Patent Description:
Endogenous opioids are found throughout the body and are involved in a variety of homeostatic functions and movement control. Receptors that are regulated by endogenous opioids include delta (δ) receptors, kappa (κ) receptors and mu (µ) receptors, all of which are located in the brain and the peripheral nervous system and play a role in analgesia. Of these receptors, the mu (µ) receptors are located in the human gastrointestinal tract on myenteric and submucosal neurons and on immune cells of the lamina propria and play a role in gastrointestinal function.

Exogenous opioids, such as morphine, oxycodone, hydrocodone, buprenorphine and fentanyl, are commonly prescribed to treat both acute and chronic pain, as their action on the opioid receptors can provide effective analgesia. However, with respect to the mu (µ) receptors, the stimulating effect exogenous opioids have on these receptors may also cause an adverse pharmacodynamic response including bowel dysfunction that can be manifested by, e.g., decreased gastric motility, delayed gastric emptying, constipation, bloating and cramping. Other adverse pharmacodynamic responses associated with opioid therapy include nausea, vomiting, somnolence, dizziness, respiratory depression, headache, dry mouth, sedation, sweats, asthenia, hypotension, dysphoria, delirium, miosis, pruritis, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance.

Opioid-induced adverse pharmacodynamic responses in patients receiving opioid therapy for pain management can be particularly troublesome, as these patients are already trying to manage severe pain, and the added discomfort of adverse side effects can add to their distress. In some cases, the side effects may be so extreme that the patient would rather discontinue use of the opioid than continue to suffer with such side effects.

In the case of opioid-induced bowel dysfunction, current treatments include administration of laxatives, opioid antagonists and prokinetic agents. However, all of these treatments are not without risk. Laxatives, such as bisacodyl and psyllium, have a long history of safety and efficacy issues, and can themselves produce severe side effects such as dehydration and bowel obstruction Opioid antagonists, such as naloxone and naltrexone, while acting to suppress the receptors causing the bowel dysfunction, can reverse the desired analgesic effect of the opioid. Prokinetic agents, such as metoclopramide, may improve gastrointestinal motility but are associated with extrapyramidal effects, such as acute dystonic reactions, pseudoparkinsonism or akathisia.

<CIT> relates to a transdermal therapeutic system (TTS) comprising two or more opioid active ingredients, a cover layer, optionally a removable protective layer and a layer containing the active ingredient(s), a reservoir containing the active ingredient(s), or several layers containing the active ingredient(s), or several reservoirs containing the active ingredient(s), the layer(s) or reservoir(s) containing the active ingredient(s) being situated between the cover layer and the optionally removable protective layer.

There remains a need in the art for a composition and method to prevent or treat an opioid-induced adverse pharmacodynamic response that minimizes the issues of the current treatment protocols.

It is an object of certain embodiments of the invention to provide methods of treating or preventing an opioid-induced adverse pharmacodynamic response.

It is an object of certain embodiments of the invention to provide methods of treating or preventing an opioid-induced adverse pharmacodynamic response in a patient on chronic opioid therapy.

It is an object of certain embodiments of the invention to provide methods of treating or preventing an opioid-induced adverse pharmacodynamic response in an opioid naive patient.

It is an object of certain embodiments of the invention to provide methods of treating or preventing an opioid-induced adverse pharmacodynamic response resulting from administration of an opioid having an Emax of greater than about <NUM>%.

It is an object of certain embodiments of the invention to provide methods of treating or preventing an opioid-induced adverse pharmacodynamic response comprising administering buprenorphine to a patient in need thereof.

It is an object of certain embodiments of the invention to provide pharmaceutical compositions for treating or preventing an opioid-induced adverse pharmacodynamic response.

It is an object of certain embodiments of the invention to provide pharmaceutical compositions for treating or preventing an opioid-induced adverse pharmacodynamic response in a patient on chronic opioid therapy.

It is an object of certain embodiments of the invention to provide pharmaceutical compositions for treating or preventing an opioid-induced adverse pharmacodynamic response in an opioid naive patient.

It is an object of certain embodiments of the invention to provide pharmaceutical compositions for treating or preventing an opioid-induced adverse pharmacodynamic response resulting from administration of an opioid having an Emax of greater than about <NUM> %.

It is an object of certain embodiments of the invention to provide pharmaceutical compositions comprising buprenorphine for treating or preventing an opioid-induced adverse pharmacodynamic response in a patient in need thereof.

It is an object of certain embodiments of the invention to provide methods of preparing the pharmaceutical compositions disclosed herein for treating or preventing an opioid-induced adverse pharmacodynamic response in a patient in need thereof.

It is an object of certain embodiments of the invention to provide kits for preventing for treating or preventing an opioid-induced adverse pharmacodynamic response in a patient in need thereof.

The objects are to be understood also to relate to use limited products and uses in a method of treatment as stated herein.

The above objects of the present invention and others can be achieved by the present invention, which is directed to a method of treating or preventing an adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof comprising administering to a patient in need thereof, an effective amount of buprenorphine to treat or prevent an adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof, wherein the fentanyl or a pharmaceutically acceptable salt thereof is administered in an effective amount to provide an analgesic effect, and wherein the buprenorphine is administered transdermally in an amount of about <NUM> mcg/hr to about <NUM> mcg/hr, and concurrently with transdermally administered fentanyl in an amount of about <NUM> mcg/hr to about <NUM> mcg/hr. The disclosure relating to a method of treatment throughout the entire disclosure of the invention is to be understood to also related to uses and product limited uses in a method of treatment as stated herein.

In certain embodiments, the present invention is directed to a method of treating or preventing an adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof comprising administering to a patient on chronic administration of an opioid having an Emax of greater than about <NUM>%, an effective amount of buprenorphine to treat or prevent the adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention is directed to a method of treating or preventing an adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof comprising administering to an opioid naive patient an opioid having an Emax of greater than about <NUM>%, and an effective amount of buprenorphine to treat the adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention is directed to a method of treating or preventing an adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof comprising concurrently administering to a patient in need thereof (i) an effective amount of buprenorphine to treat or prevent an adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof and (ii) fentanyl or a pharmaceutically acceptable salt thereof.

In describing the present invention, the following terms are to be used as indicated below. As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "an opioid" includes a single opioid as well as a mixture of two or more different opioids.

As used herein, the term "therapeutically effective" refers to the amount of drug or the rate of drug administration needed to produce a desired therapeutic result.

As used herein, the term "prophylactically effective" refers to the amount of drug or the rate of drug administration needed to produce a desired preventive result.

The term "patient" means a subject, particularly a human, who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated. The term "subject" is inclusive of the definition of the term "patient" and does not exclude individuals who are entirely normal in all respects or with respect to a particular condition.

As used here, the term "patient in need thereof' refers to a patient experiencing an opioid-induced adverse pharmacodynamic response such as, but not limited to, bowel dysfunction, nausea, vomiting, somnolence, dizziness, respiratory depression, headache, dry mouth, sedation, sweats, asthenia, hypotension, dysphoria, delirium, miosis, pruritis, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence or tolerance.

"Pharmaceutically acceptable salts" include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, discyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.

The term "buprenorphine" means buprenorphine free base, and all pharmaceutically acceptable salts, complexes, crystalline forms, co-crystals, hydrates, solvates, and mixtures thereof. In certain embodiments, the buprenorphine utilized in the present invention is buprenorphine base or a pharmaceutically acceptable salt thereof.

The term "Cmax" denotes the maximum plasma concentration obtained during a dosing interval.

