CONTROLLED-RELEASE COMPOSITIONS CONTAINING OPIOID AGONIST AND ANTAGONIST

Abstract: Controlled-release dosage forms containing an opioid agonist; and opioid antagonist; and a controlled release material release during a dosing interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to attenuate a side effect of said opioid agonist. The dosage form provides analgesia for at least about 8 hours when administered to human patients. In other embodiments, the dose of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist.

Description: CONTROLLED-RELEASE COMPOSITIONS CONTAINING OPIOID AGONIST AND ANTAGONIST BACKGROUND OF THE INVENTION Opioids, also known as opioid agonists, are a group of drugs that exhibit opium or morphme-hke properties Opioid agonists are known in the literature and to those skilled m the art (Merck Manual, 16th Ed (1992)) Because of their analgesic efficac} opioid agonists have been used to provide pain relief to patients Side effects are also associated with the use of opioid analgesics For example, it has been reported that administration of opioid agonists such as morphine are associated with side effects, including nausea, vomiting, pruπtis, urinary retention, and respiratory depression Gan, et al vol 87, No 5, 1075-1081 (1997) Chronic use of morphine has also been reported to increase physical dependence and increase tolerance of the drug, Shen et al , Bram Res , \ ol 597, 74-83 (1992), and to induce constipation Attempts to reduce the side effects of opioid agonists, without affecting its analgesic efficacy, have also been reported For example, Gan, et al Anesthesiology, \ ol 87, No 5, 1075-1081 (1997) report that the administration of 0 25 wg kg- 1 h- 1 or 1 ug kg- 1 h- 1 naloxone (opioid antagonist) by infusion concomitantly with intravenous morphine, was effectπ e in reducing certain potential side effects of morphine (e g , the incidence of nausea, vomiting and pruπties) OBJECTS AND SUMMARY OF THE INVENTION It is an object of the invention to promote patient compliance and thereby increase the efficacy of opioid agonist treatment m patients who are being treated with opioid agonist It is a further object of the invention to reduce the side effects associated with opioid agonist treatment It is also an object of the invention to provide agonist therapy in which the analgesically effective blood le\ els of the opioid agonist aie maintained duπng an extended period of time, while also maintaining the pharmacologically effective blood levels of the antagonist for reducing the side effects associated with the opioid treatment It is also an object of the invention to enhance the analgesic potency of an opioid agonist in controlled release fonn and simultaneously attenuate development of physical dependence, tolerance and other undesirable side effects caused by the chronic administration of the opioid agonist It is also an object of the invention to provide agonist therapy in which analgesically effective blood levels of the opioid agonist are maintained over an extended penod of time, while also selectively enhancing the analgesic potency of the opioid agonist Prefeiably, the selective enliancement of analgesic potency of the opioid agonist occurs while simultaneously attenuating development of physical dependence, tolerance and othei undesnable side effects caused by the chronic administration of the opioid agonist In view of the above-mentioned objects and others, the invention is dnected to a controlled release oral dosage form comprising opioid agonist and opioid antagonist, wherein the dosage form releases the opioid agonist and the antagonist in a contiolled-release mannei The invention is further directed to a controlled-release dosage fonri comprising an opioid agonist and the opioid antagonist, wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release late, such that when combined into the controlled-release dosage fonn, the opioid agonist and the antagonist aie released from the dosage form at appropriately similar times The invention is further directed to a contiolled-release dosage fonn compπsing opioid agonist and opioid antagonist, wheie the opioid agonist is present in an amount that is analgesically effective when administered to a human and wheiem the opioid antagonist is present in an amount which does not cause a reduction in the level of analgesia provided by the dosage form to a non-therapeutic level In certain embodiments, the opioid antagonist is also present in an amount that is effective in reducing opioid-related side effects ■ Z- In certain embodiments of the present invention, the controlled release dosage form comprises a transdeπnal delivery system, an oral mucosal delivery system, a composition for intranasal administration, an injectable composition, and a solid oral composition. In certain preferred embodiments, the present invention comprises a controlled release dosage form that delivers an opioid agonist and an opioid antagonist over an extended period of time. In these oral embodiments, the dosage form includes an amount of an opioid agonist, preferably a biomodally-acting opioid agonist, and an amount of an opioid antagonist, and upon " administration the dosage form delivers an analgesic or sub-analgesic amount of the opioid agonist over the dosing interval, along with an amount of the opioid antagonist effective to enhance the analgesic potency of the opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist. Certain embodiments of the invention are directed to controlled-release dosage forms comprising an opioid agonist and the opioid antagonist, wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release rate, such that when combined into the controlled-release dosage fonn, the opioid agonist and the antagonist are released from the dosage fonn at appropriately similar times. The present invention is also directed to the use of the above-mentioned controlled release foπriulations for maintenance treatement of previously detoxified opiate addicts. In certain preferred embodiments, the opioid agonist is selected from the group consisting of hydromorphone, oxycodone, hydrocodone, morphine, phamiaceutically acceptable salts thereof and mixtures thereof. In certain preferred embodiments, the opioid agonist is a bimodally-acting opioid agonist selected from, e.g., morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalins, dynorphins, endoφhins, and similarly acting opioid alkaloids and opioid peptides. In certain preferred embodiments, the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, pharmaceutically acceptable salt thereof and mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to controlled-release dosage forms comprising an opioid agonist and an opioid antagonist, the dosage form providing controlled-release of the opioid agonist and controlled-release of the opioid antagonist. In prefeπ"ed embodiments, the release rate of the agonist and the antagonist from the dosage fomi are controlled to maintain an analgesically effective amount of the agonist in the blood throughout the dosing period and to maintain the concentration of the opioid antagonist throughout the dosing period sufficient for decreasing the side effects associated with the opioid agonist but not sufficient to negate the analgesic efficacy of the agonist. In preferred embodiments, the invention is directed to controlled release solid dosage forms that release an opioid agonist and an opioid antagonist over an extended period of time. In these oral embodiments, the dosage form includes an amount of an opioid agonist, preferably a biomodally-acting opioid agonist, and an amount of an opioid antagonist, and upon oral administration the dosage form releases an analgesic or sub-analgesic amount of the opioid agonist over the dosing interval, along with an amount of the opioid antagonist effective to enhance the analgesic potency of the opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist. The present invention is further directed to a controlled-release solid oral dosage form comprising an opioid agonist and an opioid antagonist, the dosage form providing controlled- release of the opioid agonist and controlled-release of the opioid antagonist, the dosage form, when administered to patients, providing analgesia together with reduction of side effects associated with the opioid agonist. It is preferred that such dosage form releases the opioid agonist and the antagonist at substantially proportionate rates. Preferably, the release rates of the opioid agonist and antagonist are approximately proportionate over time, more preferably over a dosing period. A In certain embodiments, the controlled-release composition of the present invention provides reduction of opioid associated side effects, e.g., nausea, vomiting, pruritis, urinary retention, respiratory depression, constipation, physical dependence, tolerance, hyperexcitability, and hyperalgeia. U.S Patent Nos. 5,512,578; 5,472,943; 5,580,876; and 5,767,125, (Crain et al.), each of which are hereby incoφorated by reference in their entireties, describe combinations of opioid antagonists with moφhine or other bimodally acting opioid agonists. The combinations described therein are said to enhance the analgesic effects of the bimodal opioid agonist, while at the same time attenuating the physical dependence, tolerance, hyperexcitability, hyperalgeia, and other undesirable (excitatory) side effects associated with chronic use of bi-modally acting opioid agonists. However, these patents do not contemplate providing a mechanism or manner of preparation of the combination dosage fom in w hich the agonist and the antagonist are each released from the dosage form in a controlled-release manner, allowing the agonist and antagonist to be absorbed by (or delivered to) the patient, such that the requisite analgesia together with reduction of opioid agonist related side effects and/or increased opioid potency may be provided throughout a prolonged dosing period. The above-cited documents also do not provide controlled-release formulations for maintaining the analgesically effective blood levels of agonist during an extended period of time, w hile at the same time maintaining the pharmacologically effective blood levels of the antagonist for reducing the side effects associated with the opioid treatment. Such controlled-release compositions would be desirable, e.g., because they would allow for the limitation of peak concentrations and increase patient compliance because the drug is taken less frequently. The term "controlled-release dosage form," refers to a dosage form which provides a longer period of pharmacological response after the administration of the agonist and the antagonist than is ordinarily provided after the administration of the rapid release dosage form. In certain preferred embodiments of the invention, the controlled-release dosage form releases the opioid agonist and the opioid agonist from the dosage form at such a rate that blood (e.g., plasma) concentration (levels) are maintained within the analgesically effective range (above the minimum effective analgesic concentration or "MEAC") over a dosing period. In certain embodiments of the invention, the opioid antagonist is released from the controlled-release dosage form at such a rate that blood (e.g., plasma) concentration of the antagonist are maintained within the phaπriacologically effective range for reducing the opioid agonist associated side effects over a dosing period. In other preferred embodiments, the opioid antagonist is delivered from the controlled-release dosage form at such a rate that the controlled release formulations provide the benefits set forth in the above-mentioned Crain, et al. patents, namely, enhancement of the analgesic potency of the opioid agonist while simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist. One skilled in the art will understand that due to the enhancement of analgesia caused by the particular combinations of opioid agonist/opioid antagonist encompassed by the present invention, the analgesic efficacy may be greater than that reflected by blood plasma levels of the opioid agonist. For piiφoses of the present invention, the controlled release obtained via in-vitro dissolution testing of the formulation (i.e., measuring the release of the opioid agonist and the opioid antagonist) may serve as a surrogate measure of the dosing interval for the controlled release dosage fonn in- vivo, particularly in the case of oral formulations. Such in-vitro testing may be undertaken utilizing the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100 ipm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. The analytical method may be, e.g., high performance liquid chromatography. In preferred embodiments, the controlled-release dosage fonn of the present invention is administrable (i.e., provides the requisite effects stated above) at least every 8 hours. In certain preferred embodiments, the controlled release dosage form is administrable twice daily ( every 12 hours), or once-a-day (every 24 hours). In embodiments where the controlled release dosage fonn is a transdermal delivery system, the transdermal delivery system preferably provides the requisite effect for at least about 3 days. In certain preferred embodiments, the transdeπnal delivery system may be worn on the skin of a human patient for at least about 5 days, and preferably about 7 days, while provided attenuation of the anti- analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist. Preferably, the opioid antagonist simultaneously provides enliancement of the analgesic potency of the opioid agonist. In the present invention, a very low dose of an opioid antagonist is combined with a dose of an opioid agonist (analgesic) so as to enhance the degree of analgesia an attenuate undesired side effects. The dosage fom is prepared in a manner which causes the opioid agonist and the opioid antagonist to be delivered when the dosage fonn is administered, e g , to a human patient The rate of delivery of the opioid agonist will be such that substantially the e tne dose of opioid agonist contained in the dosage form is dehveied fiom the dosage fonn aftei administration, in those embodiments in which the contiolled release dosage fonn is an oral mucosal delivery system, a composition for mtranasal administration, an mjectable composition, and a solid oral composition The rate of delivery of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to attenuate the anti- analgesia, hyperalgesia, hyperexcitability, physical dependence and/or toleiance effects of the opioid agonist during the intended dosmg interval Preferably, rate of deliveiy of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to enhance the analgesic potency of the opioid analgesic during the dosmg interval of the controlled release dosage form It is not necessary that substantially all of the opioid antagonist be delivered from the controlled release dosage fomi to meet these goals When the controlled release dosage fonn comprises a transdennal delivery system, The rate of delivery of the opioid agonist will be such that a sufficient mean relative release rate (or flux rate) of the opioid agonist contained in the dosage form is delivered from the transdermal dosage form upon administration The rate of delivery of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or toleiance effects of the opioid agonist during the intended dosmg interval Preferably, rate of deliveiy of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to enhance the analgesic potency of the opioid analgesic during the dosmg interval of the controlled release dosage fonn It is not necessary that substantially all of the opioid antagonist be delivered from the controlled release dosage fonn to meet these goals In accordance with the present invention, the dose of opioid antagonist which is delivered from the dosage form duπng the dosing interval is prefeiably fiom about 100 