Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof

Abstract

The invention refers to a combination comprising a sigma ligand of formula (I) and an opioid or opiate for use in the prevention and/or treatment of pain developed as a consequence of surgery, especially peripheral neuropathic pain, allodynia, causalgia, hyperalgesia, hyperesthesia, hyperpathia, neuralgia, neuritis or neuropathy. The invention also refers to the sigma ligands of formula (1) for use in potentiating the analgesic effect of an opioid or opiate and/or for decreasing the dependency induced thereby when said opioid or opiate is used in the prevention and/or treatment of pain developed as a consequence of surgery.

1 - 15 . (canceled) 
     
     
         1 . A method of treatment of a patient suffering from pain developed as a consequence of surgery, or a patient likely to suffer pain as a result of a surgical treatment, which comprises administering to the patient an amount of a pharmaceutical combination, the pharmaceutical combination comprising:
 i) an opioid or opiate selected from the group consisting of morphine or a structural derivative thereof, tramadol, sufentanil, remifentanil, fentanyl, tapentadol, oxycodone, and buprenorphine; and   ii) a sigma ligand, wherein the sigma ligand is 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine or a pharmaceutically acceptable salt, isomer or solvate thereof, which amounts in combination are effective to treat the pain of the patient.   
     
     
         2 . The method of  claim 1 , comprising administering a therapeutically effective amount of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride. 
     
     
         3 . The method of  claim 1 , wherein the opiate is selected from the group consisting of morphine, hydromorphone, oxymorphone, desomorphine, diacetylmorphine, nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine, codeine, tramadol, sufentanil, remifentanil, fentanyl, tapentadol, oxycodone, and buprenorphine. 
     
     
         4 . The method of  claim 4 , wherein the opioid or opiate and the sigma ligand are part of the same medicament formulation. 
     
     
         5 . The method of  claim 1 , comprising administering the opioid or opiate and the sigma ligand simultaneously. 
     
     
         6 . The method of  claim 1 , wherein the combination comprises a first unit and a second unit, the first unit comprising the opioid or opiate and the second unit comprising the sigma ligand. 
     
     
         7 . The method of  claim 6 , comprising administering the opioid or opiate and the sigma ligand simultaneously. 
     
     
         8 . The method of  claim 6 , comprising administering the opioid or opiate and the sigma ligand separately or sequentially. 
     
     
         9 . The method of  claim 8 , comprising administering the opioid or opiate, followed by administering the sigma ligand. 
     
     
         10 . The method of  claim 9 , comprising administering the sigma ligand, followed by administering the opioid or opiate. 
     
     
         11 . The method of  claim 1 , comprising administering the combination prior to the surgery or the surgical treatment. 
     
     
         12 . The method of  claim 11 , comprising administering the combination from about 30 minutes to about 24 hours prior to the surgery or the surgical treatment. 
     
     
         13 . The method of  claim 1 , comprising administering the combination subsequent to the surgery or the surgical treatment. 
     
     
         14 . The method of  claim 13 , comprising administering the combination from about 1 hour to about 36 hours subsequent to the surgery or the surgical treatment. 
     
     
         15 . The method of  claim 14 , comprising administering the combination from about 3 to about 4 hours subsequent to the surgery or the surgical treatment. 
     
     
         16 . A method for potentiating the analgesic effect of an opioid or opiate in a patient while also decreasing the dependency of the patient induced thereby when said opioid or opiate is administered in the prevention or treatment of pain that is a consequence of surgery, wherein said opioid or opiate is selected from the group consisting of morphine or a structural derivative thereof, tramadol, sufentanil, remifentanil, fentanyl, tapentadol, oxycodone, and buprenorphine, which comprises administering to the patient a therapeutically effective amount of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine or a pharmaceutically acceptable salt, isomer or solvate thereof. 
     
     
         17 . The method of  claim 1  comprising administering a therapeutically effective amount of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride. 
     
     
         18 . The method of  claim 1 , wherein the opiate is selected from the group consisting of morphine, hydromorphone, oxymorphone, desomorphine, diacetylmorphine, nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine, codeine, tramadol, sufentanil, remifentanil, fentanyl, tapentadol, oxycodone, and buprenorphine.