Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-26
2003-05-06
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06559158
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to the treatment of certain side effects associated with the use of opioids as analgesics. In particular, the present invention is directed to treating opioid-induced inhibition of gastrointestinal motility and constipation in patients chronically administered opioids.
Opioids are effective analgesics. However, their use is associated with a number of undesirable side effects, particularly when use is prolonged or chronic. Such side effects include pruritus, dysphoria, urinary retention, and inhibition of gastrointestinal motility. Opioids are widely used long-term to treat pain in advanced cancer patients, or patients in methadone maintenance treatment programs, for example. Opioid-induced changes in gastrointestinal motility are almost universal when these drugs are used long term, and there is no evidence of gastrointestinal compensation mechanisms. Constipation is the most common chronic side effect of opioid pain medications in patients with metastatic malignancy, and can be severe enough to limit opioid use or dose. Common treatments of bulking agents and laxatives have limited efficacy and may be associated with adverse side effects such as electrolyte imbalances. The significant negative impact on the quality of life of these patients has received insufficient attention in the past from the medical community in general, and from the oncology community in particular.
One treatment that has been used for opioid side effects is the use of opioid antagonists which cross the blood-brain-barrier, or which are administered directly into the central nervous system. Opioid antagonists such as naltrexone and naloxone have been administered intramuscularly or orally to treat opioid induced side effects. Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain barrier. Therefore, although naltrexone, naloxone, nalmefene, and other opioid antagonists may reverse many opioid side effects, because they diffuse into the central nervous system they have a narrow therapeutic window before they are observed to reverse the desired analgesic effect of the opioid being used. Additionally, in methadone maintenance patients, these tertiary compounds may also induce opioid withdrawal symptoms.
Many quaternary amine opioid antagonist derivatives do not reduce the analgesic effect of opioids. These quaternary amine opioid antagonist derivatives, which have a relatively higher polarity and reduced lipid solubility when compared to the tertiary forms of the drugs, were specifically developed to not traverse the blood-brain barrier or to traverse it at a greatly reduced rate. Methylnaltrexone (MNTX) is a quaternary ammonium opioid receptor antagonist that does not cross the blood-brain barrier in humans (see, e.g., U.S. Pat. No. 4,176,186, herein incorporated by reference). It offers the therapeutic potential to reverse undesired side effects of opioid pain medications mediated by peripherally located receptors (e.g., in the gastrointestinal tract) while sparing opioid effects mediated by receptors in the central nervous system, most importantly, analgesia.
However, high levels of MNTX in the plasma can lead to undesirable side effects such as orthostatic hypotension. Furthermore, high doses of opioid derivatives such as the tertiary and quaternary derivatives discussed above can be expensive.
It is therefore clear that there is a need to enhance palliative care in terminal cancer patients and others. It is also clear that a method for the prevention of opioid-induced and inhibition of gut motility constipation which does not counteract the analgesic effects of the opioid, or risk increased levels of pain is needed. Ideally, such a treatment has few side effects and is economical because administration of small amounts is effective.
SUMMARY OF THE INVENTION
The methods of the invention address the particular needs of patients undergoing long-term or chronic opioid administration. The quaternary derivatives used in this group of patients relieve the side effects and intestinal immobility caused by opioid use at surprisingly low doses, enhancing the patient's quality of life, maintaining analgesic efficacy, reducing health risks associated with opioid side effects, and reducing possible quaternary derivative side effects and costs.
“Long-term” opioid use or administration is intended to mean periods over about one week, and “chronic” use would generally mean a longer period.
The methods comprise administering a quaternary derivative of noroxymorphone intravenously in an amount such that peak plasma concentrations of the quaternary derivative do not exceed 2000 ng/ml and are preferably much less. The invention also includes methods wherein the derivative is administered orally, and wherein the peak plasma concentrations do not exceed 500 ng/ml, more preferably 250 ng/ml, and most preferably 100 ng/ml. The invention also includes a method for treating constipation in chronic opioid maintenance patients, the method comprising orally administering a non-enterically coated quaternary derivative of noroxymorphone in an amount less than 40 mg/kg. Preferably, the derivative is administered in an amount such that peak plasma concentrations of the quaternary derivative do not exceed 2000 ng/ml. The invention also includes a method for treating constipation in chronic opioid maintenance patients, the method comprising administering a quaternary derivative of noroxymorphone non-orally at a dose of less than 0.3 mg/kg, preferably less than 0.2 mg/kg, and most preferably the dose is less than 0.1 mg/kg. Also included in the invention is a method of preventing or treating opioid-induced side effects, the method comprising administering the opioid concurrently with an enterically coated quaternary derivative of noroxymorphone, the quaternary derivative being administered orally. The invention also includes a method as above, wherein the opioid and the quaternary derivative of noroxymorphone are combined in an oral dose. Dosing may be done daily, every other day, or as needed to provide relief from occasional or persistent constipation.
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Drell William
Foss Joseph F.
Moss Jonathan
Roizen Michael F.
Yuan Chun-Su
Spivack Phyllis G.
UR Labs, Inc.
Wolf Greenfield & Sacks P.C.
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