to about 1000 times less than the dose of the opioid agonist (preferably, bimodally-acting opioid agonist) delivered from the dosage form As described in the Cram, et al patents mentioned above, excitatory opioid receptor antagonists bind to and inactivate excitatory opioid -> receptors on neurons in the nociceptive pathways. The excitatoiy opioid receptor antagonists of the invention are preferably seleted from the group consisting of naloxone, naltrexone, diprenorphine, etoφhine and dihydroetoφhine. Naltrexone and naloxone are especially preferred in certain embodiments of the invention. The controlled release dosage fomis of the present invention preferably deliver the opioid antagonist (e.g., excitatory opioid receptor antagonists) at such a level that the opioid antagonist has selective antagonist action at excitatory, but not inhibitory, opioid receptors. In addition, since the antagonists preferably enhance the analgesic potency of the agonists, the agonists become effective when administered at reduced doses which would otherwise be subanalgesic. It may be possible to achieve an analgesic effect with 10-100 times lower doses of the (bimodally acting) opioid agonists with the excitatory opioid receptor antagonists of the invention than when the opioid agonist is administered alone. This is because the excitatory opioid receptor antagonists may enhance the analgesic effects of the opoid agonists by attenuating the anti-analgesic excitatory side effects of the opioid agonists. Therefore, in certain preferred embodiments of the invention, the opioid agonist is included in the dosage fonn and is delivered in an amount which is less than that which has been typically administered for analgesia. In certain embodiments of the invention, the opioid antagonist is delivered such that the amount of opioid agonist included in the dosage fonn is, e.g., about 10 to about 100 times less than the amount of that opioid agonist typically dosed over the dosing interval. Certain embodiments of the invention are directed to controlled-release dosage fomis comprising an opioid agonist and the opioid antagonist wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release rate, such that when combined into the controlled-release dosage form, the opioid agonist and the antagonist are released from the dosage form at appropriately similar times. For example, one of the drugs may be pretreated, e.g., with a controlled release material, to modify its release rate such that when combined into a unitary dosage form with the other drug, the release rates of the two drugs will be substantially similar. It may also be possible to obtain a similar release rate for both the opioid agonist and opioid antagonist, in situations where the drugs chosen would provide different release rates S from the controlled release dosage form because, e.g., they have differing solubilities, by choosing a salt of one of the drugs which provides a closer match in solubilities. Additionally (or alternatively), the particular choice of opioid antagonist can be matched as closely as possible with respect to the solubility of the opioid analgesic. Alternatively, in certain embodiments of the present invention it is not necessary to adjust release rates, etc. as set forth above due to the choice of agonist and/or antagonist which has, for example, a long half-life. In addition, the excitatory opioid receptor antagonists can be administered in the controlled release formulations of the invention along with sub-analgesic doses of opioid receptor agonists for long-tem maintenance treatment of previously detoxified opiate, cocaine and alcohol addicts to prevent protracted physical dependence. Opioid agonists useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, bezitramide, buprenoφhine, butoφhanol, clonitazene, codeine, desomoφhine, dextromoramide, dezocine, diampromide, diamoφhone, dihydrocodeine, dihydromoφhine, dimenoxadol, dimephep- tanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene, fentanyl, heroin, hydrocodone, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levoφhanol, levophenacyl- moφhan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, moφhine, myrophine, narceine, nicomoφhine, norlevoφhanol, normethadone, naloφhine, nalbuphene, normoφhine, noφipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, mixtures of any of the foregoing, salts of any of the foregoing, and the like. In certain preferred embodiments, the bimodally-acting opioid agonist is selected from the group consisting of moφhine, codeine, fentanyl analogs, pentazocine, methadone, buprenoφhine, enkephalins, dynoφhins, endoφhins and similarly acting opioid alkaloids and opioid peptides. \ In certain preferred embodiments, the opioid agonist is selected fiom the group consisting of hydiocodone, nioiphine, hydromoφhone, oxycodone, codeine, levoiphanol, mepeπdine, methadone, or salts thereof or mixtures thereof In certain piefeπed embodiments, the opioid agonist is oxycodone or hydiocodone Equianalgesic doses of these opioids, m comparison to a 15 mg dose of hydrocodone, are set forth m Table 1 below Table 1 : Equianalgesic Doses of Opioids In certain embodiments of the invention, the opioid agonist is a bnnodally acting opioid agonist "Bimodally acting opioid agonists" are opioid agonist that bind to and activate both inhibitory and excitatory opioid receptors on nociceptive neurons which mediate pain Activation of the inhibitory receptors results in opioid analgesia, wheieas the activation of the excitatory receptors results in undesirable side effects, including the de\ elopment of physical dependence and tolerance to the opioid agonist, anti-analgesic actions, hyperexcitability and hyperalgeia Examples of bimodally acting opioid agonists include moφhine, codeine, fenfenyl analogs, pentazocine, methadone, buprenoφlnne, enkephalins, dynoφhias, endoφhins and similarly acting opioid alkaloids and opioid peptides The excitatory opioid receptor antagonists of the invention are preferably seleted from the group consisting of naloxone, naltrexone, diprenoφhme, etoφhine, dihydroetoφhine, pharmaceutically acceptable salts thereof and mixtures thereof Other opioid antagonists io include nalmefene, cyclazacine, levalloφhan, pharmaceutically acceptable salts theieof and mixtures thereof In certain preferred embodiments, the opioid antagonist is naloxone or naltrexone For puφoses of the present invention, the teπn "opioid agonist" is mtei changeable with the tenn "opioid" or "opioid analgesic' and shall include the base of the opioid, mixed agonist-antagonists, partial agonists, phannaceutically acceptable salts thereof, steieoisomers thereof, ethers and esters thereof, and mixtures thereof For puφoses of the present invention, the term "opioid antagonist" shall include the base, pharmaceutically acceptable salts thereof, stereoisomers thereof, etheis and esters thereof, and mixtures thereof The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed opioid agonists and antagonists The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, secium salt and the like, alkaline earth metals such as calcium salt, magnesium salt and the like, organic amine salts such as tπethylamme salt, pyridine salt, picohne salt, ethanolamme salt, tπ ethanolamme salt, dicyclohexylamme salt, N,N'-dιbenzylethylenedιamιne salt and the like, inorganic acid salts such as hydrochloπde, hydrobiomide, 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 argmate, asparginate, glutamate and the like Some of the opioid agonists and antagonists disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeπc forms The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof When the compounds described herein contain olefmic double bonds or other centers of geometπc asymmetiy, and unless specified otherwise, it is intended to include both E and Z geometric lsomers All tautomers are intended to be encompassed by the present invention as well As used herein, the term "stereoisomers" is a general term for all isomers of individual \ \ molecules that differ only in the orientation of their atoms is space It includes enantionieis and isomers of compounds w ith more than one chiral center that are not mirroi images of one another (diastereomers) The term "chiral center" refers to a carbon atom to which four ditfeient gioups aie attached The term "enantiomer" or "eiiantiomeπc" refers to a molecule that is nonsupeπmposeable on its minor image and hence optically active wheiem the enantiomei rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction The tenn "racemic" refers to a mixture of equal parts of enantionieis and which is optically inactive The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeπc forms of a molecule The present invention is further directed to a method of decreasing the potential foi abuse of an opioid agonist in an oral dosage fomi The method compπses piovidmg the opioid agonist in an oral dosage form as described herein The controlled-release compositions of the present invention includes, but is not limited to, a transdermal delivery system, an oral mucosal deliveiy system a composition for intranasal administration, an injectable composition, and a solid oral composition TRANSDERMAL DELIVERY SYSTEM The controlled release formulations of the present invention may be fonnulated as a transdermal delivery system, such as transdem al patches In certain embodiments of the present invention, a transdermal patch comprises an opioid agonist and an opioid antagonist contained in a reservoir or a matrix, and an adhesive which allows the transdermal device to adhere to the skin, allowing the passage of the active agent from the transdermal device through the skin of the patient Once the agonist antagonist has penetrated the sk layer, the II- dmgs are absorbed into the blood stream where they exert desired phannaceutical effects. The transdennal patch- releases both the opioid agonist and the opioid antagonist in a controlled-release manner, such that the blood levels of the opioid agonist is maintained at an analgesically effective level through out the dosing period, and the blood levels of the antagonist is maintained at a concentration that is sufficient to reduce side effects associated with the opioid agonist but not sufficient to negate the analgesic effectiveness of the opioid. Preferably, the amount of antagonist delivered from the transdennal delivery system is effective to enhance the analgesic potency of the opioid agonist delivered from the dosage form. Transdermal delivery system providing a controlled-release of an opioid agonist is known. For example, Duragesic ® patch (commercially available from Janssen Phannaceutical) contains an opioid agonist (fentanyl) and is said to provide adequate analgesia for up to 48 to 72 hours (2 to 3 days). Transdermal delivery systems containing buprenoφhine (an opioid agonist), for providing prolonged analgesia, are also described. Although other types of opioid analgesic transdermal formulations have been reported in the literature (such as fentanyl, discussed above), buprenoφhine transdermal delivery systems are of particular interest because buprenoφhine is a potent, partial agonist opioid analgesic with desirable therapeutic properties. For example, buprenoφhine is 50 to 100 times more potent than moφhine, but has a much safer therapeutic index than moφhine (see Wallenstein SL, et al. , Crossover Trials in Clinical Analgesic Assays: Studies of Buprenoφhine and Moφhine, Phannacotherapy, G(5): 225-235, 1986 hereby incoφorated by reference). There are several types of transdermal fonnulations of buprenoφhine reported in the literature. See, for example, U.S. Patent No. 5,240,711 (Hille et al), U.S. Patent No. 5,225,199 (Hidaka et al), U.S. Patent No. 5,069,909 (Sharma et al), U.S. Patent No. 4,806,341 (Chien et al), and U.S. Patent No. 5,026,556 (Drust et al), all of which are hereby incoφorated by reference. The transdermal delivery system used in the present invention may also be prepared in accordance with U.S. Patent No. 5,069,909 (Sharma et al), hereby incoφorated by reference. This patent describes a laminated composite for administering buprenoφhine transdermally \ 2> to treat pain. The transdermal delivery system used in the present invention may also be prepared in accordance with U.S. Patent No. 4,806,341 (Chien et al), hereby incoφorated by reference. This patent describes a transdermal moφhinan narcotic analgesic or antagonist (including buprenoφhine) pharmaceutical polymer matrix dosage unit having a backing layer which is substantially impervious to the buprenoφhine, and a polymer matrix disc layer which is adhered to the backing layer and which has microdispersed therein effective dosage amounts of the buprenoφhine. The transdermal delivery system used in the present invention may also be that described in U.S. Patent No. 5,026,556 (Drust et al), hereby incoφorated by reference. Therein, compositions for the transdennal delivery of buprenoφhine comprise buprenoφhine in a carrier of a polar solvent material selected from the group consisting of C3-C4 diols, C3- C triols, and mixtures thereof, and a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures thereof; wherein the polar solvent material and the lipid material are present in a weight ratio of solvent materiaklipid material of from 60:40 to about 99: 1. The transdennal delivery system used in the present invention may also be that described in U.S. Patent No. 4,588,580 (Gale, et. al), hereby incoφorated by reference. That system comprises a reservoir for the drug having a skin proximal, material releasing surface area in the range of about 5-100 cm 2 and containing between 0.1 and 50% by weight of a skin penneable form of the buprenoφhine. The reservoir contains an aqueous gel comprising up to about 47-95% ethanol, 1-10% gelling agent, 0.1-10%) buprenoiphine, and release rate controlling means disposed in the flow path of the drug to the skin which limits the flux of the buprenoφhine from the system through the skin. The present invention is contemplated to encompass all transdennal formulations, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist. The transdermal delivery systems of the invention preferably deliver an analgesic or sub- analgesic amount of the opioid agonist together with an amount of the opioid antagonist effective to attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist. Preferably, the amount of opioid antagonist delivered simultaneously enhances the analgesic potency of the opioid agonist delivered from the transdermal delivery system. \ - The transdermal delivery systems may deliver the opioid agonist and/or the opioid antagonist in accordance with first order pharmacokinetics, zero order pharmacokmetics, or both first and zero order phannacokinetics during the dosing interval. The term "first order" phannacokinetics is defined as plasma concentrations which increase over a specified time period. The term "zero order" pharmacokinetics contemplates an amount of drug released from a buprenoφhine formulation which substantially maintains plasma concentrations at a relatively constant level. For puφoses of the present invention, a relatively constant plasma concentration is defined as a concentration which does not decrease more than about 30% over a 48 hour time period. The term "delivers" when used with respect to transdennal delivery devices means that the transdennal delivery device provides a mean relative release rate or flux of the drug out of the device and through the skin of the patient. The term "mean relative release rate" is determined from the amount of drug released per unit time from the transdermal delivery device through the skin and into the bloodstream of a human patient. Mean relative release rate may be expressed, e.g, as g drug/cm^/hr. For example, a transdermal delivery device that releases 1.2 mg of buprenoφhine over a time period of 72 hours is considered to have a relative release