The term "bioavailability" is defined for purposes of the present invention as the relevant extent to which the drug (e.g., oxycodone) is absorbed from the unit dosage forms. Bioavailability is also referred to as AUC (i.e., area under the plasma concentration/time curve).

The term "opioid-induced bowel dysfunction" means a symptom associated with the digestive system, including the gastrointestinal tract caused or exacerbated by an opioid. The symptoms include but are not limited to constipation, decreased gastric emptying, abdominal cramping, spasm, bloating, delayed gastro-intestinal transit and the formation of hard dry stools.

The term "opioid analgesic" means any material that produces an analgesic effect through modulation of an opioid receptor, whether or not approved by a government agency for that purpose. The term includes all pharmaceutically active forms of the opioid analgesic, including the free base form of the agent, and all pharmaceutically acceptable salts, complexes, crystalline forms, co-crystals, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active.

The term "opioid-induced adverse pharmacodynamic response" means an unintended side effect experienced by a patient receiving opioid therapy for an intended therapeutic effect. Typically, the intended affect is analgesia. The intended effect can also be the treatment of diarrhea, cough, anxiety (e.g., due to shortness of breath) and opioid dependence. Unintended side effects associated with opioid therapy include bowel dysfunction, nausea, vomiting, somnolence, dizziness, respiratory depression, headache, dry mouth, sedation, sweats, asthenia, hypotension, dysphoria, delirium, miosis, pruritis, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance.

The term "peripherally restricted opioid-induced adverse pharmacodynamic response" means a non-central nervous system-mediated unintended side effect (e.g., bowel dysfunction) experienced by a patient receiving peripheral opioid therapy for an intended therapeutic effect (e.g., analgesia).

The term "peripherally restricted opioid analgesic" means any material that produces an analgesic effect through modulation of a peripheral opioid receptor (whether or not approved by a government agency for that purpose) and does not cross or significantly cross the blood brain barrier. The term includes all pharmaceutically active forms of the peripherally restricted opioid analgesic, including the free base form of the agent, and all pharmaceutically acceptable salts, complexes, crystalline forms, co-crystals, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active.

The term "concurrently" means that a dose of one agent is administered prior to the end of the dosing interval of another agent. For example, a dose of an opioid analgesic with a <NUM>-hour dosing interval would be concurrently administered with a buprenorphine dose administered within <NUM> hours of the opioid administration.

The term "Emax" means the maximal µ GTP effect elicited by a compound relative (expressed as a %) to the effect elicited by [D-Ala<NUM>, N-methyl-Phe<NUM>, Gly-ol<NUM>]-enkephalin (a/k/a DAMGO), which is a µ agonist standard. Generally, the Emax value measures the efficacy of a compound to treat or prevent pain or diarrhea.

The term "opioid naive" refers to patients who are not receiving opioid analgesics on a daily basis.

The term "opioid tolerant" means patients who are chronically receiving opioid analgesics on a daily basis.

The term "first administration" means a single dose at the initiation of therapy to an individual subject, patient, or healthy subject or a subject population, patient population, or healthy subject population.

The term "steady state" means that the amount of the drug reaching the system is approximately the same as the amount of the drug leaving the system. Thus, at "steady-state", the patient's body eliminates the drug at approximately the same rate that the drug becomes available to the patient's system through absorption into the blood stream.

Buprenorphine is commonly used for its analgesic properties and is formulated, e.g., in a transdermal patch (Butrans® buprenorphine transdermal system) to provide <NUM> mcg/hour, <NUM> mcg/hour or <NUM> mcg/hour of buprenorphine. Butrans® is indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. The prescribing information states that the most common adverse events (≥ <NUM>%) reported by patients in clinical trials include constipation. By virtue of the present invention, buprenorphine can be administered to patients at a dose that will treat or prevent opioid-induced bowel dysfunction (e.g., opioid-induced constipation) or other adverse pharmacodynamic responses induced by fentanyl or a pharmaceutically acceptable salt thereof.

The adverse pharmacodynamic response is induced by administration to the patient of an opioid that is exogenous to the patient (fentanyl, or a pharmaceutically acceptable salt thereof).

In certain embodiments, the buprenorphine is administered concurrently with fentanyl or a pharmaceutically acceptable salt thereof, and the buprenorphine serves to prevent, minimize, inhibit, ameliorate or reverse the opioid-induced adverse pharmacodynamic response that might otherwise be associated with or caused by fentanyl or a pharmaceutically acceptable salt thereof. Fentanyl or a pharmaceutically acceptable salt thereof is administered in an effective amount to provide an analgesic effect. In other embodiments, the fentanyl or a pharmaceutically acceptable salt thereof is administered in an effective amount to treat diarrhea, cough, anxiety (e.g., due to shortness of breath) or opioid dependence.

A patient receiving the buprenorphine therapy of the present invention may be opioid naive. Opioid naive patients may have initiated therapy with the fentanyl or a pharmaceutically acceptable salt thereof prior to initiation of the buprenorphine therapy, or they may have initiated therapy with the fentanyl or a pharmaceutically acceptable salt thereof concurrently with the initiation of the buprenorphine therapy. In other embodiments, the buprenorphine therapy can be initiated prior to the initiation of therapy with the fentanyl or a pharmaceutically acceptable salt thereof so as to provide a prophylactic effect.

Alternatively, a patient receiving the buprenorphine therapy of the present invention may previously have been dosed chronically with another opioid so that he or she is now opioid tolerant.

The buprenorphine therapy of the present invention can be administered after the patient begins to exhibit symptoms of an opioid-induced adverse pharmacodynamic response. Alternatively, the buprenorphine therapy of the present invention can be administered prior to or at the same time as a patient begins treatment with the fentanyl or a pharmaceutically acceptable salt thereof in order to reduce or avoid symptoms that might otherwise occur due to administration of the fentanyl or a pharmaceutically acceptable salt thereof alone.

In certain embodiments, the fentanyl or a pharmaceutically acceptable salt thereof is administered before, concurrently with, or after the buprenorphine therapy of the present invention and has an Emax of greater than about <NUM>%, greater than about <NUM>%, greater than about <NUM>%, greater than about <NUM>%, greater than about <NUM>%, greater than about <NUM>%, or greater than about <NUM>%.

The buprenorphine administered in the present invention can be selected from buprenorphine base, pharmaceutically acceptable salts, solvates, polymorphs, and mixtures thereof.

The buprenorphine used according to the present invention is administered by the same route as the fentanyl or a pharmaceutically acceptable salt thereof. The buprenorphine and the fentanyl or a pharmaceutically acceptable salt thereof are administered by the transdermal route.

In one embodiment, the buprenorphine is administered in a transdermal system to provide, e.g., a dosing interval of about <NUM> hours, a dosing interval of about <NUM> days, or a dosing interval of about <NUM> days. Butrans® is transdermal patch available with an administration rate of 5mcg/hour, <NUM> mcg/hour and <NUM> mcg/ hour for the dosing interval of <NUM> days. With patch size adjustment administration rates below <NUM> mcg/hour can be achieved.

The transdermal buprenorphine system can be formulated to administer buprenorphine, e.g., at a rate from about. <NUM> mcg/hour to about <NUM> mcg/hour, from about. <NUM> mcg/hour to about <NUM> mcg/hour, from about. <NUM> mcg/hour to about <NUM> mcg/hour, from about <NUM> mcg/hour to about <NUM> mcg/hour or from about <NUM> mcg/hour to about <NUM> mcg/hour.

