Memorial Sloan Kettering Cancer Center

Epicept Corporation

Yuri Kolesnikov

Gavril W Pasternak

Feng Zhang

Robert O Williams, Iii

John Joseph Koleng, Jr

Many chemical and pharmaceutical compositions are known to produce antinociceptive effects that are helpful in relieving pain and inflammation. Both opioids and local anesthetics serve an important function in providing peripheral pain relief. Topical administration of pain-relieving drugs to the periphery offers important advantages over systemic or local, non-topical administration. The present invention provides topical pharmaceutical compositions, formulated with at least one local anesthetic and at least one opioid analgesic in a topical excipient. The present invention also provides methods for relieving pain in a subject through topical administration of the pharmaceutical composition in an amount and a duration sufficient to synergistically potentiate an antinociceptive response. Synergistic potentiation of analgesia through topical administration of a local anesthetic/opioid pharmaceutical composition provides a new and improved approach to peripheral pain management.

Topical anesthetic/opioid formulations and uses thereof

A topical opioid paradigm was developed to determine analgesic peripheral effects of morphine. Topical morphine as well as peptides such as [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO) produced a potent, dose-dependent analgesia using the radiant heat tailflick assay. The topical drugs potentiated systemic agents, similar to the previously established synergy between peripheral and central sites of action. Local tolerance was rapidly produced by repeated daily topical exposure to morphine. Topical morphine tolerance was effectively blocked by the N-Methyl-D-Aspartate (NMDA) receptors antagonist MK801 and ketamine given either systemically or topically. NMDA receptor antagonists reversed pre-existing morphine tolerance. The activity of topical NMDA antagonists to block local morphine tolerance suggests that peripheral NMDA receptors mediate topical morphine tolerance. Morphine was cross tolerant to [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO), but not to morphine-6&#x3b2;-glucuronide, implying different mechanisms of action. These observations have great importance in the design and use of opioids clinically. Topical pharmaceutical compositions comprising an analgesic that functions through an opiate receptor and an NMDA receptor antagonist for producing analgesia without inducing tolerance are described.

Topical compositions comprising an opioid analgesic and an NMDA antagonist

Compositions useful for long-lasting pain relief from mucosal damage, such as mucosal inflamation, abrasions, ulcerations, lesions, trauma and incisions, without significant systemic absorption. The compositions of the invention are particularly suitable for application to the mucous membrane of the nasal cavity and buccal cavity. To relieve pain, the compositions or the invention are topically applied directly to the affected area.

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Tenafly, NJ, United States of America

Yuri Kolesnikov