rate of 16.67 g/hr. For puφoses of the invention, it is understood that relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval. For puφoses of the present invention, relative release rate should be considered synonomous with the term "flux rate". For example, delivery of buprenoφhine transdermally to human patients has previously been reported, e.g., in U.S. Patent No. 5,968,547, hereby incoφorated by reference, such that mean relative release rates are achieved as follows: a mean relative release rate of from about 3 g/hr to about 86 g/hr from initiation of the dosing interval until about 72 hours thereafter; and a mean relative release rate of about 0.3 g/hr to about 9 g/hr from about 72 hours after the initiation of the dosing interval until at least about 120 hours after the initiation of the dosing interval. In certain embodiments of transdermal dosage form is a transdermal patch comprising a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and optionally a removable protective layer, the reservoir layer by weight \ c comprising 20 to 90% of a polymeric matrix, 0.1 to 30%) of a softening agent, 0.1 to 20% of said opioid agonist and opioid antagonist and 0.1 to 30%o of a solvent for the opioid agonist and opioid antagonist. The controlled release dosage fonn can also comprise a transdennal plaster comprising: (1) a film layer which comprises a polyester film of 0.5 to 4.9 μm thickness, 8 to 85 g/mm strength, respectively in the two directions intersecting substantially at right angles, 30 to 150%o elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of 1.0 to 5.0, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B, and wherein said polyester film comprises 0.01 to 1.0% by weight, based on the total weight of said polyester film, of solid fine particles in which (a) the average particle size is 0.001 to 3.0 . μm, and (b) the average particle size is substantially not more than 1.5 times the thickness of said polyester film; and (2) an adhesive layer (a) which is composed of an adhesive containing said opioid agonist and opioid antagonist and further wherein said adhesive layer (a) is laminated on said film layer over the surface in a 2 to 60 μm thickness. The controlled release dosage can be a transdermal patch comprising a laminated composite for administering said opioid agonist and opioid antagonist to an individual transdermally comprising: (a) a polymer backing layer that is substantially impermeable to said opioid agonist and opioid antagonist; and (b) a reservoir layer comprising a water-base acrylate pressure-sensitive adhesive, 1 to 12%) by weight opioid agonist and opioid antagonist and 2 to 25%o by weight of a permeation enhancer comprising propylene glycol monolaurate in combination with capric acid or oleic acid, wherein the skin contact area of the composite is 10 to 100 cm. sup.2 and the rate of administration from the composite is about 1 to about 100 μg/hr. The controlled release dosage form can be a transdermal comprising: (a) a backing layer which is substantially impervious to said opioid agonist and opioid antagonist; and (b) a polymer matrix layer which is adhered to said backing layer and which has dispersed therein said opioid agonist and opioid, said polymer being bioacceptable and \t permitting said opioid agonist and opioid antagonist to be transmitted for transdemial absoφtion, said opioid agonist and opioid antagonist being stable in said polymer matrix. The controlled release dosage form can be a transdermal patch comprising (a) a polar solvent material selected from the group consisting of C 3 -C 4 diols, C 3 -C 6 triols, and mixtures thereof; and (b) a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures thereof; wherein said polar solvent material and said polar lipid material are present in a weight ratio of solvent materiaklipid material of from about 60:40 to about 99:1. ORAL MUCOSAL DELIVERY SYSTEM In certain embodiments of the present invention, the controlled release opioid agonist/antagonist formulation may be prepared as a controlled-release oral mucosal delivery system. Such a system is described by McQuinn, R. L. et al, "Sustained Oral Mucosal Delivery in Human Volunteers J. Controlled Release; (34) 1995 (243-250). Therein, oral mucosal patches were prepared by homogeneously mixing buprenoφhine free base (8%), Carbopol 934 (52%), polyisobutylene (35%) and polyisoprene (5%, w/w) via a two-roll mill and then compressing the mixture to the appropriate thickness. A membrane backing (ethylcellulose) was applied to one side of the compressed material and then circular disks (0.5 cm 2 ) were punched from the material. The backing was included in order to retard drug release from one side of the disk and to prohibit adhesion to opposing side tissues. Each soft, flexible disk was approximately 0.6 mm thick and contained 2.9 mg buprenoφhine. These patches were worn by the subjects for 12 hours. Gum and lip application was tested, although adhesion at the gum site was considered superior. After the initial appearance of serum buprenoφhine (> 25 pg/ml), levels generally increased relatively rapidly and persisted until the patch was removed. After the patch was removed, buprenoφhine levels fell promptly and were at a relatively low (but measureable) level by 24 hours post-dose. It was estimated that 0.42 ± 0.18 mg were delivered via the gum treatment. From this discussion, it is apparent that an oral mucosal patch can be prepared which will provide plasma concentrations considered desirable according to the present invention. I The present invention is contemplated to encompass all oral mucosal delivery systems, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist. For example, the oral mucosal delivery device can comprise a compressed mixture comprising a polymer with a cellulose backing. The polymer can be selected from the group consisting of Carbopol 934, polyisobutylene, polyisoprene and mixtures thereof and said cellulose can be an alkylcellulose, e.g., ethylcellulose. SUPPOSITORIES The controlled release formulations of the present invention may be formulated as a phannaceutical suppository for rectal administration comprising an opioid agonist and an opioid antagonist in a controlled release matrix, and a suppository vehicle (base). Preparation of controlled release suppository formulations is described in, e.g., U.S. Patent No. 5,215,758, hereby incoφorated by reference in its entirety. Prior to absoφtion, the drug must be in solution. In the case of suppositories, solution must be preceded by dissolution of the base, or the melting of the base and subsequent partition of the drug from the base into the rectal fluid. The absoφtion of the drag into the body may be altered by the suppository base. Thus, the particular base to be used in conjunction with a particular drug must be chosen giving consideration to the physical properties of the drug. For example, lipid-soluble drugs will not partition readily into the rectal fluid, but drugs that are only slightly soluble in the lipid base will partition readily into the rectal fluid. Among the different factors affecting the dissolution time (or release rate) of the drags are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Generally, factor affecting the absoφtion of drugs from suppositories administered rectally l £ include suppository vehicle, absoφtion site pH, drug pKa, degiee of lonization, and lipid solubility The suppository base chosen should be compatible with the opioid agonist antagonist to be mcoφorated into the composition Further, the suppositoiy base is pieferablv non-toxic and nomrπtatmg to mucous membranes, melts or dissolv es in lectal fluids, and is stable during storage In certain preferred embodiments of the present invention for both water-soluble and water-insoluble drugs, the suppository base comprises a fatty acid wax selected from the group consisting of mono-, di- and triglycerides of saturated, natural fatty acids of the chain length C 12 to C 18 In preparing the suppositories of the present invention other excipients may be used For example, a wax may be used to form the proper shape foi administration via the lectal route This system can also be used without wax, but with the addition of diluent filled in a gelatin capsule for both rectal and oral administration Examples of suitable commercially available mono-, di- and triglycerides include saturated natural fatty acids of the 12-18 carbon atom chain sold under the trade name Novata TM (types AB, AB, B,BC, BD, BBC, E, BCF, C, D and 299), manufactured by Henlcel, and Witepsol TM (types H5, H12, H15, H175. H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58, E75, E76 and E85), manufactured by Dynamit Nobel Other pharmaceutically acceptable suppository bases may be substituted in whole or in part for the above-mentioned mono-, di- and triglycerides The amount of base in the suppository is determined by the size (I e actual weight) of the dosage fonn, the amount of alginate and drug used Generally, the amount of suppository base is from about 20 percent to about 90 percent by weight of the total weight of the suppository Preferably, the amount of base in the suppository is fiom about 65 percent to about 80 percent, by weight of the total weight of the suppository In certain embodiments, the controlled-release matrix comprises a pharmaceutically acceptable sodium alginate and a pharmaceutically acceptable calcium salt, the calcium salt being in an amount sufficient to cross-link with the sodium alginate and thereby provide controlled-release of the opioid agonist and the antagonist from the matrix when the suppository base melts subsequent to administration. The present invention is contemplated to encompass all suppository systems, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist. For example, the suppository can comprise a controlled release matrix comprising a pharmaceutically acceptable sodium alginate and a pharmaceutically acceptable calcium, and a suitable vehicle which melts or dissolves in rectal fluids, said calcium salt being in an amount sufficient to cross-link with the sodium alginate and thereby provide a controlled release of said therapeutically active agent from said matrix when said vehicle melts or dissolves. The calcium salt can be selected from the group consisting of calcium phosphate, dicalcium phosphate, calcium chloride, calcium carbonate, calcium acetate, calcium gluconate, and mixtures thereof. COMPOSITIONS FOR INTRANASAL ADMINISTRATION The controlled release formulation of the present invention includes compositions for nasal administration. Controlled release dosage forms containing an opioid agonist is described in European Patent No. EP 205282 and PCT Application No. WO 8203768 (both providing controlled release of moφhine), and also in U.S. Patent No. 5,629,01 1 (moiphine- 6-glucuronide and moφhine-6-sulfate, both being metabolites of moφhine). Each of these documents are incoφorated herein by reference in their entireties. The present invention is contemplated to encompass all such nasal fomiulations as described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner. In certain embodiments, the nasal composition comprises an opioid agonist and the opioid antagonist in bioadhesive microspheres. Preferably the microspheres are prepared ' O from a bio-compatible material that will gel in contact with the mucosal surface. Substantiall}' unifoπn solid microspheres are preferred. Starch microspheres (crosslinked if necessary) are a preferred material. Other materials that can be used to form microspheres include starch derivatives, modified starches such as amylodextrin, gelatin, albumin, collagen, dextran and dextran derivatives, polyvinyl alcohol, polylactide-co-glycolide, hyaluronic acid and derivatives thereof such as benzyl and ethyl esters, gellan gum and derivatives thereof such as benzyl and ethyl esters and pectin and derivatives thereof such as benzyl and ethyl esters. By the term "derivatives" we particularly mean esters and ethers of the parent compound that can be unfunctionalised or functionalised to contain, for example, ionic groupings. Suitable starch derivatives include hydro xyethyl starch, hydroxypropyl starch, carboxymethyl starch, cationic starch, acetylated starch, phosphorylated starch, succinate derivatives of starch and grafted starches. Such starch derivatives are well known and described in the art (for example Modified Starches: Properties and Uses, O. B. Wurzburg, CRC Press Boca Raton (1986)). Suitable dextran derivatives include, diethylaminoethyl-dextran (DEAE-dextran) , dextran sulphate, dextran methyl-benzylamide sulphonates, dextran methyl-benzylamide carboxylates, carboxymethyl dextran, diphosphonate dextran, dextran hydrazide, palmitoyldextran and dextran phosphate. Preparation of these microspheres is well described in the pharmaceutical literature (see for example Davis et al., (Eds), "Microspheres and Drug Therapy", Elsevier Biomedical Press, 1984, which is incoφorated herein by reference). Emulsion and phase separation methods are both suitable. For example, albumin microspheres may be made using the water- in-oil emulsification method where a dispersion of albumin is produced in a suitable oil by homogenization techniques or stirring techniques, with the addition if necessary of small amounts of an appropriate surface active agent. The size of the microspheres is largely dictated by the speed of stirring or homogenization conditions. The agitation can be provided by a simple laboratory stirrer or by more sophisticated devices such as a microfluidizer or homogenizer. Emulsification techniques are also used to produce starch microspheres as described in GB 1 518 121 and EP 223 303 as well as for the preparation of microspheres of gelatin. Proteinaceous microspheres may also be prepared by coacervation methods such as 1 simple or complex coacervation or by phase separation techniques using an appropnate solvent oi electrolyte solution Full details of the methods of piepaimg these systems can be obtained from standaid text books (see for example Floience and Attwood, Physicochemical Principles of Phannacy 2nd Ed , MacMillan Press, 1988, Chaptei 8) The controlled-release nasal composition according to the invention can be administered by any appropriate method according to their fomi A composition comprising microspheres or a powder can be administered using a nasal insufflatoi device Examples of these are already employed for commercial powder systems intended for nasal application (e g Fisons Lomudal System) The insufflator produces a finely divided cloud of the dry powder or microspheres The insufflator is preferably provided with means to ensure administration of a substantiall) fixed amount of the composition The powder or microspheres may be used directly with an insufflator which is provided with a bottle or container for the powdei oi microspheres Alternatively the powder or microspheres may be filled into a capsule such as a gelatin capsule, oi other single dose device adapted for nasal administration The insufflatoi preferably has means to break open the capsule or other device A composition comprising a solution or dispersion in an aqueous medium can be administered as a spray using an appropriate device such as a metered dose aerosol valve or a metered dose pump A gas or liquid propellant can be used Details of other devices can be found in the pharmaceutical literature (see for example Bell, A Intranasal Delivery Devices, in Drag Delivery Devices Fundamentals and Applications, Tyle P (ed), Dekker, New York, 1988), Remington's Pharmaceutical Sciences, Mack Publishing Co , 1975 The present invention is contemplated to encompass all nasal formulations, e g , the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-ielease manner along with the opioid agonist For example, the intranasal formulation can comprise an effective amount of an absoφtion promoting agent to allow nasal absoφtion of