The buprenorphine of the present invention can be administered transdermally to provide at steady state, e.g., from about. <NUM>/kg to about <NUM>/kg, from about. <NUM>/kg to about <NUM>/kg or from about. <NUM>/kg to about <NUM>/kg. In other embodiments, the buprenorphine of the present invention can be administered transdermally to provide at steady state, e.g., about <NUM>/kg, about <NUM>/kg, about <NUM>/kg, about. <NUM>/kg, about. <NUM>/kg or about. The buprenorphine can be administered for any suitable time, e.g., for the full duration of therapy with the fentanyl or a pharmaceutically acceptable salt thereof or for a fraction of the full duration of therapy with the fentanyl or a pharmaceutically acceptable salt thereof.

The buprenorphine of the present invention can be administered transdermally to provide after first administration or at steady state, a Cmax, e.g., from about. <NUM> ng/ml to about <NUM> ng/ml, from about. <NUM> ng/ml to about <NUM> ng/ml, from about. <NUM> ng/ml to about <NUM> ng/ml, from about. <NUM> ng/ml to about <NUM> ng/ml, from about. <NUM> ng/ml to about <NUM> ng/ml from about <NUM> ng/ml to about <NUM> ng/ml, from about <NUM> ng/ml to about <NUM> ng/ml, or from about <NUM> ng/ml to about <NUM> ng/ml.

In other embodiments, the buprenorphine of the present invention can be administered transdermally to provide after first administration or at steady state, a Cmax, e.g., of about. <NUM> ng/ml, about. <NUM> ng/ml, about <NUM> ng/ml, about <NUM> ng/ml, about <NUM> ng/ml, about <NUM> ng/ml, about <NUM> ng/ml, or about <NUM> ng/ml.

In other embodiments, the buprenorphine of the present invention can be administered transdermally to provide after first administration or at steady state, a Cmax, e.g., of less than about <NUM> ng/ml, less than about <NUM> ng/ml, less than about <NUM> ng/ml, less than about <NUM> ng/ml, less than about <NUM> ng/ml, less than about <NUM> ng/ml, less than about. <NUM> ng/ml, less than about. <NUM> ng/ml or less than about. <NUM> ng/ml.

In other embodiments, the buprenorphine of the present invention can be administered transdermally to provide after first administration or at steady state, an AUC, e.g., from about <NUM> ng/ml*hr to about <NUM> ng/ml*hr, from about <NUM> ng/ml*hr to about <NUM> ng/ml*hr, from about <NUM> ng/ml*hr to about <NUM> ng/ml*hr, from about <NUM> ng/ml*hr to about <NUM> ng/ml*hr, or from about <NUM> ng/ml*hr to about <NUM> ng/ml*hr.

The fentanyl can be disposed in a transdermal system that delivers the fentanyl in an amount, e.g., of about <NUM> mcg/hr; about <NUM> mcg/hr; about <NUM> mcg/hr; about <NUM> mcg/hr or about <NUM> mcg/hr. Fentanyl utilized in the present invention can be Duragesic® (fentanyl film, extended release).

In certain embodiments, the ratio of the daily dose of buprenorphine to the fentanyl or a pharmaceutically acceptable salt thereof is, e.g., less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), less than about <NUM>:<NUM> (w/w), or less than about <NUM>:<NUM> (w/w).

In certain embodiments, the buprenorphine is administered transdermally in an amount of about <NUM> mcg/hr or less concurrently with oral controlled release oxycodone hydrochloride in a unit dose of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. Preferably, the buprenorphine dosing interval is about <NUM> days or about <NUM> days and the oxycodone dosing interval is about <NUM> hours.

In certain embodiments, the buprenorphine is administered transdermally in an amount of about <NUM> mcg/hr or less concurrently with oral controlled release oxymorphone hydrochloride in a unit dose of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. Preferably, the buprenorphine dosing interval is about <NUM> days or about <NUM> days, and the oxymorphone dosing interval is about <NUM> hours.

In certain embodiments, the buprenorphine is administered transdermally in an amount of about <NUM> mcg/hr or less concurrently with oral controlled release hydrocodone bitartrate in a unit dose of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. Preferably, the buprenorphine dosing interval is about <NUM> days or about <NUM> days, and the hydrocodone dosing interval is about <NUM> hours or about <NUM> hours.

In certain embodiments, the buprenorphine is administered transdermally in an amount of about <NUM> mcg/hr or less concurrently with oral controlled release morphine sulfate in a unit dose of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. Preferably, the buprenorphine dosing interval is about <NUM> days or about <NUM> days, and the morphine dosing interval is about <NUM> hours or about <NUM> hours.

In certain embodiments, the buprenorphine is administered transdermally in an amount of about <NUM> mcg/hr or less concurrently with oral controlled release hydromorphone hydrochloride in a unit dose of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>. Preferably, the buprenorphine dosing interval is about <NUM> days or about <NUM> days, and the hydromorphone dosing interval is about <NUM> hours.

In certain embodiments, the buprenorphine is administered transdermally in an amount of about <NUM> mcg/hr or less concurrently with transdermally administered fentanyl in an amount of about <NUM> mcg/hr; about <NUM> mcg/hr; about <NUM> mcg/hr; about <NUM> mcg/hr or about <NUM> mcg/hr. Preferably, the buprenorphine dosing interval is about <NUM> or <NUM> days and the fentanyl dosing interval is about <NUM> or <NUM> days.

The buprenorphine can be contained in an amount that (i) does not cause a decrease in the analgesic effectiveness of the fentanyl or a pharmaceutically acceptable salt thereof, or (ii) does not cause a substantial decrease in the analgesic effectiveness of the fentanyl or a pharmaceutically acceptable salt thereof, or (iii) provides an increase in analgesia as compared to the administration of the fentanyl or a pharmaceutically acceptable salt thereof alone.

The concentration of buprenorphine that affects the analgesic efficacy of the concurrently administered other opioid as compared to the concentration of buprenorphine that prevents or treats opioid induced adverse pharmacodynamic response (e.g., bowel dysfunction) depends on the identity of the other opioid that is concurrently being administered. Preferably, the window of separation is sufficient such that the buprenorphine effectively prevents or treats the opioid induced adverse pharmacodynamic response without affecting the analgesic potency of the opioid. Oxycodone is a specific opioid with a sufficient window that enables the prevention or treatment of the opioid-induced adverse pharmacodynamic response with buprenorphine with a reduced likelihood of the oxycodone having its analgesic effect compromised.

In preferred embodiments, the minimal concentration of buprenorphine that affects the analgesic efficacy of the concurrently administered fentanyl or a pharmaceutically acceptable salt thereof is about <NUM> times the concentration of buprenorphine that prevents or treats opioid induced adverse pharmacodynamic response. In other embodiments, the minimal concentration of buprenorphine that affects the analgesic effectiveness of the concurrently administered fentanyl or a pharmaceutically acceptable salt thereofis about <NUM> times, about <NUM> times, about <NUM> times, about <NUM> times, about <NUM> times, about <NUM> times, about <NUM> times, about <NUM> times <NUM> times, about <NUM> times, or about <NUM> times the minimal concentration of buprenorphine that prevents or treats the opioid induced adverse pharmacodynamic response.

The buprenorphine for use in a method of the invention and/or the fentanyl or a pharmaceutically acceptable salt thereof can be administered as a component of a pharmaceutical composition that comprises a pharmaceutically acceptable carrier or excipient. The buprenorphine and/or the fentanyl or a pharmaceutically acceptable salt thereof can be formulated as separate formulations intended for the same route of administration, or in the same formulation to be administered together by the same route of administration, i.e. transdermal.

