine and other conventional bimodally-acting opioid agonists and simultaneously attenuating undesirable side effects, including physical dependence, caused by the chronic administration of said opioid agonists. Morphine and other bimodally-acting (inhibitory / excitatory) opioid agonists bind to and activate both inhibitory and excitatory opioid receptors on nociceptive neurons which mediate pain. Activation of inhibitory receptors by said agonists causes analgesia. Activation of excitatory receptors by said agonists results in anti-analgesic effects, hyperexcitability, hyperalgesia, as well as development of physical dependence and tolerance and other undesirable side effects. A series of antagonists which bind to excitatory opioid receptors (e.g., diprenorphine, naltrexone and naloxone) selectively block excitatory opioid receptor functions of nociceptive types of DRG neurons at 1,000 to 10,000-fold lower concentrations than are required to block inhibitory opioid receptor functions in these neurons. The co-administration of a bimodally-acting opioid agonist together with an ultra-low dose of an opioid antagonist which binds to and inactivates excitatory, but not inhibitory, opioid receptors results in the blocking of excitatory anti-analgesic side effects of said opioid agonists on these neurons, thereby resulting in enhanced analgesic potency. This enhanced analgesic potency permits the use of lower doses of morphine or other conventional opioid analgesics.

The preferred excitatory opioid receptor antagonists of the invention include naltrexone and naloxone, in addition to etorphine, dihydroetorphine, and diprenorphine which are disclosed in parent U.S. patent application Ser. No. 08 / 097,460 and similarly acting opioid alkaloids and opioid peptides. Prior hereto, clinical uses of naloxone and naltrexone have been formulated to be administered at much higher doses (e.g. 50 mg), which block inhibitory opioid receptor functions mediating analgesia in addition to blocking excitatory opioid receptors. These high doses of antagonist are required as an antidote for acute opiate agonist overdose (e.g., respiratory depression). However, in the instant invention, long-term oral administration of ultra-low doses of naltrexone (for example about 1 .mu.g) alone or in combination with low doses of methadone (e.g. mg) prevents protracted physical dependence which underlies resumption of drug abuse in previously detoxified opiate, cocaine and alcohol addicts. This is in contrast to clinical use of naltrexone prior hereto, wherein large (50 mg) tablets (Trexan) are administered, which produce dysphoria and other aversive side effects, and long-term treatment with high doses of methadone which results in physical dependence on methadone.

Further, in chronic pain patients, the excitatory opioid receptor antagonists of the invention are administered alone in ultra-low doses to enhance the analgesic potency and decrease the dependence liability of endogenous (as opposed to exogenous) opioid peptides, including enkephalins, dynorphins and endorphins, so as to facilitate physiologic mechanisms which normally regulate opioid responsivity and nociceptive systems.

Problems solved by technology

Activation of excitatory receptors by said agonists results in anti-analgesic effects, hyperexcitability, hyperalgesia, as well as development of physical dependence and tolerance and other undesirable side effects.

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