the agents after nasal admimstiation of the composition The absoφtion promoting agent can be selected from the group 1Z consisting of a cationic polymer, a surface active agent, a chelating agent, a mucolytic agent, a cyclodextrin, and combinations thereof. INJECTABLE FORMULATIONS The controlled-release injectable compositions containing an opioid antagonist is described in, e.g., U.S. Patent No. 5,942,241 to Chasin et al, which is incoφorated herein by reference in its entirety. The present invention is contemplated to encompass all such injectable formulations, with the inclusion of an opioid antagonist, such that the opioid antagonist is also released in a controlled-release manner along with the opioid agonist. In certain embodiments, the controlled-release injectable composition comprise an opioid agonist and antagonist in controlled-release microparticles, e.g., microspheres or microcapsules. The slow release of the drugs is brought about through controlled diffusion out of the matrix and/or selective breakdown of the coating of the preparation or selective breakdown of a polymer matrix. In certain embodiments, the slow release formulation is prepared as microspheres in a size distribution range suitable for local infiltration or injection. The diameter and shape of the microspheres or other particles can be manipulated to modify the release characteristics. For example, larger diameter microspheres will typically provide slower rates of release and reduced tissue penetration and smaller diameters of microspheres will produce the opposite effects, relative to microspheres of different mean diameter but of the same composition. In addition, other particle shapes, such as, for example, cylindrical shapes, can also modify release rates by virtue of the increased ratio of surface area to mass inherent to such alternative geometrical shapes, relative to a spherical shape. The diameter of injectable microspheres are in a size range from, for example, from about 5 microns to about 200 microns in diameter. In a more preferred embodiment, the microspheres range in diameter from about 20 to about 120 microns. A wide variety of biodegradable materials may be utilized to provide the controlled release injectable dosage forms. Any pharmaceutically acceptable biodegradable polymers known to those skilled in the art may be utilized. It is preferred that the biodegradable ^i controlled release material degrade in vivo over a period of less than about two years, with at least 50%) of the controlled release material degrading within about one year, and more preferably six months or less. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50%o of the material degrading into non- toxic residues which are remov ed by the body, and 100%o of the drag being released within a time period from about two weeks to about two months. The controlled release material should preferably degrade by hydrolysis, and most preferably by surface erosion, rather than by bulk erosion, so that release is not only sustained but also provides desirable release rates. However, the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local anesthetic effect over the desired time period. The controlled release material should be biocompatible. In the case of polymeric materials, biocompatibility is enhanced by recrystallization of either the monomers forming the polymer and/or the polymer Using standard techniques. Suitable biodegradable polymers can be utilized as the controlled release material. The polymeric material may comprise a polylactide, a polyglycolide, a poly(lactide-co- glycolide), a polyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters or mixtures or blends of any of these. The polysaccharides may be poly-l,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof. The biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-l,4-glucan, including hydrolyzed amylopectin, hydroxyalkyl derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like. Preferred controlled release materials which are useful in the fomiulations of the invention include the polyanhydrides, co-polymers of lactic acid and glycolic acid wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 (i.e., 80%o or less lactic acid to 20%o or more glycolic acid by weight), and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride. Other useful polymers include protein polymers such as gelatin and fibrin and polysaccharides such as hyaluronic acid. Since polylactic acid takes at least one year to 14- degrade in vivo, this polymer should be utilized by itself only in circumstances where such a degradation rate is desirable or acceptable. The polymeric material may be prepared by any method known to those skilled in the art. For example, where the polymeric material is comprised of a copolymer of lactic and glycolic acid, this copolymer may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539 (Ludwig, et al.), the disclosure of which is hereby incoφorated by reference in its entirety. In brief, Ludwig prepares such copolymers by condensation of lactic acid and glycolic acid in the presence of a readily removable polymerization catalyst (e.g., a strong acid ion-exchange resin such as Dowex HCR-W2-H). The amount of catalyst is not critical to the polymerization, but typically is from about 0.01 to about 20 parts by weight relative to the total weight of combined lactic acid and glycolic acid. The polymerization reaction may be conducted without solvents at a temperature from about 100 C. to about 250 C. for about 48 to about 96 hours, preferably under a reduced pressure to facilitate removal of water and byproducts. The copolymer is then recovered by filtering the molten reaction mixture to remove substantially all of the catalyst, or by cooling and then dissolving the reaction mixture in an organic solvent such as dichloromethane or acetone and then filtering to remove the catalyst. The substrates of the presently described formulations in certain preferred embodiments are manufactured using a method that evenly disperses the local anesthetic throughout the formulation, such as emulsion preparation, solvent casting, spray drying or hot melt, rather than a method such as compression molding. A desired release profile may be achieved by using a mixture of polymers having different release rates. Methods for manufacture of microspheres are well known and are typified in the following examples. Examples of suitable methods of making microspheres include solvent evaporation, phase separation and fluidized bed coating. In solvent evaporation procedures, the local anesthetic agent, if soluble in organic solvents, may be entrapped in the biodegradable polymer by dissolving the polymer in a volatile organic solvent, adding the drag to the organic phase, emulsifying the organic phase in water which contains less than 2%> polyvinyl alcohol, and finally removing the solvent under vacuum to form discrete, hardened monolithic microspheres. .5 Phase separation microencapsulation procedures are suitable for entrapping water- soluble agents in the polymer to prepare microcapsules and microspheres. Phase separation involves coacervation of the polymer from an organic solvent by addition of a nonsolvent such as silicone oil. In a preferred embodiment, the microspheres may be prepared by the process of Ramstack et al., 1995, in published international patent application WO 95/13799, the disclosure of which is incoφorated herein in its entirety. The Ramstack et al. process essentially provides for a first phase, including an active agent and a polymer, and a second phase, that are pumped through a static mixer into a quench liquid to fonn microparticles containing the active agent. The first and second phases can optionally be substantially immiscible and the second phase is preferably free from solvents for the polymer and the active agent and includes an aqueous solution of an emulsifier. In fluidized bed coating, the drag is dissolved in an organic solvent along with the polymer. The solution is then processed, e.g., through a Wurster air suspension coating apparatus to fonn the final microcapsule product. The present invention is contemplated to encompass all injectable formulations, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist. For example, injectable composition can comprise a plurality of substrates in a phaπnaceutically acceptable medium for injection, said substrates comprising an effective amount of a biocompatible, biodegradable controlled release material comprising a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof. CONTROLLED RELEASE ORAL DOSAGE FORMS The opioid agonist and antagonist combination may be formulated as a controlled- release oral dosage fomi, including tablets and capsules. In preferred embodiments, the controlled-release oral dosage form provides a controlled release of an opioid agonist and a X.G controlled-ielease of an opioid antagonist, such that when the dosage fonn is admmisteied to a human, the blood levels of the agonist is maintained throughout the dosmg period at an analgesically effective level, and the antagonist at a level sufficient to decrease the side effects associated with the opioid agonist but not sufficient to negate the analgesic effect of the opioid agonist The tenn "release rate," as used m the application, refers to a rate at which a diug is released from the dosage fomi The release pattern of a drug is a function of its properties, such as its physicochemical properties Solubility is one such property Since drug must be in solution before they can be absorbed into the body The release rate of the diug from an oral dosage form may be measured, for example, by measuring the dissolution rate of the drug from the dosage fonn using an in \ ltro test method conducted undei standardized conditions, e g , U S P paddle, 100 φm m simulated gastπc fluid for the first hour and thereafter in simulated intestinal fluid For puφoses of the present invention, lelease rate may be used as a sunogate measure of drug delivery m-vivo In certain embodiments of the present invention, the ratio of the opioid agonist to the antagonist in the controlled-release oral dosage form is about 1 1 to about 100 1 by weight In preferred embodiments, the ratio of the opioid agonist with the antagonist is about 40 1 to about 50 1 by weight, more preferably about 20 1 In other preferred embodiments of the invention the amount of the opioid receptor antagonist administered is about 100 to about 1000 fold less than the amount of the opioid agonist administered Controlled-release oral dosage forms accoiding the invention may be prepared using the methods available to one skilled in the art In certain embodiments of the present invention, controlled-release tablets comprise the opioid agonist and antagonist in a controlled release matrix The controlled-release matrix may include hydrophilic and/oi hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials, the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the opioid may be used in accordance with the present invention The opioid agonist particles may, alternatively or additionally, be film coated with a material that pennits lelease of the opioid agonist at a sustained rate in an aqueous medium The film coat is chosen so as f to achieve, in combination with the other stated properties, a desired in-vitro release rate. The sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free. The dosage forms comprising an opioid agonist and opioid antagonist may optionally be coated with one or more materials suitable for the regulation of the opioid agonist release or for the protection of the formulation. In one embodiment, coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid. A pH-dependent coating serves to release the opioid in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an absoφtion profile is provided which is capable of providing at least about eight hours and preferably about twelve hours to up to about twenty- four hours of analgesia to a patient. When a pH-independent coating is desired, the coating is designed to achieve optimal release of the opioid regardless of pH- changes in the environmental fluid, e.g., the GI tract. It is also possible to foπnulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine. Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract. Coatings which are pH- dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like. In certain preferred embodiments, the substrate (e.g., tablet core bead, matrix particle) containing the opioid agonist/opioid antagonist combination is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The coating may be applied in the form of an organic or aqueous solution or dispersion. The coating may be applied to obtain a weight gain from about 2 to about 25%) of the substrate in order to obtain a desired sustained release profile. Coatings derived from aqueous dispersions 2- §r are described, e.g., in detail in U.S. Patent Nos. 5,273,760 and 5,286,493, assigned to the Assignee of the present invention and hereby incoφorated by reference. Other examples of sustained release formulations and coatings which may be used in accordance with the present invention include Assignee's U.S. Patent Nos. 5,324,351 ; 5,356,467, and 5,472,712, hereby incoφorated by reference in their entirety. Alkylcellulose Polymers Cellulosic materials and polymers, including alkylcelluloses, provide hydrophobic materials well suited for coating the beads according to the invention. Simply by way of example, one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating according to the invention. One commercially-available aqueous dispersion of ethylcellulose is Aquacoaf (FMC Coφ., Philadelphia, Pennsylvania, U.S.A.). Aquacoat 8 is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incoφorated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat with a suitable plasticizer prior to use. Another aqueous dispersion of ethylcellulose is commercially available as Surelease (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by incoφorating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates. Acrylic Polymers In othei prefened embodiments of the piesent invention, the hydrophobic mateiial comprising the controlled release coating is a phannaceutically acceptable acrylic polymei, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acryhc acid), poly(methacryhc acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(meth> l methacrylate) copolymer, polyaciylamide, aminoalkyl methacrylate copolymer, poly(methacryhc acid anhydride), and glycidyl methacrylate copolymers In certain preferred embodiments, the acrylic polymer is comprised of one oi more ammonio methacrylate copolymers Ammomo methaciylate copolymers aie well known the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium gioups In order to obtain a desirable dissolution profile, it may be necessary to incoφorate two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acryhc esters Certain methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention For example, there are a family of copolymers synthesized from diethylammoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit " from Rohm Tech, Inc There are several different types of Eudragit " For example, Eudragit E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media Eudragit " L is a methacrylic acid copolymei hich does not swell at about pH < 5 7 and is soluble at about pH > 6 Eudragit S does not swell at about pH < 6 5 and is soluble at about pH > 7 Eudragit " RL and Eudragit " RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit " RL and RS are pH-independent In certain preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit * RL30D and Eudragit " RS30D, respectively. Eudragit " RL30D and Eudragit RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1 :20 in Eudragit *8 RL30D and 1 :40 in Eudragit 8 RS30D. The mean molecular weight is about 150,000. The code designations RL (high peπneability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids. The Eudragit RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release fonnulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit " RL, 50%o Eudragit " RL and 50%> Eudragit * RS, and 10% Eudragit 8 RL:Eudragit β 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit 8 L. In embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under nonnal coating conditions, it is preferable to incoφorate a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-fonner. Concentration of the plasticizer, however, can only be properly detennined after careful experimentation with the particular coating solution and method of application. Examples of suitable plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention. Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention. It has further been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing, and acts as a polishing agent. When a hydrophobic controlled release coating material is used to coat inert pharmaceutical beads such as nu pariel 18/20 beads, which are already coated with an opioid agonist, a plurality of the resultant solid controlled release beads may thereafter be placed in a gelatin capsule, with the opioid antagonist in a substantially non-releasable fonn. The dosage form provides an effective controlled release dose of the opioid agonist when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media. The controlled release bead formulations of the present invention slowly release the opioid agonist, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the hydrophobic material, altering the manner in which the plasticizer is added to the hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. The dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating. Spheroids or beads coated w ith an opioid agonist may be prepaied, e g , by dissoh mg the drug in water and then spiaymg the solution onto a substiate, foi example, nu panel 18 20 beads, using a Wuster insert Optionally, additional ingiedients aie also added pnoi to coating the beads m order to assist the binding of the opioid to the beads, and/or to color the solution, etc For example, a product which includes hydioxypropylmethylcellulose, etc with or without colorant (e g , Opadry " , commercially available from Colorcon, Inc ) may be added to the solution and the solution mixed (e g , for about 1 hour) prior to application of the same onto the beads The resultant coated substrate, in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating An example of a suitable barrier agent is one which comprises hydroxypropylmethylcellulose However, any film-former known in the art may be used It is preferred that the barrier agent does not affect the dissolution rate of the final product The beads may then be overcoated with an aqueous dispersion of the hydrophobic material The aqueous dispersion of hydrophobic mateπal prefeiably further includes an effective amount of plasticizer, e g triethyl citrate Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat " or Surelease " , may be used If Surelease ' is used, it is not necessary to separately add a plasticizer Alternatively, pre-formulated aqueous dispersions of acrylic polymers such as Eudragit 8 can be used The coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (l e , water), a colorant to provide elegance and product distinction Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material For example, color may be added to Aquacoat via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low sheai to the plasticized Aquacoat Alternatively, any suitable method of providing color to the fomiulations of the present invention may be used Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments The incoφoration of pigments, may, however, increase the retard effect of the coating Plasticized hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known m the art In a preferred method, a Wurstei fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymei coating is sprayed on A sufficient amount of the hydiophobic niateiial to obtain a predetennined controlled release of the opioid agonist and opioid antagonist hen the coated substrate is exposed to aqueous solutions, e g gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutically active agent, the manner of incoφoration of the plasticizer, etc After coating with the hydrophobic mateπal, a further overcoat of a film-former, such as Opadry , is optionally applied to the beads This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads The release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, I e , adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating The ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility chaiacteπstics of the materials selected The release-modifying agents which function as pore-formeis may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use The pore-formers may comprise one or more hydiophihc materials such as hydroxypropylmethylcellulose The release-modifying agent may also comprise a semi-permeable polymer In certain preferred embodiments, the release- modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing The sustained release coatings of the present invention can also include erosion-promoting agents such as starch and gums The sustained release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain The sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like. The passageway may be fonned by such methods as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby incoφorated by reference). The passageway can have any shape such as round, triangular, square, elliptical, irregular, etc. In other embodiments of the present invention, the controlled release formulation is achieved via a matrix having a controlled release coating as set forth above. The present invention also comprises sustained-release tablets comprising an opioid agonist and opioid antagonist particles, wherein the agonist and the antagonist are dispersed in a controlled release matrix that affords in-vitro dissolution rates of the opioid agonist within the preferred ranges and that releases the opioid agonist in a pH-dependent or pH-independent manner. The materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix. For example, a matrix in addition to the opioid agonist and the opioid antagonist, may include hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials. Such matrices may also include digestible, long chain ( - C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol; and polyalkylene glycols. Of these polymers, acrylic polymers, especially Eudragit " RSPO - the cellulose ethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses, are preferred. The oral dosage fonn may contain between 1% and 80%> (by weight) of at least one hydrophilic or hydrophobic material. When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point of between 25 ° and 90°C. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon. In certain embodiments, the oral dosage form contains up to 60% (by weight) of at least one polyalkylene glycol as part of the controlled release matrix.. The hydrophobic material is preferably selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof. In certain preferred 3S embodiments of the present invention, the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(mefhacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In other embodiments, the hydrophobic material is selected from materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing. Preferred hydrophobic materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends. Preferably, the hydrophobic materials useful in the invention have a melting point from about 30° to about 200 °C, preferably from about 45 ° to about 90 °C. The list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the opioid agonist and opioid antagonist may be used in accordance with the present invention. The hydrophobic material may comprise natural or synthetic waxes , fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri- glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones. Suitable waxes include, for example, beeswax, glycowax, castor wax and camauba wax. For puφoses of the present invention, a wax-like substance is defined as any material which is normally solid at room temperature and ha&a melting point of from about 30° to about 100°C. Suitable hydrophobic materials which may be used in accordance with the present invention include digestible, long chain (C 8 -C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between 25 ° and 90°C are preferred. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certain embodiments. The oral dosage form may contain up to 60%) (by weight) of at least one digestible, long chain hydrocarbon. 3C A combination of two or more hydrophobic materials may be included in the matrix formulations. If an additional hydrophobic material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, camauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive. An example of a suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C n -C 3b , preferably C 14 -C 22 , aliphatic alcohol and, optionally, at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy (C, to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. The amount of the at least one hydroxyalkylcellulose in the present oral dosage form will be determined, inter alia, by the precise rate of opioid release required. The at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of the at least one aliphatic alcohol in the present oral dosage form will be detem ined, as above, by the precise rate of opioid release required. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage fonn. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20%o and 50%o (by wt) of the at least one aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol preferably constitutes between 20%o and 50%. (by wt) of the total dosage. In one embodiment, the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol/ polyalkylene glycol determines, to a considerable extent, the release rate of the opioid from the formulation. A ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol of between 1 :2 and 1 :4 is preferred, with a ratio of between 1 :3 and 1 :4 being particularly preferred. The at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol. The number average molecular weight of the at least 3f one polyalkylene glycol is preferred between 1,000 and 15,000 especially between 1,500 and 12,000. Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), a C 12 to C 36 aliphatic alcohol and, optionally, a polyalkylene glycol. In another preferred embodiment, the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials. In addition to the above ingredients, a controlled release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. In order to facilitate the preparation of a solid, controlled release, oral dosage form according to this invention, any method of preparing a matrix fomiulation known to those skilled in the art may be used. For example incoφoration in the matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and opioid agonist/opioid antagonist; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C 12 - C 35 aliphatic alcohol; and (c) optionally, compressing and shaping the granules. Preferably, the granules are fonned by wet granulating the hydroxyalkylcellulose/opioid agonist/opioid antagonist with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the opioid. In yet other alternative embodiments, a spheronizing agent, together with the active ingredient can be spheronized to fomi spheroids. Microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Coφoration). In such embodiments, in addition to the active ingredient and spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, 3S aie preferred Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymei, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose In such embodiments, the sustained release coating will generally include a hydiophobic material such as (a) a wax, either alone oi in admixture with a fatty alcohol, or (b) shellac or zein Sustained release matrices can also be prepared via melt-granulation or melt-extrusion techniques Generally, melt-granulation techniques involve melting a normally solid hydrophobic material, e g a wax, and mcoφoratmg a powdered drug therein To obtain a sustained release dosage form, it may be necessary to incoφorate an additional hydrophobic substance, e g ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic material Examples of sustained release formulations prepared via melt- granulation techniques are found in U S Patent No 4,861 ,598, assigned to the Assignee of the present invention and hereby incoφorated by reference in its entirety The additional hydrophobic material may comprise one or more water-insoluble waxlike thermoplastic substances possibly mixed with one or more wax-like thennoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances In order to achieve constant release, the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1 5,000 (w/w) In addition to the above ingredients, a sustained release matrix may also contain suitable quantities of other materials, e g , diluents, lubricants, binders, granulating aids, colorants, flavorants and ghdants that are conventional in the pharmaceutical art The quantities of these additional materials will be sufficient to provide the desned effect to the desired formulation In addition to the above ingredients, a sustained release matrix incoφorating melt-extruded multiparticulates may also contain suitable quantities of other materials, e g diluents, lubricants, binders, granulating aids, colorants, flavoiants and ghdants that are conventional m the pharmaceutical art in amounts up to about 50%o by weight of the particulate if desired 2 Specific examples of pharmaceutically acceptable carriers and excipients that may be used to fonnulate oral dosage forms are described in the Handbook of Phannaceutical Excipients, American Pharmaceutical Association (1986), incoφorated by reference herein. The preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the opioid agonist, opioid antagonist, together with at least one hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same. The resulting homogeneous mixture is then extruded to form strands. The extrudate is preferably cooled and cut into multiparticulates by any means known in the art. The strands are cooled and cut into multiparticulates. The extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the opioid agonist and antagonist for a time period of from about 8 to about 24 hours. An optional process for preparing the melt extrusions of the present invention includes directly metering into an extruder a hydrophobic material, the opioid agonist and antagonist, and an optional binder; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles having a size from about 0.1 mm to about 12 mm. In this aspect of the invention, a relatively continuous manufacturing procedure is realized. The diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded strands. Furthermore, the exit part of the extruder need not be round; it can be oblong, rectangular, etc. The exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc. The melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit orifice. For puφoses of the present invention, the terms "melt-extruded multiparticulate(s)" and "melt-extruded multiparticulate system(s)" and "melt-extruded particles" shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic material as described -o herein In this regard, the melt-extruded multiparticulates will be of a range of fiom about 0 1 to about 12 mm in length and e a diameter of from about 0 1 to about 5 mm In addition, it is to be understood that the melt-extruded multiparticulates can be an> geometrical shape within this size range Alternate ely, the extrudate may simply