Pharmaceutical compositions preferably comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the patient. Such a pharmaceutical excipient can be a diluent, suspending agent, solubilizer, binder, disintegrant, buffer, glidant, preservative, coloring agent, lubricant, and the like. The pharmaceutical excipient can be a liquid, such as water or an oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. The pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to a patient. Water is a particularly useful excipient when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

In certain embodiments, both the buprenorphine for use in a method of the invention and the fentanyl or a pharmaceutically acceptable salt thereof can be included in the same dosage form. For example, the buprenorphine and the fentanyl can both be included in a transdermal dosage form such that each agent is administered according to the desired rate. In certain embodiments, the two agents can be segregated from each other in a dual reservoir system.

In certain embodiments, wherein the buprenorphine is administered in a transdermal device, the formulation can, e.g., be a transdermal patch, a transdermal plaster, a transdermal disc or an iontophoretic transdermal device.

Transdermal dosage forms used in accordance with the method of the invention can include a backing layer made of a pharmaceutically acceptable material which is impermeable to the buprenorphine. The backing layer can serve as a protective cover for the buprenorphine and may also provide a support function. Examples of materials suitable for making the backing layer are films of high and low density polyethylene, polypropylene, polyvinylchloride, polyurethane, polyesters such as poly(ethylene phthalate), metal foils, metal foil laminates of suitable polymer films, textile fabrics, and the like. The backing layer can be any appropriate thickness which will provide the desired protective and support functions. A suitable thickness can be, e.g., from about <NUM> microns to about <NUM> microns.

In certain embodiments, the transdermal dosage forms used in accordance with the method of the invention contain a biologically acceptable polymer matrix layer. Generally, the polymers used to form the polymer matrix layer are capable of allowing the buprenorphine to pass through at a controlled rate. A non-limiting list of exemplary materials for inclusion in the polymer matrix includes polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylenevinyl acetate copolymers, silicones, natural or synthetic rubber, polyacrylic esters and copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, polymethacrylates, polyvinylidene chloride, poly(ethylene terephthalate), ethylenevinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones, silicone copolymers such as polysiloxane-polymethacrylate copolymers, cellulose polymers (e.g., ethyl cellulose, and cellulose esters), polycarbonates, polytetrafluoroethylene and mixtures thereof.

The polymer matrix layer may optionally include a pharmaceutically acceptable cross-linking agent such as, e.g., tetrapropoxy silane.

In certain embodiments, the transdermal delivery systems used in accordance with the methods of the present invention include an adhesive layer to affix the dosage form to the skin of the patient for a desired period of administration, e.g., about <NUM> day, about <NUM> days, about <NUM> days, about <NUM> days, about <NUM> days, about <NUM> days, or about <NUM> days. If the adhesive layer of the dosage form fails to provide adhesion for the desired period of time, it is possible to maintain contact between the dosage form with the skin, e.g., by affixing the dosage form to the skin of the patient with an adhesive tape.

The adhesive layer may include an adhesive such as polyacrylic adhesive polymers, acrylate copolymers (e.g., polyacrylate) and polyisobutylene adhesive polymers.

The transdermal dosage forms which can be used in accordance with the method of the present invention may optionally include a permeation enhancing agent. Permeation enhancing agents are compounds which promote penetration and/or absorption of the buprenorphine into the blood stream of the patient. A non-limiting list of permeation enhancing agents includes polyethylene glycols, surfactants, and the like.

In one embodiment, the transdermal dosage form which may be used in accordance with the method of the present invention includes a non-permeable backing layer comprising, e.g., a polyester; an adhesive layer comprising, e.g., a polyacrylate; and a matrix containing the buprenorphine and other excipients such as softeners, permeability enhancers, viscosity agents and the like.

The buprenorphine may be included in the device in a drug reservoir, drug matrix or drug/adhesive layer. Preferably, the active agent is buprenorphine or a pharmaceutically acceptable salt thereof.

Certain preferred transdermal delivery systems also include a softening agent. Suitable softening agents include higher alcohols such as dodecanol, undecanol, octanol, esters of carboxylic acids, diesters of dicarboxylic acids and triglycerides. Further examples of suitable softeners are multivalent alcohols such as levulinic acid, caprylic acids, glycerol and <NUM>,<NUM>-propanediol, which can also be etherified by a polyethylene glycol.

A buprenorphine solvent may also be included in the transdermal delivery systems which may be used in the method of the present invention. A non-limiting list of suitable solvents includes those with at least one acidic group such as monoesters of dicarboxylic acids (e.g., monomethylglutarate and monomethyladipate).

In certain embodiments, the transdermal dosage form which may be used in the method of the present invention includes a removable protective layer. The removable protective layer is removed prior to application, and may comprise the materials used for the production of the backing layer disclosed above provided that they are rendered removable, e.g., by silicone treatment. Other removable protective layers include polytetra-fluoroethylene, treated paper, allophane, polyvinyl chloride, and the like. Generally, the removable protective layer is in contact with the adhesive layer and provides a convenient means of maintaining the integrity of the adhesive layer until the desired time of application.

The transdermal system which may be utilized in the method of the present invention is used by adhering the transdermal system to a dermal surface of a patient. The dermal surface should be clean and unbroken. In certain embodiments, the transdermal system will be sufficiently adhesive to remain adhered to the patient's skin during normal everyday activities and for an adequate period of time. In other embodiments, it may be necessary to further secure the transdermal system to the patient, e.g., by wrapping tape or a medical bandage around the area to which the transdermal system has been applied.

In some embodiments, the transdermal system which may be used in the method of the present invention can be cut or otherwise separated into two or more separate pieces to adjust the amount of buprenorphine that will be delivered to the patient. For example, the transdermal system may include perforations or lines along which to cut for dividing the transdermal system into multiple doses.

In the below reference examples and the related graphical depictions: morphine sulphate is referred to as morphine, morphine sulphate and MS; buprenorphine free base is referred to as buprenorphine, burprenorphine free base and bup; oxycodone hydrochloride is referred to as oxycodone, oxycodone hydrochloride and oxy.

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>/group.

Morphine sulfate (<NUM>-<NUM>/kg) or <NUM>% normal saline (vehicle) was administered subcutaneously (SC) to the test subjects. <NUM> hour later, a charcoal meal (<NUM>/<NUM> grams) was orally administered (PO) to the test subjects.

One hour after the charcoal meal, the test subjects were euthanized by CO<NUM> and the gastrointestinal tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of the charcoal were recorded. Data were analyzed using a one-way ANOVA followed by the Dunnett's Multiple Comparisons test where *P<<NUM>, **P<<NUM> and***P < <NUM>. Data are represented as the means ± S. The results shown in <FIG> demonstrate that morphine decreases gastrointestinal transit as evidenced by the decreased % of the small intestine travelled by a charcoal meal following morphine treatment as compared to vehicle treated animals. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Morphine sulfate (<NUM>-<NUM>/kg) or <NUM>% normal saline (vehicle) was administered SC to the test subjects. <NUM> hour later, a charcoal meal (<NUM>/<NUM> grams) was administered PO to the test subjects. One hour after the charcoal meal, the test subjects were euthanized by CO<NUM> and the stomachs were removed and weighed. Data were analyzed using a one-way ANOVA followed by the Dunnett's Multiple Comparisons test where *P<<NUM>, **P<<NUM> and ***P < <NUM>. Data are represented as the means ± S. Results are shown in <FIG>. The results shown in <FIG> demonstrate that morphine decreases gastrointestinal transit as evidenced by increased stomach weight due to delayed gastric emptying. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>/group.