be cut into desned lengths and divided into unit doses of the therapeutically active agent without the need of a spheromzation step In one preferred embodiment, oral dosage fomis are prepaied to include an effective amount of melt-extruded multiparticulates ithin a capsule For example, a pluiahty of the melt-extruded multiparticulates may be placed in a gelatin capsule m an amount sufficient to provide an effective sustained release dose when ingested and contacted b> gastric fluid In another preferred embodiment, a suitable amount of the multiparticulate extuidate is combined with the coated opioid antagonist particles and compressed into an oral tablet using conventional tabletmg equipment using standard techniques Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980), incoφorated by reference herein In yet another preferred embodiment, the extrudate can be shaped into tablets as set forth in U S Patent No 4,957,681 (Khmesch, et al ), described in additional detail above and hereby incoφorated by reference Optionally, the sustained release melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be furthei coated, with a sustained release coating such as the sustained release coatings described above Such coatings piefeiably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat may be greater depending upon the physical properties of the particular opioid analgesic compound utilized and the desired release rate, among other things The melt-extruded unit dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more of the therapeutically active agents disclosed above before being encapsulated Furthennoie, the unit dosage forms can also include an amount of an immediate lelease opioid agonist for piompt theiapeutic effect The immediate release opioid agonist may be incoφorated, e g , as separate pellets within a gelatin capsule, or may be coated on the suiface of the multiparticulates aftei preparation of the dosage forms (e g , controlled release coating or matrix-based) The unit dosage forms of the present invention may also contain a combination of controlled release beads and matrix multiparticulates to achieve a desired effect The sustained release formulations of the present invention preferably slowly release the opioid agonist, e g , when ingested and exposed to gastric fluids, and then to intestinal fluids The sustained release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of retardant, I e , hydrophobic mateiial, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc In other embodiments of the invention, the melt extruded mateπal is piepaied without the inclusion of the opioid agonist and/or coated opioid antagonist particles, which aie added thereafter to the extrudate Such formulations typically will have the drugs blended together with the extruded matrix material, and then the mixture would be tableted m order to provide a slow release of the opioid agonist Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to tempeiatures needed for softening the hydrophobic material and/ or the retardant material In certain embodiments, the opioid antagonist is present as granulates conipπsmg the opioid antagonist dispersed in a first controlled release matrix, and the opioid agonist is present as granulates comprising the opioid agonist dispersed in a second controlled-release matrix, the first controlled-release matrix providing controlled-release of the opioid antagonist and the second matrix providing controlled-release of the opioid agonist In certain preferred embodiments, the first and second matrices cause the opioid agonist and the opioid antagonist to be released at substantially the same rate In other embodiments, the opioid antagonist is prepared as granulates comprising the antagonist dispersed m a controlled-release matrix, said granulates being combined with the opioid agonist and a further controlled release material, such that the opioid antagonist and opioid agomst are preferably released at substantially the same rate -VL Additional Drugs The oral dosage form of the present invention may further include, in addition to an opioid agonist and antagonist, one or more drugs that may or may not act synergistically therewith. Thus, in certain embodiments, a combination of two opioid agonists may be included in the dosage form, in addition to the opioid antagonist. For example, the dosage form may include two opioid agonist having different properties, such as half-life, solubility, potency, and a combination of any of the foregoing. In yet further embodiments, one or more opioid agonist is included and a further non-opioid drug is also included, in addition to the opioid antagonist. Such non-opioid drags would preferably provide additional analgesia, and include, for example, aspirin, acetaminophen; non-steroidal anti-inflammatory drugs ("NSAIDS"), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a moφhinan such as dextromethoφhan or dextroφhan, or ketamine; cycooxygenase-II inhibitors ("COX-II inhibitors"); and/or glycine receptor antagonists. In certain preferred embodiments of the present invention, the invention allows for the use of lower doses of the opioid analgesic by virtue of the inclusion of an additional non- opioid agonist, such as an NSAID or a COX-2 inhibitor. By using lower amounts of either or both drags, the side effects associated with effective pain management in humans are reduced. Suitable non-steroidal anti-inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piro- profen, caφrofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like. Useful dosages of these drags are well known to those skilled in the art. N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art, and encompass, for example, moφhinans such as dextromethoφhan or dextroφhan, ketamine, d- methadone or pharmaceutically acceptable salts thereof. For puφoses of the present invention, the term "NMDA antagonist" is also deemed to encompass drugs that block a major intracellular consequence of NMDA-receptor activation, e.g. a ganglioside such as GM, or GT lb a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N- (6-aminothexyl)-5-chloro-l-naphthalenesulfonamide. These drags are stated to inhibit the development of tolerance to and/or dependence on addictive drugs, e.g., narcotic analgesics such as moφhine, codeine, etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al), and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.), all of which are hereby incoφorated by reference. The NMDA antagonist may be included alone, or in combination with a local anesthetic such as lidocaine, as described in these Mayer, et.al. patents. The treatment of chronic pain via the use of glycine receptor antagonists and the identification of such drugs is described in U.S. Pat. No. 5,514,680 (Weber, et al), hereby incoφorated by reference. COX-2 inhibitors have been reported in the art and many chemical structures are known to produce inhibition of cyclooxygenase-2. COX-2 inhibitors are described, for example, in U.S. Patent Nos. 5,616,601 ; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311, all of which are hereby incoφorated by reference. Certain preferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6- methoxy-2 naphthylacetic acid (6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrag for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof. Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg to about 140 mg per kilogram of body weight per day are therapeutically effective in combination with an opioid analgesic. Alternatively, about 0.25 mg to about 7 g per patient per day of a COX-2 inhibitor is administered in combination with an opioid analgesic. In yet further embodiments, a non-opioid drag can be included which provides a desired effect other than analgesia, e.g., antitussive, expectorant, decongestant, antihistamine drugs, local anesthetics, and the like. In certain preferred embodiments of the invention, the controlled release oral dosage fonn comprises an opioid agonist and an opioid antagonist m combination with acetominophen Acetaminophen is an analgesic/antipyretic drug which has been utilized for treating mild to moderate pam such as headache, neuralgia, and musculoskeletal pam The recommended daily adult dose is about 325 to about 650 mg every 4 hours, not to exceed a total dose of 4 g in 24 hours The maximum dose of immediate release acetaminophen is generally considered to be about 1000 mg It is contemplated that the combination fomiulations and methods of the piesent invention may include such acetaminophen doses as those set forth abo\ e, or lower doses pei 4 hour dosmg interval Thus, it is possible that controlled release formulations prepared m accordance with the present invention include a greater total acetominophen dose than the 325 - 650 mg dose, but that dose will be released in a controlled-release manner over a longer dosmg interval (e g , over 8 hours or more) It is contemplated that the dosage of acetaminophen and opioid agonist in the formulations and method of the present invention may be similar or the same as dosages which are already commercially available and accepted by clinicians Acetaminophen is commercially available in the United States in fixed combination with opioid agonists , namely, codeine, oxycodone and hydrocodone Typical oral capsule dosages of acetaminophen codeine combinations include 325 mg acetaminophen and 15 mg codeine phosphate, 325 mg acetaminophen and 30 mg codeine phosphate and 325 mg acetaminophen and 60 mg codeine phosphate Tablets typically include 300 mg acetaminophen and 7 5 mg codeine phosphate, 300 mg acetaminophen and 15 mg codeine phosphate, 300 mg acetaminophen and 30 mg codeine phosphate, and 300 mg acetaminophen and 60 mg codeine phosphate Hydrocodone/acetammophen capsules are typically available in fixed combinations of 5 mg hydrocodone (as the bitartrate salt) and 500 mg acetaminophen Hydrocodone/acetammophen tablets are typically available m fixed combinations of 500 mg acetaminophen and 2 5 mg hydrocodone bitartrate, 500 mg acetaminophen and 5 mg S hydrocodone bitartrate, 500 mg acetaminophen and 7.5 mg hydrocodone, 7.5 mg hydrocodone bitartrate and 650 or 750 mg acetaminophen, and 10 mg hydrocodone bitartrate and 500, 650, 660 mg acetaminophen. Oxycodone/acetaminophen capsules and caplets are available in fixed combination of 5 mg oxycodone (as the hydrochloride salt) and 500 mg acetaminophen, and in tablets as 5 mg oxycodone hydrochloride and 325 mg acetaminophen. The fixed combinations described above are for infonnation puφoses only and are not meant to limit the possible relative amounts of opioid and acetaminophen contained in the formulations encompassed within the present invention. As disclosed herein and in accordance with the present invention, it is contemplated that in certain embodiments, the opioid agonist/opioid antagonist/acetaminophen combinations encompassed herein will have greater or lesser dosages of either the opioid agonist or acetaminophen, and that the ratio of opioid agonist to acetaminophen will vary based on the particular opioid agonist and opioid antagonist chosen for a formulation and the amount of opioid antagonist included therein, among other things. In certain preferred embodiments, the oral dosage fomi comprises an opioid agonist (hydrocodone or oxycodone) and opioid antagonist (naltrexone, naloxone and nalmefene) and acetaminophen. In yet further embodiments, a non-opioid drug can be included which provides a desired effect other than analgesia, e.g., antitussive, expectorant, decongestant, antihistamine drags, local anesthetics, and the like. All of the documents cited in this application are incoφorated herein by reference in their entireties. DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever. EXAMPLE 1 Controlled Release Morphine/Naltrexone Beads The objective of this Example is to prepare a controlled release naltrexone bead (antagonist) to be incoφorated into controlled release opioid products (agonist). Morphine/Naltrexone CR capsule A Naltrexone controlled release bead (NXCR) is developed which can be incoφorated into hard gelatin capsules containing other opioid controlled release beads. Moφhine sulfate controlled release beads (MSCR) is formulated as an example to be mixed with NXCR beads and the mixture is encapsulated. Formula IA. NXCR beads 4- " Bead Manufacturing Procedure (NXCR beads) 1. Dissolve naltrexone HCl and plasdone in water. Spray the drug solution onto non-pareil beads in a fluid bed coater with Wurster insert. Spray Opadry clear solution as seal coat. 2. Spray Opadry Clear onto the drug loaded beads as seal coat in the fluid bed coater. 3. Disperse Eudragit RS30D, tributyl citrate, Tween 80 and talc in water. Spray the dispersion onto the beads in the fluid bed coater. 4. Dissolve Opadry Clear in water. Spray the solution onto the beads in the fluid bed coater. 5. Cure the beads at 60°C for 24 hours. Dissolution Method 1. Apparatus- USP Type II (paddle), 50 φm at 37°C. 2. Sampling time- 1, 2, 4, 12, 24, and 36 hours. 3. Media- 900 ml pH 6.5 phosphate buffer. 4. Analytical method- High performance liquid chromatography. Results and Discussion: The NXCR beads were found to have the following dissolution results: Time (hr) 1 4 8 12 18 Mean % 10 13 24 40 75 dissolved nd=none detected The dissolution results show that the drug release rate of naltrexone could be suitable for dosing every 24 hours. 4τ<6 Formula IB (Formulation for the Morphine beads- MSCR beads) Manufacturing Procedure (MSCR beads) 1. Disperse povidone and Eudragit RS30D in water. Blend moφhine sulfate and lactose. 2. Load beads in Rotor processor. Spray the drug powder blend and the binder solution onto beads. 3. Film-coat the above beads in the Rotor processor. 4. Disperse Eudragit RS30D, RL 30D, Triethyl citrate, talc and triehtyl citrate in water. Coat the above beads in a fluid bed coated with Wurster insert. 5. Cure the beads. 4*1 Dissolution Method 1 Apparatus- USP Type II (paddle), 100 φm at 37°C. 2 Sampling time- 1, 2, 4, 12, 24, and 36 hours 3 Media- 700 ml SGF for first 55 mm then converted to 900 ml SIF 4. Analytical method- High perfomiance liquid chromatography Results and Discussion: The MSCR beads were found to have the following dissolution results- Mean % 4 8 23 49 70 83 85 dissolved nd=none detected The dissolution results show that the drag release rate of nioφhine sulfate could be suitable for dosing every 24 hours Example IC. Morphine CR/ Naltrexone CR Capsule Manufacturing Procedure (MSCR NXCR Capsule) Fill 112.675mg of the MSCR beads (Example IB) and 140 mg of the naltrexone CR beads (Example IA) into a suitable sized capsule 3 θ EXAMPLE 2 Hydromorphone/Naltrexone CR capsule Naltrexone controlled release pellets are developed which can be incoiporated into hard gelatin capsules containing other opioid controlled release pellets. Hydromoφhone HCl controlled release pellets (HHCR) are fomiulated as an example to be mixed with Naltrexone CR pellets and the mixture is encapsulated. Formula 2A Naltrexone HCl CR Pellets Ingredient Amt/unit Amt/batch (mg) (gm) Naltrexone HCl 2.0 33.3 Eudragit RSPO 70.0 1166.7 Eudragit RLPO 8.0 133.3 Stearic Acid 40.0 666.7 Total 120.0 2000.0 PROCESS: 1. Blend Naltrexone HCl, Eudragit RSPO, Eudragit RLPO, and Stearic Acid in a twin shell blender. 2. Continuously feed the blended material into a twin screw extrader and collect the resultant strands on a conveyor. 3. Allow the strands to cool a Conveyor. 4. Cut the cooled strands into pellets using a Pelletizer. 5. Screen the pellets and collect desired sieve portion. Dissolution Method 1. Apparatus- USP Type I (Basket), 75 φm at 37°C 2. Sampling Time: 1, 2, 4, 8, 12 3. Media: 700 mL of SGF for one hour/ 900 mL SIF thereafter 3V 4. Analytical Method: High Performance Liquid Chromatography Results Formula 2B (Hydromorphone HCl CR Pellets) Ingredient Amt/unit Amt/batch (mg) (Kg) Hydromoφhone HCl 12.0 3.2 Eudragit RSPO 76.5 20.4 Ethylcellulose 4.5 1.2 Stearyl Alcohol 27.0 7.2 Total 120.0 32.0 Process: 1. Pass Stearyl Alcohol flakes through an impact mill. 2. Blend the Hydromoφhone HCl, Eudragit, Ethycellulose and milled Stearyl Alcohol in a twin shell blender. 