Morphine sulphate (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. Data were analyzed by a two-way ANOVA using a Bonferroni Multiple Comparison Test,***P < <NUM>.

The results shown in <FIG> demonstrate that morphine provides analgesia as evidenced by increased latency to nocifensive response. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Morphine sulphate (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. %MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff-baseline). Data was analyzed using a Bonferroni Multiple Comparison Test,***P < <NUM>.

The results shown in <FIG> demonstrate that morphine provides analgesia as evidenced by increased % of the maximal possible effect (a normalized transformation of the latency to nocifensive response). This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Morphine sulphate (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. Data were analyzed by a two-way ANOVA using a Bonferroni post-hoc test, *P < <NUM>, ***P < <NUM>.

The results, shown in <FIG> demonstrate that morphine provides analgesia as evidenced by increased latency to nocifensive response. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Morphine sulphate (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. %MPE= Percent of Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff(<NUM>)-baseline)*<NUM>. Data were analyzed by a two-way ANOVA using a Bonferroni post-hoc test, *P < <NUM>, **P < <NUM>, ***P < <NUM>.

Morphine sulfate (<NUM>/kg), buprenorphine free base (<NUM>-<NUM>/kg) (Bup) or <NUM>% hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was administered SC to test subjects. <NUM> hour later, test subjects were given a PO administration of a charcoal meal (<NUM>/<NUM> grams).

One hour after the charcoal meal, the test subjects were euthanized by CO<NUM> and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of the charcoal were recorded. Data were analyzed using a one-way ANOVA followed by Bonferroni's Multiple Comparisons Test where *P<<NUM>, **P<<NUM> and ****P<<NUM> vs. vehicle. Data are represented as the means + S.

The results shown in <FIG> demonstrates that buprenorphine decreases gastrointestinal transit as evidenced by the decreased % of the small intestine travelled by a charcoal meal following buprenorphine treatment as compared to vehicle treated animals. The effect was less in magnitude as compared to either morphine or oxycodone and a "floor effect" was observed such that with increasing dose further retardation of GI transit was not observed.

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>-<NUM>/group.

Rats were dosed with buprenorphine/Bup or vehicle (<NUM>% HPBCD) PO <NUM> hour prior to PO administration of a charcoal meal (<NUM>/<NUM> grams), while some others were given <NUM>/kg of morphine sulfate <NUM> hour before the charcoal meal. One hour after charcoal, all rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA with Bonferonni's Post-Test where ****P< <NUM> vs. vehicle. Data are represented as the means + S.

Results shown in <FIG> demonstrate that <NUM>-<NUM>/kg PO Bup alone does not alter GI Transit in the rat.

Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% HPBCD (vehicle). Morphine sulphate (<NUM>/kg), the positive control, was dissolved in <NUM>% NSS (vehicle). The formulations were administered SC <NUM> hour prior to testing against vehicle. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where *P < <NUM> and ***P < <NUM>. Data are represented as the means + S.

The results shown in <FIG> demonstrate that buprenorphine provides analgesia as evidenced by increased latency to nocifensive response. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% HPBCD (vehicle). Morphine sulphate (<NUM>/kg) was dissolved in <NUM>% NSS (vehicle). The formulations were administered SC <NUM> hour prior to testing against vehicle. %MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff (<NUM>)-baseline). Data were analyzed by a two-way ANOVA using Bonferroni Multiple Comparisons test for post-hoc analysis, where *P< <NUM> and ***P < <NUM>. Data are represented as the means + SEM.

The results shown in <FIG> demonstrate that buprenorphine provides analgesia as evidenced by increased % of the maximal possible effect (a normalized transformation of the latency to nocifensive response). This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Test Subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>-<NUM>/group.

BuprenorphineBup or vehicle (<NUM>% HPBCD) were administered PO <NUM> hour prior to testing. The positive control, morphine sulfate in <NUM>% NS, was administered SC <NUM> hour prior to testing. Rats were assessed one day prior (BL) and then <NUM>, <NUM> and <NUM> hours post-dosing. Hot Plate was set to <NUM> and cutoff was <NUM> seconds. Data were analyzed by a two-way ANOVA using a Bonferroni Multiple Comparisons Test, where *P< <NUM>, ***P< <NUM> and ****P< <NUM> versus vehicle. Data are represented as the means + S. M from two combined studies.

Results shown in <FIG> demonstrate that buprenorphine mitigates acute pain at MED <NUM>/kg.

Subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>/group Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% NSS (vehicle). Morphine sulphate (<NUM>/kg) was dissolved in <NUM>% NSS (vehicle). The formulations were administered SC <NUM> hour prior to testing against vehicle. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, *P < <NUM>, ***P < <NUM>.

Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% HPBCD (vehicle). Morphine sulphate (<NUM>/kg) was dissolved in <NUM>% NSS (vehicle). The formulations were administered SC <NUM> hour prior to testing against vehicle. %MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff(<NUM>)-baseline)*<NUM>. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, ***P < <NUM>.

The results shown in <FIG> demonstrate that buprenorphine % of the maximal possible effect (a normalized transformation of the latency to nocifensive response). This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Buprenorphine base/Bup or vehicle (<NUM>% HPBCD) were administered PO <NUM> hour prior to testing. The positive control, morphine sulfate in <NUM>% NS was administered SC <NUM> hour prior to testing. Rats were assessed the day prior (BL) and then <NUM>, <NUM> and <NUM> hours post-dosing. Tail Flick was set to <NUM> intensity and cutoff <NUM> seconds. Data were analyzed by a two-way ANOVA using a Bonferroni Multiple Comparisons Test, where *P< <NUM>,***P <<NUM> and ****P<<NUM>. Data are represented as the means + S. M of two combined studies.

Results shown in <FIG> demonstrate that buprenorphine mitigates acute pain at MED ≤ <NUM>/kg PO.

Morphine sulfate (<NUM>/kg), oxycodone hydrochloride (<NUM>-<NUM>/kg), or saline (vehicle) were administered SC <NUM> hour (morphine) or <NUM> hour (oxycodone, vehicle) prior to the PO administration of a charcoal meal (<NUM>/<NUM> grams). One hour later, the rats were euthanized by CO<NUM> and the gastrointestinal tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal were recorded. Data were analyzed using a one-way ANOVA followed by the Dunnett's Multiple Comparisons test where ***P < <NUM>. Data are represented as the mean + S.

The results shown in <FIG> demonstrate that oxycodone decreases gastrointestinal transit as evidenced by the decreased % of the small intestine travelled by a charcoal meal following oxycodone treatment as compared to vehicle treated animals. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Morphine sulfate, the positive control, oxycodone HCl, or saline (vehicle) were administered SC either <NUM> hr (morphine) or <NUM> hour (oxycodone, vehicle) prior to the PO administration of a charcoal meal (<NUM>/<NUM> grams). One hour later, rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA followed by the Dunnett's Multiple Comparisons test where ***P < <NUM>. Data are represented as the mean + S.

Oxycodone HCl, or water (vehicle) were administered PO, while morphine sulfate, the positive control, was administered SC, either <NUM> hr (morphine) or <NUM> hour (oxycodone HCl, vehicle) prior to the PO administration of a charcoal meal (<NUM>/<NUM> grams). One hour later, rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA followed by the Dunnett's Multiple Comparisons test where **P < <NUM> and ***P < <NUM>. Data are represented as the mean + S.

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM> on the day of testing; n=<NUM>-<NUM>/group.

Rats were dosed with Oxycodone HCl/Oxy or vehicle (water) PO once daily for <NUM> days (chronic). Additional groups were dosed only once on day <NUM> (acute). One hour after the oxy dosing, a PO administration of a charcoal meal (<NUM>/<NUM> grams) was given. One hour after charcoal, all rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA with Bonferonni's Multiple Comparison Test where * P<<NUM>, ****P< <NUM> vs. vehicle (chronic), ### vs. oxycodone (acute). Data are represented as the means + S.

The results shown in <FIG> demonstrate that repeated oxycodone dosing produces some tolerances to its acute effect on the inhibition of GI transit.

Oxycodone hydrochloride (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. Hot plate was set to <NUM> and cutoff was <NUM> seconds. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where ****P < <NUM>. Data are represented as the means + S.

The results shown in <FIG> demonstrate that oxycodone provides analgesia as evidenced by increased latency to nocifensive response. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>/group. Compound was administered SC <NUM> hour prior to testing. Oxycodone hydrochloride (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. Hot plate was set to <NUM> and cutoff was <NUM> seconds. Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff (<NUM>)-baseline). Data were analyzed by a two-way ANOVA using Bonferroni Multiple Comparisons test for post-hoc analysis, ****P < <NUM>. Data are represented as the means + SEM.

The results shown in <FIG> demonstrate that oxycodone provides analgesia as evidenced by increased % of the maximal possible effect (a normalized transformation of the latency to nocifensive response). This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>/group.

Oxycodone HCl was administered SC <NUM> hour prior to testing. Thermal latency was assessed the day prior (BL) and then <NUM>, <NUM> and <NUM> hours post-oxycodone dosing. The hotplate was set to <NUM> and the cutoff was <NUM> seconds. Oxycodone was dissolved in <NUM>% NS (vehicle). Note: at <NUM>/kg, <NUM> out of <NUM> were found dead at the <NUM> hr time point. Data were analyzed by a two-way ANOVA using the Bonferroni Multiple Comparisons test for post-hoc analysis where, ***P < <NUM>. Data are represented as the means + SEM.

The results shown in <FIG> demonstrate that oxycodone mitigates acute pain in the rat; MED = <NUM>/kg SC.

Oxycodone HCl was administered PO <NUM> hour prior to testing, while morphine sulfate, the positive control, was administered SC <NUM> hour prior to testing. Behavior was assessed the day prior (BL) and then <NUM>, <NUM>, <NUM> and <NUM> hours post-compound administration. The hot plate was set to <NUM> and the cutoff was <NUM> seconds. Oxycodone was dissolved in water (vehicle), while morphine sulfate was dissolved in <NUM>% NS. Data were analyzed by a two-way ANOVA using a Bonferroni Multiple Comparisons Test, where ****P< <NUM>.

The results shown in <FIG> demonstrate that oxycodone mitigates acute pain in the rat; MED = <NUM>/kg PO.

Oxycodone hydrochloride (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, ****P < <NUM>.

Oxycodone hydrochloride (<NUM>-<NUM>/kg) was dissolved in <NUM>% normal saline solution (NSS)(vehicle) and administered SC <NUM> hour prior to testing against vehicle. %MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff(<NUM>)-baseline)*<NUM>. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, ****P < <NUM>.

Oxycodone HCl and vehicle were administered SC <NUM> hour prior to testing. Rats were assessed one day prior (BL) and then <NUM>, <NUM> and <NUM> hours post-oxycodone administration. The tail flick was set to an intensity of <NUM> and the cutoff was <NUM> seconds. Oxycodone was dissolved in <NUM>% (vehicle). Note: for the <NUM>/kg dosing group, <NUM> out of <NUM> rats were found dead at the <NUM> hr time point. Data were analyzed by a two-way ANOVA followed by the Bonferroni Multiple Comparisons Test where, *P < <NUM> and ****P < <NUM>.

The results shown in <FIG> demonstrate that oxycodone mitigates acute pain in the rat, MED = <NUM>/kg SC.

Oxycodone HCl was administered PO <NUM> hour prior to testing, while morphine sulfate, the positive control, was administered SC <NUM> Hour prior to testing. Behavior was assessed the day prior (BL) to dosing, and then <NUM>, <NUM>, <NUM> and <NUM> hours post-compound administration. The tail flick was set to an intensity of <NUM> and <NUM> seconds was used as the cutoff. Oxycodone was dissolved in water (vehicle), while morphine was dissolved in <NUM>% NS. Data were analyzed by a two-way ANOVA using a Bonferroni Multiple Comparisons Test, where *P< <NUM>, **P< <NUM>, ***P< <NUM> and ****P< <NUM>.

The results shown in Figure 9D demonstrate that oxycodone mitigates acute pain in the rat; MED = <NUM>/kg PO.

Buprenorphine free base (<NUM>-<NUM>/kg) (Bup) or <NUM>% hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was administered SC to the test subjects. <NUM> hour later, a SC dose of <NUM>/kg morphine sulfate or saline was administered. <NUM> hour after morphine or saline injection, the test subjects were given a PO administration of a charcoal meal (<NUM>/<NUM> grams).

One hour after the charcoal meal, the test subjects were euthanized by CO<NUM> and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of the charcoal were recorded. Data were analyzed using a one-way ANOVA with Bonferroni's multiple comparisons test. *P<<NUM>, ***P<<NUM> vs. vehicle/saline and ###P<<NUM> vs. vehicle/morphine. Data are represented as the means ± S. The results shown in <FIG> demonstrate that buprenorphine when administered prior to morphine prevents the morphine induced retardation of GI transit. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Buprenorphine free base (<NUM>-<NUM>/kg) (Bup) or <NUM>% hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was administered SC to the test subjects immediately prior to a SC dose of <NUM>/kg morphine sulfate or saline (co-administration; different sites). <NUM> hour after morphine injection, the test subjects were given a PO administration of a charcoal meal (<NUM>/<NUM> grams).

One hour after the charcoal meal, the test subjects were euthanized by CO<NUM> and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of the charcoal were recorded. Data were analyzed using a one-way ANOVA with Bonferroni's multiple comparisons test. *P<<NUM>, ****P<<NUM> vs. vehicle/saline and ####P<<NUM> vs. vehicle/morphine. Data are represented as the means ± S. The results shown in <FIG> demonstrate that buprenorphine when co-administered with morphine prevents the morphine induced retardation of GI transit. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% HPBCD (vehicle) while morphine sulphate (<NUM>/kg), the positive control, was dissolved in <NUM>% NSS (vehicle). Buprenorphine free base (<NUM>-<NUM>/kg) was administered SC <NUM> hour prior to morphine sulfate (<NUM>/kg). Rats were assessed for thermal latency the day prior to dosing, then <NUM>, <NUM> and <NUM> hours post-morphine administration. Data were analyzed by a two-way ANOVA using the Bonferroni Multiple Comparisons Test, where ****P < <NUM> compared to vehicle + vehicle. Data are represented as the means + S.

The results shown in <FIG> demonstrate that buprenorphine when administered prior to morphine produces some erosion of the analgesic efficacy of morphine, as evidenced by a statistically significant reduction in latency to nocifensive response as compared to morphine alone. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% HPBCD (vehicle) while morphine sulphate (<NUM>/kg), the positive control, was dissolved in <NUM>% NSS (vehicle). Buprenorphine free base (<NUM>-<NUM>/kg), was administered SC <NUM> hour prior to morphine sulfate (<NUM>/kg). Rats were assessed for thermal latency <NUM>, <NUM> and <NUM> hours post-morphine administration. %MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff (<NUM>)-baseline). Data were analyzed by a two-way ANOVA using Bonferroni Multiple Comparisons test for post-hoc analysis, where **P< <NUM> and ****P < <NUM>. Data are represented as the means + SEM.