3. Continuously feed the blended material into a twin screw extruder and collect the resultant strands on a conveyor. 4. Allow the strands to cool a Conveyor. 5. Cut the cooled strands into pellets using a Pelletizer. 6. Screen the pellets and collect desired sieve portion. 3_ Dissolution Method 1. Apparatus- USP Type I (Basket), 100 rpm at 37°C 2. Sampling Time: 1, 2, 4, 8, 12, 18, 24 3. Media: 900mL (USP) SIF -r 3 g NaCl/L 4. Analytical Method: High Performance Liquid Chromatography Results Formula 2C. Hydromorphone HCl CR/ Naltrexone CR Capsule Process 1. Fill 120.0mg of Hydromoφhone HCl CR Pellets (Example 3B) and 120 mg of the Naltrexone HCl CR Pellets (Example 3A) into a suitable sized capsule. EXAMPLE 3 CR Opioid Agonist/ Antagonist Granulate (Tableted) Controlled release tablets containing an opioid agonist (oxycodone HCl) and opioid antagonist (naltrexone HCl) are prepared in which both drags are present as granulates, the granulates comprising the opioid agonist and the antagonist dispersed in a controlled release matrix. The granulates are combined with melted wax (stearyl alcohol) to produce waxed 55 granulates, which are then milled and mixed with other excipients and compressed into tablets. Remains in product as residual moisture only. Process: 1. Solution Preparation Plasticize the Eudragit with Triacetin by mixing. Dissolve Naltrexone HCl into the plasticized solution. 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, and Povidone into a fluid bed granulator and apply the above solution. 3. Milling Pass the granulation through a rotating impeller mill. 4. Drying Dry granulation if moisture content is too high. 5. Waxing Melt Stearyl Alcohol and wax the above granulation by adding melted Stearyl Alcohol onto granulation while mixing. 6. Cooling Cool the waxed granulation in a fluid bed dryer. 7. Milling Pass the cooled waxed granulation through a rotating impeller mill. 8. Blending Blend the milled waxed granulation, Talc and Magnesium Stearate. 9. Compression Compress the resultant granulation using a tablet press. 10. Coating Prepare a film coating solution by dispersing the Opadry in Purified Water and applying it to the tablet cores. 64- EXAMPLE 4 CR Opioid Agonist/Antagonist Granulate (Tableted) Controlled release tablets containing an opioid agonist (moφhine sulfate) and opioid antagonist (naltrexone HCl) are prepared. The controlled release tablets comprise granulates comprising the opioid agonist and the antagonist dispersed in a controlled-release matrix. The granulates are combined with melted wax (cetostearyl alcohol) to produce waxed granulates, which are then milled and mixed with other excipients and compressed into tablets. * Remains in product as residual moisture only. Process: 1. Solution Preparation Dissolve Naltrexone HCl in Purified Water by mixing. 2. Granulation Place Moφhine Sulfate, Spray Dried Lactose, and Hydroxyethyl Cellulose in a mixer and granulate with Naltrexone HCl solution above. 3. Drying Dry the above granulation in a fluid bed dryer. 4. Milling Pass the granulation through a mill. 5. Drying Dry granulation if moisture content is too high. 6. Waxing Melt Cetostearyl Alcohol and wax the above granulation by adding melted Cetostearyl Alcohol onto granulation while mixing. 7. Cooling Cool the waxed granulation in a fluid bed dryer. 8. Milling Pass the cooled waxed granulation through a mill. S3 9. Blending Blend the milled waxed granulation, Talc and Magnesium Stearate. 10. Compression Compress the resultant granulation using a tablet press. 1 1. Coating Prepare a film coating solution by dispersing the Opadry in Purified Water and applying it to the tablet cores. EXAMPLE 5 Tableted CR Opioid Agonist/Antagonist Extrudate Controlled-release capsules containing an opioid agonist (hydromoφhone HCl) and opioid antagonist (naltrexone ) are prepared. Extruded drag-containing pellets are prepared by combining a wax with ethylcellulose and Eudragit and feeding the mixture into a twin screw extruder. The pellets are then filled into hard gelatin capsules. Formula: Process: 1. Milling Pass stearyl alcohol flakes through an impact mill. 2. Blending Mix Hydromoφhone HCl, Eudragit, Ethycellulose, milled Stearyl Alcohol, and Naltrexone HCl in a twin shell blender. 3. Extrusion Continuously feed the blended material into a twin screw extruder and collect the resultant strands on a conveyor. 4. Cooling Allow the strands to cool a Conveyor. 5. Pelletizing Cut the cooled strands into pellets using a Pelletizer. 6. Screening Screen the pellets and collect desired sieve portion. 7. E Ennccaappssuullaattion Fill the extruded pellets into hard gelatin capsules at 120 mg. EXAMPLE 6 Tableted CR Opioid Agonist/ Antagonist Extrudate Controlled-release tablets containing an opioid agonist (hydrocodone bitartrate) and opioid antagonist (naltrexone HCl) are prepared. The tablets contain the drugs in the fonn of extruded pellets. Formula * Remains in product as residual moisture only. Process: 1. Milling Pass the Stearyl Alcohol flakes through an occillating mill. 2. Blending Mix the Hydrocodone Bitartrate, Naloxone HCl, milled Stearyl Alcohol, Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, and Glyceryl Behenate in a twin shell blender. 3. Extrusion Continuously feed the blended material into a twin screw extruder and collect the resultant heated material on a conveyor. 4. Cooling Allow the extrudate to cool on the conveyor. 5. Milling Mill the cooled extrudate using an occillating mill. 6. Blending Blend the milled extrudate and Magnesium Stearate. 7. Compression Compress the resultant granulation using a tablet press. 8. Coating Prepare a film coating solution by dispersing the Opadry in Purified Water and applying it to the tablet cores. 33 EXAMPLE 7 Tableted CR Opioid Agonist/Antagonist (Modified Release) Controlled release tablets containing an opioid agonist (moφhine sulfate) and opioid antagonist (naltrexone HCl) are prepared. In this Example, opioid antagonist is treated with a controlled-release carrier (Eudragit RS 30D) to modify its release rate before it is combined with the opioid agonist and fonnulated into a controlled-release tablet. Formula: * Remains in product as residual moisture only. Process: 1. Solution Preparation Plasticize the Eudragit by mixing with Triacetin. 2. Pre-Granulation Pre-granulate the Naltrexone HCl in a fluid bed granulator by applying the above solution. 3. Granulation Place Naltrexone HCl granulation (from above), Moφhine Sulfate, Spray Dried Lactose, and Hydroxyethyl Cellulose in a mixer and granulate with Purified Water. 4. Drying Dry the above granulation in a fluid bed dryer. 5. Milling Pass the granulation through a mill. 6. Drying Dry granulation if moisture content is too high. 3 ^ 7. Waxing Melt Cetostearyl Alcohol and wax the above granulation by adding melted Cetosteaiyl Alcohol onto granulation while mixing. 8. Cooling Cool the waxed granulation in a fluid bed dryer. 9. Milling Pass the cooled waxed granulation through a mill. 10. Blending Blend the milled waxed granulation, Talc and Magnesium Stearate. 11. Compression Compress the resultant granulation using a tablet press. 12. Coating Prepare a film coating solution by dispersing the Opadry in Purified Water and applying it to the tablet cores. EXAMPLE 8 Transdermal Delivery System A transdermal patch is prepared in accordance with the disclosure of WO 96/19975 for Example 1 therein as follows, with the modification that a requisite amount of naltrexone is included: 1.139 g of a 47.83 w/% polyacrylate solution with a selfnetting acrylate copolymers containing 2-ethylhexylacrylates, vinyl acetates, acrylic acid (dissolving agent:ethylacetate:heptan:isopropanol:toluol:acetylacetonate in the ratio of 37:26:26:4:1), 100 g laevulinic acid, 150 g oleyloleate, 100 g polyvinylpyrollidone, 150 g ethanol, 200 g ethyl acetate and 100 g buprenoφhine base and 1 g naltrexone are homogenized. The mixture is stirred for about 2 hours and then examined visually to detennine if all solid substances have been dissolved. One has to control the evaporation loss by method of weighing back and makes up for the solvent with the help of ethylacetate, if necessary. Thereafter, the mixture is put onto a 420 mm wide, transparent polyester foil, since the surface weight of the dried layer of paste is 80 g per m.sup.2. The polyester foil which can be dissolved again with treatment of silicone serves as a protective layer. The solvent is removed by drying with heated air which is led over a moist lane. With this treatment of warmth not only do solvents evaporate but the the laevulinic acid melts as well. Thereafter, the sealing film is covered with a polyester foil 15 .mu.ab. A surface of about 16 cm 2 is cut with the help of the appropriate cutting tool, and the rims that have been left between the individual systems are removed. EXAMPLE 9 The fonnulation utilized for Example 8 is substantially the same as that described in Example 3 of WO 96/19975, which is prepared in accordance with Example 8 and is stated therein to include 10% buprenoφhine (with a proportional amount of naltrexone as set forth in Example above), 10%) levulinic acid, 10% polyvinylpyrollidone, 10% oleyloeate, the remainder comprising polyacrylate. In order to achieve the nominal delivery rate of 25 ug/hr expected for the fomiulation of Example 1 , the total of buprenoφhine included in the transdennal patch is about 10 mg, the active surface area is about 12.5 cm 2 and the patch size may be, e.g., about 30.6 cm 2 . The dosing regimen was one (1) patch containing 10 mg buprenoφhine base and O.lmg naltrexone /patch reservoir applied to the subject's skin and maintained in contact with the skin for a time period of seven (7) days. EXAMPLE 10 TRANSDERMAL DEVICE The following ingredients are used in making the pharmaceutical-containing polymer matrix discs: active agent, 10 parts (consisting of hydromoφhone and naltrexone in a 10:1 ratio); DC-360 polysiloxane medical fluid (20 cps), 10 parts; silicone (medical-grade) 382 elastomer, 80 parts; catalyst M, 20 drops per 100 g. of the mixture. The active agent is thoroughly dispersed in the 80 parts of Silastic medical-grade 382 elastomer by using a high torque mixer (sold by Cole-Parmer Company) at about 1000 RPM. With continued agitation, 20 parts of DC-360 (silicone medical fluid) and 20 drops (for every 100 g of the mixture) of a cross-linking agent, designated as catalyst M, which is stannous octanoate, are added to the active agent-elastomer microdispersed mixture. After each addition of the mixture, material is thoroughly mixed, and the dispersed mixture is placed under vacuum to remove entrapped air. The active agent-polydimethylsiloxane dispersion is placed into a device maker and is cross-linked at an elevated temperatuie (25 degrees-100 degrees C) to fonn a cross-linked, medicated polymer sheet, which has a thickness of 0 2-3 mm The medicated polymer sheet is removed from the device maker and is cut into circular discs of about 3-20 sq cm The discs are attached to a backing layer of heat sealable polyester film which is laminated to aluminum foil This laminate is sold by 3M Company as Scotchpak 1006 The medicated discs are attached using an adhesive polymei solution, which is a silicone adhesive polymer sold by Dow Coming as DC-355 Alternately, the discs can be fonned directly on the backing layer The skm permeation enhancei -adhesive film is made using the following ingredients skm permeation enhancer, 6 5 parts, acetone 30 parts, and adhesive polymer solution, 100 parts The skm permeation enhancer-adhesive layer is made by dissolving the 6 5 parts by weight of a skin permeation enhancer in 30 parts of acetone The acetone solution then is added to 100 parts of a silicone adhesive solution sold by Dow-Commg undei the designation DC-355 The mixture is thoroughly mixed to form a homogeneous mixture of skm permeation enhancer and adhesive polymer, which is applied to a strip of a release liner which is a sihconized, or a Teflon-coated polyester film to permit easy removal of the release liner just prior to application of the final polymer niatπx disc dosage unit to the subject to be transdennally treated The adhesive mixture is applied at a controlled thickness The fonned layer has a thickness of about 50-200 microns The layer is dπed completely in \ acuum to remove volatile matter The skin permeation enhancer-adhesive polymer layer with release liner is applied onto the active agent-containing polymer matrix disc with the attached backing layei undei a constant pressure to provide a firmly adhered strip of a four-layeied structuie as follows 1 Backing layer 2 Active agent-containing polymer matrix layer 3 Skm permeation enhancer-adhesive layer =Λ 4. Release film layer which can be readily removed to pemiit application to the skin of the subject to receive transdennally the active agent. By use of an appropriate cutter, the strip is cut to provide the transdennal polymer matrix dosage units which are circular in shape and have an area of about 10 sq. cm. The above polymer matrix disc dosage units are made using the following skin permeation enhancers: 1 -dodecylazacycloheptan-2-one (sold under the trademark Azone), propyl myristate and propyl oleate. The transdermal absoφtion of the active agent from the polymer matrix dosage units of this invention is evaluated by using a skin specimen from a "hairless" mouse or human cadaver by following the procedure described by P. R. Keshary and Y. W. Cliien, in Drug Develop. & Ind. Pharm., 10 (6) 883-913 (1984). EXAMPLE 11 ORAL MUCOSAL DELIVERY SYSTEM Oral mucosal patches are prepared by homogeneously mixing buprenoφhine free base and naltrexone (8%>, in a 20: 1 ratio), Carbopol 934 (52%>), polyisobutylene (35%>) and polyisoprene (5%>, w/w) via a two-roll mill and then compressing the mixture to the appropriate thickness. A membrane backing (ethylcellulose) is applied to one side of the compressed material and then circular disks (0.5 cm 2 ) are punched from the material. The backing is included in order to retard drug release from one side of the disk and to prohibit adhesion to opposing side tissues. Each soft, flexible disk is approximately 0.6 mm thick and contains approximately 3 mg buprenoφhine and an appropriate amount of naltrexone. The patches are suitable for gum and lip application. EXAMPLES 12-14 SUPPOSITORIES Moφhine and naltrexone were tested in the controlled release system of the invention. The following three suppository fonnulations set forth in Table 1 demonstrate the principle of the <o . invention with regard to a controlled release suppository: TABLE 1 Moφhine Suppository Fomiulations EXAMPLE INGREDIENT 1 2 3 Moφhine Sulphate 30.0 mg 30.0 mg 30.0 mg Naltrexone HCL .5 mg .5 mg .5 mg Sodium Alginate 327 mg 409 mg 450 mg (low viscosity LF grade) DiCalcium phosphate 32.5 mg 40.5 mg 45.0 mg Novata-B 1410.0 mg 1320.0 mg 1275.0 mg Total 1800.0 mg 1800.0 mg 1800.0 mg Novata-B is a mixture of mono-, di- and triglycerides based on saturated natural fatty acids of the chain lengths C I2 to C lg , with a specific melting range (33.4 degrees C-25.5 degrees C). The suppositories were prepared according to the following method: moφhine sulphate powder, naltrexone HCL powder, sodium alginate and calcium phosphate were all passed through a #200 sieve, individually. All three powders were intimately mixed in a suitable mixing apparatus. Novata B was melted in a stainless steel pot, keeping the temperature below 60 degrees C. The mixed powder was then added to the completely melted wax (around 50 degrees C) with constant stirring. The temperature was then cooled slowly to 40 degrees C and kept constant at that temperature. The uniform suspension was then transferred to a automated suppository filing kettle, and continuously stirred at 38 degrees C. After the fill weight was determined, the suppository shells were filled to the suggested fill weight at a temperature of about 37 degrees C (e.g., between 36 degrees-38 degrees C). The suppositories were allowed to cool, then sealed. t3 EXAMPLES 15 - 19 COMPOSITIONS FOR NASAL ADMINISTRATION In Examples 15-19, formulations exemplified in U S Patent No 5,629,01 1 aie modified in order to include an opioid antagonist, in accordance with the present invention In Example 15, a bioadhesive powder formulation of moφhιne-6-glucuromde and naltrexone is prepared using microspheres of cross-linked starch The microspheies aie prepared by the method described in EP 223302 A preferred size of microspheres is 1-100 μm The formulation may be prepared by dissolving 75mg of the agonist and a sufficient amount of naltrexone in 30 ml water and mixed with 1 g of starch microspheres The product is freeze-dned to produce a free flowing powder The powder can be administered to the nasal cavity using an insufflator device In Example 16, the bioadhesive microsphere system disclosed in Example 15 are prepared but in addition an absoφtion enhancing agent is employed A preferred matenal is lysophosphatidyl glycerol (LPG) 100 mg LPG is added to the suspension of the moφhme metabolite and microspheres In Example 17, a liquid fomiulation is prepared with added absoφtion enhancing agent as follows 150 mg of moφhme-6-glucuronιde and a sufficient amount of naltrexone are dissolved in 10 ml of a 0 5%o solution of medium viscosity grade of Chitosan (80% degiee of deacetylation, Protan Limited) The substituted cyclodextπn material dimethyl- beta - cyclodextπn (Sigma Chemical Comp) is added to provide a concentration of 5% The liquid formulation can be administered using a conventional pump spray device In Example 18, the formulation disclosed in Example 17 is prepared but in the place of the dimethyl-beta-cyclodextπn, alpha-cyclodextrm (Sigma Chemical Co ) at the same concentration of 50 mg/ml is added 4r In Example 19, the microsphere fomiulation described in Example 16 is prepared but instead of the enhancing agent, a chelating agent in the fonn of EDTA is employed. 