The results shown in <FIG> demonstrate that buprenorphine administered prior to morphine produces some erosion of the analgesic efficacy of morphine, as evidenced by a statistically significant reduction in the % of the maximum possible effect (a normalized transformation of the latency to nocifensive response) as compared to morphine alone. This effect was dose dependent with a greater magnitude of effect observed with increasing dose.

Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% HPBCD (vehicle) while morphine sulphate (<NUM>/kg), the positive control, was dissolved in <NUM>% NSS (vehicle). Buprenorphine free base (<NUM>-<NUM>/kg), was administered SC <NUM> hour prior to, morphine sulfate (<NUM>/kg). Rats were assessed for tail flick latency the day prior to dosing, then <NUM>, <NUM> and <NUM> hours post-morphine administration. Data were analyzed by a two-way ANOVA using the Bonferroni Multiple Comparisons Test, where ****P < <NUM> compared to vehicle + vehicle. Data are represented as the means + S.

Buprenorphine free base (<NUM>-<NUM>/kg) was formulated in <NUM>% HPBCD (vehicle) while morphine sulphate (<NUM>/kg), the positive control, was dissolved in <NUM>% NSS (vehicle). Buprenorphine free base (<NUM>-<NUM>/kg), was administered SC <NUM> hour prior to morphine sulfate (<NUM>/kg). Rats were assessed for thermal latency <NUM>, <NUM> and <NUM> hours post-morphine administration. %MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff(<NUM>)-baseline)*<NUM>. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test for post-hoc analysis where *P<<NUM> and ****P < <NUM>. Data are represented as the means + SEM.

Rats were dosed with buprenorphine free base (<NUM>-<NUM>/kg) or vehicle (<NUM>% HPBCD) SC <NUM> hour prior to an SC dose of <NUM>/kg oxycodone hydrochloride, <NUM>/kg morphine sulphate, or vehicle (<NUM>% saline). <NUM> hr (in the case of morphine) or <NUM> hour (other treatments) later the rats received PO administration of a charcoal meal (<NUM>/<NUM> grams). One hour after charcoal administration, all rats were euthanized by CO<NUM> and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal were recorded. Data were analyzed using a one-way ANOVA with Bonferonni's Post-Test where **P<<NUM>, ****P< <NUM> vs. vehicle and ####P<<NUM> vs. vehicle + oxycodone. Data are represented as the means + S.

The results shown in <FIG> demonstrate that buprenorphine when administered prior to oxycodone prevents the oxycodone induced retardation of GI transit. This effect was dose dependent with a greater magnitude of effect observed with increasing dose. Buprenorphine displays a higher potency (i.e. significant effects observed at lower doses) against oxycodone induced retardation of GI transit as compared to morphine induced retardation of GI transit.

Rats were dosed with buprenorphine free base (<NUM>-<NUM>) or vehicle (<NUM>% HPBCD) SC <NUM> hour prior to an SC dose of <NUM>/kg oxycodone hydrochloride, <NUM>/kg morphine sulphate, or vehicle (<NUM>% saline). <NUM> hr (in the case of morphine) or <NUM> hour (other treatments) later the rats received PO administration of a charcoal meal (<NUM>/<NUM> grams). One hour after charcoal administration, all rats were euthanized by CO<NUM> and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal were recorded. Data were analyzed using a one-way ANOVA with Bonferonni's Post-Test where **P<<NUM>, ****P< <NUM> vs. vehicle and ####P<<NUM> vs. vehicle + oxy. Data are represented as the means + S.

The results shown in <FIG> demonstrate that buprenorphine when administered prior to oxycodone prevents the oxycodone induced retardation of GI transit. A "ceiling effect" was observed whereby increasing doses of buprenorphine did not produce greater magnitude of effects.

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM> or <NUM>/group.

Buprenorphine free base (<NUM>-<NUM>/kg) (Bup) or <NUM>% hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was orally administered to the test subjects one hour prior to an oral administration of <NUM>/kg oxycodone or water. One hour after the oral oxycodone administration, the test subjects were given a PO administration of a charcoal meal (<NUM>/<NUM> grams).

One hour after the charcoal meal, the test subjects were euthanized by CO<NUM> and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of the charcoal were recorded. Data were analyzed using a one-way ANOVA with Bonferroni's Post-Test where *P< <NUM>, **P<<NUM>, ***P<<NUM> and ****P< <NUM> vs. veh+ veh, and ####P<<NUM> vs. veh + oxycodone. Data are represented as the means + S.

One hour after the charcoal meal, the test subjects were euthanized by CO<NUM> and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of the charcoal were recorded. Data were analyzed using a one-way ANOVA with Bonferroni's Post-Test where * P<<NUM>, **P<<NUM>, ****P< <NUM> vs. vehicle + vehicle and #P<<NUM> vs. veh + Oxy. Data are represented as the means + S.

Buprenorphine free base (<NUM>-<NUM>/kg) or vehicle (<NUM>% HPBCD) were administered SC <NUM> hour prior to a SC injection of <NUM>/kg oxycodone or vehicle (<NUM>%saline). Rats were tested <NUM> hour after oxycodone injection. Hot plate was set to <NUM> and cutoff was <NUM> seconds. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where ####P<<NUM> vs. veh + oxy. All oxy-dosed groups were significantly different from vehicle + vehicle at <NUM> hour (P<<NUM>) and *P<<NUM> at <NUM> hours. Data are represented as the means + S.

The results shown in <FIG> demonstrate that buprenorphine when administered prior to oxycodone does not produces erosion of the analgesic efficacy of oxycodone, as evidenced by a lack of statistically significant reduction in latency to nocifensive response as compared to oxycodone alone. Importantly the same dose range was effective in prevention of oxycodone induced retardation of GI transit.

Buprenorphine free base (<NUM>-<NUM>/kg) or vehicle (<NUM>% HPBCD) were administered SC <NUM> hour prior to a SC injection of oxycodone or vehicle (<NUM>%saline). Rats were tested <NUM> hour after oxycodone injection. Hot plate was set to <NUM> and cutoff was <NUM> seconds.

%MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff (<NUM>)-baseline). Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where ####P<<NUM> vs. vehicle + oxycodone. **** < P <NUM> significantly different from veh + veh at <NUM> hour (P<<NUM>). Data are represented as the means + S.

The results shown in <FIG> demonstrate that buprenorphine when administered prior to oxycodone does not produces erosion of the analgesic efficacy of oxycodone, as evidenced by a lack of statistically significant reduction in the % of the maximum possible effect (a normalized transformation of the latency to nocifensive response) as compared to oxycodone alone. Importantly the same dose range was effective in prevention of oxycodone induced retardation of GI transit.

Buprenorphine free base (<NUM>-<NUM>/kg) or vehicle (<NUM>% HPBCD) were administered SC <NUM> hour prior to a SC injection of <NUM>/kg oxycodone or vehicle (<NUM>%saline). Rats were tested <NUM> hour after oxycodone injection. Tail Flick was set to <NUM> Intensity and cutoff was <NUM> seconds. Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where ##P<<NUM> vs. veh + oxy. ****P<<NUM> were significantly different from vehicle + vehicle at <NUM> hour. Data are represented as the means + S.