50 mg of EDTA is added to the suspension of nioφhine metabolite and niicrospheres. The product is freeze dried as detailed in Example 15. EXAMPLE 20 MICROSPHERES FOR INJECTION In Examples 20, buprenoφhine/naltrexone microspheres are prepared by dissolving the agents and the polymer in ethyl acetate. The polymer is 50:50 poly (D,L) lactic co- glycolic acid which has a mole percent composition of 50%) lactide and 50%o glycolide. This dispersed phase is then added to a solution of polyvinyl alcohol (PVA) in water (the continuous phase) with stirring. The resulting emulsion is monitored for droplet size, which is in turn controlled by the rate of stirring. The emulsion is then added to water to extract the solvent and to harden the microspheres. The mixture is then filtered and the niicrospheres are dried under vacuum at room temperature. The desired particle size fraction is then collected by sieving. The microspheres are then suspended in a suitable media for injection such as water. CONCLUSION Although the invention has been described above with respect to certain examples, the embodiments depicted in these examples are merely illustrative of various aspects of the invention. In particular, the above Examples are meant to provide a guide to those skilled in the art as to the manufacture of controlled release dosage forms that perform in accordance with the present invention. One skilled in the art will appreciate that these dosage fonns have not been tested in- vivo to assure that the requisite effects of the invention are achieved, namely, that the amount of the opioid antagonist included and delivered from the controlled release dosage form during the intended dosing interval is indeed effective to enhance the analgesic potency of the opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist, or to enhance the analgesic potency of the opioid agonist to the extent that a sub-analgesic amount of the opioid agonist can be delivered from the controlled release dosage fonn over the dosing ^ 3 interval. However, based on the data contained in U.S Patent Nos. 5,512,578; 5,472,943; 5,580,876; and 5,767,125, all to Crain et al. ("the Crain patents"), each of which are hereby incoφorated by reference in their entireties, one skilled in the art utilizing the infoπiiation contained herein would be able to adjust the dosage of the opioid antagonist contained in the dosage fonn and its release rate without undue experimentation to achieve the requirements of the appended claims. Furthennore, one skilled in the art utilizing the infonnation contained herein will recognize that the dose of opioid agonist included in the examples set forth herein are generally regarded as "analgesic doses" and that the dose of opioid agonist may be adjusted downward to compensate for the enhancement of analgesic potency afforded by the concurrent delivery of the opioid antagonist Many obvious modifications may be made to the illustrated examples, and such modifications are considered to be within the scope of the present invention. .

Claims: WHAT IS CLAIMED IS: 1. A controlled-release dosage form comprising an opioid agonist; an opioid antagonist; and a controlled release material; said dosage form releasing during a dosing interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to attenuate a side effect of said opioid agonist selected from the group consisting of anti-analgesia, hyperalgesia, hyperexcitability, physical dependence, tolerance, and a combination of any of the foregoing, said dosage form providing analgesia for at least about 8 hours when administered to human patients. 2. The controlled release dosage form of claim 1 , wherein the dose of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist. 3. The controlled-release dosage form of claim 1, wherein the amount of the opioid receptor antagonist administered is about 100 to about 1000 fold less than the amount of the opioid agonist administered. 4. The controlled-release dosage form of claims 1 -3, wherein the opioid agonist and the opioid antagonist are released at substantially proportionate rates. 5. The controlled-release dosage form of claims 1-3, wherein the dosage form is administered via a route selected from the group consisting of orally for gastrointestinal absoφtion, transdermally, via oral mucosa, intranasally, via injection, and rectally. 6. The controlled-release dosage form of claims 1 - 3, wherein the dosage form comprises a solid, oral dosage form. 7. The controlled-release dosage fomi of claims 1 - 3, wherein the dosage fomi comprises a transdermal delivery system. 8. The controlled-release dosage form of claims 1 -3, wherein the dosage form comprises an injectable formulation. 9. The controlled-release dosage form of claims 1 -3, wherein the dosage form comprises an intranasal formulation. 10. The oral controlled-release dosage form of claims 1-3, wherein the opioid agonist and the antagonist are contained in a plurality of substrates coated with a coating comprising said controlled-release material, said substrates being selected from the group consisting of granules, pellets, beads and spheroids. 1 1. An oral controlled release oral dosage form in accordance with claim 4, wherein the opioid antagonist is treated to modify its release rate before it is combined with the opioid agonist, such that when the opioid agonist and the treated antagonist are combined into the controlled-release dosage form, the opioid agonist and antagonist are released from the dosage form at substantially proportionate rates. 12. An oral controlled release dosage form in accordance with claim 4, wherein the dosage form is orally administered and said opioid antagonist is treated to modify its release rate before it is combined with the opioid agonist, such that when the opioid agonist and the treated antagonist are combined into the controlled-release dosage form, the dosage form releases the agonist and the antagonist at such rate that the opioid agonist and the opioid antagonist are therapeutically effective over the dosing interval. 13. An oral controlled release dosage form in accordance with claim 4, wherein the opioid antagonist is present as granulates comprising the opioid antagonist dispersed in a first controlled release matrix, and wherein the opioid agonist is present as 3 granulates comprising the opioid agonist dispersed m a second contiolled-ielease matrix, the first contiolled-ielease matπx pioviding contiolled-ielease of the opioid antagonist and the second mati x pioviding controlled-release of the opioid agonist An oral controlled i elease dosage form in accordance w ith claims 1 -3 whei em the opioid antagonist is prepared as granulates comprising the antagonist dispeised in a controlled-release matrix, said granulates being combined with the opioid agonist and a further controlled release material, such that the opioid antagonist and opioid agoinst are preferably released at substantially the same proportionate rate The controlled release dosage fomi of claims 1 -14, wheiem the opioid antagonist is selected from the group consisting of naloxone, naltiexone, dipienoiphme, etoiphine dihydroetoφhme, pharmaceutically acceptable salts thereof and mixtmes thei eof The controlled release dosage form of claim 15, wherein said opioid agonist is a bimodally-acting opioid agonist selected from the group consisting of moiphme, codeine, fentanyl analogs, pentazocine, methadone, buprenoφhine, enkephalins, dynoφhins, endoφhins and similarly acting opioid alkaloids and opioid peptides The contiolled release dosage fonn of claim 6, wherein the dosage ioim ides controlled-release of the opioid agonist and opioid antagonist over about a 12 houi period The controlled-release dosage fonn of claim 6, wherein the dosage form piovides controlled-release of the opioid agonist and opioid antagonist over about a 24 houi period A controlled-release dosage form comprising an opioid agonist, an opioid antagonist, and a controlled release material, said dosage form releasing during a dosmg mteival an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to enhance the potency of said amount of opioid ^ agonist released from the dosage form, said dosage form providing analgesia foi at least about 8 hours when administered to human patients The controlled-release dosage form of claim 19, wherein the amount of the opioid receptor antagonist administered is about 100 to about 1000 fold less than the amount of the opioid agonist administered The controlled release dosage form of claims 19-20, wheiem said amount of opioid antagonist is simultaneously effective to attenuate a side effect of said opioid agonist selected from the gioup consisting of anti-analgesia, hyperalgesia, hyperexcitabilm physical dependence, tolerance, and a combination of any of the foiegomg The controlled-release dosage form of claim 21 , wheiem the opioid antagonist is selected from the group consisting of naloxone, naltrexone, diprenoφhme, etoφhme dihydroetoφhine, pharmaceutically acceptable salts thereof and mixtures thereof The controlled release dosage form of claim 22, wherein said opioid agonist is a bimodally-actmg opioid agonist selected from the group consisting of moφlnne, codeine, fentanyl analogs, pentazocine, methadone, buprenoφhine, enkephalins, dynoφhins, endoφhins and similarly acting opioid alkaloids and opioid peptides A method for preparing a controlled release opioid analgesic dosage fomi with enhanced analgesic potency, comprising preparing a controlled release dosage fonn containing an opioid agonist, an opioid antagonist, and a contiolled lelease material in a manner such that said dosage form delivers to human patients during an intended dos g interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to enhance the potency of said amount of opioid agonist released from the dosage form, said dosage form providing analgesia for at least about 8 hours when admmisteied to human patients CJ 25. A method for preparing a controlled release opioid analgesic dosage fonn in which a side effect of the opioid analgesic is attenuated, said side effect selected from the group consisting of anti-analgesia, hyperalgesia, hyperexcitability, physical dependence, tolerance, and a combination of any of the foregoing, comprising preparing a controlled release dosage form containing an opioid agonist; an opioid antagonist; and a controlled release material in a manner such that said dosage fomi delivers to human patients during the intended dosing interval an analgesic or sub- analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to enhance the potency of said amount of opioid agonist released from the dosage form, said dosage form providing analgesia for at least about 8 hours when administered to human patients. 26. The method of claims 24 - 25, further comprising preparing the dosage form such that the the amount of the opioid receptor antagonist contained therein is about 100 to about 1000 fold less than the amount of the opioid agonist contained therein. 27. The method of claim 24, wherein said amount of opioid antagonist is simultaneously effective to attenuate a side effect of said opioid agonist selected from the group consisting of anti-analgesia, hyperalgesia, hyperexcitability, physical dependence, tolerance, and a combination of any of the foregoing. 28. The method of claims 24-26, wherein the opioid antagonist is selected from the group consisting of naloxone, naltrexone, diprenoφhine, etoφhine, dihydroetoφhine, pharmaceutically acceptable salts thereof and mixtures thereof. 29. The method of claim 28, wherein said opioid agonist is a bimodally-acting opioid agonist selected from the group consisting of moφhine, codeine, fentanyl analogs, pentazocine, methadone, buprenoφhine, enkephalins, dynoφhins, endoφhins and similarly acting opioid alkaloids and opioid peptides. ? ' 30. The method of claims 24-26, wherein the opioid agonist and the opioid antagonist are delivered from the dosage form at substantially the same proportionate rate. 31. The method of claims 24-26, further comprising: (i) pretreatmg either the opioid agonist or the opioid antagonist to modify its release rate; and (ii) combining the pretreated drug with the other drug to produce the dosage fomi in which the opioid agonist and the opioid antagonist are delivered from the dosage form at substantial!} the same proportionate rate. 32. A transdermal delivery system for an opioid analgesic, comprising an opioid agonist and an opioid antagonist contained in a reservoir or matrix and capable of deliver}. from the device in a controlled manner, such that when the device is applied to the skin of a human patient, the opioid agonist is delivered at an mean relative release rate effective to provide analgesia to said patient for at least 3 days, and the opioid antagonist is delivered at a mean relative release rate sufficient to reduce side effects associated with the opioid agonist but not sufficient to negate the analgesic effectiveness of the opioid. 33. The transdermal delivery system of claim 32, wherein the amount of antagonist delivered from the transdermal delivery system is effective to enhance the analgesic potency of the opioid agonist delivered from the device. 34. The transdermal delivery system of claim 34, wherein the amount of the opioid receptor antagonist delivered from the device is about 100 to about 1000 fold less than the amount of the opioid agonist delivered. ^

Inventors: CURTIS WRIGHT, OSHLACK BENJAMIN, CURTIS, WRIGHT, OSHLACK, BENJAMIN
Applicants: CURTIS WRIGHT, EURO CELTIQUE SA, OSHLACK BENJAMIN, CURTIS, WRIGHT, EURO-CELTIQUE, S.A., OSHLACK, BENJAMIN
Application year: 2001
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K38, A61K45, A61K47, A61P25, A61P39, A61P43