Buprenorphine free base (<NUM>-<NUM>/kg) or vehicle (<NUM>% HPBCD) were administered SC <NUM> hour prior to a SC injection of oxycodone or vehicle (<NUM>%saline). Rats were tested <NUM> hour after oxycodone injection. Tail Flick was set to <NUM> Intensity and cutoff was <NUM> seconds.

%MPE= Percent Maximum Possible Effect. %MPE= (test latency-baseline)/(cutoff (<NUM>)-baseline). Data were analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where #P<<NUM> vs. vehicle + oxycodone and ****P,<NUM> vs. vehicle + vehicle. Data are represented as the means + S.

Test subjects: Male Sprague-Dawley rats, <NUM>-<NUM>, n=<NUM>/group
Oxycodone HCl (<NUM>/kg), buprenorphine free base (<NUM>/kg - <NUM>/kg)(Bup) or <NUM>% hydroxylpropyl-beta-cyclodextrin/saline (HPBCD/saline; vehicle) were co-administered subcutaneously (SC) albeit at different sites. Rats were assessed one day prior (BL) and then <NUM>, <NUM>, and <NUM> hours post co-administration. Tail Flick was set to <NUM> Intensity and cutoff was <NUM> seconds. Data was analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where all groups were significantly different from veh + veh at <NUM> hour, ****P< <NUM>. Data are represented as the means + S.

The results shown in <FIG> demonstrate that buprenorphine pretreatment does not attenuate the analgesic effect of <NUM>/kg oxycodone.

Oxycodone HCl (<NUM>/kg), buprenorphine free base (<NUM>/kg - <NUM>/kg)(Bup) or <NUM>% hydroxylpropyl-beta-cyclodextrin/saline (HPBCD/saline; vehicle) were co-administered subcutaneously (SC) albeit at different sites. Rats were assessed one day prior (BL) and then <NUM>, <NUM>, and <NUM> hours post co-administration. Hot plate was set to <NUM> and cutoff was <NUM> seconds. Data was analyzed by a two-way ANOVA using a Bonferroni multiple comparisons test, where all groups were significantly different from veh + veh at <NUM> hour, ****P< <NUM> and ####P<<NUM> and ###P<<NUM> vs. veh + <NUM>/kg Oxycodone. Data are represented as the means + S.

Test subjects: Male Sprague-Dawley rats, <NUM>-<NUM>, n=<NUM>-<NUM>/group
Rats were dosed with buprenorphine free base (<NUM>/kg - <NUM>/kg)(Bup) or <NUM>% hydroxylpropyl-beta-cyclodextrin (HPBCD vehicle), <NUM>/kg morphine, or vehicle (<NUM>% saline), ½ hour (in the case of morphine) or <NUM> hour (all other treatments) later, the rats received a charcoal meal PO (<NUM>/<NUM>). One hour after charcoal, all rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA with Bonferroni Post-Test, where **P< <NUM>, ****P< <NUM> vs. veh + veh, and ####P<<NUM> vs. veh + oxycodone. Data are represented as the means + S.

The results shown in <FIG> demonstrate that <NUM>/kg SC buprenorphine attenuates the constipating effect of SC oxycodone.

Test subjects: Male Sprague-Dawley rats, <NUM>-<NUM>, n=<NUM>-<NUM>/group
Oxycodone or vehicle (<NUM>% HPBCD) were administered SC immediately prior to SC buprenorphine; BUP or saline (co-admin; different sites). One hour later, rats were given a PO administration of a charcoal meal (<NUM>/<NUM> grams). One hour after charcoal, all rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal were recorded. Subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>/group. Data were analyzed using a one-way ANOVA with Bonferonni's Post-Test where ***P< <NUM>, and ****P< <NUM> vs. veh+ veh and ###P<<NUM>, ####P<<NUM> vs. veh + oxycodone. Data are represented as the means + S.

The results shown in <FIG> demonstrate that when co-Administered, <NUM>/kg SC buprenorphine can attenuate the constipating effect of SC oxycodone.

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM>; n=<NUM>-<NUM>/group (<NUM> studies combined).

Rats were dosed PO with BuprenorphineBup or vehicle (<NUM>% HPBCD) PO. One hour later they were dosed PO with Oxycodone/Oxy or vehicle (water). One hour after Oxy or veh, a PO administration of a charcoal meal (<NUM>/<NUM> grams) was given. One hour after charcoal, all rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA with Bonferonni's Multiple Comparison Test, where *P< <NUM>, **P< <NUM>, ***P< <NUM> vs. vehicle + vehicle and #P< <NUM>, ##P< <NUM>, ###P< <NUM>, ####P< <NUM> vs. vehicle + <NUM>/kg oxycodone. Data are represented as the means + S.

The results shown in <FIG> demonstrate that <NUM>/kg is the lowest PO dose that attenuates the constipating effect of oral oxycodone (combined data sets).

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM> on the day of testing; n=<NUM>- <NUM>/group.

Rats were dosed once daily for <NUM> days with Oxycodone/Oxy or saline SC. On the 5th day, Buprenorphine/Bup or vehicle (<NUM>% HPBCD) was administered SC at the same time as the last oxycodone dose. One hour later, a PO administration of a charcoal meal (<NUM>/<NUM> grams) was given. One hour after charcoal, all rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA with Bonferonni's Multiple Comparisons Test where **P<<NUM>, ****P< <NUM> vs. vehicle + vehicle and #P<<NUM> vs. veh + Oxy. Data are represented as the means + S.

The results shown in <FIG> demonstrate that acute <NUM>/kg SC buprenorphine administration reverses oxycodone-induced inhibition of GI Transit.

Test subjects: male Sprague-Dawley rats, <NUM>-<NUM> on the day of testing; n=<NUM>-<NUM> /group.

Rats were co- dosed for <NUM> days with Oxycodone/Oxy or water and Buprenorphine/Bup or vehicle (<NUM>% HPBCD) SC. One hour after the 5th dose of each, a PO administration of a charcoal meal (<NUM>/<NUM> grams) was given. One hour after charcoal, all rats were euthanized by CO2 and the GI tract was removed from the stomach to the cecum. The length of the small intestine and the distance (cm) to the leading edge of charcoal was recorded. Data were analyzed using a one-way ANOVA with Bonferonni's Multiple Comparison Test where **P<<NUM>, ****P< <NUM> vs. vehicle + vehicle and #P<<NUM>, ####P<<NUM> vs. veh + Oxy. Data are represented as the means + S.

The results shown in <FIG> demonstrate that repeated dosing with SC buprenorphine x <NUM> days lowers the MED needed to attenuate the effect of oxycodone on GI Transit (<NUM> vs. <NUM>/kg).

Claim 1:
Buprenorphine for use in a method of preventing or treating an adverse pharmacodynamic response induced by fentanyl or a pharmaceutically acceptable salt thereof comprising administering to a patient in need thereof an effective amount of buprenorphine to prevent or treat the adverse pharmacodynamic response induced by the administration of the fentanyl or a pharmaceutically acceptable salt thereof, wherein the fentanyl or a pharmaceutically acceptable salt thereof is administered in an effective amount to provide an analgesic effect, and wherein the buprenorphine is administered transdermally in an amount of <NUM> mcg/hr to <NUM> mcg/hr, and concurrently with transdermally administered fentanyl in an amount of <NUM> mcg/hr to <NUM> mcg/hr, wherein the administration of the buprenorphine is initiated prior to initiating the administration of the fentanyl, or wherein the administration of the buprenorphine is initiated at the same time as the administration of the fentanyl.